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Editorial
Bahl et al. Elective Stenting in Small Coronary Arteries
275
Indian Heart J 2001; 53: 275–281
Elective Stenting in Small Coronary Arteries:
Lessons Learnt from Recent Trials
VK Bahl, R Narang
Department of Cardiology, Cardiothoracic Sciences Center,
All India Institute of Medical Sciences, New Delhi
I
ntracoronary stenting is an established treatment
modality for patients with symptomatic coronary artery
disease. It has been shown to be superior to conventional
balloon angioplasty in reducing the incidence of abrupt
vessel closure and late restenosis. However, most studies that
have documented the benefit of elective stent implantation
following angioplasty, including the BENESTENT1 and
STRESS2 trials, had excluded lesions in vessels with a
diameter of less than 3.0 mm. Currently, more than a third
of coronary lesions treated with angioplasty are estimated
to be in vessels smaller than 3.0 mm (in a few studies, the
proportion is even about 50%).3,4 As the population is aging
and with the increasing incidence of diabetes mellitus, this
proportion is likely to increase further. The issue of small
vessel stenting has special importance for us, as Indians are
believed to have smaller coronary arteries. In addition, stent
use continues to have several limitations, such as high cost
and in-stent restenosis. In small vessels, the stents remain
useful if the result of conventional balloon angioplasty are
suboptimal or in bail-out situations (provisional stenting).
However, the role of elective stenting (stenting all cases,
even if the result of balloon angioplasty is optimal) is not
well defined. In the last few years, new data have emerged
addressing this question.
Definition of “Small” Coronary Artery
Evaluation of data on stenting in this subgroup of patients
is complicated by the fact that different criteria have been
used by studies to define “small” coronary artery. The upper
cut-off for reference vessel diameter has varied from 2.5 to
3.0 mm. Earlier studies had mostly defined vessels <3.0 mm
in diameter as small coronary vessels while more recent
trials have tended to use cut-off values of 2.75 or 2.5 mm.
The lack of a uniform definition makes it difficult to compare
results of different trials.
Correspondence: Dr VK Bahl, Professor of Cardiology, All India Institute
of Medical Sciences, New Delhi 110029. e-mail: [email protected]
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Important Issues Involved in Small Vessel Stenting
There are a number of procedural concerns and long-term
issues while performing angioplasty in small coronary
arteries. Since smaller vessels have little margin for error,
the risks of procedural complications and restenosis rates
may be higher in these vessels.
Procedural issues: These are: (i) difficulty in reaching the
lesion site as small vessels tend to be peripheral and the stent
may have to pass through a number of bends and curves
before reaching the site. Therefore, the primary success rate
of stenting such arteries may not be as high as that of larger
vessels, especially if the stents used are not trackable and
flexible. (ii) The chances of stent dislodgement are higher
as stents may need to be placed in distal lesions after passing
through a small and tortuous vessel. With the availability
of balloon-mounted stents, this is usually not a major
problem. (iii) The choice of stent itself may be an issue since
routine stents deployed in small coronary vessels have a
higher metal-to-artery ratio. This may increase the risk of
subsequent problems such as subacute thrombosis and
restenosis.
In spite of these procedural difficulties, most of the recent
studies have shown that stents can be safely placed in small
coronary arteries and with good immediate results. This has
been possible due to the availability of better stents, which
are more trackable and less rigid compared to the Palmaz–
Schatz stent. The primary success rate and incidence of
major adverse cardiac events (MACE) in the first 48 hours
post-stenting is comparable to that for large vessel stenting.
Pascual Figal et al.5 studied 234 patients with 300 stents,
of which 84 stents were implanted in 79 lesions located in
small vessels. They found the procedural success rate
without any in-hospital complication to be 94% in both the
<3.0 mm and ≥3.0 mm reference vessel groups. However,
the long-term outcome in the small coronary vessel group
was worse; subacute thrombosis was higher (3.8% v. 0%;
p=0.006) and event-free survival was less (69% v. 87%;
p<0.001).
Subacute thrombosis: Earlier studies reported the rate
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276 Bahl et al. Elective Stenting in Small Coronary Arteries
of subacute thrombosis to be higher with stents placed in
small coronary vessels as compared with those in larger
vessels.6,7 Karrillon et al.6 in the large French multicenter
registry (n=2900) found the stent thrombosis rate to be 10%
for vessels with a reference diameter of ≤2.5 mm, 2.3% for
those between 2.5 and 3.5 mm and 1% for those ≥3.5 mm
(p<0.001). With improvement in technique, availability of
stents especially designed for smaller vessels and better
antiplatelet regimens, subacute thrombosis is no longer an
important problem, especially for sizes between 2.5 and 3.0
mm.8–10 Moussa et al.8 found the rate to be 0.6% following
stenting of both small and large vessels, while Lau et al.9
found it to be 0.5% in 197 consecutive Asian patients
undergoing small vessel stenting.
Restenosis: Higher clinical and angiographic restenosis
rates are a major concern of small vessel stenting. The exact
reason for this higher risk is not known. Several
explanations have been suggested, such as greater late
luminal loss, higher balloon-to-artery ratio and increased
plaque burden. Hoffmann et al.11 demonstrated that the
degree of intimal hyperplasia is relatively constant and
independent of stent size. Thus, there is greater
encroachment on the lumen by intimal hyperplasia if a
stent is placed into a small coronary vessel as compared with
stents implanted into larger vessels. The same volume of
neointimal thickness is more likely to reduce the lumen by
more than 50% in smaller arteries than in larger arteries.
As balloon angioplasty in small vessels leads to a higher
restenosis rate than that in larger arteries, stents designed
to ameliorate restenosis could have a greater relative impact
if applicable to smaller vessels.
Earlier studies had shown that there was an inverse
relationship between vessel size and in-stent restenosis rates.
Akiyama et al.4 in a study of 1298 patients, found the
restenosis rate to be 20% in vessels ≥3.0 mm in diameter
while it was 33% in vessels <3.0 mm in diameter.
Independent predictors of freedom from restenosis were
found to be larger baseline reference diameter, larger postprocedure minimal stent cross-sectional area and shorter
lesions. At long-term clinical follow-up, patients with small
vessels had a lower rate of event-free survival (63% v. 71%;
p=0.007). Elezi et al.12 in a study of 2602 patients also
found the restenosis rates to be 39%, 28% and 20% for
vessels sizes <2.8 mm, 2.8–3.2 mm and >3.2 mm,
respectively. The restenosis rate is influenced by the
complexity of lesions treated and by the presence of diabetes
mellitus. Within the subgroup of patients with small vessel
disease, the restenosis rate was 30% if there was no
additional risk factor and 54% in patients with diabetes
mellitus and complex lesions. Wong et al.13 found the
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restenosis rate after stenting of small coronary arteries to
be about 35% on pooling of available data.
Non-randomized Trials of Small Vessel Stenting
Many operators had started stenting even the lesions in
small coronary arteries soon after stents had become
commercially available. Chan et al.14 reported the use of
intracoronary stents for treatment of acute or threatened
closure in small coronary arteries (<3.0 mm diameter) as
early as 1995. They used 2.0 or 2.5 mm Flex-Stents in 42
such patients. The procedural success rate was 95% with a
primary clinical success rate (freedom from myocardial
infarction, coronary artery bypass surgery or death) of
90%. Subacute stent thrombosis occurred in 2.4%. Clinical
follow-up at a mean of 14.8±7.6 months revealed
recurrence of angina in 53% with angiographic restenosis
in 66%. They concluded that intracoronary stenting is an
effective and safe nonsurgical alternative for the treatment
of acute or threatened closure for this subset of patients.
However, the data do indicate that stenting in small
coronary arteries carries a significant risk of subacute
thrombosis as well as relatively high restenosis rates. The
feasibility and safety of provisional small vessel stenting has
also been demonstrated by Moer et al.15 They studied
patients who had undergone stent implantation following
suboptimal results of balloon angioplasty in vessels with a
diameter of <3 mm. The overall restenosis rate was found
to be 22.5%.
Stents designed for larger vessels could also be deployed
successfully in smaller vessels. Cohen et al.16 reported
outcomes following the use of hand-crimped Palmaz–
Schatz stents (designed for vessels >3.0 mm diameter) in
the small coronary arteries of 117 patients. In-hospital
clinical composite end-points occurred in 6.8% (death 1%,
myocardial infarction 5.1% and revascularization 1%).
Studies have not only shown the safety and usefulness
of stenting focal, discrete type A lesions in small vessels,
but also those in complex lesions. Miketic et al.17 reported
the use of high-pressure stenting in small coronary arteries
(<3 mm reference diameter) with type C lesions. They found
a high procedural success rate (98.2%). The 6-month
angiographic restenosis rate was 36%. It was concluded
that high-pressure stenting with flexible stents is a safe and
feasible option in small vessels, even in those with
unfavorable lesion morphology.
As the experience with small vessel stenting increased,
even vessels smaller than 2.5 mm were successfully stented.
Huang et al.18 reported the outcomes of 2.5 mm stent
deployment using high pressure in small coronary arteries
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(<2.5 mm reference diameter; mean 2.3±0.2 mm). The
clinical and/or angiographic restenosis rate on follow-up
was 24%.
Two large non-randomized trials with small vessel
stenting have been recently reported. Lau et al.19 reported
early and long-term results in 197 consecutive patients who
underwent stent implantation in 207 vessels with a
diameter <3.0 mm. The procedural success rate was 97.3%,
lesion severity reduced from 85±9% to 3±7%, with a
subacute stent thrombosis rate of 0.5%. Survival without
major target lesion-driven events was 77% and 74% at 1
and 2 years of follow-up, respectively. The 6-month
angiographic restenosis rate was 30.1%. Diabetes mellitus,
small vessel size and stent size <2.7 mm were found to be
independent predictors of in-stent restenosis. In a similar
study, Morice et al.20 reported that among 190 patients
stented with 2.5 mm stents, the procedural success rate was
98%, subacute thrombosis rate was 2.6% and repeat
intervention rate on follow-up was 24.5%.
Thus, a number of non-randomized trials of small vessel
stenting have been reported. The initial procedural success
rate ranged from 93% to 98%, subacute thrombosis rate
from 0.5% to 3.8% and the restenosis rate from 21% to 36%.
Adverse clinical events ranged from 11% to 26%. The initial
and long-term success rates of stenting in small coronary
vessels were nearly the same as those for large vessel
stenting. These studies conclusively established the
feasibility, safety and efficacy of small vessel stenting,
especially in situations where balloon angioplasty results
were suboptimal (provisional stenting). However, the real
issue of whether elective stenting is better than provisional
stenting could not be resolved from these studies.
Randomized Trials of Elective Stenting versus
Balloon Angioplasty
To clarify the crucial issue of elective stenting, Savage et
al. 3 performed retrospective, post-hoc analysis of the
STRESS I and II trials which were originally designed for
lesions in coronary vessels with a reference diameter larger
than 3 mm. In this trial, 331 out of 598 patients had a
vessel diameter of <3 mm by quantitative coronary
angiography. The data of these patients were analyzed (163
in the stent group and 168 in the balloon angioplasty only
group). The procedural success rate was 100% with stenting
versus 92% with angioplasty (p<0.001). Abrupt closure
within 30 days occurred in 3.6% of patients in both groups.
The primary end-point of 6-month binary angiographic
restenosis rate was 34% with stenting versus 55% with
angioplasty alone (p<0.001). The minimum luminal
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diameter at 6 months was larger in the stent group than in
the balloon group (1.54 v. 1.27 mm; p<0.001). One-year
event-free survival was 78% in the stent group versus 67%
in the balloon group (p=0.019). The target lesion
revascularization rate was also lower at 16.1% in the stent
group as compared with 26.6% in the balloon group
(p=0.015). On the whole, this analysis revealed that elective
stent placement in small vessels was better than balloon
angioplasty alone. However, STRESS I and II were not
originally designed to test the role of stenting in small vessels
and such analyses cannot replace prospective randomized
controlled trials, which is the only way to answer such a
question definitively. A number of such trials were thus
initiated and the results of many of these are now
available.21–28
Eight major prospective, randomized, controlled trials of
elective stenting in small vessels involving 2687 patients
have been reported (Table 1). The main end-points of
interest are angiographic restenosis rate and major adverse
cardiac events at follow-up. The angiographic restenosis rate
at follow-up (usually 6 months) was available in 6 of these
8 studies and was found to be similar in the balloon
angioplasty and the stent groups in 4 of these 6 studies.
Only 2 studies (BESMART and RAP) found that elective
stenting significantly reduced the angiographic restenosis
rate. The average restenosis rate in the balloon angioplasty
group was 37% while that in stent group was 32%. Clinical
events at follow-up were found to be no different in 7 of
these 8 studies. Only the SISCA study found these to be
significantly reduced in the elective stenting group. In the
BESMART study, the target lesion revascularization rate was
reduced significantly, though there was no difference in the
mortality or myocardial infarction rate. However, these
trials are not exactly comparable due to a number of
variables, e.g. baseline characteristics, type of lesions
treated, type of stents used, antiplatelet regimen used, use
of high pressure stenting, use of glycoprotein IIb/IIIa
inhibitors, etc. Evaluation of individual data from these
trials provides important insight into this problem.
The BESMART (BeStent in Small Arteries) trial21 is a
French prospective, multicenter, randomized study that
evaluated the role of stenting in de novo lesions 15 mm or
less in length with vessel diameter <3.0 mm (mean 2.2
mm). Three hundred and eighty-one patients were
randomized. The procedural success rates were similar in
both groups, and the in-hospital rates of major adverse
events did not differ significantly. Death or myocardial
infarction rate at 6 months also did not differ. Target lesion
revascularization at 6 months was 25% for the balloon
angioplasty group versus 13% for the stent group
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278 Bahl et al. Elective Stenting in Small Coronary Arteries
(p=0.016). The primary end-point of a 6-month
angiographic restenosis rate was 49% for the balloon
angioplasty group versus 23% for stent group (p=0.0001).
The rate of cross-over to stenting because of suboptimal
result following balloon angioplasty was high (24%).
Suwaidi et al. 22 compared immediate and 1-year
outcomes in 651 patients with stenosis in small coronary
arteries treated with either 2.5 mm stent implantation
(n=108) or 2.5 mm balloon angioplasty (n=543).
Angiographic success was higher in the stent group (97%
v. 90%; p=0.02). In-hospital myocardial infarction rates
were comparable (4.6% v. 2.4%; p=0.2). At 1 year of followup, MACE was higher in the stent group (35% v. 22%;
p=0.05). Amongst successfully treated patients, there was
no difference at 1 year with respect to survival (3.8% v.
4.8%; p=0.37). It was concluded that stents could be
deployed in small coronary arteries with high success and
low in-hospital complication rates. However, stent use was
not associated with improved outcome at 1 year of followup, compared with balloon angioplasty.
Park et al.23 randomly assigned 120 patients with lesions
in small coronary arteries (de novo, nonostial lesions with
reference diameter <3.0 mm) to optimal balloon
angioplasty or elective stenting (7-cell NIR stent). The
primary end-point was restenosis at 6 months. Optimal
balloon angioplasty (residual stenosis <30%) was aimed at
in all cases and cross-over to stenting was allowed. The
procedure was successful in all patients. Twelve patients in
the balloon angioplasty group were stented for suboptimal
result or major dissection. The post-procedural lumen
diameter was larger in the stent group but late loss was also
greater (1.12±0.67 mm v. 0.63±0.48 mm; p<0.01). The
angiographic restenosis rate was 30.9% in the angioplasty
group and 35.7% in the stent group (p=NS). Clinical events
during follow-up were also similar. It was concluded that
optimal balloon angioplasty with provisional stenting may
be a reasonable approach for these lesions.
Briguori et al.24 compared 209 patients with complex
lesions (type B2 or C) in arteries <3.0 mm treated either
with balloon angioplasty or elective stenting. At a mean
follow-up of 20±4 months, MACE (39% in the angioplasty
group v. 44% in the stent group), target lesion
revascularization (33% in the angioplasty group v. 34% in
the stent group) and restenosis rates (47% in the
angioplasty group v. 38% in the stent group) were not
statistically different in the two groups. It was concluded
that elective stent implantation in small vessels with
complex lesions does not improve early and late outcomes.
The results are different from those of the STRESS trial as
instead of focal lesions, the present study was carried out
in complex lesions.
ISAR-SMART25 was a randomized trial in 404 patients
comparing stenting (using MultiLink stents) with balloon
angioplasty in small native coronary arteries (vessel size
between 2 and 2.8 mm). All patients received abciximab,
ticlopidine and aspirin. The primary end-point was 6-month
angiographic restenosis rate (>50% diameter stenosis);
adverse clinical events constituted secondary end-points.
No significant difference was found in the two groups with
respect to any of the primary or secondary end-points at
follow-up: angiographic restenosis (35.7% v. 37.4%), net
luminal gain (0.76±0.78 mm v. 0.76±0.63 mm), infarctfree survival (96.6% v. 97%), and target vessel
revascularization (20% v. 16.5%). Angiographic restenosis
at 6-month follow-up was 35.7% in the stent group versus
37.4% in the angioplasty group. It was concluded that
Table 1. Randomized trials comparing elective stenting with angioplasty alone for lesions in small coronary vessels
Trial
Number of
patients
Reference
vessel size
included
Angiographic restenosis
at follow-up
Balloon
21
Stent
Clinical events
at follow-up
p value
BESMART
381
<3.0 mm
49%
23%
<0.0001
Suwaidi22
Park23
Briguori24
ISAR-SMART25
SISA26
RAP27
SISCA28
651
120
209
404
351
426
145
<3.0 mm
<3.0 mm
<3.0 mm*
2-2.8 mm
2.3–2.9 mm
2.2–2.7 mm
2.1–3.0 mm
NA
31%
38%
37%
32%
37%
NA
NA
36%
41%
36%
28%
27%
NA
—
NS
NS
NS
NS
<0.05
—
Balloon
@
TLR
25%
27%
14%
24%
Stent
@
TLR
13%
22%
11%
10%
p value
0.016
NS
NS
NS
NS
NS
NS
0.025
NS: not significant; NA: indicate data not available; MI: myocardial infarction; TLR: target lesion revascularization; *: type B2 and C lesions; @: values
for MI and death not available
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elective stenting does not reduce restenosis rates compared
with the strategy of provisional stenting in small coronary
arteries.
The SISA (Stenting in Small Arteries) trial26 was a
randomized, multicenter trial in which balloon angioplasty
was compared with elective stenting (using Medtronic
BeStent) for lesions in vessels 2.3–2.9 mm in diameter in
351 patients. Angiographic restenosis at 6 months was the
primary end-point. There was no significant reduction in
this primary end-point (32.4% for balloon angioplasty v.
28% for stent group). There was a trend for less non-Q wave
myocardial infarction at 6 and 12 months in the stent
group, but there was no reduction in total cardiac events or
re-angioplasty rates.
The RAP (Restenosis en Arterias Pequenas) trial27 was a
multicenter, prospective randomized trial comparing
elective BeStent implantation with balloon angioplasty
alone in 426 patients with lesions in small vessels (2.2–2.7
mm reference diameter). Angiographic restenosis at 6
months was the primary end-point. Immediate postprocedure as well as 6-months minimum luminal diameter
was higher in the stent group (1.47 mm v. 1.31 mm at 6
months; p=0.01). The restenosis rate at 6 months was less
with stent implantation (27% v. 37%; p<0.05) as also the
vessel occlusion rate (1.4% v. 3.7%; p<0.01). At 6 months,
MACE was no different in the two groups (11% v. 14%).
The results of the RAP study demonstrate that coronary
artery stenting significantly reduces the rate of restenosis
and vessel reocclusion in small coronary arteries.
SISCA (Stenting in Small Coronary Arteries) is a
multicenter, randomized trial28 comparing elective stenting
using the 15 mm heparin-coated BeStent and balloon
angioplasty in 145 patients with lesions in the small
coronary arteries (2.1–3.0 mm reference diameter). The
procedural success rate was 94.6% in the stent group versus
80% in the balloon angioplasty group (p=0.008). During
6 months of follow-up, occurrence of cardiac events was
significantly reduced (9.5% in stent group and 23.9% in
balloon angioplasty group; p=0.025). Target lesion
revascularization was required in 8% of patients in the stent
group versus 25% of patients in the balloon angioplasty
group. It was concluded that in small vessels, elective
placement of a heparin-coated BeStent significantly
improves both procedural and 6-month clinical outcomes
compared with balloon angioplasty.
What conclusions can we draw from the above data?
Results of most of the above studies point to provisional
stenting as a better option, with stent placement only for
suboptimal results or complications. Routine elective
stenting was not found to have better long-term results in
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most of the trials. However, the data have been conflicting
regarding many issues, and a number of patient and
procedure-related factors could be responsible for these
differences.
Role of Intravascular Ultrasound Guidance
The role of intravascular ultrasound (IVUS) in optimization
of stent implantation in larger coronary arteries is well
documented. Quantitative coronary angiography (QCA) has
several fallacies in evaluating the “true” diameter of vessels.
Intravascular ultrasound may be of significant importance
in choosing the correct stent diameter and its length in small
vessels. Atherosclerosis is frequently a diffuse process and
the diseased vessel may be reduced in caliber along its entire
length (diffusely diseased artery), giving the angiographic
impression of “small” vessel disease; IVUS helps to
differentiate between a “small” vessel and a diffusely
diseased artery. One should also keep in mind the fact that
there is a progressive decline in luminal diameter as
coronary arteries course distally. This tapering is an
important consideration in small vessels (especially in long
lesions) in order to avoid overdilatation of distal lesions with
stents.
Ortolani et al.29 studied the feasibility and safety of IVUS
guidance during stenting of small coronary arteries. In this
pilot study, they included 14 patients who were to undergo
stent implatation in small coronary arteries (mean reference
vessel diameter 2.3±0.2 mm). They showed that IVUSguided coronary stenting can be performed in small vessels
with a high success rate and low incidence of in-hospital
complications. However, though the initial results showed
improvement with IVUS guidance, the long-term clinical
and angiographic outcomes were less favorable. The 6month angiographic restenosis rate was 30.7% and late loss
in stent diameter was 1.1±0.6 mm. Akiyama et al.4 showed
the benefit of optimal IVUS-guided stenting. The restenosis
rate was 26% when optimal IVUS outcome was achieved,
as compared with 37% when IVUS outcome was suboptimal.
Effect of Stent Design
The stent design may have important implications for
outcome in terms of both subacute thrombosis and longterm restenosis. It is necessary to develop stents specially
designed for small arteries so as to obtain an optimal radial
force at a smaller diameter with a lower metal-to-vessel
ratio. Caputo et al.30 compared the outcomes of small vessel
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280 Bahl et al. Elective Stenting in Small Coronary Arteries
stenting using Palmaz–Schatz (slotted tube) stents with that
using modular XT stents in the EXTRA trial. Six-month
results showed that MACE, death, target lesion
revascularization and binary restenosis rates were all
similar in the two groups. However, there was a significant
increase in the occurrence of Q-wave myocardial infarction
with the use of modular XT stents (5.1% v. 0%; p=0.004).
The effect of stent design on clinical outcomes following
small vessel stenting needs to be studied in a larger number
of cases. A number of stents specifically designed for small
vessels are now becoming commercially available. These
include, among others, BioDivYsio phosphorylcholinecoated stent (Biocompatibles International), Multi-Link
Pixel coronary stent (Guidant Corporation) and BeStent
(Medtronic).
Treatment of In-stent Restenosis in Small Vessels
In-stent restenosis following small vessel stenting can also
be treated with repeat angioplasty. Gross et al.31 studied instent restenotic lesions in small vessels (reference diameter
<2.85 mm) in patients who underwent a repeat
interventional revascularization procedure. Seventy-three
patients with 79 lesions were treated either by angioplasty
alone (47%), by restenting (28%) or by excimer laser
angioplasty (25%). Though the procedure was initially
successful in all patients, 57% patients had restenosis at 6
months (78% for the laser group, 47% for the restenting
group and 47% for the angioplasty alone group). The results
are comparable to those of large vessel in-stent restenosis
treatment.
Conclusions
Should stenting be performed routinely in all cases after
angioplasty of lesions in small coronary arteries (elective
stenting) or only if there is a complication after balloon
angioplasty such as acute or threatened vessel closure,
major dissection or suboptimal result (provisional stenting)?
According to the ACC expert consensus document on
coronary artery interventions, stents are recommended in
small vessels if the result of balloon angioplasty is
suboptimal. 32 Data currently available indicate that
provisional stenting may be a better option, as elective
stenting has not been consistently shown to improve longterm results on follow-up. However, the situation may
change with newer developments, especially the availability
of stents designed specifically for small coronary arteries,
routine use of glycoprotein IIb/IIIa inhibitors, introduction
IHJ-Editorial.p65
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of effective antiplatelet regimes including clopidogrel and
use of antioxidants such as probucol. In addition, early
studies with drug-coated stents have shown promise in
significantly reducing restenosis rates, a major concern in
small vessel stenting.
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282 Enas
et al. Coronary Artery Disease in Women
Review
Article
Indian Heart J 2001; 53: 282–292
Coronary Artery Disease in Women
Enas A Enas, A Senthilkumar, Vijaya Juturu, Rajeev Gupta
Coronary Artery Disease in Indians Research, Lisle, USA and
Mahatma Gandhi National Institute of Medical Sciences, Jaipur, India
W
omen now outlive men by 10 years, thanks to the
dramatic (>99%) decline in obstetrical death rate
over the past 100 years. Women represent 60% of those
over the age of 65 years in the United States (US) and more
women than men have died of cardiovascular disease (CVD)
since 1984.1 There has been an explosive increase in the
knowledge of the natural history of coronary artery disease
(CAD) in women in the past decade. This is due to a
combination of greater participation of women in research
studies, improved medical technology, and perhaps political
pressure. Among women, the lifetime risk of death from
CAD is more than 10-fold greater than that from breast
cancer.2 It is estimated that 31% of women will die from
CAD; yet, about 70% of university educated women
consider their risk of CAD to be <1%. They worry
profoundly about breast cancer, although the risk of death
from breast cancer is <3%. This lack of concern for CAD by
women and perhaps their physicians could explain why the
decline of CAD in women in western countries has been
only half that of men. The excess of CAD among overseas
Indians has been similar or greater in women than in
men,3 and offers a broad “window to the world” for the
impending epidemic of CAD among Indian women. In this
article, the term “Indian” refers not only to people of Indian
origin but all those originating from the entire Indian
subcontinent.
This review discusses the progress in understanding the
major risk factors leading to the high rates of CAD in
women, especially in India. The potential role of genetic
susceptibility to CAD mediated by elevated lipoprotein (a)
[Lp(a)] levels and its synergistic adverse effects with both
conventional and emerging risk factors are highlighted.
Important differences in the presentation, diagnosis and
treatment of CAD in women, and the unique role of
hormone replacement therapy (HRT) are addressed. Finally,
we offer recommendations to both Indian women and their
physicians in reducing the morbidity and mortality from
CAD.
Correspondence: Dr Enas A Enas, Coronary Artery Disease in Indians
Research, 1935 Green Trails Dr, Lisle, IL 60523 USA
e-mail: [email protected]
IHJ-IA-012.p65
282
Magnitude of CAD in Indian Women
CAD rates in India: Since 1960, life expectancy in India
has increased by 20 years to 61 years of age.4 From 1960
to 1995, the prevalence of CAD in adults increased from
3% to 10% in urban Indians and from 2% to 4% in rural
Indians, with women having rates similar to men. 5
Although the prevalence of CAD in rural India is half that
of urban India, this is still two-fold higher than the overall
CAD rates in the US and several-fold higher than in rural
China.6 In 1990, there were 783 000 deaths due to CAD in
India and this is projected to double by the year 2015,
primarily due to affluence and urbanization. Young Indians
with CAD have extensive coronary atherosclerosis, with
even premenopausal women having multivessel disease, a
pattern rarely seen in the West.
CAD rates among overseas Indians: Although more
women than men die annually from CAD, the age-adjusted
standardized mortality rate (SMR) for CAD among women
is about one-third that of men all over the world. This is
due to a higher age (average 10 years) in women at the time
of death. The excess of mortality due to CAD among
overseas Indians is equal or greater in women than men.
This is particularly noteworthy since smoking is rare among
Indian women. In the US, Indian women have the highest
CAD mortality—30% higher than Whites and 325% higher
than the Chinese.7
Excess CAD morbidity and mortality in women:
Women have a poorer prognosis and a more severe outcome
than men after myocardial infarction (MI), percutaneous
transluminal coronary angioplasty (PTCA), and coronary
artery bypass grafting (CABG). Women are more likely than
men to die after a first MI, and for survivors, there is a higher
risk of recurrent MI, heart failure, or death. 8 In the
Framingham Heart Study (FHS), the one-year mortality
following an MI was 44% in women versus 27% in men.9
The overall short-term and long-term CAD mortality
following an MI are about 40% higher in women after
adjustment for age and other risk factors. The excess inhospital CAD mortality in women compared to men almost
balances their lower prehospital mortality.10 Despite their
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Enas et al. Coronary Artery Disease in Women 283
excess risk, women are only half as likely as men to receive
aspirin, betablockers or thrombolytic therapy, or to be
referred for coronary angiogram or revascularization
procedures.11 This difference is rapidly disappearing in the
US but not all over the world. Recently, Vaccarino et al.12
found that mortality from MI in women <50 years of age
was double that of men and the excess mortality in women
is limited to <60 years of age. This is in sharp contrast to a
report from India showing lower rates of morbidity and
mortality in young women and deserves greater scientific
scrutiny.
(TG), low density lipoprotein (LDL), and Lp(a) are correlated
with CAD.17 Compared with Whites, Indian men and
women have a lower prevalence of hypertension,
hypercholesterolemia, obesity and smoking, but a higher
prevalence of high TG, low HDL, glucose intolerance and
central obesity. The prevalence of most risk factors is lower
in rural than in urban India with the exception of smoking/
tobacco use.18 The higher rates of CAD in urban areas
despite a low rate of tobacco use (Tobacco Paradox)
underscore the critical importance of factors associated
with urbanization.
Presentation of CAD: Although women are more likely
than men to present with angina as the initial complaint,
the reliability of typical angina as a sign of CAD is poor. In
the FHS, only 17% of women with typical angina developed
an MI compared with 44% of men.13 In the Coronary Artery
Surgery Study (CASS), only 50% of women with typical
angina had significant CAD compared with 83% of men.
Whether this discrepancy is due to over-reporting of chest
pain by women or under-reporting by men is unclear.
Women having an MI are more likely to present with
atypical chest pain (midback pain) and atypical symptoms
(indigestion, nausea, vomiting and dyspnea).14 They present
to the hospital significantly later than men, which may
decrease the benefit of reperfusion therapy.
Asian Indian ethnicity: At a given level of risk factors,
compared to Americans, the CAD risk is 50% lower among
southern Europeans but 50% higher among northern
Europeans.19 The risk of CAD among Indians is even greater
than in northern Europeans at any given level and/or
combination of conventional risk factors—at least double
that of Americans and several-fold higher than other
Asians.20 At any given level of TC the CAD risk varies >5fold depending on ethnicity and level of other risk factors.21
Indian ethnicity has now been demonstrated to be a risk
factor by itself.22
Sudden death: More than half of sudden deaths occur
within six hours of the onset of symptoms. Early diagnosis
is important, since two-thirds of women who experience
sudden death have no previous symptoms of CAD,
compared with about half of men.15 The risk factors and
mechanisms of sudden coronary death differ between older
and younger women. Older women who die of CAD often
have dyslipidemia, with severe coronary narrowing
and plaque ruptures. Young women who die of CAD
are often smokers with plaque erosions and little
coronary narrowing. However, most young Indian women
with CAD have advanced CAD resembling that in older
women.16
Coronary Risk Factors
Women, in comparison with men, tend to have a better risk
factor profile at younger ages, whereas the opposite is true
at older ages. Although most risk factors for CAD are similar
in men and women, gender differences have been
documented, particularly for diabetes, central obesity and
dyslipidemia. Among Indian women, the presence of
hypertension, diabetes, low levels of high density lipoprotein
(HDL) and high levels of total cholesterol (TC), triglycerides
IHJ-IA-012.p65
283
Family history: Among women, a history of an MI or
sudden death before the age of 55 in a sister is more strongly
associated with risk of MI than that in a brother or parent.
A family history of premature CAD in a sister is associated
with a 12-fold higher risk versus 6-fold for a brother and 3fold for a parent.23 Since choosing one’s parents or siblings
is not an option, this topic will not be discussed further
except that women with a family history of premature CAD,
especially in a sister, should follow a course of action similar
to the one recommended for those who had survived an MI
or had coronary revascularization at a young age.
Age: Compared with the age group 34–44, CAD mortality
among women increases 40-fold by the age of 80, when its
incidence become identical in men and women. Women are
about 10 years older than men at first manifestation of CAD,
although they have a similar plaque burden.24 Women lose
this 10-year advantage if they smoke, have diabetes, or had
a premature menopause. The postmenopausal increase in
the risk of CAD is related to a higher incidence of
hypertension, diabetes, dyslipidemia and obesity. The steady
increase in CAD mortality with age is in sharp contrast to
that of breast cancer, which peaks between the ages of 40
and 50 years and declines steadily thereafter.
Height: Height is inversely associated with CAD in women
as it is in men. In a large study involving about 2000
women, short women (<59 inches) had a 3-fold higher risk
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284 Enas et al.
of CAD than taller women (>69 inches), after adjusting for
age, weight, educational status, religion and other factors.25
Generalized obesity: Obesity is associated with increased
risk of hypertension, diabetes, dyslipidemia and CAD. Body
Mass Index (BMI), which is defined as the weight in
kilograms divided by height in squared meters (kg/m2) is
now accepted as the single best measure of obesity.26 In the
16-year data from the Nurses’ Health Study (NHS), CAD
mortality was 4-fold lower in lean (BMI <21) than in obese
women.27 For Asians, the optimum BMI is <23, whereas
>23 is considered overweight and >25 obese.28 Thus the
BMI cut-off points for overweight is 2 units, and obesity 5
units lower in Asians than in Whites.
Central obesity: The distribution of fat is of equal or
greater importance as the total amount of fat. Marked
adverse metabolic consequences are seen with central
obesity (android or apple-type) but rarely with gluteofemoral obesity (gynoid or pear-type). The waist-to-hip ratio
(WHR) has been traditionally used to measure central
obesity. This is a better marker for CAD death than BMI in
women under 50 years of age. Because the excess fat is
usually concentrated in the hip in women and the waist in
men, the optimum WHR is lower in women (<0.75) than
in men (<0.95).29
Recently, waist circumference has been found to be a
simple and better marker of central obesity than WHR. In
women, the optimum waist circumference is 10 cm lower—
<80 cm in women and <90 cm in men. These values are
about 8–10 cm lower than that recommended for Whites
and underscore the need for instituting a weight
management program at much lower BMI and waist
circumference in Indian men and women. At a given level
of WHR or waist circumference, CAD rates are identical in
men and women. It is plausible that sex differences in central
obesity are the key to the gender gap in CAD.
The recognition of the significance of central obesity
should not divert attention from the metabolic
consequences of noncentrally obese individuals who
need to reduce weight. Among Indians, as in other
populations, both BMI and WHR are related to CAD risk
factors in a graded manner; the maximum risk occurs in
apple-shaped overweight and minimum in pear-shaped lean
individuals.30
Adult weight gain and weight reduction: Atherogenic
risk factor clustering is common in both sexes and worsens
with weight gain. Age-related increase in weight and waist
circumference is greater in women than in men and is
closely related with decrease in physical activity. A weight
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Coronary Artery Disease in Women
284
gain of even 7–11 kg after the age of 18 years has
substantial health consequences, with a doubling of risk
for diabetes and CAD in women.27 Middle-aged women who
lose ≥5 kg of weight have a significantly reduced risk for
diabetes. The recommended weight reduction is about 0.5
kg per week and this requires a negative caloric balance of
3500 calories equal to walking 56 km per week.
Physical activity: Physically active women have a 50%
lower risk of CAD than sedentary women.31 Increased
physical activity along with diet can prevent a rise in LDL
and weight gain, especially around the waist. Daily walking
for 45–60 minutes is necessary to prevent weight gain in
most women. However, even walking 2 km per week
produces a favorable risk factor profile, especially fibrinogen
and insulin levels, and reduces the CAD risk. Home physical
activity is positively related to favorable lipoprotein levels,
with those engaging in heavy home physical activity having
higher HDL levels. Other benefits of exercise include reduced
risk of breast cancer (relative risk 0.28).
Socioeconomic status (SES) and psychosocial factors:
CAD has now become a disease of the poor in rich countries
and of the rich in poor countries. Women with less than a
high school education have a 30%–50% higher CAD
mortality than those with higher education. Depression,
high hostility, low social support and low education level
are associated with CAD, after controlling for adverse health
behaviors. Indians with low literacy have a higher
prevalence of CAD and risk factors such as smoking and
hypertension. However, differences in SES failed to explain
the excess burden of CAD among Indians in the UK. Despite
having a lower level of TC, Indians had a 3- to 4-fold higher
odds ratio for a high-risk lipid profile, after controlling for
SES, age and sex. 32 The impact of psychosocial and
behavioral factors on CAD in Indian women requires further
investigation.
Paradox of healthy lifestyle and shorter lifespan in
women physicians: Women physicians in the US report
having generally good health habits and exceed all examined
national goals for personal screening practices and other
personal health behaviors. Women physicians’ behaviors
may provide useful standards for other women. Ironically,
women physicians die an average of 10 years earlier than
their male counterparts, the opposite of what happens in
the general population. The suicide rate among female
physicians is higher than that for male physicians and four
times higher than the age-matched female population and
may partially explain their lower life span despite a healthy
lifestyle.
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Tobacco abuse: Due to its anti-estrogenic effects, smoking
quadruples the risk of MI in young premenopausal women.
It is a stronger risk factor in women than in men. Over 50%
of MI in middle-aged women in the US is attributable to
cigarette smoking. The risk of CAD begins to decline within
months of cessation of smoking and disappears within 3–
5 years. The smoking cessation rates have declined more
slowly in women in the US, especially younger ones than in
men and parallel slower rates of decline of CAD in women.
The overall rate of smoking is low among Indian women,
particularly in urban areas.
Passive smoking: Although only 8% of the women in
Asian countries smoke, >60% of the men are smokers.33
Therefore, vast numbers of women and children are exposed
to environmental tobacco smoke (ETS), which increases
platelet activity, accelerates atherosclerosis, reduces exercise
tolerance, and increases the risk of both fatal and nonfatal
cardiac events. Urgent public health measures are needed
to reduce the dangers of both active and passive smoking
in India.
Hypertension: Hypertension confers a 4-fold risk of CAD
in women versus a 3-fold one in men. Hypertension tends
to be more common in women than in men after 45 years
of age (White women 60% and Black women 79%). The
systolic blood pressure (BP) continues to increase
disproportionately in women until the age of 80.
Hypertension is closely correlated with obesity and is 6-fold
higher in women with a BMI >30 versus BMI <20.
Conversely, a weight reduction of 9 kg can lower systolic
BP by 6 mmHg and diastolic BP by 3 mmHg in hypertensive
patients.34
Insulin resistance syndrome or Syndrome X: This is a
precursor of diabetes and a common pathogenic
mechanism for the development of CAD. This syndrome is
particularly common among Indians and consists of
hyperinsulinemia, atherogenic dyslipidemia, glucose
intolerance, prothrombotic state, central obesity and
hypertension. This is different from the cardiac syndrome
X (angina with abnormal treadmill test and normal
coronary angiogram), which is also more prevalent in
women. It is unclear if the cardiac risk in this syndrome
exceeds that of the constituent risk factors.35
Diabetes mellitus: In the National Cholesterol Education
Program Adult Treatment Panel III (NCEP ATP III), diabetes
is regarded as a CAD risk equivalent.36 Diabetes is a stronger
risk factor for CAD in women than in men, with a 3- to 7fold higher CAD incidence and mortality compared to a 2to 3-fold higher risk in men.37 Diabetes increases the risk of
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Enas et al. Coronary Artery Disease in Women 285
heart failure by 8-fold in women compared to 4-fold in men;
diabetes eliminates the protective effects of estrogens and
removes the normal sex difference in the prevalence of
CAD.38 Premenopausal women with diabetes face a similar
risk of developing CAD as nondiabetic men of the same
age.39 Following an MI, diabetic women have double the rate
of recurrence and shorter survival than men.
Diabetic dyslipidemia: Approximately 80% of deaths in
diabetic patients are attributable to CVD, which in turn is
highly correlated with dyslipidemia.40 Diabetic dyslipidemia
consists of elevated TG, low HDL, and an increased
proportion of small dense LDL. Recently, the NCEP ATP III
has also recommended an LDL goal of <100 mg/dl in
diabetic patients, irrespective of the presence or absence of
CAD.36 Diabetic women with HDL ≤50 mg/dl and TG ≥100
mg/dl have high CAD mortality and should be treated
aggressively. Treatment of dyslipidemia with statins in
patients with both impaired fasting glucose and diabetes is
highly cost-effective.
Crucial Role of Dyslipidemia
Total cholesterol (TC): Total cholesterol levels in women
compared to men are about 10 mg/dl lower before the age
of 45 and 10 mg/dl higher after the age of 65. A 20%
difference in TC level is associated with a 50%–60%
difference in CAD risk over a lifetime.41 The optimum TC
level appears to be <160 mg/dl.
LDL: The LDL fraction of TC is a strong predictor of CAD
mortality in women as well as in men. Unlike in men whose
LDL levels plateau at the age of 50 years, the LDL levels in
women increase steadily by an average of 2 mg/dl/year
between the ages of 40 and 60 (total of 40 mg/dl).42 The
optimum LDL level is <100 mg/dl.36
HDL: Low HDL is an important risk factor even if TC and
TG levels are normal. It is a stronger predictor of CAD in
women than in men, especially after the age of 65; indeed,
the protective effect of HDL is twice as important as the
atherogenic effect of LDL. High density lipoprotein levels
are about 10 mg/dl higher in premenopausal women than
in men. Among women, the HDL levels vary markedly
depending on the ethnicity, with Indian women having the
lowest levels. The HDL level among Indian women (45 mg/
dl) is about 10 mg/dl lower than in Whites (55 mg/dl) and
20 mg/dl lower than in Blacks, the Chinese and Japanese
(65 mg/dl). These high levels of HDL among Black, Chinese
and Japanese women also parallel their low rates of CAD,6
whereas the low levels of HDL in Indian women parallel
their high rates of CAD.43
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286 Enas et al.
The NCEP ATP III has classified HDL <40 mg/dl as low
HDL and >60 mg/dl as high HDL.36 In India, 32% of urban
and 18% of rural women have HDL levels <40 mg/dl. Many
experts consider HDL <50 mg/dl to be low in women. In
the Coronary Artery Disease in Indians (CADI) study,44 70%
of Indian women had HDL levels <50 mg/dl. If the level is
<35 mg/dl, it confers an 8-fold higher CAD risk than an
HDL of >75 mg/dl in women.45
Total cholesterol/HDL (TC/HDL) ratio: This ratio is now
widely recognized as the single best predictor of CAD. At
any given level of TC/HDL ratio, the CAD risk is virtually
identical in men and women.9 Indian women worldwide
have a high TC/HDL ratio by virtue of low HDL, even
when TC levels are not elevated.46 The optimum TC/HDL
ratio is 3 and the average ratio is 4. A TC/HDL ratio >5
appears to be a strong predictor of CAD, and is observed in
25% of industrial and 32% of urban female populations in
India.18
Triglycerides: A high TG level is a stronger predictor of
CAD in women than in men. An increase in TG level of 90
mg/dl increases the CAD risk by 75% in women versus 30%
in men.47 A high TG level was significantly associated with
cardiac and total mortality in a 20-year follow-up of
Swedish women.48 Conversely, low TG (<97 mg/dl) and
high HDL (>57 mg/dl) is associated with very low risk of
CAD,49 but is uncommon among Indians. A low level of HDL
often accompanies a high TG. The optimum TG level is <150
mg/dl.
Lipid triad: The combination of high TG, low HDL and high
small dense LDL is called the lipid triad. The TG level is the
principal determinant of small dense LDL, which in turn is
the link between cholesterol and TG metabolism.50 The
predominant form of LDL is small and dense when HDL is
<40 mg/dl and TG >100 mg/dl.51 Recently, a TG/HDL ratio
of >3 was found to be a simple, accurate and inexpensive
predictor of small dense LDL.52 Individuals with small dense
LDL have a 3-fold higher risk of CAD, which increases to
20-fold when apolipoprotein B (Apo B) and insulin levels
are also raised.53 All these abnormalities are common
among Indian men and women, rendering them highly
susceptible to CAD.54
Lipoprotein(a): An elevated level of Lp(a) is a powerful
risk factor for the presence and severity of premature CAD
in women as well as in men. Since its pathological effects
begin in infancy, Lp(a) is a stronger determinant of CAD in
premenopausal than in postmenopausal women. The
pathogenicity of Lp(a) is markedly influenced by other risk
factors, especially low HDL, a high TC/HDL ratio, and high
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Coronary Artery Disease in Women
286
homocysteine levels. For example, high levels of Lp(a)
increase the risk of CAD by a factor of 5 when associated
with hypertension, by a factor of 7 with high TC/HDL ratio,
by a factor of 8 with low HDL and by a factor of 9 with high
homocysteine. The combination of all four of the above
increases the risk of CAD by a factor of 122.55 Lipoprotein(a)
level was a powerful predictor of mortality in the 4S study.56
Lipoprotein(a) appears to be a stronger risk factor than
diabetes in young women. Indian women in the US have a
higher CVD risk than their American counterparts, by
virtue of central obesity, high Lp(a) levels, and an
atherogenic lipid profile. Although Lp(a) levels are largely
genetically determined, there is a 10% increase in Lp(a)
levels in postmenopausal women. Hormone replacement
therapy (HRT) reduces Lp(a) levels by an average of 20%
(up to 50% in women with high Lp(a) levels). The role of
Lp(a) among Indians has been reviewed recently.57
Homocysteine: An elevated homocysteine level is a risk
factor for MI, especially among young women. After
adjusting for other CVD risk factors, women with
homocysteine levels ≥15.6 µmol/L have twice the risk of
MI as women with homocysteine levels <10 µmol/L. The
most common cause of elevated homocysteine is low folate
levels, though many patients also have low levels of
vitamins B6 and B12.58 Prolonged cooking of vegetables, a
common practice in India, can result in the destruction of
up to 90% of the B group of vitamins.59 The optimum
homocysteine level is <10 µmol/L. The combination of high
Lp(a) and high homocysteine levels is very common among
Indians and carries a 32-fold increased risk of CAD.55 The
multiplicative effects of the emerging and conventional risk
factors best explain the excess burden of CAD among Indian
men and women.
Diagnostic Testing and Coronary Revascularization
Noninvasive diagnostic testing: Although women with
resting ischemic electrocardiographic findings have an
increased risk for CAD, false-positive stress tests may be seen
in as high as 50% of women with chest pain.60 This is
particularly true in those on HRT, which produces ST
segment depression similar to a digitalis-like effect.
Therefore, the accuracy of stress testing depends on the
Bayesian principles.
Stress imaging, including thallium myocardial perfusion
imaging, has lower sensitivity and specificity in women than
in men, possibly due to smaller left ventricular chamber size,
hormonal milieu, and autonomic imbalance.60,61 Estimation
of coronary calcification by electron beam computerized
tomography has a low sensitivity among premenopausal
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Indian Heart J 2001; 53: 282–292
Enas et al. Coronary Artery Disease in Women 287
women and its role in detection of CAD is currently
evolving. Stress echocardiography appears to be superior
in identifying women who require further expensive
diagnostic and therapeutic interventions.
suggest that the gender differences in mortality related to
CAD do not exist, or may even be lower in women, after
adjusting for age, risk factors and interventions.74
Coronary angiography: Of the 323 women enrolled in
the pilot phase of the Women’s Ischemia Syndrome
Evaluation (WISE) study, 57% had no significant CAD (34%
not detectable, 23% minimal stenosis) versus 43% with
significant CAD (stenosis >50%) on coronary angiogram.62
The contemporary common finding of “no CAD” and
“extensive CAD” at coronary angiography among
symptomatic women with similar presentations is similar
to the CASS data reported 20 years earlier.63 These findings
underscore the need for better use of noninvasive tests
to identify women who are candidates for invasive
procedures.
Preventive and Therapeutic Implications
PTCA: Women who are hospitalized for CAD undergo fewer
invasive procedures than men. Whether this difference
represents overtreatment of men or undertreatment of
women or both remains to be determined.64 Although
women have excellent long-term prognosis after successful
PTCA and stent insertion, similar to that observed in men,65
the procedural morbidity and mortality are 3-fold higher
in women, 66 which may be due to severity of their
underlying disease rather than gender alone.67 Recent
evidence suggests that the gender bias against aggressive
intervention and treatment of CAD in women is
disappearing in the West.68
CABG: Women in general are more severely ill than men
and have double the mortality following CABG.69 People
with small body size have small coronary arteries but
women have smaller coronary arteries than men despite
controlling for differences in body size.70 Small coronary
artery diameter is associated with substantially increased
risk of in-hospital mortality following CABG. Thus, smaller
coronary artery diameter is one explanation for the higher
perioperative mortality and poorer long-term success with
CABG in women.71 Women have less graft patency and
symptom relief and higher reoperations within the initial
five years following CABG. A high TG level is particularly
dangerous in women who undergo CABG.72 Aggressive
lipid-lowering therapy can stabilize the vulnerable plaque
and thus provide a more stable milieu for CABG to avoid
the need for repeats and “3-peats”.73 A strategy of delayed
revascularization with optimum medical therapy is
advisable. Women have higher risk profiles and are older;
yet, the unadjusted 5-year mortality rates in women and
men undergoing CABG and PTCA are similar. This would
IHJ-IA-012.p65
287
Asymptomatic progression of CAD: Atherosclerosis is
a disease that manifests clinical symptoms only late in its
development. Coronary artery disease is not a categorical
event but rather a continuum of a progressive process.75
Sudden cardiac death may be the first symptom and such
patients obviously cannot benefit from secondary
prevention. Furthermore, women fare worse following an
MI than men; therefore primary prevention is even more
important in women.
Comprehensive guide to risk reduction in women:
The American Heart Association recommendations can be
modified to suit Indian conditions.76 Caloric intake should
be balanced to caloric expenditure to achieve and maintain
optimum BMI. Regular exercise is mandatory for both men
and women. Women who have gained 5 kg of weight or 5
cm of waist should be advised by physicians to make gradual
but permanent adjustments in physical activity and eating
patterns. The essential ingredients and goals for risk
reduction in women are given in Table 1.77
Undertreatment of dyslipidemia in women: About
50% of women >55 years of age qualify for drug treatment
under NCEP ATP III guidelines in the US.36 In the Heart and
Estrogen/Progestin Replacement Study (HERS), only 9%
met the LDL goal of <100 mg/dl.78 Another study found
only 12% of women achieved the LDL goal compared to 31%
of men. This underscores the need for a more aggressive
approach to the treatment of dyslipidemia in women.
Statins in the prevention and treatment of CAD: Most
physicians do not wait for the development of stroke to treat
hypertension, or coma to treat diabetes. The benefit of
dyslipidemia treatment with statins is several-fold greater
than treatment of hypertension or diabetes. There is no
justification to delay or deny the use of statins to treat
dyslipidemia in asymptomatic women until a cardiac
catastrophe. Development of angina should be considered
a medical failure rather than the first indication for
mechanical intervention.
Landmark trials and benefits of statins: Convincing
evidence now exists about the substantial reduction in CAD
morbidity and mortality due to lowering of lipid levels with
statins in women. In the Cholesterol And Recurrent Events
(CARE) trial, the reduction in major acute coronary events
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288 Enas et al.
Indian Heart J 2001; 53: 282–292
Coronary Artery Disease in Women
Table 1. Guide to CAD risk reduction for women
Lifestyle factors
Goal(s)
Cigarette smoking
Complete cessation
Avoid passive smoking
Physical activity
Accumulate >30 min of moderate-intensity physical activity daily
Women who have had recent cardiovascular events or procedures should participate in cardiac
rehabilitation, a physician-guided home exercise program, or a comprehensive secondary
prevention program
Nutrition
Low SAFA diet (<7% energy and <200 mg/dl cholesterol)
High MUFA diet (up to 20% energy) for those with high TG and low HDL
Nuts up to 30 g per day
Total dietary fiber intake of 25–30 g/day
Five or more servings of fruits and vegetables per day
Avoid prolonged cooking of vegetables
Limit salt intake to 6 g/day (lower in women with high blood pressure)
Weight management
Achieve and maintain desirable weight (BMI <23 kg/m2)
Desirable waist circumference <80 cm
Psychosocial factors
Positive adaptation to stressful situations
Improved quality of life
Maintain or establish social connections
Risk factors
Goal(s)
Blood pressure (BP)
Achieve and maintain BP <140/90 mmHg (optimal <120/80 mmHg)
Lipids, lipoproteins
LDL <100 mg/dl; TC <160 mg/dl; TG <150 mg/dl; HDL >50 mg/dl; Lp(a) <20 mg/dl
Diabetes
Maintain blood glucose: preprandial 80–120 mg/dl, bedtime 100–140 mg/dl
Maintain HbA1c <7%
BP <130/85 mmHg
Medications
Goal(s)
HRT
Initiation or continuation of HRT in women for whom the potential benefits may exceed the risks
(Lp(a) >20 mg/dl; HDL <50 mg/dl)
Oral contraceptives
Minimize risk of adverse cardiovascular effects while preventing pregnancy. Use the lowest effective
dose of estrogen/progestin
Antiplatelet agents/
anticoagulants
Prevention of clinical thrombotic and embolic events in women with established CAD. Primary
prevention studies are in progress
Beta-blockers
To reduce the reinfarction rate, incidence of sudden death, and overall mortality in women after MI
ACE inhibitors
To reduce the morbidity and mortality among MI survivors and patients with or without LV dysfunction
SAFA: saturated fatty acid; MUFA: monounsaturated fatty acid; HRT: hormone replacement therapy (Adapted from Mosca L, 199977)
(MACE) in women (46%) was more than double that in
men (20%). 79 Other statin studies with substantial
enrolment of women have also shown an impressive risk
reduction (RR); 4S80 (827 women, RR 37%), LIPID81 (1508
women, RR 15%), and AFCAPS/TexCAPS82 (997 women,
RR 46%).83
Statins reduce clinical coronary events by stabilizing the
vulnerable plaques, disruption of which results in MACE.84
In women this disruption is usually related to plaque
erosion, in contrast to plaque rupture in men.85 Other
differences in CAD between men and women are shown in
Table 2. Recently, statins have been shown to increase bone
IHJ-IA-012.p65
288
density and decrease fractures, dementia and stroke, all of
which provide additional benefits in women. 86,87
Preliminary data also indicate a reduced risk of breast
cancer among statin users.
Lipoprotein goals among Indian women: NCEP ATP
III recommends levels of LDL <100 mg/dl, TG <150 mg/
dl, HDL >40 mg/dl as optimum.36 These levels must be
achieved in women with or at high risk of CAD. Since the
overall risk of MACE in Indians without CAD is similar to
Whites with CAD, all Indians should strive to achieve and
maintain these optimum levels. This is especially true for
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Indian Heart J 2001; 53: 282–292
Enas et al. Coronary Artery Disease in Women 289
Table 2. Cardinal differences in CAD between men and
women
Men
Women
Manifestation of CAD
Age at first clinical manifestation
Age at first MI
Age at CAD death
Silent MI
CAD presenting as unstable angina
Acute MI presenting with atypical angina
Acute MI presenting as atypical symptoms
Sudden death
Sudden death without prior symptoms
CAD presenting as acute MI
Plaque rupture as the mechanism of acute MI
Plaque erosion as the mechanism of acute MI
— 10 years later
— 20 years later
—
8 years later
+
++
++
+++
+
++
+
++
++
+++
++
+++
+++
++
+++
+
+
+++
Relative risk of CAD with risk factors
High LDL
Low HDL
High Lp(a)
High TG
Diabetes
Severity of risk factors at the time of acute MI
Number of risk factors at the time of acute MI
+++
+++
++
++
++
++
++
++
++++
++++
+++
++++
+++
+++
+++
++
+++
+++
++
+++
++
++
++
++
+++
++
+
+
+
+++
+++
+++
++++
++
+++
++
++
++
+
++
Diagnostic testing
Sensitivity and specificity for exercise
treadmill test
Sensitivity and specificity with thallium
treadmill test
Sensitivity and specificity with stress
echocardiography
Complications and prognosis
Good prognosis with typical angina
Poor prognosis following MI
Morbidity from MI
CAD mortality with diabetes
Prehospital death with acute MI
Post-MI in-hospital mortality
Post-PTCA complications
Post-PTCA mortality
Post-CABG complications
Post-CABG mortality
Conclusions
PTCA: percutaneous transluminal coronary angioplasty;
CABG: coronary artery bypass grafting; MI: myocardial infarction;
CAD: coronary artery disease
those with high Lp(a) and low HDL levels or high TC/HDL
ratio. The results of the AFCAPS/TexCAPS support this
recommendation. There was a 46% reduction in MACE by
lowering LDL levels to <110 mg/dl in low-risk
asymptomatic American women (one-fourth the risk of
Indian women) with no CAD or risk factors.82 Statins
are highly effective in reducing the TC/HDL ratio (goal <4)
in women with low HDL unresponsive to lifestyle
measures.88
Hormone replacement therapy (HRT): More than 30
IHJ-IA-012.p65
289
observational studies suggest a 35%–55% reduction in CAD
incidence and mortality among women who receive HRT.89
However, the first two randomized clinical trials of HRT
failed to demonstrate any cardiovascular benefit.90–92 In the
HERS, there was a suggestion of early harm and late benefit
overall. Women who were in the highest quartile of Lp(a)
levels and received HRT had an impressive 54% decrease in
MACE with no suggestion of early harm.93 Over 40% of
Indian women have Lp(a) levels >20 mg/dl, which is
associated with a high risk of CAD.93,94 The benefits of HRT
may be greater in Indian women, who have substantially
higher rates of CAD (3-fold) and lower rates of breast cancer
(one-half)95 compared with Whites.
CAD is the leading cause of death in women. Health care
providers need to be sensitive to gender differences in
presentation, prognosis and responsiveness to treatment of
CAD. The prognosis of women with CAD differs according
to age, mode of presentation, accuracy of diagnosis, and
number of risk factors and is generally more ominous in
women. The failure to treat women as vigorously as men
contributes to their worse outcome although the gap is
narrowing rapidly in western countries.96 Doctors need to
understand the risk as well as risk factors of CAD in women
and the importance of prevention, diagnosis and timely
intervention. Most of the modifiable risk factors such as
obesity, smoking, hypertension, diabetes and dyslipidemia
are the same in both sexes and should be identified and
treated early. Reducing saturated fat in the diet and
simultaneously increasing the consumption of fish, fruits,
vegetables, nuts and fiber are the dietary ingredients for a
healthy heart. Exercising regularly, maintaining an ideal
BMI and waist size, quitting tobacco, controlling
hypertension and diabetes can substantially reduce the risk
of CAD and its complications. Health care systems need a
paradigm shift that emphasizes a healthy lifestyle for young
men and women.
Because of the high rate of CAD despite maximum
modification of lifestyle, pharmacological therapy may be
necessary in many Indians.97 The underdiagnosis and
undertreatment of dyslipidemia is greater in women
worldwide and appears to be worse in India.98 Use of statins
for dyslipidemia should not be delayed until a cardiac
catastrophe. The collective efforts of the government,
professional organizations, food industry and academic
community should be directed toward realizing a significant
health benefit by the society. Advances in the prevention
and treatment of CAD should not be denied to women.
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290 Enas et al.
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Review
Article
Investigative Approaches for Sudden Cardiac
Death
293
Mechanisms of Sudden Cardiac Death: A Review of
Investigative Approaches for a Global Dilemma
Sumeet S Chugh
Cardiac Arrhythmia Research Laboratory,
Oregon Health and Science University, Portland, Oregon, USA
If a man will begin with certainties, he shall end in doubts;
but if he is content to begin with doubts, he shall end in
certainties.
—Francis Bacon (1561–1626)
R
ecent analyses of disease progression patterns have
revealed a globally increased incidence of cardiac
disease.1–3 With a burgeoning population of patients with
coronary disease as well as heart failure, this translates
directly into a rising incidence of sudden cardiac death
(SCD). With the economic scale tipped in their favor,
warning symptoms of cardiac disease may allow the
industrialized world to pre-empt SCD in approximately 50%
of cases. However, in the remainder, fatal arrhythmia is the
first and only manifestation of SCD.4 Thus, SCD is a shared
and indiscriminate worldwide medical catastrophe.
Diverse Etiologies but a Common Terminal Event
Despite the broad spectrum of etiologic conditions, in the
overwhelming majority of cases, SCD results from a fatal
cardiac arrhythmia, either ventricular tachycardia/fibrillation
or severe bradycardia.4,5 As is often the case with medical
therapies, effective treatment of fatal arrhythmia with
electrical or pharmacologic maneuvers has long preceded the
complete understanding of culprit mechanisms. The
significant delay in the development of effective measures for
the prevention and risk stratification of SCD can thus be
attributed directly to a poor understanding of mechanisms
involved in fatal arrhythmogenesis. At the close of the
twentieth century, awareness of this important deficiency has
focused considerable interest on the mechanisms of SCD. This
review discusses selected present and future directions for
research in this area.
Magnitude of the Problem
Due to significant logistic issues, there is a conspicuous lack
Correspondence: Dr Sumeet S Chugh, Cardiology Division, UHN-62,
Oregon Health and Science University, 3181 SW Sam Jackson Park Road,
Portland OR 97201, USA. e-mail: [email protected]
IHJ-AI-10.p65
293
of data regarding a directly measured population-based
incidence of SCD. In the United States of America, an
estimate was recently reported by the Centers for Disease
Control and Prevention. In 1996, there were 452 675
estimated SCDs, accounting for 63.4% of all cardiac deaths
and 0.16% of the total population.6 When compared with
the estimated incidence in 1989, this represented a 10%
increase in SCD cases. In the absence of such figures for
India, extrapolation of the US data would provide a crude
estimate of at least 1.6 million SCDs per year; probably an
underestimate, given the relatively poor availability of outof-hospital emergency cardiac life-support services.
Does Sudden Cardiac Death Equal Sudden
Coronary Death?
The most common cause of SCD is coronary artery disease
(CAD). However, culprit etiologies also include a wide
variety of other disease conditions (Table 1) which, in the
face of growing concerns regarding risk stratification, are
receiving renewed attention. While approximately 80% of
SCDs are attributed to CAD,5 accurate risk stratification for
sudden death remains ineffective even in this largest
subgroup.7 Recently, large randomized trials (e.g. AVID,
MADIT, MUSTT and CIDS) have underscored our improved
ability to predict risk in specific high-risk groups; however,
these account for a small percentage of overall SCD.7 To
develop new means of risk stratification for SCD, our search
for risk factors must extend beyond sudden coronary death.
Prevailing Concepts of Arrhythmogenesis
In the majority of patients with SCD, the terminal
arrhythmia is ventricular fibrillation.8 In a significant
percentage of patients who present with ventricular
fibrillation, it is likely that ventricular tachycardia precedes
ventricular fibrillation. Ventricular tachycardia can be
monomorphic (as in most cases of CAD-related SCD) or
polymorphic, as in patients with the long QT syndrome. In
general, all tachycardias have been attributed to one of two
broad mechanisms—re-entry or triggered activity. The
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294 Chugh Investigative Approaches for Sudden Cardiac Death
Table 1. Diverse etiologies of sudden cardiac death
Coronary artery disease
Myocarditis
Drug abuse
Hypertrophic cardiomyopathy
Idiopathic dilated cardiomyopathy
Arrhythmogenic right ventricular dysplasia/cardiomyopathy
Congenital cardiac syndromes (coronary anomalies, cyanotic/
non-cyanotic syndromes)
Myocardial infiltrative diseases (e.g. sarcoidosis, amyloidosis)
Long QT syndrome
Brugada syndrome
Unexplained sudden cardiac death (idiopathic polymorphic
tachycardia/ventricular fibrillation)
phenomenon of re-entry results from conditions that cause
heterogeneous patterns of action potential duration in the
ventricular myocardium, e.g. heart failure or coronary
ischemia. 9,10 An important additional factor may be
abnormal propagation of the electrical impulse through the
myocardium, due to the presence of a scar or quantitative
changes in the distribution of proteins that facilitate
electrical conduction, such as gap junction proteins or
connexins.11 The phenomenon of triggered activity results
from premature electrical potential called early afterdepolarizations (EADs) or delayed after-depolarizations
(DADs). Early after-depolarizations may occur during
the second or third phases of the action potential and
the essential prerequisite is prolongation of the action
potential duration. 12–17 Delayed after-depolarizations
have been observed during the fourth and final phase
of the monophasic action potential. 12,18,19 While
bradyarrhythmias are likely to constitute the minority, a
distinct subgroup of SCD manifests with severe bradycardia
as the terminal arrhythmia.8,20
Animal Models of Sudden Cardiac Death
In attempts to understand the mechanisms of fatal
arrhythmogenesis, several animal models have been
utilized. Of these, the rat model of myocardial infarction
(MI) and the canine pacing-induced heart failure model
have been well characterized.
The rat infarct model: Myocardial infarction is induced
by surgical ligation of the left coronary artery via a left
thoracotomy. There is a high incidence (up to 65%) of
sudden death within 48 hours of a large MI. 21 With
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moderate-sized infarcts (30% of the total myocardium),
acute mortality is estimated to range between 10% and
30%. Within 4–6 weeks, the animals consistently develop
signs of heart failure with evidence of significant
postinfarction remodelling and dilated cardiomyopathy.22
Multiple observations vis-a-vis hemodynamic,
neurohormonal, anatomic and cellular properties point to
distinct similarities between human and rat hearts in the
post-MI period.22–26 In fact, beneficial interventions in the
model have been directly transported to the human heart
failure population with remarkable success. An important
example is the survival benefit of captopril observed in this
model, which led to the large clinical trials of angiotensinconverting enzyme (ACE) inhibitors and their subsequent
widespread use in patients with heart failure.27,28
Studies of the mechanisms of arrhythmia in this model
have focused on ion channel pathophysiology as well as
evidence of altered genetic expression in potentially
arrhythmogenic cardiac-specific genes. Ion channel
abnormalities lead to alterations in inward or outward flow
of current from the cardiac myocyte, which can lead to
prolongation or heterogeneity of the action potential
duration. In this model, a significant decrease in the
potassium transient outward current (Ito) is known to
contribute to action potential prolongation.17 In the rat, the
myocardial voltage gated K+ channel is constituted by
multiple pore-forming alpha subunits. Of these, genetic
expression of Kv 2.1, Kv 4.2 and Kv 4.3 subunits is
decreased in postinfarct ventricular myocytes and this
downregulation may account for the decrease in I to
current.29 El-Sherif et al.30 have also reported reversion of
the fetal:adult isoform ratio of two other ionic currents in
post-MI rat ventricular myocytes. Messenger RNA levels of
the fetal isoform of the L-type Ca2+ current are significantly
increased. In addition, the T-type Ca2+ current, which is
normally expressed only in fetal rat ventricular myocytes,
is re-expressed in postinfarct myocytes. All of these
described changes in ion channel function due to altered
expression of ion channel genes are likely to contribute to
the genesis of after-depolarizations. It is likely that re-entry
is also promoted by spatial alterations in expression of
connexin 43 in the rat ventricle. Decreased expression of
connexin 43 has been observed in the left ventricular
endocardium, septum and right ventricle but not in the left
ventricular epicardium.31 Also, significant downregulation
occurs of connexin 43 gap junctions in myocardium remote
from the infarction and these changes may occur as early
as three days after MI.31
Canine pacing-induced heart failure: In dogs,
ventricular pacing at rapid rates (250 bpm) over a period
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Chugh
of 3–5 weeks consistently results in contractile dysfunction
and four-chamber dilated cardiomyopathy.14,32 As a result,
significant abnormalities of cardiac repolarization occur,
with an increased risk of spontaneous ventricular
arrhythmias and sudden death.33 Ion channel abnormalities
identified include downregulation of the transient outward
potassium channel as well as the potassium inwardly
rectifying channel.33 The resultant prolongation of the
monophasic action potential produces a distinct
vulnerability to the effects of type III antiarrhythmic
agents.14 ,32 There is increased sensitivity to the effects of
ibutilide as well as d,l-sotalol, as measured by prolongation
of the action potential duration in vivo. In the case of
ibutilide, there is a tendency for increased occurrence of
polymorphic ventricular tachycardia, also caused by early
after depolarizations.14
In general, the likelihood of successful resuscitation from
ventricular fibrillation is significantly lower in patients with
heart failure as well as animal models of congestive heart
failure (CHF).34–36 This has long been attributed to the
structural and hemodynamic aspects of ventricular
remodelling in heart failure. However, a recent study in a
canine model of heart failure induced with combined MI
and rapid ventricular pacing, indicates that other
mechanisms may be involved.37 Ventricular fibrillation
induced by AC shock was quantified using a special multielectrode device placed in the left ventricle of both heart
failure and sham animals. As expected, both structural and
hemodynamic deterioration was observed in the heart
failure group. In addition, however, the nature of terminally
induced ventricular fibrillation in heart failure was
significantly different from control animals. There were
fewer re-entrant ventricular fibrillation circuits in heart
failure animals compared to controls. While the significance
of these findings remains to be elucidated, it is clear that
ventricular fibrillation occuring in heart failure may be
distinct from that occuring in the absence of left ventricular
dysfunction.37 Further investigations of possible unique
ventricular patterns in this model may facilitate the
development of more effective defibrillation therapies for
the prevention and treatment of SCD in heart failure.
Transgenic and knockout mouse models: These
genetically engineered animal models represent the vital
link between genetics and physiology. Transgenic
technology involves expression of foreign genes by the
introduction of foreign DNA into fertilized mouse eggs via
the process of microinjection. In contrast, the gene
knockout procedure involves inactivating or “knocking out”
genes in the mouse. Specific genes are isolated, inactivated
and subsequently introduced into mouse embryonic stem
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Investigative Approaches for Sudden Cardiac Death
295
cells. Recently, both techniques have been employed to
produce distinct mouse models of SCD. In one such
investigation, transgenic mice were produced that
overexpressed calreticulin, a calcium-binding protein in the
endoplasmic reticulum. 38 These transgenic animals
exhibited decreased myocardial systolic function and inward
calcium current, as well as low levels of the proteins
connexins 43 and 40. Clinically, these animals manifested
with sinus bradycardia and prolonged atrioventricular node
conduction, followed by complete heart block and sudden
death. In addition, Chien et al. 39 have reported that
knockout mice deficient in HF-1b, a transcription factorrelated protein, manifest with SCD despite having normal
systolic function. Ambulatory electrocardiographic
recordings in these mice revealed both ventricular
tachycardia and severe bradycardia as culprit fatal
arrhythmias. Interestingly, there is abnormal distribution
of the conduction proteins connexins 43 and 40 in this
model as well. Similar gene-targeted mouse models are likely
to enhance our understanding of mechanisms related to
specific genes involved in fatal arrhythmogenesis.40 In the
era of functional genomics, new techniques such as gene
expression profiling with microarray technology will
facilitate such investigations.41,42
Human Investigations
Autopsy series: Autopsy-based studies have contributed
greatly to our understanding of the mechanisms of SCD.43–45
In the majority of SCD cases, a structural or functional
abnormality can be identified, CAD being the most
common.5 Other causes include drug use, hypertrophic
cardiomyopathy, dilated cardiomyopathy, arrhythmogenic
right ventricular dysplasia/cardiomyopathy, several
congenital cardiac syndromes (coronary anomalies,
cyanotic/noncyanotic syndromes), myocarditis and
infiltrative diseases such as sarcoidosis and amyloidosis.
However, in 5%–15% of SCD patients, the culprit etiology
cannot be identified. 8,46–51 As a consequence, there is
insufficient knowledge of both substrates and triggers of
SCD in this subset. For these patients, inherited or de novo
genetic defects leading to SCD need to be excluded. The list
of heritable syndromes leading to SCD is growing
steadily.52,53
The genetic basis of sudden cardiac death: The long
QT syndrome: This inherited primary electrophysiologic
disorder is characterized by prolongation of the QT interval
on ECG and increased risk of sudden death due to
polymorphic tachycardia.54–56 The condition is relatively
rare, with an estimated incidence in the general population
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296 Chugh Investigative Approaches for Sudden Cardiac Death
of 1 in 10 000. Disease-causing mutations have been
identified in five culprit genes, each encoding a cardiac ion
channel or channel subunit. For the autosomal dominant
form of the long QT syndrome (Romano–Ward syndrome)
the genes implicated are KVLQT1 (long QT syndrome 1),
HERG (long QT syndrome 2), SCN5A (long QT syndrome
3), KCNE1 (long QT syndrome 5), and KCNE2 (long QT
syndrome 6).57–62 For long QT syndrome 4, a chromosomal
locus has been identified but the search for a specific gene
is ongoing. In the case of the autosomal recessive form
associated with deafness (Jervell and Lange-Nielsen
syndrome), mutations in KVLQT1 and KCNE1 have been
identified. For the identification of carriers of the long QT
syndrome, genetic screening remains the most important
tool.52 Important issues confronting researchers include the
development of cheap and effective tools for diagnosis, as
well as prevention and risk stratification. Beta-blockers and
implantable defibrillators remain the mainstay of therapy
for the long QT syndrome.
The Brugada syndrome: This condition is characterized
by an apprently normal heart, distinct ECG abnormalities
and a propensity for sudden death. 63 The
electrocardiographic features include a right bundle branch
block pattern and ST segment elevation in the right
precordial leads (leads V1 through V3) but the QT interval is
normal.63 In a small number of patients with a Brugada
pattern ECG, structural abnormalities have been observed
in the right ventricle, which has led some researchers to
conclude that a “right ventricular” cardiomyopathy may
form the basis for this condition.64 In general, the majority
opinion would indicate that the Brugada syndrome is an
inherited primary electrophysiologic disorder with
autosomal dominant transmission. In affected patients,
mutations have been detected in the cardiac sodium channel
gene (SCN5A), which is also the gene implicated in long QT
syndrome 3.65 Interestingly however, the ion channel
phenotype is expressed differently. In the Brugada
syndrome, there is loss of function of the cardiac sodium
channel, as opposed to gain of function in long QT syndrome
3.66,67 It is likely that the syndrome of sudden unexpected
nocturnal death in South-east Asian males is identical to
the Brugada syndrome.68 Furthermore, a third cardiac
rhythm disorder has been attributed to the SCN5A gene.
Mutations in this gene were also detected in members of a
family who manifested with cardiac conduction system
disease or Lev-Lenegre syndrome.69
The typical ECG findings of the Brugada syndrome can
be transient, but intravenous ajmaline (1mg/kg),
procainamide (10 mg/kg), or flecainide (2 mg/kg) can
effectively unmask these ECG features.70 An earlier study
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showed that permanent or transiently induced ECG
abnormalities were predictive of patients having a higher
risk of sudden death.70 However, these findings have been
refuted in a more recent investigation, which concluded that
the only significant prognostic indicator of sudden death
was the presence of prior symptoms.71 In addition, due to a
low overall prevalence of mutations of the cardiac sodium
channel (15%), the authors concluded that significant
genetic heterogeneity may be an inherent feature of the
condition. Another recent investigation also concluded that
asymptomatic patients with a Brugada-type pattern on the
ECG are likely to have a benign course.72 At present, the
implantable defibrillator is widely accepted as the most
effective treatment modality for symptomatic patients.
Idiopathic ventricular fibrillation (unexplained
sudden cardiac death): In cases where there are no
identifiable structural or genetic abnormalities attributable
to the event, SCD may remain unexplained. These cases have
also been grouped under the category of idiopathic
ventricular fibrillation. Due to a relative lack of co-morbid
conditions, these patients constitute a human model for the
understanding of this common terminal event. Since
knowledge regarding substrates and triggers of SCD in this
subgroup could be applied to other subgroups such as CAD,
idiopathic ventricular fibrillation is currently the subject of
active investigation.
The diagnosis of this condition is by exclusion, and can
be made in the absence of clinical or laboratory findings
that could account for the occurrence of fatal arrhythmia.73
The first observations of patients with ventricular
fibrillation, a normal baseline electrocardiogram and no
structural heart disease were reported in 1987. 74
Subsequently, survivors have been followed up in US as well
as European registries. It is likely that idiopathic ventricular
fibrillation may constitute 5%–10% of all cases of out-ofhospital cardiac arrest.73 Patients tend to be relatively young
(age range 27–55 years) and both sexes are affected equally.
In up to two-thirds of patients, there is no prior history of
syncope,74 but risk of recurrent syncope is significant and
events tend to occur in clusters. As a rule, ventricular
stimulation protocols have been ineffective for the purpose
of risk stratification. 75–77 Clinical subtypes have been
reported as well. Based on the mode of onset of the
ventricular arrhythmia, some patients have been classified
as short-coupled torsades de pointes.78 Ambulatory ECG
recordings in these patients showed that a premature
ventricular beat with a short coupling interval initiates the
tachycardia, as opposed to the long QT syndrome, where
the premature beat generally follows a pause. Another
clinical subtype is catecholamine-dependent polymorphic
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Sudden Cardiac Death: Investigative Strategy
A Comprehensive Approach
Human Investigation
Animal Studies
Population-based studies
Identification of substrates/triggers
Pathophysiology (In vivo/vitro)
Effects of interventions
ß
ß
Functional genomics/genetics
New genetic abnormalities in patients
Transgenic/Knockout mouse models
Microarray gene expression
Identification of genomic pathways
ß
Mechanisms of Fatal Arrhythmia
ventricular tachycardia,79 a condition which mainly affects
children and is induced by stress, especially exercise.
Recently, mutations in the human cardiac ryanodine
receptor gene (hRyR2) were identified in families of patients
with catecholamine-dependent polymorphic tachycardia.80
Thus, genetically determined abnormal intracellular
calcium handling is likely to be a key pathophysiologic
mechanism for the genesis of this arrhythmia. Again, while
beta-blockers have proven beneficial in many cases, they
have not replaced the implantable defibrillator as the
therapy of choice.79
There are several conditions associated with sudden
death which merit further investigation. In patients with
unexplained SCD, it is not uncommon to find relatively
minimal or nonspecific cardiac abnormalities.73 In a recent
analysis of cardiac pathologic findings from a relatively
young (mean age 42 years) autopsy series of SCD, 29%
hearts had evidence of nonspecific cardiac structural
abnormalities but no clearly identifiable cause of SCD.46
These abnormalities included left ventricular hypertrophy,
mitral valve prolapse and myocardial interstitial fibrosis. It
is conceivable that in the presence of a critical trigger
mechanism, even these relatively minimal abnormalities
may constitute an arrhythmogenic substrate. Further
investigations in this subgroup may be of high yield. Also,
in subjects with an otherwise normal heart and no evidence
of significant CAD or MI, coronary artery spasm cannot be
ruled out as a possible etiology of ventricular fibrillation
arrest.81–85 Lastly, two noncardiac conditions, seizure
disorder86–89 and obesity,90 have strong associations with
SCD. Abnormal alterations in autonomic inputs to the heart
have been implicated in both conditions, but specific
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Investigative Approaches for Sudden Cardiac Death
297
etiologic mechanisms are unclear.91–93
Population-based investigations of sudden cardiac
death: The importance of prospective population-based
investigations was emphasized by two recently published
studies of SCD. Both studies examined the occurence of
overall sudden death, one including 500 cases94 and the
other 128 cases 95 and the conclusions are similar. These
studies provide strong evidence for aggregation of SCD in
families, independent of the distribution of classic risk
factors. While the latter factors have been the primary focus
of preventive measures, these studies underscore the need
to expand research toward chromosomal as well as other
shared nongenetic risks, such as common in utero or
postnatal environmental exposure.96,97 Identification of
such factors will proceed only with population-based studies
to identify familial clustering of SCD.
Conclusions
The significant worldwide incidence of SCD must be
confronted with matching developments in prevention and
risk stratification for this condition. Since fatal arrhythmia
is the most common terminal event, a complete
understanding of the mechanisms of arrhythmogenesis is
essential. The investigative strategy will continue to include
both animal studies and human investigations. In the era
of functional genomics, transgenic and knockout mouse
models form the crucial link between the pathophysiology
and genetics of cardiac arrhythmia. Such investigations will
be enhanced by the rapid development of techniques such
as microarray gene expression profiling. While CAD is the
most common cause of fatal arrhythmia, its prevention has
not affected the incidence of SCD. In the future, it is likely
that the power of CAD to predict SCD may be enhanced in
combination with other, yet unexplored factors. Genetic
testing in patients with ostensibly normal hearts or only
nonspecific cardiac abnormalities may provide important
clues. In this context, a combination of population-based
studies and human molecular genetic investigations is likely
to be of high yield in the search for novel mechanisms of
SCD.
Acknowledgment
This work was funded, in part, by the Collins Medical Trust.
References
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Indian Heart J 2001; 53: 301–307
Original
Article
Jain et al. Neurohumoral Activation
in PCI
301
Neurohumoral Activation in Percutaneous Coronary
Interventions: Apropos of Ten Vasoactive Substances
During and Immediately Following Coronary Rotastenting
Deepak Jain, Ulrich Schäfer, Andreas Dendorfer, Thomas Kurz,
Cornelia Lindemann, Ralph Tölg, Franz Hartmann, Hugo A Katus, Gert Richardt
Medizinische Klinik II, Universitätsklinikum Lübeck, Germany
Background: Ischemia, left ventricular dysfunction, endothelial damage and hemodynamic changes during
percutaneous coronary intervention can lead to neurohumoral activation. This may partly explain the frequent
episodes of coronary spasm, hypotension and bradycardia which occur during the procedure. Rotastenting, by
employing the two basic mechanisms for coronary interventions—debulking and dilatation—epitomizes
percutaneous coronary interventions in general. We sought to investigate the neurohumoral changes during
and immediately following coronary rotastenting.
Methods and Results: Eighteen patients undergoing elective rotablator atherectomy followed by balloon
predilatation and stenting for chronic stable angina were studied. Four femoral vein blood samples were drawn
from each patient at the start of the intervention (baseline), and 2 (postdebulking-2), 10 (postdebulking-10)
and 60 (postdebulking-60) minutes, respectively, after the first complete passage of the rotablation burr across
the whole length of lesion. Levels of 10 neurohormones, namely, endothelin-1, bradykinin, arginine vasopressin,
norepinephrine, dopamine, epinephrine, angiotensin II, serum angiotensin-converting enzyme activity, atrial
natriuretic peptide and kininogen were estimated in each sample. Endothelin-1 and bradykinin attained their
peak levels in the postdebulking-2 samples, and the rise from 0.34±0.07 pmol/ml and 235.8±17.7 pg/ml to
0.42±0.06 pmol/ml and 337.2±41.0 pg/ml, respectively, was statistically significant (p<0.05). The level of
arginine vasopressin showed a significant (p<0.05) rise from baseline (108.5±31.8 pg/ml) to postdebulking-60
samples (136.5±39.4 pg/ml). The other neurohormones did not show significant changes.
Conclusions: The results suggest a definite but differential neurohumoral activation during and immediately
following rotastenting. These neurohumoral changes may have a role in untoward intra- and postprocedural
vasomotor and hemodynamic effects. This study establishes the concept of neurohumoral activation during
percutaneous coronary interventions. (Indian Heart J 2001; 53: 301–307)
Key Words: Rotational atherectomy, Neurohormones, Vasoactive peptides
T
he incidence of myocardial necrosis in patients
undergoing routine percutaneous coronary
interventions (PCIs) is between 30% and 40%. This suggests
that microembolization is common and that many patients
actually suffer some extent of measurable myocyte
damage.1 Ischemia and left ventricular dysfunction coupled
with hemodynamic changes and local endothelial injury
can lead to neurohumoral, paracrine and autocrine
activation during PCI. Besides this, pharmacological
Correspondence: Dr Deepak Jain, Medizinische Klinik II,
Universitätsklinikum Lübeck, Ratzeburger Allee 160, D-23538 Lübeck,
Germany. e-mail: [email protected]
IHJ-163-01.p65
301
manipulations and constitutional accompaniments can
also modulate neurohumoral milieu. Morphine, which is
routinely used intraprocedurally, can stimulate the release
of arginine vasopressin (AVP). While nausea and vomiting
may also stimulate the release of AVP,2 anxiety and pain
can cause sympathetic activation. Attempts have been made
to study vasoactive peptides and neurohumoral parameters
during coronary angioplasty3–6 and coronary artery bypass
surgery.7 Correlation has been made between the levels of
these peptides and the severity of coronary artery disease7
and unstable plaque mechanisms.8 Our group has reported
the release of catecholamines during elective and primary
angioplasty.9 Recently, the effects of rotational coronary
8/16/01, 7:11 AM
302 Jain et al.
atherectomy on plasma levels of peripheral endothelins
(ET-1), atrial natriuretic peptide (ANP) and cyclic adenosine
monophosphate (cAMP) have been studied and compared
with those of percutaneous transluminal coronary
angioplasty (PTCA).10 It was found that the level of ET-1
increased less, that of ANP increased more and that of
cAMP decreased more during atherectomy than during
plain balloon angioplasty. None of the studies so far,
however, has comprehensively studied the phenomenon of
neurohumoral activation during coronary interventions.
We hypothesized that since PCIs exploit two basic
mechanisms—dilatation and debulking—and since
rotastenting, comprising rotablator atherectomy followed
by balloon predilatation and stenting uses both these
mechanisms, it can epitomize PCI in general from the
viewpoint of the study of neurohumoral activation. The
procedure should then embrace the composite effects of
plain balloon, stenting and atherectomy, the three
commonest techniques employed. Moreover, rotastenting
will also include the effects, if any, of the interaction of blood
elements with intracoronary metallic prostheses resulting
in the release of vasoactive substances. We further
hypothesized that there should be substantial
neurohumoral activation during rotastenting, which may
partly explain some of the cardiovascular and
hemodynamic disturbances, such as repeated coronary
spasms, bradycardia and hypotension, which are common
during PCI. The aim of the present study was to study the
whole gamut of neurohumoral, autocrine and paracrine
substances in central venous blood samples during coronary
rotastenting.
Methods
Study population: The study included eighteen patients
with chronic stable angina referred to the Department of
Cardiology, Medical University Hospital, Lübeck, in whom
rotablator atherectomy followed by balloon predilatation
and stenting were electively done as the intervention of
choice. The exclusion criteria were acute or recent
myocardial infarction, unstable angina pectoris,
decompensated heart failure, total coronary artery
occlusion, uncontrolled hypertension, peripheral vascular
disease and significant psychiatric, neurologic, endocrine,
hepatic or inflammatory disease. Patients undergoing
rotational atherectomy alone or those undergoing
rotastenting in whom balloon predilatation was not used
before deploying a stent were also excluded from the study.
All patients gave informed written consent.
Protocol: The patients were allowed their usual cardiac
IHJ-163-01.p65
Indian Heart J 2001; 53: 301–307
Neurohumoral Activation in PCI
302
medications and routine pre- and postangioplasty orders
were followed. Four femoral vein blood samples were drawn
from the sheath of each patient. The first (baseline) sample
was obtained at the time the venous sheath was introduced
at the inception of the procedure. The second
(postdebulking-2), third (postdebulking-10) and fourth
(postdebulking-60) samples were drawn 2, 10 and 60
minutes, respectively, after the first complete passage of the
rotablator burr across the whole length of lesion.
Biochemical analysis: The serum activity of angiotensinconverting enzyme (ACE) was determined by incubation
with the ACE-specific tripeptide substrate oaminobenzoylglycyl-p-nitro-L-phenylalanyl-L-proline.
Angiotensin-converting enzyme hydrolyzes the substrate,
producing the highly fluorescent o-amino-benzoylglycine.11
Quantitative determination was performed by
spectrofluorimetric detection (Shimadzu RF 551; Ex 320
nm; Em 412 nm) after separation by HPLC (Nova-Pak C 18column, 3,9×150 mm, Waters USA). Angiotensin II,
bradykinin (BK) and kininogen were extracted and
quantified by specific radioimmunoassays (RIA). The
procedures of ethanol precipitation and solid phase
extraction described by Pellacani et al.12 were applied in
combination. Radioimmunoassays were set up as described
by Menard et al.13 Kinin-specific antiserum was obtained
after immunization of a female rabbit with albumin-coupled
kallidin14 following the method of Shimamoto et al.15 The
chloramine-T method16 was used for the preparation of
[125I-Tyr8]-BK and [125I]-angiotensin II which was purified
by RP-HPLC. Rabbit polyclonal anti-angiotensin II was
purchased from Peninsula (Belmont, CA, USA). Bovine
serum used for RIA was obtained from Sigma, Deisenhofen,
Germany and was treated with fumed silica (Serva,
Heidelberg, Germany). 125 Iodine was bought from
Amersham Buchler, Braunschweig, Germany. Plasma
norepinephrine, dopamine and epinephrine were assayed
by HPLC and electrochemical detection was done as
described by Smedes et al.,17 while commercially available
ELISA kits were used to determine ET-1, N-terminal of
proatrial natriuretic peptide (Biomedica GmbH-A 1210
Vienna, Austria) and AVP (Assay design, Inc. 1327 Ann
Arbor, MI 48105, USA).
Statistical analysis: For descriptive purposes, quantitative
variables are presented as mean±SEM. The means of the
baseline and the subsequent samples were compared using
the paired samples t test and a p value <0.05 was considered
significant. Data processing and analysis were performed
with SPSS software for Windows, version 7.5.
8/16/01, 7:11 AM
Indian Heart J 2001; 53: 301–307
Jain et al. Neurohumoral Activation in PCI
Results
Eighteen patients, 9 males and 9 females, age range 61–81
years, were included in this study (Table 1). All were on
medication for more than three months with cardioactive
drugs (94.4% on beta-blockers, 77.8% on ACE inhibitors,
44.4% on calcium-channel blockers and 27.8%
on diuretics), besides other routine antianginal,
antihypertensive and lipid-lowering drugs, as required. The
mean ejection fraction was 64.4±4.0%. There was an
assortment of target vessels with 11% left main stem
(protected), 72% left anterior descending, 17% left
circumflex and 11% right coronary arteries. The final result
of intervention in all patients ranged from good to
acceptable angiographically. There were no major adverse
clinical events in any patient during the hospital stay.
The results are summarized in Table 2. Endothelin-1
and BK levels demonstrated a significant rise from
Table 1. Demographic, clinical and angiographic profile
of the patients undergoing rotational atherectomy
Patients
Age (in years)
Males
Females
Clinical history
Chronic stable angina
Unstable angina/acute MI
Prior MI
Prior PTCA
Prior CABG
Risk factors
Hypertension
Hypercholesterolemia
Diabetes mellitus
Smoker
Cardioactive drugs
ACE inhibitor
Beta-blocker
Calcium-channel blocker
Diuretics
Angiographic and procedural variables
Ejection fraction
Coronary artery treated
Left main stem
Left anterior descending
Left circumflex
Right coronary artery
Mean target lesion MLD (mm)
Mean target lesion length (mm)
18
70.8±1.8
9 (50)
9 (50)
18 (100)
0 (0)
11 (61.1)
2 (11.1)
5 (27.8)
17 (94.4)
12 (66.7)
10 (55.5)
6 (33.3)
14 (77.8)
17 (94.4)
8 (44.4)
5 (27.8)
64.4±4.0%
2 (11.1)
13 (72.2)
3 (16.7)
2 (11.1)
0.68±0.06
22.60±1.84
MI: myocardial infarction; PTCA: percutaneous transluminal coronary
angioplasty; CABG: coronary artery bypass grafting; MLD: minimal
luminal diameter
Figures in parentheses are percentages
IHJ-163-01.p65
303
303
0.34±0.07 pmol/ml and 235.8±17.7 pg/ml, respectively,
at baseline to 0.42±0.06 pmol/ml and 337.2±41.0 pg/ml,
respectively, in the second (postdebulking-2) samples. The
mean levels of both declined thereafter. Arginine
vasopressin, however, demonstrated a different temporal
pattern. A significant rise from 108.5±31.8 pg/ml to
136.5±39.4 pg/ml (p<0.05) was seen in the postdebulking60 sample. Norepinephrine, dopamine and epinephrine
(sympathetic system), angiotensin II and serum ACE
activity (renin–angiotensin system), and N-terminal of
proatrial natriuretic peptide showed a similar pattern of rise
in plasma concentrations, with the highest mean values
occurring in the last, i.e. postdebulking-60 samples, but in
neither case was this rise statistically significant. Although
kininogen showed a pattern of fall, with the steepest fall in
the second sample, the levels did not reach statistical
significance.
Discussion
Percutaneous coronary interventions may cause
neurohumoral activation through a variety of mechanisms.
While anxiety and pain are important accompaniments, the
procedure may induce ischemia and left ventricular
dysfunction, cause a drop in arterial blood pressure and
mechanical endothelial damage, all of which can
potentially stimulate autocrine, paracrine and endocrine
systems either directly or through cardiosystemic reflexes.
A distinct neurohumoral activation shown by the rise of
vasoactive peptides such as ET-1, BK and AVP was the
principal finding of the present study. Mediators of the
sympatho-adrenergic and renin–angiotensin systems,
however, showed minor, insignificant rise. A differential
pattern in the rise of levels with time was also documented.
Endothelin-1 is the most potent endothelium-derived
vasoconstrictor peptide identified so far.18 The effect is more
pronounced in small-sized coronary vessels compared to
large epicardial vessels. The deluge of studies on the release
of ET-1 during PTCA have shown an increase in its levels.
The kinetics of release have been somewhat disparate in
different studies. It was found to be biphasic with an early
peak occurring within the first 10 minutes and a late peak
90 minutes after PTCA,19 while a recent study published
from our laboratory established an instantaneous elevation,
with the levels gradually falling thereafter to normal within
6 hours. 3 In another study, during reperfusion after
transient (10-minute) periods of ischemia, the release of
ET-1 occurred early and lasted for about 10 minutes even
in the absence of endothelial damage, suggesting that
hypoxia is the main mechanism responsible for the release.20
8/16/01, 7:11 AM
304 Jain et al.
Indian Heart J 2001; 53: 301–307
Neurohumoral Activation in PCI
Table 2. Mean values with SEM of plasma vein neurohormone levels at baseline, i.e. at the start of the intervention, and
2 (postdebulking-2), 10 (postdebulking-10) and 60 (postdebulking-60) minutes after the first complete passage of the
burr across the whole length of the lesion, respectively, and comparison between the baseline and latter values
Neurohormone concentrations
Neurohormone
Endothelin-1
(pmol/ml)
Bradykinin (pg/ml)
Arginine vasopressin
(pg/ml)
Norepinephrine (pg/ml)
Dopamine (pg/ml)
Epinephrine (pg/ml)
Angiotensin II (pg/ml)
Serum ACE activity
(nmol/h/ml serum)
NT-proANP (fmol/ml)
Kininogen (pg/µl BK)
Baseline
Postdebulking-2
(A)
(B)
p value
Postdebulking-10 Postdebulking-60
(C)
(D)
A
A
A
and
and
and
Mean
SEM
Mean
SEM
Mean
SEM
Mean
SEM
B
C
D
0.34
235.8
0.07
17.7
0.42
337.2
0.06
41.0
0.40
306.2
0.06
31.9
0.34
273.3
0.06
20.7
0.03*
0.01*
0.07
0.06
0.79
0.10
108.5
308.5
51.8
46.1
7.3
31.8
40.9
6.6
11.9
2.8
122.0
320.5
55.2
37.6
8.1
35.5
42.6
8.8
5.8
3.2
113.4
377.6
62.3
44.7
8.3
31.4
64.8
8.7
8.9
3.1
136.5
396.1
62.9
66.8
9.5
39.4
67.1
7.4
17.7
3.1
0.13
0.69
0.59
0.48
0.35
0.41
0.23
0.24
0.79
0.66
0.04*
0.15
0.14
0.25
0.41
15.4
4.6
14.9
4.6
15.3
4.7
16.7
5.2
0.15
2425.1 1456.5 2487.2 1478.9 2598.6 1542.9 3336.3 2076.2 0.19
1528.2 139.0 1433.0 122.6 1383.0 130.8 1377.6 139.9 0.07
0.93
0.12
0.06
0.22
0.17
0.07
NT-proANP: N-terminal of proatrial natriuretic peptide; * significant (p<0.05)
Thus, an instantaneous or early release has been noted and
our data conform with these observations. We observed a
significant instantaneous rise of ET-1 levels in the
postdebulking-2 samples which was then followed by a fall
till the levels reached the baseline in the postdebulking-60
samples (Fig. 1). This rise may be important in the context
of frequent, relatively resistant spasms occurring during
rotational atherectomy. The hypothesis that ET-1 plays a
role in the pathogenesis of coronary spasm during PTCA
has been investigated. 5,6 A significant increase in the
coronary sinus and arterial blood was observed immediately
after PTCA. Because this increase did not occur after
coronary angiography, it is unlikely to represent a
nonspecific response to contrast medium or the
catheterization procedure. The mechanisms that may
account for the increase in ET-1 levels during PTCA include
Base: Baseline
Pdeb: Postdebulking
Fig. 1. Graphic representation of the mean values of endothelin, bradykinin and arginine vasopressin. Standard error (SEM) bars have not been added to the figure in
order to express the means more explicitly. Significantly high values (p<0.05) were attained at the instance of second, i.e. the postdebulking-2, samples with both
endothelin and bradykinin. There is a gradual fall after this peak and while the levels reach the baseline at the end of the observation window in case of endothelin, they
tend to be above the baseline in case of bradykinin. With arginine vasopressin, the significant (p<0.05) rise in mean levels is attained at the instance of the last, i.e. the
postdebulking-60, sample (Pdeb stands for postdebulking).
IHJ-163-01.p65
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Indian Heart J 2001; 53: 301–307
mechanical endothelial damage, hypoxia from transient
coronary occlusion, and activation of clotting factors such
as thrombin, though the latter mechanism has been
considered unimportant.21 Increased levels of ET-1 during
rotastenting can be attributed to these mechanisms. It may
be noted that the vasoconstrictor effect of ET-1 depends
strictly on extracellular Ca 2+ concentrations,22 and is
noncompetitively inhibited by voltage-operated calciumchannel blockade with dihydropyridine calcium
antagonists. The use of intraprocedural intravenous
verapamil (a phenylalkylamine and not a dihydropyridine)
infusion during rotablator atherectomy, which forms the
standard protocol in most centers including ours, may be
questioned from this perspective. Kyriakides et al.,10 in
contradiction to our observations, did not find a change in
ET-1 levels following rotational atherectomy.
Bradykinin and related kinins have a definite role in
the control of vascular tone. Bradykinin induces
endothelium-dependent vasodilation of large epicardial and
resistance coronary arteries through nitric oxide (NO)
mediation. 23 Our study with rotastenting showed a
significant instantaneous increase in the postdebulking-2
samples, following which the levels started falling (Fig. 1).
The mean levels did not, however, reach the baseline till
the last sampling. Kininogen levels fell correspondingly, and
arguably so, as BK is its cleavage product, but though the
fall was the steepest in the postdebulking-2 samples, it did
not reach statistical significance. It is interesting to note
that the kinetics of release of BK, a potent vasodilator and
ET-1, a potent vasoconstrictor, are similar and both reach
a significant instantaneous peak followed by a fall. This
might suggest a counter-regulatory mechanism between
the two, and also that, while all other hormones maintained
a rising curve during our observation window and may be
responsible for relatively long-term regulation, these two
hormones are mainly involved in immediate and short-time
regulation. If our assumption is substantiated, the counterregulatory nature of BK can be exploited to counteract the
untoward effects of ET-1. We have recently shown that the
intracardiac availability of BK can be increased by
intracoronary administration of enalaprilat.24 The pre- or
intraprocedural administration of ACE inhibitors may be
useful in this context as well as from another point of view.
The role of BK in ischemic preconditioning has been
extensively studied and lately, direct evidence of this
beneficial effect in patients undergoing coronary
angioplasty was reported. 25 It was suggested that
pretreatment with BK may be just as effective as ischemic
preconditioning and could be used prophylactically to
attenuate ischemia in selected patients undergoing PTCA.
IHJ-163-01.p65
305
Jain et al. Neurohumoral Activation in PCI
305
The release of BK consequent upon small ischemic episodes
may also explain our observation of a significant rise in its
level during rotastenting.
Arginine vasopressin is a pituitary hormone that plays
a central role in the regulation of free water and plasma
osmolality. In addition, it is a vasoconstrictor. Its role in
producing coronary vasoconstriction in nondiseased small
vessels has been studied and this effect seems to be
intensified after ischemia and reperfusion.26 Two types of
AVP receptors (V1 and V2) have been identified in a variety
of tissues. Regulation of free water is through the V2
receptors while V1 receptors are mainly responsible for
vasoconstriction. 27 During rotastenting, we found a
significant rise in the mean postdebulking-60 levels of AVP
compared to baseline (Fig. 1). In the light of the abovementioned observations pertaining to its vasoconstrictive
properties, this rise may be important from a
pathophysiological standpoint. The kinetics of the rise were,
however, different from the two vasoactive peptides
discussed above, inasmuch as the rise was delayed rather
than instantaneous. While blood pressure fluctuations are
common during PCI, decrease in mean arterial and pulse
pressure have been shown to increase AVP levels and
the release is predominantly through baroreceptor
unloading. Other mechanisms, like changes in plasma
osmolality and blood volume, can also be potentially
involved, as administration of radiographic contrast
medium, nitroglycerine, morphine, etc. form an integral
part of the procedure. The deleterious potential of AVP is
evinced by the evidence that low-dose infusions which alter
the levels within a physiological range are shown to cause
a fall in cardiac output and increase in total peripheral
vascular resistance without modifying mean arterial
pressure.28
The other neurohormones studied did not reach
significantly high levels, even though they maintained
rising curves during the study period. Thus, three
observations accrue from our study. First, there is definite
evidence of neurohumoral activation during PCI and the
potent vasoactive peptides can explain the frequently seen
abnormalities in vasomotion and cardiovascular
hemodynamics during and after the procedure. Second, the
kinetics of release of these peptides is different and the
effects may persist beyond the immediate postprocedure
period; and third, if PCI is compared to the chronic heart
failure model in which there is a generalized pattern of
neurohumoral activation, a differential pattern seems to be
present. Several plausible explanations can be put forth for
the last observation. The situation might be truly reflective
of a different pathophysiological state. It is likely that
8/16/01, 7:11 AM
306 Jain et al.
different trigger mechanisms are involved in the release of
various vasoactive substances. From this perspective, an
insult comprising ischemia or transient left ventricular
dysfunction or both of relatively short duration, as for
instance during PCI, may have an effect different from that
of a long-lasting chronic insult which leads to congestive
heart failure. It could also be that ischemia with reperfusion
may behave differently from prolonged ischemia as during
myocardial infarction. Not only this, differences may exist
in the amount and component of injury, e.g. ischemic versus
endothelial injury during PCI. Though there are several
studies of vasoactive substances released during coronary
interventions, we could not find any which dealt with a wide
array of these. Almost all have reported a differential
pattern of neurohumoral activation. Thus, while studying
the influence of PTCA on cardiac release of ET-1,
neuropeptide Y and noradrenaline, only the level of ET-1
was found to be significantly increased, and it was
postulated that endothelial damage rather than ischemia
was the cause of this increase.4 In another instance, PTCA
was associated with a rise of ET-1 and ANP, but a reciprocal
decrease of epinephrine and nonepinephrine levels. 6
Differences were also found in relation to techniques of
intervention, e.g. when PTCA was compared to rotational
atherectomy.10
Limitations of the study: The most striking limitation of
the present study is the small cohort size. Initially, a much
larger sample size was enrolled, but the rigorous exclusion
criteria reduced the evaluable numbers to less than half.
Second, the observation window was short. All the
substances (except kininogen) that could not reach
significant values had rising curves during the observation
window. The third limitation is the lack of a control group
against which the present changes could have been gauged
in order to attribute them to have been caused by the
intervention. Rotational atherectomy entails several
elements, which directly or indirectly, individually or
collectively, have a potential to cause neurohumoral
activation. Thus, introduction of a large vascular access,
application of drugs such as verapamil, nitroglycerine,
morphine and volume load, etc. are unavoidable. Fourth,
cardioactive drugs were not stopped for a few days before
the procedure. This would have made the patients unstable,
and doing a second-generation device angioplasty after
destabilizing the patient would have been unjustified on
ethical grounds. Fifth, no attempts have been made to
evaluate the mechanisms underlying neurohumoral
activation. Finally, circulating plasma concentrations of
vasoactive substances does not necessarily reflect the
IHJ-163-01.p65
Indian Heart J 2001; 53: 301–307
Neurohumoral Activation in PCI
306
activity of cardiac neurohumoral activation. This is
particularly so in case of the sympatho-adrenergic and
renin–angiotensin systems.
Clinical implications of the study: Our study, along with
several others during PTCA, offers compelling evidence of
neurohumoral activation during PCI. However, attempts to
study this important aspect of PCI have been at best halfhearted and disconcerted. There is a need to study this
extensively, as has been done during congestive heart failure
and following myocardial infarction. The fact that
neurohumoral substances have independent prognostic
value and that the overall prognosis can be improved by
pharmacological modification of their effects, makes this
field an area of great importance. The evidence that some
of these peptides, especially ET-1,18 may have a possible role
in restenosis further lends credence to the notion. Our
observations are important from the angle of procedural
success also. The vasoconstrictive and hemodynamic
disturbances that occur during coronary interventions can
possibly be managed by pharmacological modifications, e.g.
by using ACE inhibitors, BK or ET-1 and V1 receptor
antagonists.
Acknowledgments
The study was supported by a grant of the Deutsche
Forschungsgemeinschaft (Ku774/3-1). We are grateful to
Mrs Anke Constanz and Dorit Kemken for their technical
support.
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308 Sapra et
al. Direct Coronary Stent Implantation
Original
Article
Indian Heart J 2001; 53: 308–313
Coronary Stent Implantation without Lesion
Predilatation (Direct Stenting):
Our Experience with this Evolving Technique
R Sapra, U Kaul, B Singh, D Sudan, HS Isser, T Ghose, R Kachru
Department of Interventional Cardiology, Batra Hospital and Medical Research Centre, New Delhi
Background: Until recently, conventional intracoronary stent deployment required predilatation of the lesion
with a balloon. However, “direct stenting” of the lesion without predilatation offers certain theoretical and
practical advantages. We assessed the safety and feasibility of direct stenting in a select group of patients who
were likely to benefit most from these advantages, namely, those with acute coronary syndromes, saphenous
vein graft lesions, associated renal or left ventricular dysfunction and those requiring multivessel intervention.
Methods and Results: After direct stenting, intravascular ultrasound was used to assess the adequacy of stent
expansion in 51 patients. One hundred and twenty patients with a total of 125 lesions (83.3% males, average
age 54.6±12.4 years) were enrolled for direct stenting. Of these, 90% of patients had presented with acute
coronary syndromes, 21.6% of patients had associated moderate-to-severe left ventricular systolic dysfunction,
6.7% of patients had associated renal dysfunction and 30.8% of patients required multivessel intervention.
Angiographically visible thrombus was present in 35.2% of patients. The mean reference diameter of the lesion
was 3.18±0.32 mm and mean percentage diameter stenosis was 76.4±11.2%. Almost all varieties of stents
were used (8.8% bare and 91.2% mounted). Procedural success was achieved in 98.3% of patients (98.4% of
lesions). In two cases, the lesion had to be predilated prior to stenting. On angiography, the need for postdilatation
of the stent was apparent in 29 (23.6%) lesions. In contrast, on intravascular ultrasound evaluation done in 51
lesions after stent deployment, the need for postdilatation to optimize stent expansion was seen in 43 (84.3%)
lesions. There was one instance of acute stent thrombosis and two instances of slow-flow phenomenon. There
were no deaths, myocardial infarction or need for urgent bypass surgery.
Conclusions: We conclude that direct stenting is feasible and safe in selected groups of patients. Optimization
of stent expansion after direct stenting may often require aggressive postdilatation. (Indian Heart J 2001; 53:
308–313)
Key Words: Stents, Coronary disease, Ultrasound
U
ntil recently, conventional intracoronary stent
deployment required predilatation of the lesion with a
balloon before delivery of the stent to the lesion. The basic
aim of this predilatation is to increase the minimum luminal
diameter (MLD) of the lesion site so as to ensure a relatively
safe and uncomplicated passage of the stent across the
lesion. In addition, the process of predilatation allows lesion
compliance to be tested and so alerts the operator to rigid,
calcified lesions unresponsive to balloon/stent dilatation.
The concept of direct stenting of the lesion without
predilatation offers certain theoretical and practical
Correspondence: Professor Upendra Kaul, Director, Interventional
Cardiology, Batra Hospital and Medical Research Centre, 1, Tughlakabad
Institutional Area, Mehrauli Badarpur Road, New Delhi 110062
IHJ-125-01.p65
308
advantages,1,2 viz. shorter procedure and fluoroscopy time,
lesser cost (by dispensing with the need for a predilatation
balloon), use of a smaller quantity of contrast medium (by
reducing the number of check angiographic runs), reduction
in the risk of major dissection and distal embolization, and
possibly reduction of in-stent restenosis (by reducing vessel
trauma and hence the degree of neointimal proliferation).
Besides the potential universal advantages of reduction
in cost and possibly restenosis, patients who are especially
likely to benefit most by direct stenting are those with acute
coronary syndromes or with lesions in degenerated venous
grafts in whom the risk of distal embolization of
thrombotic/degenerated material is significant,3,4 patients
with left ventricular or renal dysfunction in whom reduction
in the amount of contrast used would be desirable, and
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Indian Heart J 2001; 53: 308–313
patients requiring multivessel or complex interventions in
which the procedure and fluoroscopy time as well as the
amount of contrast used are likely to exceed desirable
limits.5 This technique, however, is not feasible in all types
of coronary lesions and is generally avoided in chronic total
occlusions, and in lesions with marked proximal tortuosity
and extensive calcification to minimize the risk of stent
malpositioning, incomplete stent expansion or stent
embolization.
In this prospective observational study, we assessed the
feasibility and safety of the technique of coronary stent
implantation without predilatation of the lesion in a group
of patients who were likely to benefit most from this strategy.
In addition, we evaluated the impact of intravascular
ultrasound (IVUS) assessment in guiding direct stenting.
Methods
Patient population: Between June 1999 and December
2000, direct coronary stenting without predilatation of the
lesion was attempted in 120 consecutive carefully selected
patients (with a total of 125 lesions). The exclusion criteria
in this prospective study were lesions with: (i) extensive
calcification; (ii) marked proximal tortuosity; and (iii)
chronic total occlusion.
Total occlusions in a setting of acute myocardial
infarction (MI) were considered for direct stenting only
when Thrombolysis in Myocardial Infarction (TIMI) flow
>0 was obtained after the guidewire had passed through
the lesion and if the infarct-related lesion was clearly
identified. High-grade stenosis (>90%) was not an exclusion
criterion.
Study protocol: The procedure was performed using the
femoral approach with 6 F or 7 F guiding catheters. A left
Judkin’s or an extra back-up guiding catheter was used to
cannulate the left anterior descending (LAD) artery; a left
Judkin’s or left Amplatz 2 was used for the circumflex (LCx)
artery; and a right Judkin’s or left Amplatz 1 was used for
the right coronary artery (RCA). The lesion was crossed with
a 0.014" floppy tip, Balance Middle WeightTM (Advanced
Cardiovascular Systems Inc. Guidant, CA, USA) guidewire,
and the stent was then advanced over the guidewire across
the lesion. If the lesion could not be negotiated by the stent,
a sustained gentle push of the stent catheter and, if
necessary, deep intubation of the guiding catheter was
attempted, if considered safe. If even such an attempt was
unsuccessful, the stent was withdrawn and the lesion was
predilated with a low-profile balloon after which the lesion
was stented. Stent deployment was done under high
pressure (≥12 atm) inflation. Based on angiographic and/
IHJ-125-01.p65
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Sapra et al.
Direct Coronary Stent Implantation
309
or IVUS findings, stent deployment was optimized by
redilatation of the stent with a short balloon of bigger size or
at a higher pressure. Intravascular ultrasound guidance was
used to assess the adequacy of stent deployment in 51 lesions,
especially in the later half of the study period. Although the
choice of the stent used was based on the operator’s
preference, premounted lower-profile stents were preferred.
All the patients received 10 000 IU of intravenous
heparin at the beginning of the procedure unless they were
already on the drug prior to the procedure. The initial dose
of heparin was guided by the activated clotting time (ACT)
and further doses were given during the procedure to keep
the ACT >300 seconds. If not already on heparin, the
patients also received 500 mg ticlopidine and 325 mg
aspirin just prior to the procedure. Thereafter, ticlopidine
(500 mg/day) was continued for one month and aspirin
(165 mg/day) was continued indefinitely. After the
procedure, the sheaths were removed when the ACT fell to
<160 seconds. Patients with acute MI and some of those with
unstable angina—in whom it was felt necessary on the basis
of clinical or angiographic features—were given lowmolecular weight heparin for 48–72 hours after removal of
the sheath. A bolus injection and infusion of abciximab were
given electively in 24 patients. The administration of heparin
in these patients was as per the EPILOG trial.6 Abciximab
was also used for stent thrombosis and for the treatment of
slow-flow phenomenon in one patient each.
Angiographic analysis and definitions: Angiographic
measurements were performed using an automated
computer-based system (Philips Medical Systems,
Eindhoven, The Netherlands). All the angiograms were
analyzed to assess lesion characteristics according to the
modified American College of Cardiology/American Heart
Association classification,7 the location of the target lesion,
antegrade flow graded by the TIMI trial criteria 8 and
occurrence of the slow-flow or no-reflow phenomenon. The
presence of an angiographically visible thrombus was
defined as a filling defect in the vessel surrounded by the
contrast medium. Occurrence of the slow-flow or no-reflow
phenomenon was defined as sudden reduction of flow to
TIMI 2 or TIMI ≤1, respectively, not attributable to dissection
of the dilated lesion or to a spasm of the coronary artery.
During hospital stay, the occurrence of major adverse
coronary events (MACE) such as death, Q or non-Q
wave MI, stent thrombosis, requirement of repeat
revascularization by angioplasty or emergency bypass
surgery was recorded. Angiographic success was defined
as successful stenting of the vessel with residual stenosis
<30% and TIMI flow ≥2. Clinical success was defined as
angiographic success without any in-hospital MACE.
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Indian Heart J 2001; 53: 308–313
310 Sapra et al. Direct Coronary Stent Implantation
Intravascular ultrasound evaluation: Intravascular
ultrasound evaluation was performed using the UltracrossTM
3.2 30 MHz coronary imaging catheter (SCIMED Boston
Scientific Corporation, MN, USA) in 51 lesions. In most of
these cases, IVUS evaluation was performed only after stent
deployment to assess the adequacy of stent expansion and
to detect edge dissections. The criteria for adequate stent
expansion were the same as those in the MUSIC trial,9 i.e.
in-stent minimum lumen area ≥90% of the average
reference lumen area or ≥100% of the lumen area of the
reference segment with the lowest lumen area, with in-stent
lumen area of proximal stent entrance ≥90% of the
proximal reference lumen area. In addition, complete
apposition of the stent over its entire length and the
symmetry index were also evaluated.
Statistical analysis: Data are presented as mean±SD or
percentages. The Student’s t test and Chi-square test were
performed to compare continuous and categorical variables,
respectively. Probability values <0.05 were considered
significant.
Table 1. Baseline clinical characteristics
Age (years)
Males
54.6±12.4
100 (83.3)
Clinical presentation
Acute myocardial infarction
Recent myocardial infarction
Unstable angina
Chronic stable angina
14 (11.7)
55 (45.8)
39 (32.5)
12 (10)
Moderate–severe LV systolic dysfunction
(LVEF <35%)
26 (21.6)
Associated renal insufficiency
(Serum creatinine ≥2 mg%)
8 (6.7)
Requiring multivessel intervention (≥2 vessels)
37 (30.8)
Risk factors
Hypertension
Diabetes
Hyperlipidemia
Smoking
Family history of CAD
62 (51.7)
31 (25.8)
54 (45)
44 (36.7)
11 (9.2)
n: 120; CAD: coronary artery disease; LV: left ventricle; LVEF: left
ventricular ejection fraction
Figures in parentheses are percentages
Results
The baseline clinical and angiographic characteristics of
patients enrolled in the study are described in Tables 1 and
2, respectively. The quantitative coronary analysis (QCA)
data are depicted in Table 3. The procedure of direct stenting
was successful in 98.3% of patients (98.4% of lesions). Two
examples of successful direct stenting are shown in Figs 1
and 2. In two instances, the lesion could not be crossed by
the stent (both stents <18 mm in length) because of
proximal tortuosity in one and poor guiding catheter
support in the other. In both these, the stent could be
retrieved and there were no instances of stent embolization.
The same stents were then successfully deployed after
predilatation of the lesion with a balloon at a mean inflation
pressure of 13.9±0.9 atm. Of the 123 lesions in which
direct stenting was performed, the stents were postdilated
with a short balloon of bigger size and/or at a higher
pressure in 54 lesions (43.9%). The decision to postdilate
the stent was based on angiographic and/or IVUS findings
suggestive of inadequate expansion of the stent.
Angiography showed the need for postdilatation of the stent
in 29 (23.6%) lesions. In contrast, on IVUS evaluation of
51 lesions, inadequate stent expansion requiring
postdilatation was seen in 43 (84.3%) lesions. Of the lesions
evaluated by both IVUS and angiography, the need for
postdilatation of the stent based on angiographic findings
alone (i.e. prior to IVUS evaluation) was apparent in only
13 (25.5%) lesions. An example of IVUS-guided
IHJ-125-01.p65
310
Table 2. Baseline angiographic characteristics*
Target vessel
Left anterior descending artery
Left circumflex artery
Right coronary artery
Saphenous vein graft
Lesion type (ACC/AHA)
A
B1
B2
C
Location of lesion
Ostial
Proximal
Mid
Distal
Angiographically visible thrombus
52 (41.6)
23 (18.4)
44 (35.2)
6 (4.8)
8 (6.4)
65 (52)
40 (32)
12 (9.6)
4 (3.2)
46 (36.8)
60 (48)
15 (12)
44 (35.2)
*Number of lesions=125; ACC/AHA: American College of Cardiology/
American Heart Association classification
Figures in parentheses are percentages
Table 3. Quantitative coronary analysis results
Reference vessel
diameter (mm)
Minimum lumen
diameter (mm)
Diameter stenosis (%)
*p<0.01
8/16/01, 7:13 AM
Before
After
3.18±0.32
3.28±0.41
0.75±0.38
76.4±11.2
3.02±0.32*
8±7*
Indian Heart J 2001; 53: 308–313
postdilatation of the stent in which results of angiography
appeared satisfactory is shown in Fig. 3.
Almost all varieties of stents were used; the most
frequently used was the NIR ROYALTM advance (Boston
Scientific Corp., Ireland) in 37 (29.6%) lesions. A majority
of these stents (91.2%) were premounted, and manually
crimped stents were used in only 11 (8.8%) instances.
Fig. 1. An example of direct stenting in a case of acute myocardial infarction.
Coronary angiogram in RAO caudal view: (A) showing total occlusion of the
LAD artery at the ostium; (B) after crossing the lesion with the guidewire; and
(C) after direct stenting.
Fig. 2. An example of direct stenting in a thrombus-containing lesion. Coronary
angiogram in RAO caudal view showing: (A) thrombus-containing lesion in
the LAD artery (marked by arrow); and (B) TIMI 3 flow after direct stenting.
Sapra et al.
Direct Coronary Stent Implantation
311
Thirty-seven (29%) stents were >18 mm in length (long
stents). All of them could be negotiated and deployed
without problems. TIMI grade 3 flow was achieved in all
except two cases. In one of these cases, injection abciximab
was used as a bail-out measure to treat the slow-flow
phenomenon. No instance of extensive edge dissection
requiring an additional stent was encountered.
Angiographic success was obtained in all patients in whom
direct stenting could be performed. There was one instance
of stent thrombosis. This patient had presented with recent
anterior MI (post-thrombolysis) with post-MI angina, and
underwent successful direct stenting of the LAD artery. The
angiographic result was good with no residual stenosis and
TIMI grade 3 flow, and no angiographically visible edge
dissection. He had also undergone IVUS asessment and was
confirmed to have adequate stent expansion after
postdilatation of the stent, and there was no edge dissection.
Eleven hours after the procedure and 6 hours after removal
of the sheath, he developed chest pain with ST segment
elevation in the precordial leads. Repeat angiography
revealed total occlusion of the stented segment, which was
then redilated after administering injection abciximab. No
additional stenting was done. The electrocardiogram (ECG)
reverted to normal without any Q waves or residual ST
segment–T wave abnormality. He received low-molecular
weight heparin for 48 hours and remained asymptomatic
during the subsequent hospital stay. Clinical success was
thus achieved in 99.1% of patients (99.2% of lesions).
There were no in-hospital deaths or need for emergency
bypass surgery and all the patients were discharged after a
mean hospital stay of 2.6±0.8 days. During clinical followup after one month, no major adverse events were observed
in any of the patients.
Discussion
Fig. 3. An example of IVUS assessment of direct stenting. Coronary angiogram
in RAO caudal view of a proximal LAD lesion: (A) at baseline; (B) after direct
stenting; and (C) after aggressive postdilatation of the stent. Corresponding
IVUS images (D) at baseline; (E) after direct stenting; and (F) after
postdilatation. Note that the angiographic result appears acceptable just after
direct stenting (B); however, the corresponding IVUS image demonstrates
suboptimal expansion of the stent (E), which is significantly improved after
postdilatation (F).
IHJ-125-01.p65
311
This study demonstrates the feasibility and safety of the
strategy of direct coronary stent implantation without
predilatation of the lesion in a cohort of patients who are
considered to be at high risk for coronary angioplasty,
especially those with acute coronary syndromes. Although
this was a nonrandomized observational study, it highlights
certain important issues about this technique, viz. (i) direct
stenting in acute coronary syndromes is feasible and safe;
(ii) it is also feasible in patients with acute total occlusions
if passage of the guidewire establishes antegrade flow
sufficient to clearly identify lesion characteristics, especially
the length of the lesion; and (iii) despite the use of high
pressure (≥12 atm) for stent deployment, IVUS assessment
suggests that stent expansion is often suboptimal and
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Indian Heart J 2001; 53: 308–313
312 Sapra et al. Direct Coronary Stent Implantation
requires optimization by redilatation at a higher pressure
or with an oversized balloon.
In this study, the majority (90%) of the total of 120
patients had presented with acute coronary syndromes. The
culprit coronary lesions in such patients, including those
with acute MI, have complex morphological features such
as baseline total occlusions, ulcerations and presence of a
thrombus. Balloon angioplasty in such complicated
atherosclerotic plaques is associated with a greater risk of
complications such as extensive dissection, distal
embolization of tissue, thrombus or atherosclerotic debris
and occurrence of slow-flow or no-reflow phenomenon.10,11
This study demonstrates a procedural success rate of 98.3%
and an angiographic success rate of 100% (in those patients
in whom direct stenting was performed). Of note is the fact
that complications were rare; in fact, there were no
instances of extensive dissection/stent loss. There was only
1 (0.9%) instance of stent thrombosis and the slow-flow
phenomenon was observed in only 2 (1.7%) patients. These
results compare favorably with the much higher incidence
of slow-flow/no-reflow phenomenon reported in patients
undergoing revascularization for acute coronary
syndromes.12–14 Direct stenting was thus associated with
high success and low complication rates in this subset of
high-risk patients, making it an ideal indication for this
technique. A similar beneficial effect of direct stenting in
acute coronary syndrome was recently reported by Hamon
et al.,15 with a 2.5% incidence of no-reflow phenomenon.
Another subset of patients likely to benefit from direct
stenting are those undergoing angioplasty in degenerated
saphenous vein grafts, in whom the friable material may
embolize less when predilatation is omitted.3,4 Our series,
however, had only 6 patients belonging to this category. In
one of the studies assessing the feasibility of direct stenting,
in addition to patients with acute coronary syndromes, those
with restenotic lesions were thought to be particularly suited
for direct stent implantation because these lesions are usually
free from hard, resistant and fibrocalcific elements.16 Other
potential advantages of direct stenting are reduction in
ischemic time, amount of contrast agent used, procedure
time, radiation exposure and cost of the procedure.
Reduction of ischemic time and the amount of contrast
agent used would be beneficial in patients with severe left
ventricular dysfunction and unstable clinical presentation.
Although we did not assess the effect of direct stenting on
procedure and fluoroscopy time in this study, a beneficial
effect on these parameters was previously reported by
Figulla et al.1 A recent study by Briguori et al.17 also reported
a reduction in procedure time by 30%, radiation exposure
by 25%, use of contrast agent by 28% and cost by 41% when
direct stenting was compared with conventional stent
IHJ-125-01.p65
312
implantation with predilatation.
The cost benefit derived from direct stenting by avoiding
the use of a balloon for predilataton is obvious; however, in
our setting, where balloons are frequently reused, this issue
may not be very important. In addition, frequent use of a
balloon to optimize the final result under IVUS guidance
may offset this potential advantage.
Finally, direct stenting might be helpful in reducing
restenosis rates. This postulation is based on certain
experimental studies.18,19 It has been observed in animal
models that balloon dilatation leads to endothelial
denudation and that when a stent is placed without balloon
predilatation, sufficient endothelium remains within the
stented segment to allow repopulation with a much reduced
requirement for endothelial proliferation and migration,
which is the key step in the restenotic process. It has also
been observed that occurrence of dissection by balloon
dilatation exposes subendothelial tissue in which platelets
and macrophages accumulate. These cells get trapped by
subsequent stent deployment and eventually play a key role
in inducing proliferation and migration of subendothelial
smooth muscle cells, which again play an instrumental role
in the process of restenosis. It is likely that dissections also
occur during direct stent implantation without
predilatation, but in a more controlled manner, and the
stent immediately seals the dissection plane, thus preventing
accumulation of macrophages and platelets. This potential
advantage of direct stenting, however, has not been
confirmed so far by any of the ongoing studies.20
One important issue regarding direct stenting which
deserves attention is the adequacy of stent expansion
compared with conventional stenting owing to no or less
aggressive pre- and postdilatation. This issue can be
confirmed by IVUS assessment. Although we did not
systematically perform IVUS in all our patients, from the
IVUS evaluation of 51 lesions in our study, it appears that
direct stenting often leaves stents inadequately expanded.
Among those patients evaluated by IVUS, the need for
postdilatation to optimize stent expansion was felt in 84.3%
of lesions compared to 25.5% of lesions based on
angiographic evaluation alone. This has important
implications since inadequately expanded stents may
predispose the patient to an increased risk of stent
thrombosis and restenosis. Such a discrepancy, although
of lesser magnitude, between angiographic and IVUS
evaluation after angioplasty and stenting, has been reported
earlier with conventional stenting.21–23 In these studies, it
was found that after stent placement, angiography
overestimates lumen dimensions and thus the adequacy of
stent expansion. Our study, however, had too small a sample
size to address this issue. The angiographic method of
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Indian Heart J 2001; 53: 308–313
determining stent expansion has the inherent limitations
of one-dimensional assessment. In contrast, cross-sectional
imaging by IVUS from within the lumen of the stent is a
superior method of confirming adequate stent expansion
and obtaining a better final result which leads to a reduced
target vessel revascularization rate during follow-up.24
Our analyses of the results of IVUS evaluation suggest
that direct stenting may lead to inadequate expansion of
the stent in a large number of patients because of the
omission of pre- and postdilatation. This raises the question
of whether IVUS evaluation should be done routinely to
confirm adequate stent expansion after direct stenting or
whether aggressive postdilatation of the stent should be
done routinely in all cases of direct stenting. Larger,
multicentric studies with a control group in which IVUS
evaluation is not done are warranted to confirm this
observation and to answer these questions.
Study limitations: The present study is a nonrandomized
one without a control group, in which all the patients
underwent direct stenting; hence, comparison with a group
in which routine predilatation was done is not possible.
Intravascular ultrasound guidance,which was used in 51
lesions, was done randomly and not according to any
predetermined angiographic criteria. Cost–benefit analysis
was not done because of the frequent reuse of balloons and
refurbished IVUS catheters.
Conclusions: From this nonrandomized observational
study, we conclude that direct stenting without lesion
predilatation appears to be safe, feasible and possibly
beneficial in this selected cohort of patients. Optimization
of stent deployment after direct stenting may often require
postdilatation of the stent at a higher pressure or with a
bigger balloon. Intravascular ultrasound helps significantly
in assessing the adequacy of stent expansion and the need
for subsequent aggressive postdilatation. Larger,
multicentric randomized studies are warranted to confirm
these observations and to further refine this evolving
therapeutic strategy.
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8/16/01, 7:14 AM
314 Meharwal
et al.
Original
Article
Indian Heart J 2001; 53: 314–318
Is Off-pump Bypass Surgery Safe for LMCS?
Is Off-pump Coronary Artery Bypass Surgery Safe for
Left Main Coronary Artery Stenosis?
ZS Meharwal, N Trehan
Department of Cardiovascular Surgery, Escorts Heart Institute and Research Centre, New Delhi
Background: The feasibility of off-pump coronary artery bypass surgery has been well demonstrated. The
purpose of the present study was to assess the safety and efficacy of off-pump coronary artery surgery in patients
with left main coronary artery disease.
Methods and Results: Between January 1997 and December 2000, 174 patients with significant left main
coronary artery stenosis underwent coronary artery bypass grafting without a pump. During the same period,
991 patients who also had significant left main coronary artery stenosis underwent coronary artery surgery on
a pump. The patients in the two groups were matched in preoperative variables except that those in the off-pump
group were slightly older, and more required urgent surgery. Hospital mortality was 2/174 and 21/991 in the
off-pump and on-pump groups, respectively (p=0.560). The incidence of perioperative myocardial infarction
(1.74 v. 14/991, p=0.712), atrial fibrillation (17/174 v. 157/991, p=0.050) and blood transfusion requirement
(63/174 v. 476/991, p=0.050) were significantly less in the off-pump group. The intubation time (15±3 hours
v. 22±4 hours, p=0.001), blood loss (365±61 ml v. 582±76 ml, p<0.001), intensive care unit stay (23±10
hours v. 36±11 hours, p<0.001) and hospital stay (6±4 days v. 9±5 days, p<0.001) were also less in the offpump group.
Conclusions: Off-pump coronary artery bypass surgery is safe and effective for patients with left main coronary
artery disease. (Indian Heart J 2001; 53: 314–318)
Key Words: Coronary disease, Surgery, Cardiopulmonary bypass
B
oth observational1,2 and randomized3,4 trials carried out
on patients with left main coronary artery stenosis
(LMCS) have shown prolonged survival of surgically treated
patients compared with those treated medically. In longterm follow-up of patients listed in the Coronary Artery
Surgery Study (CASS) registry, the 15-year cumulative
survival of those with initial coronary artery bypass
grafting (CABG) was 44% v. 31% in medically treated
patients; median survival in the surgical group was 13.1
years compared with only 6.2 years in the medical group.2
Left main coronary artery stenosis has been identified
as an independent predictor of postoperative morbidity and
mortality after CABG by several investigators5–7 and is
considered a definite indication of CABG regardless of
symptomatology.
The presence of critical LMCS has been considered a
relative contraindication for the off-pump coronary artery
bypass (OPCAB) technique due to concerns over the well
Correspondence: Dr Zile Singh Meharwal, Senior Consultant Cardiac
Surgeon, Escorts Heart Institute and Research Centre, Okhla Road, New
Delhi 110025. e-mail: [email protected]
IHJ-132-01.p65
314
demonstrated hemodynamic changes during displacement
of the heart, even though it is now being used more
commonly and the results are encouraging even in highrisk and elderly patients.8,9
We analyzed our data to determine whether OPCAB can
be used safely in patients with critical LMCS.
Methods
Patients with significant (>50%) LMCS operated between
January 1997 and December 2000 were included in the
study. Of these, 174 patients were operated without
cardiopulmonary bypass (OPCAB Group) and 991 patients
were operated on cardiopulmonary bypass (CCAB Group).
One patient in the OPCAB Group required conversion to
cardiopulmonary bypass and was excluded from the study.
Preoperative and intraoperative variables, and postoperative
results of the two groups were analyzed and compared. Risk
assessment was done preoperatively using the Parsonnet score.
Intra-aortic balloon pump (IABP) was used preoperatively in
patients who were unstable and had significant ST changes.
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Indian Heart J 2001; 53: 314–318
Meharwal et al.
Anesthesia and anticoagulation protocol: Patients
were premedicated using morphine (0.1 mg/kg) and
lorazepam (2–4 mg). Induction was achieved by midazolam
(15–20 µg/kg) and fentanyl (10–100 µg/kg). Muscle
relaxation was achieved by vacuronium bromide (0.10–15
mg/kg). Anesthesia was maintained by oxygen, air and
incremental doses of midazolam and fentanyl. Heparin was
injected in a dose of 3 mg/kg in patients operated on a pump
and activated clotting time (ACT) was maintained at >400
seconds. In patients who were operated upon without a
pump, the initial dose of heparin used was 1.5 mg/kg. The
ACT, which was measured initially and repeated every 30
minutes, was maintained at >300 seconds. Protamine
sulphate was used in a 1:1 ratio to reverse the effect of
heparin after the procedure.
A femoral arterial line was used in all the patients to
insert IABP if the patient became unstable during induction
of anesthesia or at a later stage before revascularization.
Hemodynamic monitoring: Hemodynamic monitoring
consisted of a six-channel electrocardiogram (ECG). A
combination of leads II and V5 was continuously displayed
and used for ST segment trend analysis. Radial arterial
pressure was monitored. A pulmonary artery catheter was
used in all the patients. Recorded variables were mean
arterial pressure (MAP), central venous pressure (CVP),
mean pulmonary pressure (PAP), pulmonary capillary
wedge pressure (PCWP), cardiac index (CI), stroke volume
(SV) and systemic vascular resistance (SVR). Oxygen
saturation was continuously monitored with a pulse
oximeter. Arterial blood gases and ACT were monitored every
20 minutes. Continuous intraoperative transesophageal
echocardiographic (TEE) monitoring was done using a
multiple transducer and Sonos 5500 imaging system. The
parameters specifically monitored by TEE were: regional
wall motion abnormalities; changes in global left ventricle
(LV) function; LV filling; right atrial filling; mitral
regurgitation and right ventricular outflow tract obstruction.
Technique of off-pump CABG: All procedures were
performed through a median sternotomy. The left internal
mammary artery (LIMA) was harvested by the standard
technique using hemoclips. It was harvested as a pedicled
graft in most patients. The radial artery and saphenous vein
were harvested simultaneously. Patients were heparinized
with a dose of 1.5 mg/kg body weight. Octopus 2, Octopus
2+ and Octopus 3 (Octopus tissue stabilization system,
Medtronic Inc., Minneapolis MN) were used as the
mechanical stabilizers in most of the patients. Intracoronary
shunts (Baxter AnastaFLO Intravascular shunt, Irvine, CA)
were used in most of the patients. The oxygen blower was
IHJ-132-01.p65
315
Is Off-pump Bypass Surgery Safe for LMCS?
315
used to assist in anastomosis. Hemodynamic monitoring
was performed using the Swan–Ganz catheter.
The left anterior descending (LAD) artery was the first
coronary artery to be grafted in most cases. The right
coronary artery (RCA) was normally the second artery to
be grafted. The vessels on the lateral and posterior wall were
grafted last. However, the sequence of grafting was
individualized for a particular patient, depending on the
patient’s hemodynamics. The LAD and RCA could be grafted
without much displacement of the heart. For exposure of
the circumflex vessels, three pericardial traction sutures
were used to pull the heart vertically. The right pleura was
opened in the majority of the patients and vertical
pericardiotomy was performed to herniate the heart to the
right of the chest under the sternum. Other maneuvers,
such as the Trendelenburg position and tilting the table,
were performed as required. Inotropes were used as and
when necessary during surgery.
Proximal anastomosis was performed using standard
techniques. Normally, proximal anastomosis was performed
after every distal anastomosis.
Techniques of CABG on cardiopulmonary bypass
(CPB): Standard cardiopulmonary bypass (CPB) was
established using ascending aortic and two-stage venous
cannulation. Patients were not actively cooled but the
temperature was allowed to drift. Most patients were
operated under cardioplegic arrest, using warm blood
cardioplegia, both antegrade and retrograde. Cardioplegia
was repeated after every distal anastomosis. Warm blood
without potassium was infused after completing all distal
anastomoses, and while performing proximal anastomosis.
Some patients were operated on CPB without arresting the
heart. The LV vent was inserted through the right superior
pulmonary vein in some patients. Hemodynamic
monitoring was performed using a Swan–Ganz catheter and
TEE as in patients operated without CPB.
Postoperative management: A standard postoperative
management protocol was followed. Patients were
extubated in the intensive care unit (ICU) as soon as possible,
depending on their hemodynamic stability. Antibiotic
therapy was continued as long as patients had central lines
or chest drains (normally 24–48 hours).
Definitions: Perioperative myocardial infarction (MI) was
defined as the development of new q waves on postoperative
electrocardiogram or loss of R wave progression, new left
bundle branch block or new ST and T wave changes in
association with increase in CPK level >40 U/L or CPK-MB/
CPK ratio more than 5%. Prolonged ventilation was defined
as ventilation for more than 48 hours. Mediastinitis was
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Indian Heart J 2001; 53: 314–318
316 Meharwal et al. Is Off-pump Bypass Surgery Safe for LMCS?
defined as mediastinal collection which was positive on
culture. Acute renal failure was defined as the requirement
of peritoneal or hemodialysis. Total operative time was
defined as the time from incision to closure of the skin.
Urgent surgery was defined as surgery undertaken
within 24 hours of the angiogram. Emergency surgery was
that undertaken when the patient was shifted directly to
the theatre from the catheterization laboratory or if the
surgery was required within a few hours of admission or
of performing the angiogram.
Statistical analysis: Data are reported as mean±SD. The
Chi-square test and Fisher’s exact t test were used to
compare categorical variables. Unpaired Student’s t test was
used to compare inter-group means. A p value of less than
0.05 was accepted as significant. Variables that are not
normally distributed were compared using the Mann–
Whitney test.
Results
The demographics of the group of patients are shown in
Table 1. The patients were matched in terms of sex, diabetes,
hypertension, smoking, history of cerebrovascular
accidents (CVA), peripheral vascular disease (PVD) and
obesity but the mean age was slightly higher in the OPCAB
Group. The two groups were matched for the number of
patients with angina, and those in NYHA functional Class
III or IV but there were more patients in the OPCAB Group
with chronic obstructive pulmonary disease (COPD). The
number of patients with poor LV function was comparable
in the two groups. There were more urgent procedures in
the OPCAB Group than the CCAB Group. The Parsonnet
risk score was comparable in the two groups.
The LIMA was used for grafting in the majority of
patients in both the groups (Table 2). The right internal
mammary artery (RIMA) was used in more patients in the
OPCAB Group. The other grafts used were the radial artery
and veins. The number of patients in whom the radial
artery was used as one of the conduits was comparable in
the two groups. The average number of grafts was slightly
higher in the CCAB Group.
Hemodynamically, the ECG showed some ST segment
changes during LAD anastomosis, which returned to
normal after the flow was established from the LIMA to the
LAD. The MAP, SV and CI decreased during anastomosis to
vessels on the lateral and posterior wall of the heart. The
CVP increased while pulmonary artery pressure and PCWP
did not show much rise or decreased slightly. Pacing the
patient in the Trendelenburg position increased the CVP
though pulmonary pressure still remained within normal
IHJ-132-01.p65
316
limits in the majority of patients.
Intraoperatively, IABP was used in more patients in the
OPCAB Group. The total operating time was significantly
less in the OPCAB Group than in the CCAB Group
(Table 2).
Table 1. Preoperative variables of patients with left main
coronary artery stenosis
Variables
OPCAB Group
(n=174)
CCAB Group
(n=991)
p value
59.2±8.9
891 (89.9)
100 (10.1)
213 (21.5)
8 (0.8)
111 (11.2)
365 (36.8)
277 (28.0)
21 (2.1)
252 (25.4)
158 (15.9)
75 (7.6)
132 (13.3)
61 (6.2)
40±8
158 (15.9)
119 (12.0)
416 (42.8)
16 (1.6)
213 (21.5)
7.6±6.2
<0.001
0.379
0.379
0.757
0.650
0.841
0.630
0.010
0.423
0.410
0.071
0.745
0.932
0.971
0.002
0.150
0.347
0.014
0.826
0.998
0.244
Age in years (mean±SD) 62.2±9.8
Male (%)
152 (87.4)
Female (%)
22 (12.6)
NIDDM (%)
35 (20.1)
IDDM (%)
2 (1.1)
Hypertension (%)
18 (10.3)
Smokers (%)
68 (39.1)
COPD (%)
66 (37.9)
History of CVA (%)
6 (3.4)
Unstable angina (%)
50 (28.7)
NYHA Class III or IV (%) 38 (21.8)
PVD (%)
15 (8.6)
Obesity (%)
23 (13.2)
Redo CABG (%)
10 (5.7)
Mean EF (mean±SD) (%)
42±9
EF <30%
36 (20.7)
Preop IABP (%)
16 (9.2)
Urgent surgery (%)
91 (52.2)
Emergency surgery (%)
3 (1.7)
CHF (%)
38 (21.8)
Parsonnet score (mean±SD) 8.2±6.6
NIDDM: noninsulin-dependent diabetes mellitus; IDDM: insulin-dependent diabetes
mellitus; COPD: chronic obstructive pulmonary disease; CVA: cerebrovascular
accident; NYHA: New York Heart Association; PVD: peripheral vascular disease;
CABG: coronary artery bypass grafting; EF: ejection fraction; IABP: intra-aortic
balloon pump; CHF: congestive heart failure; Preop: preoperative
Table 2. Intraoperative variables of patients with left main
coronary artery stenosis
Variables
OPCAB Group
(n=174)
LIMA (%)
164 (94.3)
RIMA (%)
15 (8.6)
RA (%)
125 (71.8)
CPB time (mean±SD) (min)
NA
AoXL time (mean±SD) (min)
NA
Number of grafts
2.9±0.8
(mean±SD)
Total operating time (min)
178±47
(mean±SD)
Intraoperative IABP (%)
11 (6.3)
CCAB Group
(n=991)
p value
933 (94.1)
38 (3.8)
773 (74.0)
85±13
36±8
3.1±0.8
0.904
0.009
0.092
—
—
0.002
238±54
<0.001
13 (2.1)
<0.001
LIMA: left internal mammary artery; RIMA: right internal mammary artery; CPB:
cardiopulmonary bypass; AoXL: aortic cross clamp; RA: radial artery; IABP: intraaortic balloon pump; NA: not applicable
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Indian Heart J 2001; 53: 314–318
Meharwal et al.
Table 3. Postoperative outcome of patients with left main stenosis
Variables
OPCAB Group CCAB Group
(n=174)
(n=991)
Perioperative MI (%)
1 (0.6)
Reoperation for bleeding (%)
1 (0.6)
Postoperative inotropes (%)
22 (12.6)
Blood loss (mean±SD)
365±61
Blood transfusion (%)
63 (36.2)
Atrial fibrillation (%)
17 (9.8)
Intubation time in hours
15±3
(mean±SD)
Prolonged ventilation (%)
6 (3.4)
Postop IABP (%)
1 (0.6)
Stroke (%)
0 (0)
Pulmonary complications (%)
3 (1.7)
Mediastinitis (%)
1 (0.6)
Acute renal failure (%)
1 (0.6)
Hospital mortality (%)
2 (1.1)
ICU stay in hours (mean±SD)
23±10
Hospital stay in days (mean±SD)
6±4
p value
14 (1.4)
24 (2.4)
184 (18.6)
582±76
476 (48)
157 (15.8)
22±4
0.712
0.158
0.075
<0.001
0.005
0.050
<0.001
73 (7.4)
12 (1.2)
3 (0.3)
34 (3.4)
7 (0.7)
12 (1.2)
21 (2.1)
36±11
9±5
0.083
0.730
0.932
0.342
0.761
0.705
0.560
<0.001
<0.001
MI: myocardial infarction; IABP: intra-aortic balloon pump; ICU: intensive care unit;
Postop: postoperative
Postoperative complications and hospital mortality are
shown in Table 3. The overall mortality was slightly less in
the OPCAB Group than in the CCAB Group but this was not
statistically significant. The incidence of perioperative MI
was slightly less in the OPCAB Group than in the CCAB
Group though it was not statistically significant (p=0.712).
Only 1 (0.6%) patient in the OPCAB Group was re-explored
for bleeding while 24 (2.4%) patients in the CCAB Group
required re-exploration for bleeding (p=0.158). The mean
blood loss was significantly less in the OPCAB Group and a
smaller number of patients required blood or blood product
transfusion. The requirement of inotropes, prolonged
ventilation and postoperative IABP was comparable in the
two groups.
The patients in the OPCAB Group required shorter
ventilation and were extubated more quickly than the
patients in the CCAB Group. None of the patients in the
OPCAB Group, but 3 (0.3%) patients in the CCAB Group
suffered a stroke (p=0.932). The incidence of pulmonary
complications, mediastinal infection and acute renal failure
was comparable in the two groups. The mean ICU stay and
total hospital stay were significantly less in the OPCAB
Group.
Discussion
Off-pump coronary bypass surgery through a medial
sternotomy has recently gained renewed interest for
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Is Off-pump Bypass Surgery Safe for LMCS?
317
multivessel coronary revascularization.10,11 Results of this
technique are encouraging and many reports have shown
lower postoperative morbidity and cost with the OPCAB
technique compared with the conventional coronary bypass
technique.8,9,12 The OPCAB technique is now being used
even in high-risk patients including the elderly and those
with poor LV function.13,14,15
Patients with significant LMCS present a special situation
because the hemodynamic disturbances which develop
during manipulation of the heart in OPCAB surgery, may
not be tolerated by the patient. In our experience, LIMA–
LAD anastomosis can be performed without much
displacement of the heart, and the use of an intracoronary
shunt to permit continued myocardial perfusion during
anastomosis reduces hemodynamic disturbances to a
minimum.
Left anterior descending artery grafting using LIMA via
left anterior small thoracotomy without CPB has been
shown to offer good early and mid-term results. 16
Multivessel revascularization needs full sternotomy to
access all the vessels of the heart. Access to the obtuse
marginal and posterior descending artery needs
displacement and manipulation of the heart. Various
techniques have been described to access and revascularize
the vessels on the lateral and inferior walls of the ventricle
without compromising hemodynamics significantly.17–20
Cartier et al. 20 described a technique of exposing the
circumflex vessels. They used four pericardial sutures
around the base of the heart and then used a pull-type
mechanical stabilizer. Using this technique, they could
easily access the obtuse marginal as well as the
posterolateral branches while maintaining hemodynamic
stability. They achieved complete revascularization in 95%
of patients with one patient needing conversion to
cardiopulmonary bypass. We used a combination of deep
pericardial sutures, Trendelenburg position, right
pleurotomy and vertical pericardiotomy near the
diaphragm to expose the circumflex vessels. Octopus was
used as the mechanical stabilizer.
Hospital mortality was comparable in the OPCAB and
CCAB Groups, though the patients in the OPCAB Group
were older and more often required urgent surgery. The
majority of patients were moved out of the ICU within 24
hours and the number of patients who required ventilation
for more than 48 hours was equal in both the groups, even
though the incidence of COPD was higher in the OPCAB
Group.
We use IABP preoperatively in patients with LMCS who
have unstable angina with ST and T wave changes in the
ECG or those with severely impaired LV function.
8/16/01, 7:16 AM
Indian Heart J 2001; 53: 314–318
318 Meharwal et al. Is Off-pump Bypass Surgery Safe for LMCS?
Preoperatively, 9.2% and 12.0% of patients in the OPCAB
and CCAB Groups, respectively, were on IABP. Preoperative
use of IABP has been shown to reduce myocardial ischemia
and thus improve outcome in high-risk coronary
patients.21,22 Christenson et al.23 showed that preoperative
use of IABP in high-risk patients including those with
significant LMCS was associated with a lower incidence of
low cardiac output, and a shorter intubation time and
length of stay in both the ICU and hospital. The requirement
of IABP intraoperatively was equal in the OPCAB and CCAB
Groups in our study.
We observed lower postoperative morbidity, particularly
perioperative MI, blood loss, requirement of blood or blood
products and atrial fibrillation in the OPCAB Group. The
ICU and hospital stay were shorter in this group. Similar
observations have been reported by other workers also.24–26
Conclusions: Off-pump coronary artery surgery is a safe
and effective technique in patients with significant left main
coronary artery disease. The postoperative morbidity and
length of ICU and hospital stay are shorter compared to
patients operated on CPB. Proper monitoring of various
hemodynamic parameters during surgery, including
monitoring of LV wall motion by TEE, is useful. An IABP
helps in patients with unstable angina and ischemic
changes on ECG, and in those with severely impaired LV
function.
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8. Boyd WD, Desai ND, Del Rizzo DF, Novick RJ, McKenzie FN, Menkis
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8/16/01, 7:16 AM
Indian Heart J 2001; 53: 319–322
Original
Article
Bhan et al. Surgery for Ascending Aortic
Aneurysms
319
Surgical Experience with Dissecting and Nondissecting
Aneurysms of the Ascending Aorta
A Bhan, SK Choudhary, M Saikia, R Sharma, P Venugopal
Cardiothoracic Centre, All India Institute of Medical Sciences, New Delhi
Background: Patients who underwent replacement of the ascending aorta with a prosthetic graft for treatment
of ascending aortic aneurysm and dissection between January 1992 and December 2000 were studied.
Methods and Results: Bentall’s operation, using a composite aortic valve and prosthetic graft, was performed
in 82 patients (70 males). Indications for the procedure included ascending aortic aneurysm (n=54 including
16 patients with Marfan’s syndrome); DeBakey Type I or II aortic dissection (n=26 including 10 patients with
Marfan’s syndrome) and ascending aortic aneurysm with severe aortic stenosis (bicuspid aortic valve disease)
(n=2). Bentall’s procedure with the inclusion technique was performed in 72 patients and a Cabrol fistula created
in 63 patients. In 10 other patients, coronary button transfer was done without a Cabrol fistula. There were 6
early deaths (7.3%) and 8 patients required re-exploration for excessive bleeding. Eighteen patients showed low
cardiac output while the wound of 8 became infected. Postoperative arrhythmia and renal failure was seen in 26
and 6 patients, respectively. Four patients had pericardial effusion. Follow-up ranged from 1 month to 8 years.
There were 8 late deaths, the causes of which include congestive heart failure (n=3), cerebral hemorrhage (n=3)
and sudden cardiac death (n=2). Two patients reported back with dissection of the descending thoracic aorta
and await surgery.
Conclusions: Bentall’s operation is a safe procedure with an acceptable mortality and morbidity. (Indian Heart
J 2001; 53: 319–322)
Key Words: Surgery, Aortic aneurysm, Aortic dissection
T
reatment of the various diseases which involve the
ascending aorta and the root offered a major challenge
to surgeons. In 1968, Bentall and de Bono1 described a
technique for replacement of the ascending aorta and aortic
valve using a composite graft. It was a major advancement
in the surgical procedures for aortic root replacement. Since
then, many techniques have also been proposed and
successfully used to insert a composite valve graft and reattach the coronary artery for repair of the ascending
aorta 2–4. Of these, the Bentall’s procedure has been
successful in patients with annuloaortic ectasia, Marfan’s
syndrome, aortic dissection, and aneurysm involving the
ascending aorta and the aortic valve. The original technique
was associated with poor hemostasis and, in some cases,
formation of pericoronary and distal pseudoaneurysm.3–5
To prevent these complications, Cabrol et al.3,6 introduced
the technique of constructing a drainage from the wrapped
Correspondence: Dr A Bhan, Additional Professor of Cardiothoracic and
Vascular Surgery, All India Institute of Medical Sciences, Ansari Nagar, New
Delhi 100029. e-mail: [email protected]
IHJ-124-01.p65
319
perigraft space to the right atrial appendage, and modified
coronary implantation by a tube graft. Subsequently, the
coronary button technique has been shown to yield better
results in terms of complications.7,8
The purpose of this study is to review our experience
and analyze the mid-term results of ascending aortic
replacement with a prosthetic graft in patients with
ascending aortic disease.
Methods
Between January 1992 and December 2000, 82 patients
(70 males) underwent aortic root replacement with a
composite graft at the All India Institute of Medical
Sciences, New Delhi. Hospital charts and records were
reviewed and detailed notes of preoperative, perioperative
and postoperative variables and outcomes were made. The
mean age of the patients was 41±13.6 years (range 9–74
years). Preoperatively, the patients were evaluated with
echocardiography, computed axial tomography and
angiography. Magnetic resonance imaging was also done
8/16/01, 7:17 AM
320 Bhan et al.
to determine the extent of the intimal flap in case of
dissection and coronary angiography was done in 68
patients. Indications for Bentall’s operation included
ascending aortic aneurysm (n=54 including 16 patients
with Marfan’s syndrome); DeBakey Type I or II aortic
dissection (n=26 including 10 patients with Marfan’s
syndrome) and ascending aortic aneurysm with severe
aortic stenosis (bicuspid aortic valve disease) (n=2). Among
patients with dissection, 10 had acute and 16 had chronic
aortic dissection. Out of the 8 patients with DeBakey Type I
dissection, 3 had an intimal tear involving the arch vessels.
In one patient, the intimal tear had involved the right
coronary ostium. Fifty-two patients had severe aortic
valvular incompetence while 30 had moderate aortic
regurgitation. Five patients had moderate-to-severe mitral
regurgitation, 42 had left ventricular dysfunction (ejection
fraction <50%) and 3 had associated coronary artery
disease. Preoperatively, 15 patients were in New York Heart
Association (NYHA) Class I, 28 patients were in Class II,
30 patients were in Class III and 9 patients were in Class IV.
Preoperative characteristics are summarized in Table 1.
Operative considerations: The Bentall’s procedure,
which involves replacement of the ascending aorta with a
composite graft and reimplantation of the coronary ostia,
was undertaken in 82 patients. In 72 cases, direct reattachment of the coronary artery ostia to the opening in
the composite graft was performed using the inclusion
technique. In 10 patients, the coronary button technique
was used for anastomoses of the coronary ostia to the
prosthetic graft.
Table 1. Preoperative characteristics of patients (n=82)
Variable
Value
Age (years)
Range
Mean±SD
9–74
41±13.6
Male/Female
70/12
Marfan’s syndrome
26 (32%)
Coronary artery disease
3 (4%)
Aortic regurgitation
Moderate
Severe
30 (37%)
52 (63%)
Mitral regurgitation (moderate/severe)
5 (6%)
Left ventricular dysfunction (EF <50%)
42 (51%)
Ascending aortic pathology
Aneurysm
Type I or II dissection
56 (68%)
26 (32%)
NYHA Class III/IV
39 (48%)
IHJ-124-01.p65
Indian Heart J 2001; 53: 319–322
Surgery for Ascending Aortic Aneurysms
320
Technique: In all the patients, the groin was routinely
prepared for cannulation. Cardiopulmonary bypass was
instituted either by cannulating the high ascending aorta
or femoral artery, and single atrial, bicaval or the femoral
route was used for venous cannulation. Depending upon
the individual case, moderate-to-severe hypothermia was
induced. Moderate systemic hypothermia (28 ºC) was
instituted in 70 patients and severe hypothermia with total
circulatory arrest in the remaining 12. After aortic crossclamping, myocardial protection was achieved with
hyperkalemic cold blood cardioplegia and topical cooling.
In the initial 72 cases, the inclusion technique with direct
coronary re-attachment was performed. In these cases, the
aneurysm was incised longitudinally at the center and direct
coronary ostial cardioplegia given. After adequate
cardioplegic arrest, the aortic valve was carefully assessed
for incompetence and valve leaflets were either excised or
left intact to be used as part of the buttressing material.
Composite graft replacement was then carried out with the
use of interrupted, pledgetted 2-0 ethibond sutures
(Johnson and Johnson, Somerville, New Jersey). Either a St
Jude composite graft (St Jude Medical, Brussels, Belgium)
or a Medtronic composite graft (Medtronic Inc.,
Minneapolis, MN) was used. After completion of the suture
line between the aortic annulus and the sewing ring of the
prosthetic valve, holes for coronary implantation were made
in the aortic graft with graft cautery. The aortic wall
surrounding the coronary ostia was then sutured to these
openings with continuous 5-0 polypropylene sutures. When
needed, this suture line was reinforced with pledgetted
mattress sutures.
The tube graft was then cut to the appropriate length
and the aorta was transected as high as possible just below
the aortic clamp. In the 52 cases in which there was no
dissection, the grafts were directly anastomosed to the distal
cut portion of the aorta. In the 26 cases in which dissection
was present, the separated layers of the distal aorta were
prepared with inner and outer layers of Teflon felt (Impra
Inc. Tempe AZ, USA) and strip sutured with continuous
4-0 polypropylene sutures. The graft was sewn to this cuff
with continuous sutures.
After completion of both proximal and distal
anastomoses, the aortic wall was wrapped around the
prosthesis and sutured. In 63 patients, a Cabrol shunt was
created between the aneurysmal wrap and the right atrium
in order to avoid the formation of a tense hematoma in the
periprosthetic space.
In 10 patients, the coronary ostia were carefully excised
with a button of aortic wall to serve as a Carrel patch and
were anastomosed to the buttonhole made in the graft with
8/16/01, 7:17 AM
Indian Heart J 2001; 53: 319–322
a 5-0 polypropylene suture. In these patients, the Bentall
inclusion wrap was abandoned.
In the 12 cases of ascending aortic dissection in which
the extent of involvement of the dissection flap was beyond
the aortic arch, the distal anastomosis was done under total
circulatory arrest after removing the aortic cross-clamp.
Three patients required hemi-arch replacement and in
1 patient the Bentall procedure was accompanied by the
elephant trunk procedure. Circulatory arrest time varied
between 20 and 45 minutes. In 6 cases of circulatory arrest,
retrograde cerebral perfusion was performed to decrease
cerebral ischemia.
Concomitant procedures included coronary artery
bypass grafting (n=4), mitral valve repair (n=3) and mitral
valve replacement (n=2).
Follow-up: Patients were followed up postoperatively in the
outpatient department (OPD) at 1 month, 3 months, 6
months and 1 year in the first year and once a year
thereafter. All the patients were given oral anticoagulants
on the basis of prothrombin time and International
Normalized Ratio (INR). Patients who failed to attend the
OPD for a prolonged period after initial follow-up were
contacted through letters and asked to come to the OPD for
follow-up on specified dates. On each follow-up visit, they
were evaluated clinically, echocardiographically and, when
required, by computed axial tomography and magnetic
resonance imaging.
Statistical analysis: Continuous or interval-related data
were expressed as mean±standard deviation (SD).
Categorical variables were expressed as percentages. A stepwise logistic regression analysis was performed to determine
predictors of early mortality. A probability of 0.10 was a
criterion for inclusion or exclusion cut-off in step-wise
analysis and a final probability of 0.05 was considered
significant.
Results
There were 6 early deaths (7.3%). One death occurred on
postoperative day 6. This patient had preoperative renal
dysfunction and developed severe acute renal failure on
postoperative day 1. He was put on peritoneal dialysis but
gradually developed multiorgan failure and died on
postoperative day 6. Two patients, who had acute dissection
and were in Class IV preoperatively, developed low output
syndrome postoperatively. They died on days 10 and 12
postoperatively. One patient, whose platelet count and
coagulation profile were borderline preoperatively,
developed disseminated intravascular coagulation. He was
IHJ-124-01.p65
321
Bhan et al. Surgery for Ascending Aortic Aneurysms 321
re-explored on postoperative day 1 for excessive bleeding
but no surgical site could account for the bleeding.
Subsequently, he developed endotracheal tube bleeding on
postoperative day3 and gastrointestinal bleeding on
postoperative day 4 and died on postoperative day 5. One
patient died on postoperative day 22 owing to severe
respiratory insufficiency. One patient died due to severe right
ventricular failure on postoperative day 3. This patient had
an abnormal right coronary ostium which was involved by
a dissection flap. Initially, both the right and left coronary
ostia were implanted in the aortic graft by direct inclusion
but there was difficulty in weaning away the patient from
cardiopulmonary bypass and on electrocardiogram,
changes were seen in the inferior leads. We then applied a
venous graft to the right coronary artery and were able to
wean her away from cardiopulmonary bypass but the
patient died on postoperative day 3 due to severe right
ventricular failure.
A number of risk factors (Table 2) were analyzed to
determine independent predictors of early death. The
presence of acute dissection was the only significant
predictor (p=0.03) of early death.
Eight patients (9.7%) required re-exploration for
excessive bleeding. The cause was surgical in only one
patient who had bled from the aorta. Eighteen patients had
low cardiac output syndrome and were managed with high
inotropic support. Eight patients had infected wounds and
2 of them developed mediastinitis. Postoperative
arrhythmias were seen in 26 patients. Two patients, in
whom atrial fibrillation persisted for more than 2 months,
required prolonged amiodarone therapy. Postoperative renal
insufficiency requiring peritoneal dialysis occurred in 6
Table 2. Risk factors analyzed for early deaths
Age
Sex
Marfan’s syndrome
Acute dissection
Involvement of the arch
Involvement of the coronary arteries
Mitral valve involvement
Left ventricular dysfunction
Preoperative renal dysfunction
NYHA Class
Surgical technique (inclusion v. button technique)
Cabrol fistula (yes v. no)
Deep hypothermic circulatory arrest
Cardiopulmonary bypass time (minutes)
Aortic cross-clamp time (minutes)
8/16/01, 7:17 AM
322 Bhan et al.
patients. Four patients had pericardial effusion and required
pericardial drainage. Three patients developed right-sided
pleural effusion postoperatively.
Long-term results: The duration of follow-up for hospital
survivors was from 1 month to 8 years and follow-up
information was available for all. Twenty-five patients have
been followed up for more than 5 years and 15 for more
than 7 years.
There have been 18 late deaths among the 76 early
survivors. Three patients died of cerebral hemorrhage
18–24 months postoperatively. Three patients, who had left
ventricular ejection fraction ranging from 20%–25%
preoperatively, died of cardiac failure. Left ventricular
function deteriorated postoperatively and death occurred
after 30–42 months. Two other patients died suddenly, one
after 24 months and the other after 54 months. The cause
of these deaths could not be determined.
No patient required reoperation for graft-related
complications. There was no clinical, echocardiographic or
tomographic evidence of any pseudoaneurysm formation
or periprosthetic leak. Two patients who had come back
with pain in the chest and showed evidence of descending
thoracic aortic dissection on computed axial tomographic
scan, now await surgery. No patient had flow through the
Cabrol fistula on echocardiography, suggesting closure and
thrombosis of the periprosthetic space. Two patients had
prosthetic valve thrombosis which was treated with
streptokinase. One patient had an episode of transient
ischemic attack, followed by right-sided hemiparesis
two years after surgery but improved on conservative
treatment. Three patients had minor anticoagulant-related
hemorrhages. They improved on readjustment of the
anticoagulant dose. Two patients had prolonged fever
which persisted for 2 months. Their blood cultures did not
grow any organism and both recovered after 6 weeks of
aggressive antibiotic therapy.
Functional status of the survivors: At the last followup, 49 patients (72%) were in NYHA Class I or II. Sixteen
patients (23.5%) were in NYHA Class III and 3 (4.4%) in
NYHA Class IV.
Discussion
Bentall’s operation for ascending aortic aneurysm and
ascending aortic dissection gives good early and long-term
results for all elective cases.8 Investigators4,7,8 have reported
an operative mortality of 4%–10.5%. In our experience, the
operative mortality was 7.9% which suggests that the
procedure has an acceptable mortality. The major morbidity
IHJ-124-01.p65
Indian Heart J 2001; 53: 319–322
Surgery for Ascending Aortic Aneurysms
322
associated with this procedure was that of intraoperative
and postoperative hemorrhage. However, with
standardization of the technique and the availability of
nonporous grafts, the incidence of bleeding has been
reduced to a minimum. In our series, bleeding occurred in
only 8 patients (9.7%).
The inclusion technique is safe and yields good results.
However, there is a possibility of a leak from the coronary
anastomotic site and formation of a pseudoaneurysm.6,7
Furthermore, coronary anastomosis is difficult with this
technique if the coronary arteries are placed very low in
the native aorta. As bleeding from the graft does not appear
to be a major problem with the availability of nonporous
grafts, we have switched over to the coronary button
technique and obtained equally good results.
The entire aorta is abnormal in these patients. Hence, a
strict and regular follow-up is necessary since they can
develop a pseudoaneurysm/leak at the site of the operation
or a dissection/aneurysm in the distal aorta. Furthermore,
anticoagulation monitoring of the prosthetic valve in the
composite graft is also required.
Considering the generalized involvement of the aorta in
the disease process, the Bentall’s procedure appears to be a
palliative one. However, dramatic improvement in
symptoms and a drastic reduction in disease-related
mortality makes it a valuable procedure. A low operative
mortality and morbidity have added value to this procedure.
References
1. Bentall H, de Bono A. A technique for complete replacement of the
ascending aorta. Thorax 1968; 23: 338–339
2. Edwards WS, Kerr AR. A safer technique for replacement of the entire
ascending aorta and aortic valve. J Thorac Cardiovasc Surg 1970; 59:
837–839
3. Cabrol C, Pavie A, Gandjbakhch I, Villemot JP, Guiraudon G, Laughlin
L, et al. Complete replacement of the ascending aorta with
reimplantation of the coronary arteries: new surgical approach. J
Thorac Cardiovasc Surg 1981; 81: 309–315
4. Kouchoukos NT, Wareing TH, Murphy SF, Perillo LB. Sixteen-year
experience with aortic root replacement: results of 172 operations.
Ann Surg 1991; 214: 308–318
5. Barbetseas J, Crawford ES, Safi HJ, Coselli JS, Quinones MA, Zoghbi
WA. Doppler echocardiographic evaluation of pseudoaneurysm
complicating composite grafts of the ascending aorta. Circulation
1992; 85: 212–222
6. Cabrol C, Pavie A, Mesnildrey P, Gandjbackhch I, Laughlin L, Bros V,
et al. Long-term results with total replacement of the ascending aorta
and reimplantation of the coronary arteries. J Thorac Cardiovasc Surg
1986; 91: 17–25
7. Svensson LG, Crawford ES, Hess KR, Coselli JS, Safi HJ. Composite valve
graft replacement of the proximal aorta: comparison of techniques
in 348 patients. Ann Thorac Surg 1992; 54: 427–439
8. Kouchoukos NT, Marshall WG, Wedige-Stecher TA. Eleven-year
experience with composite graft replacement of the ascending aorta
and aortic valve. J Thorac Cardiovasc Surg 1986; 92: 691–705
8/16/01, 7:17 AM
Indian Heart J 2001; 53: 323–327
Jhaj et al.
Original Article
Prescribing Patterns and Cost of Antihypertensives
323
Prescribing Patterns and Cost of Antihypertensive
Drugs in an Internal Medicine Clinic
R Jhaj, NK Goel, CS Gautam, D Hota, B Sangeeta, A Sood, A Sachdev
Departments of Pharmacology and Internal Medicine, Government Medical College, Chandigarh
Background: Antihypertensive agents are selected primarily for their ability to prevent morbidity and mortality
related to hypertension.
Methods and Results: Prescribing trends and the cost of antihypertensive drugs were studied in 300 patients
attending an internal medicine clinic. Beta-blockers were the most frequently used group of drugs (46.7%),
followed by calcium-channel antagonists (34.3%) and angiotensin-converting enzyme inhibitors (30%). Diuretics
were used in only 13.2% of the prescriptions. Atenolol (36%), amlodipine (29.3%) and enalapril (19%) were the
most frequently used individual drugs. Propranolol, furosemide, amlodipine and atenolol were the least expensive
drugs used, with annual drug acquisition costs of Rs 80, 102, 182 and 318, respectively. Benazepril (Rs 1778),
diltiazem SR (Rs 1777), lisinopril (Rs 1660), prazosin (Rs 1416) and losartan (Rs 1365) were the most expensive
drugs in terms of annual drug acquisition costs.
Conclusions: The results of our study emphasize the need to encourage frequent use of diuretics. Since the
costs of different antihypertensives vary considerably, newer and relatively expensive antihypertensives should
be prescribed only when clearly indicated. (Indian Heart J 2001; 53: 323–327)
Key Words: Hypertension, Cost–benefit analysis, Drugs
T
he primary goal of antihypertensive therapy is to
prevent morbidity and mortality related to
hypertension. Selection of antihypertensive agents should
therefore be based primarily on their comparative ability to
prevent these complications. Such an ability has been well
established for β-adrenergic blockers and diuretics.1–3
Although a reduction in adverse cardiovascular events has
also been reported recently with an angiotensin-converting
enzyme inhibitor (ACEI),4 further studies are necessary to
corroborate these findings. Over the last decade, there has
been a dramatic increase in the use of new
antihypertensives, i.e. ACEIs and calcium-channel
antagonists (CCA), without convincing evidence of their
ability to decrease cardiovascular morbidity and mortality
in hypertension.5,6 Earlier justifications for their widespread
use, which were based on their improved side-effect profile
and the possibility of a better quality of life, have not
withstood the test of large randomized studies. Several longterm, double-blind clinical trials have shown no consistent
Correspondence: Dr Ratinder Jhaj, Senior Lecturer, Department of
Pharmacology, Government Medical College, Chandigarh, India 160047
e-mail: [email protected]
IHJ-903-00.p65
323
differences in antihypertensive efficacy, side-effects and
quality of life within these four major classes of drugs.7–9
Moreover, some of the newer agents are more expensive
than β-blockers and diuretics, cost being an important
consideration for therapy of a chronic disease like
hypertension, often requiring lifelong medication.
In view of this apparent disparity between a rational
therapy for hypertension based on available scientific
evidence and what is actually prescribed, we studied the
pattern of use and cost of antihypertensive agents in the
internal medicine clinic of a teaching hospital.
Methods
The study was conducted in the internal medicine
outpatient department (OPD) of the Government Medical
College and Hospital, Chandigarh. From June to November
1999, prescriptions of patients with essential hypertension
were studied. Only prescriptions written by consultant
doctors were included, which were collected and
photocopied by team members from the internal medicine
OPD. Hypertension was defined and staged according to the
guidelines of the sixth report of the Joint National
8/16/01, 7:18 AM
Indian Heart J 2001; 53: 323–327
324 Jhaj et al. Prescribing Patterns and Cost of Antihypertensives
Committee on prevention, detection, evaluation, and
treatment of high blood pressure (JNC VI).10
The age and sex of patients, diagnosis (including
hypertension and other diseases) and drugs prescribed were
recorded. Brand names as well as generic names of
prescribed drugs were noted. Costs of drugs were obtained
from the Current Index of Medical Specialities (CIMS), Oct–
Dec 199911 and the Indian Pharmaceutical Guide 1999.12
Drug acquisition costs (cost of buying a drug) were
calculated, using the cost of the cheapest available
preparation and the most commonly prescribed dosage, for
each drug on a daily and annual basis. Total annual drug
expenditure (money spent on buying required doses of all
antihypertensives prescribed in the study population for a
year) was also calculated. Drug expenditure due to a single
drug was expressed as a percentage of total drug
expenditure, e.g. annual drug expenditure due to atenolol
was calculated as
Cost of daily treatment with atenolol×Number of prescriptions of atenolol×365
Total annual drug expenditure on antihypertensives
Results
Demographic profile of the study population: A total
of 300 prescriptions for essential hypertension were studied.
Out of these, 173 (57.7%) patients were newly diagnosed
hypertensives. Among the new cases, 45 patients had Stage
I, 76 had Stage II and 47 had Stage III hypertension. Five
patients had isolated systolic hypertension. The number of
men (51%) and women (49%) were nearly equal. The mean
age of both sexes was also nearly the same (53.4±12.7 years
for men and 51.8±11.6 years for women). A total of 99
(33%) patients had one or more concurrent disease which
could influence the choice of antihypertensives, including
coronary artery disease (18.7%), diabetes mellitus (DM)
(14.3%), bronchial asthma (2.7%), heart failure (2.7%) and
gout (1 patient).
Antihypertensives prescribed: Thirty-five (11.7%)
patients received no antihypertensive therapy. All of these
had Stage I hypertension and 27 (9%) were newly diagnosed
cases. Among the patients prescribed an antihypertensive,
the majority (58.7%) received a single drug, while 29.7%
patients were prescribed 2 or more drugs (counting a fixeddose combination [FDC] with 2 or more ingredients as 2 or
more drugs). The majority of the patients received singleingredient preparations, with only 27 (9%) receiving an
FDC.
Table 1 lists the drugs prescribed for hypertension in the
study population. Beta-blockers were the most commonly
IHJ-903-00.p65
324
prescribed drug group (46.7%, including FDCs), followed
by CCAs (34.3%) and ACEIs (30%). Diuretics were used in
only 13.2% of the patients, mostly as part of FDCs. Atenolol
(36%), amlodipine (29.3%) and enalapril (19%) were the
most frequently used β-blocker, CCA and ACEI, respectively.
Furosemide was the most commonly used diuretic. None
of the patients received a thiazide diuretic as a single agent—
thiazides were used only as part of FDCs. Of the 27
prescriptions which contained an FDC (Table 1), the
majority (10) were a combination of amlodipine and
atenolol or triamterene and benzthiazide (9). The remaining
FDCs contained combinations of other diuretics, CCA,
atenolol and lisinopril.
Various drug combinations were used (Table 2) for
treating 89 (29.7%) patients. Most of these (26% of total
patients) were on 2-drug combinations, while 3.3% of the
patients received 3-drug combinations. Only 1 patient was
prescribed 4 drugs. Thirty-five patients receiving ≥2 drugs
had coronary artery disease and/or heart failure. BetaTable 1. Drugs prescribed for essential hypertension in an
internal medicine clinic
Drug
Number of prescriptions
(n=300)
Single drugs
β-blockers
140
Atenolol
108
Metoprolol
21
Propranolol
7
Carvedilol
4
Calcium-channel antagonists
103
Amlodipine
88
Nifedipine SR
9
Diltiazem SR
6
ACE inhibitors
90
Enalapril
57
Lisinopril
15
Ramipril
14
Benazepril
4
Diuretics and others
48
Furosemide
16
Triamterene
10
Benzthiazide
9
Hydrochlorothiazide
1
Chlorthalidone
1
Indapamide
2
Amiloride
1
Prazosin
2
Losartan
6
Fixed-dose combinations
27
Triamterene+benzthiazide
9
Triamterene+furosemide
1
Amiloride+hydrochlorothiazide
1
Amlodipine+atenolol
10
Nifedipine+atenolol
3
Chlorthalidone+atenolol
1
Amlodipine+lisinopril
2
ACE: angiotensin-converting enzyme; SR: sustained release
8/16/01, 7:18 AM
Percentage
46.7
36.0
7.0
2.3
1.3
34.3
29.3
3.0
2.0
30.0
19.0
5.0
4.7
1.3
16.0
5.3
3.3
3.0
0.3
0.3
0.7
0.3
0.7
2.0
9.0
3.0
0.3
0.3
3.3
1.0
0.3
0.7
Indian Heart J 2001; 53: 323–327
Jhaj et al.
blocker with CCA (9.3%), β-blocker with ACEI (7.3%), and
CCA with ACEI (4.3%) were the most frequently used drug
combinations.
Drug treatment of newly diagnosed patients: Of the
173 (57.7%) newly diagnosed patients, 27 (15.6%) received
no antihypertensive drug, 106 (61.3%) received a single
drug while 40 (23.1%) received 2 drugs. Similar to the
overall pattern, a β-blocker was the most commonly used
drug in new cases (45.6%), followed by CCA (33.5%) and
ACEI (26.6%), with only 9.2% patients being given a
diuretic (Table 3). Of the 40 newly diagnosed cases receiving
more than 1 antihypertensive drug, 22 had either coronary
artery disease or heart failure, while 8 presented with Stage
III hypertension. The drug combinations used (not shown
in the table) were also similar to the overall pattern, i.e. βblocker with ACEI (6.4%), β-blocker with CCA (5.8%) and
CCA with ACEI (2.9%) were the commonly used
combinations. Thirty-four patients were on 2 drugs, while
6 patients were on 3 drugs.
Drug treatment of patients with hypertension and
diabetes mellitus: There were 43 patients with coexistent
hypertension and Type 2 DM. Only 1 patient had
diabetic nephropathy. Four patients were not on any
antihypertensive drug, 21 were on a single agent and 18
patients were receiving 2 or more drugs. Angiotensinconverting enzyme inhibitors (62.8% of patients with Type
2 DM) and CCAs (39.5%) were the most commonly used
Prescribing Patterns and Cost of Antihypertensives
drugs in this group of patients (Table 3). In 5 patients, ACEI
along with CCA was used. A β-blocker was used in 10
patients—1 patient received atenolol alone while 9 patients
received a β-blocker along with a CCA, ACEI or furosemide.
All these patients received β1-receptor selective β-blockers,
i.e. atenolol or metoprolol.
Drug treatment of patients with hypertension and
bronchial asthma: There were only 8 cases with
hypertension and asthma. Of these, 4 patients received a
CCA, 2 received an ACEI and 1 patient each received a
diuretic combination (triamterene+benzthiazide) alone or
with a CCA. No patient with bronchial asthma was
prescribed a β-blocker.
Cost of antihypertensive drugs: Daily and annual drug
acquisition costs of various antihypertensives are presented
in Table 4. Propranolol and furosemide were the least
expensive agents used, followed by amlodipine and atenolol.
Benazepril, diltiazem, lisinopril, prazosin and losartan were
the most expensive drugs, with the annual drug cost nearly
(or exceeding) 20 times that of propranolol.
A total of Rs 179 402 was spent in 1 year on drug
acquisition for 300 patients of hypertension in the clinic.
Table 3. Antihypertensives prescribed in newly diagnosed cases
and patients with concomitant diabetes mellitus
Drug group
Number of prescriptions
Percentage
New cases (n=173)
Table 2. Drugs combinations used in treatment of hypertension
Drug combinations*
Number of prescriptions
(n=300)
2-drug combinations
β-blocker+CCA
β-blocker+ACEI
β-blocker+diuretic
β-blocker+losartan
CCA+ACEI
CCA+diuretic
CCA+losartan
CCA+prazosin
ACEI+diuretic
Losartan+diuretic
K-sparing+loop/thiazide diuretic
3-drug combinations
β-blocker+2 diuretics**
CCA+2 diuretics**
ACEI+2 diuretics**
Diuretic+ACEI+α-blocker
CCA+ACEI+β-blocker
4-drug combinations
β-blocker+ACEI+2 diuretics**
78
28
22
2
1
13
1
2
1
4
1
3
10
4
3
1
1
1
1
1
Percentage
26
9.3
7.3
0.7
0.3
4.3
0.3
0.7
0.3
1.3
0.3
1.0
3.3
1.3
1.0
0.3
0.3
0.3
0.3
0.3
*including fixed-dose combination; **K-sparing+loop/thiazide diuretics; CCA:
calcium-channel antagonist; ACEI: angiotensin-converting enzyme inhibitor
IHJ-903-00.p65
325
325
Single drug
β-blocker
Calcium-channel antagonist
ACE inhibitor
Diuretic
Losartan
Fixed-dose combination
Amlodipine+atenolol
Amlodipine+lisinopril
Nifedipine+atenolol
Amiloride+hydrochlorothiazide
Furosemide+triamterene
79 (3 carvedilol)
58
46 (10 ramipril,
5 lisinopril,
2 benazepril)
16
4
45.6
33.5
26.6
9.2
2.3
2
2
1
1
1
1.2
1.2
0.6
0.6
0.6
27
17
10
4
3
1
62.8
39.5
23.2
9.3
7.0
2.3
1
1
2.3
2.3
Patients with DM (n=43)
Single drug
ACE inhibitor
Calcium-channel antagonist
β-blocker
Diuretic
Losartan
Prazosin
Fixed-dose combinations
Amlodipine+atenolol
Amlodipine+lisinopril
ACE: angiotensin-converting enzyme
8/16/01, 7:18 AM
Indian Heart J 2001; 53: 323–327
326 Jhaj et al. Prescribing Patterns and Cost of Antihypertensives
Table 4. Drug acquisition (daily and annual) costs of different
antihypertensives prescribed in the clinic
Drug/combination
Daily dose
Atenolol
50 mg o.d.
Metoprolol
50 mg b.d.
Propranolol
40 mg b.d.
Carvedilol
12.5 mg o.d.
Enalapril
5 mg o.d.
Ramipril
2.5 mg o.d.
Lisinopril
10 mg o.d.
Benazepril
10 mg o.d.
Amlodipine
5 mg o.d.
Nifedipine SR
20 mg b.d.
Diltiazem SR
90 mg b.d.
Furosemide
40 mg b.d.
Indapamide
1.25 mg o.d.
Losartan
50 mg o.d.
Prazosin
1 mg b.d.
Triamterene+benzthiazide
1 tab o.d.
Triamterene+furosemide
1 tab o.d.
Atenolol+amlodipine
1 tab o.d.
Atenolol+nifedipine SR
1 tab o.d.
Atenolol+hydrochlorothiazide
1 tab o.d.
Amiloride+chlorthalidone
1 tab o.d.
Amlodipine+lisinopril
1 tab o.d.
Drug acquisition cost
(Indian Rupees)
Per day
Per year
0.87
1.38
0.22
2.50
1.12
3.60
4.55
4.90
0.50
1.98
4.84
0.28
1.20
3.74
3.88
2.05
1.85
1.50
1.97
1.21
1.90
3.28
318
504
80
912
409
1314
1660
1778
182
723
1767
102
438
1365
1416
748
675
547
646
441
693
1197
Although β-blockers constituted 46.7% of the prescriptions,
they were responsible for only 24.9% of the total annual
drug expenditure. Similarly, CCAs made up 34.3% of the
prescriptions but only 16% of the expenditure. However,
ACEIs were advised in 30% of the prescriptions but were
responsible for 39.2% of the annual drug expenditure. Drug
expenditure due to diuretics was not calculated separately
since these were used mostly in FDCs.
Discussion
In India, hypertension (blood pressure >140/90 mmHg) is
present in 25%–30% of urban and 10%–15% of rural
adults13 while Stage II and high levels of hypertension
(>160/100 mmHg) are present in 12%–15% of urban and
5%–7% of rural adults. These figures increase with age and
prevalence rates of up to 51.8% have been reported in an
elderly Indian population.14 There is thus little doubt that
hypertension is no longer a disease of the developed world
alone. It is, therefore, important to lay stress on the optimal
management of hypertension by making the best use of the
drugs available to us.
In our study of 300 prescriptions for hypertension, we
observed that a majority (58.7%) contained a single
antihypertensive. Another 11.7% of the patients were
managed without drug treatment. Of the remaining 29.7%
who received combination therapy, 12.7% had concomitant
IHJ-903-00.p65
326
heart failure or coronary artery disease, which could be
additional indications for some of the drugs used for the
treatment of hypertension. Thus, only a small percentage
of patients were on combination therapy for the treatment
of hypertension alone, as compared to 49.2% of patients
receiving 2 or more drugs in a study reported by Lee et al.15
from Hong Kong.
The JNC VI 10 report states that in the absence of
compelling or specific indications for another drug, a
diuretic or β-blocker should be chosen as initial therapy for
hypertension. These recommendations are seconded by the
British Hypertension Society.16 Despite these guidelines,
diuretics were prescribed in only 13.2% of the prescriptions
in our clinic, compared to 24% in Hong Kong15 and 26.5%
in a study from Bangalore (South India).17 However, the use
of β-blockers (46.7% of the prescriptions) was only slightly
less than that reported from Hong Kong (51%) and much
higher than that reported from Bangalore (19%).
Angiotensin-converting enzyme inhibitors and CCAs
together made up 63.3% of the prescriptions. This
percentage was higher than expected from the number of
patients (33%) with concurrent diseases which are
indications for either of these drug groups or
contraindications for diuretics or β-blockers, i.e. Type 2 DM,
heart failure, coronary artery disease, bronchial asthma
and gout. This propensity to use ACEIs and CCAs is in
keeping with the trend of increasing use of these drugs,
accompanied by a decreasing utilization of β-blockers and
diuretics, even in developed countries.5,6
Some choices of individual drugs within the drug groups
used need comment. Although thiazide diuretics are
preferred over loop diuretics for hypertension, furosemide
was more commonly used (in 40% of diuretic prescriptions).
Of these, 4 patients had congestive heart failure which could
explain the use of furosemide. Fewer patients (27.5% of
diuretic prescriptions) received a thiazide diuretic, that too
only as an FDC.
The use of some newer drugs such as carvedilol, ramipril,
lisinopril and benazepril (in 40 patients of whom 20 were
newly diagnosed) which are much more expensive than the
prototypes (atenolol/enalapril) without significant clinical
advantage over them, 18 can probably be ascribed to
aggressive marketing of these agents, often combined with
the prescriber’s desire to keep up with the latest trends.
Similarly, losartan, which should be used only if an ACEI is
indicated but not tolerated,9 was used in 6 patients, 4 of
whom were newly diagnosed.
Beta-blockers are by and large not recommended in
DM,10 because of their possible adverse effects on glucose
metabolism. In fact, a recent large cohort study has reported
8/16/01, 7:18 AM
Indian Heart J 2001; 53: 323–327
Jhaj et al.
a 28% increase in the risk of DM in non-diabetic
hypertensives treated with β-blockers.19 On the other hand,
β-blockers have shown long-term protective effects against
cardiovascular disease in hypertensive patients, including
those with DM.20 In our study, β1-selective blockers were
prescribed in 10 (23.2%) patients with DM. We found that
β-blockers, though used in 46.7% of the patients, accounted
for only 24.9% of the annual drug expenditure because of
their low cost. Their low cost, in addition to proven efficacy,
cannot be ignored in a developing country like ours.
Calcium-channel antagonists also showed this favorable
picture (34.3% of prescriptions and 16% of drug
expenditure). Angiotensin-converting enzyme inhibitors,
on the other hand, accounted for 39.2% of drug expenditure
but were prescribed for only 30% of the patients. Drug costs
for diuretics could not be calculated separately since they
were used mostly as FDCs, but furosemide was one of the
least expensive single agents used.
Conclusions: In our study of drug prescribing patterns for
hypertension in an internal medicine clinic, we found that
most patients were being treated with single drugs.
Although β-blockers were the most frequently prescribed
antihypertensive agents, diuretics were prescribed sparingly.
Calcium-channel antagonists and ACEIs were prescribed for
a number of patients, many more than can be explained by
the presence of concurrent diseases which are either
indications for these drugs or contraindications for βblockers or diuretics. Newer and more expensive drugs, e.g.
benazepril, ramipril, carvedilol and losartan, were advised
in a significant number of prescriptions, which added to
the cost of drug treatment. Perhaps more serious
consideration of available scientific evidence should go into
writing a prescription for hypertension, especially in a
developing country, to avoid unnecessary and expensive
treatment.
Prescribing Patterns and Cost of Antihypertensives
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Acknowledgments
The authors wish to thank Dr Arvinderpal Singh, Dr Rishi
Kad, Dr Sanjeev Bhagat and Dr Spinder Gill for their
invaluable help in collecting data for this study.
18.
19.
References
1. Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester
PO. Morbidity and mortality in the Swedish Trial in Old Patients with
hypertension (STOP—Hypertension). Lancet 1991; 338: 1281–1285
2. SHEP Cooperative Research Group. Prevention of stroke by
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20.
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antihypertensive drug treatment in older persons with isolated
systolic hypertension: final results of the Systolic Hypertension in
the Elderly Program. JAMA 1991; 265: 3255–3264
Medical Research Council Working Party. MRC trial of treatment in
mild hypertension: principal results. Br Med J (Clin Res Ed) 1985;
291: 97–104
Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of
an angiotensin converting enzyme inhibitor, ramipril, on
cardiovascular events in high risk patients. N Engl J Med 2000; 342:
145–153
Manolio TA, Cutler JA, Furberg CD, Psaty BM, Whelton PK, Applegate
WB. Trends in pharmacological management of hypertension in the
United States. Arch Intern Med 1995; 155: 829–837
Seigel D, Lopez J. Trends in antihypertensive drug use in the United
States. Do the JNC V recommendations affect prescribing? JAMA
1997; 278: 1745–1748
The treatment of mild hypertension study. A randomized, placebocontrolled trial of a nutritional–hygienic regimen along with various
drug monotherapies. Arch Intern Med 1991; 151: 1413–1423
Grimm RH Jr, Grandits GA, Culter JA, Stewart AL, Mc Donald RH,
Svendsen K, et al. Relationships of quality-of-life measures to longterm lifestyle and drug treatment in the Treatment of Mild
Hypertension Study. Arch Intern Med 1997; 157: 638–648
Wassertheil-Smoller S, Blaufox D, Oberman A, Davis BR, Swencionis
C, Knerr MO, et al. Effect of antihypertensives on sexual function and
quality of life: the TAIM study. Ann Intern Med 1991; 114: 613–620
The Sixth Report of the Joint National Committee on prevention,
detection, evaluation and treatment of high blood pressure. Arch
Intern Med 1997; 157: 2413–2445
Current Index of Medical Specialities Volume 22; Bangalore: Bio-Gard
Private Limited, Oct–Dec 1999
Indian Pharmaceutical Guide 37th ed, New Delhi: PamPosh
Publication, 1999
Gupta R, al-Odat NA, Gupta VP. Hypertension epidemiology in India:
meta-analysis of fifty-year prevalence rates and blood pressure trends.
J Hum Hypertens 1996; 10: 465–472
Kalavathy MC, Thankappan KR, Sarma PS, Vasan RS. Prevalence,
awareness, treatment and control of hypertension in an elderly
community-based sample in Kerala, India. Natl Med J India 2000;
13: 9–15
Lee PK, Li RK, Chan JC, Chang S, Lee SG, Tomlinson B, et al. A
prescription survey in a hospital hypertension outpatient clinic. Br J
Clin Pharmacol 1997; 44: 577–582
Ramsay L, Williams B, Johnston G, MacGregor G, Poston L, Potten J,
et al. Guidelines for management of hypertension: report of the third
working party of the British Hypertension Society. J Hum Hypertens
1999; 13: 569–592
Xavier D, Rani N, Srishyla MV. Drug utilization study of
antihypertensives and anti-diabetics in an Indian referral hospital.
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Oates JA. Antihypertensive agents and drug therapy of hypertension
In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG
(eds). Goodman and Gilman’s The Pharmacological Basis of Therapeutics,
9th ed. New York: McGraw Hill 1996; pp. 780–808
Gress TW, Nieto, Shahar E, Wofford MR, Brancati FL Hypertension
and antihypertensive therapy as risk factors for type 2 diabetes
mellitus. Atherosclerosis Risk in Communities Study. N Engl J Med
2000; 342: 905–912
UK Prospective Diabetes Study group. Efficacy of atenolol and
captopril in reducing risk of macrovascular and microvascular
complications in type 2 diabetes: UKPDS 39. BMJ 1998; 317:
713–720
8/16/01, 7:19 AM
Original Article
Serous Fluid Leakage Following Modified Blalock–Taussig
Operation Using PTFE Grafts
Manoranjan Sahoo, Manoj Sahu, Shailaja Kale, Nita Saxena
Department of Cardiac Anaesthesia, Cardiothoracic Centre
All India Institute of Medical Sciences, New Delhi
Background: Serous fluid leakage is an unusual but often devastating complication following the placement of
a modified Blalock–Taussig shunt using a polytetrafluoroethylene graft.
Method and Results: Between September 1994 and September 1999, out of 268 patients undergoing a modified
Blalock–Taussig shunt using polytetrafluoroethylene grafts, 10 developed massive pleural effusion or seroma
due to a leak from the surface of the shunt. The age of the patients ranged from 9 days to 7 years. There were 7
males and 3 females. Nine patients presented with respiratory distress between 2 and 12 weeks of shunt surgery
and one presented with sudden cardiac arrest. The shunt was patent in all the patients. Initial management was
conservative, i.e. by pharmacological means and tube thoracostomy. Reoperation was undertaken in 9 patients
when conservative treatment failed. All patients survived except one who had a cardiac arrest before any
intervention could be carried out.
Conclusions: Patients with serous effusion have significant morbidity and mortality and often require
reoperation. The initial management remains conservative but, if unsuccessful, re-exploration can be undertaken
as it proved to be uniformly successful in our experience. (Indian Heart J 2001; 53: 328–331)
Key Words: Shunts, Congenital heart defects, Pleural effusion
F
luid ultrafiltration through a graft wall and the
formation of a perigraft seroma are phenomena
associated with several vascular bypass materials. Serous
leak was first recognized as a complication of
polytetrafluoroethylene (PTFE) tubular grafts used in
creating an arteriovenous fistula.1 Subsequently, it was
reported that this complication could also occur when PTFE
tubular grafts are used to create systemic–pulmonary artery
shunts (modified Blalock–Taussig [BT] shunt).2,3 The exact
etiology, frequency, severity, natural history and optimal
treatment remain uncertain.
This retrospective study describes 10 cases of excess
serous fluid leak through the PTFE tubular grafts used for
modified BT shunt and our experience in managing such
cases.
Methods
Between September 1994 and September 1999, 10 patients
who underwent a BT shunt were diagnosed to have massive
Correspondence: Dr Manoranjan Sahoo, Assistant Professor, Department
of Cardiac Anaesthesia, All India Institute of Medical Sciences, Ansari Nagar,
New Delhi 110029, e-mail: [email protected]
IHJ-860-00.p65
328
pleural effusion. The patients included 7 males and 3
females with ages ranging from 9 days to 7 years and had a
mean weight of 9.6 kg. During this period, 268 modified
BT operations were performed using PTFE grafts for a
variety of cyanotic congenital heart defects (Table 1). All
PTFE grafts were Gore-Tex vascular grafts (WL Gore &
Associates, Inc.) with an internal diameter of 4–6 mm.
Nine patients (#1–9, Table 1) presented with respiratory
distress between 2 and 12 weeks of shunt surgery and chest
X-ray showed signs of pleural effusion. A chest tube was
inserted in all the patients to drain the pleural fluid which
was found to be clear and acellular. Biochemical analysis
of the fluid was consistent with serum, but the total protein
and glucose contents were lower than the normal serum
values. Cultures for pathogenic organisms were negative in
repeated samples. A continuous murmur of the shunt flow
could be heard and Doppler echocardiographic evaluation
confirmed the patency of the shunt in all the patients. They
were treated with digitalis and diuretics, but a decision for
re-exploration was taken as there was continuous drainage
through the chest tube.
All patients were managed with either orotracheal or
nasotracheal general anesthesia, which was induced with
intravenous ketamine 1.5–2 mg/kg and vecuronium
8/16/01, 7:20 AM
Indian Heart J 2001; 53: 328–331
Sahoo et al. Serous Fluid Leakage Following BT Shunt 329
Table 1. Patient characteristics and treatment received
Patient
Age
Weight
(kg)
Sex
Congenital
defect(s)
Operation
(modified BT
shunt)
Treatment
#1
1 year
7
M
TA, PA, ASD, PDA
Right
Bidirectional Glenn
#2
5 years
14
F
TGV, PS, SV
Left
Topical thrombin
#3
3 years
10
F
SV, Common AV
Left
Topical fibrin glue
Right
Re-do PTFE graft
valve, PA, TAPVC
#4
1 month
3
M
Large VSD, PA
#5
3 months
6
M
TA
Right
Topical thrombin
#6
5 years
14
M
TA
Right
Topical fibrin glue
#7
7 years
20
M
TA, PA
Right
Topical thrombin
#8
3 years
9
F
TOF, RAA
Left
Topical fibrin glue
#9
4 years
10
M
TOF
Right
Total correction
#10
9 days
3.5
M
VSD, PA, RAA
Right
—
TA: tricuspid atresia; PA: pulmonary atresia; ASD: atrial septal defect; PDA: patent ductus arteriosus; TGV: transposition of great vessels; PS: pulmonary
stenosis; SV: single ventricle; TAPVC: total anomalous pulmonary venous connection; RAA: right aortic arch; TOF: tetralogy of Fallot; BT Shunt: Blalock–
Taussig shunt
Fig. 1. Chest X-ray showing large serous pleural effusion on the right side
0.1 mg/kg. An arterial line and a central venous cannula
were inserted in the nonshunted side. Maintenance
of anesthesia was achieved with O2 /N2O and isoflurane
0.6%–1%. Incremental morphine was given as an analgesic.
Induction of general anesthesia was well tolerated with
minimal changes in blood pressure and heart rate.
Dopamine (5–10 µg/kg/min) was administered for 1–2 days
as and when needed to maintain adequate cardiac output.
Each patient received broad spectrum antimicrobial drugs
IHJ-860-00.p65
329
from pre-incision till the thoracic catheter was removed.
Re-exploration confirmed the diagnosis of a perigraft
serous effusion. There were no lymphatic leaks or distended
lymphatic vessels. The shunt was found to be patent in all
the patients. The seroma was cleared away. It was dull grey,
semi-translucent and oozed continuously. Out of 9 patients,
topical thrombin was used in 3 patients and in 3 other
patients topical fibrin glue was used.
One patient (#4, Table 1), who had received a 5 mm graft
earlier, also showed features of congestive heart failure due
to overshunting. The 5 mm graft was replaced with a 4 mm
graft, though this had nothing to do with the management
of the seroma. Two patients underwent open reparative
surgery (#1 and 9, Table 1). Patient #1, who underwent a
right-sided BT shunt for tricuspid atresia with pulmonary
atresia, was readmitted with respiratory distress 2 weeks
after he was discharged. Pharmacological management and
tube thoracostomy failed to reduce the pleural effusion/
seroma, hence, a decision for reoperation was made. A
bidirectional Glenn along with PDA ligation and takedown
of the BT shunt was performed. Another patient (#9), in
whom a BT shunt was performed for severe cyanotic spells,
was readmitted with resistant pleural effusion 4 weeks after
he was discharged. Considering the suitable morphology,
total correction of tetralogy of Fallot was undertaken. In
all these patients, recovery after reoperation was uneventful,
and the patients were discharged after 10–14 days.
In addition to these 9 patients, one patient (#10, Table 1),
who had undergone a BT shunt, developed sudden cardiac
arrest on day 9 postoperatively. The cause was cardiac
8/16/01, 7:20 AM
Indian Heart J 2001; 53: 328–331
330 Sahoo et al. Serous Fluid Leakage Following BT Shunt
tamponade due to persistent and massive leakage from the
shunt.
Discussion
In spite of a trend towards early corrective surgery for
infants and small children with complex cyanotic congenital
heart diseases,4 systemic-to-pulmonary artery shunts
continue to be necessary for initial palliation. Excessive
serous fluid leakage constitutes a rare complication
following the insertion of a vascular prosthesis. LeBlanc et
al.2 reported this complication after a modified PTFE BT
shunt. The incidence of this complication in the setting of
PTFE aortopulmonary shunt is unclear.
We performed 268 BT shunts using PTFE tubular grafts
between September 1994 and September 1999. Ten
patients (3.7%) required reoperation for persistent serous
leakage. Maitland et al.5 and Noyez et al.6 had a reoperation
rate of 2.3% and 2.5%, respectively. In a previous study by
LeBlanc et al.2, serous fluid complications occured in 20%
of the patients. Leakage may occur as soon as the prosthesis
has been implanted.3 In our series, presentation of serous
leakage occurred between 2 and 12 weeks after the initial
shunt procedure. According to another study, patients who
underwent reoperation did so within 90 days of the initial
operation.1
The mechanism of this leakage is unknown. Plasma
leakage may occur due to wetting the graft with organic
solvents such as antiseptics, excessive manipulation with
blood, an initial high blood flow through the graft or forcing
irrigating solutions through the wall. Despite avoiding these
factors, we have encountered several patients in whom
excessive leakage of serous fluid persisted for several days
following graft insertion. It is difficult to evaluate the
incidence of serous fluid leakage in the patient population
under study. Persistent serous leak is usually managed
adequately by thoracocentesis5 but in our experience it did
not prove to be sufficient. However, when drainage does not
diminish, reoperation is indicated.
All patients with a serous leak presented with marked
respiratory distress. One patient (#10, Table 1) had a cardiac
arrest due to tamponade following a massive pleural
effusion. Large pleural effusions clearly impair gas exchange
and attenuate cardiac output. Recent findings suggest that
effusions can impair right ventricular relaxation, 7–9
effectively resulting in a state of “thoracic tamponade”.
However, the mechanisms of impairment of gas exchange
are incompletely understood. One of the reports10 suggests
that improvement in lung mechanics and oxygenation
occur after aspiration of unilateral pleural effusion in
IHJ-860-00.p65
330
humans. The current recommendation is that a large
pleural effusion should be drained before induction of
anesthesia11–13 because it can restrict lung expansion11 and
drainage will enhance ventilation,12 whereas others13
suggest that drainage of pleural effusion should be done a
day before the operation to avoid re-expansion pulmonary
edema. However, this was not the problem with our patients
as they had already undergone pleural drainage for a
prolonged period.
Induction of general anesthesia was achieved with
careful titration of intravenous agents. Volatile anesthetics
are known to inhibit hypoxic pulmonary vasoconstriction
(HPV), which in turn impairs oxygenation. Isoflurane was
used during maintenance as, among all the volatile
anesthetics, it causes the least inhibition of HPV. Chest Xrays were taken daily to ensure lung expansion and to check
for any pneumothorax or residual effusion.
Postoperative serous ultrafiltration through the graft
wall has been successfully treated by evacuating seroma
from around the graft,14,15 replacing the graft with the same
or another type of graft,5 replacing the graft material at the
ultrafiltration site, drainage of perigraft fluid,16 using fibrin
glue and topical thrombin to “preclot” the graft in situ2,5,6
and, finally, monitoring the patient closely over a period of
time.2,16 We also had good results with combinations of
these techniques.
Conclusions: We conclude that serous fluid leakage is an
unusual but often devastating complication of a modified
BT shunt using a PTFE graft. Patients with serous effusion
have significant morbidity and mortality and often require
reoperation. As these patients present late after being
discharged, they should undergo frequent chest X-rays so
that the effusion can be diagnosed at the earliest. The initial
management remains conservative but, if this is not
successful, one should not hesitate to carry out reexploration, as it proved to be uniformly successful in our
experience.
References
1. Bolton W, Cannon JA. Seroma formation associated with PTFE
vascular grafts used as arteriovenous fistulae. Dial Transplant 1981;
10: 60–66
2. LeBlanc J, Albus R, Williams WG, Moes CA, Wilson G, Freedom RM,
et al. Serous fluid leakage: a complication following the modified
Blalock–Taussig shunt. J Thorac Cardiovasc Surg 1984; 88: 259–262
3. Damus PS. Seroma formation after implantation of Gore-Tex vascular
grafts in cyanotic children. J Thorac Cardiovasc Surg 1984; 88:
310–311
4. Jennings RB, Innes BJ, Brickman RD. Use of microporous expanded
polytetrafluoroethylene grafts for aorta–pulmonary shunts in infants
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76: 489–494
8/16/01, 7:20 AM
Indian Heart J 2001; 53: 328–331
5. Maitland A, Williams WG, Coles JG, Freedom RM, Trusler GA. A
method of treating serous fluid leak from a polytetrafluoroethylene
Blalock–Taussig shunt. J Thorac Cardiovasc Surg 1985; 90: 791–793
6. Noyez L, Daenen W. The modified polytetrafluoroethylene Blalock–
Taussig shunt: case report of an unusual complication. J Thorac
Cardiovasc Surg 1987; 94: 634–635
7. Vaska K, Wann LS, Sagar K, Klopfenstein HS. Pleural effusion as a
cause of right ventricular diastolic collapse. Circulation 1992; 86:
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ventricular diastolic collapse without hemodynamic compromise in
a patient with large, bilateral pleural effusions. J Am Soc Echocardiogr
1995; 8: 551–553
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echocardiographic and hemodynamic evidence of cardiac
tamponade caused by large pleural effusions. Am J Respir Crit Care
Med 1995; 151: 904–908
10. Wang JS, Tseng CH. Changes in pulmonary mechanics and gas
exchange after thoracocentesis on patients with inversion of a
IHJ-860-00.p65
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Sahoo et al. Serous Fluid Leakage Following BT Shunt 331
11.
12.
13.
14.
15.
16.
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8/16/01, 7:20 AM
Original
332 GuptaArticle
et al. Lipid Abnormalities in Coronary Heart Disease
Indian Heart J 2001; 53: 332–336
Lipid Abnormalities in Coronary Heart Disease:
A Population-based Case–Control Study
Rajeev Gupta, Vijay Kaul, H Prakash, Mukesh Sarna, Shalini Singhal, VP Gupta
Departments of Medicine and Pathology, Monilek Hospital and Research Centre, Jaipur and
Departments of Medicine and Biostatistics, Mahatma Gandhi National Institute of Medical Sciences, Jaipur
Background: We performed a case–control study to estimate lipid–cholesterol fractions in patients with coronary
heart disease and compared them with population-based controls.
Methods and Results: A total of 635 newly diagnosed patients with coronary heart disease (518 males and
117 females) and 632 subjects (346 males and 286 females) obtained from an ongoing urban coronary heart
disease risk factor epidemiological study were evaluated. Age-specific lipid values (total cholesterol, low-density
lipoprotein, high-density lipoprotein, triglycerides, and total:high-density lipoprotein cholesterol ratio) were
compared using the t-test. Age-adjusted prevalence of dyslipidemia as defined by the US National Cholesterol
Education Program was compared using the Chi-square test. In all the age groups, and in both males and
females, levels of total and low-density lipoprotein cholesterol were not significantly different. In males, the
high-density lipoprotein cholesterol (mg/dl) was significantly lower in patients with coronary heart disease as
compared to controls in the age groups 30–39 years (35.1±11v. 43.7±9), 40–49 years (39.0±10 v. 47.1±8),
50–59 years (38.9±11 v. 43.8±9) and 60–69 years (38.6±11, v. 42.8±7) (p<0.05). In females, high-density
lipoprotein cholesterol was less in the age groups 30–39 years (30.2±9 v. 40.7±9), 50–59 years (39.7±12 v.
44.7±8) and 60–69 years (35.6±11 v. 42.2±9). The level of triglycerides was significantly higher in male patients
in the age groups 40–49 years (195.3±96 v. 152.8±78), 50–59 years (176.7±76 v. 162.9±97), 60–69 years
(175.5±93 v. 148.1±65) and >70 years (159.8±62 v. 100.0±22); and in female patients in the age group 30–
39 years (170.8±20 v. 149.9±9) (p<0.05). The total:high-density lipoprotein cholesterol ratio was significantly
higher in all age groups in male as well as female patients with coronary heart disease (p<0.05).
Conclusions: An age-adjusted case–control comparison showed that the prevalence of hypertension, diabetes,
high total cholesterol (>200 mg/dl) (males 48.8% v. 20.2%; females 59.8% v. 33.4%) and high low-density
lipoprotein cholesterol (>130 mg/dl) (males 42.1% v. 15.0%; females 52.1% v. 31.0%) was significantly more in
cases than in controls. The prevalence of low high-density lipoprotein cholesterol (<35 mg/dl) (males 39.6% v.
6.2%; females 39.3% v. 9.5%), high total:high-density lipoprotein ratio (>5.0) and high triglycerides (>200 mg/
dl: males 39.6% v. 10.2%; females 17.1% v. 11.9%) was also significantly higher in cases (p<0.05). (Indian
Heart J 2001; 53: 332–336)
Key Words: Lipids, Coronary disease, Population
S
tudies among emigrant Indians have reported a very
high incidence of and mortality from coronary heart
disease (CHD).1,2 Risk factor studies have shown that these
subjects have a unique dyslipidemia characterized by
normal to borderline-high levels of low-density lipoprotein
(LDL)-cholesterol, raised triglycerides, low high-density
lipoprotein (HDL)-cholesterol and higher small-dense LDL
Correspondence: Dr Rajeev Gupta, 16 Hospital Road, C-Scheme,
Jaipur 302001
IHJ-105-01.p65
332
particles. 1–4 Insulin resistance and increased serum
lipoprotein(a) have been reported to be other important CHD
risk factors.2,4 A high prevalence of abnormalities of
coagulation and platelet functions have also been reported
in some studies.5
Conversely, studies within India have shown that on
case–control comparison, there is a higher prevalence of
smoking, sedentary lifestyle, hypertension and
hypercholesterolemia in patients with CHD.6–14 Higher levels
of total- and LDL-cholesterol and triglycerides, and lower
8/16/01, 7:21 AM
Indian Heart J 2001; 53: 332–336
Gupta et al.
levels of HDL-cholesterol have also been reported.7,9,11,13
Epidemiological studies within India have shown that in
urban subjects, who show a three-fold greater prevalence
of CHD compared to rural subjects, levels of total- and LDLcholesterol and triglycerides are higher while there is no
significant difference in HDL-cholesterol levels.14,15 Most of
the CHD case–control studies within India have been
performed in tertiary-care hospitals and used hospital-based
controls. These subjects are neither appropriate cases nor
controls, as has been commented upon previously.16 To
remove this possible bias, we performed a case–control
comparison of lipid levels using cases presenting to a
charitable hospital and population-based controls obtained
from an ongoing epidemiological study.
Methods
Successive patients presenting to this charitable hospital
between 1997 and 1999 were enrolled in the study. These
patients were all newly diagnosed as having CHD according
to the criteria reported previously 17 and were either
survivors of a recent myocardial infarction (>28 days old)
or had classical angina pectoris confirmed either by a
positive stress test or coronary angiogram. Of the 750
patients seen during this period, 635 (84.7%) patients with
CHD (518 males and 117 females) were found to be eligible.
History of risk factors such as smoking, hypertension and
diabetes was obtained and fasting blood glucose and lipid
levels were determined. The methodology of determination
and standardization of lipid levels has been described in
earlier studies.18
Controls were obtained from an ongoing populationbased epidemiological study in Jaipur. The recruitment
strategy was similar to that reported in a previous study.19
In brief, individuals from randomly selected locations
(municipal wards) in the city were recruited using the
stratified random sampling technique. Population
proportionate adults >20 years of age according to the
voters’ lists were examined by a house-to-house survey in
these locations. In each location, 500 subjects were
contacted for examination. Subjects in two of the six
locations that have been covered so far have been included
in the present study. History of coronary risk factors was
obtained and a physical examination and fasting blood
analysis for lipids and glucose was performed. Serum lipid
levels in 632 of the 1000 eligible subjects (345 males and
286 females) were available (response rate 63.2%).
Statistical analysis: Numerical variables are reported as
mean ±1SD. Case–control comparison was performed using
IHJ-105-01.p65
333
Lipid Abnormalities in Coronary Heart Disease 333
the Chi-square test for categorical variables and unpaired
t-test for continuous variables. Comparison in lipid levels
at various age groups was done using the t-test. Age
distribution was significant in both the patient and control
populations, hence an age-adjusted comparsion was
performed after matching controls with cases using
the indirect method of age-standardization as described
by Rao and Richards.20 A p value of <0.05 was considered
significant.
Results
We studied 635 cases (518 males and 117 females) and
632 controls (346 males and 286 females) within an age
range of 20–75 years. Age-group distribution and
cholesterol, lipoprotein and triglyceride values are shown
in Table 1. In all the age groups, and in both males and
females, the levels of total- and LDL-cholesterol were not
significantly different, although there was a trend towards
higher LDL-cholesterol in cases.
In males, the level of HDL-cholesterol (mg/dl) was
significantly lower in patients with CHD compared to
controls in the age groups 30–39 years (35.1±11 v.
43.7±9), 40–49 years (39.0±10 v. 47.1±8), 50–59 years
(38.9±11 v. 43.8±9) and 60–69 years (38.6±11 v.
42.8±7), (p<0.05). In females, HDL-cholesterol was less in
the age groups 30–39 years (30.2±9 v. 40.7±9), 50–59
years (39.7±12 v. 44.7±8) and 60–69 years (35.6±11 v.
42.2±9). The level of triglycerides was significantly higher
in male patients in the age groups 40–49 years (195.3±96
v. 152.8±78), 50–59 years (176.7±76 v. 162.9±97), 60–
69 years (175.5±93 v. 148.1±65) and >70 years
(159.8±62 v. 100.0±22); and in female patients at 30–39
years (170.8±20 v. 149.9±9) (p<0.05). Total:HDLcholesterol ratio was significantly higher in all age groups
in male as well as female patients with CHD (p<0.05).
Age-adjusted case–control comparison of risk factors
(Table 2) showed that prevalence of smoking (current or
previous tobacco use) was similar in cases as compared with
controls in both males (24.3% v. 21.2%) and females (2.6%
v. 10.6%). The prevalence of hypertension either in known
hypertensives on drug therapy or patients with a current
blood pressure >140 mmHg systolic and/or >90 mmHg
diastolic on repeated measurements, as well as prevalence
of diabetes, were significantly higher in cases than in
controls.
In cases as compared to controls, the prevalence of high
total cholesterol (>200 mg/dl) (males 48.8% v. 20.2%;
females 59.8% v. 33.4%), high LDL-cholesterol (>130 mg/
dl) (males 42.1% v. 15.0%; females 52.1% v. 31.0%), and
8/16/01, 7:21 AM
Indian Heart J 2001; 53: 332–336
334 Gupta et al. Lipid Abnormalities in Coronary Heart Disease
Table 1. Cholesterol and other lipids in cases and controls
Males
Cases
No.
(346)
Controls
No.
(117)
Females
Cases
No.
(286)
Age
(in years)
Lipids
No.
(518)
Controls
<30
CHOL
LDL
HDL
TG
CHOL/HDL
5
163.0±16
89.9±6
42.6±12
152.4±110
4.24±1.8
65
189.3±39
119.4±35
42.5±9
137.1±64
4.66±1.5
—
—
53
187.7±33
121.7±33
41.8±9
121.0±44
4.69±1.3
30–39
CHOL
LDL
HDL
TG
CHOL/HDL
29
188.9±35
116.2±32
35.1±11*
187.8±97
5.82±1.7*
104
201.8±41
125.5±34
43.7±9.3
162.8±101
4.82±1.5
5
200.4±25
136.2±33
30.2±9*
170.8±20*
7.41±3.6*
66
198.3±40
127.7±35
40.7±9
149.9±9
5.10±1.6
40–49
CHOL
LDL
HDL
TG
CHOL/HDL
118
211.4±49
133.4±41*
39.0±10*
195.3±96*
5.70±1.7*
180
202.2±38
123.1±31
47.1±8
152.8±78
4.35±1.0
34
207.6±56
131.7±54
44.9±13
155.3±56
5.20±2.6*
65
204.5±40
131.7±35
42.1±9
153.5±79
5.03±1.3
50–59
CHOL
LDL
HDL
TG
CHOL/HDL
163
200.6±40
126.8±45
38.9±11*
176.7±76*
5.53±1.8*
41
199.6±38
123.2±35
43.8±9
162.9±97
4.76±1.5
58
207.6±36
137.7±36
39.7±12*
150.9±58
5.70±2.0*
61
223.7±39
145.1±40
44.7±8
169.1±70
5.21±1.5
60–69
CHOL
LDL
HDL
TG
CHOL/HDL
189
200.5±50
126.8±45
38.6±11*
175.5±93*
5.59±2.1*
16
189.5±36
117.1±32
42.8±7
148.1±65
4.53±1.1
16
191.9±28*
122.1±25*
35.6±11*
170.8±44
5.68±1.3
32
219.8±36
145.4±37
42.2±9
161.5±55
5.48±1.6
>70
CHOL
LDL
HDL
TG
CHOL/HDL
14
204.1±27*
130.5±19*
41.6±13*
159.8±62*
5.16±1.0*
5
175.2±20
110.0±15
45.2±9
100.0±22
3.95±0.6
4
192.5±9*
110.0±10*
48.0±2
122.5±20
4.32±0.1*
9
219.0±37
145.6±37
41.8±13
158.0±68
5.67±2.0
CHOL: cholesterol; LDL: low-density lipoprotein cholesterol; HDL: high-density lipoprotein cholesterol; TG: triglycerides
All the values are in mg/dl with ±1SD No.: number of cases/controls
*p <0.05
low HDL-cholesterol (<35 mg/dl) (males 39.6% v. 6.2%;
females 39.3% v. 9.5%) was significantly higher (p<0.01).
High total:HDL-cholesterol ratio (>5.0) was significantly
higher in both males (56.9% v. 10.4%) and females (51.3%
v. 16.7%) (p>0.01). The prevalence of borderline-high
triglycerides (150–199 mg/dl: males 53.9% v. 9.1%; females
37.6% v. 8.8%) as well as high triglycerides (>200 mg/dl:
males 39.6% v. 10.2%; females 17.1% v. 11.9%) was also
significantly higher in cases (p<0.05) as compared to
controls.
Discussion
This case–control study shows that low HDL-cholesterol,
high total:HDL-cholesterol and high triglyceride levels,
IHJ-105-01.p65
334
apart from high total- and LDL-cholesterol, are important
lipid abnormalities in Indian patients with CHD. These lipid
abnormalities are similar to those reported in emigrant
Indians in Britain1,4 and the USA.2,3
Case–control studies within India have reported high
total- and LDL-cholesterol and triglyceride levels in patients
suffering from CHD,6–9, 11–13 while low HDL-cholesterol was
reported in only a few studies. Kumar et al. 6 from
Chandigarh, Misra et al.7 from Madras, Wasir et al.8, Vashist
et al.9 and Bahl et al.12 from Delhi, Sahi et al.11 from Bombay
and Krishnaswamy13 from Vellore reported that total
cholesterol levels were 20%–40% more in patients with
CHD compared to hospital-based controls (p<0.05). Vashist
et al.9 from Delhi studied 702 clinically documented CHD
cases and 186 normal healthy controls and reported that
8/16/01, 7:21 AM
Indian Heart J 2001; 53: 332–336
Gupta et al.
Table 2. Age-adjusted coronary risk factor prevalence
Males
Cases
(n=518)
Controls
(n=346)
Females
Cases
(n=117)
Controls
(n=286)
Smoking
(current/previous)
126 (24.3)* 73 (21.2)
3 (2.6)* 30 (10.6)
Hypertension
(past diagnosis or
BP >140/90 mmHg)
176 (34.0)* 43 (12.4) 35 (29.9)* 41 (14.3)
Diabetes (past
diagnosis or fasting
glucose >126 mg/dl)
104 (20.1)*
Cholesterol
(>200 mg/dl)
253 (48.8)* 70 (20.2) 70 (59.8)* 95 (33.4)
11 (3.1) 29 (24.8)* 14 (4.8)
LDL-cholesterol
100–129 mg/dl
>130 mg/dl
166 (32.0)* 52 (15.0) 30 (25.6)* 36 (12.7)
218 (42.1)* 52 (15.0) 61 (52.1)* 89 (31.0)
HDL-cholesterol
<35 mg/dl
Total:HDL >5.0
205 (39.6)* 21 (6.2) 46 (39.3)* 27 (9.5)
295 (56.9)* 36 (10.4) 60 (51.3)* 48 (16.7)
Triglycerides
150–199 mg/dl
>200 mg/dl
279 (53.9)* 31 (9.1) 44 (37.6)* 25 (8.8)
205 (39.6)* 35 (10.2) 20 (17.1)) 34 (11.9)
Numbers in parentheses are percentages
* significant difference p<0.05
total- and LDL-cholesterol, LDL/HDL ratio and triglyceride
levels were significantly higher in CHD cases while HDLcholesterol was not different. Sahi et al.11 additionally
reported low HDL-cholesterol along with higher
apolipoprotein-B levels in cases.
On the other hand, Pais et al.10 studied 200 patients with
acute myocardial infarction and compared coronary risk
factors with 200 hospital-based controls and reported no
difference in total-, LDL- and HDL-cholesterol, and
total:HDL-cholesterol ratio as well as triglyceride levels. In
angiographic studies, no significant correlation of
cholesterol levels with angiographic disease was seen.8,12
All these studies were performed in tertiary-care hospitals
where only patients suffering from advanced disease are
seen. The socio-economic characteristics of these patients
are also different from those seen in primary care centres.16
Many of these patients are diagnosed elsewhere and follow
a modified lifestyle or drug therapy which influence lipid
levels and, hence, are not representative. Controls in these
studies were also hospital-based patients collected from
other wards and hence biased. In the present study, cases
were recently diagnosed and treated only in a primary care
charitable hospital and controls were taken from a
population-based survey; thus, some biases were eliminated.
Age-adjusted prevalence of smoking was similar in male
cases and controls. The absolute number of smokers in
female cases was low and thus not comparable with
IHJ-105-01.p65
335
Lipid Abnormalities in Coronary Heart Disease 335
controls. Prevalence of hypertension and diabetes was
significantly higher in both male and female cases. Unlike
some recent Indian10 and international studies,1,4 we found
that lipid profile abnormalities in Indian patients with CHD
are similar to many other ethnic groups characterized by
mixed dyslipidemia (increased levels of LDL and triglycerides
and low HDL). A high prevalence of diabetes in cases with
CHD explains the diabetic dyslipidemia characterized by low
HDL and high triglycerides.21 Diabetes is a major risk factor
in emigrant Indians with CHD1, 2, 4 and this study highlights
its importance. One drawback of the present study is that
we did not measure small-dense LDL which is an important
lipid abnormality in Asian Indians settled in the USA.22
Studies have reported increasing total- and LDLcholesterol and triglyceride levels in Indian urban subjects,
associated with increasing prevalence of CHD.23–25 Dietary
and lifestyle-related coronary risk factors could thus be
important in accelerating the CHD epidemic in India23,25 but
more studies are needed. The importance of LDLcholesterol, total:HDL-cholesterol ratio, triglycerides, HDLcholesterol and small-dense LDL particles should be
confirmed by well-designed Indian prospective studies.
References
1. Williams B. Westernised Asians and cardiovascular disease: nature
or nurture? Lancet 1995; 345: 401–402
2. Enas EA, Mehta JL. Malignant coronary artery disease in young Asian
Indians: thoughts on pathogenesis, prevention and therapy. Clin
Cardiol 1995; 18: 131–135
3. Enas EA, Garg A, Davidson MA, Nair VM, Heut BA, Yusuf S. Coronary
heart disease and its risk factors in first-generation immigrant Asian
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4. Bhatnagar D, Anand IS, Durrington PN, Patel DJ, Wander GS,
Mackness MI, et al. Coronary risk factors in people from the Indian
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1995; 345: 405–409
5. Markovitz H, Kulkarni K, Goldschmidt-Clermont P, Kiefe CI, Rustagi
P, Sekar P, et al. Increased platelet activation and fibrinogen in Asian
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6. Kumar M, Chakravarti RN, Singh A, Wahi PL. Serum lipid profiles in
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7. Misra KP, Suresh S, Balachandran G, Reddy KN, Rao PM,
Radhakrishnan T, et al. Plasma lipoprotein cholesterol and coronary
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11. Sahi N, Pahlajani DB, Sainani GS. Apolipoproteins A-1 and B as
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Gupta R, Gupta KD. Total cholesterol and mortality in patients with
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Gupta et al.
Brief
Report
Transcatheter Fenestration of a TCPC
Baffle
337
Transcatheter Fenestration of a Total
Cavopulmonary Connection Baffle
Anoop K Gupta, AV Ganesh, Bhavesh U Vajifdar, Alok Maheshwari,
Jagdish M Khandeparkar, Prafulla G Kerkar
Departments of Cardiology and Cardiothoracic Surgery, KEM Hospital, Mumbai
Transcatheter creation of a de novo fenestration of a total cavopulmonary connection baffle has not been
previously reported from India. We present our experience with such a procedure in a 4-year-old child with
recurrent pleural effusions in the early postoperative period. (Indian Heart J 2001; 53: 337–339)
Key Words: Congenital heart defects, Surgery, Balloon
S
urgical management of patients with cardiac
malformations characterized by a functionally single
ventricle is based upon the concept that systemic venous
blood can be made to pass through healthy mature lungs
without the assistance of a ventricular pump.1 The staging
of univentricular repair has been associated with a
significant reduction in perioperative mortality and
morbidity.2 Introducing a right-to-left shunt at the atrial
level by the creation of a fenestration3 or adjustable atrial
septal defect (ASD)4 preserves cardiac output and oxygen
delivery despite some degree of systemic arterial
desaturation. We report a case of postoperative recurrent
pleural effusion after total cavopulmonary connection
(TCPC), in which transcatheter TCPC baffle fenestration was
carried out to reduce venous congestion.
Case Report
A cardiac murmur was detected at birth in a 4-year-old boy
weighing 12 kg. He had cyanosis since the age of two years
(no cyanotic spells) with recurrent lower respiratory tract
infection not requiring hospitalization. A color Doppler
study done at that time showed transposition of the great
arteries with a large, nonrestrictive, sub-pulmonic
ventricular septal defect (VSD) and severe valvar pulmonary
stenosis (PS) (peak systolic gradient [PSG] 87 mmHg).
Cardiac catheterization performed prior to intracardiac
repair revealed equalization of the systolic pressures in the
left ventricle (LV) and right ventricle (RV) (110 mmHg). The
RV and LV end-diastolic pressures (EDP) were 8 mmHg and
6 mmHg, respectively, and the pulmonary venous wedge
Correspondence: Professor Prafulla G Kerkar, Department of Cardiology,
KEM Hospital, Mumbai 400012. e-mail: [email protected]
IHJ-117-01.p65
337
pressure was 32/17 mmHg with a mean of 24 mmHg (the
pulmonary artery could not be entered). There was no
pressure gradient between the left and right atria.
Angiography confirmed the findings of the color Doppler
study. In addition, the pulmonary arteries were confluent
and not distorted. The sizes of the right and left pulmonary
arteries were 9 mm and 8 mm, respectively. Basal saturation
of the ascending aorta was 79% at the time of
catheterization.
Though the patient was suitable for a biventricular
repair, our surgeons decided to perform TCPC with a
pericardial baffle due to the inherent problems of conduits
in this age group (i.e. nonavailability of conduit, need for
replacement at a later date and complexity of surgery). A
lateral tunnel, which was not fenestrated, was created with
a pericardial patch. The ASD was left untouched during the
procedure. The surgery was uneventful and the child
recovered from bypass after TCPC. The immediate postbypass central venous pressure was 12 cm of water. The
child had repeatedly accumulating, large (500 ml per day)
bilateral pleural effusion which was treated by chest tube
drainage. The large amount of the effusion resulted in
hypoproteinemia (total protein 3.6 g%, albumin 1.6 g%)
with progressive edema of the feet, despite vigorous diuretic
therapy. In view of a high lymphocyte count and protein
content in the pleural fluid, the child was put on
antitubercular therapy (ATT). However, despite ATT, the
pleural effusion persisted.
On examination, the patient had a heart rate of 110
beats/min, BP of 100/70 mmHg, grade 3/4 clubbing, mildly
dusky appearance and generalized edema, with an ejection
systolic murmur (Grade III/VI) at the left parasternal border
and bilateral pleural effusion. The hemoglobin was 13.7g%
8/16/01, 7:22 AM
338 Gupta et al.
with an oxygen saturation of 95%. Chest X-ray showed a
cardiothoracic ratio of 55% with pulmonary venous
congestion and moderate bilateral pleural effusion. A
transthoracic echocardiogram showed a dilated and
congested inferior vena cava (IVC) suggestive of high venous
pressure; there was no obstruction between the baffle and
the pulmonary artery. A provisional diagnosis of
postoperative high intra-atrial baffle pressure with systemic
venous congestion was made, which was refractory to
medical (diuretic) therapy.
Three weeks postoperatively, cardiac catheterization was
performed to assess the hemodynamics of the pulmonary
artery and pericardial baffle. A raised pericardial baffle and
IVC pressure (mean pressure 24 mmHg) but normal
pulmonary artery pressure (mean pressure 22 mmHg) were
recorded. There was no pull-back gradient from the
pulmonary artery to the pericardial baffle. The left
ventricular EDP was 8 mmHg at the time of catheterization.
Pericardial baffle angiography (Fig. 1) through the IVC
showed opacification of the baffle and pulmonary arteries
with no narrowing or obstruction.
In view of raised intra-baffle pressure, fenestration of
the pericardial baffle was planned. The baffle was punctured
with a Brockenbrough trans-septal needle which was passed
into the left atrium. A double length 0.021 guidewire was
exchanged over a Mullin’s dilator and kept in the left
superior pulmonary vein. Serial dilatation of the pericardial
baffle (up to 15 mm) was done using a Tyshak II balloon
over the guidewire (Fig. 2). After balloon dilatation, there
was a significant reduction in the elevated intrapericardial
baffle and IVC pressure (mean pressure 10 mmHg); there
Fig. 1. Pericardial baffle angiogram in PA view, showing opacification of the
pericardial baffle and pulmonary arteries (arrow denotes pericardial baffle).
PA: pulmonary artery
IHJ-117-01.p65
Indian Heart J 2001; 53: 337–339
Transcatheter Fenestration of a TCPC Baffle
338
was no gradient between the left atrium and pericardial
baffle and the saturation fell to 87% after fenestration. A
widely patent fenestration in the baffle was demonstrated
on check angiography at the end of the procedure (Fig. 3).
Clinically, edema and pleural effusion started subsiding
rapidly. The quantity of pleural fluid drained was 300 ml
after 24 hours and 150 ml on days 2 and 3. The drain was
removed after 5 days. The child was discharged on ATT and
diuretics. The ESR was 80 mm in the first hour. As per our
chest physician’s advice, ATT was continued.
At one-year follow-up, the child was totally
asymptomatic with no evidence of pleural effusion or a
congestive state. The basal saturation was 89%; color
Doppler studies showed a normally functioning shunt
between the superior vena cava (SVC) and baffle to the
pulmonary artery. The pericardial baffle fenestration
(7 mm, nonrestrictive) was patent with right-to-left shunt
(Fig. 4). A diagnostic catheterization has been planned at
a later date.
Discussion
Fenestration of the pericardial baffle increases the number
of candidates suitable for the Fontan procedure, although
the exact inclusion criteria for these patients are not well
defined. Despite the reduction in early mortality, significant
postoperative morbidity in the form of effusions (pleural
and pericardial effusions and ascites) continues to be
common in patients undergoing definitive surgical
management of cardiac malformations with one effective
Fig. 2. Inflated Tyshak II balloon over 0.021 gauge guidewire across the
pericardial baffle (arrow denotes the waist)
8/16/01, 7:23 AM
Indian Heart J 2001; 53: 337–339
Fig. 3. Pericardial baffle angiogram after balloon dilatation in PA view, showing
opacification of the left atrium (suggestive of patent baffle) (arrow denotes
patent baffle). PB: pericardial baffle; LA: left atrium
ventricle.5 The benefit of fenestration is likely to be greatest
in the early postoperative period when the patient may
experience increased pulmonary vascular resistance and
decreased ventricular function due to the effects of a
cardiopulmonary bypass, aortic cross-clamping and positive
pressure ventilation.6
However, with an extracardiac conduit, fenestration
need not be performed initially. The requirement for
fenestration should be assessed after cardiopulmonary
bypass when the hemodynamic status can be evaluated
accurately. If required, the fenestration can be made and
revised easily at this stage without a bypass.6
In our patient, the baffle was intracardiac and in view
of the high-risk repeat surgery on a cardiopulmonary
bypass, we decided to create a transcatheter fenestration of
the TCPC baffle. The pericardial lateral tunnel baffle was
dilated with serial balloon inflations of up to 15 mm, after
puncturing the baffle with a Brockenbrough trans-septal
needle. Perforation of the baffle wall was very difficult in
view of the fact that the anatomy was distorted and there
was no anatomical landmark. Hence, it was performed
using contrast injections frequently to delineate the baffle
anatomy. Post-procedure effusion reduced significantly and
the pleural drain was removed. The child improved and is
asymptomatic after 1-year follow-up. There was a weight
gain of 4 kg over 1 year. At the time of follow-up, the arterial
oxygen saturation was 92%. Few de novo transcatheter
fenestration of baffle have been reported in the literature.7–12
This case of transcatheter fenestration of TCPC baffle is
probably the first of its kind in India.
IHJ-117-01.p65
339
Gupta et al.
Transcatheter Fenestration of a TCPC Baffle
339
Fig. 4. 2D-echocardiogram in subcostal view (inverted view) showing
communication between pericardial baffle and right atrium (arrow denotes
pericardial baffle fenestration). RA: right atrium
References
1. Fontan F, Baudet E. Surgical repair of tricuspid atresia. Thorax 1971;
26: 240–246
2. Norwood WI, Jacobs ML. Fontan’s procedure in two stages. Am J Surg
1993; 166: 548–551
3. Bridges ND, Mayer JE, Lock JE, Jonas RA, Hanley FL, Keane JF, et al.
Effect of baffle fenestration on outcome of the modified Fontan
operation. Circulation 1992; 86: 1762–1769
4. Laks H, Pearl JM, Haas GS, Drinkwater DC, Milgalter E, Jarmakani
JM, et al. Partial Fontan. Advantages of an adjustable interatrial
communication. Ann Thorac Surg 1991; 52: 1084–1094
5. Lemes V, Murphy AM, Osterman FA, Laschinger JC, Kan JS.
Fenestration of extracardiac Fontan and reversal of protein-losing
enteropathy: case report. Pediatr Cardiol 1998; 19: 355–357
6. Thompson LD, Petrossian E, McElhinney DB, Abrikosova NA, Moore
P, Reddy VM, et al. Is it necessary to routinely fenestrate an
extracardiac Fontan? J Am Coll Cardiol 1999; 34: 539–544
7. Nishimoto K, Keane JF, Jonas RA. Dilation of intra-atrial baffle
fenestrations: results in vivo and in vitro. Cathet Cardiovasc Diagn 1994;
31: 73–78
8. Miga DE, Clark JM, Cowart KS, Radtke WA. Transcatheter fenestration
of hemi-Fontan baffles after completion of Fontan physiology using
balloon dilatation and stent placement. Cathet Cardiovasc Diagn 1998;
43: 429–432
9. Hijazi ZM, Ruiz CE, Patel H, Cao QL, Dorros G. Catheter therapy for
Fontan baffle obstruction and leak, using an endovascular covered
stent. Cathet Cardiovasc Diagn 1998; 45: 158–161
10. El-Said HG, Ing FF, Grifka RG, Nihill MR, Morris SC, GettyHousewright D, et al. 18-year experience with transseptal procedure
through baffles, conduits, and other intra-atrial patches. Catheter
Cardiovasc Interv 2000; 50: 434–439
11. Kreutzer J, Lock JE, Jonas RA, Keane JF. Transcatheter fenestration
dilatation and/or creation in postoperative Fontan patients. Am J
Cardiol 1997; 79: 228–232
12. Henneveld HT, Hutter P, Hitchcock FJ, Sreeram N. Catastrophic
transcatheter baffle fenestration for failing Fontan physiology. Ann
Thorac Surg 1998; 65: 268–270
8/16/01, 7:23 AM
Brief
Report
340 Saxena
et al.
Indian Heart J 2001; 53: 340–342
Left Ventricular Intramyocardial Hematoma
Spontaneous Resolution of Intramyocardial Hematoma
of the Left Ventricle
Anita Saxena, G Karthikeyan, Meera Rajani, Rajesh Dhopeshwarkar
Departments of Cardiology and Cardiac Radiology, Cardiothoracic Centre, All India Institute of Medical Sciences, New Delhi
A 40-year-old male with hematoma of the left ventricular myocardium is described. On echocardiography, the
hematoma was initially diagnosed as a cyst-like structure located at the apex and adjoining anterolateral wall of
the left ventricle. A contrast-enhanced computerized tomography scan and magnetic resonance imaging further
confirmed this lesion to be a hematoma. On follow-up, the hematoma gradually subsided and could not be seen
on a repeat echocardiography and computerized tomography scan at four weeks. (Indian Heart J 2001; 53:
340–342)
Key Words: Echocardiography, Magnetic resonance imaging, Tomography
I
ntramyocardial hematoma of the left ventricle (LV) is a
rare entity, usually described after acute myocardial
infarction and is considered to be an incomplete form of
cardiac rupture.1,2 It has occasionally been described
secondary to chest trauma.3 Diagnosis is made by twodimensional echocardiography in cases where it is suspected
during life. We describe a case of intramyocardial
hematoma, occurring in a patient without any obvious
evidence of acute myocardial infarction or trauma, which
resolved spontaneously.
Case Report
A 40-year-old male presented to the emergency room with
sudden onset of dyspnea at rest, which had begun 24 hours
earlier. There was no history of chest pain or trauma to the
chest wall. There was no suggestion of any viral illness in
the preceding fortnight. The patient was a chronic smoker.
He had no other known risk factors for coronary disease.
On examination, the patient was dyspneic and tachypneic.
The heart rate was 120/min, the extremities were cold and
clammy, and blood pressure was not recordable. The neck
veins were full but the jugular venous pressure could not
be ascertained. On auscultation, there was a left ventricular
third heart sound and bilateral crepitations over the lung
fields, extending into the upper third. He was intubated and
Correspondence: Dr Anita Saxena, Professor of Cardiology, All India
Institute of Medical Sciences, New Delhi 110029
e-mail: [email protected]
IHJ-112-01.p65
340
ventilated mechanically and an infusion of dopamine was
started. The electrocardiogram (ECG) revealed normal sinus
rhythm, left axis deviation and right bundle branch block
with 2 mm ST segment elevation in leads I, aVL and V2–V6.
There were Q waves from leads V2 to V5. A diagnosis of acute
extensive anterior myocardial infarction was made, and the
patient was admitted to the coronary care unit. A bedside
echocardiogram revealed a dilated LV showing akinesia of
the middle and apical part of the septum and anterior wall
with an ejection fraction of 25%. The basal segments of
the LV showed good contractility. In addition, there was a
2×2 cm cyst-like structure within the myocardium at the
LV apex and adjoining anterolateral wall (Fig. 1). No
Doppler signals could be obtained in this cyst-like space and
no communication with the main cavity of the LV could be
demonstrated. The creatine kinase (CK) was elevated to 213
IU/ml and its MB isoform was 49 IU/ml (the normal value
in our laboratory is <6% of the total CK). A diagnosis of
intramyocardial hematoma, probably secondary to an acute
myocardial infarction, was made. The patient improved with
supportive therapy and could be weaned off the ventilator
and inotropic support after two days. However, the initial
ST segment elevation persisted and there was no evolution
of the changes on serial ECGs. The serum levels of lactic
dehydrogenase (LDH) and aspartate aminotransferase
(AST) were normal. Also, a technetium pyrophosphate
scan, done three days after admission, was negative for acute
infarction, and there was no diffuse uptake to suggest
myocarditis. As the nature of the intramyocardial lesion was
not clear, further investigations were performed. A contrast-
8/16/01, 7:25 AM
Indian Heart J 2001; 53: 340–342
Saxena et al. Left Ventricular Intramyocardial Hematoma 341
2a
Fig. 1. Two-dimensional echocardiogram showing a cyst-like space (arrow) in
the myocardium of the left ventricle at the apex and adjacent anterolateral
segment.
enhanced computerized tomography (CT) scan
demonstrated a hypodense filling defect at the apex and
adjoining anterolateral wall of the LV (Fig. 2a). Magnetic
resonance imaging (MRI) of the chest was also done to
further define this cyst-like space (Figs 3a, b and c). The
space was hyperintense on T1-weighted images and
remained hyperintense after fat suppression. Gradient echo
T2-weighted sequences showed hyperintensity in this
region, suggesting clotted blood. Coronary angiography did
not show any evidence of atherosclerotic disease. The LV
angiogram showed a dilated, poorly contracting LV with
an akinetic and partially dyskinetic anterolateral wall and
apex. Only the basal segments showed good contractility.
The global LV ejection fraction was 20%.
The patient was managed with standard oral
decongestive therapy. Oral carvedilol was initiated before
discharge. Repeat echocardiography performed two weeks
later showed a decrease in the size of the hematoma. By 4
weeks, the hematoma had resolved completely and could
not be detected by echocardiography or CT scan
(Fig. 2b).
Discussion
Most of the cases of intramyocardial hematoma reported
in the literature have occurred secondary to acute
myocardial infarction. 4 The cause of intramyocardial
hematoma in our patient is not entirely clear. The strongest
evidence for acute myocardial infarction is provided by the
characteristic wall motion abnormality of a left anterior
territory infarction considered in the light of the temporal
course of the illness. But the cardiac enzyme levels do not
IHJ-112-01.p65
341
2b
Fig. 2. Contrast-enhanced CT scan of the chest showing (a) a well demarcated
hypodense lesion (arrows) abutting on the apex and anterolateral wall of the
left ventricle. (b) A repeat contrast-enhanced CT scan after four weeks shows
complete disappearance of the lesion.
suggest a large infarction. The diagnosis of acute myocardial
infarction is, therefore, difficult to substantiate, especially
as the coronary arteries were normal at angiography.
Cases of spontaneous intramyocardial hematomas have
been reported in the literature. One such case involving the
interatrial septum communicated with the noncoronary
sinus producing complete heart block. The diagnosis was
made at autopsy in this case.5 Another case presented as a
large intramural hematoma in the right ventricle.6
A series of 15 cases of intramyocardial dissecting
hematomas, compiled from the literature, was published by
Pliam et al.4 in 1993. Eight of these hematomas were
diagnosed postmortem (all cases published before 1977).
Of the remaining 7, the diagnosis was made by twodimensional echocardiography in 4 cases, ventriculography
in 1 case and at the time of surgery in the other 2 cases.
Two-dimensional echocardiography is an excellent bedside
8/16/01, 7:25 AM
Indian Heart J 2001; 53: 340–342
342 Saxena et al. Left Ventricular Intramyocardial Hematoma
modality for the diagnosis of intramyocardial hematoma
and is better than the LV angiogram, particularly if the
hematoma does not communicate with the LV cavity, as was
seen in our case. In addition to echocardiography, which
suggested the diagnosis in our case, we used CT scan and
MRI to further characterize the lesion. We were able to
determine the nature of the contents of the intramyocardial
lesion using a standard MRI algorithm. The size and extent
of the lesion was delineated accurately by CT scan. These
investigations can, therefore, be of help in difficult cases.
In the series by Pliam et al.,4 5 of the 7 cases with a
diagnosis of hematoma during life required surgery for the
evacuation of the hematoma and coronary artery bypass
grafting (CABG). One patient, who was managed medically,
expired and another showed spontaneous resolution. The
case reported by Kanemoto et al.7 showed spontaneous
disappearance after six months of a hematoma in the
ventricular septum in a patient with acute inferior
myocardial infarction. We did not contemplate surgery
because of the rapid improvement in the patient’s condition
and the absence of significant coronary artery disease. We
observed spontaneous resolution of the hematoma over a
period of 4 weeks.
3a
References
3b
3c
Fig. 3. Magnetic resonance imaging of the heart. (a) Axial spin Echo T1weighted image showing the crescent shaped hyperintensity (T1 shortening)
at the apex and adjoining anterolateral wall of the left ventricle (arrow).
(b) Fat suppressed T1-weighted image showing hypointensity at the site of the
lesion (arrow). (c) Gradient echo T2-weighted image showing hyperintensity
(T2 shortening) in the region of hematoma (arrow).
IHJ-112-01.p65
342
1. Meyers DG, Lund GB, Moulton AL, Robinson LA. Dissecting
intramyocardial hematoma masquerading as a pseudoaneurysm of
the left ventricle. Cathet Cardiovasc Diagn 1989; 17: 31–33
2. Peel AAF. Dissecting aneurysm of the interventricular septum. Br
Heart J 1948; 10: 239–243
3. Maselli D, Micalizzi E, Pizio R, Audo A, De Gasperis C. Posttraumatic
left ventricular pseudoaneurysm due to intramyocardial dissecting
hematoma. Ann Thorac Surg 1997; 64: 830–831
4. Pliam MB, Sternlieb JJ. Intramyocardial dissecting hematoma: an
unusual form of subacute cardiac rupture. J Card Surg 1993; 8: 628–
637
5. Miyazki T, Shiotani H, Kado T, Kazumi T, Matsunaga K, Mizojiri G, et
al. Hematoma of the interatrial septum associated with complete
atrioventricular block. Jpn Circ J 1990; 54: 636–643
6. Mohan JC, Agarwala R, Khanna SK. Dissecting intramyocardial
hematoma presenting as a massive pseudotumor of the right
ventricle. Am Heart J 1992; 124: 1641–1642
7. Kanemoto N, Hirose S, Goto Y, Matsuyama S. Disappearing false
aneurysm of the ventricular septum without rupture: a complication
of acute inferior myocardial infarction—a case report. Angiology
1988; 39: 263–271
8/16/01, 7:25 AM
Indian Heart J 2001; 53: 343–345
Yadav et al. Angioplasty in Transplant
343
BriefCAD
Report
Intravascular Ultrasound-guided Angioplasty and Stenting
in a Case of Transplant Coronary Artery Disease
R Yadav, C Anbarasan, S Mullasari Ajit, Ammu Sivaraman
Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai
Allograft vasculopathy in cardiac transplant recipients occurs commonly at 5 years post transplantation. We
report a case of post-transplant right coronary discrete stenosis which was treated with balloon angioplasty and
stent implantation under intravascular ultrasound guidance. (Indian Heart J 2001; 53: 343–345)
Key Words: Stents, Transplantation, Coronary disease
A
therosclerosis of the coronary arteries is the leading
cause of death after the first year following cardiac
transplantation. In our center, we have performed 8 cardiac
transplants since the inception of the transplant program
in 1995. The prevalence of transplant coronary
arteriopathy is approximately 30%–50% at 5 years posttransplantation. 1 Allograft vasculopathy in cardiac
transplant recipients in the Indian scenario has been
described previously.2 Angiographic evidence of transplant
coronary artery disease (CAD) is evident in at least 50% of
patients at 5 years following cardiac transplant3 and up to
92% have intimal thickening on intravascular ultrasound
(IVUS) at the end of 4 years.4 Intravascular ultrasound
imaging can provide excellent quantitative information on
the plaque cross-sectional area, which is not available by
angiographic imaging.5,6 Keogh et al.7 reported decreased
survival in untreated patients with significant lesions in the
proximal and mid-portions of the epicardial vessels.
Retransplantation and coronary artery bypass grafting have
been used, with disappointing results,8 in an attempt to
reduce ischemia-related morbidity and mortality in this
patient population. Hence, percutaneous revascularization
procedures, when indicated, are a rational way of dealing
with post-transplant CAD under IVUS guidance. Coronary
artery stenting has an advantage over balloon angioplasty
due to its lower restenosis rates and ability to resolve lesion
disruption. Intravascular ultrasound is a useful tool in
assessing the intrastent dimension along the segment of
artery where a stent has been used.9 We report the case of
a patient who developed post-transplant CAD and required
Correspondence: Dr S Mullasari Ajit, Institute of Cardiovascular Diseases,
Madras Medical Mission, 4A, JJ Nagar, Mogappair, Chennai 600050
e-mail: [email protected], [email protected]
IHJ-138-00.p65
343
a balloon angioplasty with stent implantation in the right
coronary artery. Pre-procedure IVUS was used to study the
coronary arteries which helped in optimal stent
deployment.
Case Report
A 49-year-old female, who underwent an orthotopic cardiac
transplant six years earlier for dilated cardiomyopathy,
presented to us with functional Class II dyspnea. She was
optimally immunosuppressed with azathioprine,
cyclosporine and prednisolone. The age of the donor at the
time of surgery was 18 years. Echocardiography showed
moderate left ventricular dysfunction. Ischemic coronary
artery disease and multiple episodes of acute tissue
rejection, previously treated with methylprednisolone and
OKT3, were the factors that contributed to left ventricular
dysfunction in this patient. A trans-jugular myocardial
biopsy showed changes of ischemic vacuolation.
Angiographically, the left main (LM), left anterior
descending (LAD) and the circumflex (CX) arteries were free
of disease.An IVUS pull-back through the LAD showed the
LAD and LM to have intimal hyperplasia with calcification
but no flow-limiting disease (Fig. 1). There was a discrete
90% lesion in the dominant proximal right coronary artery
(RCA) (Fig. 2) which was confirmed on IVUS (Fig. 3).
In view of the discrete significant stenosis, the patient
was subjected to coronary angioplasty. The RCA was
engaged with a 7 F Judkin right guiding catheter and the
stenosis in the proximal RCA crossed with a 0.14 ACS Hitorque floppy wire. Direct stenting with a 3.5×12 mm
Medtronic AVE S 670 stent at 11 atm was done. The
minimum luminal diameter (MLD) and luminal area were
3 mm and 8.1 mm2, respectively, after direct stenting. In
8/16/01, 7:26 AM
Indian Heart J 2001; 53: 343–345
344 Yadav et al. Angioplasty in Transplant CAD
view of the residual plaque burden seen on the IVUS study,
intrastent dilatation was done with a 3.5×10 mm balloon
at 16 atm. The final IVUS study showed an MLD of 3.2 mm
and a stent luminal area of 9.9 mm2. The post-PTCA stent
implantation angiogram (Fig. 4) showed a well deployed
stent in the proximal RCA with no residual stenosis and a
TIMI-3 antegrade flow. The post-PTCA IVUS image (Fig. 5)
also showed a well deployed stent in the proximal RCA. The
patient had an uncomplicated postoperative course and was
discharged 2 days after the procedure. She is to undergo a
stress thallium test at 6 months and an elective coronary
angiography at 1 year post-procedure.
Fig. 1. IVUS image of the LAD artery reveals mild intimal plaque with
calcification
Fig. 2. Pre-PTCA right coronary angiogram which shows 90% stenosis in the
proximal RCA
Fig. 3. Pre-PTCA IVUS imaging which shows fibrous atheroma in the proximal
RCA
IHJ-138-00.p65
344
Fig. 4. Post-PTCA stent implantation image which shows a well deployed stent
in the proximal RCA
Fig. 5. Post-PTCA IVUS image which shows a well deployed stent in the
proximal RCA
8/16/01, 7:27 AM
Indian Heart J 2001; 53: 343–345
Discussion
The development of CAD has been associated with reduced
survival as compared to heart transplant recipients without
the disease. The incidence, as seen on coronary angiography,
is 18% at 1 year and up to 50% at 5 years following
transplantation.3 Intravascular ultrasound studies have
shown that the incidence of post-transplant CAD may be
as high as 80% at 1 year, 79% in the second and third years
and 92% in the fourth year.4 Most of the patients present
with congestive heart failure, acute myocardial infarction
and sudden death but with no pain as the transplanted heart
is denervated. It was previously assumed that posttransplant CAD is more diffuse, concentric and distal in
nature, but IVUS studies have confirmed the presence of
proximal focal and noncircumferential plaques in addition
to the diffuse distal disease. Proximal segments of the large
coronary arteries are most frequently involved, containing
focal, noncircumferential obstructions that resemble
nontransplant coronary atherosclerosis. Diffuse concentric
narrowing is more common in the middle and distal
segments of the epicardial vessels. 4 Though balloon
angioplasty and stenting have been reported to be successful
in selected patients with transplant CAD,10,11 restenosis
remains a major problem. Christensen et al.12 have shown
that the loss in percent area stenosis at late follow-up
correlated significantly with percent area stenosis
immediately after angioplasty and with gain in percent area
stenosis during the procedure. Optimizing the results of
angioplasty and stenting will go a long way in reducing
restenosis and IVUS can be used as a tool for achieving this.
However, there are some technical limitations to the use of
IVUS in transplant CAD. Its safety in vessels of diameter
less than 2 mm is debatable. In addition, acute angulation
of the origin of the vessel and proximal tortuosity may
create difficulties in tracking the IVUS catheter.4
Information derived from angiography is often limited
to providing an accurate assessment with regard to vessel
size, plaque calcification or stent deployment. Use of
vascular dimensions with the help of IVUS may assist in
the optimal choice of balloon size. 9 Intravascular
ultrasound imaging after stent insertion is useful in
documenting satisfactory stent expansion. It is an
important and novel method for the establishment of proper
stent placement, and guidance with IVUS imaging may be
superior to angiography. 13 Intravascular ultrasound
guidance can reduce the rate of subacute thrombosis and
restenosis after intracoronary stent implantation.
The current report of endovascular stent placement
IHJ-138-00.p65
345
Yadav et al. Angioplasty in Transplant CAD
345
under IVUS guidance in this post cardiac transplantation
patient suggests the feasibility of coronary artery stenting
in patients who have undergone cardiac transplantation.
Hence, we conclude that IVUS is a valuable tool in defining
transplant CAD and in assessing the results of angioplasty
and stent implantation. In view of its potential uses,
imaging with IVUS should be routinely recommended in
transplant recipient patients who require coronary
angioplasty, coronary artery stenting or both for allograft
atherosclerosis.
References
1. Barnhart GR, Pascoe EA, Mills AS, Szentpetery S, Eich DM,
Mohanakumar T, et al. Accelerated coronary arteriosclerosis in
cardiac transplant recipients. Transplant Rev 1987; 1: 31–46
2. Trivedi S, Mullasari AS, Arumugam SB, Cherian KM. Allograft
vasculopathy in cardiac transplant recipients: an early experience.
Indian Heart J 1999; 51: 548–550
3. Mehra MR, Ventura HO, Stapleton DD, Smart FW, Collins TC, Ramee
SR. Presence of severe intimal thickening by intravascular
ultrasonography predicts cardiac events in cardiac allograft
vasculopathy. J Heart Lung Transplant 1955; 14: 632–639
4. Tuzcu EM, De Franco AC, Goormastic M, Hobbs RE, Rinco G, BottSilverman C, et al. Dichotomous pattern of coronary atherosclerosis
1 to 9 years after transplantation: insights from systemic
intravascular ultrasound imaging. J Am Coll Cardiol 1996; 27: 839–
846
5. Nissen SE, Grines CL, Gurley JC, Sublett K, Haynie D, Diaz C, et al.
Application of a new phased-array ultrasound imaging catheter in
the assessment of vascular dimensions. In vivo comparison to
cineangiography. Circulation 1990; 81: 660–666
6. Niklewski T, Sikora J. Intravascular ultrasound. Wiad Lek 1999; 52:
393–401
7. Keogh AM, Valantine HA, Hunt SA, Schroeder JS, McIntosh N, Oyer
PE, et al. Impact of proximal or midvessel discrete coronary artery
stenosis on survival after heart transplantation. J Heart Lung Tansplant
1992; 11: 892–901
8. Hallee AA 3rd, Disciascio G, Massin EK, Wilson RF, Johnson MR,
Sullivan HJ, et al. Coronary angioplasty, atherectomy and bypass
surgery in cardiac transplant recipients. J Am Coll Cardiol 1995; 26:
120–128
9. Goldberg SL, Colombo A, Nakamura S, Almago Y, Maiello L, Tobis
JM. Benefits of intracoronary ultrasound in the deployment of
Palmaz–Schatz stents. J Am Coll Cardiol 1994; 24; 996–1003
10. von Scheidt W, Uberfuhr P, Reichart B, Steinbeck G. The role of PTCA
in the management of focal critical lesions in transplant coronary
artery disease. Transplant Proc 1995; 27: 1936–1938
11. Topaz O, Cowley MJ, Mohanty PK, Vectrovec GW. Percutaneous
revascularization modalities in heart transplant recipients. Catheter
Cardiovasc Interv 1999; 46: 227–237
12. Christensen BV, Meyer SM, Iacarella CL, Kubo SH, Wilson RF.
Coronary angioplasty in heart transplant recipients: a quantitative
angiographic long-term follow up study. J Heart Lung Transplant 1994;
13: 212–220
13. Kapadia SR, Ziada KM, L’Allier PL, Crowe TD, Rincon G, Hobbs RE, et
al. Intravascular ultrasound imaging after cardiac transplantation:
advantage of multi-vessel imaging. J Heart Lung Transplant 2000; 19:
167–172
8/16/01, 7:27 AM
Brief
Report
346 Madhu
Sankar et al.
Indian Heart J 2001; 53: 346–347
Ross procedure in an Infant
Ross Procedure in an Infant
N Madhu Sankar, Pankaj Goel, Hemant Agarwal, Shardha Srinivas, KM Cherian
Institute of Cardiovascular Diseases, Chennai
The Ross procedure is gaining acceptance as the procedure of choice for aortic valve replacement in children.
We present the case of a 4-month-old child (weight 3.2 kg) suffering from congenital valvar aortic stenosis who
underwent a Ross procedure. We believe that this is the youngest patient to have undergone this procedure
successfully in the Indian subcontinent. (Indian Heart J 2001; 53: 346–347)
Key Words: Valves, Aortic stenosis, Congenital heart defects
T
he Ross procedure, first described in 1967, involves
replacement of a diseased aortic valve with a
pulmonary autograft and placement of a pulmonary or
aortic homograft between the right ventricle and
pulmonary artery. After the Ross procedure, there is no need
for anticoagulation, and the autograft has proved to be
durable and to grow in proportion to somatic growth.1
Although aortic valve homografts have excellent
postoperative hemodynamics, do not require
anticoagulation and are associated with a low risk of
thromboembolism, these homografts have limited durability
and do not grow.2 Thus a pulmonary autograft is the most
attractive alternative to mechanical, porcine and homograft
valves in the treatment of aortic valve disease in children.
We report a 4-month-old patient with congenital aortic
stenosis who had an excellent outcome following treatment
with the Ross procedure. To the best of our knowledge, this
is the youngest patient to have undergone a successful Ross
procedure in the Indian subcontinent.
Case Report
A 4-month-old male child was admitted with a history of
progressive respiratory distress. He was diagnosed to have
a heart ailment at birth and had a history of repeated
hospitalization for respiratory distress. He weighed 3.2 kg
and had a grade 4/6 systolic murmur at the base. The
electrocardiogram revealed normal sinus rhythm with
biventricular hypertrophy. Chest X-ray revealed
cardiomegaly with a cardiothoracic ratio of 0.7. A bicuspid
aortic valve with severe aortic stenosis was seen on
Correspondence: Dr KM Cherian, Director and Chief of Cardiac Surgery,
Institute of Cardiovascular Diseases, 4A, Dr JJ Nagar, Mogappair,
Chennai 600050. e-mail: [email protected]
IHJ-131-01.p65
346
transthoracic echocardiography, with a maximum gradient
of 75 mmHg. The aortic annulus measured 6.8 mm. There
was grade II/IV aortic regurgitation (jet area 2.4 cm2) and
mild tricuspid regurgitation (TR). In view of the associated
aortic regurgitation, balloon valvotomy was not considered
as an option.
The child underwent a Ross procedure using the root
replacement technique. Cardiopulmonary bypass (CPB) was
instituted using aortic, bicaval cannulation and the body
temperature was brought down to 32°C. Antegrade cold
blood cardioplegia was used for myocardial protection. The
technique involves assessment of the aortic and pulmonary
valves followed by excision of the aortic valve. A pulmonary
autograft was harvested and implanted in the aortic position
as a mini root, using continuous sutures. The left and right
coronary arteries were reimplanted as a button and the
aorta was re-anastomosed. The right ventricular outflow
tract was reconstructed using a 14 mm size cryopreserved
pulmonary homograft. The child was weaned away from
CPB on minimal inotropic support. In the ICU, the child
remained hemodynamically stable. Respiratory efforts were
inadequate initially and the child was extubated on the
seventh day. Thereafter, his recovery was uneventful. The
postoperative transthoracic echocardiogram revealed grade
I /IV aortic regurgitation and mild pulmonary regurgitation
with good biventricular function. There was no significant
gradient across the autograft (Fig. 1). The child was
discharged on the fourteenth postoperative day and is being
followed up regularly. At one-year follow-up, the patient is
doing well and has mild aortic regurgitation.
Discussion
Treating aortic stenosis in children is a challenge. Though
8/16/01, 7:28 AM
Indian Heart J 2001; 53: 346–347
Fig. 1. Postoperative echocardiogram showing good result
valve repair is the ideal procedure, not all valves are
amenable to repair. Replacement with a prosthetic valve is
avoided due to the small size of the annulus, need for redo
surgery as the child grows and the requirement for
anticoagulation. Aortic valve replacement with a
homograft does not require anticoagulation but has a
limited life span and does not grow with the child, thus
necessitating redo surgical procedures.2
The Ross procedure using a pulmonary autograft seems
to be the ideal alternative for aortic valve replacement in
children. The procedure does not require anticoagulation,
the valve has excellent hemodynamics, is durable and has
been shown to grow with the child, thus reducing the
chances of reoperation.1 Despite all the obvious advantages
of using a pulmonary autograft, the use of the Ross
procedure in the initial period was tardy. This was due to
the following reasons: (i) technical difficulty in children;
(ii) concern regarding the fate of the autograft in the
systemic position; (iii) doubt regarding the growth of the
autograft in keeping with the child’s somatic growth.
Ever since the procedure was first described, various
surgeons have reported their results.3–5 Hospital mortality
is comparable in all the series. At 17 years, freedom from
intrinsic tissue degeneration was 100% for the pulmonary
autograft group versus 24%–51% in the homograft group.3
Patient survival was also significantly better with the Ross
procedure.
Stelzer et al.6 modified the Ross procedure and introduced
the root replacement technique. This led to increasing use
of the procedure and today it is the most commonly used
technique. Recently, Elkins7 reported the results in 328
patients. The age of the patients ranged between 10 days
and 62 years. One hundred and twenty patients were less
IHJ-131-01.p65
347
Madhu Sankar et al. Ross Procedure in an Infant 347
than 16 years old. The operative survival was 95.4% with
an actuarial survival of 89±5% at 8 years.
Marino et al.8 have reported their results of the Ross
procedure in children. The age range was 6 days to 34.8
years (median 10.8 years), and the operative mortality was
1.5%. They concluded that for small children the Ross
procedure has low morbidity and mortality. A similar
conclusion can be drawn from the reviews of Reddy et al.9
One concern with this procedure has been the ability of
the pulmonary valve to withstand systemic pressure. Ross
et al.10 reviewed their results in 1992 and concluded that
there was no evidence of primary tissue degeneration in
the autograft. Further, they have shown that the autograft
not only withstands the systemic pressure but also grows
with the patient, making it an ideal operation for children.10
The fact that the autograft is capable of growing has been
shown experimentally by Krietmann et al.11 and has been
confirmed clinically.3,4
Conclusions: The present literature suggests that the Ross
procedure is perhaps the ideal alternative for aortic
valve replacement in children, and has an acceptable
mortality and morbidity. The autograft does not require
anticoagulation and has been shown to grow with the
child’s somatic growth.
References
1. Elkins RC, Knott-Craig CJ, Randolph JD, Razook JR, Ward KE,
Overholt ED, et al. Medium-term follow-up of pulmonary autograft
replacement of aortic valves in children. Eur J Cardiovasc Surg 1994;
8: 379–383
2. Gerosa G, McKay R, Davies J, Ross DN. Comparison of the aortic
homograft and the pulmonary autograft for aortic valve or root
replacement in children. J Thorac Cardiovasc Surg 1991; 102: 51–61
3. Gonzalez-Lavin L, Robles A, Graf D. Morbidity following the Ross
operation. J Card Surg 1988; 3 (Suppl): 305–308
4. Stelzer P, Elkins RC. Pulmonary autograft: an American experience.
J Card Surg 1987; 2: 429–433
5. Gonzalez-Lavin L, Geens M, Ross DN. Pulmonary valve autograft for
aortic valve replacement. J Thorac Cardiovasc Surg 1970; 60: 322–
330
6. Stelzer P, Jones DJ, Elkins RC. Aortic root replacement with pulmonary
autograft. Circulation 1998; 80: III209–III213
7. Elkins RC. The Ross operation: a 12-year experience. Ann Thorac Surg
1999; 68: S14–S18
8. Marino BS, Wernovsky G, Rychik J, Bockoven JR, Godinez RI, Spray
TL. Early results of the Ross procedure in simple and complex left
heart disease. Circulation 1999; 100 (Suppl): II-162–II-166
9. Reddy VM, Rajasinghe HA, McElhinney DB, van Son JA, Black MD,
Silverman NH, et al. Extending the limits of the Ross procedure. Ann
Thorac Surg 1995; 60 (Suppl): S600–S603
10. Ross D, Jackson M, Davies J. The pulmonary autograft—a permanent
aortic valve. Eur J Cardiothorac Surg 1992; 6: 113–117
11. Krietmann B, Riberi A, Jimeno MT, Metras D. Experimental basis for
autograft growth and viability. J Heart Valve Dis 1995; 4: 379–383
8/16/01, 7:28 AM
Brief
Report
348 Tyagi
et al.
Indian Heart J 2001; 53: 348–349
Aortoarteritis Presenting with Hypoparathyroidism
Aortoarteritis Presenting with Hypoparathyroidism
Sanjay Tyagi, Mukul Aggarwal, Sanjeev Bhardwaj, Upkar A Kaul, Ramesh Arora
Departments of Cardiology and Medicine, GB Pant Hospital and
University College of Medical Sciences, New Delhi
Clinical manifestations of aortoarteritis (Takayasu’s arteritis) are varied, depending on the involved segment of
the aorta and its branches. A case of a young Indian woman with aortoarteritis presenting primarily with
hypoparathyroidism is reported. Aortogram showed total occlusion of the arch arteries. To the best of our
knowledge, the occurrence of hypoparathyroidism in aortoarteritis has not been reported. Possible mechanisms
of such an involvement are discussed. (Indian Heart J 2001; 53: 348–349)
Key Words: Aortoarteritis, Takayasu’s arteritis, Hypoparathyroidism
A
ortoarteritis is a nonspecific inflammatory
arteriopathy involving the aorta, its major branches
and sometimes the pulmonary arteries. Involvement of the
arch vessels is common. Stenosis and occlusion of the
subclavian, carotid and vertebral arteries in various
combinations are responsible for the multiplicity of cerebral
and visual disturbances.1 However, its association with
hypoparathyroidism has not been reported. We report the
case of a young Indian woman who presented with
hypoparathyroidism and aortoarteritis.
Case Report
A 25-year-old female presented with a history of generalized
bone pain, episodes of muscle cramps and carpopedal
spasm, along with decreased visual acuity for the last
eighteen months. The patient had a history of one short
episode of syncope. She also had constitutional symptoms
with low-grade intermittent fever and loss of appetite and
weight for the same duration of time. There was no history
of pulmonary tuberculosis or neck surgery.
On physical examination, she had mild pallor and jugular
venous pulsations were normal. Carotid and upper limb
pulses were not palpable while lower limb pulsations could
be well palpated. Blood pressure in the lower limbs was 150/
80 mmHg and no bruit was audible. Examination of the
cardiovascular system, chest, abdomen and central nervous
system did not reveal any abnormality. Chvosteck’s sign and
Trousseau’s sign were present. Both eyes had an immature
cataract and the vision was 6/60. A clinical diagnosis of
aortoarteritis with hypoparathyroidism was made.
Correspondence: Dr Sanjay Tyagi, Professor of Cardiology, GB Pant
Hospital, New Delhi 110023
IHJ-864-00.p65
348
Her hematological parameters revealed a raised ESR
(130 mm fall in the first hour) while the total and differential
leucocyte counts were normal. Biochemical parameters
such as liver and kidney functions, and serum electrolytes
were within normal limits. The level of serum phosphorus
was high (6.6 mg/dl) while serum calcium (4.6 mg/dl) and
serum parathormone (8.2 ng/dl) levels were low. The
Mantoux test was positive (16×16 mm). The
electrocardiograph (ECG), chest X-ray, skull X-ray, and Xray of the hands, feet and pelvis were normal.
Echocardiography was also normal, and a peripheral
Doppler study revealed involvement of the carotid and
subclavian arteries. The lower limb arteries were normal.
Diagnostic angiogram was done via the right femoral
artery under local anesthesia. An arch aortogram revealed
total occlusion of both the common carotid and both the
subclavian arteries. Late frames showed collateral
circulation to the vertebral arteries (Fig. 1). An abdominal
aortogram revealed normal renal arteries and aorta.
Pulmonary artery angiogram revealed normal pulmonary
arteries. A diagnosis of Type 1 aortoarteritis with
hypoparathyroidism was made and the patient was started
on steroids (in view of activity), oral calcium gluconate and
calciferol (Vitamin D3) and put on regular follow-up. A
follow-up angiographic re-study done after five years
showed that all the arch arteries continued to be occluded
while the abdominal aorta and its branches were spared.
Serum parathormone (7.2 ng/dl) and serum calcium (6.1
mg/dl) levels continued to be low.
Discussion
Signs and symptoms in patients with Takayasu’s arteritis
8/16/01, 7:29 AM
Indian Heart J 2001; 53: 348–349
Tyagi et al. Aortoarteritis Presenting with Hypoparathyroidism
Fig. 1. Intra-arterial digital subtraction angiogram of the arch of aorta
showing total occlusion of the left subclavian, left common carotid, right common
carotid and right subclavian arteries at their origin. Late frames showed collateral
circulation to the vertebral arteries.
349
of our knowledge, it has not been described in patients
with aortoarteritis. Hypoparathyroidism in this case
could be because of the compromised vascular supply to
the parathyroids or a common autoimmune process
involving them. 6 A chance association of idiopathic
hypoparathyroidism cannot be ruled out. Rare cases of
ulcerative colitis with Takayasu’s aortitis have been reported
and common immunological mechanisms have been
postulated but not proved.7 An immunological study from
India of 50 patients with aortoarteritis did not find any role
of an autoimmune mechanism in aortoarteritis. 8
Interestingly, the patient’s symptoms improved following
medical treatment with steroids, calcium and vitamin D3,
but angiographic improvement on adequate, long-term
steroids, as reported by some workers,9 was not seen in this
case. No improvement of arterial obstruction has been
reported in other studies.10 Kerr et al.4 reported a relapse in
half the patients who had initially achieved remission on
steroids.
References
(aortoarteritis), a disease of worldwide distribution and
geographic variations, can show considerable clinical
variation with regard to severity, duration and quality.2 The
onset of the disease is often insidious and it progresses at a
variable rate from the active inflammatory phase to the
chronic, sclerotic phase with intimal hyperplasia, medial
degeneration and adventitial fibrosis.3 Stenotic lesions are
more common than aneurysms.4 The narrowing starts near
the orifice of the artery and extends for a variable distance;
progressive narrowing leads to occlusion with ischemic
symptoms. In such an extreme form of brachiocephalic
arteritis, all or most of the arch vessels are occluded and
the entire circulation to the brain is provided through
collateral vessels. Peculiarly, this case presented with
symptoms of hypoparathyroidism.
Hypoparathyroidism is most commonly seen following
surgery for thyroid disorders, hyperparathyroidism and
radical dissection of the neck for cancer.5 Very rarely, it
follows X-ray irradiation of the neck or massive radioactive
iodine administration for cancer of the thyroid. To the best
IHJ-864-00.p65
349
1. Lande A, Bard R, Bole P, Guranaccia M. Aortic arch syndrome
(Takayasu’s arteritis)—arteriographic and surgical considerations.
J Cardiovasc Surg 1978; 19: 507–613
2. Ishikawa K. Patterns of symptoms and prognosis in occlusive
thromboaortopathy (Takayasu’s disease) J Am Coll Cardiol 1986; 8:
1041–1046
3. Sekiguchi M, Suzuki J. An overview on Takayasu’s arteritis. Heart
Vessels 1992 (7 suppl); 6–10
4. Kerr GS, Hallanhan CW, Giordano J, Leawitt RV, Fauci AS, Rottem M,
et al. Takayasu’s arteritis. Ann Intern Med 1994; 120: 919–929
5. Rude RK. Hypocalcemia and hypoparathyroidism. Curr Ther
Endocrinol Metab 1997; 6: 546–551
6. Hofbauer LC, Heufelder AE. Antibodies targeting the calcium sensing
receptor: acquired hypoparathyroidism—an autoimmune disease at
last? Eur J Endocrinol 1996; 135: 172–173
7. Ikenaga H, Ogihara T, Iyori S, Kou S, Yoshikawa H, Okura MM. Does
a common pathophysiological basis exist in the association of
ulcerative colitis and Takayasu’s aortitis?—report of a case. Postgrad
Med J 1989; 65: 761–764
8. Chopra P, Datta RK, Dasgupta A, Bhargava S. Immunological studies
in aortoarteritis. Indian J Med Res 1982; 76: 436–443
9. Ishikawa K. Effects of prednisolone therapy on arterial angiographic
features in Takayasu’s disease. Am J Cardiol 1991; 68: 410–413
10. Morales E, Pineda C, Martinez-Lavin M. Takayasu’s arteritis in
children. J Rheumatol 1991; 18: 1081–1084
8/16/01, 7:29 AM
Brief
Reportet al.
350 Ghadage
Indian Heart J 2001; 53: 350–351
Infective Endocarditis due to Salmonella
Infective Endocarditis due to an Unusual
Serotype of Salmonella
DP Ghadage, AM Bal
Department of Microbiology, BJ Medical College, Pune
Salmonellae are a rare cause of infective endocarditis. We report a case in which Salmonella enterica serotype
Worthington was isolated from a case of endocarditis. The isolate was resistant to ampicillin, gentamicin, amikacin
and chloramphenicol and sensitive to ciprofloxacin and cefotaxime. (Indian Heart J 2001; 53: 350–351)
Key Words: Infection, Endocarditis, Heart diseases
E
ndocarditis due to nontyphoidal Salmonella is a rare
clinical entity and is associated with a high mortality
rate. Approximately 75% of cases suffering from this
condition have an underlying cardiac abnormality such as
rheumatic heart disease and congenital heart defects.1 We
report a case where an unusual serotype of Salmonella was
isolated from a case of infective endocarditis in a patient
with a predisposing valvular abnormality.
Case Report
A 21-year-old woman was admitted with complaints of
fever, anorexia and general weakness of 15 days’ duration.
The patient had been suffering from aortic stenosis with
mitral valve prolapse for 10 years. There was no history of
cough, breathlessness, hemoptysis and palpitations. On
examination, the patient was found to be febrile (101°F).
There was no edema, cyanosis, clubbing or icterus. Her
blood pressure was 110/80 mmHg, jugular venous pressure
was normal and bilateral carotid thrill was present. An early
systolic click and an aortic ejection murmur radiating to
both the carotids could be auscultated at the aortic area
and at the apex. Respiratory system, central nervous system
and per abdomen examination were normal. Hematological
investigations revealed a normocytic, normochromic
anemia (Hb 8.5 g%), a total leukocyte count of 12 000/
mm3, a normal platelet count (200×109/L) and an ESR of
65 mm at the end of one hour. The patient’s serum was
positive for rheumatoid factor but other immunological
Correspondence: Dr Abhijit M Bal, 47/A, Ideal Colony, Radheya
Apartments, Flat-2, Kothrud, Pune, Maharashtra 411038
e-mail: [email protected]
IHJ-127-01.p65
350
manifestations such as Roth spots and Osler nodes were
absent. Urinalysis was normal. A provisional diagnosis of
aortic stenosis with infective endocarditis was made.
Echocardiography did not reveal any vegetation. Three
blood samples were collected at 4-hour intervals for
bacterial culture and sensitivity on the day of admission.
Empirical therapy with intravenous crystalline penicillin
and gentamicin was administered pending culture and
sensitivity reports. On the 3rd day of admission, a brief
high-pitched diastolic murmur was heard on auscultation
and repeat echocardiography revealed aortic stenosis with
regurgitation. This was associated with a fall in peripheral
blood pressure (90/60 mmHg) and a positive hepatojugular
reflex indicating the onset of congestive cardiac failure, for
which drug therapy with digitalis was started. Blood
cultures were repeated on the 7th and 14th day of
admission. In the later part of the patient’s stay in hospital,
serial stool cultures were also carried out.
Blood and stool samples were processed as per standard
microbiological methods. 2 The bacterial isolate was
identified with the help of biochemical reactions and
antibiotic sensitivity was determined with the help of the
Kirby–Bauer disk diffusion method.3
Salmonellae were isolated from all three blood samples
collected on the day of admission. The isolate was found to
be resistant to ampicillin, gentamicin, amikacin and
chloramphenicol, and sensitive to ciprofloxacin and
cefotaxime. After the sensitivity report was obtained, the
patient was treated with intravenous cefotaxime and
ciprofloxacin. This led to an improvement in the patient’s
clinical condition and follow-up blood cultures did not
reveal any bacterial growth. None of the stool cultures
revealed Salmonella.
8/16/01, 7:30 AM
Indian Heart J 2001; 53: 350–351
The isolate was sent for confirmation to the National
Salmonella and Escherichia Centre, Research and
Development Division at the Central Research Institute,
Kasauli where it was identified as Salmonella enterica
serotype Worthington.
Discussion
Infective endocarditis commonly occurs in the setting of a
prior valvular abnormality and is characterized by fever and
systemic complaints such as anorexia, weakness, myalgia
and arthralgia. Aerobic Gram-negative bacilli including
Salmonella, Proteus, Pseudomonas and Klebsiella are rare
causes of bacterial endocarditis, accounting for 1.3%–4.8%
of cases.4
In the present case, the patient had a consistently positive
blood culture, a predisposing cardiac ailment, fever, a
positive test for rheumatoid factor and a raised ESR, all of
which pointed towards a diagnosis of infective endocarditis.
Cardiac vegetations were not detected by echocardiography.
However, the sensitivity of echocardiography to the
detection of cardiac vegetations has been found to be in the
range of 60%–65%.4
Salmonellae have a predilection for involving previously
diseased cardiac valves. Valvular perforation, atrial thrombi,
myocarditis and pericarditis are common complications of
Salmonella endocarditis and these events are associated with
grave prognosis.4 In this case, the appearance of a new
murmur and signs of congestive heart failure indicated
deteriorating cardiac function.
The common serotypes of Salmonella that have been
implicated as causative agents of endocarditis include
choleraesuis, typhimurium and enteritidis.4 Amongst the
infrequent Salmonella serotypes, Schneider et al.5 reported
a case of Salmonella endocarditis due to serotype Thompson.
In a study on salmonellosis in patients with neoplastic
diseases, Wolfe et al.6 reported a case of endocarditis due to
serotype Derby. In a review of endocarditis caused by
nontyphoidal Salmonella, 5 case reports implicating
serotypes Fayed, Sendai, Dublin, Oranienburg, Infantis and
Minnesota have been described. In this review, only 3 out
of 22 cases of Salmonella endocarditis had a favorable
outcome.
Endocarditis due to Salmonella is usually associated with
an apparent focus in the gastrointestinal tract.5 However,
despite serial stool cultures on selective media, we could not
isolate Salmonella from any of the samples.
Serotype Worthington is an uncommon pathogen. It has
been previously incriminated as a cause of neonatal
septicemia and meningitis.7 However, to our knowledge, this
IHJ-127-01.p65
351
Ghadage et al. Infective Endocarditis due to Salmonella
351
is the first report of endocarditis caused by this serotype. In
the present case, the organism was found to be resistant to
commonly used antibiotics such as ampicillin, gentamicin
and chloramphenicol. Resistance to multiple antibiotics has
been increasing in isolates of nontyphoidal Salmonella and
this is one of the important causes of the poor prognosis
associated with Salmonella endocarditis.5 In other cases in
which serotype Worthington has been isolated, the
organism was found to be sensitive only to ciprofloxacin and
a combination of amoxycillin–clavulanic acid.7 Infection
of endocardium with multidrug-resistant Salmonella is
associated with grave prognosis.4 In our patient, close
monitoring and intensive therapy with cefotaxime and
ciprofloxacin led to a favorable microbiological response and
clinical improvement in the congestive cardiac failure.
Although further monitoring for valvular dysfunction and
cardiac failure was warranted, the patient was discharged
after 17 days against medical advice. At discharge, she was
advised to undergo consultation for prophylaxis of
endocarditis before any surgical intervention. Surgical
management for valvular heart disease was not planned
due to economic reasons.
Acknowledgments
We would like to acknowledge the assistance rendered by
the Central Research Institute, Kasauli in identification of
the Salmonella serotype and the Dean, B.J. Medical College
and Sassoon Hospitals, Pune for providing the necessary
facilities.
References
1. Miller SI, Hohmann EL, Pegues DA. Salmonella (Including Salmonella
Typhi). In: Mandell GL, Bennett JE, Dolin R (eds). Principles and Practice
of Infectious Diseases 4th ed. New York: Churchill Livingstone; 1995
2. Collee JG, Marr W. Culture of bacteria. In: Collee JG, Fraser AG,
Marmion BP, Simmons A (eds), Mackie and McCartney Practical Medical
Microbiology 14th ed. New York: Churchill Livingstone; 1996
3. Collee JG, Miles RS, Watt B. Laboratory control of antimicrobial
therapy. In: Collee JG, Fraser AG, Marmion BP, Simmons A (eds).
Mackie and McCartney Practical Medical Microbiology 14th ed. New
York: Churchill Livingstone; 1996
4. Michael Scheld W, Sande ME. Endocarditis and intravascular
infections. In: Mandell GL, Bennett JE, Dolin R (eds). Principles and
Practice of Infectious Diseases 4th ed. New York: Churchill Livingstone;
1995
5. Schneider PJ, Nernoff J, Gold JA. Acute Salmonella endocarditis. Arch
Intern Med 1967; 120: 478–486
6. Wolfe MS, Louria DB, Armstrong D, Blevins A. Salmonellosis in
patients with neoplastic disease. Arch Intern Med 1971; 128: 546–
554
7. Udani RH, Kabra NS, Nanavati RN, Baweja S. Outbreak of Salmonella
Worthington meningitis in neonatal intensive care unit. Indian Pediatr
1999; 36: 300–303
8/16/01, 7:30 AM
Brief
Report Rao et al.
352 Venkateswar
Indian Heart J 2001; 53: 352–353
Absent Coronary Venous Sinus
Absent Coronary Venous Sinus: A Rare Anomaly
C Venkateswar Rao, K Raghu, K Sharada, S Jaishankar
Department of Cardiology, Nizam’s Institute of Medical Sciences, Hyderabad
A 42-year-old man, presenting with dyspnea on exertion and ST segment depression on treadmill test, was
found to have absent coronary venous sinus on coronary angiography. We report this case of isolated congenital
absence of coronary venous sinus because of its rarity. (Indian Heart J 2001; 53: 352–353)
Key Words: Congenital heart defects, Atrium, Coronary sinus
A
bnormalities of the coronary venous system are rare
congenital anomalies. We report a case of isolated
congenital absence of the coronary venous sinus without
associated structural abnormalities.
Case Report
A 42-year-old man presented with complaints of exertional
dyspnea of 2 years’ duration and occasional giddiness. The
dyspnea was not progressive and there was no paroxysmal
nocturnal dyspnea or orthopnea. There was very few
episodes of giddy spells and none of them was associated
with syncope or presyncope. The patient was normotensive,
non-diabetic and a nonsmoker, and had no other symptoms.
Clinical examination revealed a normally disposed
individual with a normal pulse, blood pressure and heart
sounds with no cardiac murmurs. There was no pedal
edema and the neck veins were normal.
The chest X-ray was normal and electrocardiography
revealed an incomplete right bundle branch block. The
echocardiograph showed a normal-sized heart with good
ventricular function. The situs was normal and the infraand intrahepatic portions of the inferior vena cava were
normally visualized. The pulmonary veins drained normally
into the left atrium, while the interatrial and ventricular
septum were intact. A treadmill exercise test showed
horizontal ST segment depression in the inferolateral leads
at 7 METS. A 24-hour ambulatory electrocardiogram was
normal. There was no systemic desaturation and an
oximetry run did not reveal any significant oxygen step-up
at any level. Coronary angiography was carried out to rule
out coronary artery disease. It revealed normal epicardial
Correspondence: Dr K Sharada, Department of Cardiology, Nizam’s
Institute of Medical Sciences, Panjagutta, Hyderabad 500082
e-mail: [email protected]
IHJ-897-00.p65
352
coronary arteries with a normal branching pattern (Fig. 1).
The contrast from the coronaries during the venous phase
emptied into the left ventricle through multiple small
fistulous connections giving a unique striate appearance
(Fig. 2). However, the coronary veins and the coronary sinus
were not visualized during the venous phase (Fig. 3). A
contrast injection was given into the left brachial vein to
rule out associated anomalies. The left brachial, subclavian
and the innominate veins were anatomically normal, but
there was no left superior vena cava (SVC). The patient was
advised conservative management and showed no clinical
deterioration at follow-up after 3 months.
Discussion
Abnormalities of the coronary sinus are rare congenital
anomalies and the accumulated literature on this
interesting entity is meagre and limited to isolated case
Fig. 1. Angiogram of the left coronary arteries of the patient (30° right
anterior oblique view): epicardial coronary arteries are normal
8/16/01, 7:31 AM
Indian Heart J 2001; 53: 352–353
Fig. 2. Coronary angiogram of the patient (right anterior oblique cranial view):
striate appearance due to multiple coronary–cameral fistulae
Venkateswar Rao et al.
Absent Coronary Venous Sinus 353
atrium. The patient underwent successful surgical
correction with improvement in hemodynamics. Fujimura
et al.5 reported the case of a 27-year-old male with Raghib’s
syndrome, characterized by abnormal drainage of the left
SVC into the left atrium, ASD and absent coronary sinus.
The patient had an associated cortriatriatum, and was
diagnosed during a surgical procedure for the primary
cardiac disease.5 The coronary sinus may be partially or
completely unroofed producing a coronary sinus type of
ASD with significant left-to-right shunting.6 Several such
cases have been reported with associated mild systemic
desaturation due to an abnormal connection of the left SVC
to the left atrium.2,3 Coronary sinus defect has also been
described with tricuspid atresia.7
Multiple coronary–cameral fistulous connections,
through which the blood empties into one of the cardiac
chambers, are well known in patients with coronary sinus
abnormalities. In our patient, the flow through these
fistulous connections produced a peculiar striated
appearance in the wall of the left ventricle. Additionally,
the abnormality of the venous system was present in
isolation without any of the associated conditions described
above. The physiological effect of this abnormality on the
patient was not studied. Whether it could lead to myocardial
ischemia due to tissue hypoxia whenever the left ventricular
diastolic pressure rises due to any cause, is a moot question.
The diagnosis of an absent coronary sinus requires
careful observation of the structure during coronary
angiography. A diligent search should be made for
associated defects and the physiology of the coronary blood
flow studied in detail. The natural history is unknown.
References
Fig. 3. Coronary angiogram of the patient (right anterior oblique cranial view):
lack of opacification of the coronary sinus even late in the venous phase
reports. The abnormalities include complete absence,
hypoplasia, atresia—either whole or ostial—and partial or
complete unroofing.1–3 There may be several anomalies
associated with any of the above.
Foale et al.1 reported a case of isolated congenital absence
of the coronary sinus with the cardiac veins draining
separately into the left and right atria, in whom stenosis of
an anomalous vein had produced a continuous murmur.
Defects commonly associated with an absent coronary sinus
include atrial septal defect (ASD), persistent left SVC and
abnormalities of systemic and pulmonary venous drainage.
Sheikhzadeh et al.4 reported the case of a 20-year-old
woman with an absent coronary sinus associated with a
large ASD and a persistent left SVC draining into the left
IHJ-897-00.p65
353
1. Foale RA, Baron DW, Rickards AF. Isolated congenital absence of
coronary sinus. Br Heart J 1979; 42: 355–358
2. Adatia I, Gittenberger-de Groot AC. Unroofed coronary sinus and
coronary sinus orfice atresia. Implications for management of complex
congenital heart disease. J Am Coll Cardiol 1995; 25: 948–953
3. Santoscoy R, Walters HL 3rd, Ross RD, Lyons JM, Hakimi M. Coronary
sinus ostial atresia with persistent left superior vena cava. Ann Thorac
Surg 1996; 61: 879–882
4. Sheikhzadeh A, Tarbiat S, Atai M, Ghabusi P, Mehranpur M. Persistent
left superior vena cava draining into left atrium, atrial septal defect,
and absence of the coronary sinus. Recognition and surgical
correction. Jpn Heart J 1981; 22: 267–273
5. Fujimura Y, Katoh T, Koizumi S. Raghib’s syndrome associated with
cor triatriatum—a rare surgical case report. Nippon Kyobu Geka Gakkai
Zasshi 1989; 37: 2417–2421
6. Bertram H, Paul T, Kaulitz R, Luhmer I, Kallfelz HC. Coronary sinus
defects: rare form of interatrial communication. Z Kardiol 1996; 85:
899–905
7. Rumisek JD, Pigott JD, Weinberg PM, Norwood WI. Coronary sinus
septal defect associated with tricuspid atresia. J Thorac Cardiovasc Surg
1986; 92: 142–145
8/16/01, 7:31 AM
Drugs
in Cardiology
354 Gupta
et al. Newer Antiarrhythmic Drugs
Indian Heart J 2001; 53: 354–360
Newer Antiarrhythmic Drugs
Anoop K Gupta, Alok Maheshwari, Ranjan K Thakur, Yash Y Lokhandwala
Michigan State University, Lansing, MI, USA and KEM Hospital, Mumbai, India
I
n the 1970s and early 1980s, the target or models used
in drug development were based on the suppression of
premature ventricular contractions (PVCs) recorded in
animal models or in patients with PVCs after myocardial
infarction (MI). More recently, drug development has
evolved in two general areas: amiodarone analogues and
agents that block one or more components of the delayed
rectifier potassium channel (Table 1). The remarkable
clinical efficacy of amiodarone in the treatment of a wide
variety of arrhythmias has led to the search for a new class
III drug with a better safety profile. Interestingly, almost all
the drugs in this new wave of development resemble sotalol
more than amiodarone, both chemically and electrophysiologically. They can be grouped chemically based on the fact
that they contain a methane sulfonamide moiety.
Table 1. Mechanism of action of newer antiarrhythmic
drugs on K+ channels
Ibutilide Dofetilide Azimilide Dronedarone
IKS
IKR inhibits inhibits
IKI activates
ITO
IKUR
inhibits
inhibits
multiple
actions
Tedisamil
Trecetilide
inhibits
?inhibits
?activates
inhibits
At least nine potassium channels have been identified,
and it is being recognized that most antiarrhythmic drugs
that prolong repolarization have overlapping specificity for
different groups of channels.1 A great deal of effort has been
expended in developing agents that are selective for the more
discrete ion currents that contribute to repolarization. In
atrial tissue, the candidate currents are the transient
outward current (ITO) and the ultra-rapid component of IK
(IKUR). In the ventricles, the major repolarizing currents are
IK (composed of slow and rapid component, IKS and IKR) and
the outwardly rectifying component of IKI, a current termed
the inward rectifier. Of these currents, pharmaceutical
companies have focused primarily on developing drugs to
block IKR and IKS. Yet, at this point, there is no evidence that
a selective effect on either of these components will provide
any clinical advantages.
Correspondence: Dr Yash Lokhandwala, Associate Professor of Cardiology,
KEM Hospital, Parel, Mumbai 400012
e-mail: [email protected]
IHJ-133-01.p65
354
The transient outward current is prominent in atrial
tissue, and specific agents could be developed to block this
current and, therefore, be selectively useful in treating atrial
and supraventricular arrhythmias. Furthermore, the
potassium channel that is activated by the low cellular
concentration of adenosine triphosphate (ATP), called IKATP,
has been proposed as a target for drugs that would be
selective in treating arrhythmias occurring during
ischemia. 2 All these concepts are appealing, but are
complicated by species and tissue differences in the ion
channels that are responsible for normal electrophysiology,
and a poor understanding of how they are altered by age,
gender and disease, especially acute ischemia or reperfusion.
It is also important to recognize that actions on other
channels may indirectly prolong the cardiac action
potential. Another important aspect of these drugs has been
the association between prolongation of the action potential
duration (APD) and the risk of torsade de pointes (TdP).
This association suggests that any antiarrhythmic benefit
from an effect on refractoriness must be weighed against
the risk of TdP that may result from increasing the APD.
Ibutilide
In 1991, the methane sulfonamide derivative ibutilide was
reported to have highly potent class III activity.3 Ibutilide is
a potent inhibitor of I KR, (EC 50 20nM),4 and displaces
3
H-dofetilide binding (Ki 16 nM) to the IKR channel.5 The
precise contribution of IKR blockade versus inward current
enhancement to ibutilide’s electrophysiological actions is
uncertain.
Ibutilide is effective against the induction of re-entrant
ventricular tachycardia (VT) in dogs studied 24 hours after
coronary artery occlusion and is relatively ineffective
against spontaneous automatic arrhythmias.6 It prevents
ventricular fibrillation (VF) in a hypoxic rabbit heart model,7
and decreases the energy required for ventricular
defibrillation in anesthetized dogs. 8 Ibutilide has less
proarrhythmic potential than other class III drugs in a rabbit
model of TdP. It increases the QT and QTc intervals in
humans, without altering the PR and QRS duration, as
expected for class III drugs.9 The drug produces small
hemodynamic changes, not significantly different from
those occurring with a placebo.9
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Indian Heart J 2001; 53: 354–360
Ibutilide has been introduced as an intravenous agent
for the termination of re-entrant atrial tachyarrhythmias.
Termination efficacy is dose related, and is maximal at
0.0015 mg/kg.10 The drug is usually given as a 10-minute
infusion, with an initial dose of 1 mg followed by a second
dose of 0.5 to 1 mg, if necessary.11 The most significant
potential adverse effect of ibutilide is polymorphic VT in
association with excess QT prolongation. Heart failure,
female sex, non-White race and a slower heart rate are all
associated with a greater risk of polymorphic VT.
Cardioversion for atrial fibrillation: In some patients,
atrial fibrillation (AF) cannot be converted to sinus rhythm
(SR) with external cardioversion. Pretreatment with
ibutilide can be useful in these patients. Ibutilide probably
decreases the atrial defibrillation threshold (DFT), as was
recently observed by Oral et al.12 in a study at the University
of Michigan. One hundred consecutive patients with AF
were examined in a prospective trial in which patients were
randomly assigned to undergo DC cardioversion with or
without pretreatment with 1 mg of intravenous (IV)
ibutilide. Cardioversion terminated AF in 36 out of 50
patients (72%) who were not receiving ibutilide. In patients
receiving ibutilide, AF was terminated acutely by ibutilide
alone in 10 patients (20%) while the other 40 (80%) were
all successfully converted to SR with transthoracic
cardioversion (100% compared with 72% of patients not
receiving ibutilide; p>0.001). When the energy
requirement for atrial defibrillation was examined in the
patients initially assigned to ibutilide pretreatment rather
than no pretreatment, ibutilide significantly reduced the
amount of energy required for cardioversion to SR from
228±93 J to 166±80 J (p>0.001).
This important study shows that ibutilide significantly
reduces atrial DFTs and can lead to successful transthoracic
cardioversion to SR in patients in whom transthoracic
cardioversion would otherwise have failed. Wesley et al.8
evaluated ibutilide-induced reduction in ventricular DFTs
in a canine model and hypothesized that the effect was
secondary to the prolongation of repolarization without
changes in ventricular conduction. However, the
mechanism responsible for reducing DFTs has not been fully
determined.
Dofetilide
Dofetilide has been approved by the cardiorenal panel of
the US Food and Drug Administration (FDA) and is expected
to be clinically available in the next few months. It is being
developed for the treatment of life-threatening ventricular
arrhythmias and for the prevention of recurrent AF or atrial
IHJ-133-01.p65
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Gupta et al.
Newer Antiarrhythmic Drugs
355
flutter (AFL). It is one of the methane sulfonamide
compounds that has relative selectivity at 10 to 30 nM for
blocking the rapidly activating component of the delayed
rectifier potassium current, IKR.13,14 At these concentrations,
it does not block IKS or IKI, nor does it affect the sodium or
calcium currents. This yields a selective effect on the QT
interval of the surface ECG. In clinical electrophysiological
studies (EPS), it has been found to prolong the QT interval
with little effect on QT dispersion,15 and no effect on
conduction parameters (PA, AH, HV, PR or QRS intervals),
sinus cycle length, or sinus node recovery.16
Dofetilide, like most other potassium-channel blockers,
is metabolized predominantly by the CYP 3A4 family.17 It is
therefore likely to interact with drugs such as erythromycin
or ketoconazole. Kobayashi et al.18 evaluated the clinical
and electrophysiological effects of IV dofetilide in patients
with paroxysmal AF of recent onset (<7 days) and
paroxysmal supraventricular tachycardia (PSVT). They
administered 2.5–5 µg/kg of dofetilide for the termination
of arrhythmias; and for the EPS, they administered 3.0 µg/
kg as a loading dose, followed subsequently by 2 µg/kg IV
over 45 minutes as a maintenance dose. Dofetilide
proportionately lengthened the effective refractory period
(ERP) of the atrium, ventricle and the accessory pathways
(AP) without slowing intracardiac conduction.
Falk et al.19 reported a placebo-controlled study of the
safety and efficacy of a single bolus dose of IV dofetilide for
the termination of sustained AF or AFL. Ninety-one patients
with sustained AF (75 patients) or AFL (16 patients) were
entered into a double-blind, randomized, multicenter study
of one or two doses of dofetilide (4 or 8 µg/kg body weight)
or placebo. Dofetilide effectively terminated the arrhythmia
in 31% of patients receiving 8 µg/kg and in 12.5% of those
receiving 4 µg/kg compared to zero conversion after placebo
(p<0.01). Although the number of patients with AFL was
small, this group had a greater response to dofetilide (54%)
compared to those with AF (14.5%, p<0.001).
Echt et al.20 evaluated the efficacy of dofetilide in patients
with life-threatening sustained VT or VF using a novel
placebo-controlled, dose-ranging protocol. The study was
designed to define the range of effective doses and to
evaluate the clinical electrophysiology of IV dofetilide in
patients in whom sustained VT and VF was reproducibly
inducible at baseline EPS. The initial 4 patients received low
doses that were increased in the subsequent groups of 4
patients if there were no adverse effects. In each group of 4
patients, 1 patient was randomly assigned to placebo
(double blind). Twenty-four patients were studied at six
incremental loading and infusion regimens. Dofetilide
(0.1–8.0 ng/ml in plasma) produced a concentration-
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Indian Heart J 2001; 53: 354–360
356 Gupta et al. Newer Antiarrhythmic Drugs
related increase in the QT=0.79 (p<0.001), QTc=0.60
(p=0.02), RR=0.62 (p<0.02), and right ventricular
ERP (cycle length 600 ms; r=0.68, p=0.04). Placebo
infusion produced no changes in any of these
measurements. Sustained VT or VF was no longer inducible
in 1 of the 6 patients receiving placebo and 8 of 18 patients
receiving dofetilide (4–13 seconds non-sustained
ventricular tachycardia [NSVT] was induced in 4 of these
8 patients). One patient developed TdP at a high
concentration (5.3 ng/ml).
Bashir et al. 21 for the Dofetilide Arrhythmia Study
Group21 reported a multicenter open trial of dofetilide in
patients with sustained VT. These investigators evaluated
the acute electrophysiological effects, antiarrhythmic
efficacy and safety of different doses of IV dofetilide in 50
patients with sustained monomorphic VT inducible by EPS,
who had previously been unsuccessfully treated with 0 to 7
(median 3) other drugs. Dofetilide was administered over
60 minutes at doses of 1.5, 3, 6, 9 and 15 µg/kg. Doses of
3–15 µg/kg prolonged the QTc interval by 13.4%–14.2%,
the ventricular ERP by 7.9%–20.6%, and the ventricular
functional refractory period (FRP) by 7.3%–25%. The
corresponding plasma dofetilide concentrations ranged
from 1.45±0.52 to 6.48±1.31 ng/ml. The investigators
failed to see any evidence of reverse use dependence. At
these dosages, IV dofetilide suppressed or slowed inducible
VT in 17 of 41 patients (41%) compared with 0 of 9 patients
receiving the lower electrophysiologically inactive dose of
1.5 µg/kg. The response rate was fairly uniform among the
groups receiving 3–15 µg/kg.
In humans with ejection fractions (EF) of 20%–30%,
dofetilide has been shown to be essentially devoid of
significant hemodynamic effects.22 Its effect on mortality
in patients with CHF or those at high risk after MI were
prospectively evaluated in the Danish Investigations of
Arrhythmia and Mortality on Dofetilide (DIAMOND)
trials,23,24 which randomly assigned patients to placebo or
dofetilide. Entry criteria included a cardiac index less than
1.2 (which corresponds to a left ventricular ejection fraction
[LVEF] of 35% or less) and an acute MI (n=1510) within
the past 2 to 7 days (MI trials), or recent new or worsened
CHF (n=1518; CHF trial). Placebo or dofetilide
administration was initiated during a 3-day hospitalization,
and patients were evaluated for QT interval prolongation
and TdP. After one year of follow-up, the overall mortality
rate was 22% in the MI study and 27% in the CHF study,
and mortality did not differ in the dofetilide and placebo
groups. In both studies, dofetilide recipients had a greater
conversion rate from AF to SR. In the CHF trial, the
development of new onset AF was also significantly
IHJ-133-01.p65
356
reduced.23,24 Dofetilide is renally excreted and the dosage
of the drug must be adjusted as per the renal function. In
the DIAMOND-CHF trials,25 dofetilide was stopped most
commonly because of QT interval prolongation (2% v. 0.4%
for placebo), which usually occurred on the second day of
medication. Torsade de pointes was seen in 25 patients
(3.2%); 76% of the episodes occurred during the first three
days after dose initiation and two of them were fatal.
The results of the DIAMOND-MI trials are markedly
different from those of the Survival with Oral d-Sotalol
(SWORD) trial. 26 In the SWORD trial, d-sotalol was
associated with an increased mortality rate (5.7% compared
with 3.1%; p<0.01). This is of interest because dofetilide
and d-sotalol exert similar electrophysiological actions; both
are IKR blockers (although d-sotalol also blocks IKI and
possibly ITO). The different results probably stem from several
factors and are due, in part, to the fact that the DIAMOND
trial enrolled a much sicker patient cohort (mortality rate
in the placebo group: 22% in the DIAMOND trial and 3%
in the SWORD trial). Patients in the SWORD trial were at a
low risk for death, and the use of an antiarrhythmic drug
that can cause TdP subjected them to a proarrhythmic risk
with little likelihood of decreasing arrhythmic events. In
addition, the SWORD trial, unlike the DIAMOND-MI trial,
started antiarrhythmic therapy on an outpatient basis.
Thus, patients who had excessive QT interval prolongation
or short runs of TdP were more likely to be identified and
have the study drug discontinued in the DIAMOND-MI trial.
In the SAFIRE trial,27 325 patients with persistent AF
(lasting 14 days to 7 months) were randomly assigned to
receive placebo or one of three dofetilide regimens: 125 µg,
250 µg, or 300 µg twice daily. Patients were hospitalized
and blinded administration of the drug started. If the
patients did not convert to SR within 3 days, they were
electrically converted to SR, and only those patients who
were successfully converted continued in the study. Of note,
67% of patients had structural heart disease and 40% had
CHF. After 6 months of follow-up, 62% of the patients
receiving the highest dosage (500 µg every 12 hours) of
dofetilide and 36% of placebo recipients remained in SR
(p<0.05). Of interest is the fact that 32% of patients
receiving the highest dosage and 1% of placebo recipients
were converted to SR pharmacologically. Patients who
maintained SR had fewer arrhythmic symptoms than
patients who had a recurrence of AF (35% and 48%,
respectively; p<0.05). This shows that maintenance of SR
is significantly associated with symptom reduction. The
incidence of TdP in this study was 0.6%.
In a related investigation, the European and Australian
Multicenter Evaluative Research on Atrial Fibrillation
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Indian Heart J 2001; 53: 354–360
Dofetilide (EMERALD) study28 randomly assigned patients
after cardioversion to receive placebo or one of the three
regimens of dofetilide: 125 µg, 250 µg, or 500 µg twice daily.
All dosages of dofetilide significantly increased the number
of patients in SR, and a dose–response curve was seen, with
the greatest benefit at the highest dose. After 6 months of
follow-up, 71% of patients receiving the 500 µg of dofetilide
and 26% of placebo recipients remained in SR (p<0.001).
The incidence of TdP was 0.75%. Maintenance of SR was
shown to improve the quality of life and exercise capacity.29
In summary, these studies show that dofetilide, a pure
IKR blocker, prolongs atrial repolarization and prevents
recurrent AF. It seems to have an acceptable safety profile
in patients with heart failure and in those after MI.
Azimilide
Azimilide (NE-10064) blocks the slowly activating (IKS) and
rapidly activating (IKR) components of the delayed rectifier
potassium current, which distinguishes it from most other
potassium channel blockers such as sotalol and dofetilide,
which block only IKR. Azimilide is being tested for its ability
to delay the time to recurrence of AF, AFL and PSVT in
patients with and without structural heart disease.
Azimilide is also being studied for its ability to prevent
sudden cardiac death (SCD) in high-risk patients after MI.
Preclinical and clinical studies indicate that azimilide
prolongs the cardiac refractory period in a dose-dependent
manner, as manifested by an increase in APD, QTc interval,
and ERP.30 Azimilide does not effect the PR or QRS intervals
and has minimal hemodynamic effects on blood pressure
and heart rate. In preclinical experiments, its effects appear
to be rate independent and are maintained under ischemic
or hypoxic conditions. As with other drugs that prolong
cardiac refractoriness, azimilide has been demonstrated to
suppress supraventricular arrhythmias effectively (>85%)
in a variety of dog models. It also suppressed complex
ventricular arrhythmias in infarcted dogs and decreased
mortality in an SCD model.30
The safety and efficacy of azimilide in preventing
recurrent AF, AFL and PSVT was assessed in more than
1000 patients randomly assigned to receive placebo or
escalating doses of oral azimilide for 6–9 months.31–33 In
these studies, almost all patients received azimilide on an
outpatient basis. In the preliminary data33 on the first 367
patients with AF or AFL randomly assigned to placebo
(n=87); azimilide 50 mg/day (n=99); or azimilide 100– 125
mg/day (n=181), a significant increase was shown at the
higher dose level, in the median time to the development of
arrhythmia (60 days compared to 17 days; p<0.005). In a
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Gupta et al.
Newer Antiarrhythmic Drugs
357
combined analysis32 of three trials of AF and AFL that
examined 906 patients, azimilide significantly prolonged
the hazard ratio for recurrence of arrhythmia when it was
given at a dosage of 100 mg/day (hazard ratio 1.32;
p=0.02) and 125 mg/day (hazard ratio 1.81; p<0.01).
However, in a fourth study evaluating the 125 mg/day dose,
azimilide did not significantly reduce the recurrence of AF.32
The effect of azimilide was also evaluated in 133 patients
with PSVT. Fifty patients received placebo and 83 received
azimilide, which significantly prolonged the arrhythmiafree interval (hazard ratio 2.4 for azimilide 100 mg/day;
p=0.01).34 The overall incidence of TdP in the PSVT studies
has been less than 0.8%, and the incidence of all serious
adverse events in the AF trials was not significantly
increased compared with the placebo (6.4% for placebo
compared with 8.5% for azimilide; p=ns). The incidence of
other side-effects was low. An early reversible neutropenia
was observed in approximately 0.39% of patients. The risk
of death31 was 0.77 (95% CI: 0.2–3.1; p=ns) in patients
with SVT who were receiving azimilide compared with
patients receiving placebo; thus mortality was not increased
in azimilide recipients.
The Azimilide Post-Infarct Survival Evaluation (ALIVE)
trial designed by Camm et al.35 will examine the potential
of azimilide for improving survival in post-MI patients at
high risk of SCD. It is a double-blind, placebo-controlled,
multinational trial that uses LVEF and heart rate variability
(HRV) as predictors to target a post-MI patient population
at high risk of SCD. The major inclusion criteria for the study
are adult patients of either gender with an LVEF of 15% to
35% who have had a recent MI (6–21 days). Additional
stratification will be based on the patients’ HRV. Exclusion
criteria include factors that may predispose a patient to
nonarrhythmic death or to low risk of SCD caused by
arrhythmia. Sample size is based on the assumption that
all-cause mortality rates (the primary end-point) at oneyear in placebo patients at high risk for SCD are 15% and
that azimilide will decrease the all-cause mortality by at
least 45% in these patients. The trial consists of three
groups—patients receiving 75 mg azimilide orally each day,
patients receiving 100 mg azimilide orally each day, and
patients receiving placebo. No dose adjustment for age,
gender, renal or hepatic failure, or the concomitant use of
digoxin and warfarin are necessary with azimilide.
Enrollment for the trial is expected to continue for 24
months, and treatment is scheduled to be administered for
a one-year follow-up period. The similarity of the two
dosages chosen and the lack of dose individualization are
the two potential drawbacks of this trial.
In summary, azimilide has unique electrophysiological
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358 Gupta et al. Newer Antiarrhythmic Drugs
actions: it blocks both IKR and IKS, and lacks frequencydependent effects. It has been shown to be efficacious as a
prophylaxis for recurrent AF and PSVT, and has been
associated with a low incidence of TdP. It is unique in that
it is being developed for outpatient use, which seems safe in
patients with supraventricular arrhythmias and is being
further assessed in the ongoing ALIVE trial.
Dronedarone
Dronedarone is an experimental agent that has multiple
electrophysiological actions, including all four Vaughan
Williams class effects.36 Thus, it is similar to amiodarone.
However, it does not have the iodine moiety of amiodarone,
therefore there may be lesser side-effects. It has been shown
to have antiadrenergic effects37,38 and to prolong atrial and
ventricular refractory periods, atrioventricular node
conduction, and the paced QRS complex;39 these effects are
consistent with class I drug-induced slowing of ventricular
conduction. In a recent study,40 acute electrophysiological
effects of IV dronedarone were studied in a canine model
with complete chronic AV block (a model with high
sensitivity for acquired TdP). The IV dronedarone did not
result in short-term class III effects; on the contrary, it
showed a dose-dependent decrease in ventricular
repolarization parameters including the QT interval,
whereas the ventricular ERP (VERP) remained the same,
thus increasing the VERP/QT ratio. Dronedarone
suppressed spontaneous and pacing-induced TdP, early
afterdepolarizations (EADs) and premature beats in this
study.
In another study,41 the effects of oral dronedarone were
compared with amiodarone in rabbit heart after 3 weeks of
therapy with two different dosages. The main findings of
this study indicate that despite the lack of iodine from the
molecule, the major electrophysiological properties of
dronedarone were similar to those of amiodarone. During
short-term superfusion, dronedarone shortened the APD,
as reported for amiodarone,42 but reduced the ventricular
Vmax. In contrast, after 3 weeks of oral administration of
both drugs, there was significant slowing of the sinus
frequency in vivo and in vitro associated with a significant
prolongation of ventricular APD. In the sinus node, the
slowing of the rate after long-term treatment was due to
the depression of phase 4 depolarization and lengthening
of the APD. Both drugs produced comparable degrees of
depression of V max as an index of inhibition of the
ventricular myocardial sodium channel activity. The effects
of dronedarone were more potent than those of
amiodarone, despite deletion of iodine from its molecular
IHJ-133-01.p65
358
structure. Whether these effects will translate into a less
toxic and at least as effective drug as amiodarone remains
to be seen.
Tedisamil
Tedisamil differs from other class III antiarrhythmic agents
in that it blocks ITO in addition to IKR.43–45 Tedisamil has been
shown to reduce the incidence of VF and AF in experimental
studies.44 Clinically, it produces bradycardia, presumably via
a direct action on the sinus node APD, and prolongs the QT
interval without affecting QRS or QT intervals.46 Reversefrequency dependency has been seen with this agent,46
which is currently undergoing evaluation in humans for
the treatment of AF and AFL.
Trecetilide
Trecetilide, a congener of ibutilide, is being evaluated in
both IV and oral preparations for the termination and
prevention of AF and AFL. In addition to blocking IKR,
it seems to prolong repolarization through other
mechanisms that are still being delineated. It also
significantly prolongs the action potential in animals and
repolarization in humans without exerting other
electrophysiological effects.
Conclusions
Class III agents are being increasingly used as prophylaxis
in patients who have AF and AFL, and for the reduction of
supraventricular tachyarrhythmias after cardiac surgery.
In addition to terminating AF and AFL, ibutilide
significantly reduces human atrial defibrillation thresholds
and increases the percentage of patients who can be
cardioverted from AF to SR. Apart from SVTs, in patients
with ventricular arrhythmias and implantable
cardioverter–defibrillators (ICDs), class III agents are being
increasingly used as an adjuvant therapy to decrease the
frequency of ICD discharges. FDA has approved dofetilide
for clinical use. Azimilide, which seems to be devoid of
frequency-dependent effects on repolarization, is being
actively investigated for the prophylaxis of AF and AFL.
Dronedarone, tedisamil and trecetilide are now being
studied to determine their usefulness in the treatment of
patients with cardiac arrhythmias. Experimental studies are
in progress to identify pharmacological agents that will
selectively prolong repolarization in the atria without
exerting electrophysiological effects in the ventricles.47–49
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Indian Heart J 2001; 53: 354–360
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Egstrup K, et al. Dofetilide in patients with congestive heart failure
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Agarwal
Current
Perspective
Treatment of Hypertension in Patients
with Diabetes
361
Treatment of Hypertension in Patients
with Diabetes Mellitus
Rajiv Agarwal
Indiana University School of Medicine, Indianapolis, USA
W
e are in the midst of a worldwide epidemic of Type 2
diabetes mellitus, the major brunt of which will fall
upon developing countries.1 In the next 25 years, the burden
of diabetes mellitus is predicted to double in India, with
the number of cases increasing from 22.9 million to 57.2
million.1 The cause of this is multifactorial and includes an
ageing population, increasing obesity, a sedentary lifestyle
and genetic background.2 The genetic factor is of particular
importance in the Indian population because of a high
prevalence of the metabolic syndrome or the syndrome of
insulin resistance.3–5 Although there is substantial ethnic
heterogeneity in the prevalence of atherosclerosis and its
risk factors,6 immigrants of South Asian origin have a high
cardiovascular mortality rate.7 An increased prevalence of
diabetes mellitus will undoubtedly increase the
cardiovascular disease burden which has also reached
epidemic proportions and is likely to grow with time.8 By
the time most cardiologists see patients with diabetes,
macrovascular disease has already been established.
Hypertension is very common at this stage of the disease
and its management is the subject of the present review.
The Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure regards
diabetes mellitus as a “vascular disease equivalent” in the
management of hypertension.9 This is because patients with
diabetes mellitus have as high a rate of cardiovascular
events as that seen in patients with established coronary
artery disease.10 The goal of treatment of hypertension in
patients with diabetes is the prevention of morbidity and
mortality due to microvascular and macrovascular
complications. This is particularly relevant to India because
the probability of adults dying from noncommunicable
diseases, predominantly cardiovascular, is greater in India
than in established market economies.11 Hypertension is an
important risk factor for the development of vascular
complications of diabetes mellitus,12 and results from recent
Correspondence: Dr Rajiv Agarwal, Clinical Associate Professor of
Medicine, Indiana University School of Medicine, VA Medical Center 111N,
1481 West 10th Street, Indianapolis, IN 46202, USA
e-mail: ragarwal@ iupui.edu
IHJ-1A-005.p65
361
trials show that lowering blood pressure (BP) in patients
with diabetes mellitus is more cost-effective than tight blood
glucose control, and beneficial results are apparent earlier.13
Emerging data on the treatment of hypertension in patients
with Type 2 diabetes and the proliferation of new
antihypertensive drugs warrants a closer examination of
the drug therapy and target BP in these patients. Major
studies that involve patients with Type 2 diabetes mellitus
or as subgroups are summarized in Table 1 and discussed
in greater detail below.
Evidence for Aggressive BP Control
Evidence for aggressive BP control comes from two large
outcome studies—the United Kingdom Prospective Diabetes
Study-38 and -36 and the Hypertension Optimal Treatment
trial.
In the United Kingdom Prospective Diabetic Study-38
(UKPDS),14 patients with Type 2 diabetes were randomized
to tight control and less tight control: <150/85 mmHg
(n=758) and <180/105 mmHg (n=390), respectively.14 At
follow-up over 8.4 years, the group with aggressive BP
control achieved an average BP of 144/82 mmHg compared
to 154/87 mmHg in the group with less tight control.
Despite a modest difference of 10/5 mmHg, the difference
in outcomes of microvascular and macrovascular
complications of diabetes was dramatic. Those assigned to
tight control showed a 24% reduction for any end-points
related to diabetes, 32% for deaths related to diabetes, 44%
for stroke, and 37% for microvascular disease. In
comparison, intensive blood glucose control decreased
the risk of diabetes-related end-points by 12% and
microvascular disease by 25%. Therefore, good control of
BP was found to be more rewarding than control of diabetes.
In the UKPDS, the group assigned to more aggressive BP
control was randomly allocated to captopril (25–50 mg b.d.)
or atenolol (25–50 mg q.d.).15 There was no difference in
outcomes between the angiotensin-converting enzyme
(ACE) inhibitor or beta-blocker treated groups. Failure to
detect differences between the two groups should not be
8/16/01, 7:34 AM
362 Agarwal
interpreted to mean that the two drugs are equivalent in
efficacy in patients with diabetes mellitus. The study had
adequate power to detect a 30% difference in relative risk,
but the effect that is more realistic is around 10% difference
in relative risk. In other words, in contrast to the placebo
used in some trials (the HOPE trial is discussed below), an
active control group receiving beta-blocker, which by itself
is cardioprotective, requires a substantially larger number
of patients to detect a difference.
The UKPDS-3616 determined the relationship over a
period of time between systolic blood pressure and the risk
of macrovascular and microvascular complications in
patients with Type 2 diabetes in a prospective observational
study of Caucasians, Asian Indians and Afro-Carribbeans
in the UK.16 Of the 3642 patients included in the analysis
of relative risk, the incidence of clinical cardiovascular
complications was reduced by between 11% and 15% for
each 10 mmHg reduction in systolic BP. The lowest risk of
vascular events was seen in those with a systolic BP of <120
mmHg. The present guideline of the National Kidney
Foundation calls for a target BP of <130/80 mmHg in
patients with diabetes mellitus;17 UKPDS-36 may well set
this bar lower.
The other major trial that demonstrated the benefit of
aggressive BP control in patients with diabetes mellitus and
hypertension was the Hypertension Optimal Therapy (HOT)
trial. 18 In this trial (n=18 790), 1501 diabetics were
included, who were randomized to diastolic BP targets of
≤80, ≤85 and ≤90 mmHg. A step-care combination drug
therapy approach was used to control BP. The first-line agent
was a long-acting dihydropyridine calcium-channel blocker,
felodipine (5 mg q.d.). If BP was not controlled, an ACE
inhibitor or beta-blocker was added. Step 3 required
doubling of the felodipine dose and step 4 required doubling
of the ACE inhibitor or beta-blocker dose. Finally, a diuretic
was added. The trial had a 3×2 factorial design. The
achieved diastolic BPs were about 2–2.5 mmHg higher than
the target and there was no overall increase in
cardiovascular outcomes with aggressive BP control. Only
patients with diabetes mellitus and hypertension derived
any benefit from aggressive BP reduction. Cardiovascular
mortality in groups randomized to diastolic BP targets of
≤80, ≤85 and ≤90 mmHg were 3.7, 11.2 and 11.1/1000
patient-years, respectively. Similarly, major cardiovascular
events were 11.9, 18.6 and 24.4/1000 patient-years,
respectively, in the three groups. Thus, the lowest
cardiovascular mortality, myocardial infarction and
cardiovascular event rates were seen in patients randomized
to the lowest diastolic BP. However, the rate of strokes and
total mortality did not change. Furthermore, the fact that
IHJ-1A-005.p65
Indian Heart J 2001; 53: 361–369
Treatment of Hypertension in Patients with Diabetes
362
there were statistically significant differences in
cardiovascular event rates between the groups
demonstrates that seemingly trivial reductions in the range
of 5 mmHg in diastolic BP can translate into a large
reduction in mortality in patients with diabetes and
hypertension.
ACE Inhibitors as First-line Agents
The maximum experience with an ACE inhibitor has come
to us from the Heart Outcomes Prevention Evaluation
(HOPE) study.19 The criteria for inclusion in this trial are
listed in Table 1 (under the heading “Study Population”).
Patients with diabetes mellitus (n=3577) had at least one
other cardiovascular risk factor, such as hypertension, high
levels of serum total cholesterol, low high-density
lipoprotein (HDL) levels, cigarette smoking or documented
microalbuminuria. Ramipril was started at a dose of 2.5
mg/day for the first week, 5 mg/day for the next three weeks
and then escalated to a dose of 10 mg/day. Angiotensinconverting enzyme inhibitor therapy resulted in a 25%
overall reduction in the rates of death, myocardial
infarction and stroke, the primary end-points of the study
in patients with diabetes mellitus. 20 The overall trial
results reported a 22% reduction in relative risk of the
primary end-point.19 Thus, the subgroup of patients with
diabetes derived at least as much benefit in reduction of
cardiovascular events and deaths as those without
diabetes. This trial demonstrates that ACE inhibitors not
only improve the survival of patients with heart failure,
asymptomatic left ventricular dysfunction and myocardial
infarction,21 and reduce the rate of fall in renal function in
those with nephropathy,22–24 but also benefit those with
diabetes and hypertension. The cardiovascular protection
afforded by ramipril could not be accounted for by BP
reduction alone and occurred in the presence or absence of
a history of hypertension, cardiovascular disease or
microalbuminuria. A sub-study demonstrated prevention
of nephropathy 20 and reduced progression of carotid
atherosclerosis with ramipril therapy.25 Also, the drug was
well tolerated and provided as much cardiovascular
protection in patients with renal failure.26 These data
provide strong support for the use of ACE inhibitors in highrisk patients with diabetes mellitus, even in those without
hypertension, for the prevention of cardiovascular and
microvascular events. Of note is the fact that these drugs
cannot be used during pregnancy and can cause
hypotension and renal failure, particularly in patients with
renal artery stenosis, heart failure or those on diuretics.
Also, in predisposed patients such as those with renal
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Indian Heart J 2001; 53: 361–369
Agarwal
failure, these drugs can cause hyperkalemia. Thus, it is
important to monitor BP, serum creatinine and potassium
levels within a week or two of starting therapy or escalating
the dose.
Equally impressive protection with ACE inhibitor-based
therapy comes from the Captopril Prevention Project
(CAPPP) Randomized Trial. 27 In this study, 10 985
hypertensive patients, 5% of whom were diabetics, were
enrolled to either captopril (50 mg in one or two divided
doses) or conventional therapy (thiazides or beta-blockers)
to compare their efficacy in preventing myocardial
infarction, stroke or cardiovascular death.27 Eligible patients
had to have a diastolic BP of ≥100 mmHg on two occasions
and a step-care approach was used to reduce this pressure
to at least 90 mmHg. The average age of diabetics was about
55 years and they had an average BP of 163/97 mmHg. In
the overall trial, there was no difference in the primary
outcome between the two treatments. However, results in
the diabetic subpopulation showed that the composite
primary end-point was 41% less common in those treated
with captopril (RR 0.59, p=0.019). Myocardial infarction
was reduced by 66% (p=0.002), cardiovascular events by
33% (p=0.030) and total mortality by 46% (p=0.034).
Although the overall systolic BP was higher in the captopril
group, those randomized to captopril or conventional
therapy in the diabetic cohort had similar baseline BPs. Also,
the BP was slightly but significantly higher in the captopril
group throughout the trial. Despite poorer BP control and
once-daily dosage in 48% of the patients, the protective
effect of captopril was remarkable in the diabetic cohort.
These findings further support the nonhemodynamic
benefits of ACE inhibitors.28
Two smaller trials also support the evidence of the
cardiovascular protection provided by ACE inhibitors in
patients with diabetes and hypertension. The Appropriate
BP Control in Diabetes (ABCD) trial29 was a single-center,
randomized, controlled trial comparing the effects of
moderate control of BP (80–89 mmHg) with those of
intensive control (target diastolic BP <75 mmHg) on the
incidence and progression of complications of diabetes. In
each of the two groups, patients received enalapril or
nisoldipine, a long-acting dihydropyridine calcium-channel
blocker. Four hundred and seventy patients participated in
the trial and the primary end-point was the rate of change
of creatinine clearance measured every six months.
Cardiovascular end-points were secondary outcomes. The
trial was halted early at 67 months of the study by the Data
and Safety Monitoring Committee who observed a
significant difference in the rate of cardiovascular events
between the subgroups of patients treated with the study
IHJ-1A-005.p65
363
Treatment of Hypertension in Patients with Diabetes
363
drugs in the hypertensive cohort of the study. Patients had
an almost identical control of BP, diabetes and serum lipid
levels through the 5 years of the study; however, 25 episodes
of myocardial infarction were seen in the nisoldipine group
and 5 in the enalapril group. The risk ratio was 5.5 (95%
CI: 2.1–14.6) and 7.0 after adjustment for baseline
variables. The study demonstrates the cardiovascular
protection afforded by ACE inhibitors in diabetic patients
as compared to a long-acting calcium-channel blocker.
Fosinopril versus Amlodipine Cardiovascular Events Trial
(FACET)30 was an open-label trial of 380 hypertensive
patients with Type 2 diabetes assigned to fosinopril (20 mg/
day) or amlodipine (10 mg/day) and followed for up to 3.5
years. If BP was not controlled by one drug, the other was
added, such that at the end of the trial approximately onethird of the patients in each group were on fosinopril or
amlodipine, or both. The trial was designed to assess
comparability of lipid levels and glucose control, but like
the ABCD trial, cardiovascular outcomes were secondary
end-points. In this trial as well, there were more
cardiovascular events in the amlodipine group than the
fosinopril group. The combined risk of acute myocardial
infarction, stroke or angina requiring hospitalization was
14/189 v. 27/191 in the fosinopril and amlodipine groups,
respectively (hazards ratio 0.49, 95% CI: 0.26–0.95). This
was despite greater BP reduction (–19 mmHg systolic) in
the amlodipine group compared to the fosinopril (–13
mmHg systolic) group. In crude analyses, according to postrandomization treatment given to control BP, the patients
who received fosinopril only (n=131), amlodipine only
(n=141), and a combination of fosinopril plus amlodipine
(n=108) experienced 10, 27 and 4 major vascular events,
respectively. The study was not powered to measure the
benefit of combination therapy against monotherapy;
however, compared with the use of amlodipine only, the risk
of major vascular events was significantly decreased with
the use of fosinopril only and with the combination
treatment (hazards ratio 0.37, 95% CI: 0.18–0.77,
p=0.008 and hazards ratio 0.17, 95% CI: 0.06–0.50,
p=0.001, respectively).
Trials Reporting Older Antihypertensivebased Therapy
Other antihypertensive agents are effective in preventing
cardiovascular outcomes in patients with Type 2 diabetes
mellitus. The UKPDS trial, which used predominantly older
antihypertensive agents for treating patients with diabetes
and hypertension, has already been discussed. Three other
trials using older agents are discussed below.
8/16/01, 7:34 AM
364 Agarwal
Antihypertensive and Lipid-lowering therapy to
reduce Heart-attack (ALLHAT) trial: Since alphablockers are metabolically favorable and do not perturb
dyslipidemia in diabetics, they were recommended for these
patients. 31 However, the alpha-blocker arm of the
Antihypertensive and Lipid-lowering therapy to reduce
Heart-attack (ALLHAT) trial32 comparing four drugs—
chlorthalidone, lisinopril, doxazosin, and amlodipine—has
been halted. This was because the doxazosin group, as
compared to that given chlorthalidone, had a 19% higher
risk of stroke, 25% higher risk of combined cardiovascular
disease, double the risk of CHF, 16% higher risk
of angina and 15% higher risk of coronary
revascularization.33 These risks were also increased in the
diabetic subpopulation of the trial and were similar to the
non-diabetic population. This trial also confirms the
increased risk of cardiovascular events in patients with
diabetes; in this study, the risk was increased by 24% (12%–
38%), and that of heart failure by 114% (76%–159%)
compared to non-diabetics with hypertension and one
coronary risk factor. In the ALLHAT trial, the favorable
effect of chlorthalidone was demonstrated despite a fall in
potassium and increase in fasting glucose levels, and a
smaller decline in cholesterol compared to that in the
doxazosin group.
Systolic Hypertension in the Elderly Program (SHEP)
trial: In the Systolic Hypertension in the Elderly Program
trial,34 12% of the 4736 patients studied were diabetics and
were randomized to either a diuretic or beta-blocker-based
regimen compared to a group given a placebo to evaluate
cardiovascular end-points. Placebo-corrected fall in BP was
9.8/2.2 mmHg. There was improvement in all
cardiovascular end-points (34% reduction) and coronary
events (56% reduction). However, there was statistically
insignificant reduction in total mortality (–26%, 95%
CI: –54–18) and strokes (–22%, 95% CI: –55%–34%). These
results represent the most compelling evidence that
diuretics or beta-blockers are effective in reducing
hypertension-related complications even in a diabetic
population.
Swedish Trial in Old Patients with Hypertension-2
(STOP-2) trial: The primary objective of this randomized
controlled open-label trial was to compare fatal
cardiovascular events with calcium-channel blockers
(felodipine, isradipine) and ACE inhibitors (benazepril,
lisinopril), with conventional agents (diuretics or betablockers) in older hypertensives (age 70–84 years).35 Eleven
percent of the 6614 patients were diabetics. The primary
outcome of diabetics did not differ among the three
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Treatment of Hypertension in Patients with Diabetes
364
groups, suggesting that all these agents are equally
efficacious.
Trials Reporting Calcium-Channel
Blockers-based Therapy
Long-acting dihydropyridine calcium-channel
blockers: The diabetic subgroup of the HOT trial used
felodipine, a long-acting dihydropyridine calcium-channel
blocker, as first-line therapy for treatment of hypertension.
It was found to confer cardiovascular protection. This has
already been discussed. Three other trials using long-acting
dihydropyridine calcium-channel blockers are discussed
below.
Systolic Hypertension in Europe (Syst-Eur) and
Systolic Hypertension in China (Syst-China) trials:
Both these trials tested the utility of nitrendipine-based
therapy in preventing strokes in older patients with isolated
systolic hypertension. Other cardiovascular events were also
recorded as secondary end-points. The study groups of these
trials included10% and 4% of patients with diabetes
mellitus, respectively.
In the diabetic subgroup (n=492) of the Syst-Eur trial,36
BP was reduced by an average of 8.6/3.9 mmHg after a
median follow-up of 2 years. In the treated diabetic group,
after adjustment for confounding variables, strokes were
reduced by 73%, all cardiovascular end-points by 69% and
all combined cardiac events by 63%. Total mortality was
reduced by 55% and cardiovascular mortality by 76%.
These benefits were larger than those seen in the nondiabetic subgroup. For example, in the non-diabetic
subgroup, there was a 38% reduction in strokes and a 38%
reduction in combined cardiovascular events.
In the diabetic subgroup (n=98) of the Syst-China trial,37
placebo-corrected blood pressure reduction was 6/4.7
mmHg at 2 years. There were trends in reduction of
cardiovascular and total mortality, strokes and cardiac
events. Due to the small number of subjects, only total
cardiovascular end-points reached statistical significance
(risk reduction 74%, p=0.03).
Intervention as a Goal in Hypertension Treatment
(INSIGHT): This study asked the question: Does long-acting
nifedipine (GITS) reduce cardiovascular mortality in a highrisk hypertensive population compared to those treated by
a diuretic-based therapy?38 The primary end-points were
cardiovascular death, stroke, myocardial infarction and
congestive heart failure. Nifedipine was given to 3157
patients and 3164 patients received a hydrochlorothiazide
(HCTZ)/amiloride combination. A step-care approach was
used to reduce BP to <140/90 mmHg or cause a fall of at
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Agarwal
least 20/10 mmHg. The overall rate of primary outcome
was 18.2 events/1000 patient-years in the nifedipine group
and 16.5/1000 patient-years in the diuretic group (risk
ratio 1.11, p=0.34). There were 1302 diabetics in the study
who required additional treatment compared to nondiabetics for an equivalent fall in BP. The relative risk of
primary outcome was increased 1.47-fold with the presence
of diabetes. Amongst the diabetics, 8.3% in the nifedipine
group and 8.4% in the diuretic group had events—there
was no significant difference between the groups. Thus, the
trial results suggest that long-acting dihydropyridine
calcium-channel blockers were not damaging in patients
with diabetes mellitus when compared to diuretics.
Nondihydropyridine Calcium-Channel Blockers
The Nordic Diltiazem Study (NORDIL): The Nordic
Diltiazem Study (NORDIL)39 evaluated the role of diltiazem,
compared to older antihypertensive drugs, diuretics or betablockers in reducing cardiovascular morbidity and
mortality. It was an open-label, prospective randomized
study with blinded evaluation of end-points in 5410
patients receiving diltiazem and 5471 patients receiving
older antihypertensive drugs. A step-care approach was
used to reduce diastolic BP to <90 mmHg. In this trial, 727
patients were diabetics. Combined cardiovascular events
were similar in the two groups; however, strokes occurred
less in the diltiazem group (relative risk 0.8, p=0.04). The
diabetic subgroup had an almost two-fold higher
cardiovascular event rate but there were no differences
between diltiazem and diuretic/beta-blocker-based
regimens in cardiovascular outcomes.
Conclusions
In patients with diabetes, the target BP must be lower than
that for the general hypertensive population. The Joint
National Committee (JNC) VI9 guidelines call for a target
BP of <130/85 mmHg in diabetics. Based on data from the
HOT study, UKPDS and other trials, a target BP of <130/
80 mmHg in patients with diabetes and hypertension has
been suggested by the National Kidney Foundation to
prevent cardiovascular and microvascular complications.17
Analysis of observational data from the UKPDS cohort
suggests no threshold effect and a continuous reduction in
cardiovascular events with fall in systolic BP.16 The lowest
cardiovascular event rate was seen in diabetic patients with
a systolic BP of <120 mmHg. Thus, target BP in patients
with diabetes mellitus with hypertension may need to be
revised to <120/80 mmHg. In patients with overt
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365
Treatment of Hypertension in Patients with Diabetes
365
proteinuria of at least 1 g/day or more in a population of
largely non-diabetic patients, a mean arterial pressure of
<92 mmHg (BP <125/75 mmHg) was associated with the
best preservation of renal function.40 Therefore, proteinuric
patients, especially those with diabetes mellitus, need
aggressive BP control. Those with microalbuminuria may
also benefit from similar BP reduction. Should BP in
diabetics be lowered to below normotensive levels? Large
randomized trials are needed to answer this question.
Angiotensin-converting enzyme inhibitors should be
used as first-line agents in patients with diabetes and
hypertension. The cost-effectiveness of ACE inhibitors as
first-line agents for all patients with diabetes has also been
confirmed.41 But, as emphasized above, reaching the target
BP is even more important. Interestingly, both the HOPE
and CAPPP trials show less incidence of recent diabetes in
those randomized to the ACE inhibitor. In patients who are
intolerant to ACE inhibitors, for instance due to cough,
angiotensin-receptor (AT1) blockers are a logical second
choice. In fact, these guidelines may soon change and
emerging data suggest that AT1 blockers may be as valuable
as ACE inhibitors, at least in preventing microvascular
complications. Two large trials, the Reduction of Endpoints
in NIDDM with Angiotensin II Antagonist Losartan
(RENAAL) and the Irbesartan Type II Diabetic Nephropathy
Trial (IDNT), designed to demonstrate renal protection in
patients with Type 2 diabetes, showed a similar benefit of
about 28% reduction in death, dialysis or transplantation,
or doubling of serum creatinine with AT1 receptor
blockade. Other trials to assess the outcome with
angiotensin-II receptor blocking agents are ongoing. The
protective effects of ACE inhibitors are out of proportion to
those conferred by BP reduction alone. For example, the
difference between the placebo and ACE inhibitor arms of
the HOPE trial was only 3/2 mmHg in favor of the ACE
inhibitor; this magnitude of BP reduction would not be
sufficient to explain a 22% overall reduction in the rates of
death, myocardial infarction and strokes. Thus, this trial
lends support to the nonhemodynamic effects of these
agents in laboratory animals, which show reduction in
tissue fibrosis, cell proliferation, hypertrophy, inflammation
and vascular injury and improvement in fibrinolysis and
endothelial function.42
The target BP being lower in hypertensive diabetics, these
patients require the use of multiple agents over a period of
time as demonstrated by the UKPDS. Furthermore, it may
be harder to reduce BP in patients with diabetes.43 These
data suggest that more than two-thirds of patients will need
two or more agents to reach the target BP.17 Which secondline agent should be used? Diuretics or long-acting calcium-
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366 Agarwal
Indian Heart J 2001; 53: 361–369
Treatment of Hypertension in Patients with Diabetes
Table 1. Large randomized trials reporting outcomes in patients with diabetes mellitus and hypertension
Total number of
patients randomized
Diabetic
patients
% with
diabetes
Primary aim
Assess the role of BP control in patients with Type 2 diabetes to prevent
microvascular and macrovascular complications
Trials supporting aggressive BP lowering
United Kingdom Prospective Diabetes
Study-38 (UKPDS-38)
1148
1148
100%
18 790
1501
8%
Evaluate the role of diastolic BP or addition of aspirin on cardiovascular outcomes in
patients with essential hypertension
9541
3577
37%
Evaluate the role of ACE inhibitor, ramipril, or addition of vitamin E on outcomes in
patients with high risk for cardiovascular events
10 985
572
5%
Appropriate Blood Pressure Control in
Diabetes (ABCD) trial
470
470
100%
Evaluate the role of BP control in patients with Type 2 diabetes with enalapril or
nisoldipine on renal function
Fosinopril v. Amlodipine Cardiovascular
Events trial (FACET)
380
380
100%
Assess the role of fosinopril or amlodipine on lipid and glucose control in patients
with hypertension and diabetes
24 335
8664
36%
Evaluate the role of newer antihypertensive drugs (doxazosin, lisinopril, amlodipine)
to that of a diuretic (CTD) in preventing fatal coronary events or nonfatal MI
Systolic Hypertension in Elderly
Program (SHEP) trial
4736
583
12%
Test the role of diuretic-based regimens to prevent cardiovascular events in elderly
Americans with ISH
Swedish Trial in Old Patients with
Hypertension-2 (STOP-2) study
6614
719
11%
Compare the effects of ACE inhibition and calcium-channel blockers to conventional
therapy on cardiovascular morbidity and mortality in elderly patients with
hypertension
Systolic Hypertension in Europe Trial
(Syst-Eur)
4695
492
10%
Test the role of nitrendipine-based therapy to prevent stroke in elderly Europeans
with ISH
Systolic Hypertension in China Trial
(Syst-China)
2394
98
4%
Evaluate the role of nitrendipine-based therapy to prevent stroke in older Chinese
with ISH
Intervention as a Goal in Hypertension Treatment
(INSIGHT)
6575
1302
20%
10 881
727
7%
Hypertension Optimal
Treatment Trial (HOT)
ACE inhibitor-based trials
Heart Outcomes Prevention Evaluation
Trial (HOPE) diabetes subgroup
The Captopril Prevention Project
(CAPPP) trial
Compare the effects of ACE inhibition and conventional therapy on cardiovascular
morbidity and mortality in patients with hypertension
Older antihypertensive agents-based trials
Antihypertensive and Lipid-Lowering Therapy to
prevent Heart-attack Trial (ALLHAT) Doxazosin v.
CTD report
Calcium-channel blocker-based trials
The Nordic Diltiazem Study (NORDIL)
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366
Compare the reduction in cardiovascular morbidity and mortality with long-acting
nifedipine compared to diuretic (HCTZ-amiloride)-based therapy
Compare the reduction in cardiovascular morbidity and mortality with ditiazem
compared to diuretics and beta-blockers
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Treatment of Hypertension in Patients with Diabetes
367
Study population
Study design
Outcomes evaluated
Reference
Age 25–65 years, diabetes and hypertension
RCT, BP goal <180/105 mmHg (n=390) or <150/85 mmHg
(n=758). Latter group randomized to atenolol or captopril
First clinical end-point related to diabetes:
sudden death, death from hypo- or
hyperglycemia, or microvascular or
macrovascular complications
14
Age 50–80 years, essential hypertension
Patients randomized to 3 different DBPs, <80 mmHg,
<85 mmHg or <90 mmHg (n=6264 in each group). Half
in each group received aspirin 75 mg once daily. Step-care
approach with felodipine as first-line drug
All MI, strokes and cardiovascular deaths
counted
18
Age >55 years, previous cardiovascular event or
diabetes and one risk factor (smoking,
microalbuminuria, hypertension, high TC, low HDL)
DBRCT, ramipril (n=1808) or placebo (n=1769). Not a blood
pressure reduction trial. Half the patients in each group
randomized to vitamin E or placebo
Composite outcome of stroke, MI or death from
cardiovascular cause
19, 20
Age 25–66 years, treated or untreated primary
hypertension if diastolic BP was 100 mmHg or more
on two separate occasions. Patients with secondary
hypertension, renal failure or those needing betablockers excluded
PROBE, captopril (n=5492) or thiazide/beta-blocker (n=5493)based therapy. Step-care approach to lower DBP to 90 mmHg or
less. Initial therapy was with captopril 50 mg/day in one or two
doses, atenolol/metoprolol 50–100 mg/day in single dose or HCTZ
25 mg/day or bendrofluazide 2.5 mg/day
Composite end-point of stroke, MI and
cardiovascular deaths
27
Age 40–75 years, Type 2 diabetes, diastolic BP >80
mmHg, on no antihypertensive medications. Patients
with hypertension (DBP >90 mmHg) reported here
DBRCT, enalapril (n=235) or nisoldipine (n=235). Factorial 2×2
design. Aggressive BP control (DBP <75 mmHg) or less aggressive
BP control (DBP 80–89 mmHg). Follow-up mean of 6.1 years
Renal function measured every 6 months with
creatinine clearance. Cardiovascular outcomes
counted for secondary aim
29
Hypertensive Type 2 diabetics, patients with preexisting cardiovascular or renal disease excluded
Open-label trial with 380 hypertensive diabetics randomly assigned
to fosinopril (20 mg/day) or amlodipine (10 mg/day) and followed
up for up to 3.5 years. If BP not controlled, another study drug was
added. Thus, 58 patients in the fosinopril group and 50 patients in
amlodipine group received both drugs
Lipid profiles and HbA1C assessed.
Cardiovascular outcomes counted for
secondary aim
30
Age >55 years, hypertension plus one other
cardiovascular risk factor (previous MI, stroke, LVH,
Type 2 diabetes, smoking, low HDL)
DBRCT, active control. Present data limited to 24 335 patients
randomized to receive either CTD (12.5–25 mg o.d.) (n=15 268)
or doxazosin (2–8 mg q.d.), for a planned follow-up of 4–8 years.
BP target <140/90 mmHg with the least dose of the study drug.
Step 2 agent (atenolol 25–100 mg/day, reserpine 0.05–2 mg/day,
clonidine 0.1–0.3 mg/day). Step 3 drug (hydralazine 25–100 mg
b.,d.)
Composite outcome of fatal CHD and nonfatal
MI. Secondary outcomes:
1. all-cause mortality ,
2. combined CHD (CHD death, nonfatal MI.
revascularization, hospitalized angina),
3. stroke,
4. combined CVD: CHD death, nonfatal MI,
stroke, revasc, angina, CHF, PVD
32
Elderly, ISH
DBRCT. Placebo v. chlorthalidone (12.5–25 mg q.d.) +
atenolol (25–50 mg q.d.) or reserpine (0.05–0.1 mg q.d.)
to reduce systolic BP to <160 mmHg or by least 20 mmHg
for those with BP 160–179 mmHg
5-year rates of major cardiovascular events,
strokes, fatal and nonfatal MI, major CHD
events and total mortality
34
Age 70–84 years, BP 180/105 mmHg or higher.
PROBE, enalapril or lisinopril 10 mg/day (n=2205) or thiazide/
beta-blocker (n=2213) or feldodipine or isradipine 2.5 mg
(n=2195)-based therapy. Step–care approach to lower
BP <160/95 mmHg
Composite end-point: fatal stroke, fatal MI and
cardiovascular deaths
35
Elderly, ISH
DBRCT, placebo-(n=2297) or nitrendipine-(n=2398)-based
therapy. If BP not controlled, HCTZ (12.5–25 mg/day)
or enalapril (5–20 mg/day) or both were added. BP was
reduced by at least 20 mmHg systolic to <150 mmHg
Stroke. Other cardiovascular events were also
recorded as secondary objectives
36
Elderly, ISH
DBRCT, placebo-(n=1141) or nitrendipine (n=1253)-based therapy.
If BP not controlled, HCTZ or captopril was added. Patients were
stratified by center, sex and previous cardiovascular complications
Strokes. Other cardiovascular events were also
recorded as secondary objectives
37
Age 55–80 years, SBP > or =150 and DBP > or = 95
SBP = or > 160 mmHg after a 4-week placebo run-in
DBRCT, nifedipine 30 mm q.d. (n=3289) v. HCTZ–amiloride
(n=3286), target BP <140/90 mmHg or fall of at least 20/10
mmHg. Step-care approach to lower BP
Composite end-point: cardiovascular death,
strokes, MI, CHF
38
Age 50–69 years, DBP > or = 100 mmHg×2
PROBE, diltiazem or thiazide/beta-blocker-based therapy. Step-care
approach to lower DBP to <90 mmHg
Composite end-point: strokes, MI and
cardiovascular deaths
39
DBRCT: double-blind randomized controlled trial; RCT: randomized controlled trial; TC: total cholesterol; SBP: systolic blood pressure; DBP: diastolic blood pressure; HCTZ: hydrochlorothiazide; Elderly: >60 years age;
ISH: isolated systolic hypertension; PROBE: prospective, randomized, open-label, blinded end-point; MI: myocardial infarction; LVH: left ventricular hypertrophy; PVD: peripheral vasular disease; HDL: high-density lipoprotein; CTD:
chlorthalidone; CVD: cerebrovascular disease; CHF: congestive heart failure; CHD: coronary heart disease
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368 Agarwal
channel blockers would be a logical second choice because
of the synergistic BP reduction seen with ACE inhibitors
and their safety in the diabetic population as noted in
trials.44 My first choice is the addition of a diuretic. Shortacting dihydropyridine calcium-channel blockers, such as
nifedipine, that may cause a sudden and unpredictable drop
in BP and increase mortality, should not be used.45 The
UKPDS and SHEP studies have shown the benefit of betablockers which should be included in the regimen of any
patient with coronary artery disease. However, alphablockers should be used as a last resort because they
compare unfavorably with diuretics. In patients with renal
disease, loop diuretics may be required to reduce sodium
and volume overload, and improve BP control.46 Physicians
should not hesitate to use combination therapy to improve
patient compliance, and patient participation should be
encouraged through simple programs such as home BP
monitoring.47 Attention to other modifiable risk factors such
as dyslipidemia, hyperglycemia and atherosclerosis (aspirin
use) is important. Trials that reduce homocysteine with
folic acid and vitamins B6 and B12 are still being carried out
(Table 2).
Finally, the importance of diabetes prevention cannot be
overemphasized. In a recent study, a program of regular
exercise, weight loss and dietary control (restricting total
and saturated fat, and increasing dietary fiber) was effective
in reducing the risk of developing diabetes mellitus by 58%
over less than 3.5 years in patients with impaired glucose
tolerance. 48 Such programs may not only curtail the
epidemic of diabetes mellitus but also its attendant
cardiovascular complications. Dietary interventions such
as the institution of a diet rich in fruits and vegetables and
Table 2. Management of hypertension in diabetes mellitus
Target BP <130/80 mmHg
If proteinuria >1 g/day, target BP <125/75 mmHg
There is no threshold limit of benefit, the lower the BP the less
the cardiovascular mortality
Agent of choice: ACE inhibitors
If BP not at goal, add low-dose HCTZ (6.25–12.5 mg/day)
If BP not at goal, titrate up ACE inhibitor
If BP not at goal, increase diuretic dose (maximum dose 25 mg
HCTZ, if patient has no renal failure)
Add third agent, beta-blockers preferred due to cardioprotective
effect
Add fourth agent, long-acting calcium-channel blockers
If still not at goal; assess compliance, dietary sodium intake, renal
function
Assess and treat: atherosclerosis (aspirin), dyslipidemia (goal LDL
<100 mg/dL) and glucose
?Folic acid, vitamin B6 and vitamin B12 for reducing homocysteine
HCTZ: hydrochlorothiazide
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Treatment of Hypertension in Patients with Diabetes
368
low-fat dairy products, such as the “DASH diet”,49 adopted
with the aid of a dietitian, are also useful in reducing blood
pressure, the public health benefits of which can be
substantial. As we strive to maximize the value of our
resources, these nonpharmacologic interventions can be of
particular value in the care of patients with diabetes
mellitus and hypertension.
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to Prevent Heart Attack Trial. JAMA 2000; 283: 2013–2014
34. Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Black H, et
al. Effect of diuretic-based antihypertensive treatment on
cardiovascular disease risk in older diabetic patients with isolated
systolic hypertension. Systolic Hypertension in the Elderly Program
Cooperative Research Group [published erratum appears in JAMA
1997; 277: 1356]. JAMA 1996; 276: 1886–1892
35. Hansson L, Lindholm LH, Ekbom T, Dahlof B, Lanke J, Schersten B, et
al. Randomised trial of old and new antihypertensive drugs in elderly
patients: cardiovascular mortality and morbidity: the Swedish Trial
in Old Patients with Hypertension-2 study. Lancet 1999; 354: 1751–
1756
36. Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L, Antikainen R,
Bulpitt CJ, et al. Effects of calcium-channel blockade in older patients
with diabetes and systolic hypertension. Systolic Hypertension in
Europe Trial Investigators. N Engl J Med 1999; 340: 677–684
37. Wang JG, Staessen JA, Gong L, Liu L. Chinese trial on isolated systolic
hypertension in the elderly. Systolic Hypertension in China (SystChina) Collaborative Group. Arch Intern Med 2000; 160: 211–220
38. Brown MJ, Plamer CR, Castaigne A, de Leeuw PW, Mancia G,
Rosenthal T, et al. Morbidity and mortality in patients randomised to
double-blind treatment with a long-acting calcium-channel blocker
or diuretic in the International Nifedipine GITS study: Intervention
as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000; 356:
366–372
39. Hansson L, Hedner T, Lund-Johansen P, Kjeldsen SE, Lindholm LH,
Syvertsen JO, et al. Randomised trial of effects of calcium antagonists
compared with diuretics and beta-blockers on cardiovascular
morbidity and mortality in hypertension: the Nordic Diltiazem
(NORDIL) study. Lancet 2000; 356: 359–365
40. Lazarus JM, Bourgoignie JJ, Buckalew VW, Greene T, Levey AS, Milas
NC, et al. Achievement and safety of a low blood pressure goal in
chronic renal disease. The Modification of Diet in Renal Disease Study
Group. Hypertension 1997; 29: 641–650
41. Golan L, Birkmeyer JD, Welch HG. The cost-effectiveness of treating
all patients with type 2 diabetes with angiotensin-converting enzyme
inhibitors. Am Intern Med 1999; 131: 660–667
42. Goodfriend TL, Elliott ME, Catt KJ. Angiotensin receptors and their
antagonists. N Engl J Med 1996; 334: 1649–1654
43. Brown MJ, Castaigne A, de Leeuw PW, Mancia G, Palmer CR,
Rosenthal T, et al. Influence of diabetes and type of hypertension on
response to antihypertensive treatment. Hypertension 2000; 35:
1038–1042
44. Dickerson JE, Hingorani AD, Ashby MJ, Palmer CR, Brown MJ.
Optimisation of antihypertensive treatment by crossover rotation of
four major classes. Lancet 1999; 353: 2008–2013
45. Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose-related increase in
mortality in patients with coronary heart disease. Circulation 1995;
92: 1326–1331
46. Shemin D, Dworkin LD. Sodium balance in renal failure. Curr Opin
Nephrol Hypertens 1997; 6: 128–132
47. Kleinert HD, Harshfield GA, Pickering TG, Devereux RB, Sullivan PA,
Marion RM, et al. What is the value of home blood pressure
measurement in patients with mild hypertension? Hypertension 1984;
6: 574–578
48. Tuomilehte J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H,
Ilanne-Parikka P, et al. Prevention of type 2 diabetes mellitus by
changes in lifestyle among subjects with impaired glucose tolerance.
N Engl J Med 2001; 344: 1343–1350
49. Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks FM,
et al. A clinical trial of the effects of dietary patterns on blood pressure.
DASH Collaborative Research Group. N Engl J Med 1997; 336:
1117–1124
8/16/01, 7:34 AM
How To Do It
Indian Heart J 2001; 53: 370–371
Extrathoracic Subclavian Venepuncture
for Pacemaker Implantation
AK Kar, Debabrata Roy, Manoranjan Mondal, Indranil Dutta
Department of Cardiology, IPGMER, Calcutta
S
everal techniques are used for the introduction of a
permanent pacing lead. These are cephalic venotomy,
intrathoracic subclavian venepuncture (ISV) and
extrathoracic subclavian venepuncture (ESV).
The most widely used technique is ISV, first introduced
by Littleford et al.1 in 1979. However, this procedure is
expensive since it requires a percutaneous lead introducer
(PLI) and lead wastage could occur due to lead fracture or
insulation damage due to the crush syndrome, or entry of
the lead at an acute angle into the subclavian vein. It is also
associated with a small but significant percentage of serious
complications such as pneumothorax, hemothorax and
brachial plexus injury.
These shortcomings led to a renewal of interest in the
older procedure of cephalic venotomy. Though an old
technique, it still remains the easiest, safest and most
economical of the three procedures. Unfortunately, cephalic
venotomy fails in 15% of patients due to absence or extreme
slenderness of the vein, or due to an inadvertent tear of the
vein during the introduction of the lead. This calls for an
alternative approach.
In 1993, Magney et al.2 introduced the technique of ESV,
which is easier and safer than ISV. In this procedure, the
subclavian vein is entered more laterally than in the ISV
technique.
rib (Fig. 1). For venepuncture, the needle is directed from
the entry point to below and behind the target point on the
clavicle. The entry and target points are marked on the skin
by superficial abrasions, preferably before antiseptic
dressing and draping, when the patient is in a supine
position on the table. Using the needle (18 G) of the PLI,
ESV is accomplished either before or after making an
incision for the pacemaker pocket (Fig. 2). In the former
situation, the pacemaker pocket is made by an incision
starting from the entry point and extending up to the
deltopectoral groove laterally, 2 cm below and parallel to
the clavicle. At the time of venepuncture, the patient is put
in the Trendelenburg position (to dilate the subclavian vein)
and the needle is advanced from the entry point to the
under-surface of the clavicle behind the target point or a
little (1–2 cm) below it. If the puncture is not successful,
the needle is withdrawn, landmarks verified and the
Technique of extrathoracic subclavian
venepuncture (ESV)
First, body landmarks are identified: (i) the coracoid process;
(ii) the middle of the sternal angle; and (iii) the medial
and lateral ends (i.e. acromioclavicular joint and
sternoclavicular joint) of the clavicle. For ESV, the entry
point of the needle is the junction of the medial two-third
and lateral one-third of the line joining the coracoid process
of the scapula and the mid-point of the sternal angle. The
target point is the junction between the medial one-third
and lateral two-third of the clavicle,3 which is the site where
the subclavian vein (SV) enters the thorax crossing the first
Correspondence: Professor AK Kar, 82A, Chowringhee Road,
Calcutta 700020
IHJ-161-01.p65
370
Fig. 1. Relationships between the extrathoracic subclavian vein, clavicle, first
rib, and the soft tissues of the costoclavicular region. The two lines identify
anatomical landmarks.
Cp: coracoid process; E: needle entry point; L: lateral border of the clavicle;
M: medial border of the clavicle; Sa: sternal angle; T: target point
8/16/01, 7:35 AM
Indian Heart J 2001; 53: 370–371
Kar et al.
Extrathoracic Subclavian Venepuncture
371
without any major adverse outcome. The safety of this
procedure is explained by the relationships between the
extrathoracic portion of the subclavian vein and
surrounding vital structures.3 At the site of the puncture,
the first rib protects the underlying apex of the lung and
the subclavian artery behind the vein. The major
lymphatics, other blood vessels and nerves are medial to
the path of the venepuncture needle. In difficult cases, i.e.
in obese patients and those with a deformed chest wall
anatomy, one can use fluoroscopy to determine the
relationship between the first rib and the needle path. Even
in the hands of the inexperienced, complications are
remarkably few. Fracture or insulation damage of the lead
is rare. This is due to the fact that the lead is not entrapped
in the subclavius muscle or costoclavicular ligament and is
thus protected from the mechanical stress of certain
shoulder girdle movements.
Fig. 2. Illustration of the extrathoracic subclavian venepuncture technique with
the needle inserted through a classic infraclavicular pacemaker pocket. The arrow
indicates the point where the operator’s thumb should be located to shield the
subclavius muscle from the needle.
procedure repeated without moving the needle sideways so
as to avoid vascular injury. If the venepuncture is successful,
a guidewire is introduced through the needle up to the right
atrium under fluoroscopic control. The Trendelenburg
position is then reversed to avoid bleeding. The lead is
inserted by substituting the guidewire with the sheath of
the PLI in the usual manner. If two leads are to be inserted,
a second guidewire is inserted before peeling off the sheath.
The technique of ESV described above is the anatomic
blind method. We have successfully used this technique in
102 cases of pacemaker implantation in the last 18 months.
Other methods using echocardiography, fluoroscopy and
contrast guidance have also been reported.5–8 At times we
took the help of fluoroscopy to visualize the relationships
between the needle path, rib and clavicle if initial attempts
at the anatomic blind method failed.
Discussion
For inserting a lead during the implantation of a pacemaker, ESV is an easy and safe procedure. The success rate
of this technique (>90%) is higher than that for ISV and it
is free from major complications such as pneumothorax,
hemothorax and brachial plexus injury. 2 The only
complication encountered by us was an inadvertent
puncture of the subclavian artery in 2 cases (out of 102),
IHJ-161-01.p65
371
Conclusions: Extrathoracic subclavian venepuncture is a
safe and effective technique of inserting one or two
permanent pacing leads either through the classic
pacemaker pocket or before making the pocket. Proper
localization of bony landmarks is an important prerequisite
for successful ESV. The failure rate and incidence of
complications with the ESV are less than that with the ISV
technique. Moreover, ESV is not only simpler and therefore
preferable to ISV, but long-term lead-related complications
are also less.
References
1. Littleford PO, Parsonnet V, Spector SD. Method for the rapid and
atraumatic insertion of permanent endocardial pacemaker electrodes
through the subclavian vein. Am J Cardiol 1979; 43: 980–982
2. Magney JE, Staplin DH, Flynn DM, Hunter DW. A new approach to
percutaneous subclavian venipuncture to avoid lead fracture or
central venous catheter occlusion. Pacing Clin Electrophysiol 1993;
16: 2133–2142
3. Gardini A, Benedini G. Blind extrathoracic subclavian venipuncture
for pacemaker implant: a 3-year experience in 250 patients. Pacing
Clin Electrophysiol 1998; 21: 2304–2308
4. Magney JE, Flynn DM, Parsons JA, Staplin DH, Chin-Purecell MV,
Milstein S, et al. Anatomical mechanisms explaining damage to
pacemaker leads, defibrillator leads and failure of central venous
catheters adjacent to the sternoclavicular joint. Pacing Clin
Electrophysiol 1993; 16: 445–457
5. Fyke FE III. Doppler guided extrathoracic introducer insertion. Pacing
Clin Electrophysiol 1995; 18: 1017–1021
6. Nash A, Burrell CJ, Ringh NJ, Marshall AJ. Evaluation of an
ultrasonically guided venepuncture technique for the placement of
permanent pacing electrodes. Pacing Clin Electrophysiol 1998; 21:
425–455
7. Byrd CL. Clinical experience with the extrathoracic introducer
insertion technique. Pacing Clin Electrophysiol 1993; 16: 1781–1784
8. Spencer W III, Kirkpatrick C, Zhu DWX. The value of venogram
guided percutaneous extrathoracic subclavian venipuncture for lead
implanation (Abstr). Pacing Clin Electrophysiol 1996; 19: 700
8/16/01, 7:35 AM
Cardiovascular Images
Indian Heart J 2001; 53: 372–373
Extensive Arterial Calcification in Aortoarteritis
V Sivakumar, Shekhar Rao, A Yadagiri Lakshmi, C Krishna Reddy
Departments of Nephrology and Cardiovascular Surgery
Sri Sathya Sai Institute of Higher Medical Sciences, Prashanthi Gram, Anantapur, Andhra Pradesh
Fig. 2. Calcification of carotid and subclavian arteries
Fig. 1. Extensive calcification of the brachial artery
Correspondence: Dr V Sivakumar, Head of Nephrology, Sri Sathya Sai
Institute of Higher Medical Sciences, Prashanthi Gram, Anantapur District,
Andhra Pradesh 515134
IHJ-839-00.p65
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Fig. 3. Calcification of celiac trunk and left femoral artery
8/16/01, 7:37 AM
Indian Heart J 2001; 53: 372–373
A
Sivakumar et al.
33-year-old male presented with a history of painless
progressive swellings in both elbows, the upper part
of the neck, popliteal fossae and the left groin. He was a
known hypertensive for the past 10 years. He had symptoms
of crural vascular claudication for the past one year but on
examination there were no ischemic changes. He gave no
history of syncope, dizziness, post-prandial abdominal
discomfort, tuberculosis or syphilis. On evaluation, the
swellings were vascular in origin; pulsations were absent
in the carotid, brachial, popliteal and femoral arteries
bilaterally. The blood pressure could not be recorded in any
of the four limbs. There was no parathyroid enlargement.
On investigation, the hemoglobin level was 9.2 g%, total
leukocyte count was 6800/cmm, differential leukocyte
count showed 59% polymorphs, 38% lymphocytes, 3%
eosinophils and the ESR showed a 5 mm fall in the first hour.
Urinalysis showed a 2+ proteinuria and no abnormal
sediments. The serum creatinine level was 1.9 mg%, blood
urea 40 mg% and blood sugar 99 mg%. Serum total proteins
were 7.8 g%, albumin:globulin ratio 5.3:2.5, serum sodium
140 mEq/L, serum potassium 4.4 mEq/L, serum calcium
9.3 mg% and serum phosphate 2.7 mg%. The fundus
showed Grade II hypertensive retinopathy. Plain X-rays
showed extensive calcified arteries with large mass
formation in the brachials (Fig. 1), carotids, subclavians
(Fig. 2), left femoral (Fig. 3) and abdominal visceral arteries.
Echocardiography showed concentric left ventricular
hypertrophy with mild mitral regurgitation. Ultrasound of
the kidneys revealed a contracted right kidney with loss of
cortico-medullary differentiation and a normal-sized left
kidney with calcification at its hilum. In view of these
findings, a diagnosis of aortoarteritis with significant
IHJ-839-00.p65
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Extensive Arterial Calcification in Aortoarteritis
373
arterial calcification was made.
Aortoarteritis is a chronic panarteritis of the large
elastic arteries. Though this disease has a worldwide
distribution, it is common in South-East Asia and rare in
European and North American countries.1 Aortoarteritis
is a chronic disorder of the great arteries resulting in
diminished caliber and insufficient blood flow to the areas
supplied by these vessels.2 Initial descriptions were recorded
by Davy (1839), Broadbent (1875), Turp (1901) and
Takayasu (1908).3 Etiologically, though tuberculosis and
syphilis were suspected initially, autoimmunological and
genetic abnormalities with specific HLA associations (A9,
A10, B5, B40, BW2) are presently under consideration.1
Pathologically, it is a panarteritis of the large elastic arteries
with mononuclear and giant cell infiltration of all the layers
of the arterial wall. Additional findings include intimal
proliferation, fibrosis, disruption of the elastic lamina,
aneurysm formation and calcification. In a study by Jain et
al.1 calcification was reported in the abdominal aorta in
0.4% and in the arch of the aorta in 3.2% of cases. The
point of interest in this patient was the finding of unusual,
extensive, dense and nodular calcification of all the major
arteries.
References
1. Jain S, Sakhuja J, Chugh KS. Takayasu’s arteritis—an oriental or a
worldwide disease. In: Chugh KS (ed). Asian Nephrology. Delhi: Oxford
University Press, 1994; pp. 311–316
2. Hedges TR. The aortic arch syndromes. Arch Ophthalmol 1964; 71:
27–34
3. Tour RL, Hoyt WF. The syndrome of the aortic arch: ocular
manifestations of “pulseless disease” and report of a surgically treated
case. Am J Ophthalmol 1959; 47: 35–48
8/16/01, 7:37 AM
Selected Summaries
Indian Heart J 2001; 53: 374–377
Randomized, Single-blind, Placebo-controlled Pilot Study of Catheter-based Myocardial
Gene Transfer for Therapeutic Angiogenesis Using Left Ventricular Electromechanical
Mapping in Patients with Chronic Myocardial Ischemia
Vale PR et al.
Circulation 2001; 103: 2138–2143
Summary
Comments
In this pilot study by Jeffery Isner and his group, 6 patients
of drug refractory, end-stage coronary artery disease (CAD),
unsuitable for angioplasty or coronary artery bypass
grafting (CABG) were randomized (1:1) to receive catheterbased myocardial gene transfer of naked plasmid DNA
encoding vascular endothelial growth factor-2 (ph VEGF2) or placebo (mock procedure) into ischemic myocardium.
Patients received 6 injections of ph VEGF-2 (total dose
200 µg) or placebo by a steerable, deflectable 8 F catheter
incorporating a 27-gauge needle advanced percutaneously
to the left ventricular myocardium. Injections were guided
by NOGA left ventricular electromechanical mapping.
Patients in the placebo arm became eligible for crossover
into the gene therapy group if they had no clinical
improvement 90 days after the mock procedure. Catheter
injections (n=36) were well tolerated and there were no
complications as a result of the procedure. Patients in the
gene therapy group experienced reduced angina (36.2±2.3
v. 3.5±71.2 episodes/week) and reduced nitroglycerin
(NTG) consumption (33.8±2.3 v. 4.1±1.5 tablets/week)
after gene delivery and the effect persisted for at least 360
days. Electromechanical mapping also demonstrated a
reduction in the mean area of ischemia (10.2±3.5 v.
2.8±1.6 cm2, p=0.04) and improved myocardial perfusion
by SPECT sestamibi scanning for up to 90 days. In contrast,
in patients randomized to the placebo arm, clinical
improvement was not sustained beyond 30 days. Similarly,
patients in the placebo arm demonstrated no improvement
in electromechanically obtained mean area of ischemia
(9.9±6.7 v. 9.6±6.3 cm2) at 90 days and no improvement
in SPECT myocardial perfusion. In fact, all the 3 patients
randomized to the placebo group crossed over to the gene
therapy group as per the provision made in the protocol of
the trial. This trial demonstrates the feasibility, safety and
potential efficacy of percutaneous myocardial gene transfer
to human left ventricular myocardium.
The number of patients with end-stage CAD is continuously
increasing, with some of the western reports quoting the
prevalence to be as high as 30%. However, these patients
pose a therapeutic dilemma. They are drug refractory and
their lesions are unsuitable for conventional therapy such
as angioplasty or CABG. Several emerging therapies have
been tried in this situation with variable results. Initially,
transmyocardial laser revascularization was found to
provide clinical benefits in terms of relief of angina and
decrease in NTG consumption, but this therapy failed to
show improvement when objective hard end-points such
as improvement in thallium images were taken into
consideration. Recently, the DIRECT trial, a randomized,
placebo-controlled trial, showed no advantage in the laser
group. In this context, angiogenic gene therapy has
consistently shown improvement in objective parameters
of ischemia on radionuclide imaging and electromechanical
mapping in animal models and in human subjects. This is
the first randomized, placebo-controlled pilot study which
has shown both subjective and objective improvement in
ischemia after delivery of the plasmid VEGF-2 gene to
ischemic myocardium as compared to no improvement in
the placebo group. However, there are several limitations
of the present study. First of all, the sample size is too small
and the primary end-point of the study was safety and
feasibility of gene delivery, not efficacy. Second, VEGF is
associated with capillary angiogenesis (i.e. capillary
collaterals less than 15 µ in size) and not arterial collaterals
(approximately 100 µ in size), and therefore the dramatic
and sustained improvement in the VEGF gene therapy group
seems remarkable. Recently, it has been realized that
arteriogenesis rather than angiogenesis should be the goal
of this therapy and therefore therapy with the VEGF gene
alone may be inadequate. Finally, in this study, patients but
not the physicians were blinded to the treatment and
therefore a possibility of bias exists. This report suggests that
it is feasible to replace currently employed operative
approaches with catheter-based techniques for gene
therapy.
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Indian Heart J 2001; 53: 374–377
Selected Summaries 375
Stenting Versus Thrombolysis in Acute Myocardial Infarction Trial (STAT)
Le May MR et al. J Am Coll Cardiol 2001; 37: 985–991
Summary
Comments
STAT was a randomized trial comparing the efficacy of
primary stenting with that of accelerated tissue
plasminogen activator (t-PA) in patients presenting with
acute ST elevation myocardial infarction (AMI). One
hundred and twenty-three Canadian patients presenting
with AMI were randomized to primary stenting (n=62) or
thrombolysis (n=61). Exclusion criteria for enrollment in
the study were cardiogenic shock, active bleeding, history
of stroke, previous coronary artery bypass grafting (CABG),
renal failure and percutaneous transluminal coronary
angioplasty (PTCA) within the preceding 6 months.
Immediate angiography was performed in 61 patients
assigned to primary stenting and based on the angiographic
picture, stents could be successfully deployed in 50 patients
(81%). Plain balloon angioplasty was performed in 2
patients. Four had primary CABG for left main coronary
artery stenosis or triple vessel disease (TVD) and the
remaining 5 were treated with medical therapy (diffuse
disease or <70% stenosis in infarct-related artery [IRA]).
Abciximab was given to only 12 patients (19.4%). An
average of 1.3 stents were implanted per patient, at a mean
pressure of 14.2±2.3 atm. A residual diameter stenosis
<50% was achieved in all stented patients. Patients in the
thrombolysis group received accelerated t-PA and heparin.
Unscheduled angiography was performed in 39 patients
(63.9%) in the t-PA group for unabated chest pain associated
with ST segment elevation, or deteriorating hemodynamic
status. The primary end-point of the study was the
composite of death, reinfarction, stroke or repeat target
vessel revascularization (TVR) for ischemia at six months.
The event rates for the stent versus the t-PA group were as
follows: mortality 4.8% v. 3.3%, reinfarction 6.6% v. 16.4%,
stroke 1.6% v. 4.9%, (no statistically significant difference).
However, repeat TVR for ischemia was statistically lower in
stent group (14.5% v. 49.2%, p<0.001). Overall, the
primary end-point at six months was significantly reduced
in the stent group as compared to the t-PA group (24.2% v.
55.7%, p<0.001).
Thrombolytic therapy is widely used for AMI despite
continuing controversy about its clinical effectiveness.
Historically, the use of intravenous thrombolytic therapy
has resulted in a 13%–50% decline in short-term mortality,
depending upon the time of initiation of therapy . Primary
angioplasty is better in establishing vessel patency and in
achieving grade 3 TIMI flow (an important consideration
for subsequent prognosis). Concerns with primary
angioplasty are delay in administering treatment and
higher cost. Trials comparing primary PTCA with t-PA, such
as PAMI and GUSTO-IIB, have shown that PTCA reduces
death, reinfarction or stroke at 30 days but not at 6 months.
This loss of benefit has been presumed to be due to reocclusion and restenosis. In this context, primary stenting
may provide several clinical benefits over plain balloon
angioplasty, namely better immediate result,bigger
minimum luminal diameter (MLD) and lower rate of
restenosis. Indeed, randomized trials comparing primary
PTCA with primary stenting, as in the stent–PAMI and
STENTIM-2 studies, have shown reduction in the 6-month,
composite end-point of death, reinfarction, stroke or repeat
TVR, as well as reduced restenosis rates with stenting.
However, in these studies randomization was performed
only after angiography and therefore may not represent the
actual clinical situation. In the present study, randomization
was performed at the outset and patients enrolled on an
intention-to-treat basis. This study has shown that a policy
of primary stenting is clearly superior to accelerated t-PA.
However, the study has several limitations. Because of the
small sample size, the effect of primary stenting on
mortality could not be addressed. In fact, mortality was
slightly higher in the primary stenting group (4.8% v. 3.3%).
Out of 218 patients presenting with AMI, only 123 could
be randomized due to various reasons. Furthermore, the
crossover rate from the t-PA to the angioplasty group was
11.5%. The routine use of abciximab was discouraged early
in the trial; as a result only 12 patients (19.4%) received
this therapy in the stent group. Several studies have shown
that concomitant use of abciximab in high-risk situations
such as AMI leads to better myocardial salvage and a better
clinical outcome.
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Indian Heart J 2001; 53: 374–377
376 Selected Summaries
Novel Dosing Regimen of Eptifibatide in Planned Coronary Stent Implantation
(ESPRIT): A Randomized Placebo-controlled Study
The ESPRIT Investigators. Lancet 2000; 358: 2037–2044
Summary
The ESPRIT was a double-blind, randomized, placebocontrolled trial conducted at 92 centers in the USA and
Canada to test the efficacy of a new dosing regimen of the
glycoprotein (Gp) IIb/IIIa inhibitor—eptifibatide—in 2064
low-risk patients undergoing percutaneous coronary
interventions (PCIs) with elective stent implantation. Of
note was the fact that all patients with accepted indications
for these drugs were excluded, i.e. fresh myocardial
infarction within 24 hours and unstable angina needing
PCI. Other exclusion criteria were PCI within the previous
90 days, previous stent implantation at the site, treatment
with a Gp IIb/IIIa inhibitor or a thienopyridine within the
last 30 days, and any history suggestive of a bleeding
diathesis or recent stroke. The other important aspect was
the use of a novel dosing strategy of two boluses of 180
µg/kg given 10 min apart and an infusion of 2 µg/kg/min
for 18–24 hours, so as to achieve >80% inhibition of
platelet Gp IIb/IIIa receptor. The primary end-point was a
composite of death, myocardial infarction, urgent target
vessel revascularization and bail-out Gp IIb/IIIa inhibitor
therapy within 48 hours. The secondary end-point was the
composite of death, myocardial infarction and urgent target
vessel revascularization at 30 days. Heparin was given in a
dose of 60 U/kg (not exceeding 6000 U) to achieve an
activated clotting time (ACT) of 200–300 seconds. Any
stent design was allowed as per operator preference (over
20 types), though no Palmaz–Schatz stents were used. A
bail-out strategy was also provided for patients with abrupt
closure, no-reflow and coronary thrombosis, where the
study drug was discontinued and open-labelled eptifibatide
was given. Almost all patients received a thienopyridine
(97%) as well as stents (96.2% in the treated group and
98.2% in the placebo group). Though total mortality was
not different (0.1% v. 0.2%), the 43% reduction in the endpoints of death or myocardial infarction at 48 hours (5.5%
v. 9.2%, p=0.0013) and the 40% reduction in the primary
end-point (6.6% v. 10.5%, p=0.0015) in the eptifibatide
group led to the premature termination of the trial by the
data and safety monitoring board. The benefit was found
to be consistent to the same degree at 30 days, and occurred
irrespective of baseline variables such as age, weight, sex,
diabetes and disease presentation. The rate of major
bleeding was higher (1.1% v. 0.4%, p=0.027), and 2 cases
of severe thrombocytopenia occurred in the treated group.
Investigators concluded that routine pretreatment with
IHJ-Selected Summary.p65
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eptifibatide substantially reduces ischaemic complications
in coronary stent intervention.
Comments
The results of this study are concordant with the available
data on the GpIIb/IIIa inhibitor abciximab, in the EPISTENT,
EPIC and EPILOG studies, though this is the first time such
salutary benefits have been reported with eptifibatide. This
may stress the point that the real determinant of outcome
following PCI is perhaps the degree of platelet inhibition
achieved (>80%), and not the type of Gp IIb/IIIa inhibitor
used. The reduction in the secondary end-point at 30 days
is similar to the observed benefit in EPISTENT (10.5% to
6.9%, in ESPRIT v. 8.9% to 5.2% in EPISTENT). This is
despite the fact that the ESPRIT patients were a low-risk
PCI population in whom abciximab is generally not used,
compared with the high-risk patients included in EPISTENT.
In addition, bail-out use of eptifibatide would have lowered
the event rate in the placebo group of ESPRIT, thus narrowing
the difference between the two groups. In contrast, previous
studies (IMPACT-II), with a conventional dose of eptifibatide
in which only approximately 50%–60% inhibition of platelet
aggregation was achieved, could not duplicate the benefits
seen with abciximab. This highlights the importance of
optimal platelet inhibition in routine elective PCI utilizing
stents. One factor that could have increased events in the
placebo group was the use of a low dose of heparin (60 U/
kg), but the event rates in the placebo group were not different
in the lowest versus highest tertiles of ACT. However, major
bleeding was higher in the highest tertile of ACT in the
eptifibatide group, thus leading the investigators to suggest a
target ACT of 200–250 seconds, when this drug is used in
the recommended dose. The incidence of thrombocytopenia
was lower (0.2%) in this study, compared to the 0.7% reported
with abciximab. The Gp IIb/IIIa inhibitors are the only
therapeutic modality thus far to have decreased the
incidence of fatal and non-fatal myocardial infarction and
repeat target vessel revascularization, an outcome that was
not seen even with the use of stents.
These findings support the use of Gp IIb/IIIa inhibitors
in patients undergoing PCI, whether elective or high-risk.
Cost constraints have thus far militated against their routine
use, at least in countries like India. The cost advantage of
eptifibatide over abciximab, while preserving the
therapeutic utility, may help in increasing its use during
routine PCI in our country.
8/16/01, 7:38 AM
Indian Heart J 2001; 53: 374–377
Selected Summaries 377
Stable Ventricular Tachycardia is not a Benign Rhythm: Insights from the AVID Registry
Rait MH et al.
Circulation 2001; 103: 244–252
Summary
Comments
The Antiarrhythmics versus Implantable Defibrillators
(AVID) trial showed significantly reduced mortality with
implantable cardioverter–defibrillator (ICD) in patients with
unstable ventricular tachycardia (VT), i.e. patients with
VT having syncope, left ventricular ejection fraction
(LVEF) <0.40%, and angina or significant hemodynamic
compromise during VT. Patients with sustained, stable VT
were not included in the trial because the risk of arrhythmic
death in this group was thought to be too low. However,
these patients were enrolled in the AVID registry and their
clinical characteristics and discharge treatments were
recorded. Mortality data were obtained through the
National Death Index. Thus, in the AVID registry, two
groups of patients were available for comparison—440
patients with stable VT and 1029 patients with unstable
VT. The group with stable VT had a higher LVEF, less
congestive heart failure, were less likely to be smokers, and
more likely to have a history of previous VT or to be on
antiarrhythmic therapy at the time of the index arrhythmia.
Patients with stable VT were less likely to receive an ICD,
were more likely to receive antiarrhythmic drug therapy
without an ICD, were more likely to receive no specific
antiarrhythmic therapy and were more likely to have
catheter ablation for VT.
The stable VT patients tended to have a higher mortality
(33.6% v. 27.6%) at 3 years with a relative risk (RR) of death
of 1.22 (p=0.07). The most important interaction was
found between β-blocker therapy and type of VT. The
mortality was similar in both types of VT not on β-blockers,
but there was significant mortality reduction in the unstable
VT but not in stable VT patients given β-blockers. The
investigators concluded that stable VT is not a low-risk
arrhythmia and that ICD implantation may reduce
mortality in this group of patients.
This is a retrospective analysis of a non-randomized group
of patients with VT of different etiologies and presentations.
Thus, this strong conclusion of increased risk of stable VT
has been derived from a heterogeneous group of patients.
In the end, the authors have also commented that ICD “may
decrease mortality in patients presenting with stable VT”.
It is acceptable that patients with structural heart disease
and left ventricular dysfunction are at increased risk of
malignant ventricular arrhythmis. The conclusions drawn
from the study should be seen in their proper perspective.
There are several limitations of these observational data.
The patients were not randomized, there was no correction
for baseline differences in the 2 groups at entry and therapy
was not randomly assigned or planned, but left to physician
preference. In 1993, Olson et al. showed that mortality due
to sudden death was identical in 122 patients with tolerated
versus nontolerated VT at 19.5 months (25% v. 24%), and
that the single best predictor of mortality was LVEF. In the
present study also, mortality correlated significantly with
LVEF (p<0.001 for LVEF >0.25%), as it did in the main AVID
trial. A meta-analysis of the 3 large secondary prevention
trials of ICD versus amiodarone (AVID, CIDS and CASH)
showed that the survival benefit of 28% in the ICD arm
(p=0.0006) that was achieved by reduction of sudden death
by 50%, led to a net improvement in survival of only 4.4
months over 6 years of follow-up. So even in the groups
with established benefit of ICD, the actual survival benefit
in real terms is not impressive. Though it would now be
unethical to withhold ICD therapy in the subgroups dealt
with in these large trials, this is definitely not the status for
patients covered by the AVID registry, and as such, the
conclusions of this paper should be read with all the
shortcomings of the data in mind.
IHJ-Selected Summary.p65
377
8/16/01, 7:38 AM
Calendar of Conferences
July 29–Aug 10, 2001, 27th 10-Day Seminar on the
Epidemiology and Prevention of Cardiovascular
Diseases, Granlibakken Conference Centre, Tahoe, CA
Contact: David C Goff Jr, Seminar Director, c/o American
Heart Association, 7272 Greenville Avenue,
Dallas, Texas 75231, USA
Fax: 1 214 373 3406
September 1–5, 2001, XXIII Congress of the
European Society of Cardiology, Stockholm, Sweden
Contact: European Congress Organization (ECOR),
The European Heart House, Stockholm, Sweden
Fax: 33 4 9294 7620
e-mail: [email protected]
October 3–6, 2001, 13th Asia-Pacific Congress of
Cardiology, Manila, Philippines
Contact: Dr Noe A Babilonia, Chairman, Organizing
Committee, 13th APCC, Suite 1108, 11th Floor,
East Tower, PSE Centre, Exchange Road, Ortigas
Commercial Complex, Pasig City, Manila 1605,
Philippines
Fax: 632 634 7441
October 5–7, 2001, 8th Annual Conference of Indian
College of Cardiology, Bhubaneswar, India
Contact: Professor HN Mishra, Organizing Secretary,
Manavilas Lane, Ice Factory Road, College Square,
Cuttack 753 003, Orissa
e-mail: [email protected]
or
Dr Rajeev Lochan, Chairman, Scientific
Committee, Apollo Hospitals, Mathura Road,
New Delhi 110 044
e-mail: [email protected]
Indian Heart J 2001; 53: 378
December 6–9, 2001, 53rd Annual Conference of
Cardiological Society of India, Hyderabad, India
Contact: Professor P Krishnam Raju, Organizing Secretary,
Care Hospital, D. No. 6-3-248/1, Former Hotel
Bhaskara Palace, Road No. 1, Banjara Hills,
Hyderabad 34
Fax: 040-6668888
e-mail: [email protected]
or
Dr Anjan Lal Dutta,
Chairman, Scientific Committee, Indian Heart
House, P-60, C.I.T. Road, Scheme VII M,
Kankurgachi, Calcutta 700 054
Fax: (033) 355 6308
e-mail: [email protected]
February 8–10, 2002, VIth World Congress of
Echocardiography and Vascular Ultrasound,
New Delhi, India
Contact: Dr (Col) SK Parashar, Secretary General,
C-144, Sarita Vihar, New Delhi 110044,
Fax: 6942222
e-mail: [email protected]
March 17–20, 2002, 51st Annual Scientific Sessions,
American College of Cardiology, Atlanta, Georgia, USA
Contact: American College of Cardiology, 9111 Old
Georgetown Road, Bethesda, MD 20814, USA
Fax: 1 301 897 9745
May 5–9, 2002, XIV World Congress of Cardiology,
Sydney, Australia
Contact: The Congress Secretariat, QVB Post Office Locked
Bag Q4002, Sydney, NSW 1230, Australia
Fax: 61 2 9290 2400
e-mail: [email protected]
October 13–16, 2001, VII Asian-Pacific Symposium
on Cardiac Pacing and Electrophysiology, Beijing, China
Contact: Dr Hu Da Yi, Secretary-General, VII APSPE,
Beijing Red Cross Chaoyang Hospital,
8 Baijiazhang Road, Chaoyang District, Beijing
100020, People’s Republic of China
Fax: 86 10 6593 7858
e-mail: [email protected]
July 17–21, 2002, 14th Asean Congress of Cardiology
Kuala Lumpur, Malaysia
Contact: Dr David KL Quek, Chairman, Organizing
Committee, c/o Letter Box 1, 15th Floor, Menara
Merais, 1 Jal Petaling Jaya 46300, Selangor,
Malaysia
Fax: 60 3757 8363
November 11–14, 2001, 74th Scientific Session,
American Heart Association, Anaheim, California, USA
Contact: American Heart Association, 7320, Greenville
Avenue, Dallas, Texas 75231, USA
Fax: 1 214 373 3406
August 31–September 4, 2002, XXIV Congress of the
European Society of Cardiology, Berlin, Germany
Contact: European Society of Cardiology (ECOR), B.P. 174,
Sophia Antipolis Cedex F-06903, France
Fax: 33 49244 7601
Cal of Conference.p65
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8/16/01, 7:40 AM