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Kothari et al. Cardiac Amyloidosis
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Editorial
Indian Heart J 2004; 56: 197–203
Cardiac Amyloidosis – An Update
SS Kothari, S Ramakrishnan, VK Bahl
Department of Cardiology, All India Institute of Medical Sciences, New Delhi
A
myloidosis is a rare, mysterious and serious disorder.
The extracellular deposition of seemingly
homogenous and amorphous material actually represents
the expression of very diverse pathologies.1-3 All amyloid
fibrils share apple green birefringence under polarized light
with Congo-red staining, and are arranged in beta-pleated
structure on electron microscopy. More than 21 proteins
have been identified that may give rise to amyloid in vivo
including light chain immunoglobulins, transthyretin,
acute phase reactant - protein A, fibrinogen Aα, apolipoprotein A etc.4 There are similarities and differences in
the clinical manifestations of amyloidosis resulting from
different precursor proteins.1-4 An accurate diagnosis of the
type of amyloid has now become important as therapy for
some forms of amyloidosis is emerging, and also the
prognosis varies amongst different amyloidoses.1-4 Exciting
progress is being made in our understanding of the process
of amyloidogenesis, mechanisms of tissue damage due to
amyloidosis, in genetics of amyloidosis and related areas4, 5
raising the hope of effective treatment of the disease.5, 6
However, a cure for all patients with amyloidosis is still afar.
At a clinical level, systemic amyloidosis is a disease with
protean manifestations and the diagnosis is often delayed
in the era of compartmentalized care.2 An early diagnosis
may facilitate therapy before the end organ damage is
severe. Cardiac involvement is the cause of death in nearly
50% of patients with systemic amyloidosis.7 In this article,
we highlight the selected aspects of cardiac amyloidosis
from a clinical standpoint and review the recent progress
in the treatment of amyloidosis.
Types of Systemic Amyloidosis
The classification and terminology of amyloidosis is
sometimes confusing. The deposits of AL amyloid, ATTR
amyloid and AA amyloid result in the so-called primary,
familial/senile amyloidosis, and secondary amyloidosis
respectively.1 The commonly occurring types of systemic
amyloidoses are shown in Table 1. Cardiac involvement
most often results from the deposition of fragments of light
chain immunoglobulins (primary or AL amyloidosis)
produced by the clone of plasma cells in the bone marrow
with or without multiple myeloma.11 Familial amyloidosis
Correspondence: Professor VK Bahl, Department of Cardiology, All India
Institute of Medical Sciences, New Delhi 110029
e-mail: [email protected]
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Table 1. Classification of commonly occurring systemic
amyloidoses
Type
% of cardiac
amyloidosis
Frequency
of clinical
cardiac involvement (%)
Primary1–5
85
33 – 50
AL
Ig λ, Ig κ
CT, ASCT
Familial8
10
25
ATTR
Transthyretin
Liver
transplant
Secondary
Rare
Rare
AA
apoSAA
Control of
inflammation
Senile†9
<5
10
ATTR
#
–
AANF
Isolated atrial
amyloid10
Amyloid
protein*
Protein Treatment
precursor
Transthyretin Supportive
Atrial
natriuretic
factor
–
*
Prefix A denotes amyloid, and the following letters indicate the precursor protein involved.
AL: light chain amyloid; ATTR: transthyretin amyloid; AA: serum protein A amyloid; AANF: atrial
natriuretic factor amyloid
†
Senile amyloidosis is universally present in the heart of patients above 80 years of age, but leads
to significant heart failure in a minority
#
Not usually included as part of systemic amyloidosis
Ig: immunoglobulins; CT: chemotherapy; ASCT: autologous stem cell transplant
results from deposition of amyloid derived from mutant
transthyretin. 12 Transthyretin (previously called
prealbumin) is a soluble plasma protein involved in the
transport of thyroxine and vitamin A. Given sufficient time,
the normal transthyretin may also get deposited in the
heart, as in elderly with senile amyloidosis. 4 Cardiac
involvement in amyloidosis secondary to inflammatory
disorders, like rheumatoid arthritis, Crohn’s disease,
tuberculosis, or leprosy is very rare (amyloid AA – deposits
of acute phase reactant protein A) and only occasionally a
clinical issue.13 Dialysis-related amyloidosis resulting from
β2-microglobulin deposition occasionally involves the
heart.14 Interestingly, atrial deposits of small polypeptide
atrial natriuretic peptide (ANP) result in isolated atrial
amyloidosis (IAA).10
Cardiac Amyloidosis
In the primary or AL amyloidosis, cardiac involvement at
presentation is seen in nearly 30% of patients, but
eventually occurs in the majority.7,15 Typical patient of
cardiac amyloidosis is an older (> 40 years) man11 with
dominant right-sided heart failure and evidence of multisystem involvement i.e. nephrotic syndrome, orthostatic
hypotension, or carpal tunnel syndrome. The pathognomonic features of amyloidosis like macroglossia and
easy bruising (Raccoon eyes resulting from trivial trauma)
occur in only 10-15% of patients with primary
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198 Kothari et al. Cardiac Amyloidosis
amyloidosis.11 Marked hepatomegaly or weight loss despite
edema suggests gastrointestinal involvement and is a poor
prognostic sign.11 Absence of systemic hypertension despite
renal disease may be seen with systemic amyloidosis.2
Orthostatic hypotension due to autonomic neuropathy
occurs in 40% of patients. Resting hypotension (systolic
blood pressure < 100 mmHg) occurs in nearly 15% of
patients, and amyloid-induced hypoadrenalism or
hypothyroidism as a cause of hypotension may remain
unrecognized. 11 The combination of restrictive
cardiomyopathy and peripheral neuropathy is also found
in other diseases like sarcoidosis, hemochromatosis,
lymphoma, carcinomatosis and Fabry’s disease.2 Recurrent
pleural effusions may occur due to pleural amyloidosis, but
is seen usually in the presence of associated cardiac
amyloidosis.16 Nail dystrophy, testicular enlargement, or
hoarseness of voice are seen in 5 - 10% of patients.11
Cardiac amyloidosis accounts for nearly 10% of nonischemic cardiomyopathies.17 It is estimated that 25% of
myocardial mass is replaced with amyloid by the time the
patient has clinical heart failure.18 The typical picture is
that of a rapidly progressive congestive heart failure (CHF)
due to restrictive cardiomyopathy, but systolic dysfunction
occurs later in the course of the disease. 11 Dilated
cardiomyopathy is seen in only 5% of the patients and
occasionally cardiac amyloidosis may masquerade as
hypertrophic cardiomyopathy.19,20 Typical angina may
occur due to deposition of amyloid in intramural vessels
and a pseudoinfarct pattern on electrocardiogram may
mislead toward atherosclerotic coronary artery disease
(CAD). 21 However, atherosclerotic CAD may coexist.
Unstable angina, myocardial infarction (MI), and silent
ischemia in a patient with amyloidosis may also occur due
to obstructive intramural amyloidosis22 or very rarely,
epicardial obstructive amyloidosis as well.23
Sudden cardiac death accounts for 30% to 50% of all
cardiac deaths in systemic amyloidosis and may be due to
ventricular arrhythmias, atrioventricular block, or acute
electromechanical dissociation.24, 25 Atrial fibrillation (AF)
is found in 10-20% of cardiac amyloidosis, due to atrial
enlargement, atrial infiltration or congestive heart failure.11
Atrial thrombi are described even in sinus rhythm related
to an impairment of atrial emptying26 or deranged clotting
factors.27 Thickened valves and valvular regurgita-tions are
seen on echocardiography, but are not clinically apparent.
Pericardial tamponade or pulmonary artery hypertension28
due to systemic amyloidosis are very rare.
Investigations
Anemia is uncommon without associated myeloma.
Thrombocytosis and hypogammaglobulinemia are helpful
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pointers seen in a minority of AL amyloidosis. Low voltage
in the limb leads on electrocardiogram in the presence of
increased left ventricle (LV) mass is highly suggestive of
cardiac amyloidosis, but has a sensitivity of 63 - 80%.29,30
The sensitivities of commonly used investigations for
cardiac amyloidosis are shown in Table 2.
Table 2. Sensitivity of diagnostic tests in cardiac amyloidosis
Test
Finding
Sensitivity (%)
Electrocardiography Low Voltage
Q Waves
63 - 80
60 - 93
Echocardiography
IVS thickening
Sparkled appearance
IAS thickening
Valve thickening
Biatrial dilation
Pericardial effusion
Restrictive pattern on Doppler
87
45 - 87
40 - 60
65
45
45
35 - 50
Biochemistry
Urine/Serum monoclonal protein
80 - 90
Tissue biopsy
Abdominal fat pad aspiration
Rectal biopsy
Bone marrow biopsy
Abdominal fat pad with bone marrow
Skin biopsy
Endomyocardial biopsy
80
70 - 85
50 - 56
90
50 - 90
100*
Radionucleotide
imaging
99Tc pyrophosphate scintigraphy
23
* If at least 3 samples tested, occasionally negative; IVS: interventricular septum; IAS: interatrial
septum; Tc: technetium; Adapted and modified from Ref. 30
Echocardiography: Echocardiogram remains a very
important tool for the diagnosis of amyloidosis.31 Typically,
increased thickness of left ventricular walls in the absence
of secondary causes like hypertension is seen. A granular
sparkling appearance of myocardium is seen, but it cannot
be qualitatively differentiated from the speckling seen
occasionally in hypertrophied hearts from other causes.32
Dilated atria, interatrial septal hypertrophy (> 7 mm), small
pericardial effusion, thickened valves, and thickened right
ventricular free wall are also seen. 11, 31 Such an
echocardiographic picture in the clinical context is
considered diagnostic even without an endomyocardial
biopsy. Further, the echocardiographic picture correlates
with clinical severity and prognosis. Ventricular septal
thickness more than 15 mm is considered a poor prognostic
sign.31 These echocardiographic findings are seen in nearly
70% of patients with AL amyloidosis.31 Transmitral and
pulmonary venous Doppler findings progress from
abnormalities suggestive of impaired relaxation to those of
severe restrictive pattern as the severity of the disease
progresses.33 Pulmonary venous A wave reversal duration
that exceeds the mitral inflow A wave duration suggests
that the LV end-diastolic pressure is greater than 15 mmHg,
and this finding is seen in nearly all patients with
amyloidosis, the magnitude of difference is higher in
patients exhibiting restrictive pattern. 34 Tei index, a
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measure of systolic and diastolic function, is abnormal in
both the left35 and right ventricles36 in cardiac amyloidosis,
and is shown to be an independent marker of prognosis in
some studies.35
Tissue Doppler imaging (TDI), strain rate imaging, and
ultrasonic tissue characterization may be useful in the early
diagnosis of cardiac amyloidosis.33, 37 TDI measured E wave
velocities at lateral (≤12 cm/s) and medial (≤10 cm/s) mitral
annulus have a good overall accuracy, but are not
independent of age and LV hypertrophy. Age independent
color TDI velocities like, early isovolumetric relaxationmean myocardial velocity (IVR-MMV) accurately identify
cardiac involvement even in patients with borderline or no
LV thickening.38 These parameters help in the early diagnosis of cardiac involvement, but are seen in other hypertrophied hearts as well. Recently, a distinct serrated pattern of myocardial velocity profile on color-coded TDI has
been reported in the ventricular septum and the posterior
wall in patients with advanced amyloidosis.39 Such a pattern is highly specific for amyloidosis and is not observed in
hypertensive LV hypertrophy or hypertrophic cardiomyopathy. It is proposed that the serrated pattern results from inhomogeneity of segments with regards to thickening, probably related to amyloid deposition.39
Strain and strain rate imaging are shown to be more
sensitive than TDI in identifying early amyloid involvement
of the heart. Basal strain and basal peak systolic strain rate
identify patients with cardiac involvement and CHF.40 An
early impairment in systolic function, as identified by strain
and strain rate imaging, precedes the onset of CHF and the
onset of reduced fractional shortening.40 Ultrasonic tissue
characterization using cycle-dependent variation of
myocardial integrated backscatter (CV-IB) is shown to be a
better predictor of clinical outcome in cardiac amyloidosis
than the other standard echocardiographic measures.41
Familial Amyloidosis
Familial amyloidosis commonly results from the deposition
of transthyretin derived-amyloid (ATTR amyloidosis) in
various organs.8 The mutant transthyretin is inherently
more amyloidogenic, more than 60 such mutations have
been described.42 In familial amyloidosis, neuropathy, and
renal manifestations predominate and cardiac involvement
is seen in only 25% of patients. The clinical picture of
familial cardiac amyloidosis differs somewhat from AL or
primary amyloidosis, but is not sufficiently distinct to make
a diagnosis solely on the clinical grounds.8 A family history
may not be available in nearly 30 - 50% of patients with
familial amyloidosis, and late onset of the disease is
common in them as well. 4 The onset and severity of
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manifestations vary with specific mutation. Some mutations may result mainly in cardiac amyloidosis e.g., Ile122
mutation. This transthyretin mutation (Ile122) is seen in
up to 4% of black population, and may be responsible for
the higher prevalence of heart failure in elderly blacks.43
Similar cases may be present in India as well. Normal
echocardiographic findings, better preserved electrocardiographic voltages, and a dominant conduction system disease have been described with some mutations of
transthyretin.4,8 The distinction between AL or primary, and
familial cardiac amyloidosis is important since liver transplantation can cure familial amyloidosis by providing normal transthyretin.44
Senile Amyloidosis
Previously considered benign local deposits in the heart of
the elderly, senile amyloidosis is now known to be
widespread and occasionally responsible for CHF.4,9 The
deposits result from normal or wild transthyretin and are
universally present in the heart of patients above 80 years
of age. In patients with senile amyloidosis, amyloid causes
CHF in 10 - 20% of patients. 24,45 Since the age of
presentation may overlap in various forms of systemic
amyloidoses, a definite diagnosis cannot be made on the
basis of age alone. Cardiovascular findings including
echocardiography may not be able to distinguish senile
amyloidosis from primary or familial amyloidosis.46,47
However, macroglossia and other systemic involvement do
not occur in senile amyloidosis; but carpal tunnel syndrome
may occur in both.9 Thus in senile amyloidosis, abdominal
fat aspirates are negative, no light chains are seen in serum/
urine, bone marrow biopsy is normal, and no mutation in
transthyretin gene is detected. It is important to recognize
senile amyloidosis since the median survival in senile
amyloidosis is 5 years, in contrast to only 5 months in
primary amyloidosis.9
Isolated Atrial Amyloidosis
Isolated atrial amyloidosis (IAA) is very commonly found
histologically in people in the ninth decade, and results from
atrial natriuretic peptide (ANP) deposition. The
contribution of IAA in the pathogenesis of AF in the elderly
is not clear. In a study of 245 patients undergoing open
heart surgery for valvular or coronary heart disease, biopsy
evidence of ANP amyloid deposition in the right atrial
appendage correlated with prevalence of persistent AF, and
the association was independent of the age of patients.10
IAA may play a role in the genesis of idiopathic AF in the
elderly, but the question remains to be better studied.
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Approach to the Diagnosis
of Cardiac Amyloidosis
After the clinical suspicion, the most appropriate initial
screening test would be immunofixation of serum and
urine for monoclonal protein spikes. The presence of
abnormal light chain suggests the diagnosis of primary
(AL) amyloidosis. Routine serum electrophoresis alone is
inadequate for this purpose, and is negative in 50% of
patients. A negative immunofixation test alone will not rule
out amyloidosis, as it can occur in non-secretory
amyloidosis48 (10% of AL amyloidosis) or in other forms of
amyloidosis (familial or senile amyloidosis).
The confirmation of amyloidosis requires some tissue
biopsy (fat pad aspirate or other tissues). A bone marrow
biopsy is required to characterize the monoclonal
gammapathy and usually more than 5% plasma cells are
found in primary amyloidosis.11 Fat pad aspiration and bone
marrow biopsy together can identify amyloid in 90% of AL
amyloidosis patients.3 Endomyocardial biopsy is extremely
sensitive, but is often not required. 3 However,
endomyocardial biopsy is always required in isolated
cardiac involvement, which may be seen rarely with AL
amyloidosis (4%),11 and more frequently with senile or
familial amyloidosis.
On histopathology, the pattern of arrangement of
amyloid deposits may be of help in distinguishing primary
from senile amyloidosis. 24 A vascular pattern is more
common in primary amyloidosis, whereas an interstitial
nodular pattern is more common in senile cardiac
amyloidosis.24 However, the confirmation of the type of
amyloid on tissue biopsy requires staining with antibody
to κ, λ, or transthyretin or serum amyloid protein A, but
these are not widely available.49
The diagnosis of familial amyloidosis requires
demonstration of abnormal transthyretin.50 Isoelectric
focusing of the serum identifies the variant forms of
transthyretin. Further, the distinction between familial and
senile amyloid requires genetic studies for mutation in
transthyretin gene (the senile amyloid being normal
transthyretin).50
Further, the quantitative studies of volume of amyloid
deposit have been described. The amyloid P scan
utilizes labeling of amyloid P component (which is present
in all amyloid fibrils) with 123-indium, and such
quantitations have been found useful for monitoring
therapy. 51 Unfortunately, these scans are unsuitable
for cardiac amyloidosis. Recently, the measurement
of amyloidogenic serum-free light chain (FLC)
concentration has been utilized as a measure of amyloid
load. 52 A 50% decrease in FLC is associated with
stabilization or regression of amyloid deposits, with
potential for extended survival.53
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Prognosis
Majority of deaths in patients with systemic amyloidoses
include secondary to cardiac involvement. The major
cardiac prognostic factors are clinical CHF, LV ejection
fraction less than 50% and ventricular septal thickness
more than 15 mm. 31 Syncope, exercise capacity, 54
VO2max,54 and right ventricular dilation55 are also shown
to be independent factors determining survival. The
prognosis depends on the type of amyloidosis, and the
number and extent of organ involvement. AL amyloidosis
has the worst prognosis with a median survival of one to
two years. The survival in familial transthyretin amyloidosis
varies with the type of mutation and the age of diagnosis,
but may be as high as 15 years.1-4
Recently, prognostication using serum markers like ANP
and brain natriuretic peptide (BNP) have been utilized. A
N-terminal pro-BNP level of 152 pmol/L indicates heart
involvement, and is a marker of myocardial dysfunction
and of heart toxicity caused by amyloidogenic light
chains.56 Cardiac troponins (Trop T and Trop I) are modestly
elevated in patients with advanced cardiac amyloidosis.57
Trop T provides a better prediction of survival than does
Trop I. Median survival was worse for patients with
detectable levels of Trop T than that for those with
undetectable values (6 months v. 22 months).58 Recently,
troponins and pro-BNP are incorporated into a staging
system for assessing the eligibility for stem cell
transplantation, and both identify high risk group.59
Treatment
Symptomatic treatment: Management of cardiac failure
in patients with amyloidosis is difficult. Usually larger doses
of diuretics are required and careful monitoring for
dyselectrolytemia is essential.60 Digoxin avidly binds to
amyloid fibrils and drug toxicity may occur at therapeutic
levels.3 Digitalis should only be used in selected patients in
atrial fibrillation to control heart rate. High incidence of
sudden death in patients treated with digoxin has been
reported.61 Angiotensin-converting enzyme inhibitors
should be used cautiously because of orthostatic
hypotension and associated renal disease. 60 Calcium
channel blockers bind to amyloid fibrils, and therapy with
these agents results in exacerbation of heart failure.62
Nitrates are effective in relieving angina.22 Utility of βblockers is not known in amyloidosis. Midodrine, an alpha
agonist, is very useful for orthostatic hypotension in
amyloidosis.2 Aspirin and anticoagulation are indicated in
atrial fibrillation, atrial dilation, atrial standstill, and
documented throm-boembolism. However, anticoagulants
should be used cautiously as systemic amyloidosis may be
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associated with coagulation abnormalities predisposing to
clotting or bleeding.27
Patients with symptomatic bradyarrhythmia should
receive a permanent pacemaker implantation. In contrast
to AL amyloidosis, familial and senile amyloidosis are
associated with a high prevalence of conduction
disturbances. The atrial and ventricular pacing threshold
may be higher than usual in some patients.63 Treatment of
ventricular arrhythmia in cardiac amyloidosis is not
standardized, and the safety of antiarrhythmic agents is
not well known. Perhaps an implantable defibrillator may
be indicated as in other cardiomyopathies, but the decision
is more difficult due to poor prognosis in amyloidosis.
Specific treatment: Resolution of secondary amyloidosis
with the control of the offending inflammatory disorder in
the secondary (AA) amyloidosis led to the hope that
amyloidosis may be treatable, if diagnosed before the advent
of irreversible organ damage.4-6 Progress in the treatment
of multiple myeloma has led to similar therapy for patients
with primary (AL) amyloidosis as both are basically similar
disorders. After many painstaking trials, high-dose
melphalan with autologus stem cell therapy (ASCT) has
shown remarkable success in selected patients of primary
amyloidosis.64,65 In a recent case-control study involving
63 patients, high-dose melphalan with ASCT was
associated with better 4-year survival rates (71%) than
conventional therapy (41%).66
However, patients with cardiac amyloidosis do not
tolerate high-dose melphalan with ASCT therapy.67 A
procedural mortality of 20% or more is reported, and the
mortality rises to almost 100% in patients with advanced,
symptomatic cardiac amyloidosis. 64 With high-dose
melphalan, a 20% occurrence of second malignancy is
reported. Further, the benefits are seen after a median
duration of 1 year and many cardiac patients may not
survive that long enough.64 An aggressive approach of
heart transplantation followed by ASCT has been tried.68
The studies of high-dose melphalan with ASCT have
included relatively less sicker patients and with the proposed
selection criteria, only a minority of AL amyloidosis patients
are eligible for high-dose melphalan with ASCT. 64
Alternatively, oral melphalan and prednisolone in patients
too sick to undergo stem cell transplant have also been
found useful.69 It is remarkable that 5% of patients with
AL amyloidosis have survived beyond 10 years with
chemotherapy.70 In another multicentric trial of primary
amyloidosis involving 93 patients, high-dose dexamethasone induction, followed by dexamethasone and
alpha interferon maintenance therapy had achieved
hematologic complete remissions in 24% of patients and
resulted in a median survival of 31 months.71
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These studies have shown that amyloidosis is not an
inert, irremovable substance, and a decrease in as much as
2 mm septal thickness in patients was associated with
remarkable symptom relief. In patients with severe CHF,
heart transplantation has been done, but the results are
less than encouraging.72 Recurrence of amyloid in the
transplanted heart is seen73 and peri-procedural mortality
remains high (20%). It may be considered after careful
selection of many variables. Of course, liver transplantation
that supplies normal transthyretin (instead of mutant
thyretin synthesized in patients with TTR amyloidosis) is
the treatment of choice for familial amyloidosis.44 Several
hundreds of patients have undergone this procedure with
relief of symptoms. Intriguingly, sometimes cardiac
amyloidosis has progressed after liver transplantation in
these patients74 possibly due to precipitation of normal
transthyretin-induced amyloid on the seeding set up by the
mutant variety previously.75
With better understanding of the mechanisms of
amyloidosis, several other lines of therapy are being tried.6
Disintegration of amyloid fibril by compounds like iodinated
anthracycline 4-iodo-4-deoxydoxorubicin has been shown
in experimental animals and in a small clinical study.76
Decreasing the fibrillogenesis of amyloid precursor protein
using small molecules that bind to the protein or interfere
with the process of aggregation are being actively pursued.
Further, drugs that displace fundamental cofactors
important for amyloidogenesis like serum amyloid P (a
substance found in all amyloid fibrils in addition to the
precursor proteins) favors the dissolution of amyloid fibrils.
Phase II trials of such compounds have recently been
completed.6
Immunotherapy using monoclonal antibodies against
appropriate peptides may inhibit the process of
amyloidogenesis or increase its resorption.77 Trials with
amyloid reactive antibodies are being planned.
Immunomodulation with thalidomide is not tolerated by
patients with primary amyloidosis.78 Etanercept, a tumor
necrosis factor α-antagonist is well tolerated, but produces
limited benefits in cardiac amyloidosis.79 Etanercept therapy
resulted in a 10% decrease in septal thickness in a few
patients. A combination of these approaches is expected to
bring changes in the management of patients with cardiac
amyloidosis.
However, the majority of patients with cardiac
amyloidosis do not benefit from these therapies. An earlier
diagnosis, when the disease burden is not high and the
organ damage is not severe, may allow greater benefits of
treatment. In conclusion, increased awareness of cardiac
amyloidosis is warranted for early diagnosis. Advances in
the understanding and treatment of amyloidosis are raising
expectations of curative therapy in the future.
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204 RajaArticle
et al. Statins: More than Lipid-Lowering Therapy
Review
Indian Heart J 2004; 56: 204–209
Statins: Much More than Just A Lipid-Lowering Therapy
Shahzad G Raja, Gilles D Dreyfus
Alder Hey Hospital, Liverpool and Harefield Hospital, Middlesex, United Kingdom
C
linical studies have clearly demonstrated that reduction
of plasma cholesterol, particularly cholesterol
transported in low-density lipoproteins (LDL), lowers the
risk of cardiovascular events for both primary and
secondary prevention. Significant cholesterol reductions
may be produced by the 3-hydroxy-3-methylglutaryl
(HMG)-CoA reductase inhibitors, commonly named as
statins. It is implicit that the beneficial effect of statins on
coronary events is related to their hypocholesterolemic
properties. However, the immediate product of HMG-CoA
reductase, mevalonic acid, is not only the substrate for
cholesterol synthesis but also the precursor of isoprenoids
and other metabolites involved in different cellular
pathways of atherogenesis and thrombosis. 1 As a
consequence, statins have the potential to result in
pleiotropic effects, which are independent of cholesterol
reduction and may explain many of the direct
antiatherosclerotic and antithrombotic properties of these
compounds.1-6
Better understanding of the various pleiotropic effects
of statins has prompted a new surge of interest in their use
to treat and/or prevent a wide range of chronic and lifethreatening disorders. Among the disorders targeted for
statin therapy are ventricular arrhythmias, peripheral
arterial disease (PDA), idiopathic dilated cardiomyopathy,
cancer, osteoporosis, and even depression. Their effectiveness in treating these and other disorders suggest that the
benefits of statins may not be limited to cholesterol lowering
and that indications for the drugs’ use may extend to patient
populations not considered traditional candidates for this
therapy.
Statins as Antiarrhythmic Therapy
Recently, it has been proposed that statins reduce the
incidence of arrhythmias in patients with atherosclerotic
heart disease.7-9 According to a substudy of the Antiarrhythmic Versus Implantable Defibrillators (AVID) trial,
in patients with atherosclerotic heart disease treated for
ventricular tachycardia/ventricular fibrillation (VT/VF)
Correspondence: Dr Shahzad G Raja, Alder Hey Hospital, Liverpool
L12 2AP, UK. e-mail: [email protected]
IHJ-666-04.p65
204
with implantable cardioverter defibrillators (ICDs), the use
of statins and other lipid-lowering agents (e.g. fibric acid
derivatives and bile acid resins) significantly reduced the
probability of VT/VF recurrence.7 In addition, lipid lowering
therapy was associated with significant reduction in both
cardiac mortality and all-cause death in a larger cohort of
patients treated with either ICDs or antiarrhythmic drug
therapy.
A recent study8 suggests that the antiinflammatory
effects of statins can reduce the recurrence of atrial
fibrillation (AF) in patients who undergo successful
cardioversion. This study was based on the hypothesis that
inflammation, evidenced by high levels of C-reactive
protein, can induce AF and promote its persistence. Siu et
al.8 found that after 2 years of follow-up, patients treated
with statin therapy for high cholesterol had a significantly
lower AF recurrence rate than the patients not on lipid
lowering therapy (40% v. 84%, respectively; p=0.007). The
benefits observed in patients on statin were observed early,
and persisted throughout the follow-up period.
The results of the above studies do not necessarily
confirm a direct antiarrhythmic effect associated with
statin therapy. However, both groups of authors attribute
their findings to the slowing of atherosclerotic plaques,
which lowers the risk of plaque rupture, “thereby
preventing the ischemia-induced electrophysiologic effects
that predispose to VT/VF.” Further, as AF in patients with
coronary artery disease (CAD) is proposed to be caused by
atrial ischemia,10 it is possible that in these patients, the
beneficial effect of statin therapy in preventing AF may be
mediated through its effects on the progression of CAD.11
Also, in addition to this indirect antiarrhythmic effect,
statins may exhibit direct antiarrhythmic effects by
modulating the fatty acid composition and physiochemical
properties of cell membranes, with resultant alterations in
transmembrane ion channel properties.12,13 Moreover,
statins have multiple pleiotropic effects (independent of lipid
lowering).11 They decrease the messenger ribonucleic acid
(mRNA) levels for interleukin-8, monocyte chemoattractant protein-1, plasminogen activator inhibitor-1,
endothelin-1 and increase the levels of thrombomodulin
and endothelial nitric oxide synthase (eNOS).14 Statins also
act on G-proteins (small GTPases, Rho, Rac, Cdc 42). This
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Indian Heart J 2004; 56: 204–209
leads to reduced eNOS mRNA degradation and higher eNOS
protein levels and activity.14 In addition, by scavenging free
radicals and reactive oxygen species statins prevent nitric
oxide degradation and preserve endothelial function.14All
these mechanisms result in improved endothelial function
leading to coronary vasodilation, increased coronary blood
flow and less myocardial ischemia with reduced likelihood
of AF.
Statins and Peripheral Arterial Disease
According to a recent randomized, double-blind, paralleldesign study by Mohler et al. 15,atorvastatin achieved
greater improvement in pain-free walking time and
participation in physical activity in patients with
intermittent claudication than did inactive placebo.15 The
authors assessed the effects of low- and high-dose
atorvastatin on maximal walking time (MWT). They
randomised 354 patients with intermittent claudication
caused by PAD to 1 of 3 regimens: atorvastatin 10 mg/day,
atorvastatin 80 mg/day, or placebo for 1 year.
After 1 year of atorvastatin therapy, MWT did not
change significantly. However, the time in which patients
could walk without pain improved by 63% (81±15 sec) in
patients receiving atorvastatin 80 mg/day, whereas the
placebo group exhibited only 38% improvement (39±8
sec), which was similar to the group receiving atorvastatin
10 mg/day. In post hoc analyses performed to determine
whether smoking status or LDL-cholesterol (LDL-c)
influenced the results, investigators found that neither
variable had a response in overall MWT or pain-free walking
time. They noted, however, that there was a slight trend
toward greater improvement in patients with LDL-c levels
>123 mg/dl. According to investigators, such improvements in pain-free walking time are consistent with those
achieved with other approved pharmacotherapies.
Physical activity questionnaires reported significant
improvement in physical activity with both doses of
atorvastatin compared with placebo, but no significant
differences were seen between the groups on the qualityof-life questionnaires. Although not adequately powered to
assess the effect of atorvastatin on vascular events in
patients with PAD, fewer vascular events occurred in the
atorvastatin group versus placebo (1.3% v. 7.9%). Mohler
et al. 15 attributed their findings to several potential
mechanisms, including a reduction in plaque size
associated with statins, which may improve blood flow in
the large arteries of the legs, and an increase in
endothelium-dependent vasodilation.
In another randomized controlled trial, McDermott et
IHJ-666-04.p65
205
Raja et al.
Statins: More than Lipid-Lowering Therapy 205
al.16 demonstrated that, in persons with and without PAD,
statin use is associated with superior leg functioning
compared with no statin use, independent of cholesterol
levels and other potential confounders. Their findings
support the findings of the Scandinavian Simvastatin
Survival Study (4S) which concluded that subjects
randomized to simvastatin had a 38% reduction in new or
worsening claudication compared with subjects
randomized to placebo over a median follow-up of 5.4 years
(p=0.008).17
The beneficial effects of statins in PAD may be attributed
to increased production of nitric oxide in the endothelium,
which has local vasodilatory properties in addition to
antithrombogenic, antiproliferative, and leukocyteadhesion inhibiting effects.18,19 Other mechanisms by which
statins favorably influence lower limb ischemia include
enhancement of endothelium-dependent relaxation,20
inhibition of platelet function,21 and inhibition of endothelin-1, a potent vasoconstrictor and mitogen.22 Reduction
of vascular inflammation may be an additional mechanism
by which statins are associated with better functioning in
patients with PAD. Statin-associated reduction of
inflammatory cytokines could improve blood flow, regress
atherosclerosis, or improve end-organ function (such as
skeletal muscle).23
Statins and Non-ischemic Cardiomyopathy
The antiinflammatory properties of statins may confer
greater benefit than just reducing the risk of AF. The results
of a recently published randomized controlled trial by Node
et al.24 suggest that the antiinflammatory effects of statin
therapy result in improved neurohormonal imbalance and
cardiac function and may benefit patients with
symptomatic, non-ischemic dilated cardiomyopathy. The
study involved 63 patients (average age, 54 years) with
symptomatic non-ischemic dilated cardiomyopathy [New
York Heart Association (NYHA) class II-IV; left ventricular
ejection fraction (LVEF) <40%] who were randomized to
either simvastatin (5 mg/day, increased to 10 mg/day at 4
weeks; n=24) or placebo (n=27). Patients with a history or
evidence of ischemic heart disease were excluded from the
study.
Over the course of 14 weeks of treatment, the use of
simvastatin was associated with significantly improved
functional capacity compared with placebo (39.1% v. 16%
of patients had an improved functional status; p<0.01).
Reductions in NYHA class also translated into significant
improvements in LVEF from baseline to follow-up (34%±3%
to 41%±4%; p <0.05), which were predominantly due to a
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206 Raja et al.
Statins: More than Lipid-Lowering Therapy
decrease in LV end-systolic volume. Investigators reported
that there were positive correlations between changes in
ejection fraction and reductions in circulating
inflammatory cytokines, suggesting that “statins may
improve cardiac function, in part, by modulating the
inflammatory state.”
These findings, according to investigators, indicate that
statins may be therapeutically useful in patients with nonischemic congestive heart failure in whom statins may not
otherwise be indicated.24
Statins and Neuroinflammatory Disorders
Clinically, there is emerging evidence that statins have
beneficial effects in patients with multiple sclerosis,
Alzheimer’s disease, and ischemic stroke.25 Recent studies
indicate that statins have immunomodulatory
properties.25,26 Statins decrease the migration of leukocytes
into the central nervous system, inhibit major histocompatibility complex class II and costimulatory signals
required for activation of proinflammatory T cells, induce
a T(H)2 phenotype in T cells, and decrease the expression
of inflammatory mediators in the central nervous system,
including nitric oxide and tumor necrosis factor alpha.25
These immunomodulatory effects can either inhibit or
reverse chronic and relapsing experimental autoimmune
encephalomyelitis, a model of multiple sclerosis.25,27,28
Data from epidemiologic trials indicate that statins may
have some protective effect against the development of
Alzheimer’s disease. 29 However, at present, available
evidence does not lend credence to the use of statins in the
general non-demented population without hyperlipidemia.
Statins and Psychological Well-Being
Challenging the premise that the use of statins increases
the risk of depression, two recent studies have associated
long-term use of statin with a reduced risk of depression in
patients with CAD.30,31
Young-Xu et al.30 assessed the psychological well-being
of 590 patients with underlying CAD who were classified
into groups according to frequency of statin use
(continuous statin use (n=140), intermittent statin use
(n=219), or no use of any cholesterol-lowering drugs
(n=231).30 The mean age at entry for the 3 groups was 64,
66, and 70 years, respectively. At study enrolment, the
researchers recorded the patients’ sociodemographic,
psychological, and clinical status. Patients completed
annual follow-up questionnaires, including the Kellner
Symptom Questionnaire, which is used to measure
IHJ-666-04.p65
206
Indian Heart J 2004; 56: 204–209
depression, anxiety, and hostility.
After an average follow-up of 4 years (maximum followup, 7 years), comparison of psychometric scores between
patients using statins continuously and patients not using
cholesterol-lowering drugs showed that statin use was
associated with lower risk of abnormal scores for
depression, anxiety, and hostility. Investigators also noted
that intermittent statin use was not associated with the
same beneficial effects. In addition, the risk of mental illness
continued to decline with each additional year of
treatment. The progressive reduction observed in
continuous statin users over the 7-year study period also
seemed to be independent of the cholesterol-lowering effect
of the drug or baseline cholesterol levels. Although it
requires additional study, Young-Xu and colleagues
hypothesize that the “penetration of the blood-brainbarrier by the lipophilic statins accounts for most of the
observed impact on psychological well-being.”30
The findings of another study yielded results similar to
those reported by Young-Xu and colleagues. Yang and
colleagues31 found that statin use was associated with
reduced risk of depression, especially in long-term users
and in patients with pre-existing CAD.31 These investigators
identified patients with newly treated depression, who
needed either hospitalization or referral, and patients with
first-recorded diagnosis of suicidal behavior. They found
that neither lipid-lowering therapy (LLT) nor untreated
hyperlipidemia was associated with an increased risk of
depression. In fact, the risk of depression actually decreased
with statin therapy; risk of depression was 60% less in
individuals using statins than in hyperlipidemic individuals
not using LLT. The use of non-statin LLT yielded a similar,
but weaker effect. In addition, the risk of suicidal behavior
in individuals using statins did not differ significantly from
the risk in other groups, according to the authors.
The investigators observed that use of statin was
inversely associated with depression but such an
association was not likely to be directly causal because there
is no known pharmacological mechanism for this effect.
However, they suggested that a possible explanation could
be an indirect effect of statins on the risk of depression
through improved quality of life due to decreased incidence
of cardiovascular events or more health consciousness and
compliance among patients having longer lipid-lowering
treatment.31
Statins and Cancer
Statins have been shown to inhibit proliferation and to
induce apoptosis in a variety of tumor cells.32 They have
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Indian Heart J 2004; 56: 204–209
also been found to display antitumor effects against
melanoma, mammary carcinoma, pancreatic
adenocarcinoma, fibrosarcoma, glioma, neuroblastoma,
and lymphoma in animal tumor models resulting in
retardation of tumor growth, and/or inhibition of the
metastatic process.32-34 In pre-clinical studies statins have
also been demonstrated to potentiate the antitumor effects
of some cytokines and chemotherapeutics.32 The molecular
mechanisms underlying antitumor activity of statins have
not been fully elucidated but interference with the function
of Ras and Rho family GTPases, inhibition of the activity
of certain cyclin-dependent kinases (CDK), and activation
of CDK inhibitors, all seem to participate in this activity.32
phase I trials of statins in humans have demonstrated
myotoxicity as their main dose-limiting toxicity, and phase
II trials in various tumor types are ongoing to evaluate their
efficacy.35
Future directions in the development of the statins as
anticancer agents include combinations with chemotherapeutic or other molecular-targeted agents,
combinations with radiotherapy, maintenance therapy in
minimal disease status, and as chemopreventive therapy.
Statins and Osteoporosis
Statins have been linked to a reduction in the incidence of
fractures in elderly patients.36,37 In a recent study, Bauer
et al.37 analyzed statin use and fracture rates in 4 large
prospective studies of older women taking statin therapy
for hyperlipidemia (the Study of Osteoporotic Fractures, the
Fracture Intervention Trial, the Heart and Estrogen/
Progestin Replacement Study, and the Rotterdam Study).
They also conducted 2 cumulative meta-analyses
consisting of data from 8 observational studies and 2
clinical trials that reported statin use and documented
fractures.37
The investigators found interesting, yet somewhat
conflicting results. After adjusting for multiple factors, such
as age, body mass index, and estrogen use among statin
users in each of the 4 prospective studies, a trend toward
fewer hip and non-spine fractures was observed. Similar
reductions in risk were reported in the meta-analysis of
observational studies; statin use was associated with an
estimated 57% reduction in hip fracture, and an estimated
31% reduction in non-spine fracture. However, these
proposed protective effects of statins were not observed in
the meta-analysis of clinical trials. Based on their findings,
investigators called for controlled trials specifically designed
to test the effect of statins on skeletal metabolism and
fracture.37
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Raja et al.
Statins: More than Lipid-Lowering Therapy 207
Statins and Age-Related Maculopathy
Age-related maculopathy (ARM) is the leading cause of
irreversible vision loss among older adults in the Western
world.38 Based on the presence of similar risk factors, some
suggest that the pathophysiologies of ARM and
cardiovascular disease have similar causal pathways and,
therefore, both groups of patients may benefit from the
same drug treatment.39 Two recent studies assessing the
impact of statin therapy in patients with ARM draw
opposing conclusions.
Results from a nested case-control study suggest that
statin use is associated with a significant risk reduction of
ARM.39 In their study, McGwin and associates39 identified
550 incident cases of ARM and compared them to 5500
age-matched patients (controls). Compared with controls,
ARM patients had a significantly higher incidence of
diabetes, hypertension, cardiovascular and cerebrovascular
disease; however, there were no differences between the 2
groups with respect to lipid metabolism disorders or arterial
disease. Investigators found that 70% of ARM patients were
less likely to have received and filled a statin prescription
relative to controls, regardless of whether statin use was
current or occurred more than 6 months before the ARM
diagnosis. In addition, the results remained consistent after
adjusting for other medical conditions, such as those listed
above. Similar findings were noted when assessing nonstatin LLT.
Compared with non-statin LLT, the use of only statins
was associated with a significant risk reduction; the same
results held true when statin and non-statin users were
combined, but there was no significant association for nonstatin users alone. Interestingly, with the exception of
cardiovascular and cerebrovascular disease, the riskreduction effects of statin therapy on ARM were stronger
in the presence of an existing medical condition than in its
absence. However, the investigators cautioned against
presuming this association to represent a cause-and-effect
relation; future research will also be required to address
this issue. On the other hand, an earlier study conducted
by van Leeuwen and colleagues40 concluded that the use
of LLT did not change a patient’s risk of developing ARM.
Their conclusions were based on data collected from 4822
patients who were followed at mean intervals of 2.0 and
6.5 years. Of these patients, 457 used cholesterol-lowering
drugs for >1 day, and 419 incident cases of ARM were
identified throughout the course of the study.
Compared with patients who had never used a
cholesterol-lowering drug, the risk of ARM did not differ
for those who had used cholesterol-lowering drugs at any
9/29/2004, 5:07 PM
208 Raja et al.
Statins: More than Lipid-Lowering Therapy
time, be it for 1 month, 1-12 months, or > 1 year. Based on
their findings the authors suggested that the lack of an
association between LLT and ARM makes a protective effect
of statins unlikely.
Conclusions
Statins are currently the most effective method to
pharmacologically decrease total plasma cholesterol levels.
Apart from the well known LDL and cholesterol lowering
effect, statins have been postulated to exert beneficial effects
due to so-called ‘pleiotropic’ or ‘non-lipid’ effects. However
at present although the clinical implications of these
beneficial ‘non-lipid’ effects seem promising yet properly
designed, large, multi-center, prospective, controlled trials
are needed to validate the use of statins for indications other
than primary and secondary prevention of vascular
diseases.
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9/29/2004, 5:07 PM
210 Jose etArticle
al. AMI Mortality in Current Era
Original
Indian Heart J 2004; 56: 210–214
Mortality and Morbidity of Acute ST Segment Elevation
Myocardial Infarction in the Current Era
V Jacob Jose, Satya N Gupta
Department of Cardiology, Christian Medical College, Vellore
Background: The mortality rate of acute myocardial infarction has come down considerably in the past three
decades. In view of paucity of literature on this issue, present study was done to find out the in-hospital mortality
and 30-day event rate in patients with acute ST segment elevation myocardial infarction presenting to a tertiary
care hospital in India.
Methods and Results: Consecutive patients (n=1320) with the diagnosis of acute ST segment elevation
myocardial infarction admitted in our institution were included in this study. The in-hospital mortality and 30day event rates (mortality, reinfarction, recurrent angina and heart failure) were analyzed. The mean age of
study population was 56±13 years. There were 1106 (83.8%) males and 214 (16.2%) females; 569 (43.1%)
patients were smokers, 504 (38.2%) patients had hypertension, 531 (40.2%) patients were diabetic and 154
(11.7%) patients had past history of myocardial infarction. Anterior wall infarction was present in 752 (57%)
patients, 517 (39.1%) patients had inferior wall infarction, 324 (62.7%) patients had associated right ventricular
or posterior wall infarction and 51 (3.9%) patients had antero-inferior infarction; 1093 patients (82.8%) received
thrombolytic therapy while 227 patients were not thrombolyzed due to various reasons. Of the total 1320
patients, 223 (16.9%) patients died during in-hospital stay while 1097 patients were discharged from the hospital
in stable condition after a mean stay of 5.3±3.4 days. Thirty-day event rates of death, reinfarction and recurrent
angina following hospital discharge was 18.8% (134/715 patients) and 36 (5%) patients presented with heart
failure.
Conclusions: The in-hospital mortality rate of acute ST segment elevation myocardial infarction in a tertiary
care hospital is 16.9%, which is higher compared to reports from the West. (Indian Heart J 2004; 56:
210–214)
Key Words: Myocardial infarction, Mortality, Coronary artery disease
A
cute ST segment elevation myocardial infarction
(STEMI) is a major health problem both in the
developed, and developing countries like India. The
mortality due to STEMI has declined dramatically over the
past three decades. This decline has been attributed to the
introduction of coronary care units, thrombolytic therapy,
percutaneous coronary interventions and due to drugs
such as aspirin, angiotensin-converting enzyme inhibitors
(ACEIs) and β-blockers.1-3
The overall mortality in STEMI is approximately 4-7%
or even less in the published clinical trials.4-6 However, this
is not the case in the real world situation.7-9 This is because
Correspondence: Dr V Jacob Jose, Head, Department of Cardiology,
Christian Medical College, Vellore 632004. e-mail: [email protected]
IHJ-594-04.p65
210
the patients enrolled in the randomized clinical trials are
the selected ones and represent a low-risk subgroup.
Therefore, the results of these trials are not applicable to
about 50% of patients in clinical practice.10 A realistic view
can be obtained from the registry data. In the registry data
from Europe, the mortality with acute myocardial
infarction (AMI) is around 3 times higher than what has
been observed in clinical trials. 10 Hence, it has been
suggested that we need more prospective registries of
patients with AMI to get the real world picture.
Data showing mortality and treatment trends in Indian
patients after STEMI are scarce in the current era. Hence
this study was done to find out the in-hospital mortality
rate and 30-day event rates in patients with STEMI
presenting at a tertiary care center.
9/29/2004, 4:58 PM
Indian Heart J 2004; 56: 210–214
Methods
Between March 1999 and July 2003, patients who were
diagnosed to have acute STEMI and admitted to our hospital
were included in the study in a prospective manner. Patients
who had non-ST elevation myocardial infarction (MI) and
unstable angina were excluded from the present analysis.
Patients’ baseline characteristics such as age, gender,
hypertension, diabetes mellitus, and smoking status were
recorded. History of previous MI and angina pectoris were
also assessed. All patients received standard clinical care
including monitoring of vital functions in a coronary care
unit during the initial hospital stay and thrombolytic
treatment was given as per eligibility. We used 1.5 million
units of streptokinase over 1 hour for the thrombolytic
therapy.
Following criteria was used for the definition of STEMI:
chest pain of >20 min duration and ST segment elevation
>1 mm in at least two standard limb leads or >2 mm in at
least two contiguous precordial leads or the presence of left
bundle branch block in the electrocardiogram (ECG). STEMI
was later confirmed by the elevation of cardiac enzymes
either with CK-MB or troponin-I.
Besides in-hospital mortality, the occurrence of reinfarction, development of heart failure, cardiogenic shock
and other important in-hospital complications were
recorded. At 30-day follow-up, outcome variables recorded
were death, reinfarction, recurrent angina and heart
failure.
The diagnosis of post-infarction angina was based on
presence of chest pain suggestive of ischemia occurring 24
hours after infarction while the reinfarction was defined
as reelevation of CK-MB above the upper limit of normal
and increase by at least 50% of the previous value or by
the presence of new Q waves in the ECG. Diagnosis of heart
failure was based on Framingham criteria.
Statistical analysis: All data were analyzed using SPSS
Software (7.5 version). Categorical variables were
compared by the likelihood ratio X2 test or Fisher’s exact
test. Continuous variables are presented as mean ± SD and
were compared by one-way ANOVA or unpaired t test.
Baseline demographic features, treatment received, inhospital and 30-day event rates were evaluated using
logistic regression. A probability value of <0.05 was
considered statistically significant.
Results
Clinical presentation: Over a 4-year period, 1320
patients were admitted to our institution with a diagnosis
IHJ-594-04.p65
211
Jose et al. AMI Mortality in Current Era 211
Table 1. Baseline characteristics
Variables
Total
Males
Females p value
n (%)
n (%)
n (%)
1320 (100) 1106 (83.8) 214 (16.2)
Age (years)
Time delay from onset
of symptoms to
hospitalization (hours)
Overall
< 6 hours
7-12 hours
>13 hours
Smoking
Diabetes mellitus
Hypertension
Past MI
Family history of IHD
56±13
55±11
60±11
0.01
10.8±12.4
679 (51.5)
337 (25.5)
304 (23.0)
569 (43.1)
531 (40.2)
504 (38.2)
154 (11.7)
128 (9.7)
10.5±12.2
590 (53.3)
275 (24.9)
241 (21.8)
569 (51.4)
420 (38.0)
393 (35.5)
137 (12.4)
104 (9.4)
12.3±13
89 (41.6)
62 (29.0)
63 (29.4)
0
111 (51.9)
111 (51.9
17 (7.9)
24 (11.2)
0.06
0.01
0.10
0.02*
–
0.01*
0.01*
0.04*
0.24
Values in parentheses are percentages
*,
Statistically significant; MI: myocardial infarction; IHD: ischemic heart
disease
of acute STEMI. Their clinical and demographic
characteristics are summarized in Table 1. Most of the
patients were male with a mean age of 56±13 years. The
mean duration between symptom onset and hospital
admission was 10.8±12.4 hours. Females presented to
hospital later than the males; 53% of the males presented
to hospital within 6 hours of onset of symptoms, while 42%
of females were admitted to hospital within 6 hours of chest
pain.Prevalence of diabetes mellitus and hypertension was
higher in females than in males, while less number of
females had previous history of MI.
Location of infarction, Killip class and therapy: More
than half of our patient population had anterior wall MI;
of that almost equal proportion of patients had anteroseptal
and extensive anterior wall MI; 517 (39.2%) patients
presented with inferior wall MI of which 324 (24.5%)
patients had associated right ventricular or posterior wall
involvement and 51 (3.9%) patients had antero-inferior MI.
Males had high prevalence of anteroseptal MI while inferior
wall with associated right ventricular MI was common in
females. Most of the patients presented with Killip class I,
while 103 patients presented with Killip class IV. Overall
82.8% of patients received thrombolytic therapy and 7
patients underwent percutaneous coronary intervention
as an alternative to thrombolysis (Table 2).
In-hospital events: The mean duration of hospital stay
was 5.4±3.2 days for anterior wall MI patients, 5.1±3.7
days for inferior wall MI, and 6.1±3.2 days for patients who
had antero-inferior MI; 223 (16.9%) patients died during
hospital stay. The mortality was 25.2% for females, which
was significantly higher when compared with males
9/29/2004, 4:58 PM
Indian Heart J 2004; 56: 210–214
212 Jose et al. AMI Mortality in Current Era
Table 2. Location of myocardial infarction and therapy
Table 3. Morbidity and mortality data
Variables
Variables
MI location
ASMI
ExtAWMI
IWMI
IWMI +RVMI
IW+RV + PWMI
Antero-inferior MI
Overall
n (%)
1320 (100)
Males
n (%)
1106 (83.8)
381(28.9)
371(28.1)
193(14.6)
129(9.8)
195(14.8)
51(3.9)
337 (30.5)
310 (28.0)
159 (14.4)
98 (8.9)
163 (14.7)
39 (3.5)
Females
p value
n (%)
214 (16.2)
44 (20.6)
61 (28.5)
34 (15.9)
31 (14.5)
32 (15.0)
12 (5.6)
0.01*
0.47
0.32
0.01*
0.50
0.11
Killip class
I
II
III
IV
772(58.5)
320(24.2)
125(9.5)
103(7.8)
660 (59.7)
263 (23.8)
105 (9.5)
78 (7.1)
112 (52.3)
57 (26.6)
20 (9.3)
25 (11.7)
0.03*
0.21
0.53
0.02*
Thrombolysis
1093(82.8)
930 (84.1)
163 (76.2)
0.01*
1225(92.8)
791(60.0)
863(65.4)
430(32.6)
886(67.1)
105(8.0)
1032 (93.3)
665 (60.1)
729 (65.9)
364 (32.9)
749 (67.7)
81 (7.3)
193 (90.2)
126 (58.9)
134 (62.6)
66 (30.8)
137 (64.0)
24 (11.2)
0.07
0.38
0.21
0.23
0.10
0.04*
Other therapy
Aspirin
ACE inhibitor
Beta blockers
Nitrate
Heparin
Temporary pacing
Values in parentheses are percentages
Statistically significant; MI: myocardial infarction; ASMI: anteroseptal MI;
ExtAWMI: extensive anterior wall MI; IWMI: inferior wall MI; RVMI: right
ventricular MI; PWMI: posterior wall MI; ACE: angiotensin-converting enzyme
*
(15.3%). The main cause of death was cardiogenic shock/
pulmonary edema or pump failure in both male and females
followed by cardiac asystole. Males had higher incidence
of death due to ventricular arrhythmias than females.
Other important in-hospital complications are shown in
Table 3. In the multivariate analysis, the most significant
variables for the mortality were, cardiogenic shock and
Killip class III and IV.
30-day follow-up: 30-day follow-up data was available
for 715 patients. Of these, 124 (17.3%) patients presented
with recurrent angina, 36 (5%) patients developed heart
failure, and 9 (1.3%) patients had reinfarction. One patient
had died during this period.
Discussion
In our study, mortality rate during hospitalization with
acute STEMI was 16.9%. Though this is considerably
higher than what has been reported from randomized
clinical trials, it compares well with the observational data
from the West.7-10 We feel that there is an urgent need at
the national level to bring this mortality further down.
Symptom onset to hospitalization: In our study, there
was an inordinate delay in presenting to the hospital; the
mean duration between symptom onset and hospitalization
IHJ-594-04.p65
212
Total
n (%)
1320 (100)
Females
n (%)
214 (16.2)
p value
169 (15.3)
54 (25.)
0.01*
41(24.2)
18(33.3)
0.18
68(40.2)
39(23.1)
23(42.6)
9 (16.7)
0.16
0.04*
5/114 (4.4)
21/313 (6.7)
85/453 (18.8)
71/313 (22.7)
41/127 (32.3)
05/102 (4.9)
21/287 (7.3)
62/380 (16.3)
51/243 (21.0)
30/94 (31.9)
0/12 (0)
0/26 (0)
23/73 (31.5)
20/70 (28.6)
11/33 (33.3)
0.57
0.15
0.01*
0.12
0.52
324 (24.5)
176 (13.3)
61 (4.6)
39 (3.0)
38 (2.9)
13 (1.0)
21 (1.6)
11 (0.8)
88 (6.7)
263 (23.8)
148 (13.4)
46 (4.2)
32 (2.9)
34 (3.1)
11 (1.0)
16 (1.4)
10 (0.9)
77 (7.0)
61 (28.5)
28 (13.1)
15 (7.0)
7 (3.3)
4 (1.9)
2 (0.9)
5 (2.3)
1 (0.46)
11 (5.1)
0.10
0.47
0.06
0.45
0.24
0.65
0.25
0.45
0.19
Overall mortality
223 (16.9)
Cause of death
Asystole
59(26.5)
Cardiogenic shock/
Pulmonary edema/
Pump failure
91(40.8)
VT/VF
48(21.5)
Mortality in age
subsets (years)
≤44
45-54
55-64
65-74
≥75
In-hospital
complications
LV dysfunction
Post-MI angina
Reinfarction
Infarct extension
Cardiogenic shock
VSD
Severe MR
Bleeding
Pericarditis
30-day event rates
Asymptomatic
Angina pectoris
Heart failure
Reinfarction
Males
n (%)
1106 (83.8)
556/715 (77.8) 482/615 (78.4) 74/133 (55.6) 0.02*
124715 (17.3) 101/615 (16.4) 23/133 (17.3) 0.11
36/715 (5.0)
31/615 (6.4)
5/133 (3.6)
0.44
9/715 (1.3)
7/615 (1.5)
2/133 (1.5)
0.37
Values in parentheses are percentages
*
Statistically significant; VT: ventricular tachycardia; VF: ventricular fibrillation;
LV: left ventricle; MI: myocardial infarction; MR: mitral regurgitation;
VSD: ventricular septal defect
was 10.8±12.4 hours. This delay was mainly due to lack
of emergency transport facilities and failure to recognize
the seriousness of the problem. In the Western studies, the
mean duration of delay ranges from 3 to 4 hours. In the
GRACE registry and GUSTO IIb trial, the mean time delay
was only 2-4 hours.11-13 Hence there is a need to improve
transport facilities and patient education in our country to
reduce this time delay.
Duration of hospital stay: The duration of hospital stay
with STEMI was 5.3±3.4 days in our study, which is
comparable with the data from other developed countries.
In ENACT study,14 the total hospital stay was 7.9 days in
UK/Ireland and 12.6 days in Eastern Europe.
In-hospital mortality: The overall in-hospital mortality
rate was 16.9% in our study. In the randomized trials on
fibrinolysis for STEMI,4-6 the reported mortality ranged from
4% to 7%. As per CREATE registry15 data from India,
mortality rate was 7.9% at tertiary care centers for acute
coronary syndrome which included both, patients with
9/29/2004, 4:58 PM
Indian Heart J 2004; 56: 210–214
unstable angina and AMI. However, in non-randomized
trials, especially in the registry data, the reported mortality
is usually higher. In a study published in Scotland,16 the
case fatality following AMI was 22.2% in a group of 11,778
patients. In the MITRA and MIR registries data17 from
Germany, the overall mortality was 15%.
Gender and age: Women had higher prevalence of
hypertension, diabetes mellitus and higher in-hospital
mortality than men (25.2% v. 15.3%, p<0.001). The
demographic characteristics and mortality rate in females
in our study match the report from Trappolini et al.18 In
their study, the overall mortality rate during hospitalization
was 24.4% for women and 13.2% for men; women were
significantly older than men, had higher prevalence of
hypertension and diabetes mellitus, and thrombolytic
therapy was prescribed less often in them. In the MONICA
project 19 also diabetes mellitus was more common in
women and they had higher in-hospital mortality (21.2%
v. 12.7%).
In our study, the in-hospital mortality in patients above
75 years of age was 32.3%. In the study by Ruiz-Bailen
et al.20 the mortality was 17.7% in patients between age
of 75-84 years and 25.8% in patients more than 84 years
of age.
Reasons for high mortality: The higher mortality
observed in our patients can have several reasons. Firstly,
most of our patients received only thrombolytic therapy and
primary percutanous coronary angioplasty was done only
in few patients. Secondly, our hospital being tertiary care
center, there could be a referral bias in the enrolment of
patients. Patients who are sicker may be referred from
primary and secondary level hospitals to our institution.
However, this higher mortality compared well with the
observational data from the West.13
Post-infarct angina: We have no data in our country
regarding incidence of angina following MI. In our study,
we found that 13% of patients had post-infarction angina
and 5% had reinfarction. In GRACE registry, post-infarct
angina was observed in 14% patients and 3% patients had
reinfarction. In the SPRINT trial,21 the prevalence of postinfarction angina and reinfarction was 9% and 4%
respectively. Thus, the incidence of post-infarct angina and
reinfarction in our country is comparable to the published
data.
Cardiac failure: Cardiac failure is one of the most
important complications that is observed during the first
month of MI. In our study, heart failure was observed in
24.5% of patients during hospital stay, while in the GRACE
IHJ-594-04.p65
213
Jose et al. AMI Mortality in Current Era 213
registry this was observed in 18% of patients. Spencer
et al.22 reported heart failure in 20.4% of the 606,500
patients with AMI during hospitalization and 8.6% patients
developed heart failure thereafter.
30-day event rates: In our study, 30-day event rates of
death, reinfarction and recurrent angina following hospital
discharge was 18.1% . In the Western studies, these outcome
data were in the range of 4-22%.7,23,24 In a study by Capewell
et al.16 the reported case fatality was 22.2% at 30-day, while
the SPRINT trial reported a 30-day mortality of 10.8%.21
Limitations of the study: The number of patients with
STEMI in our study is very small compared to published
trials from the West. Secondly, our data is only from one
center from South, hence our results are not generalizable.
We also had a number of patients lost to follow-up during
the study period. The mean hospital stay was shorter in
our study population due to early discharge of
uncomplicated patients. It is likely that we might have
missed a few mechanical complications like ventricular
septal defect and papillary muscle rupture.
Conclusions: To the best of our knowledge, this is the first
acute STEMI segment elevation myocardial infarction
registry data from a single tertiary care center in India
looking at the in-hospital mortality and 30-day event rates.
Though our results are comparable to the Western data,
there is an urgent need to bring down this mortality.
Enormous effort is, therefore, required to educate the public
regarding heart attacks and there is an urgent need to
establish heart attack centers/hospitals across the country
that serve only the MI patients. We still need large welldesigned prospectively performed registries in patients with
AMI.
Acknowledgements
We are extremely thankful to Mr. Selva Raj for helping and
guiding us in statistical analysis.
References
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for fibrinolytic therapy in suspected acute myocardial infarction:
collaborative overview of early mortality and major morbidity results
from all randomized trials of more than 1000 patients. Lancet 1994;
343: 311–322
2. Collins R, Peto R, Baigent C, Sleight P. Aspirin, heparin, and fibrinolytic therapy in suspected acute myocardial infarction. N Engl J
Med 1997; 336: 847–860
3. Grines CL, Browne KF, Marco J, Rothbaum D, Stone GW, O’Keefe J, et
al. Primary Angioplasty in Myocardial Infarction study group. A
comparison of immediate angioplasty with thrombolytic therapy for
acute myocardial infarction. N Engl J Med 1993; 328: 673–679
9/29/2004, 4:58 PM
Indian Heart J 2004; 56: 210–214
214 Jose et al. AMI Mortality in Current Era
4. The GUSTO investigators. An international randomized trial
comparing four thrombolytic strategies for acute myocardial
infarction. N Engl J Med 1993; 329: 673–682
5. The Global Use of Strategies to Open Occluded Coronary Arteries
(GUSTO III) investigators. A comparison of reteplase with alteplase
for acute myocardial infarction. N Engl J Med 1997; 337: 1118–1123
6. Assessment of the Safety and Efficacy of a New Thrombolytic
(ASSENT-2) investigators. Single-bolus tenecteplase compared with
front-loaded alteplase in acute myocardial infarction. Lancet 1999;
354: 716–722
7. Stevenson R, Ranjadayalan K, Wilkinson P, Roberts R, Timmis AD.
Short and long term prognosis of acute myocardial infarction since
introduction of thrombolysis. BMJ 1993; 307: 349–353
8. Brown N, Young T, Gray D, Skene AM, Hampton JR. Inpatient deaths
from acute myocardial infarction,1982-1992: analysis of data in
the Nottingham heart attack register. BMJ 1997; 315: 159–164
9. Every NR, Frederick PD, Robinson M, Sugarman J, Bowlby L, Barron
HV. A comparison of the national registry of myocardial infarction
2 with the cooperative cardiovascular project. J Am Coll Cardiol 1999;
33: 1886–1894
10. Zeymer U, Senges J. Why do we need prospective registries in patients
with acute myocardial infarction? Eur Heart J 2003; 24: 1611–1612
11. Steg AG, Goldberg RJ, Gore JM, Fox KA, Eagle KA, Flather MD, et al.
GRACE Investigators. Baseline characteristics, management
practices and in-hospital outcomes of patients hospitalized with
acute coronary syndromes in the Global Registry of Acute Coronary
Events (GRACE). Am J Cardiol 2002; 90: 358–363
12. The Global Use of Strategies to Open Occluded Coronary Arteries in
Acute Coronary Syndromes (GUSTO IIb) angioplasty substudy
investigators. A clinical trial comparing primary coronary
angioplasty with tissue plasminogen activator for acute myocardial
infarction. N Engl J Med 1997; 336: 1621–1628
13. Di Chiara A, Chiarella F, Savonitto S, Lucci D, Bolognese L, De Servi
S, et al. BLIT Investigators. Epidemiology of acute myocardial
infarction in the Italian CCU network. Eur Heart J 2003; 24: 16161629
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15. Pais P, Xavier D, Gupta R, Jaison TM, Maity AK, Naik S, et al. For
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9/29/2004, 4:58 PM
Indian Heart J 2004; 56: 215–219
Singh et al. Mahaim Automatic Accelerated
Rhythm
215
Original
Article
Mahaim Automatic Accelerated Rhythm : A Marker of
Successful Radiofrequency Ablation
Balbir Singh, Ripen Kumar Gupta, Anil Dhall, Tapan Ghose, Rahul Trehan, Upendra Kaul
Department of Cardiology, Batra Hospital and Medical Research Centre and
Department of Cardiology, R and R Hospital, New Delhi
Background: Mahaim pathways are characterized by the presence of an accessory pathway potential—the
‘M’ potential, at the tricuspid annulus. M potential is a very useful guide during radiofrequency ablation of
Mahaim pathway. During ablation, an accelerated rhythm with QRS morphology, identical to fully pre-excited
QRS complex is observed, and has been labeled as Mahaim automatic rhythm. We analyzed this rhythm during
radiofrequency ablation of these pathways.
Methods and Results: Eighteen patients with Mahaim accessory pathways were taken up for electrophysiology
study and radiofrequency ablation. Tricuspid annulus was mapped for ‘M’ potentials and targeted for ablation.
Duration of ablation and number of ablation attempts were guided by Mahaim automatic rhythm during
ablation. Mahaim tachycardia was inducible in all. ‘M’ potentials were recorded in 15/18 patients.
Radiofrequency energy was delivered at the site where Mahaim accelerated rhythm was noticed and was
continued till abolition of the rhythm. This resulted in long-term success. In 3 patients, M potentials were not
recordable, and in them other methods including 3-dimensional electroanatomical mapping was also not
successful.
Conclusions: ‘M’ potential-guided radiofrequency ablation is a useful technique. Presence of Mahaim automatic
rhythm and its abolition during ablation is associated with long-term success of the procedure. (Indian Heart
J 2004; 56: 215–219)
Key Words: Radiofrequency ablation, Accessory pathway, Arrhythmia
M
ahaim and Winston first described tracts connecting
the atrioventricular (AV) node and the ventricular
myocardium as well as discrete connections from fascicles
to the ventricles.1 Mahaim conduction is characterized by
gradual increase in the AV interval simultaneous with the
development of a left bundle branch block (LBBB) and
shortening of the His-ventricular (HV) interval in response
to atrial overdrive pacing.2,3 It was long believed that
Mahaim accessory pathways represent nodofascicular or
nodoventricular connections. However, recent evidence
from electrophysiologic studies,4 surgery5 and catheter
ablation6-11 has established that right atriofascicular fibers
crossing the tricuspid annulus are responsible for Mahaim
conduction, while nodoventricular fibers are uncommon.
Several reports have described the successful ablation of
these pathways using radiofrequency (RF) energy. The
present report describes the characteristics of automatic
‘Mahaim’ accelerated rhythm arising during the RF
ablation of these pathways.
Correspondence: Dr Balbir Singh, Senior Consultant, Interventional
Cardiology and Cardiac Electrophysiology, Batra Hospital & Medical Research
Centre, 1, Tughlakabad Institutional Area, Mehrauli-Badarpur Road,
New Delhi 110 062
Electrophysiological study: All patients underwent
electrophysiological testing after an informed written
consent. Quadripolar catheters were placed in the right
IHJ-716-04.p65
215
Methods
Study population: The study population comprised of 18
patients, who on electrophysiological testing had a preexcited tachycardia of an LBBB pattern with short
ventriculo-atrial (VA) and long AV intervals, and were
found to have an accessory pathway exhibiting only
antegrade conduction, with long antegrade conduction
time and decremental conduction properties. There were
9 males and 9 females in age range 15 to 49 years (mean
28.2±12.4 years). None of the patients had structural
heart disease on echocardiography.
9/29/2004, 5:11 PM
216 Singh et al. Mahaim Automatic Accelerated Rhythm
Indian Heart J 2004; 56: 215–219
ventricular (RV) apex, the His bundle (HB) position and,
the high right atrium. A decapolar catheter was positioned
in the coronary sinus. The HB catheter was used to record
right bundle (RB) and HB potentials from distal and
proximal poles, respectively. In case both could not be
recorded, an additional catheter was introduced to record
RB potentials.
Programmed electrical stimulation was performed using
atrial and ventricular extrastimuli and overdrive pacing.
An LBBB morphology tachycardia was inducible in all the
patients. The criteria for the presence of Mahaim fiber
conduction included (a) baseline antegrade pre-excitation
Fig. 2. Atrial pacing with extrastimulation (S1 S1 = 500 ms and S1 S2 = 300
ms) shows evidence of prolongation of AV interval with H-spike merging into
the V-complex during maximal pre-excitation confirming the decremental
conduction properties of these pathways. AV: atrioventricular
Fig. 1. 12-lead electrocardiogram of a patient with documented broad QRS
(LBBB morphology) tachycardia; subtle degree of pre-excitation is noted at
baseline. LBBB: Left bundle branch block
with LBBB morphology or normal conduction (Fig. 1), (b)
increasing ventricular pre-excitation associated with an
increasing AV interval and a short HV interval with atrial
incremental pacing or decremental atrial extrastimulation
(Fig. 2) and, (c) a reciprocating tachycardia with the same
LBBB pre-excitation morphology and the RB electrogram
preceding HB activation during antegrade pre-excitation
(Fig. 3).11 After the diagnosis of Mahaim accessory pathway
was established, the mapping was performed using a 7 F
steerable ablation catheter with a 4 mm tip (EP technologies
or Cordis Webster).
The entire tricuspid annulus was mapped during sinus
IHJ-716-04.p65
216
Fig. 3. Mahaim pre-excited tachycardia with retrograde conduction through
the AV node shows RB preceding HB, which is nearly merged in V-complex. The
12-lead QRS complex morphology is LBBB with left axis deviation. LBBB: left
bundle branch block; RB: right bundle; HB: His bundle
rhythm with position of catheter tip confirmed in left
anterior oblique (LAO) and right anterior oblique (RAO)
9/29/2004, 5:11 PM
Indian Heart J 2004; 56: 215–219
projections. The Mahaim (M) potentials were carefully
searched in all these areas. A Mahaim potential was
considered as a discrete deflection between A and V with
the interval between the accessory potential (AP) and V
remaining constant during the AV delay produced by atrial
pacing. If potentials were not recorded, then pacing was
performed from several sites along the tricuspid annulus
and the site with the shortest stimulus to delta interval was
targeted for ablation. The distal insertion was targeted for
ablation in one patient.
Radiofrequency ablation: RF energy was delivered at the
site recording M potentials (n=15) or site with shortest
stimulus to delta wave duration (n=3). The temperature
was set at 65°C and the power at 50 W. The energy was
applied during sinus rhythm for 10 sec and was continued
for 60 sec only if extrasystoles or brief accelerated rhythm
that probably originated in the accessory pathway (QRS
morphology identical to fully pre-excited QRS complexes,
early ventricular activation at RV apex and early retrograde
activation of the right bundle) – labeled as ‘Mahaim’
automatic rhythm was noted. At the completion of the
RF lesion, atrial/ventricular incremental pacing/
extrastimulation were performed to look for Mahaim
conduction or induction of other tachycardias.
3-Dimensional electroanatomical mapping: In a
patient with two previously failed attempts at ablation,
mapping was performed using 3-dimensional
electroanatomical mapping system (CARTOTM, Biosense
Webster). The tricuspid annulus was tagged all around and
a careful search for M potentials was attempted along the
annulus. However, despite extensive mapping, potentials
were not recorded at any site. The catheter was then
positioned at distal RB, RV mid septum and RV apical sites
and a ventricular activation map was constructed during
atrial pacing. The site of earliest ventricular activation was
then targeted for ablation.
Results
Electrophysiological characteristics: In all patients, the
electrophysiological study revealed that the accessory
pathway had an atrial origin located along the right free
wall and right atria was a critical component of the macro
reentrant circuit during tachycardia. An LBBB morphology
tachycardia was inducible on atrial/ventricular extrastimulation in all patients with RB potential preceding the
HB potential.
Six additional narrow QRS tachycardia were induced
in 5 patients (4 - AV nodal reentry tachycardia, 1 -
IHJ-716-04.p65
217
Singh et al. Mahaim Automatic Accelerated Rhythm 217
orthodromic tachycardia with concealed left lateral
accessory pathway and 1 - concealed right posteroseptal
accessory pathway).
Recording of accessory potentials: Potentials
consistent with accessory pathway activation were recorded in 15 of the 18 patients (Fig. 4). An accessory pathway origin was confirmed by demonstrating a constant
relationship between the AP and subsequent QRS complex
during antidromic tachycardia or atrial pacing. These
potentials were sharp deflections with an isoelectric line
between the AP and the ventricular electrogram,
resembling the HB potential.
Fig. 4. Direct recordings of the activation at the proximal end of right atriofascicular pathway during sinus rhythm at 8 O’clock position on the tricuspid
annulus depicting a distinct sharp accessory pathway potential.
Stimulus to QRS interval mapping: In three patients
where AP could not be recorded, pacing from the mapping
catheter was performed all along the tricuspid annulus to
reach a site with the shortest stimulus to QRS interval,
which was then targeted for ablation. Ablation was not
successful in any of these patients.
Mapping of the distal insertion site: The distal insertion
site was mapped during atrial pacing using the 3D
electroanatomical mapping in one patient. The earliest site
was found to be on RV apicoseptal region just beyond the
RB potential. Several attempts at RF ablation at this site
resulted in only temporary interruption of the accessory
pathway conduction.
9/29/2004, 5:11 PM
Indian Heart J 2004; 56: 215–219
218 Singh et al. Mahaim Automatic Accelerated Rhythm
Radiofrequency catheter ablation: The accessory
pathway was successfully ablated in 15 patients. The
accessory pathway potentials were recorded in all these
patients; the site of ablation was the tricuspid annulus. In
the remaining 3 patients where potentials could not be
recorded, ablation was unsuccessful despite using other
mapping techniques including electroanatomical mapping.
Mahaim-accelerated beats or rhythm were noticed
during RF energy delivery in all patients where potentials
were recorded; the presence of this rhythm also correlated
with a successful procedure (Fig. 5). The lesion was
continued till it resulted in complete abolition of these
accelerated beats. In 2 patients residual conduction was
noted after completion of these lesions; however, another
lesion at the same site resulted in complete interruption in
both. In all patients where potentials could be recorded, the
His bundle
Mitral
annulus
Anterior
Tricuspid
annulus
Right
Left
Posterior
Fig. 6. Schematic representation of the tricuspid and mitral valve annuli, as
viewed in the left anterior oblique projection, illustrating the location of 15
Mahaim pathways that were successfully ablated.
ablated near the os of the coronary sinus. AV nodal
reentrant tachycardia was inducible with atrial
extrastimulation in 4 patients, all of whom underwent an
additional successful slow pathway ablation.
Follow-up: Long-term follow-up has ranged from 6 to 60
months (mean 18±16 months). There were no further
episodes of tachycardia, and none of the successfully
treated patients received anti-arrhythmic drug therapy. Of
the 3 unsuccessfully treated patients, one is asymptomatic
on verapamil, the other 2 have had occasional episodes on
a combination of beta-blockers and disopyramide.
Discussion
Fig. 5. Mahaim accelerated rhythm during radiofrequency lesion; the first few
complexes show mild degree of pre-excitation followed by an irregular automatic
rhythm with QRS complexes, same as during the antidromic tachycardia, this
is followed by non-pre-excited complexes (last 2 beats).
RF energy was delivered during sinus rhythm and was
continued only if these accelerated beats were noticed
within 10 sec of the delivery of RF energy.
The success of the ablation was demonstrated by absence
of pre-excited complexes on atrial pacing and inability to
induce the tachycardia or single ventricular echo complexes
by atrial or ventricular stimulation. The location around
the tricuspid annulus of the successful ablation site or the
site recording the AP is illustrated in Fig. 6.
One patient had a concealed left lateral accessory
pathway which was successfully ablated by the retrograde
aortic approach. Another patient had a concealed right
posteroseptal accessory pathway, which was successfully
IHJ-716-04.p65
218
There are several reports in the literature on ablation of
Mahaim accessory pathway guided by accessory pathway
potentials. In present series, a distinct accessory pathway
activation potential was recorded close to the anterolateral,
lateral and posterolateral tricuspid annular sites, this was
a high frequency potential of short duration similar to HB
potential. The recording of AP was associated with high
degree of success similar to the experience described by
McClelland et al.7 The catheter ablation of these pathways
is not easy. As they do not conduct retrogradely, they have
decremental conduction properties. So mapping during
pre-excitation to look for a short AV interval is not useful
and because they insert close to or into right bundle branch,
targeting distal insertion may not eliminate tachycardia.11
The most significant breakthrough was made by
7
McClelland et al with the description of accessory pathway
potential mapping.
9/29/2004, 5:11 PM
Indian Heart J 2004; 56: 215–219
This report describes the presence of accelerated
automatic beats during RF ablation in patients where the
potentials were recorded with success. The accelerated and
irregular rhythm that was observed during ablation had a
morphology identical to that seen during pre-excitation.
Similar observations have been reported by McClelland et
al. in 11 of 23 patients,7 Grogin et al.12 in 1 of 4 patients
and Sternick et al.13 in 4 of 5 patients. The response to
heating of a decrementally conducting tract appears
analogous to the junctional rhythm associated with
ablation of the slow pathway. The mechanism of this
rhythm is more of the nature of enhanced automaticity.
From a practical viewpoint the rhythm appears to be a
sensitive and specific marker of success. Since Mahaim
accessory pathways are uncommon, to compute the
sensitivity and specificity of this rhythm may be difficult.
On the other hand, this response to heating adds to the list
of characteristics that atriofascicular pathways share with
AV node. Both demonstrate long conduction times,
decremental conduction in response to extrastimuli,
Wenckebach pattern conduction block, and conduction
block in response to adenosine. Mahaim-accelerated
rhythm also assumes importance as a marker of success,
like the junctional acceleration noted during the slow
pathway ablation.
Conclusions: High success rates are obtained by using AP
as the target for ablation of atriofascicular pathways.
Occurrence of ‘Mahaim’ automatic rhythm during RF
ablation seems to predict the success of the procedure.
References
1. Mahaim I, Winston MR. Recherches d’lanatomic comparee et du
pathologic experimentale sur les connexions hautes du faisceau de
His-Tawara. Cardiologia 1941; 5: 189–260
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Singh et al. Mahaim Automatic Accelerated Rhythm 219
2. Gallagher JJ, Smith WM, Kasell JH, Benson DW Jr, Sterba R, Grant
AO. Role of Mahaim fibers in cardiac arrhythmias in man. Circulation
1981; 64: 176–189
3. Gillette PC, Garson A Jr, Cooley DA, McNamara DG. Prolonged and
decremental antegrade conduction properties in right anterior
accessory connections: wide QRS antidromic tachycardia of left
bundle branch block pattern without Wolff-Parkinson-White
configuration in sinus rhythm. Am Heart J 1982; 103: 66–74
4. Tchou P, Lehmann MH, Jazayeri M, Akhtar M. Atriofascicular
connection or a nodoventricular Mahaim fiber? Electrophysiologic
elucidation of the pathway and associated reentrant circuit.
Circulation 1988; 77: 837–848
5. Klein GJ, Guiraudon GM, Kerr CR, Sharma AD, Yee R, Szabo T, et al.
"Nodoventricular" accessory pathway: evidence for a distinct
accessory atrioventricular pathway with atrioventricular node-like
properties. J Am Coll Cardiol 1988; 11: 1035–1040
6. Bhandari A, Morady F, Shen EN, Schwartz AB, Botvinick E,
Scheinman MM. Catheter-induced His bundle ablation in a patient
with reentrant tachycardia associated with a nodoventricular tract.
J Am Coll Cardiol 1984; 4: 611–616
7. McClelland JH, Wang X, Beckman KJ, Hazlitt HA, Prior MI,
Nakagawa H, et al. Radiofrequency catheter ablation of right
atriofascicular (Mahaim) accessory pathways guided by accessory
pathway activation potentials. Circulation 1994; 89: 2655–2666
8. Tchou PJ, Keim SG, Kinn RM, Rist KE, Setter SF, Adhar G.
Electrophysiologic evidence for an ectopic node-His like atrioventricular conduction system in an atriofascicular pathway [Abstr].
Pacing Clin Electrophysiol 1992; 15: 51
9. Haissaguerre M, Warin JF, Le Metayer P, Maraud L, De Roy L,
Montserrat P, et al. Catheter ablation of Mahaim fibers with
preservation of atrioventricular nodal conduction. Circulation 1990;
82: 418–427
10. Klein L, Hackett FK, Zipes DP, Miles WM. Radiofrequency catheter
ablation of Mahaim fibers at the tricuspid annulus. Circulation 1993;
87: 738–747
11. Brugada J, Martinez-Sanchez J, Kuzmicic B, Figueiredo MO, Matas
M, Pava LF, et al. Radiofrequency catheter ablation of atriofascicular
pathways guided by discrete electrical potentials recorded at the
tricuspid annulus. Pacing Clin Electrophysiol 1995; 18: 1388–1394
12. Grogin HR, Lee RJ, Kwasman M, Epstein LM, Schamp DJ, Lesh MD, et
al. Radiofrequency catheter ablation of atriofascicular and
nodoventricular Mahaim tracts. Circulation 1994; 90: 272–281
13. Sternick EB, Gerken LM, Vrandecic M. Appraisal of ‘Mahaim’
automatic tachycardia. J Cardiovasc Electrophysiol 2002; 13:
244–249
9/29/2004, 5:11 PM
220 Rathore
et al. RV Diastolic Function in TOF
Original
Article
Indian Heart J 2004; 56: 220–224
Assessment of Right Ventricular Diastolic Function: Does It
Predict Post-Operative Course in Tetralogy of Fallot
Kaushlendra Singh Rathore, Nirmal Gupta, Aditya Kapoor, Nitin Modi,
PK Singh, Prabhat Tewari, Nakul Sinha
Departments of Cardiovascular and Thoracic Surgery, Cardiology and Anesthesiology,
Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow
Background: In some cases of tetralogy of Fallot the post-operative course is characterized by episodes of low
cardiac output, elevated central filling pressures and prolonged ventilation and inotropic support. This may be
due to impaired diastolic function of the right ventricle despite preservation of biventricular systolic function.
Methods and Results: Sixty-four consecutive patients (mean age 7.06±4.9 years) undergoing repair of
tetralogy of Fallot were prospectively studied to assess right ventricular diastolic function. ‘Restrictive physiology’
was defined as presence of laminar antegrade diastolic pulmonary artery flow (A wave) throughout the
respiratory cycle, which was coincident with atrial systole. Right ventricle restriction was present in 45/64
(70%, Group 1) patients and absent in 19/64 (30%, Group 2) patients. There was a marked inspiratory
augmentation of the pulmonary artery A wave velocity, flow integral and duration. Transtricuspid flow revealed
significantly lower peak E velocity, lower E/A ratio, shorter E deceleration time and higher A velocity time integral
in those with right ventricular restriction. Biventricular systolic function and transmitral flow were normal in
all patients. Those with restrictive physiology had significantly longer mean inotrope support duration, longer
ventilation and chest drainage times. Correspondingly, the mean intensive care unit stay (56.7±9.3 v. 34.7±5.38
hours, p<0.01) and mean hospital discharge time (9.3±2.3 v. 6.2±0.5 days, p <0.001) was also significantly
longer in group 1.
Conclusions: Right ventricular restriction (as seen by laminar antegrade diastolic pulmonary artery flow
throughout the respiratory cycle) exists in a significant subset of patients with tetralogy of Fallot following
operative repair. Following surgery, such patients have higher inotropic requirement, longer ventilation times
and longer hospital stay. (Indian Heart J 2004; 56: 220–224)
Key Words: Tetralogy of Fallot, Echocardiography, Diastolic function
I
n most cases of tetralogy of Fallot (TOF) the postoperative course is uncomplicated. However in some
patients, the course is characterized by episodes of low
cardiac output, elevated central filling pressures with
consequent pleural effusions and ascites, and requirement
of prolonged ventilation and inotropic support. Despite
preservation of biventricular systolic function, impaired
diastolic function of the right ventricle (RV) is considered
to be responsible for such a clinical picture. It has been
documented that abnormalities of RV diastolic function
exist in some patients following operative repair of TOF.1,2
Often these abnormalities have been shown to be transient,
Correspondence: Dr Aditya Kapoor, Associate Professor, Department of
Cardiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences,
Rae Bareli Road, Lucknow 226014. e-mail: [email protected]
IHJ-546-03.p65
220
and are known to resolve within a few weeks.1 The aim of
the study was to prospectively study patients undergoing
repair of TOF between January 2001–December 2002 and
to assess the RV diastolic function by serial echocardiography performed immediate post-operatively and
at 12 weeks, and see if it correlates with post-operative
recovery.
Methods
All patients were studied with transthoracic imaging using
a 5 or 7.5 MHz transducer interfaced with a HewlettPackard Sonos 5500 echocardiography system. An Mmode imaging of the left ventricular cavity was performed
in all patients followed by a detailed pulsed Doppler
examination which included: (i) transtricuspid and trans-
9/29/2004, 4:55 PM
Indian Heart J 2004; 56: 220–224
mitral flow characteristics at the level of the tips of the valve
leaflets in apical 4-chamber view (ii) superior vena caval
(SVC) Doppler profile (1-2 cm proximal to the RA) and (iii)
pulmonary artery (PA) systolic and diastolic Doppler flow
with the sample volume placed at the midpoint between
the pulmonary valve leaflets and bifurcation. This included
measurement of peak velocity, integral and duration of
antegrade systolic and diastolic PA flow, and duration of
pulmonary regurgitation (PR). PR was graded according
to standard criteria.3 While recording the transtricuspid
and transmitral flow, the respective E- and A-velocity,
velocity time integral (VTI), deceleration time (EDT or ADT)
and duration were noted in each case.
Measurements were taken for simultaneous ECG and
respiratory motion recordings, with minimal filtering at a
paper speed of 100 cm/s. Three consecutive inspiratory and
expiratory cycles were recorded and analyzed by planimetry
and the values were averaged. Assessment of SVC flows
were made with special reference to presence or absence of
retrograde diastolic flow.
Definition of restrictive physiology: This was defined
as presence of laminar antegrade diastolic PA flow
throughout the respiratory cycle, which was coincident
with atrial systole (Fig. 1).
Surgical technique: All patients were operated by a single
surgeon (NG), using median sternotomy with aortic and
bicaval cannulation with right-angled canulae, SVC and
IVC snuggers. All patients were cooled to 28-32°C and blood
cardioplegia with external ice slush was used. Ventricular
septal defect (VSD) closure and infundibular resection were
Rathore et al. RV Diastolic Function in TOF 221
preformed through right atrium in all cases, using Dacron
patch and continuous prolene. Main or branch PA enhancement was performed during re-warming without
cross-clamp on beating perfused heart. Closure of patent
foramen ovale (PFO) or atrial septal defect (ASD) was
performed routinely.
Results
The study population included 64 patients (mean age
7.06±4.9 years, range 1-27 years; mean weight 17.3±4.9
kg, range 9-36 kg) of which 43 (74%) were males. A
transatrial VSD closure with infundibular resection and
pulmonary valvotomy was performed in all cases, while
patch enhancement of main pulmonary artery was
performed in 46/64 (72%) cases. No patients had a
significant residual RV outflow tract obstruction (gradient
>20 mmHg) or a residual intracardiac shunt following the
surgery.
Right ventricular restriction: Defined as laminar
antegrade diastolic PA blood flow coincident with atrial
systole, present in both inspiration and expiration (Fig. 1),
it was present in 45/64 (70%, Group 1) patients and absent
in 19/64 (30%, Group 2) patients. The A wave in the PA
flow (marker of RV restriction) accounted for 24-35% of
the total antegrade PA Doppler flow integral. A significant
inspiratory augmentation of the A wave velocity, VTI and
A wave duration was observed consistently (Table 1). PR
was noted in all 64 patients; it was trivial to mild in 58
(90%) patients, and moderate in 6 (10%) cases. The
duration of PR was significantly shorter in those with RV
restriction (248.6±48.5 ms) than those without it
(298±21.7 ms) (Table 1).
Table 1. Pulmonary artery Doppler characteristics in
those with (Group 1) versus those without (Group 2)
restriction
Characterstics
Fig. 1. Doppler examination of pulmonary arterial flow in a case of RV
restrictive physiology reveals presence of laminar antegrade diastolic PA flow
(marked as “A”) which was coincident with atrial systole.
RV: right ventricle; PA: pulmonary artery
IHJ-546-03.p65
221
A wave velocity (I)
A wave velocity (E) *
A wave duration (I)
A wave duration (E) *
A wave integral (I)
A wave integral (E) *
Systolic velocity
Systolic integral
PR duration (I)
PR duration (E) *
Group 1
Group 2
0.46±0.13
0.33±0.08
184.3±13.66
130.08±12.7
2.58±0.55
1.51±0.42
1.72±0.33
8.14±1.6
248.6±48.5
165.7±36.7
NA
NA
NA
NA
NA
NA
1.78±0.15
7.23±0.85
298±21.7
279.8±19.8
All values marked (*) are significant (p <0.05) when inspiratory values
are compared to those in expiration. All velocites are in cm/s and duration
in ms
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Indian Heart J 2004; 56: 220–224
222 Rathore et al. RV Diastolic Function in TOF
SVC flow: Satisfactory SVC flow recordings were possible
in 45/64 (70%) cases. All cases with evidence of RV
restrictive physiology had reversal of SVC flow with atrial
systole (retrograde SVC flow) while this was not seen in any
case without RV restriction. Also, those with RV restriction,
more often had predominant diastolic antegrade systolic
flow in the SVC flow recordings (30/45 cases with restrictive physiology, v. 2/19 patients without RV restriction).
Transtricuspid flow (Table 2): Transtricuspid flow was
reliably measured in 60/64 patients while in 4 patients such
an analysis was not possible because of transtricuspid
summation. Those with restrictive physiology had significantly lower peak E velocity and shorter transtricuspid E
deceleration time as compared to those with no restriction
with the difference persisting in expiration as well.
Comparison of transtricuspid VTIs revealed that those with
restriction had significantly higher A VTI. Although the E
VTI was slightly lower in these patients, it was not
statistically significant.
Biventricular systolic function and the transmitral E and
Table 2. Transtricuspid flow patterns in those with
(Group 1) and those without restriction (Group 2)
Characterstics
Restrictive
(Group 1)
No restriction
(Group 2)
EDT inspiration
EDT expiration
E velocity (I)
E velocity (E)
E VTI
E duration
A velocity (I)
A velocity (E)
A VTI
101.3±21.3
91.25±23.2
0.66±0.07
0.60±0.06
9.54±2.1
188.8±17.08
0.60±0.06
0.53±0.06
7.08±1.94
152.3±22.1
138.1±21.9
0.89±0.15
0.81±0.14
11.14±1.95
178.0±17.67
0.59±0.04
0.55±0.04
5.5±1.66
p value
0.001
0.001
0.001
0.001
0.09
0.18
NS
NS
0.05
EDT : E deceleration time (ms); E VTI: E velocity time integral (cm);
A VTI: A velocity time integral (cm)
All velocities are in cm/s and duration in ms
I and E indicate values in inspiration and expiration respectively
A flow patterns were normal in all patients.
Comparison of patients with and without RV restriction (Table 3): The mean age, weight, hemoglobin (Hb),
packed cell volume (PCV) and platelet counts were
comparable among patients with and without restrictive
physiology. The mean Nakata index (239.4±82.0 v.
252.1±102.4), mean z value (0.83±0.64 v. 0.82±0.54),
cardiopulmonary bypass (CPB) time (101.46±19.3 v.
112.0±28.8 min) and mean aortic cross clamp time (ACC:
65.54±15.86 v. 60.1±8.71 min) were comparable among
the two groups. There was no correlation between the use
IHJ-546-03.p65
222
Table 3. Comparison of parameters between those with
(Group 1) and those without restrictive physiology (Group 2)
Parameters
Restrictive
(Group 1)
Age (years)
Weight (kg)
Hb (gm%)
PCV
Nakata index
z value
CPB (min)
ACC (min)
Ventilation (hours)
Drain time (hours)
ICU stay (hrs)
Discharge time (days)
TAP
No TAP
6.6±3.5
17.13±4.77
14.6±2.1
39.7±8.33
239.4± 82.0
0.83±0.64
101.46±19.3
65.54±15.86
18.8±4.3
34.6±2.5
56.7±9.3
9.3±2.3
25
8
No restriction
(Group 2)
8.7±6.54
18±5.72
13.1±2.1
41.5±9
252.1±102.4
0.82±0.54
112.0±28.8
60.1±8.71
8.43±5.03
19.7± 6.16
34.7±5.38
7.2±0.5
21
10
p value
NS
NS
NS
NS
NS
NS
NS
NS
0.05
0.04
0.01
0.001
NS
NS
PCV : packed cell volume; CPB : cardiopulmonary bypass; ACC: aortic cross
clamp; TAP: transannular patch
of transannular patch (TAP) with the incidence of RV
restriction. Of the 46 patients who received TAP, 25 had
RV restrictive physiology, while 21 did not.
The mean inotrope duration (16.2±2.1 v. 10.3±1.9
hours, p<0.02), mean ventilation time (18.8±4.3 v.
8.43±5.03 hrs, p<0.05) and mean chest drain time
(34.6±2.5 v. 19.7±6.16 hours, p<04) were significantly
longer in those with RV restriction group. Correspondingly,
the mean ICU stay was much longer in group 1 (56.7±9.3
v. 34.7±5.38 hours, p<01). The mean hospital discharge
time was also significantly longer in those with RV
restriction (9.3±2.3 v. 6.2±0.5 days, p<001). Overall 3/
64 (4%) patients died (2 due to sudden ventricular
fibrillation, and 1 due to septicemia). All 3 patients had
documented RV restrictive physiology.
Hospital stay: Based on mean hospital stay, the patients
were divided into two groups (Group 1, <10 days, n=48;
(Group 2, >10 days, n=16). The mean age, weight, z value,
CPB time and ACC times were comparable among the two
groups. As expected, patients with longer hospital stay had
longer ventilation and chest drainage times and
consequently longer ICU stay.
The marker of RV restrictive physiology (the A wave in
the antegrade PA Doppler flow) was observed to be significantly different among these two groups. Those with
longer hospital stay had significantly higher pulmonary A
velocity (0.60±0.19 v. 0.31±0.18 cm/s, p<0.01) and
higher pulmonary A VTI (2.85±0.5 v. 1.8±1.17, p<0.01)
recorded in the antegrade PA flow. Amongst all transtricuspid flow variables, only EDT was discriminatory, being
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Indian Heart J 2004; 56: 220–224
significantly shorter in those with longer hospital stay
(118.7±28.3 in Group 1 v. 88.1±27.2 ms in Group 2,
p<0.04).
Follow-up: A follow-up echocardiographic recording for
all patients was obtained at 4 weeks (n=61, excluding the
3 patients who died; 42 with RV restriction, 19 without RV
restriction) and in 46 patients (35 in RV restrictive group,
and 11 without RV restriction) at 12 week following
discharge.
At 4 weeks all 42 patients with immediate RV restrictive
physiology continued to show persistent RV diastolic
dysfunction. Of these 42 patients, 30 were in NYHA class
I, 9 in NYHA class II while 3 were in class III. All 19 patients
without RV restriction were in NYHA class I.
At 12 weeks, of the 35 patients with immediate RV
restrictive physiology who were studied, 30 (86%)
continued to show persistent abnormalities, while 5
patients showed disappearance of antegrade PA diastolic
flow. No patient developed new onset RV restriction in
follow-up (i.e. absent RV restriction at discharge and
developing it on the follow-up echocardiographic study).
Discussion
Early biventricular repair has now become the standard
surgical treatment for most cases of TOF with good longterm results in most patients.4,5 Though the usual postoperative course in cases of TOF is uncomplicated, in some
cases it is characterized by episodes of low cardiac output,
development of systemic venous congestion and
requirement for prolonged ventilatory and inotropic
support. Assessment of RV diastolic function is important
in such cases, especially in the current era of early total
correction with its invariably higher need for TAP
application.6
Abnormalities of RV diastolic function often occur in
patients following repair of TOF,1,2 and have also been
documented in a few small studies following surgical
correction of severe RV outflow tract obstruction. 7,8
Presence of laminar antegrade PA diastolic flow
throughout the respiratory cycle indicates reduced RV
diastolic compliance. Antegrade PA diastolic flow
coincident with atrial systole is noted on pulsed Doppler
echocardiography due to premature opening of the
pulmonary valve. The RV is truly “restrictive” in such cases,
acting merely as a passive conduit between the RA and PA
during atrial systole, and the reduced RV diastolic
compliance is reflected as antegrade PA diastolic flow.1
The hemodynamic basis of this is RV end-diastolic
pressure exceeding PA diastolic pressure leading to
IHJ-546-03.p65
223
Rathore et al. RV Diastolic Function in TOF 223
antegrade PA diastolic flow. Presence of retrograde flow in
SVC and shorter transtricuspid deceleration of early rapid
filling velocity are also consistent with RV restrictive
physiology.
We observed that in our patient population, despite
normal biventricular systolic function and normal
transmitral flow patterns, abnormalities of RV diastolic
function existed in 70% (45/64) of patients, which is much
higher than what is reported by previous studies.1,2,9 This
was evident from the presence of laminar antegrade
diastolic PA flow throughout the respiratory cycle,
coincident with atrial systole. Those with a restrictive
physiology, also had abnormal transtricuspid flow patterns,
as shown by lower peak E velocity, lower E/A velocity ratio,
significantly shorter EDT and higher A VTI. The SVC flow
recordings revealed retrograde flow (coincident with atrial
systole) and predominant antegrade diastolic flow only in
patients with RV restriction.
The higher incidence of RV diastolic dysfunction in our
patients as compared to that reported in other studies could
be because of the fact that our patients were older (mean
age 7.06±4.9, range 1-27 years) as compared to those in
the other studies.1,2 The older the patient, longer would be
the duration for which the RV is subjected to chronic
pressure overload and hypoxia, possibly leading to higher
incidence of RV diastolic abnormalities.
In-hospital course: Patients with a restrictive physiology
had more adverse in-hospital course with a significantly
longer need for inotropic support, longer ventilation and
chest drain times, and longer ICU stay. The mean hospital
stay was also longer in such patients (9.3±2.3 v. 6.2±0.5
days, p<0.001).
On comparing patients with respect to hospital stay (<10
days, n=48 v. >10 days, n=16), variables like age, weight,
Hb, pre-operative aortic saturation, mean RA and RV enddiastolic pressure, z value, CPB time and ACC times were
similar. As expected, patients with longer hospital stay had
longer ventilation and chest drainage times and
consequently longer ICU stay. Patients with longer hospital
stay had significantly shorter transtricuspid EDT, higher
pulmonary A velocity and higher pulmonary A VTI
recorded in the antegrade PA flow, highlighting the fact that
restrictive RV physiology may lead to prolonged hospital
course and more adverse outcome following surgical repair
in cases of TOF.
Follow-up echocardiography: At 4 weeks following
hospital discharge, all patients with immediate RV restrictive
physiology continued to show persistent RV diastolic
dysfunction. At 12 weeks, most (30/35, 86%) patients
9/29/2004, 4:55 PM
224 Rathore et al. RV Diastolic Function in TOF
continued to show persistent RV diastolic dysfunction. No
patient developed new onset RV restriction at follow-up
(i.e. absent RV restriction at discharge and developing it
subsequently on the follow-up echocardiographic study).
In contrast, Cullen et al1 reported resolution of RV
restrictive pattern in 13/17 patients at a follow-up of 2
weeks. It is possible that the widely different age groups of
the patient populations in the two studies are responsible
for this observation. Older patients’ RV may be subjected to
more chronic pressure overload and hypoxia, leading to a
degree of endomyocardial fibrosis,10 which could explain
lack of recovery of RV function at 12 weeks follow-up.
Persistence of RV restrictive physiology late after TOF repair
has also been reported in other studies.2,9 Though Norgard
et al.9 reported that use of TAP was more often associated
with RV restrictive pattern, our observation was that the
use of TAP did not correlate with presence of RV restrictive
physiology.
Though the exact mechanisms of RV restriction are not
clear, various theories have been postulated. These include
inadequate intraoperative RV protection (due to its anterior
location)10-12 and chronic hypoxemia leading to downregulation of antioxidant defences and resultant oxygen
free-induced injury.13,14 Chaturvedi et al.15 demonstrated
that following surgical repair of TOF, acute RV restrictive
physiology was associated with severe iron loading of
transferrin and post-operative oxidative stress.
Conclusions: Abnormalities of RV diastolic function exist
in a significant proportion of patients undergoing TOF
repair. Presence of laminar antegrade diastolic PA flow
throughout the respiratory cycle, coincident with atrial
systole is an accurate marker of RV restriction in these
cases. Such patients have longer requirement for
ventilatory support, with prolonged ICU and hospital stay.
Pre-operative factors like age, weight, Hb, aortic saturation,
mean RA and RV end-diastolic pressure, z value, CPB time
and ACC times did not correlate with presence of RV
restrictive physiology. Follow-up serial echocardiographic
studies at 12 weeks demonstrated that these abnormalities
were still present in 86% of the patients. Whether longterm follow-up studies would reveal further resolution of
these abnormalities needs to be explored further.
IHJ-546-03.p65
224
Indian Heart J 2004; 56: 220–224
References
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diastolic performance after complete repair of tetralogy of Fallot.
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2. Gatzoulis MA, Clark AL, Cullen S, Newman CG, Redington AN. Right
ventricular diastolic function 15 to 35 years after repair of tetralogy
of Fallot. Circulation 1995; 91: 1775–1781
3. Williams RV, Minich LL, Shaddy RE, Pagotto LT, Tani LY. Comparison
of Doppler echocardiography with angiography for determining the
severity of pulmonary regurgitation. Am J Cardiol 2002; 89: 1438–
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4. Fuster V, McGoon DC, Kennedy MA, Ritter DG, Kirklin JW, Long-term
evaluation (12 to 22 years) of open heart surgery for tetralogy of
Fallot. Am J Cardiol 1980; 46: 635–642
5. Murphy JG, Gersh BJ, Mair DD, Fuster V, McGoon MD, Ilstrup DM, et
al. Long-term outcome in patients undergoing surgical repair of
tetralogy of Fallot. N Engl J Med 1993; 329: 593–599
6. Di Donato RM, Jonas RA, Lang P, Rome JJ, Mayer JE Jr, Castaneda
AR. Neonatal repair of tetralogy of Fallot with and without
pulmonary atresia. J Thorac Cardiovasc Surg 1991; 101: 126–137
7. Redington AN, Penny D, Rigby ML, Hayes A. Antegrade diastolic
pulmonary arterial flow as a marker of RV restriction after complete
repair of pulmonary atresia with intact ventricular septum and
critical PV stenosis. Cardiol Young 1992; 2: 382–386
8. Kisanuki A, Tei C, Otsuji Y, Natsugoe K, Kawazoe Y, Arima S, et al.
Doppler echocardiographic documentation of diastolic pulmonary
artery forward flow. Am J Cardiol 1987; 59: 711–713
9. Norgard G, Gatzoulis MA, Moraes F, Lincoln C, Shore DF, Shinebourne
EA, et al. Relationship between type of outflow tract repair and
postoperative right ventricular diastolic physiology in tetrology of
Fallot. Implications for long-term outcome. Circulation 1996; 94:
3276–3280
10. del Nido PJ, Mickle DA, Wilson GJ, Benson LN, Weisel RD, Coles JG, et
al. Inadequate myocardial protection with cold cardioplegic arrest
during repair of tetralogy of Fallot. J Thorac Cardiovasc Surg 1988;
95: 223–229
11. del Nido PJ, Mickle DA, Wilson GJ, Benson LN, Coles JG, Trusler GA,
et al. Evidence of myocardial free radical injury during elective repair
of tetralogy of Fallot. Circulation 1987; 76 (Suppl 5): 174–179
12. Fisk RL, Ghaswalla D, Guilbeau EJ. Asymmetrical myocardial
hypothermia during hypothermic cardioplegia. Ann Thorac Surg
1982; 34: 318–323
13. Li RK, Mickle DA, Weisel RD, Tumiati LC, Jackowski G, Wu TW, et al.
Effect of oxygen tension on the anti-oxidant enzyme activities of
tetralogy of Fallot ventricular myocytes. J Mol Cell Cardiol 1989; 21:
567–575
14. Morita K, Ihnken K, Buckberg GD, Sherman MP, Young HH, Ignarro
LJ. Role of controlled cardiac reoxygenation in reducing nitric oxide
production and cardiac oxidant damage in cyanotic infantile hearts.
J Clin Invest 1994; 93: 2658–2666
15. Chaturvedi RR, Shore DF, Lincoln C, Mumby S, Kemp M, Brierly J,
et al. Acute right ventricular restrictive physiology after repair of
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Indian Heart J 2004; 56: 225–228
Talwar et al.
Prosthetic Valve
Thrombosis
225
Original
Article
Anticoagulation Protocol and Early
Prosthetic Valve Thrombosis
Sachin Talwar, Chandra Kanta Kapoor, Devagourou Velayoudam, Arkalgud Sampath Kumar
Cardiothoracic Centre, All India Institute of Medical Sciences, New Delhi
Backgound: Prosthetic valve thrombosis is a major cause of morbidity and mortality following heart valve
replacement with a mechanical valve.
Methods and Results: 538 patients who underwent mechanical valve replacement between April 1999 and
June 2003 were included in the study. They were divided into two groups. Group A (n=245) consisted of patients
who underwent mechanical valve replacement between April 1999 and June 2001. Anticoagulation was started
on the first post-operative day and consisted of only oral nicoumalone. Group B (n=293) consisted of patients
who underwent mechanical valve replacement between July 2001 and June 2003; enoxaparin was started six
hours following surgery in addition to oral nicoumalone which was started on first post-operative day. Fifteen
(6.1%) patients in group A developed early prosthetic valve thrombosis at an interval of 4.33±0.97 months
(range 3-6 months) following surgery. Ten had prosthetic valve thrombosis in the mitral position and five had
prosthetic valve thrombosis in the aortic position. In group B, six (2.1%) patients developed early prosthetic
valve thrombosis at a median interval of 4.58±0.9 months (range 3.5-6 months) in the mitral position (p=0.01).
Conclusions: Addition of enoxaparin to the anticoagulation regime in the immediate post-operative period
significantly reduces early prosthetic valve thrombosis. (Indian Heart J 2004; 56: 225–228)
Key Words: Valvular heart disease, Anticoagulants, Prosthetic valve thrombosis
P
rosthetic valve thrombosis (PVT) is a major cause of
morbidity and mortality following heart valve
replacement with a mechanical valve. Thrombotic and
bleeding complications represent 57% to 92% of all valverelated complications in patients with mechanical aortic
prostheses and 55% to 79% in patients with mechanical
mitral prostheses. 1 The incidence of prosthetic valve
thrombosis is 0.1% to 5.7% per year according to the type
of the valve, its location and the adequacy of anticoagulation.2 Thrombotic complications are more common in
the first few months following operation.3 Anticoagulation
with coumarin derivatives alone in the early post-operative
period may be unreliable as their action is apparent only
after 24-48 hours after initiation of therapy.1 Proper
initiation and maintenance of anticoagulation in the early
post-operative period may prevent these complications.
Enoxaparin is a low-molecular weight heparin (LMWH)
which has been successfully used to treat acute deep vein
thrombosis and in patients with acute non-Q-wave
Correspondence: Dr Arkalgud Sampath Kumar, Professor, Department
of Cardiothoracic and Vascular Surgery, Cardiothoracic Centre, All India
Institute of Medical Sciences, New Delhi 110 029
e-mail : [email protected]
IHJ-667-04.p65
225
myocardial infarction and unstable angina pectoris.4 It has
also been used as a substitute therapy to maintain
anticoagulation in patients in whom oral anticoagulants
are contraindicated. 5 Because of an observed high
incidence of prosthetic valve thrombosis in patients
receiving oral anticoagulants alone, we evaluated the role
of enoxaparin added to the anticoagulation regime to
prevent early prosthetic valve thrombosis.
Methods
Patient population: The patient population (n=538)
consisted of two groups - Group A and Group B.
Group A consisted of 245 survivors (of 256) who underwent mechanical valve replacement in the mitral and/or
aortic position between April 1999 and June 2001. Of these
166 (68%) patients were male and 79 (32%) patients were
female. Mean age was 34.5±6.8 years (range 14-56 years).
Ninety-five (38.8%) patients underwent mitral valve
replacement (MVR), 67 (27.3%) patients underwent aortic
valve replacement (AVR) and 83 (33.9%) patients
underwent double valve replacement (DVR); 118 (48.2%)
patients were in atrial fibrillation before operation, 78
9/29/2004, 5:08 PM
226 Talwar et al.
(69%) of these were in sinus rhythm post-operatively.
Median valve size for MVR was 31 mm (range 25-33 mm)
and for AVR, it was 25 mm (range 19-31 mm).
Group B comprised of 293 survivors (of 308) who
underwent mechanical valve replacement between July
2001 and June 2003. 189 (64.5%) were males and 104
(35.5%) were females. Mean age was 36.2±7.3 years
(range 15-53 years); 124 (42.3%) patients underwent
MVR, 87 (29.7%) patients underwent AVR and 82 (28%)
patients underwent DVR; 165 (56.3%) patients were in
atrial fibrillation before operation. Of these, 103 (62.4%)
were in sinus rhythm post-operatively. Median valve size
for MVR was 31 mm (range 27-33 mm) and for AVR, it
was 25 mm (range 19-31 mm).
Surgical technique: All the patients were operated by the
senior author (ASK) and the surgical technique for valve
implantation was identical in both the groups. Standard
techniques for valve implantation were used in these
patients. In all patients, St Jude mechanical heart valve (St.
Jude Medical Inc., Minn, USA) was implanted. In patients
undergoing MVR, both the anterior and the posterior
chordal apparatus of the mitral valve were retained. No
separate surgical procedure was performed for patients in
atrial fibrillation.
Anticoagulation protocol: In Group A, anticoagulation
was started on the first post-operative day. Initially 4 mg
nicoumalone was administered to these patients and the
dose was later titrated to maintain an International
normalized ratio (INR) of 2.5 to 3.5 for patients undergoing
MVR and DVR, and 2 to 3 for patients undergoing AVR, as
per the published guidelines for antithrombotic therapy in
patients with prosthetic heart valves.6 In addition, these
patients received oral aspirin 150 mg daily beginning from
first post-operative day.
In Group B, 6 hours following surgery, patients recieved
enoxaparin sodium 1 mg/kg body weight subcutaneously
at 12-hour intervals and four such doses were administered. Simultaneously, they received nicoumalone 4
mg orally on first post-operative day along with oral aspirin
150 mg daily. Subsequent anticoagulation protocol was
similar to patients in group A.
Follow-up: In both groups of patients, cinefluoroscopy was
carried out before discharge from the hospital to confirm
normal prosthetic valve disc movements. After discharge,
these patients were followed up after 7 days, 1 month, 3
months, 6 months and then at yearly intervals. At each
outpatient visit, prothrombin time and INR values were
measured and cinefluoroscopy was carried out. In case the
cinefluoroscopy was abnormal, echocardiography was
IHJ-667-04.p65
Indian Heart J 2004; 56: 225–228
Prosthetic Valve Thrombosis
226
done to measure gradients across the prosthetic heart
valves. If abnormal, patients were thrombolyzed with
streptokinase or urokinase and repeat echocardiography
and cinefluoroscopy were performed.
PVT was defined as any thrombus in the absence of
infection, attached to or near an operated valve that
occludes part of the blood flow path or that interferes with
prosthetic valve function.7 Early PVT was defined as the one
occurring within 6 months of surgery. All the patients in
groups A and B were followed up for at least six months before
they were declared free of early prosthetic valve thrombosis.
Statistical analysis: All the data were collected and
systematically analyzed. Data are presented as frequency
distribution and simple percentages. Descriptive statistics
i.e. mean, median and standard deviation have been
calculated for all the continuous variables. A valve-related
event was defined as any episode of thromboembolism,
hemorrhage, congestive heart failure, infective endocarditis, structural deterioration, significant gradients or
prosthetic valve dysfunction as per the published criteria.7
Comparison between the two groups was made by the Chisquare test with Yates correction wherever applicable.
p value <0.05 was considered significant.
Results
Fifteen of the 245 patients in Group A developed early PVT
at an interval of 4.33±0.97 months (range 3-6 months)
following surgery (Table 1). Ten had PVT in the mitral
position and five had PVT in the aortic position. Nine
patients had undergone MVR, three had undergone DVR,
two had undergone AVR and one patient had undergone
Table 1. Profile of patients with prosthetic valve thrombosis in Group A
S.No. Surgery Valve size
(mm)
Affected
valve
Interval
(months)
INR
NYHA
class
Peak
gradient
(mmHg)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
M
M
M
M
M
A
A
M
A
M
M
M
A
A
M
3
3
3
3.5
4
4
4
4.5
4.5
4.5
5
5
5
6
6
2.8
3.2
2.8
2.6
1.81
2.59
1.63
4.22
2.8
3.1
2.9
2.59
2.8
3.2
3.1
III
II
II
II
II
I
II
II
II
III
II
II
I
II
I
20
16.3
14
23.2
18.6
46
53
15.7
68
41
19.3
17.3
57
72
16
MVR
MVR
MVR
DVR
MVR
DVR
AVR
MVR
AVR
MVR
MVR
DVR
AVR
DVR
MVR
25
29
29
25 A, 31 M
29
25 A, 29 M
27
29
31
33
33
19 A, 27 M
25
25 A, 31 M
31
INR: international normalized ratio; MVR: mitral valve replacement; M: mitral; DVR: double
valve replacement; A: aortic; AVR: aortic valve replacement
9/29/2004, 5:08 PM
Indian Heart J 2004; 56: 225–228
Talwar et al.
AVR with coronary artery bypass grafting. Target INR was
less than satisfactory in two patients (Table 1). All these
patients were successfully thrombolyzed with streptokinase
and were not re-operated. None of these patients had atrial
fibrillation or a large left atrium.
Six of the 293 patients in Group B developed early PVT
at a median interval of 4.58±0.9 months (range 3.5-6
months) following surgery (Table 2). All six had thrombosis
of the prosthesis in the mitral position. Four had undergone
DVR and two had undergone MVR. Target INR was less
than satisfactory in one patient. All the six patients were
successfully thrombolyzed. However, one patient had
another episode of PVT three months later. His INR at this
time was 1.8 and this was attributed to non-compliance
Table 2. Profile of patients with prosthetic valve thrombosis in Group B
S.No. Surgery Valve size
(mm)
Affected
valve
Interval
(months)
INR
NYHA
class
Peak
gradients
(mmHg)
1.
2.
3.
4.
5.
6.
M
M
M
M
M
M
3.5
4
4
5
5
6
2.59
2.02
3.48
3.72
3.02
3.48
II
II
III
II
II
III
19
13.8
24.6
15
18.7
21.4
DVR
MVR
MVR
DVR
DVR
DVR
29 A, 31 M
33
31
19 A, 27 M
23 A, 31 M
23 A, 31 M
INR: international normalized ratio; MVR: mitral valve replacement; M: mitral; DVR: double
valve replacement; A: aortic
with the prescribed dosage of anticoagulants. None of these
patients had atrial fibrillation or a large left atrium. None
were reoperated.
One patient in group B developed excessive drainage
from the mediastinal tubes 36 hours following surgery after
two doses of enoxaparin. Further doses were discontinued
and the drainage gradually became less. Apart from this,
there were no bleeding complications in either group.
There were no statistically significant differences in the
two groups with respect to age, sex, type of surgery
performed, incidence of pre- and post-operative atrial
fibrillation and median valve sizes. All these patients were
operated by the senior author and the surgical technique
was identical in both groups. However, the incidence of PVT
was significantly lower in patients in group B as compared
to those in group A (6/293 in group B v. 15/245 in group
A, p=0.01). Since the only difference in the two groups was
the introduction of enoxaparin sodium in group B, the
lower incidence of PVT in this group was attributed to this
change in the anticoagulation protocol.
Discussion
We postulate that thrombus formation on the
IHJ-667-04.p65
227
Prosthetic Valve Thrombosis 227
prosthesis begins soon after heparin reversal following
cardiopulmonary bypass. Therefore anticoagulation and
prevention of platelet aggregation and thrombosis should
begin in the immediate post-operative period. For
mechanical valves, anticoagulation with coumarin
derivatives is the most important factor affecting the
incidence of both thrombotic and bleeding complications.
Without coumarin derivatives, this incidence is 3 to 8 times
higher in patients with mechanical valve prostheses. 1
Addition of platelet inhibitors has reduced the incidence
of thromboembolism in some series8 but not in others.9 As
such, the advantage of coumarins plus platelet inhibitors
in not clear.
Rough surfaces, large surface area, stagnant flow,
narrow flow paths and turbulence increase thrombosis.10
Till the healing occurs, the projecting sewing rim of the
prosthetic valve is a potential site of development and
propagation of a thrombus which may later on progress to
produce prosthetic valve thrombosis and dysfunction. In a
recent study of 680 patients undergoing MVR, early PVT
was shown to occur in as many as 9.4% patients. 11
However, no such data is available from the Indian
subcontinent.
Coumarin derivatives act by completely blocking vitamin
K epoxide reductase so that less vitamin K is available to
participate as a cofactor in the addition of gammacaroxyglutamic acid residues to the vitamin K-dependent
coagulation factors VII, IX, X, protein C and protein
S. Because there is inhibition of these procoagulant
factors with plasma half-life ranging between 5 to 100
hours, the establishment of anticoagulation is slow with
these drugs.12
LMWH has been successfully used for prevention and
treatment of thromboembolism and in patients with
unstable angina pectoris4 and in those with prosthetic heart
valve where anticoagulation with oral anticoagulants is
contraindicated as in pregnancy. It has also been used
for long-term anticoagulation in patients with prosthetic
heart valves who develop adverse reaction to oral
anticoagulants.13 It has been established to be superior to
unfractionated heparin because there is a low risk of
bleeding and laboratory monitoring is minimal because of
its bioavailability, longer half-life, dose-dependent clearance
and decreased affinity to heparin-binding protein. The onset
of action is almost immediate and this helps to provide
anticoagulation cover till the effect of oral anticoagulants
is established. The efficacy of enoxaparin in the prevention
of early PVT has not been previously investigated. In
present study it has certainly brought down the incidence
of early prosthetic valve thrombosis. Because thrombi may
9/29/2004, 5:08 PM
228 Talwar et al.
Prosthetic Valve Thrombosis
form on the sewing rim of the prosthetic valve in the early
post-operative period, we believe that early therapy with
enoxaparin is essential to prevent this complication.
Study limitation: A limitation of our study is that it is not
a randomized trial. However, considering the fact that PVT
is a dreaded complication following valve replacement, such
a study may not be ethically justified specially when the
benefits of addition of enoxaparin are clear.
Conclusions: Addition of enoxaparin to the anticoagulation regime in the early post-operative period
prevents early prosthetic valve thrombosis. Our patients
who undergo prosthetic valve implantation now routinely
receive enoxaparin.
References
1. Edmunds LH Jr. Thrombotic and bleeding complications of prosthetic
heart valves. Ann Thorac Surg 1987; 44: 430–445
2. Cannegieter SC, Rosendaal FR, Briet E. Thromboembolic and bleeding
complications in patients with mechanical heart valve prostheses.
Circulation 1994; 89: 635–641
3. Miller DC, Oyer PE, Stinson EB, Reitz BA, Jamieson SW, Baumgartner
WA, et al. Ten to fifteen year reassessment of the performance
characteristics of the Starr-Edwards model 6120 mitral valve
prosthesis. J Thorac Cardiovasc Surg 1983; 85: 1–20
4. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337:
688–698
IHJ-667-04.p65
228
Indian Heart J 2004; 56: 225–228
5. Harenberg J, Schwarz F, Dietz R, Leber G, Zimmermann R, Kubler W.
Anticoagulation with low molecular-weight heparin in patients with
prosthetic heart valve replacement. Z Kardiol 1987; 76: 284–288
6. Stein PD, Dalen JE, Goldman S, Theroux P. Antithrombotic therapy
in patients with saphenous vein and internal mammary bypass
grafts. Chest 1998; 114: 658S–665S
7. Edmunds LH Jr, Clark RE, Cohn LH, Grunkemeier GL, Miller DC,
Weisel RD. Guidelines for reporting morbidity and mortality after
cardiac valvular operations. J Thorac Cardiovasc Surg 1996; 112:
708–711
8. Chesebro JH, Fuster V, Elveback LR, McGoon DC, Pluth JR, Puga FJ,
et al. Trial of combined warfarin plus dipyridamole or aspirin therapy
in prosthetic heart valve replacement: danger of aspirin compared
with dipyridamole. Am J Cardiol 1983; 51: 1537–1541
9. Steele P, Rainwater J, Vogel R. Platelet suppressant therapy in patients
with prosthetic heart valves. Circulation 1979; 60: 910–913
10. Kohanna FH, Salzman EW. Thromboembolic complications
of cardiac and vascular prostheses. In: Sabiston DC Jr, Spencer FC
(eds). Gibbon’s Surgery of the Chest. Philadelphia: Saunders, 1983,
pp1267
11. Laplace G, Lafitte S, Labeque JN, Perron JM, Baudet E, Deville C, et al.
Clinical significance of early thrombosis after prosthetic mitral valve
replacement: a postoperative monocentric study of 680 patients. J
Am Coll Cardiol 2004; 43: 1283–1290
12. Deykin D. Anticoagulant therapy in hemostasis and thrombosis. In:
Column RW, Hirsh J, Marder VJ, Salzman EW (eds). Hemostasis and
Thrombosis. Philadelphia: Lippincott, 1982, pp 1000–1012
13. Harenberg J, Leber G, Dempfle CE, Heene DL, Zimmermann R, Kubler
W. Long term anticoagulation with low molecular weight heparin
in outpatients with side effects on oral anticoagulation. Nouv Rev Fr
Hematol 1989; 31: 363–369
9/29/2004, 5:08 PM
Indian Heart J 2004; 56: 229–231
Baran et al. Heart Rate Variability in PatientsOriginal
with Syncope
229
Article
Lack of Association of Heart Rate Variability Parameters
with Head-up Tilt-Test Responses in Patients with Syncope
Ibrahim Baran, Aysel Aydin Kaderli, Bülent Özdemir, Kani Gemici, Adem Ekbul, Sümeyye Güllülü,
Ali Aydinlar, Jale Cordan
Department of Cardiology, Uludag University School of Medicine, Turkey
Background: Neurocardiogenic syncope is the most common type of syncope. Head-up tilt testing is the
investigation of choice for diagnosis of patients with neurocardiogenic syncope. In this study, we aimed to findout any association between heart rate variability parameters and type of tilt-test response in patients with
syncope.
Methods and Results: Forty-nine cases with unexplained syncopal attacks were enrolled into our study and
were grouped according to the tilt-test responses. Tilt test was performed in all patients after excluding other
causes of syncope. In case of a negative basal tilt-testing, pharmacological tilt testing was performed after 30
min of 5 mg sublingual isosorbide dinitrate. Holter monitoring was done from the beginning of tilt testing upto
two hours post-procedure. The heart rate variability parameters analyzed were the mean of all coupling intervals
between normal beats, the standard deviation about the mean of all coupling intervals between normal beats,
the mean of all 5-min standard deviations of mean of all coupling intervals between normal beats, the proportion
of adjacent normal R-R intervals differing by >50 ms, the root mean square of the difference between successive
RRs, and the standard deviation of 5-min mean of all coupling intervals between normal beats and ratio between
low and high frequencies.
Conclusions: In 35 patients, the tilt-test was positive, 16 were cardioinhibitor type (Group 1), four cases had a
vasodepressor type response (Group 2) and 15 were mixed type (Group 3). Fourteen patients had a negative test
result. The heart rate variability measures did not significantly differ among the study groups. The heart rate
variability measures were compared between the tilt-test negative (Group 4) and the tilt-test positive groups
(Groups 1, 2 and 3) and no statistically significant difference was found. (Indian Heart J 2004; 56:
229–231)
Key Words: Tilt-test, Syncope, Arrhythmia
T
he pathophysiology of neurocardiogenic syncope is
complex and not completely elucidated. Head-up tilt
testing has become the diagnostic study of choice for the
identification of patients with neurocardiogenic syncope.
We studied heart rate variability (HRV) in patients of
neurocardiogenic syncope and correlated it with tilt test
results.
Methods
Forty-nine cases with unexplained syncopal attacks were
enrolled into our study between November 2000 and
Correspondence: Dr Bülent Özdemir, Department of Cardiology, Uludag
University School of Medicine, Görükle Bursa 16059, Turkey
e-mail: [email protected]
IHJ-632-03.p65
229
December 2002 (32 female, 17 male; mean age, 34.8 ±
14.2 years). Tilt test was performed in all patients after
excluding other causative factors of syncope. In case of
having a negative basal tilt testing, pharmacological tilt
testing was performed after 30 minutes of 5 mg sublingual
isosorbide dinitrate. A Holter monitoring analysis was done
from the beginning of tilt testing upto two hours postprocedure. The tilt-test positive group was divided into three
groups according to the type of response to tilting. The
group of patients with the cardioinhibitor, vasodepressor
and mixed type responses constituted the Group 1, Group
2 and Group 3, respectively and the tilt-test negative
patients constituted Group 4. HRV was evaluated by time
and frequency analysis methods. The derived time domain
indices were the mean NN (mean of all coupling intervals
9/29/2004, 5:01 PM
230 Baran et al.
between normal beats), the standard deviation about the
mean of all coupling intervals between normal beats
(SDNN), the mean of all 5-min standard deviations of NNs
(SD), the proportion of adjacent normal R-R intervals
differing by >50 ms (pNN50), the root mean square of the
difference between successive R-Rs (rMSSD), and the
standard deviation of 5-min mean NN intervals (SDANN).
The frequency domain indices i.e. ratio between low and
high frequencies (LF/HF) was taken as a representative of
sympathovagal modulation. Syncope was defined as the
transient loss of consciousness. Our routine tilt-test was a
drug-free tilt-test (80° for 30 min) and in case of negative
result, was followed by repeat tilt-test after 30 min of
sublingual 5 mg isosorbide dinitrate. A positive tilt-test was
defined as the reproduction of clinical pre-syncope or
syncope, after either a drug-free or sublingual isosorbide
dinitrate tilt-test accompanied by relative bradycardia (20%
decrease in heart rate compared with baseline) and/or
hypotension (systolic blood pressure <80 mmHg).
Data are expressed as mean ± SD. Mann-Whitney U test;
Fisher's Exact test were used for statistical analysis. A
p value <0.05 was considered statistically significant.
Results
Tilt-test was positive in 35 patients, 16 were cardioinhibitor
type (Group 1), 4 cases had a vasodepressor type response
(Group 2) and 15 were mixed type (Group 3). Fourteen
patients had a negative test result. The HRV measures did
not significantly differ among the study groups. The HRV
measures were compared between the tilt-test negative
(Group 4) and the tilt-test positive groups (Groups 1, 2
Table 1. Heart rate variability parameters in tilt test
negative and tilt test positive groups
Parameters
Tilt-test positive group
(Groups 1, 2, 3 combined)
Age (years)
Heart rate (bpm)
pNN50 (%)
rMSSD (ms)
Variability index
SDANN (ms)
SDNN (ms)
SD (ms)
LF/HF
35.5±2.5
77.4±2.0
13.9±2.0
48.6±4.7
3.37±0.2
75.9±4.8
99.3±6.6
131.1±7.6
2.6±0.3
Tilt-test negative group
(Group 4)
33.2±4.2
84.8±4.8
10.1±3.0
35.8±4.4
2.8±0.2
70.4±5.9
111.8±14.0
139.4±15.3
3.9±0.7
*All p values are >0.05
pNN 50 : proportion of adjacent normal R-R intervals differing by >50
ms; rMSSD: root mean square of the difference between successive R-Rs;
SDANN: standard deviation of 5 min mean NN intervals: SDNN: standard deviation about mean of all coupling intervals between normal beats;
SD: mean of all 5 min standard deviations of NNs; LF/HF: ratio between
low and high frequencies
IHJ-632-03.p65
Indian Heart J 2004; 56: 229–231
Heart Rate Variability in Patients with Syncope
230
and 3) and no statistically significant difference was found.
In addition, comparisons were made according to the type
of tilt-test response and again, no statistically significant
difference in HRV parameters was found between the
groups. The HR was 79.5±14.3 beats per min (bpm). The
HR variables calculated in the tilt negative and the tilt
positive groups are given in Table 1 and the results
according to the tilt-test response types are given in
Table 2.
Table 2. Heart rate variability parameters in different
groups according to tilt-test response types
Group 1
Heart rate (bpm)
pNN50 (%)
rMSSD (ms)
Variability index
SDANN (ms)
SDNN (ms)
SD (ms)
LF/HF
77.5±2.9
11.3±2.4
42.6±3.1
3.0±0.2
67.8±4.0
79.8±6.1
109.6±7.9
2.8±0.5
Group 2
Group 3
74.4±3.7
16.4±6.1
55.3±14.3
3.6±0.8
73.5±13.8
90.6±24.5
127.1±29.1
1.6±0.1
78.1±3.5
15.6±3.4
52.6±9.4
3.6±0.5
84.2±9.0
119.8±10.0
152.2±11.4
2.7±0.4
*All p values are >0.05
pNN 50 : proportion of adjacent normal R-R intervals differing by >50
ms; rMSSD: root mean square of the difference between successive R-Rs;
SDANN: standard deviation of 5 min mean NN intervals: SDNN: standard deviation about mean of all coupling intervals between normal beats;
SD: mean of all 5 min standard deviations of NNs; LF/HF: ratio between
low and high frequencies
Discussion
Since vasovagal syncope may occur due to imbalance
between the components of the autonomic nervous system,
it is logical to assess the parameters reflecting the tone of
sympathetic or parasympathetic activity. However, Suzuki
et al.1 demonstrated that continuous spectral analysis of
the R-R intervals revealed increased vagal influence on the
heart in tilt-induced syncope.
On development of the first pre-syncopal manifestations,
HRV parameters in patients with positive head-up tilt-test
were found to be significantly higher as compared with
patients with negative test results, suggesting an increase
of the parasympathetic autonomous tone during the
development of the vasovagal syncope.2 In another study,
patients with vasovagal syncope had no basic differences
from normal subjects in autonomic nervous system
activity.3
We evaluated our cases with 2 hours of Holter
monitoring and compared the cases for differences in
autonomic profile. However, we did not gather data to see
the changes in sympathovagal tone during the tilt test
before and after the occurrence of syncope. Lazzeri et al.4
reported that vasodepressive patients had a peculiar
9/29/2004, 5:01 PM
Indian Heart J 2004; 56: 229–231
Baran et al. Heart Rate Variability in Patients with Syncope 231
autonomic profile assessed by 24-hour HRV analysis and
stated that the evaluation of the autonomic profile by
24-hour Holter recordings could be of value in the diagnosis
of patients with syncope. However the patterns of HRV and
catecholamine changes were not significantly different in
vasodepressor and control groups in the study by PrinzZaiss et al.5
In the studies by Sneddon et al.6,7 and Kochiadakis et
al.8 it was found that the mean values of HR and HRV
indices did not differ significantly between normal subjects
and patients with vasovagal syncope.6-8 Differences between
syncopal patients and normal subjects may exist, at least
around the time of a positive tilt-test, when the patients
are presumably more prone to syncopal episodes. The
timing of the HRV measurements in relation to the tilt-test
is important and it seems from our study that timing could
play an important role in the evaluation of HRV. By
evaluating the HRV during the whole tilt-test and afterward
for a total of two hours, we were unable to detect the
changes during the phases of the test and syncopal episode.
In our study we found no association between tilt-test
responses of patients and HRV measures. Though the
autonomic tone changes before and after syncope attacks,
the HRV measures did not show the differences we expected,
suggesting that the vagal tone does not have significant
impact on the type of neurocardiogenic syncope.
IHJ-632-03.p65
231
References
1. Suzuki M, Hori S, Nakamura I, Nagata S, Tomita Y, Aikawa N. Role
of vagal control in vasovagal syncope. Pacing Clin Electrophysiol 2003;
26: 571–578
2. Mitro P, Rybar R. Analysis of heart rate variability during the headup tilt test in patients with vasovagal syncope. Vnitr Lek 2002; 48:
314–319
3. Massin MM, Henrard V, Gerard P. Heart rate variability and the
outcome of head-up tilt in syncopal children. Acta Cardiol 2000; 55:
163–168
4. Lazzeri C, La Villa G, Barletta G, Franchi F. 24-hour heart rate
variability in patients with vasovagal syncope. Pacing Clin
Electrophysiol 2000; 23: 463–468
5. Prinz-Zaiss M, Yeap AN, Moguilevski V, Trigg L, McGrath BP.
Presyncopal sympathetic withdrawal is the same in patients with
vasodepressor syncope and controls who faint on head-up tilting.
Am Heart J 1997; 133: 230–239
6. Sneddon JF, Counihan PJ, Bashir Y, Haywood GA, Ward DE, Camm
AJ. Assessment of autonomic function in patients with neurally
mediated syncope: augmented cardiopulmonary baroreceptor
responses to graded orthostatic stress. J Am Coll Cardiol 1993; 21:
1193–1198
7. Sneddon JF, Bashir Y, Murgatroyd FD, Ward DE Camm AJ, Malik M.
Do patients with neurally mediated syncope have augmented vagal
tone? Am J Cardiol 1993; 72: 1314–1315
8. Kochiadakis GE, Orfanakis AE, Rombola AT, Chrysostomakis SI,
Chlouverakis GI, Vardas PE. Reproducibility of time-domain indexes
of heart rate variability in patients with vasovagal syncope. Am J
Cardiol 1997; 79: 160–165
9/29/2004, 5:01 PM
232 Kannan
et al. Coil Closure of PDA in Sick Infants
Original
Article
Indian Heart J 2004; 56: 232–234
Transcatheter Management of Patent Ductus
Arteriosus in Sick Ventilated Small Infants
Bhava RJ Kannan, Sivadasan Radha Anil, Sumanta Shekar Padhi, Raman Krishna Kumar
Department of Cardiology, Amrita Institute of Medical Sciences and Research Centre, Kochi
Background: Large patent ductus arteriosus can present in infancy with congestive cardiac failure and
superadded pulmonary infection can necessitate mechanical ventilation. Surgical intervention is traditionally
indicated for this subset of patients. We present our experience of transcatheter coil closure of the patent
ductus arteriosus in such infants.
Methods and Results: Five infants weighing between 960 gm and 4.1 kg, aged between 17 days and 3½
months were mechanically ventilated because of congestive cardiac failure with pneumonia. Echocardiography
showed patient ductus arteriosus with a size of 1.8 to 4.2 mm and adequate ampulla. Bioptome-assisted coil
delivery was done and successful patient ductus arteriosus closure was achieved in all. There were two instances
of embolization of coils with successful retrieval and redeployment. All infants could be weaned off mechanical
ventilation over the next 24-72 hours. A pre-term infant developed a Doppler gradient of 25 mmHg in the
descending aorta that decreased to 12 mmHg five months later. There was no significant obstruction to
pulmonary artery flow in any child. At three months follow-up, all the five infants were asymptomatic with no
residual flow across the patient ductus arteriosus.
Conclusions: Transcatheter coil closure of moderate to large patent ductus arteriosus is possible in sick ventilated
infants weighing below 5 kg. It may be a better alternative to surgery in selected cases in view of minimal
morbidity. (Indian Heart J 2004; 56: 232–234).
Key Words: Heart failure, Catheter intervention, Congenital heart disease
L
arge patent ductus arteriosus (PDA) is known to cause
congestive cardiac failure (CCF) in infancy.1 Superadded
respiratory infection is not uncommon and it can result in
respiratory insufficiency necessitating mechanical
ventilation. In such a situation, interruption of the PDA
becomes a necessity to break the cycle of CCF-pneumoniaCCF. Surgery is the standard treatment as the ducts are
often large. The morbidities associated with surgical
interruption can result in prolonged mechanical ventilation
and intensive care unit (ICU) stay.2 Since 1992, with the
availability of Gianturco embolization coils, coil closure of
PDA has been performed widely. However, it is largely
reserved for stable children with relatively small PDA. We
present our experience in transcatheter closure of large
PDA in five small infants who needed mechanical
ventilation to control the CCF and pneumonia.
Correspondence: Dr R Krishna Kumar, Consultant Pediatric Cardiologist,
Amrita Institute of Medical Sciences and Research Centre, PO Elamakkara,
Kochi 682026. e-mail: [email protected]
IHJ-642-04.p65
232
Methods
Gianturco embolization coils (Cook Inc., Bloomington, IN)
were used in all (0.038’’ and 0.052’’, 4 mm–8 mm). Coils
were delivered from the venous end using a 4-7 F Balkin
contralateral sheath (Cook Inc., Bloomington, IN) with a
3 F or 5.2 F bioptome (Cook Inc.) and arterial puncture
was avoided whenever possible.3 For controlled delivery, the
coils were deployed with bioptome control as described
previously. 4-6 Residual flow across the duct, right
pulmonary artery (RPA) and left pulmonary artery (LPA)
flows were checked by echocardiography in the
catheterization laboratory.3 All procedures were done
under general anesthesia.
Results
The physiological and other features of the patients are
shown in Table 1. Case 1 was being mechanically ventilated
for CCF bronchopneumonia elsewhere. As there was no
improvement with standard therapy, the infant was referred
9/29/2004, 5:02 PM
Indian Heart J 2004; 56: 232–234
Kannan et al. Coil Closure of PDA in Sick Infants 233
Table 1. Physiological and other features of patients
Case Age Weight PDA Mean PA Qp:Qs No. of Emboli- Arterial Fluoro
No. (weeks) (kg)
size pressure
coils zation access time
(mm) (mmHg)
(min)
1
2
3
4
5
12
14
5
3
11
4.30
4.10
0.96
1.80
3.40
4.2
3.4
2.0
3.0
4.0
42
26
13
22
60
4.1
2.6
2.2
3.2
6
2
1
2
3
No
Yes
No
No
Yes
Yes
No
Yes
No
No
24.8
11.8
12.4
8.5
13.0
PDA: patent ductus arteriosus; PA: pulmonary artery; Qp: Qs: ratio of pulmonary blood flow to
systemic blood flow
to us. All other children were admitted with respiratory
distress and needed mechanical ventilation subsequently.
Case 5 had sepsis with disseminated intravascular
coagulation that needed stabilization for five days with
supportive measures including a double volume exchange
transfusion before considering transcatheter treatment. All
other children underwent coil closure within 24-48 hours
of intubation. Case 2 had an associated 9 mm atrial septal
defect. Case 3 was a pre-term child with Klebsiella
pneumoniae septicemia. The platelet count was 6900 per
cmm and catheter closure was considered safer than
surgical closure.
Case 1 needed 4 additional coils that were delivered from
the arterial end. A 3 F bioptome was used to hold the coil
in the pre-term child (Case 3) and 5.2 F bioptome was used
in all other infants. Arterial access was obtained in Case 1
for delivery of additional coils and the femoral artery was
inadvertently punctured in the pre-term child (Case 3).
Arterial puncture could be avoided in all other infants.
Embolization of coils occurred in two instances. In Case 2
(Fig. 1), the coils embolized to abdominal aorta after
achieving a stable position, following endotracheal suction.
A 10 mm Gooseneck snare (Microvena) was introduced
from the venous end and passed across the ductus into the
descending aorta. The tied end of the coils was snared,
pulled back into the ductal ampulla and redeployed. In Case
5, two coils that were initially delivered simultaneously
embolized to left pulmonary artery indicating that the duct
size had been underestimated. The coils were snared out.
One more coil was tied to the same mass and redeployment
was successful. There was no procedure-related
complication. Two infants had mild residual flow at the
end of the procedure that disappeared within 36 hours.
All infants could be extubated 48-72 hours after the
procedure.
Case 3 developed a systolic Doppler gradient of 25
mmHg in the descending aorta following the procedure.
There was no diastolic spillover of the gradient. The
gradient had come down to 12 mmHg, five months later.
No infant had any significant gradient across the branch
IHJ-642-04.p65
233
A
B
C
D
Fig. 1. A – Lateral view of the aortogram showing 3.4 mm patent ductus
arteriosus with a relatively small ampulla. The small arrows indicate the
posterior border of the trachea. B – Bioptome has been shown in the open position
just after the release of the coil mass. C – The embolized coil in the abdominal
aorta is held by the snare. D – The final position of the coil mass after its release
from the snare.
pulmonary arteries. At 3-8 months follow-up, all the
infants were asymptomatic with appropriate weight gain.
Discussion
Infants with large PDA run the risk of death due to CCF5
and recurrent respiratory infections are also not
uncommon in them. Traditionally surgical management
of the patent ductus has been advocated. 7 However,
surgery-related morbidities could lead to prolonged hospital
stay, especially in sick infants with CCF who are ventilated
for respiratory failure with superadded respiratory
infection. Over the past few years, coil occlusion of PDA
has become a standard treatment for small PDAs and has
been shown to be successful even in larger ducts 4-6,8-10. The
latter has been possible especially with the availability of
thicker 0.052’’ coils.
Coil closure was successfully done in all five infants
resulting in rapid recovery from the illness. One of the
infants was a 960 gm weighing pre-term neonate. To the
best of our knowledge, this is the smallest reported child to
undergo transcatheter coil closure of the duct. We prefer
9/29/2004, 5:03 PM
234 Kannan et al. Coil Closure of PDA in Sick Infants
the transvenous coil closure and avoid arterial punctures
whenever possible.3 In three of five children, no arterial
access was obtained. In the pre-term child, the femoral
artery was accidentally punctured and in another child,
arterial access was needed for additional delivery of coils.
Various techniques have been described to reduce the
risk of embolization that include snare- or bioptomeassisted delivery.6,11 We modified the bioptome-assisted coil
delivery technique for simultaneous delivery of multiple
coils4,5 which was applied in these children. Except the preterm child, others needed two or more coils for complete
occlusion of the duct. In one infant, the coil mass embolized
to the abdominal aorta, few minutes after the release. The
coil mass was in a stable position within the ductal ampulla.
This event occurred just after the vigorous endotracheal
suctioning and it is possible that the suction catheter
mechanically dislodged the coil mass. The coil was snared
and delivered back across the ductus successfully without
the need for additional arterial puncture.
Depending on the visual assessment of the ductal
ampulla, we tailored the length of the coils delivered. Two
potential problems of coil closure of large ducts are: left
pulmonary artery stenosis and iatrogenic aortic
coarctation. The pre-term child developed turbulent flow
in the descending aorta with a Doppler gradient of 25
mmHg following coil closure. Five months later, the
gradient had decreased to 12 mmHg. Aydogan et al.12
reported a similar experience where a child developed a
pressure gradient of 47 mmHg following coil closure of
PDA that decreased to 21 mmHg at follow-up.
We believe that coil occlusion has potential advantages
over occlusive devices in small infants as the aortic retention
disk of the device can protrude into the aorta. The recent
introduction of the angled Amplatzer PDA occluder may
overcome some of these limitations. 13 Video-assisted
thoracoscopic surgery has been shown to be effective and
minimally traumatic even in small children.14 This facility
is, however, not universally available.
Conclusions: Transcatheter coil closure of PDA is safe
even in sick, mechanically ventilated infants. Bioptome
assistance, usage of thicker coils, simultaneous delivery of
multiple coils and tailoring the length of the coil contribute
to the success of this procedure. Considering the much
IHJ-642-04.p65
234
Indian Heart J 2004; 56: 232–234
lesser morbidity compared with that of conventional
surgical interruption by thoracotomy, coil closure might
be superior in such a situation. However, only ducts with
adequate ampulla are suitable for coil closure and this
procedure needs certain degree of expertise.
References
1. Alter BP, Czapek EE, Rowe RD. Sweating in congenital heart disease.
Pediatrics 1968; 41: 123–129
2. LeBlanc JG, Russell JL, Sett SS, Potts JE, Human DG, Culham JA. The
evolution of ductus arteriosus treatment. Int Surg 2000; 85: 1–5
3. Anil SR, Sivakumar K, Kumar RK. Coil occlusion of the small patent
arterial duct without arterial access. Cardiol Young 2002; 12:
51–56
4. Kumar RK, Krishnan MN, Venugopal K, Sivakumar K, Anil SR.
Bioptome-assisted simultaneous delivery of multiple coils for
occlusion of the large patent ductus arteriosus. Catheter Cardiovasc
Interv 2001; 54: 95–100
5. Kumar RK, Anil SR, Kannan BRJ, Philip A, Sivakumar K. Bioptomeassisted coil occlusion of moderate-large patent arterial ducts in
infants and small children. Catheter Cardiovasc Interv 2004; 62: 266–
271
6. Grifka RG, Jones TK. Transcatheter closure of large PDA using
0.052” Gianturco coils: controlled delivery using a bioptome
catheter through a 4 French sheath. Catheter Cardiovasc Interv 2000;
49: 301–306
7. Ramphal PS, Irvine R, Spencer HW. Surgery for patent ductus
arteriosus. Still the gold standard. West Indian Med J 2000; 49: 294–
297
8. Espino-Vela J, Cardenas N, Cruz R. Patent ductus arteriosus. With
special reference to patients with pulmonary hypertension.
Circulation 1968; 38 (Suppl): 45–60
9. Hijazi ZM, Geggel RL. Transcatheter closure of large patent ductus
arteriosus (≥4 mm) with multiple Gianturco coils: immediate and
midterm results. Heart 1996; 76: 536–540
10. Owada CY, Teitel DF, Moore P. Evaluation of Gianturco coils for
closure of large (≥3.5 mm) patent ductus arteriosus. J Am Coll Cardiol
1997; 30: 1856–1862
11. Ing FF, Sommer RJ. The snare-assisted technique for transcatheter
coil occlusion of moderate to large patent ductus arteriosus:
immediate and intermediate results. J Am Coll Cardiol 1999; 33:
1710–1718
12. Aydogan U, Batmaz G, Tansel T. Iatrogenic coarctation after coil
occlusion of arterial duct. Asian Cardiovasc Thorac Ann 2002; 10:
72–74
13. Masura J, Gavora P, Podnar T. Transcatheter occlusion of patent
ductus arteriosus using a new angled Amplatzer duct occluder: initial
clinical experience. Catheter Cardiovasc Interv 2003; 58: 261-267
14. Jacobs JP, Giroud JM, Quintessenza JA, Morell VO, Botero LM, van
Gelder HM, et al. The modern approach to patent ductus arteriosus
treatment: complementary roles of video-assisted thoracoscopic
surgery and interventional cardiology coil occlusion. Ann Thorac
Surg 2003; 76: 1421–1427
9/29/2004, 5:03 PM
Trehan et al. Instent Hourglass
Stenosis
235
Brief
Report
Indian Heart J 2004; 56: 235–238
Focal Extra Strength of a Stent Causing Instent
Hourglass Stenosis: An Unusual Complication
Vijay Trehan, Saibal Mukhopadhyay, Vineet Jain, Jamal Yusuf, Vimal Mehta, Umamahesh C Rangasetty
Department of Cardiology, GB Pant Hospital, New Delhi
We report an unusual complication of a 25 mm long stent, which did not expand at all for 1 mm in its proximal
segment, while rest of the 24 mm length of the stent got fully expanded. Repeated attempts to expand the
extremely focal unexpanded part of the stent at high pressure led to rupture of the stent balloon and its
entrapment. We failed to retrieve the balloon using various techniques and the patient had to be sent for coronary
artery bypass graft surgery. (Indian Heart J 2004; 56: 235–238)
Key Words: Stent, Coronary angioplasty, Coronary artery disease, Stents
A
n underexpanded stent predisposes to both subacute
thrombosis and restenosis. While such a problem can
be addressed by dilating the underexpanded segment using
high pressure coronary balloons, it is prudent to prevent
this problem beforehand. The best way of prevention is by
adequate pre-dilation with a balloon of proper size and by
decalcifying the calcified lesions with rotablator (rendering
the lesion more compliant), which allows proper expansion
of the balloon. We report a case, where during pre-dilation
of a lesion with an adequate-sized balloon at 6 atm, there
was no waist, signifying no restraint from the vessel wall.
However, during stent deployment a marked and extremely
focal waisting of the stent balloon was noted (due to
extremely focal unexpansion of the stent) producing an
hourglass deformity of the stent which was noted at 6 atm
and persisted even at a high pressure of 16 atm. Further
increase in pressure in the stent balloon led to rupture of
the balloon and its entrapment which could not be retrieved
percutaneously despite using all the known techniques,
forcing us to send the patient for emergency surgical
retrieval of the stent along with the entrapped balloon
followed by coronary artey bypass graft surgery (CABG).
concentric long lesion in the mid left anterior descending
(LAD) artery (Fig. 1a) and a 75% eccentric lesion in the
first obtuse marginal branch of the left circumflex (LCx)
artery. The right coronary artery (RCA) was normal.
The lesion in LAD was crossed with a Luge wire (Boston
Scientific, Scimed, France) and dilated with a 3×20 mm
Maverick balloon (Boston Scientific, Scimed, France). The
waist of the balloon disappeared completely at 6 atm
(Fig. 1b). Following balloon dilation, there was 25%
residual stenosis with TIMI II flow and a distal dissection.
Hence a 3×25 mm balloon expandable stent (Tenax,
Biotronik) was taken and positioned across the lesion. At 6
atm all but 1 mm segment of the stent balloon failed to
expand producing an hourglass appearance which
persisted even upto a high pressure of 16 atm (Fig. 1c).
Further increase in the pressure (to 17 atm) resulted in the
rupture of the balloon leaving an extremely focal
unexpanded segment of the stent in its proximal part. At
Case Report
A 45-year-old hypertensive, non-diabetic male patient with
history of exertional angina for six months had a 90%
a
Correspondence: Dr Saibal Mukhopadhyay, Senior Research Associate,
Room No. 126, Academic Block, Department of Cardiology, GB Pant Hospital,
New Delhi 110002. e-mail : [email protected]
IHJ-574-03.p65
235
b
c
Fig. 1a. Arrow showing lesion in LAD in left anterior oblique cranial view. b.
Fully inflated balloon across the lesion in LAD. c. Focally unexpanded stent at
high pressure of 16 atm. LAD: left anterior descending
9/29/2004, 4:57 PM
236 Trehan et al. Instent Hourglass Stenosis
this point of time, though the balloon could be advanced
distal to the distal end of the stent, but it could not be pulled
proximal to the proximal end of the stent because the profile
of the distal portion of the balloon had become larger after
bursting and got entangled in the focal, unexpanded
portion of the stent (Fig. 2a). At this juncture the patient
had TIMI I flow, chest pain and hemodynamic compromise.
We intended to pass a second coronary guidewire through
the center of the unexpanded portion alongside the shaft
of the previous entrapped balloon and inflate a noncompliant coronary balloon (that can withstand higher
pressures than stent balloons) at high pressure which was
likely to expand the unexpanded segment and also
disengage the previous entrapped balloon and improve
coronary blood flow. So we passed a second Luge wire and
over it a 3×20 mm Quantum balloon (Boston Scientific,
Scimed, France) and inflated it to 18 atm. This resulted in
quick restoration of blood flow, relief of chest pain and
resumption of hemodynamics. However, following
withdrawal of this balloon, the previously entrapped
balloon rather than getting disengaged got further
entrapped and started behaving as a balloon implanted
Indian Heart J 2004; 56: 235–238
within the stent. At this juncture, the balloon could not be
even advanced distally. This was because the wire had
passed through the struts of the unexpanded segment of
the stent and not through the center of the unexpanded
stent. Thus, though the high pressure balloon could
Fig. 2b. Part of the expanded balloon compressing the unexpanded segment of
the stent due to passage of guidewire through its struts.
Fig. 2a. Schematic diagram showing higher profile of the distal portion of the
ruptured stent balloon entrapped within the unexpanded segment of the stent.
IHJ-574-03.p65
236
Fig. 2c. Schematic diagram showing further narrowing of the lumen of the
unexpanded segment of the stent on inflating the second balloon which
inadvertently passed through its struts.
9/29/2004, 4:57 PM
Indian Heart J 2004; 56: 235–238
overcome the strength of this unexpanded segment of the
stent and expanded the stent through its struts creating a
new opening within the stent, it further constricted the
previously narrowed focal area of the stent thereby
impacting the balloon within the stent (Figs 2b and 2c).
This however, improved the coronary blood flow to TIMI III
by compressing the higher profile ruptured balloon (Fig. 3).
The guiding catheter was then taken deep into the LAD
within the stented segment and repeated attempts at
withdrawal of the balloon using traction resulted in
fracture of the shaft of the balloon catheter. The proximal
shaft easily came out of the guiding catheter, while the
balloon trapped distal to the underexpanded segment was
still lying over the guidewire. We passed a 2 mm Amplatz
gooseneck microsnare (Microvena, MN, USA) over this
guidewire till the underexpanded segment of the stent and
tried to snare out the fractured and entrapped balloon. After
repeated attempts failed, the guiding catheter was again
advanced till the underexpanded segment and a Cook's
flexible biopsy foreceps (3F, 120 cm, Cook Group Company,
USA) was advanced through the guiding catheter into the
stented segment in an attempt to catch a portion of the
shaft of the fractured balloon but failed to retrieve the
balloon catheter. At this point of time, although the patient
was hemodynamically stable and had a normally flowing
LAD, the situation was precarious because of a focally
unexpanded stent and a fractured and entrapped balloon
within it. So we had no other option but to send the patient
Fig. 3. Left coronary angiogram showing TIMI III flow in LAD despite the
presence of entrapped balloon within the focally unexpanded stent. LAD: left
anterior descending
IHJ-574-03.p65
237
Trehan et al. Instent Hourglass Stenosis 237
for urgent surgery to retrieve the stent with the entrapped
balloon and complete the process of revascularization by
bypass grafts. During surgery, the stent along with the
entrapped and fractured balloon was successfully retrieved
(Fig. 4) and the patient made an uneventful recovery.
Fig. 4. Stent with detached and entrapped balloon retrieved after surgery.
Discussion
In the last 2000 of our cases undergoing coronary
angioplasty, this is the only one who had to be sent for an
emergency CABG and that too in a hemodynamically stable
state with TIMI III flow. There are reports in world literature
of unexpanded stents due to slippage of stent from the
balloon, prior to the placement of stent. Subsequently,
either the distal or the proximal portion of the stent
remained unexpanded, depending on whether the stent had
slipped distal or proximal to the balloon.1 There are also
reports of stent unexpansion due to rupture of stent balloon
during stent implantation. This may occur in a calcified
lesion or with a weak balloon. Such cases are usually
managed by removing the ruptured balloon and
subsequently expanding the stent with another balloon.2
Another way of tackling this type of complication is the
usage of a power syringe to deliver a controlled powerful
injection, which expands the leaking balloon with the shear
force of injection in cases of pinhole rupture. This was used
to expand the Palmaz-Schatz stent in a case of renal
angioplasty where the stent remained underexpanded
because of balloon rupture.3
However, to the best of our knowledge there is no report
in world literature of focal unexpansion of a stent in a
situation like the one described above. The balloon was fully
expanded before stent implantation in the artery and the
waist of the balloon had disappeared completely at 6 atm.
Hence, any particular lesion characteristic like calcification
cannot explain the focal unexpansion of the stent. The most
probable mechanism was a manufacturing defect in the
stent. Tenax (Biotronik) is a tubular slotted stent, which
contains multiple segments connected by 0.75 mm long
articulations. We hypothesize that one set of articulations
all along the circumference of the stent contained extra
metal which made this focal segment relatively stronger
than the rest of the stent and prevented it from expanding
9/29/2004, 4:57 PM
238 Trehan et al. Instent Hourglass Stenosis
even at high pressure of 16 atm. This focal band of metal
ring produced focal pressure on the stent balloon resulting
in its rupture.
The purpose of this report is to make the operators and
stent companies aware of this type of complication, which
may jeopardize the success of a commonly performed
interventional procedure like stent implantation.
Conclusions: If such a situation like the one described
occurs in the catheterization laboratory one should not
overzealously try to expand the stent by inflating the stent
balloon at or near the rated burst pressure, which may
result in rupture of balloon and its entrapment as occurred
in our case. Rather, one should attempt to expand the stent
with non-compliant balloons which can withstand
IHJ-574-03.p65
238
Indian Heart J 2004; 56: 235–238
pressure higher than the stent balloon. One should be
careful to avoid bursting of the balloon, which may lead to
its entrapment as occurred in our case and thus force even
a hemodynamically stable patient for emergency surgery.
References
1. Mc Ginnity JG, Glazier JJ, Spears JR, Rogers C, Turi ZG. Successful
redeployment of an unexpanded coronary stent. Cathet Cardiovasc
Diagn 1998; 44: 52-56
2. Pitney MR, Cumpston N. A solution to the problem of an unexpanded
Palmaz-Schatz stent following balloon rupture. Cathet Cardiovasc
Diagn 1991; 24: 246–247
3. Akhtar S, Johnson KB, Dalton R, Rees CR, Marshall WS, Vallabhan
RC, et al. Balloon rupture during stent implantation: a novel
technique of salvage with a new manual power injector. Catheter
Cardiovasc Interv 1999; 48: 74–77
9/29/2004, 4:57 PM
Park et al. Apical Cardiomyopathy
239
Brief Report
Indian Heart J 2004; 56: 239–241
Apical Hypertrophic Cardiomyopathy with Apical
Necrosis and Aneurysm Formation
Jong-Seon Park, Dong-Gu Shin, Young-Jo Kim, Gu-Ru Hong, Jun-Ho Bae, Ihn-Ho Cho, Bong-Sup Shim
Division of Cardiology, Internal Medicine and Nuclear Medicine, Yeung-nam University Hospital, Korea
Apical hypertrophic cardiomyopathy, characterized by giant T-waves and spade-shaped left ventricular cavity is
prevalent in Oriental people, particularly the Japanese. We report an asymptomatic case of apical hypertrophic
cardiomyopathy progressing to myocardial necrosis and aneurysm formation because of the chronic myocardial
ischemia at the apex. (Indian Heart J 2004; 56: 239–241)
Key Words: Hypertrophic cardiomyopathy, Myocardial aneurysm, Angiography
A
pical hypertrophic cardiomyopathy (HCM), a variant
of HCM, is rare in the West but more common in
oriental people, especially in the Japanese. 1 It is
characterized by the presence of giant T-waves and a spadeshaped left ventricular (LV) cavity on ventriculography.
Transthoracic echocardiography (TTE) is a useful tool for
the diagnosis, but sometimes its value is limited due to the
poor echocardiographic window and presence of artifacts.
Therefore, other diagnostic modalities, like contrast
echocardiography and cine magnetic resonance imaging
(MRI), have emerged as more confirmative tools.2-4 Apical
HCM usually has benign prognosis although some serious
cardiovascular complications such as myocardial
infarction,5 ventricular tachycardia and syncope are also
reported.6
We report a case of asymptomatic apical HCM
complicated by apical necrosis and aneurysm formation
found on the routine chest X-ray check-up in a young man.
was clear. The chest X-ray in the posteroanterior view
demonstrated a focal curvilinear calcific density at the
phrenic area. The calcific density was located anteriorly in
the left lateral position (Figs 1A and 1B). Under the
fluoroscopy, round-shaped calcific density was noted at LV
apical area (Fig. 1C). This suggested local pericardial
calcification or a calcified tumor. The electrocardiogram
(ECG) revealed inverted T-waves in leads V4-V6, II, III and
avF. Echocardiography showed symmetric apical
hypertrophy with systolic obliteration of the LV cavity and
an ejection fraction of 66%. On the apical area of the
hypertrophied myocardium, a saccular cystic structure
with thin wall was noted and the luminal surface was
irregular without thrombus. Color flow showed systolic inflow and diastolic out-flow to the aneurysm. Left
ventriculography revealed a bottle gourd-shaped LV due to
A
B
Case Report
A 29-year-old man was referred to our institution from a
local clinic for the evaluation of abnormal chest X-ray
found on a routine check-up. He had no complaints of
dyspnea, chest pain or palpitation. He was not a smoker
but had a family history of sudden cardiac death of his
uncle in adulthood. Physical examination revealed a blood
pressure of 116/70 mmHg and pulse rate of 80 beats per
min. There was no heart murmur or gallop and the lung
Correspondence: Dr Young-Jo Kim, Division of Cardiology, Department
of Internal Medicine, Yeung-nam University Hospital, #317-1 Daemyungdong, Namgu, Daegu, Korea. e-mail: [email protected]
IHJ-719-04.p65
239
C
Fig. 1. Chest X-ray showing a focal curvilinear calcific density on the left phrenic
area in standing posteroanterior view (A), located at the anterior side in left
lateral view (B). Under the fluoroscopy, circular calcific density with patch
calcification was noted at the left subphrenic area (C).
9/29/2004, 5:13 PM
240 Park et al. Apical Cardiomyopathy
a saccular aneurysm at the apex. During diastole, the apical
aneurysm communicated with the LV and the
hypertrophied apical muscle obliterated the LV apex and
separated the aneurysm from the LV cavity (Figs. 2A and
2B). Coronary angiography showed no stenotic lesion but
the distal segment of left anterior descending artery (LAD)
was deviated to the septum because of the aneurysm. 99mTcsestamibi myocardial perfusion single-photon emission
computed tomography (SPECT) showed increased wall
thickness at the LV apex with a focally fixed perfusion defect,
but the aneurysm did not show any uptake of the tracer
(Fig. 3). Signal-averaged ECG and 24-hour ECG monitoring
did not show any abnormal finding. The patient was
discharged on coumadin to prevent thrombosis in the
aneurysm. During the 2-year follow-up period, the patient
remained asymptomatic.
B
A
Fig. 2. Left ventriculogram. During diastole the apical aneurysm was
communicated with the LV and it showed hourglass-shaped LV cavity (A). During
systole the hypertrophied apical muscle obliterated LV cavity and seperated the
LV and the aneurysm (B). LV: left ventricle
A
B
Fig. 3. 99mTc-sestamibi myocardial perfusion showed increased wall thickness
at the left ventricular apex with a focally fixed perfusion defect, but the aneurysm
did not show any uptake of the isotope. (A): End-diastolic and end-systolic
vertical long axis view; (B): End-diastolic and end-systolic horizontal long axis
view.
IHJ-719-04.p65
240
Indian Heart J 2004; 56: 239–241
Discussion
HCM shows variable clinical presentations, prevalence,
morphology and prognosis depending on the race.1 Apical
HCM, first described in Japan, is a rare form of HCM with
an apical distribution of hypertrophy and has been regarded
as an atypical phenotype of non-obstructive HCM more
prevalent in Japanese people. According to Kitaoka et al.1
apical HCM is seen in 15% of Japanese and 3% of American
patients of HCM.1 Usually it is considered as a benign
condition and is detected incidentally like in present case.
TTE is a useful diagnostic tool for the HCM, but poor
visualization of the endocardial border of the LV apex is a
limiting factor for the diagnosis of the apical HCM.7 Further,
in our patient, the endocardial border of the aneurysm was
not clearly seen in the TTE. Contrast echocardiography and
MRI are considered as useful and accurate diagnostic
modalities.2-4,7,8 HCM with midventricular obstruction and
apical hypertrophy can induce apical aneurysm
formation6,9-11 though the exact mechanism of aneurysm
formation is not known. In a case of mid-ventricular
obstruction reported by Harada et al.9 coronary angiogram
showed no stenotic lesion in the epicardial coronary artery
supplying the apex, but myocardial perfusion imaging
showed a fixed defect in the LV apex.9 Our patient also
showed no narrowing of the major coronary arteries but
there was a perfusion defect in the aneurysm. Apical HCM
can show a resting “Solar Polar” map pattern and a relative
apical ischemia on stress images even in the absence of
epicardial coronary artery obstruction.12 The mismatch
between fixed epicardial blood supply, and huge muscle
mass can lead to sustained myocardial ischemia and
necrosis. In this young patient, long-standing myocardial
ischemia and necrosis led to the severe calcification seen
on the routine chest X-ray and fluoroscopy.
The apical aneurysm can be complicated with serious
arrhythmias i.e. ventricular tachycardia6 and may require
antiarrhythmic medication or implantable defibrillator to
prevent sudden cardiac death.13,14 Thin-walled aneurysms
can increase in size in a short period and should be
considered for aneurysmectomy.10 In rare cases, thrombosis
can occur in the aneurysm which in turn causes systemic
embolization.11,15 Therefore, anticoagulation therapy is
needed for patients with large aneurysms to prevent
systemic thromboembolism.
References
1. Kitaoka H, Doi Y, Casey SA, Hitomi N, Furuno T, Maron BJ. Comparison of prevalence of apical hypertrophic cardiomyopathy in
Japan and the United States. Am J Cardiol 2003; 92: 1183–1186
9/29/2004, 5:13 PM
Indian Heart J 2004; 56: 239–241
2. Thomas CN, Maharaj P, Bodapati S, John R, Rahaman R, Henry R,
et al. The initial Trinidad experience with Cine MRI in clinical
cardiology. West Indian Med J 2002; 51: 47–51
3. Soman P, Swinburn J, Callister M, Stephens NG, Senior R. Apical
hypertrophic cardiomyopathy: bedside diagnosis by intravenous
contrast echocardiography. J Am Soc Echocardiogr 2001; 14: 311–
313
4. Garcia Tejada J, L Zamorano J, Almeria C, Rodrigo JL, Sanchez V, Serra
V, et al. Usefulness of contrast echocardiography with harmonic
imaging in a patient with hypertrophic cardiomyopathy and
midventricular obstruction. Rev Esp Cardiol 2000; 53: 1531–1533
5. Eriksson MJ, Sonnenberg B, Woo A, Rakowski P, Parker TG, Wigle
ED, et al. Long-term outcome in patients with apical hypertrophic
cardiomyopathy. J Am Coll Cardiol 2002; 39: 638–645
6. Ito N, Suzuki M, Enjoji Y, Nakamura M, Namiki A, Hase H, et al.
Hypertrophic cardiomyopathy with mid-ventricular obstruction
complicated with apical left ventricular aneurysm and ventricular
tachycardia: a case report. J Cardiol 2002; 39: 213–219
7. Florenciano R, Castillo JA, Molina E, Garcia Urruticoechea P, Egea S,
Ortega J. Diagnosis of apical hypertrophic cardiomyopathy using
contrast echocardiography. Rev Esp Cardiol 2001;54:1336-1338
8. Ulecia Martinez MA, Torres Ruiz JM, Gomez Reyes JL. Apical
hypertrophic cardiomyopathy without aneurysm. Diagnosis through
myocardial gammagraphy and magnetic resonance. Arch Cardiol Mex
2003; 73: 129–134
IHJ-719-04.p65
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Park et al. Apical Cardiomyopathy 241
9. Harada K, Shimizu T, Sugishita Y, Yao A, Suzuki J, Takenaka K, et al.
Hypertrophic cardiomyopathy with midventricular obstruction and
apical aneurysm: a case report. Jpn Circ J 2001; 65: 915–919
10. Kappert K, La Rosee K, Karasch T, Kuhn-Regnier F, Schmidt M,
Rosenkranz S. Thin-walled apical ventricular aneurysm associated
with hypertrophic obstructive cardiomyopathy. Dtsch Med
Wochenschr 2003; 128: 1342–1346
11. Matsubara K, Nakamura T, Kuribayashi T, Azuma A, Nakagawa M.
Sustained cavity obliteration and apical aneurysm formation in
apical hypertrophic cardiomyopathy. J Am Coll Cardiol 2003; 42:
288–295
12. Ward RP, Pokharna HK, Lang RM, Williams KA. Resting “Solar
Polar” map pattern and reduced apical flow reserve: characteristics
of apical hypertrophic cardiomyopathy on SPECT myocardial
perfusion imaging. J Nucl Cardiol 2003; 10: 506–512
13. Tse HF, Ho HH. Sudden cardiac death caused by hypertrophic
cardiomyopathy associated with midventricular obstruction and
apical aneurysm. Heart 2003; 89: 178
14. Okishige K, Sasano T, Yano K, Azegami K, Suzuki K, Itoh K. Serious
arrhythmias in patients with apical hypertrophic cardiomyopathy.
Intern Med 2001; 40: 396–402
15. Fujii H, Kitakaze M, Yamagishi M. Unusual morphologic changes in
apical hypertrophic cardiomyopathy. Heart 2003; 89: 1290
9/29/2004, 5:13 PM
242 Vimala
et al.
Brief
Report
Indian Heart J 2004; 56: 242–244
Stenting MAPCAs in PA-VSD
Stenting Stenosed Aortopulmonary Collateral Arteries in
Pulmonary Atresia with Ventricular Septal Defect
J Vimala, Snehal Kulkarni
International Centre for Cardiothoracic and Vascular Diseases, Chennai
We present two cases of pulmonary atresia with ventricular septal defect who were not suitable for corrective
surgery due to absent or hypoplastic native pulmonary arteries and were quite symptomatic following shunt
surgery. We dilated and stented stenosed aortopulmonary collaterals as palliative procedure with improvement
in oxygen saturation, and significant symptomatic relief. (Indian Heart J 2004; 56: 242–244)
Key Words: Pulmonary atresia, Stents, Congenital heart disease
P
ulmonary atresia with ventricular septal defect
(PA-VSD) has major abnormalities in the size and
distribution of pulmonary arterial tree. The pulmonary
blood supply may be through patent ductus arteriosus
(PDA) or well developed collaterals from the aorta. These
collaterals are stenotic in nearly 60% of cases. The stenosis
may be discrete or long and may progress with time.1 The
stenosis may be congenital or acquired. Stenosis of
collateral arteries may develop progressively and thereby
cause a decrease in pulmonary blood supply. We present
two cases of PA- VSD who were not suitable for corrective
surgery in view of absent or hypoplastic pulmonary arteries
(PAs); they improved symptomatically after dilation and
stent implantation of stenosed major aortopulmonary
collateral arteries (MAPCAs).
Case Reports
Case 1: An 8-year-old boy with PA-VSD presented with
worsening cyanosis and dyspnea. He had undergone
modified Blalock-Taussig (BT) shunt on the right and left
sides at 1 and 7 years of age, respectively. His oxygen
saturation was 50%. Echocardiography did not show any
native PAs. The subclavian ends of BT shunts were seen;
but distal ends were not visualized.
Angiography was done to define the pulmonary artery
anatomy to decide the feasibility of corrective surgery. It
showed patent shunts, from right subclavian artery to an
aortopulmonary collateral supplying the upper lobe of the
Correspondence: Dr Snehal Kulkarni, International Centre for
Cardiothoracic and Vascular Diseases, R-30C, Ambattur Industrial Estate Road,
Mogappair, Chennai 600101. e-mail: [email protected]
IHJ-650-04.p65
242
right lung and left subclavian artery to an aneurysmally
dilated part of left upper pulmonary artery. Aortogram
showed two MAPCAs supplying the right lung; the upper
MAPCA was smaller and supplied the right upper lobe to
which the right BT shunt had been done; lower MAPCA
was larger, and supplied the right middle and lower lobes.
This lower MAPCA had long segment, proximal stenosis.
The left lung had multiple small collaterals supplying it.
Pulmonary venous wedge angiography did not show native
PAs.
The patient was taken up for palliative surgery in view
of his symptomatic status. The shunt on the left was taken
down and 6 mm Goretex tube was interposed between the
left subclavian artery and one of the collaterals to left lung.
Patient did not improve symptomatically and oxygen
saturation remained at 50%.
As a palliative procedure, we decided to dilate the stenosed
right lower MAPCA to improve the systemic saturation.
Angiography showed tight narrowing at the origin (Fig. 1).
The ostium was intubated with a 6 F renal guiding catheter.
The lesion was crossed with 0.018'', SV5, 300 cm wire. The
lesion was pre-dilated with a 4 mm ×2 cm Opta-Pro balloon
at 6 atm pressure. The lesion was stented with 5 mm ×18
mm Genesis stent at 12 atm pressure (Fig. 2). The result was
good, with rapid clearance of contrast on check angiography.
Patient improved symptomatically, and systemic saturation
was stable at 71%.
Case 2: A 5-year-old girl was diagnosed to have PA-VSD.
She had tiny confluent PAs and a large MAPCA supplying
the right lung. There was a large MAPCA to the left lung.
She underwent unifocalization of the right-sided MAPCAs
and modified BT shunt on the same side at the age of 3 years.
9/29/2004, 5:04 PM
Indian Heart J 2004; 56: 242–244
Vimala et al.
Stenting MAPCAs in PA-VSD 243
unifocalized right-sided MAPCA supplied right lung with
good arborization. There was a large MAPCA to the left lung
which divided into 2 branches, both having proximal
stenoses (Fig. 3). Since PAs were hypoplastic, she was
considered unsuitable for complete repair. So we decided to
dilate the stenosed branches of left MAPCA as a palliative
Fig. 1. Angiogram showing the stenosis at the origin of the MAPCA to the
right lung in Case 1. The white arrow points to the narrowed proximal segment
of the MAPCA. MAPCA: major aortopulmonary collateral arteries
Fig. 3. Angiogram showing the stenosis at the origin of the branches of the
MAPCA to the left lung in Case 2. The black arrow points to the tight stenosis in
the upper branch and white arrow points to the stenosis in the lower branch.
MAPCA: major aortopulmonary collateral arteries
Fig. 2. Angiogram following successful dilation and stenting of the stenosed
MAPCA in Case 1. The white arrow points to the stented segment of the
MAPCA. There is no residual stenosis. MAPCA: major aortopulmonary
collateral arteries
She presented after 2 years with easy fatiguability.
Oxygen saturation was 70%. Angiogram showed
functioning BT shunt filling hypoplastic PAs. The
IHJ-650-04.p65
243
Fig. 4. Angiogram following successful dilation and stenting of the stenosed
MAPCA in Case 2. The black arrow points to minimal stenosis in the upper
branch after dilation and stenting. The white arrow points to the stented segment
in the lower branch. MAPCA: major aortopulmonary collateral arteries
9/29/2004, 5:04 PM
244 Vimala et al.
Stenting MAPCAs in PA-VSD
procedure to improve oxygen saturation. Stenosis in the
upper branch was crossed with a 0.018'', SV5, 300 cm wire
and stented with 6×18 mm Genesis stent at 14 atm
pressure. There was significant residual stenosis in the
midsegment of MAPCA, hence it was post-dilated to 20 atm
pressure. Angiogram still showed mild stenosis in the mid
segment. Stenosis in the lower branch was dilated and
stented with 5×18 mm Genesis stent (Fig. 4). The distal
MAPCA pressure improved from 12/9 mmHg (mean 10
mmHg) to 20/9 mmHg (mean 12 mmHg) in the upper
MAPCA, and from 12/4 mmHg (mean 8 mmHg) to 27/17
mmHg (mean 12 mmHg) in the lower MAPCA after
stenting. The oxygen saturation improved to 90%.
Discussion
PA-VSD has variable pulmonary blood flow. The blood
supply is either through a PDA or through MAPCAs. Many
of these collaterals are stenosed or hypertensive which pose
a problem in management. The feasibility for corrective
surgery depends on the size of native PAs. In patients with
PA-VSD who are not suitable for corrective surgery due to
unsuitable pulmonary artery anatomy, various palliative
procedures have been tried, such as BT and central
aortopulmonary shunts. Transcatheter palliation has been
achieved in symptomatic patients by dilating and stenting
the stenosed aortopulmonary collaterals.2-5 In patients who
are symptomatic following shunt surgery, symptom relief
and improvement in oxygen saturation have been seen
following dilation and stenting of the restrictive shunts.3,5,6
Balloon expandable and self expanding stents have been
used successfully in stenting the stenosed MAPCAs.3,6 Luc
et al.7 have reported successful redilation of stenosis in
collaterals which were resistant to high pressure initial
dilation, by using cutting balloon. Pettersen et al.8 have
reported successful stenting of a right coronary to PA fistula
to augment pulmonary blood flow. In neonates, stenting
of closing ductus arteriosus has been done to maintain
pulmonary blood flow.5,9
Our first patient had undergone 3 shunts and still
remained symptomatic, although all the shunts had been
patent. The shunts had failed to provide adequate increase
in systemic saturation, as they were between the systemic
arteries and smaller aortopulmonary collaterals. Native
pulmonary arteries did not grow after the shunts. So he
was thought to be unsuitable for complete repair. Hence
we dilated and stented the larger collateral, which otherwise
would have needed another surgery involving lots of
dissection to reach the collateral. Fortunately this rightsided collateral was large with good arborization and
supplied the right middle and lower lobes. After stenting,
IHJ-650-04.p65
244
Indian Heart J 2004; 56: 242–244
the diameter of the MAPCA increased from 2.3 to 4.7 mm
at the stenotic segment with improvement in oxygen
saturation. Second patient also was not suitable for
corrective surgery. The unifocalized right-sided MAPCAs
with shunt on right side was working well. But the native
PAs had not grown well. The major MAPCA on left side
had multiple stenoses which were quite distal from the
hilum. It would have been difficult surgically to address
those stenotic lesions through midsternotomy approach.
So as a palliative procedure, a decision was taken to dilate
and stent the collateral. Sometimes MAPCAs can be quite
difficult to dilate. In our second patient, in spite of dilating
with 20 atm high pressure balloon, there was narrowing
in the mid segment. Such resistant lesions have been
described earlier.7 In both of our patients improvement has
been achieved by combination of various strategies such
as shunt procedures and endovascular stenting of
MAPCAs. We accept that this is just a palliation, and
patients may become symptomatic again over a period of
time.
References
1. Mair DD, Edwards WD, Julsrud PR, et al. Pulmonary atresia and
ventricular septal defect. In: Emmanouilides GC, Allen HD,
Riemenschneider TA, Gutgesell HP, (eds). Moss and Adam’s Heart
Disease in Infants, Children and Adolescents, 5th ed. Baltimore: Williams
& Wilkins, 1995; pp 983–996
2. Brown SC, Eyskens B, Mertens L, Dumoulin M, Gewillig M.
Percutaneous treatment of stenosed major aortopulmonary
collateral balloon dilatation and stenting: what can be achieved?
Heart 1998; 79: 24–28
3. El-Said HG, Clapp S, Fagan TE, Conwell J, Nihill MR. Stenting of
stenosed aortopulmonary collaterals and shunts for palliation of
pulmonary atresia/ventricular septal defect. Catheter Cardiovasc
Interv 2000; 49: 430–436
4. Redington AN, Somerville J. Stenting of aortopulmonary collaterals
in complex pulmonary atresia. Circulation 1996; 94: 2479–2484
5. Alekyan BG, Pursanov MG, Gadzhiev AA, Kokshenev IV, Verin VV.
Interventional procedures for complex treatment of patients with
pulmonary artery atresia. 4th International Workshop, Catheter
Interventions in Congenital Heart Disease, Frankfurt/Germany,
18-20 Oct 2001
6. Bader R, Somerville J, Redington AN. Use of self expanding stents in
stenotic aortopulmonary shunts in adults with complex cyanotic
heart disease. Heart 1999; 82: 27–29
7. Luc M, Derize B, Marc G. Use of a cutting balloon catheter to dilate
severe stenoses on the pulmonary arteries and aortic to pulmonary
collateral arteries. An initial experience. 4th International Workshop,
Catheter Interventions in Congenital Heart Disease, Frankfurt/
Germany, 18-20 Oct 2001
8. Pettersen MD, Ammash NM, Hagler DJ, Rihal CS, Cabalka AK.
Endovascular stent implantation in a coronary artery to pulmonary
artery fistula in a patient with pulmonary atresia with ventricular
septal defect and severe cyanosis. Catheter Cardiovasc Interv 2001;
54: 358–362
9. Gibbs JL, Rothman MT, Rees MR, Parsons JM, Blackburn ME, Ruiz
CE. Stenting of the arterial duct : a new approach to palliation for
pulmonary atresia. Br Heart J 1992; 67: 240–245
9/29/2004, 5:04 PM
Indian Heart J 2004; 56: 245–247
Pagad et al.
RF Ablation for Atrial Tachycardia
245
Brief Report
‘Rescue’ Radiofrequency Ablation for Atrial Tachycardia
Presenting as Cardiomyopathy in Pregnancy
Sameer V Pagad, Anand B Barmade, Satish C Toal, Amit M Vora, Yash Y Lokhandwala
Quintiles ECG Services and Arrhythmia Associates, Mumbai
A young primiparous lady presented with drug-refractory atrial tachycardia which had led to cardiomyopathy. Three attempts with electrical cardioversion were also unsuccessful. She was rescued by
radiofrequency ablation. (Indian Heart J 2004; 56: 245–247)
Key Words: Radiofrequency ablation, Tachyarrhythmia, Pregnancy
I
n pregnancy, significant changes occur in the hormonal
and hemodynamic state of women that make them more
susceptible to arrhythmias.1,2 Palpitations are frequently
reported and the usual cause is sinus tachycardia. The
incidence of paroxysmal supraventricular tachycardia is
increased during pregnancy and tends to recur with each
pregnancy, whereas atrial fibrillation and ventricular
tachycardia are rarely seen.1 We describe a case of atrial
tachycardia that became incessant during pregnancy,
leading to cardiomyopathy. We performed successful
radiofrequency (RF) ablation of the atrial tachycardia,
hitherto unreported in the pregnant state.
Case Report
A 24-year-old primigravida was referred at 6 months of
pregnancy for uncontrolled symptomatic atrial tachycardia. History of episodic rapid palpitations predated her
pregnancy by 6 months. They were infrequent, abrupt in
onset and termination, without giddiness or syncope. She
was not on any treatment for the same. However, after
conceiving, the palpitations had increased in frequency
and duration. On presentation, she had associated
breathlessness on exertion of one month duration. An
attempt was made to control the ventricular rate by
pharmacologic means. Injection adenosine, metoprolol,
diltiazem and verapamil were tried but there was no
success. Synchronized 200 J DC cardioversion was then
attempted, but to no avail. She was then loaded with
intravenous amiodarone and DC cardioversion on
Correspondence: Dr Yash Lokhandwala, 603, Midas, Sahar Plaza
Complex, Andheri Kurla Road, JB Nagar, Andheri (E), Mumbai 400059
e-mail: [email protected]
IHJ-660-04.p65
245
amiodarone was again tried. However, this was also
unsuccessful and she continued to be in tachycardia,
although the rate had slowed from 240 beats per min (bpm)
to 166 bpm.
On clinical examination, the pulse was 166 bpm; jugular
venous pressure was raised; her systolic blood pressure (BP)
was 90 mmHg. There was tender hepatomegaly. An S3
gallop was heard. The electrocardiogram was suggestive of
atrial tachycardia with cycle length (CL) of 360 ms with
an upright p-wave in lead II, equiphasic p in lead III and
inverted p in lead V1 (Fig. 1). The echocardiogram revealed
generalized hypokinesia and left ventricular ejection
fraction (LVEF) of 22%. The tachycardia rate decreased on
amiodarone and propafenone (CL 460 msec), but her
symptoms of breathlessness persisted; she was in NYHA
class III by this time. A third attempt at cardioversion was
given but that was only transiently effective in restoring
sinus rhythm. A pelvic ultrasound revealed normal fetal
growth and development. Since the tachycardia was
intractable and had led to congestive heart failure, we
decided to ablate the tachycardia in spite of her pregnant
status.
Fig. 1. Surface ECG at presentation suggesting atrial tachycardia. Note the
upright p-wave in lead II, and inverted in V1.
9/29/2004, 5:06 PM
246 Pagad et al.
RF Ablation for Atrial Tachycardia
Fig. 2a. Intracardiac recording during electrophysiology study showing local
activation in the right atrium preceding surface p-wave by 20 ms.
Indian Heart J 2004; 56: 245–247
Fig. 3. Surface electrocardiogram showing termination of atrial tachycardia.
cm higher than the previous site. At this site the endocardial
activation was 29 ms ahead of the p-wave and there was
low amplitude fractioned signal with a QS pattern in the
unipolar distal RF signal (Fig. 2b). RF energy immediately
terminated the second incessant tachycardia and sinus
rhythm was restored (Fig. 3). No tachycardia was inducible
thereafter. Low-dose fluoroscopy was used and the
fluoroscopy time was 4 min.
After 2 days, she had a recurrence of atrial tachycardia
with a rate of 110 bpm but this tachycardia spontaneously
terminated after a few minutes. Her symptomatic status
improved. She had an uneventful delivery at term by
caesarian section. The child was healthy. Short episodes of
Fig. 2b. Intracardiac recording showing unipolar signals at the site of ablation
(rfu). Note the QS nature of the unipolar atrial activation (arrow). RV denotes
right ventricle.
The electrophysiology procedure was performed after
shielding the abdomen against radiation. Two electrode
catheters were placed, one in the right ventricle and the
other for mapping in the right atrium. Both bipolar as well
as tip unipolar signals from the mapping catheter were
recorded. A Webster thermocouple medium curve catheter
with Stockert ablator was used for RF ablation. Mapping
demonstrated the low crista region in the right atrium to
be the site of origin of tachycardia with local activation
preceding the onset of the p-wave by 20 ms (Fig. 2a). RF
energy at this site did terminate the tachycardia abruptly.
However, after few minutes there was a recurrence of atrial
tachycardia at a rate of 140 bpm and the morphology of
the p-wave of this teachycardia was slightly different from
the first atrial tachycardia. Mapping of the second slower
persistent tachycardia revealed earliest atrial activation 1
IHJ-660-04.p65
246
Fig. 4. Chest radiogram at 6 months follow-up showing a normal heart size.
9/29/2004, 5:07 PM
Indian Heart J 2004; 56: 245–247
well-tolerated atrial tachycardia at a rate of 110-116 bpm
continued for a few days and then disappeared spontaneously.
On 6 months follow-up after ablation she was in sinus
rhythm without any medications. Clinical examination was
normal. Chest radiogram revealed normal cardiac size
(Fig. 4). Repeat echocardiogram showed normal LVEF of
50%. Her child was growing normally. At one year after
delivery, she continues to be asymptomatic.
Discussion
Atrial tachycardias result from abnormalities of impulse
formation or conduction in atrial tissue. They usually tend
to cluster along the crista terminalis in the right atrium
and from within a pulmonary vein in the left atrium.
Underlying mechanism of atrial tachycardia is most often
abnormal automaticity. This may be from a single or
multiple foci. The majority arise from single focus; multiple
foci are present in 10-15 % of patients.3
Automatic atrial tachycardias are often poorly responsive to long-term medical treatment and are sometimes
incessant. These tachycardias have been associated
with tachycardia-induced cardiomyopathy which is
frequently reversible after termination of tachycardia.4,5 RF
ablation has been successfully applied to the treatment of
tachyarrhythmias of atrial origin. The immediate success
rate of atrial tachycardia ablation has been somewhat lower
(90%) than that for atrioventricular (AV) nodal reentrant
and AV reentrant tachycardia.3 The recurrence rate is also
generally higher. Successful ablation of one site
occasionally leads to the appearance of atrial focus at a
different site.
Acute treatment of atrial tachycardias for pregnant
women is same as that for other patients. However, chronic
drug therapy during pregnancy should be reserved for only
the frequent, hemodynamically significant arrhythmic
episodes. For rate control, digoxin and beta-blockers are the
drugs of choice. For long-term therapy, beta-blocking
agents with beta-1 selectivity are first-line drugs; class Ic
agents (flecainide) or the class III drugs (sotalol) represent
effective therapeutic alternatives.6 Flecainide is commonly
used for conversion to sinus rhythm in patients of atrial
tachycardia. However, its safety in pregnancy is not proved.
It has been classified under category C (studies in animals
have revealed adverse effects on the fetus; no controlled
studies in humans available; should be used only if the
potential benefit justifies the potential risk to the fetus).7 It
IHJ-660-04.p65
247
Pagad et al.
RF Ablation for Atrial Tachycardia 247
has a negative ionotropic effect and can cause or worsen
heart failure. It is also not readily available. Amiodarone is
not safe for the fetus.
RF ablation poses the hazard of radiation on the fetus.
Standard fluoroscopy could deliver 1-2 Rads/min, and high
level fluoroscopy or cine as much as 5-10 Rads/min. The
amount of radiation scattered to the uterus and absorbed
by the embryo is <5% of the radiation absorbed by the
directly radiated tissue. Current recommendations related
to intrauterine radiation exposure suggest that with
exposure to <5 Rads, the patient can be reassured of a very
low likelihood of risk. With 5-10 Rads, the patient should
be counseled regarding low risk of problems; and with 1015 Rads during the first six weeks, termination of
pregnancy should be considered.7
RF ablation performed as the therapeutic challenge in
this case was to balance the hazards of the procedure with
the ill effects associated with the cardiomyopathy secondary
to incessant tachycardia. While immediate success was
achieved by RF ablation, the patient continued to have atrial
tachycardia but at a much slower rate, probably due to the
hormonal and hemodynamic milieu of pregnancy. After
the delivery, she remained in sinus rhythm and the
cardiomyopathy disappeared with the ejection fraction
rising to 50% within 6 months.
Atrial tachycardia in pregnancy poses therapeutic
challenges. Incessant tachycardias resulting in tachycardiomyopathy may require RF ablation. Interestingly,
these results may be influenced by the pregnant state.
References
1. Wolbrette D. Treatment of arrhythmias during pregnancy. Curr
Women’s Health Rep 2003; 3: 135–139
2. Gowda RM, Khan IA, Mehta NJ, Vasavada BC, Sacchi TJ. Cardiac
arrythmias in pregnancy: clinical and therapeutic considerations.
Int J Cardiol 2003; 88: 129–133
3. Monahan K, Josephson M. Electrophysiologic ablation therapy:
catheterisation, angiography and intervention; 5th ed. Donald S
Baim, William Grossman. William & Wilkins
4. Bertil Olsson S, Blomstrom P, Sabel KG, William-Olsson G. Incessant
ectopic atrial tachycardia: successful surgical treatment with
regression of dilated cardiomyopathy picture. Am J Cardiol 1984; 53:
1465–1466
5. Packer DL, Bardy GH, Worley SJ, Smith MS, Cobb FR, Coleman RE,
et al. Tachycardia-induced cardiomyopathy: a reversible form of left
ventricular dysfunction. Am J Cardiol 1986; 57: 563–570
6. Trappe HJ. Cardiac arrythmias during pregnancy—what to do? Herz
2003; 28: 216–226
7. Braunwald, Zipes, Libby; Heart Disease, 6th ed, Philadelphia, 2001,
pp2184
9/29/2004, 5:07 PM
248 Roshan
et al.
Brief
Report
Indian Heart J 2004; 56: 248–249
Torsade de Pointes in Pheochromocytoma
Torsade de Pointes in a Case of Pheochromocytoma – An
Unusual Presentation of an Uncommon Disease
John Roshan, Oommen K George, S Vineet, Paul V George, V Jacob Jose
Department of Cardiology, Christian Medical College, Vellore
We report the case of a middle aged lady with dilated cardiomyopathy, presenting with recurrent syncope due
to torsade de pointes. Further evaluation revealed that she had a pheochromocytoma which caused the
arrhythmia. (Indian Heart J 2004; 56: 248–249)
Key Words: Dilated cardiomyopathy, Ventricular arrhythmia, Pheochromocytoma
P
atients with pheochromocytoma are known to have
various cardiac complications including arrhythmias,
heart failure, myocardial infarction and cardiomyopathy.1
QT prolongation has been reported in these patients and
can predispose to serious ventricular arrhythmias resulting
in syncope and cardiac death in the worst cases.2,3 We
report here the case of a lady who was diagnosed to have
dilated cardiomyopathy and had episodes of syncope in the
past, which worsened with the initiation of β-blocker
therapy. Torsade de pointes was detected on Holter
monitoring and further evaluation revealed the etiology to
be the presence of a pheochromocytoma.
Case Report
A 36-year-old lady presented to us with history of
breathlessness on exertion (NYHA class II), fatigue, loss of
weight and fearfulness of 2 years duration. She also had
two episodes of syncope in this period for which a
computerized tomography (CT) of brain was done which
was found to be normal. There was no family history of
sudden cardiac death. On examination her blood pressure
was 140/90 mmHg and heart rate was 120 beats per min.
Cardiovascular examination was unremarkable.
Hematologic findings were normal. Serum electrolytes were
as follows: sodium 140 mmol/L, potassium 4 mmol/L,
calcium 9.2 mg%, phosphorus 3.6 mg%, magnesium 1.99
mg%. Fasting blood glucose, urea, creatinine, liver and
thyroid function tests were all normal. Her baseline
electrocardiogram (ECG) showed a QTc interval of 551
Correspondence: Dr V Jacob Jose, Professor and Head, Department of
Cardiology, Christian Medical College Hospital, Vellore 632 004
e-mail : [email protected]
IHJ-693-04.p65
248
msec (Fig. 1). The echocardiogram revealed global
hypokinesia with an ejection fraction of 34%. Chest X-ray
revealed a cardiothoracic ratio (CTR) of 60% with mild
pulmonary venous congestion. Based on the above findings
a diagnosis of dilated cardiomyopathy was made and she
was started on β-blockers, angiotensin-converting enzyme
(ACE) inhibitors and diuretics. Four days later she presented
to the emergency services with palpitation followed by
syncope. She was very agitated and her blood pressure was
200/120 mmHg. There were no clinical features suggesting
secondary hypertension. Dose of β-blocker was increased.
Over the next 3 days she reported a paradoxical increase in
the number of syncopal episodes. Her Holter monitoring
revealed torsade de pointes (Fig. 2), hence she was admitted
in the coronary care unit. She had multiple episodes of
torsades which did not respond to intravenous magnesium.
Since she had a prolonged QTc on ECG, possibility of a
congenital long QT syndrome (LQTS) was considered (no
acquired causes hitherto being found) and the dose of the
β-blocker was further increased. She was found to have
paroxysmal rise in blood pressure associated with sweating
and panic attacks. Escalation in β-blocker dose was
associated with an increase in arrhythmogenicity. A
Fig. 1. Basline electrocardiogram showing QTc of 551 ms.
9/29/2004, 5:10 PM
Indian Heart J 2004; 56: 248–249
Fig. 2. Holter showing evidence of torsade de pointes.
possibility of a pheochromocytoma was considered as the
cause of an acquired LQTS. An ultrasound abdomen
revealed a 4×3 cm echogenic mass in the left adrenal
region. Her 24-hour urine vanillylmandelic acid (VMA)
excretion was 14.2 mg in 2140 ml. A CT scan and 131-meta
iodo benzyl guanidine scintigram confirmed the diagnosis.
She was started on α-blockers and her β-blocker dose was
tapered. Her arrhythmias decreased in frequency with
progressive α-blockade. She was operated and the biopsy
confirmed the diagnosis. Her post-operative period was
uneventful. Two weeks after surgery her echocardiogram
showed an improvement in ejection fraction from 34% to
45%.
Discussion
We report here a rare case of torsade de pointes occurring
in a patient with pheochromocytoma. In pheochromocytoma complications such as heart failure, myocardial
infarction and arrhythmias have been described.1 Though
several cardiac arrhythmias have been reported, the
occurrence of torsades in pheochromocytoma is rare; only
a few case reports are available in literature.4-6
Torsades occurring in pheochromocytoma is interesting
in the sense that this is a completely reversible condition
following the tumor removal. However, long QT interval in
this condition may persist as long as six years after surgery.2
In our patient, β-blocker therapy initiated for her dilated
cardiomyopathy actually caused an increase in the
frequency of arrhythmias and syncope. Further increase
IHJ-693-04.p65
249
Roshan et al. Torsade de Pointes in Pheochromocytoma 249
in the dose of β-blocker to control the blood pressure caused
an unusual increase in the frequency of arrhythmias.
Though β-blockers are used in the treatment of congenital
LQTS, they are contraindicated in acquired LQTS. This is
because the bradycardia produced by these agents can
precipitate a torsades. Besides, β-blockers are known to
decrease the outward potassium current. This increases the
susceptibility of an individual with an acquired LQTS to
arrhythmias as it is the rapid component of the delayed
rectifier potassium outward current that is most commonly
affected.7 By blocking the β-receptors in our patient with
pheochromocytoma, the α-receptor stimulation continued
unabated. Alpha adrenergic stimulation prolongs the
action potential.5 However, animal studies have shown that
α-adrenergic stimulation triggered ventricular arrhythmias
only when the myocardial potassium channels were
blocked, thus mimicking a congenital LQTS or a repolarization abnormality.8
Conclusions: QT prolongation can occur in patients with
pheochromocytoma and may give rise to dangerous
arrhythmias like torsades. It would be advisable to evaluate
patients with dilated cardiomyopathy who also have high
blood pressure to exclude secondary causes of hypertension. Our case illustrates that pheochromocytomas can
be a rare, reversible cause of torsade de pointes.
References
1. Manger WM, Gifford RW Jr. Pheochromocytoma. Berlin SpringerVerlag, 1977; 70–84, 184–192
2. Stenstrom G, Swedberg K. QRS amplitudes, QTc intervals and ECG
abnormalities in pheochromocytoma patients before, during and
after treatment. Acta Med Scand 1988; 224: 231–235
3. Khan MM, Logan KR, McComb JM, Adgey AA. Management of
recurrent ventricular tachyarrhythmias associated with Q-T
prolongation. Am J Cardiol 1981; 47: 1301–1308
4. Shimizu K, Miura Y, Meguro Y, Noshiro T, Ohzeki T, Kusakari T, et al.
QT prolongation with torsade de pointes in pheochromocytoma. Am
Heart J 1992; 124: 235–239
5. Viskin S, Fish R, Roth A, Schwartz PJ, Belhassen B. Clinical problemsolving. QT or not QT. N Engl J Med 2000; 343: 352–356
6. Kihara H, Terai H, Kihara Y, Kihara T, Takahashi H, Kosuda A, et al.
Pheochromocytoma of the left retroperitoneal paraganglion
associated with torsade de pointes: a case report. J Cardiol 1997; 30:
37–44
7. Viskin S. Long QT syndromes and torsade de pointes. Lancet 1999;
354: 1625–1633
8. Ben-David J, Zipes DP. Alpha adrenoceptor stimulation and blockade
modulates cesium-induced early after depolarizations and
ventricular tachyarrhythmias in dogs. Circulation 1990; 82:
225–233
9/29/2004, 5:10 PM
250 Gupta
et al.
Brief
Report
Indian Heart J 2004; 56: 250–251
Eptifibatide-Induced Thrombocytopenia
Eptifibatide-Induced Profound Thrombocytopenia
N Gupta, R Kapoor, S Bhandari
Department of Invasive Cardiology, Escorts Heart Institute and Research Centre, New Delhi
We report a case of profound thrombocytopenia, 2 hours following eptifibatide therapy which got reversed
within 12 hours of discontinuation of eptifibatide. (Indian Heart J 2004; 56: 250–251)
Key Words: Thrombocytopenia, Eptifibatide, Coronary angioplasty
A
cute profound thrombocytopenia is not commonly
seen in patients receiving eptifibatide. Immunologic
mechanisms are proposed for etiopathogenesis of
thrombocytopenia which are reversible. Other casues of
thrombocytopenia should also be ruled out in such cases.
The standard treatment is discontinuation of the offending
drug and providing supportive measures.
48 hours post-procedure. She developed petechial spots on
the back as well as large ecchymotic patches on the right
forearm and left leg 12 hours post-PCI (Fig. 1). No other
hematological sequelae was noted. At 6 weeks follow-up,
she is doing well with no recurrence of thrombocytopenia.
Case Report
A 54-year-old hypertensive lady underwent elective
coronary angiogram due to crescendo angina. This
revealed 90% stenosis in distal circumflex artery and
therefore, percutaneous coronary intervention (PCI) with
eptifibatide cover was planned. During the procedure she
received a total of 11,000 units of intravenous heparin and
two boluses of intravenous eptifibatide 180 mcg/kg, 10 min
apart followed by infusion at the rate of 2 mcg/kg/min.
Activated clotting time (ACT) was kept around 250 sec. A
3×18 mm sirolimus-eluting stent was successfully
deployed. She had mild gum oozing which was treated with
cold saline gargles. Her baseline platelet count was
2,32,000 per cmm. Two hours post-procedure, her platelet
count dipped to 4,000 per cmm. Repeat heparinized sample
to rule out pseudothrombocytopenia also revealed platelet
count of 6,000 per cmm. Eptifibatide therapy was
discontinued, antiplatelet drugs (asprin and clopidogrel)
were withheld, intravenous dexamethasone 8 mg 8 hourly
was started and 2 units each of platelet concentrate and
platelet apheresis were transfused, which raised the platelet
count to 35,000 per cmm. Over next 12 hours, the platelet
count stabilized at 1,26,000 per cmm, and remained so till
Correspondence: Dr Suman Bhandari, Escorts Heart Institute and
Research Centre, Okhla Road, New Delhi 110025
e-mail: [email protected]
IHJ-671-04.p65
250
Fig. 1. Large ecchymotic patches on right forearm and left leg.
Discussion
Drug-induced acute profound thrombocytopenia is defined
as a decrease in platelet count to below 20,000 per cmm
within 24 hours of exposure to the drug.1 In our patient,
normal baseline platelet count and other hematological
parameters (prothrombin time, red and white blood cell
count) ruled out bone marrow dysfunction, non-immune
and immune thrombocytopenia as a cause of thrombocytopenia. Pseudothrombocytopenia was ruled out by
manually examining peripheral smear (heparinized
sample). Resolution of thrombocytopenia within 24 hours
ruled out clopidogrel as a cause of thrombocytopenia and
9/29/2004, 5:09 PM
Indian Heart J 2004; 56: 250–251
during follow-up, the patient continued to be on clopidogrel
without recurrence of thrombocytopenia. Heparininduced thrombocytopenia (HIT) was excluded because,
without recent exposure (i.e. within the last two months)
it requires more than four days of heparin therapy to precipitate immune-mediated (Type II) HIT,2,3 whereas Type I
HIT is characterized by only mild decline in platelet count
(10-20%) with nadir platelet count that usually exceeds
1,00,000 per cmm.2 The close temporal relationship to
administration and the resolution of the adverse reaction
on discontinuation of the offending drug support the
likelihood that the profound acute reversible
thrombocytopenia in our patient was due to epitifibatide.
Acute profound thrombocytopenia associated with
abciximab has been well described. However, this
complication has not been commonly reported in
association with eptifibatide. The incidence of acute
thrombocytopenia with eptifibatide in PURSUIT trial4 was
4.9% for platelet count <1,00,000 per cmm, 0.5% for
severe thrombocytopenia (platelet count <50,000/cmm)
and 0.1% for profound thrombocytopenia (platelet count
<20,000/cmm). In ESPRIT trial 5 acute profound
thrombocytopenia (platelet count <20,000/cmm, within
24 hrs) occurred in two patients (0.2%) receiving
eptifibatide (n=1040).
Several hypotheses have been proposed to explain the
mechanism of glycoprotein (Gp) IIb/IIIa inhibitors causing
thrombocytopenia. Some patients have pre-formed
antibodies to ligand-induced binding sites (LIBSs) which are
normally not exposed on the surface of the platelets.
Binding of Gp IIb-IIIa inhibitors to the receptors on the
platelets induces conformational changes that expose the
LIBSs which leads to binding of anti-LIBSs antibodies
causing platelet clearance by reticulo-endothelial (RE)
system. This endorses the response of this subset of patients
to steroid treatment therapy. Another possible mechanism
is increased P-selectin expression with abciximab that
causes paradoxical activation and aggregation of platelets.6
Patients receiving parenteral Gp IIb/IIIa inhibitors
should be monitored for development of thrombocytopenia
within the first 24 hours of drug administration, and for
patients receiving abciximab therapy, a platelet count at 2
to 4 hours after the start of therapy is recommended. If
detected, true thrombocytopenia should be confirmed and
IHJ-671-04.p65
251
Gupta et al.
Eptifibatide-Induced Thrombocytopenia 251
all potential causes should be evaluated.7 If Gp IIb/IIIa
inhibitor is the likely culprit for thrombocytopenia, the
infusion should be stopped. Asprin should be withheld only
in patients with high risk for bleeding and whose platelets
are <20,000 per cmm. 8 The threshold for platelet
transfusion is not clear, but it is suggested that transfusion
should be considered for: (i) patients with platelet count
below 20,000 per cmm, (ii) patients scheduled for surgery,
(iii) patients with bleeding complications, and (iv) patients
with other active medical problems such as fever.7,9 Use of
intravenous immunoglobulin does not show immediate
benefit, nor does it offer additional benefit over patients
receiving platelet transfusion alone.10 Further supportive
treatment of patients with profound thrombocytopenia
includes bed rest, use of stool softeners, avoidance of
intramuscular injections and monitoring of platelet counts
every 12 hours until the condition improves.
References
1. Berkowitz SD, Harrington RA, Rund MM, Tcheng JE. Acute profound
thrombocytopenia after C7E3 Fab (abciximab) therapy. Circulation
1997; 95: 809–813
2. Brieger DB, Mak KH, Kottke- Marchant K, Topol EJ. Heparin-induced
thrombocytopenia. J Am Coll Cardiol 1998; 31: 1449–1459
3. Warkentin TE, Levine MN, Hirsh J, Horsewood P, Roberts RS, Gent
M, et al. Heparin-induced thrombocytopenia in patients treated with
low-molecular-weight heparin or unfractionated heparin. N Engl J
Med 1995; 332: 1330–1335
4. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein
IIb/IIIa with eptifibatide in patients with acute coronary syndrome.
N Engl J Med 1998; 339: 436–443
5. O’Shea JC, Hafley GE, Greenberg S, Hasselblad V, Lorenz TZ, Kitt M,
et al. Platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide
in coronary stent intervention; the ESPRIT trial: a randomized
controlled trial. JAMA 2001; 285: 2468–2473
6. Jennings LK, White MM. Expression of ligand-induced binding sites
on glycoprotein IIb-IIIa complexes and the effect of various inhibitors.
Am Heart J 1998; 135: S179–S183
7. Madan M, Berkowitz SD. Understanding thrombocytopenia and
antigenicity with glycoprotein IIb-IIIa inhibitors. Am Heart J 1999;
138: S317–S326
8. Paradiso-Hardy FL, Madan M, Radhakrishnan S, Hurden S, Cohen
EA. Severe thrombocytopenia possibly related to readministration
of eptifibatide. Catheter Cardiovasc Interv 2001; 54: 63–67
9. Beutler E. Platelet transfusions: the 20,000/microL trigger. Blood
1993; 81: 1411–1413
10. Kereiakes DJ, Essell JH, Abbottsmith CW, Broderick TM, Runyon JP.
Abciximab-associated profound thrombocytopenia : therapy with
immunoglobulin and platelet transfusion. Am J Cardiol 1996; 78:
1161–1163
9/29/2004, 5:09 PM
252 Juneja
et al.
Point
of View
Rheumatic Carditis
Indian Heart J 2004; 56: 252–255
Rheumatic Carditis: A Reappraisal
R Juneja, R Tandon
Department of Cardiology, All India Institute of Medical Sciences and
Sitaram Bhartia Institute of Science and Research, New Delhi
R
heumatic carditis is the only clinical manifestation of
rheumatic fever (RF) which results in a residual,
permanent damage. The virulence of RF is directly related
to the presence of carditis. Long after RF has subsided it is
possible to examine a patient and make a positive diagnosis
of past RF, based on the classical mitral and/or aortic valve
disease. The other manifestations of RF – arthritis, chorea,
subcutaneous nodules and erythema marginatum – do not
leave residual clinical signs, nor do they cause any longterm morbidity value. The significance of these
manifestations lies only in their ability to help in the
diagnosis of acute RF.
Magnitude of Carditis
Rheumatic fever is a clinical diagnosis and may or may not
be associated with carditis.1 Rheumatic carditis has been
reported to occur in 14% to 99% patients of acute RF
(Fig. 1).2-10 Such a wide difference in its prevalence is due
to a number of factors.
The carditis in the initial attacks of RF is generally mild
and remains unrecognized. RF has a tendency for
recurrences in the absence of secondary prophylaxis.
2 to 8 Clinical
9 & 10 Clinical plus echo diagnosis
Fig. 1. Frequency of carditis (%).
Correspondence: Dr R Tandon, Sitaram Bhartia Institute of Science and
Research, B-16, Mehrauli Institutional Area, New Delhi 110 016
IHJ-733-04.p65
252
Recurrences tend to have mimetic features, that is, the
manifestations seen in the initial attack tend to occur again
in subsequent attacks.11 Patients who have carditis in the
first attack will have it again in the subsequent attacks
causing further damage to the heart. After the second or
third attack, the patient becomes symptomatic from cardiac
damage and seeks medical help. The system of periodic
medical check-up during infancy and childhood does not
exist in many countries. Since the previous cardiac findings
are not known it is extremely difficult to be sure whether it
is the first attack or a recurrence in an individual patient,
specially because patients seek help only after they become
symptomatic from cardiac involvement. In the absence of
history indicative of past RF, the symptomatic patient is
labeled as having the first attack of RF and severe carditis.
This would obviously raise the prevalence rate of carditis
in analysis of reported data from large series.
With the availability of echocardiogram as an investigative tool, a new subset of carditis is being recognized,
namely subclinical carditis.12 The only physical finding
which can be considered as being diagnostic for rheumatic
carditis is the presence of mitral and/or aortic valve
regurgitation in an acute attack of RF. If a murmur of
mitral and/or aortic valve regurgitation is not made out
clinically, the patient is labeled as not having carditis.
Utilizing echocardiographic evaluation, a very sensitive
investigation, presence of mitral valve disease not audible
clinically, that is, subclinical carditis has been recognised.12
It is well known that a minimal physiological mitral
regurgitation can be identified in normal people by echoDoppler. 13 Hence, before labeling abnormal mitral
regurgitation by echo-Doppler, it must be beyond the
normal limits. As such, use of echocardiogram is likely to
overdiagnose presence of carditis. Combining clinical and
echocardiographic data in the diagnosis of rheumatic
endocarditis in the recent resurgence of RF in the United
States, carditis was diagnosed in 90% or more patients with
acute RF. Out of 74 children with acute RF, clinical carditis
was present in 53 (71.6%) and by echocardiogram in an
additional 14 (18.9%) cases giving a total of 90.5% with
carditis.14 Thus 18.9% patients had subclinical carditis. In
another study, carditis was clinically diagnosed in 20 (50%)
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Indian Heart J 2004; 56: 252–255
patients and by echocardiographic evaluation in another
18 (45%) of 40 children with acute RF.10 Thus carditis was
present in 95% patients of whom in 45% it was subclinical.
This has not been substantiated in a study from India
wherein echo-Doppler did not add to the diagnostic yield
over clinical examination.15 Since recurrences have mimetic
features, most of those clinically undiagnosed as carditis
will become definite carditis after a second or third attack
of RF due to further damage to the valve tissue in the
absence of echocardiographic evaluation in the first attack.
The wide difference in the reported prevalence of carditis
in the first attack could thus be related to clinically
undiagnosed carditis in the first attack which becomes
apparent after recurrences of acute RF. With the availability
of echo-Doppler providing significant additional diagnosis
of subclinical carditis, most of the past data regarding the
frequency of carditis in acute RF is now difficult to accept.
However, this statement does not imply that echo-Doppler
be made an integral part of the Jones’ criteria for the
diagnosis of carditis. Declining auscultatory skills in the
West has been cited as one of the reasons for the clinical
and echocardiographic discrepancy.16 Studies are needed
for comparing the sensitivity and specificity of auscultatory
findings with echo-Doppler findings.17 It remains to be
determined as to how many of the subclinical carditis cases
actually go on to develop frank carditis. Such data may be
difficult to obtain since not giving secondary prophylaxis
would be unethical.16
Rheumatic Pancarditis
Rheumatic pancarditis means that the patients have
pericarditis, myocarditis and endocarditis. Rheumatic
carditis is a pancarditis and an early manifestation. As a
rule, by the time a patient seeks help carditis is already
present. Almost 80% of patients who develop carditis will
have features of carditis within the first two weeks of the
onset of RF.18 Less than 20% patients develop features
indicative of carditis after the first two weeks. This data is
from pre-echocardiogram era. Since patients could have
subclinical carditis that may become apparent later on, it
is possible that a higher number of patients actually have
onset of carditis within the first two weeks of the onset of
RF as suggested by the echo-Doppler findings.10,12,14,17
Pericarditis
Rheumatic pericarditis is relatively less common clinically
and is present in up to 15% patients.4,18 Precordial pain and
an evanescent friction rub may be present. The
IHJ-733-04.p65
253
Juneja et al. Rheumatic Carditis 253
electrocardiogram may show changes of pericarditis but
lacks sensitivity and specificity. There are usually no
features of significant effusion or tamponade. Patients with
pericarditis always have findings of an underlying mitral
valve and/or aortic valve regurgitation which could be
difficult to make out at times, because of the pericardial
friction rub. However, once the friction rub subsides, the
murmurs become obvious. If there is no murmur of
valvulitis after the friction rub has subsided, the diagnosis
of rheumatic carditis and RF can be excluded. Since
pericarditis neither results in tamponade nor constriction
and clears up without leaving a residue, its limited clinical
significance lies in the fact that it provides clear cut evidence
for the presence of active carditis as well as active RF.
Pericarditis does not occur in the absence of clinical findings
indicative of valvulitis.
Myocarditis
The diagnosis of rheumatic myocarditis has traditionally
been made on the basis of soft first sound, third sound gallop
(S3 or protodiastolic gallop), cardiomegaly, Carey Coomb’s
murmur and congestive cardiac failure. As of today it is
clear that none of these clinical findings are due to
myocarditis per se. Soft first sound, S3 gallop, cardiomegaly
and congestive cardiac failure are due to an acute
hemodynamic overload on the left ventricle from acute/
subacute mitral and/or aortic regurgitation.
The delayed diastolic mitral murmur known as Carey
Coomb’s murmur is due to a large diastolic flow under
pressure due to acute mitral regurgitation across inflamed
mitral leaflets. Carey Coomb’s murmur is not heard in the
absence of mitral regurgitation. There is nothing novel
about the Carey Coomb’s murmur in terms of the etiology
of mitral regurgitation since any cause of significant mitral
regurgitation would result in a delayed diastolic flow
murmur across the mitral valve. Hence all of the clinical
findings supposed to be indicating myocarditis are actually
due to acute mitral regurgitation. The investigations for
documenting the presence of myocarditis indicate that in
RF myocyte damage is insignificant and plays no part in
the morbidity and mortality of rheumatic carditis. Markers
of myocardial damage in the form of troponin I, myoglobin
and CPK-MB were evaluated in patients with acute
rheumatic carditis with and without cardiomegaly or
congestive cardiac failure.19 The markers of myocardial
damage remained normal inspite of clinically active
carditis. In another study troponin I was evaluated in
patients with acute RF with and without carditis and in
patients with scarlet fever without RF.20 While the antiheart
9/29/2004, 5:14 PM
254 Juneja et al. Rheumatic Carditis
antibodies and antistreptolysin ‘O’ were elevated, the
troponin I was insignificantly elevated in 18% patients with
acute RF. The authors concluded: “the presence of low
troponin I levels throughout the course of RF, especially in
the face of active carditis, argues against significant
cardiomyocyte injury”.
Echocardiographic assessment of myocardial function
based on ejection fraction indices in patients with acute RF
with and without carditis, with and without mitral
regurgitation and in the presence of congestive cardiac
failure has been found to be normal.15 Normal myocardial
contractility in the presence of left heart failure is against
muscle damage per se playing a significant role in
precipitating congestive cardiac failure.
Myocardial biopsies performed during acute rheumatic
carditis failed to improve upon the clinical diagnosis
for the presence or absence of active carditis. It was
concluded that myocardial biopsies do not add to the
clinical diagnosis of active carditis due to paucity of
myocardial damage.21
The lesions of active myocarditis are primarily
perivascular and interstitial without evidence of cellular
myocardial necrosis on histological evaluation which is
against the concept of rheumatic myocarditis causing
ventricular dilation.22
Pathological studies indicate that the inflammatory cells
are localized to subendocardial, subepicardial and
perivascular connective tissue with little myocyte damage.23
Aschoff nodules, the pathognomonic marker of rheumatic
myocarditis, are localized strictly to perivascular area
leaving the rest of the myocardium both in terms of the
myofibers as well as the connective tissue normal. Aschoff
nodules, which were felt to reflect myocardial damage have
not been found by immunohistochemical studies to indicate
presence of myocardial damage. Immunohistological
studies indicate that Aschoff nodules have no cells of
myocardial origin, are negative in staining for actin with
HHF-35 monoclonal antibodies and the giant cells (owl eye/
Anitschkow) are negative for myosin, myoglobin and
desmin but positive for vimentin, which is of mesenchymal
origin. 24 In patients with acute RF, active carditis and
congestive cardiac failure, not responding to medical
management, mitral valve replacement has been shown
to be life-saving. It results in prompt relief from congestive
failure and decrease in heart size inspite of clinical evidence
for ongoing carditis.25
Thus evaluation of markers of myocardial damage –
(troponin I and CPK-MB), echocardiogram, histopathology,
immunohistology and surgical management indicate that
IHJ-733-04.p65
254
Indian Heart J 2004; 56: 252–255
in the so-called rheumatic myocarditis, there is insignificant
myocardial damage and it plays little role, if any, in the
morbidity and mortality associated with RF.
Endocarditis
Rheumatic endocarditis is the diagnostic hallmark of
rheumatic carditis in acute RF. It is represented by
involvement of mitral and/or aortic valve causing mitral
and/or aortic regurgitation. Mitral valve involvement
occurs in 92% to 95% cases of whom about 20% to 25%
also have aortic valvular disease. Isolated aortic valve
disease is seen clinically in approximately 5% to 8%
patients.18 However, pathological evaluation indicates
presence of mitral valve disease even in the clinically
diagnosed isolated aortic valve disease.26
Mitral and/or aortic valve disease results in an acute
onset of mitral or aortic valve regurgitation. It is the severity
of the mitral or aortic regurgitation which results in left
heart failure, soft first sound, third sound gallop and
cardiomegaly. Follow-up data on secondary prophylaxis
indicates that in our country, disappearance of established
mitral regurgitation occurs in about 15% patients although
figures from the West have documented disappearance of
cardiac findings in more than 50% patients.5,27 However, it
needs to be emphasized that disapperance of the murmur
does not mean that the patient has a normal heart. If a
recurrence occurs, the valvular damage would suddenly
appear as a severely damaged valve. Both mitral and aortic
valve disease cause progressively worsening regurgitation.
Over a period of time they would result in left ventricular
dysfunction compromising the functional capacity of the
patient.
Thus, of the three components of rheumatic pancarditis
– pericarditis, myocarditis and endocarditis – two, that is
pericarditis and myocarditis have no long-term morbidity.
The damage is limited to valvular tissue, subepicardial,
subendocardial and perivascular connective tissue adjacent
to vascular endothelial tissue. The valvular tissue is made
of connective tissue covered by endothelium. It has no
muscle tissue and no blood vessels. It appears that the
primary damage in RF is to the endothelium, the underlying
connective tissue damage is unfortunate.
Rheumatic endocarditis leading to mitral and/or aortic
regurgitation thus determines the morbidity and mortality
of rheumatic carditis. Research in the pathogenesis of RF,
needs to be directed toward valvulitis rather than
myocarditis, which plays no role in the adverse outcome
following rheumatic carditis.
9/29/2004, 5:14 PM
Indian Heart J 2004; 56: 252–255
Acknowledgements
The authors wish to thank Mrs. Lata Joshi for the help in
preparing the manuscript.
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Rheumatic Fever. Washington : Am Registry of Path; 1999, p 217
24. Gulizia JM, McManus BM. Immunopathological studies of rheumatic
Fever. In : Narula J, Virmani R, Reddy KS, Tandon R (eds). Rheumatic
Fever. Washington: Am Registry of Path; 1999, p 235
25. Essop MR, Wisenbaugh T, Sareli P. Evidence against a myocardial
factor as the cause of left ventricular failure in active rheumatic
carditis. J Am Coll Cardiol 1993; 22: 826–829
26. Roberts WC, Virmani R. Aschoff bodies at necropsy in valvular heart
disease. Evidence from an analysis of 543 patients over 14 years of
age that rheumatic heart disease, at least anatomically, is a disease
of the mitral valve. Circulation 1978; 57: 803–807
27. Feinstein AR, Sterno EK, Spagnuolo M. The prognosis of acute
rheumatic fever. Am Heart J 1964; 68: 817–834
9/29/2004, 5:14 PM
256 Yusuf et al. Isolated
Muscular LV Diverticulum
Cardiovascular
Images
Indian Heart J 2004; 56: 256–257
Isolated Congenital Muscular Left Ventricular
Diverticulum in an Adult
Jamal Yusuf, Saibal Mukhopadhyay, Vimal Mehta, Mohit D Gupta, Vijay Trehan
Department of Cardiology, GB Pant Hospital, New Delhi
Fig. 1. Transesophageal echocardiogram showing the left ventricular
diverticulum connected with the main left ventricular chamber through a
narrow neck.
Fig. 2a. Left ventriculogram in right anterior oblique projection showing the
diverticulum in diastole.
A
45-year-old hypertensive male patient referred for
routine echocardiographic evaluation was found to
have a digitiform accessory chamber communicating with
the apex of the left ventricle (LV) through a narrow neck.
The accessory chamber was contracting synchronously
alongwith the LV in systole and its wall had similar acoustic
properties as the ventricular wall. Color Doppler illustrated
blood entering the diverticulum from the LV during diastole
and flowing out during systole. There were no other
congenital defects. Transesophageal echocardiogram (TEE)
could better delineate the diverticulum (Fig. 1). Left
ventriculography confirmed our echocardiographic
findings showing a multilobulated contractile diverticulum
originating from the apex (Figs 2a and 2b). Selective
coronary angiography was normal. Twenty-four hour
Holter monitoring did not reveal any episode of ventricular
tachycardia.
Correspondence: Dr Jamal Yusuf, Room No. 126, Academic Block,
Department of Cardiology, GB Pant Hospital, New Delhi 110002
e-mail: [email protected]
IHJ-614-03 Cardio-Image.p65
256
Fig. 2b. Left ventriculogram in right anterior oblique projection showing the
diverticulum contracting well in systole.
9/29/2004, 5:00 PM
Indian Heart J 2004; 56: 256–257
Three types of congenital LV diverticula have been
reported in literarture. The first type, described by Cantrell
et al,1 in 1958 is a part of a syndrome of cardiac anomalies
(ventricular and atrial septal defects, pulmonary stenosis/
atresia and LV diverticulum) and midline thoracoabdominal defects. In the second type, the LV diverticula
are usually subvalvular and basal, being intimately related
to the mitral and aortic valves producing regurgitation. The
third type, first described by Hoeffel et al.2 comprised of only
isolated diverticulum, usually arising from the LV apex and
till now only 20 such cases have been reported in world
literature. Our patient falls in the third type described by
Hoeffel et al.2 While diverticula described by Cantrell et al.1
and Hoeffel et al.2 contain all the three cardiac layers and
are classified as muscular, those arising near the
atrioventricular valves have predominantly fibrous tissue
and are classified as fibrous type. Failure of normal midline
fusion of paired primitive mesoderm in combination with
abnormal fusion of the cardiac loop to the yolk sac before
its descent is believed to result in development of muscular
ventricular diverticulum.3
The natural history and management of patients with
isolated congenital LV diverticula is not well defined. There
is no agreement in the literature regarding the best
therapeutic approach. Some4-6 advocate resection in all
cases, even in asymptomatic patients, to prevent risk of
complications like heart failure, infective endocarditis and
ventricular tachyarrhythmias (sometimes causing sudden
IHJ-614-03 Cardio-Image.p65
257
Yusuf et al. Isolated Muscular LV Diverticulum 257
death). However, others7-9 recommend a conservative
approach in asymptomatic patients with close follow-up.
We preferred the conservative approach advising the
patient to come for periodic follow-up and take antibiotic
prophylaxis against endocarditis in high-risk situations.
References
1. Cantrell JR, Haller JA, Ravitch MM. A syndrome of congenital defects
involving the abdominal wall, sternum, diaphragm, pericardium and
heart. Surg Gynecol Obstet 1958; 107: 602–614
2. Hoeffel JC, Henry M, Pernot C. Heart diverticula in children:
radiological aspects. Ann Radiol 1974; 17: 411–415
3. Hudson REB. Congenital abnormalities of the heart as a whole. In:
Hudson REB (ed). Cardiovascular Pathology, Vol 2. London: Edward
Arnold Publishers Ltd. 1965; pp 1742–1746
4. Mady C. Left ventricular diverticulum: analysis of two operated cases
and review of the literature. Angiology 1982; 33: 280–286
5. Okereke OU, Cooley DA, Frazier OH. Congenital diverticulum of the
ventricle. J Thorc Cardiovasc Surg 1986; 91: 208–214
6. Uchida T, Uemura H, Yagihara T, Kawahira Y, Yoshikawa Y, Kitamura
S. Congenital diverticulum of the left ventricle. Jpn J Thorac Cardiovasc
Surg 2001; 49: 244–246
7. Ichikawa K, Makino K, Futagami Y, Fujioka H, Ito M, Hamada M,
et al. Isolated congenital left ventricular diverticulum in an adult: a
case report. Angiology 1994; 45: 743–747
8. Archbold RA, Robinson NM, Mills PG. Long-term follow up of a true
contractile left ventricular diverticulum. Am J Cardiol 1999; 83:
810–813
9. Huang G, Pavan D, Antonini-Canterin F, Piazza R, Burelli C, Nicolosi
GL. Asymptomatic isolated congenital left ventricular muscular
diverticulum in an adult: a case report. Echocardiography 2003; 20:
191–195
9/29/2004, 5:00 PM
258 Letters
to the
Editor
Letters
to the
Editor
Migration Accelerates Development
of Metabolic Syndrome – An
Interesting Pedigree
I
Indian Heart J 2004; 56: 258–263
>0.9 indicating central obesity. All second generation male
subjects developed type-2 diabetes mellitus and two of them
subsequently died because of CVS or allied disorders. These
findings heralded the beginning of metabolic syndrome in
second generation male members. The index case, who
belongs to third generation also had developed central
obesity (WHR 1.01) and hypertension at an early age which
was followed by type-2 diabetes mellitus indicated by raised
fasting and postprandial blood sugar (160 mg/dl and 300
mg/dl respectively). He subsequently developed CAD which
was detected to be triple vessel disease on angiography and
had elevated triglycerides (164 mg/dl), low high-density
lipoprotein (HDL) cholesterol (34 mg/dl), raised low-density
lipoprotein (LDL) cholesterol (144 mg/dl) and a high
comprehensive lipid tetrad index (20837.64). His sister too
had central obesity, type -2 diabetes mellitus and died of
sudden cardiac death at 58 years of age. These findings
suggest metabolic syndrome in third generation subjects.
ndian migrants living in the UK, USA, Canada, Fiji,
Mauritius, South Africa, Malaysia etc. have been reported
to have a higher prevalence of diabetes, coronary artery
disease (CAD), particularly premature CAD and
dyslipidemia compared to the native populations.1-3 The
common link seems to be genetic background, psychosocial
stress and alterations in lifestyle consequent to migration.4
The ensuing biochemical and molecular changes due to
the above factors accelerate the process of atherosclerosis
at a comparatively young age. A similar phenomenon also
seems to be operative when young people move from rural
locations to urban towns in native country itself.5 Though
this hypothesis appears logical, it may be too simplistic and
deserves in-depth anthropological,
psychosocial and molecular studies.
We recently came across a family
whose first generation elders had
migrated from a rural area to a
metropolis about 75 years ago. Many
of the second, third and fourth
generation migrant siblings exhibited
central obesity and other clinical
manifestations of metabolic syndrome
and cardiovascular (CVS) and allied
disorders.6 This prompted us to report
the pedigree of migrant family. The
diagnosis of metabolic syndrome was
based on the presence of central
obesity, raised blood pressure (130/85
mmHg) and high fasting blood sugar
(110-125 mg/dl).
The index case in the pedigree is a
61-year male who belongs to the third
generation of the migrant family (Fig.
1). Following migration from eastern
part of Uttar Pradesh to a metropolis
of Eastern India by first generation
subjects there was a quantum jump in
the economic prosperity in second
generation as evident by additional
Fig. 1. Rural to urban migration and metabolic syndrome. : index case SCD : sudden cardiac death
land purchase at home. Male members
in second generation used to chew
SES: socio-economic status; T2DM: type-2 diabetes mellitus; HTN: hypertension; CVA: cerebrovascular accident;
CAD: coronary artery disease; BPH: benign prostatic hypertrophy; DVD: double vessel disease; TVD: triple vessel
tobacco, were doing less laborious job
disease; CAG: coronary angiography; CABG: coronary artery bypass grafting; CLTI: comprehensive lipid tetrad inand had waist-hip ratio (WHR) of
dex; BMI: body mass index; WHR: waist-hip ratio
Letter-to-Editors.p65
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Indian Heart J 2004; 56: 258–263
The most striking feature was observed in fourth generation
where both male members were found to have central
obesity (WHR 0.96), frontal and crown balding at an early
age of 30 and 25 years respectively. Both of them have prediabetes. Their elder female siblings had increased WHR
(1.03 and 0.95 ) indicating upper segment obesity. These
observations point toward the presence of metabolic
syndrome in fourth generation siblings also.
Going back to the history of migration by first generation
people, it was revealed by the index case that poor socioeconomic conditions and social upheaval at home town
about 75 years ago forced the male members from rural
area to move to metropolis for better job opportunities. The
first generation subjects in the metropolis opted for cheap
accommodation; kept consuming Khaini (mixture of
tobacco and chuna i.e. lime, taken sublingually) but left
hard labour and did not exercise at all. Their food habits
changed from coarse fiber-rich diet, “clarified ghee” to refined polyunsaturated vanaspati oil and carbohydrates.
Besides tobacco, lack of exercise, sedentary habits and
faulty diet accelerated accumulation of fat around the waist
leading to central obesity and diabetes mellitus. These
lifestyle changes and the genetic proclivity for syndrome-X
made them prone to hypertension and CAD compared to
their counterparts in rural environment.
The above pedigree is an evidence supporting the
hypothesis that migration from rural area to metropolis
accelerates the development of metabolic syndrome in next
generation. Remedial lifestyle steps comprising of cessation
of smoking and/or tobacco products, adoption of some
form of active exercise and use of fiber-rich, low-fat diet
may help in mitigating the onset of metabolic syndrome
and thus prevent the premature CAD.
References
1. Enas EA, Dhawan J, Petkar S. Coronary artery disease in Asian
Indians: lessons learnt and the role of lipoprotein(a). Indian Heart J
1997; 49: 25–34
2. McKeigue PM, Miller GJ, Marmot MG. Coronary heart disease in
South Asians overseas: a review. J Clin Epidemiol 1989; 42: 597–
609
3. Toumilehto J, Ram P, Eseroma R, Taylor R, Zimmet P. Cardiovascular
diseases and diabetes mellitus in Fiji: analysis of mortality, morbidity
and risk factors. Bull World Health Organ 1984; 62: 133–143
4. Dwivedi S, Singh S, Agarwal MP, Rajpal S, Aneja A. Migration stress.
J Assoc Physicians India 2004; 52: 340–342
5. Torun B, Stein AD, Schroeder D, Grajeda R, Conlisk A, Rodriguez M,
et al. Rural - to - urban migration and cardiovascular disease risk
factors in young Guatemalan adults. Int J Epidemiol 2002; 31: 218–
226
6. Assmann G, Carmena R, Cullen P, Fruchart JC, Jossa F, Lewis B, et al.
International Task Force for the prevention of Coronary Heart
Letter-to-Editors.p65
259
Letters to the Editor 259
Disease. Coronary heart disease: reducing the risk: a worldwide view.
Circulation 1999; 100: 1930–1938
S Dwivedi, MP Agarwal, CP Suthar, G Dwivedi
Departments of Medicine and Preventive Cardiology
University College of Medical Science &
GTB Hospital, Delhi
Non-Pharmacological Therapy of
Hypertension: Practical Limitations
L
ifestyle modifications can reduce blood pressure to some
extent but significantly reduce other cardiovascular
risk factors. These should be strongly advised to all
hypertensives. We should, however, realize some practical
limitations.
For primary prevention of hypertension, weight loss,
restricted sodium intake, reduced alcohol consumption and
regular exercise have documented efficacy. Stress
management, fish oils, calcium, magnesium, micronutrients and fiber have limited or unproven efficacy.1
Weight reduction: (i) Obesity is one of the most refractory
disorder of medicines2, (ii) Odds of recovering from most
forms of cancer are substantially better than those for
controlling excess fat3, (iii) Maintenance of significant
weight loss is difficult for most of the obese people.4
Restricted sodium intake: (i) It is not practical for
persons living away from home i.e. in hostels or persons
involved in touring job, (ii) Even for those who live with the
family, it is not practical for a long time to have two
vegetables with different amount of salt. Usually the patient
compro-mises to eat what is prepared for rest of the family,
(iiii) Old, non-earning and dependents have to compromise
with what is served to them, (iv) Severe salt restriction
makes the diet unpalatable.
Reduction in alcohol consumption: (i) Prevention and
Treatment of Hypertension (PATH) study has shown that
reduction in alcohol consumption from 6 drinks to 2 drinks
per day did not have any favorable effect on blood pressure
and incidence of cardiovascular events over a 2-year
period.5
Physical exercise: (i) Regular exercise for 30-60 min/day
is difficult for persons working >12 hours a day to earn
their living. It is also not practical for middle-aged and
elderly hypertensives with osteoarthritis.
9/29/2004, 5:16 PM
260 Letters to the Editor
Stress management: It is easier said than done. It is very
difficult, if not impossible, to change personality and
reactivity. Relaxation techniques are neither practical for
the majority of hypertensives nor they are effective in
maintaining a significant long-term effect.6,7
Diet: Dietary Approaches to Stop Hypertension (DASH)
advocates diet rich in fruits, vegetables and low fat dairy
products. The study involved only 8-11 weeks of
intervention feeding. It is therefore not clear if the observed
blood pressure reduction will be sustained over longer time.
This is important because adherence to a particular diet is
likely to decline with time.8 The study was conducted in
individuals with high normal or stage 1 hypertension.
Effects in patients with higher levels of blood pressure are
not clear. A diet rich in potassium, magnesium and protein
cannot be advised to patients with impaired renal functions.
Large sections of poor population cannot afford DASH diet
which stipulates 4-5 servings of fruits, 4-5 servings of
vegetables and 2-3 servings of low-fat dairy foods per day.
Knowledge about “equals” or “alternates” needs the help
of a trained nutritionist.
Other limitations: (i) Lifestyle modifications are more
effective in reducing systolic blood pressure.9 Effect on
diastolic blood pressure is not very impressive. Except for
significant weight reduction and strict salt restriction, other
modifications can reduce systolic blood pressure only up
to 5 mmHg.10 The patient, therefore, feels discouraged if
he does not understand that the main target of these
lifestyle modifications is to reduce total cardiovascular risk
and not a significant reduction in blood pressure.
(ii) Successful implementation needs discussion by the
clinician which is not easy since clinician is always short
of time. Convincing other family members and ensuring
their involvement in patient care. Even then, many patients
do not act upon the advice11, (iii) Modifications are still more
difficult to maintain.1,12 Initially there is weight loss but
then it creeps upwards. Physical activity increases with
training but slacks off with time. Sodium intake is effectively
reduced at first but gradually returns toward baseline.
Successful maintenance needs a network of paramedical
staff for constant follow-up and encouragement. 13
(iv) Lifestyle modifications alone may not be effective in
attaining blood pressure goal in large number of patients;
it helps few patients with mild or labile hypertension.
(v) Even if blood pressure goal is achieved, most of the
benefit is tapered off by the end of 3 years10 and most of
the patients will need drug therapy to maintain blood
Letter-to-Editors.p65
260
Indian Heart J 2004; 56: 258–263
pressure level. (vi) There is no convincing data that lifestyle
modifications alone can reduce morbidity and mortality.
Drugs have been shown to provide this benefit.
The fact that the efficacy and value of blood pressure
reduction in preventing cardiovascular complications with
pharmacologic agents could be demonstrated even in
patients at low risk12,14 calls into question the current
emphasis on delaying drug therapy even in low risk
individuals.1,15
To conclude, all hypertensives should be encouraged to
adopt lifestyle modifications with clear understanding that
the main aim of these modifications is to reduce total
cardiovascular risk and that their impact on blood pressure
may not be great. These should be primarily adjunctive to
drug therapy in hypertensives since so many well tolerated,
cheap, effective and single daily dose agents are available
and it has been shown that lowering blood pressure with
drugs reduces morbidity and mortality. Cost of nutrition
and exercise regimens are greater than drug therapy.16
Lifestyle measures should never unnecessarily delay the
initiation of drug treatment or detract patients or clinicians
from compliance with drug treatment.17
References
1. Black HR, Bakris GL, Elliott WJ. Hypertension: epidemiology,
pathophysiology, diagnosis and treatment. In: Fuster V, Alexander
RW, O’Rourke RA (eds). The Heart, New York: Mc Graw Hill, 2001,
pp 1553–1604
2. Hazra B, Sengupta N, Ganguly D, Chakraborty P, Som N, Sengupta
M. Obesity: current perspective. J Assoc Physicians India 2000; 48:
541
3. Wadden TA. Psychological factors affecting medical condition
(psychosomatic disorders). In: Kaplan HI, Sadock BJ (eds).
Comprehensive Text Book of Psychiatry. 6th ed. Baltimore : Williams
and Wilkins, 1995, pp 1463–1605
4. Crawford D, Jeffery RW, French SA. Can anyone successfully control
their weight? Findings of a there-year community-based study of
men and women. Int J Obes Relat Metab Discord 2000; 24: 1107–
1110
5. Cushman WC, Cutler JA, Hanna E, Bingham SF, Follmann D, Harford
T, et al. For the PATHS Group. The Prevention and Treatment of
Hypertension Study (PATHS). Effects of an alcohol treatment
program on blood pressure. Arch Intern Med 1998; 158: 1197–1207
6. Eisenberg DM, Delbanco TL, Berkey CS, Kaptchuk TJ, Kupelnick B,
Kuhl J, et al. Cognitive behavioral techniques for hypertension: are
they effective? Ann Intern Med 1993; 118: 964–972
7. Hunyor SN, Henderson RJ, Lal SK, Carter NL, Kobler H, Jones M, et
al. Placebo-controlled biofeedback blood pressure effect in
hypertensive humans. Hypertension 1997; 29: 1225–1231
8. Conlin PR. Nonpharmacologic treatment. In: Brady HR, Wilcox CS
(eds). Therapy in Nephrology and Hypertension, 2nd ed. Philadelphia:
Saunders 2003, pp 531–536
9. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo
JL Jr, et al. The seventh report of the Joint National Committee on
Prevention, Detection, Evaluation and Treatment of High Blood
Pressure. JAMA 2003; 289: 2560–2572
9/29/2004, 5:16 PM
Indian Heart J 2004; 56: 258–263
10. The trials of Hypertension Prevention Collaborative Research Group.
Effects of weight loss and sodium reduction intervention on blood
pressure and hypertension incidence in overweight people with highnormal blood pressure. The Trials of Hypertension Prevention, Phase
II. Arch Intern Med 1997; 157: 657–667
11. Kaplan NM. Treatment of hypertension: life style modification. In:
Kaplan NM (ed). Kaplan’s Clinical Hypertension. Philadelphia:
Lippincott Williams & Wilkins 2002, pp 206–236
12. Neaton JD, Grimm RH Jr, Prineas RJ, Stamler J, Grandits GA, Elmer
PJ, et al. Treatment of mild hypertension study reasearch group. The
treatment of mild hypertension. JAMA 1993; 270: 713–724
13. Miller ER Jr, Erlinger TP, Young DR, Prokopowicz GP, Appel LJ. Lifestyle changes that reduce blood pressure: implementation in clinical
practice. J Clin Hypertens 1999; 1: 191–198
14. Cutler JA, Combinations of lifestyle modification and drug treatment
in management of mild-moderate hypertension: a review of
randomized clinical trials. Clin Exp Hypertens 1993; 15: 1193–1204
15. Yeo KR, Yeo WW. Should we treat high-normal blood pressure. J
Hypertens 2002; 20: 2057–2062
16. Johannesson M, Fagerberg B. A health-economic comparison of diet
and drug treatment in obese men with mild hypertension. J Hypertens
1992; 10: 1063–1070
17. Guidelines committee. 2003 European Society of HypertensionEuropean Society of Cardiology guidelines for the management of
arterial hypertension. J Hypertens 2003; 21: 2203–2204
SR Mittal, Monika Maheshwari
Department of Cardiology
JLN Medical College, Ajmer
Kawasaki Disease
S
ince its first description in Japan about 35 years ago,1
Kawasaki disease (KD) has been reported worldwide. It
is now believed to be the commonest vasculitic disorder seen
in children.2 It has replaced rheumatic heart disease as the
most common cause of acquired heart disease in the West.3
Although an infectious etiology is suspected based on the
epidemiology and clinical features, a definitive causative
agent has still not been identified.4 KD is an acute medium
vessel panarteritis without any evidence of chronicity.
During recovery, inflammation subsides but leaves behind
fibrous connective tissue in the vessel wall along with
proliferation of intima. This process is most pronounced in
coronary arteries.
Approximately 20 to 25% of untreated KD patients
develop coronary abnormalities, including diffuse dilation
(ectasia) and aneurysm formation.5 This process commonly
occurs from 10 days to 4 weeks after the onset of
symptoms.5 These aneurysms regress in the majority of
cases within a few months,6 but a few patients develop
coronary stenosis, which can develop as long as 10 to 21
years after the acute episode of KD.7 Larger aneurysms
Letter-to-Editors.p65
261
Letters to the Editor 261
(> 8 mm) are less likely to regress and can develop
thrombosis and rupture.
The coronary stenosis may be complicated by premature
atherosclerosis and lead to significant coronary obstruction
and myocardial ischemia later in life. Myocardial infarction
(MI) that occurs under these circumstances may be
indistinguishable from that seen in association with
primary atherosclerosis. MI has been reported in 1.9% of
all the KD patients and in as many as 39% of those having
persistent aneurysms.7 Majority of MIs develop within one
year of the onset of KD and the mortality rate in such cases
can be up to 20%.
Diagnosis of KD is based on a typical temporal sequence
of clinical features, none of them individually having any
diagnostic significance. Moreover, these clinical features
evolve over a period of days and the entire clinical spectrum
is not seen at any one particular point of time. This difficulty
is further compounded by absence of any diagnostic test
for this disease. However, it is important to make a diagnosis
in the acute phase because treatment during this phase
with intravenous immunoglobulin (and acetylsalicylic acid)
results in significant reduction in coronary complications.8
Features such as thrombocytosis and periungual
desquamation, which are said to be virtually pathognomonic of KD, are seen only in the subacute phase.4
Hence clinical diagnosis may be relatively easy in this phase
but the patient may not benefit even if intravenous
immunoglobulin is administered because coronary
vasculitis would have already developed.
Majority of children with KD remain undiagnosed in
India.9 It is our contention that since KD is not being
diagnosed properly in our country, majority of the affected
patients are at present being left untreated thereby
rendering them liable to coronary complications later in
life. It is entirely possible that such cohort of untreated
children with KD would grow up to develop coronary artery
disease (CAD) as adults. These untreated children may
therefore be contributing to the total load of CAD
encountered by our cardiologists. As a corollary, some of
the young adults with MI in our country, who have no risk
factors for CAD and no family history either of a similar
ailment, could be representing such untreated children
with KD.
References
1. Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid
involvement with specific desquamation of the fingers and toes in
children. Arerugi 1967; 16: 178–222
2. Petty RE, Cassidy JT. Kawasaki disease. In: Cassidy JT, Petty RE (eds).
Textbook of Pediatric Rheumatology, 4th ed. Philadelphia: WB
9/29/2004, 5:16 PM
Indian Heart J 2004; 56: 258–263
262 Letters to the Editor
Saunders Company, 2001; pp. 580–594
3. Taubert KA, Rowley AH, Shulman ST. A 10-year (1984-1993)
United States hospital survey of Kawasaki disease. In: Kato H (ed).
Kawasaki Disease. Amsterdam: Elsevier Science; 1995: pp 34–38
4. Rowley AH, Shulman ST. Kawasaki syndrome. Pediatr Clin North Am
1999; 46: 313–329
5. Hirose O, Misawa H, Kijima Y, Yamada O, Arakaki Y, Kajino Y, et al.
Two-dimensional echocardiography of coronary artery in Kawasaki
disease (MCLS): detection, changes in acute phase, and follow-up
observation of the aneurysm. J Cardiogr 1981; 11: 89–104
6. Kato H, Ichinose E, Yoshioka F, Takechi T, Matsunaga S, Suzuki K, et
al. Fate of coronary aneurysm in Kawasaki disease: serial coronary
angiography and long-term follow-up study. Am J Cardiol 1982; 49:
1758–1766
7. Kato H, Sugimura T, Akagi T, Sato N, Hashino K, Maeno Y, et al.
Long-term consequences of Kawasaki disease: a 10- to 21-year
follow-up study of 594 patients. Circulation 1996; 94: 1379-1385
8. Newburger JW, Takahashi M, Beiser AS, Burns JC, Bastian J, Chung
KJ, et al. A single intravenous infusion of gamma globulin as
compared with four infusions in the treatment of acute Kawasaki
syndrome. N Engl J Med 1991; 324: 1633–1639
9. Singh S. Kawasaki disease. In: Gupta S (ed). Recent Advances in
Pediatrics, Vol. 9 New Delhi: Jaypee Brothers Medical Publishers,
1999; pp 251–257
Surjit Singh, Anju Gupta
Pediatric Allergy & Immunology Unit, Advanced Pediatric Center,
Post Graduate Institute of Medical Education and Research,
Chandigarh
Contrast-Induced Nephropathy and
Cardiac Surgery
W
e read with great interest the excellent article,
‘Contrast-Induced Nephropathy [CIN]’ by Narang
et al.1 The cardiac surgeon shares with his cardiology
colleague the challenges posed by a patient with renal
impairment who needs a coronary artery bypass graft
(CABG) surgery. The problem gets compounded when the
nephropathy is contrast-induced and the patient needs an
urgent surgery, for example after a failed percutaneous
coronary intervention (PCI) or unfavorable anatomy with
unstable hemodynamics.
Post-operative renal failure remains a serious
complication of CABG surgery even in a patient with
normal renal parameters. The rate of post-operative renal
failure varies between 1% and 30%, and the mortality
between 7% and 38%.2 When post-operative renal failure
is severe enough to require dialysis, the magnitude of
mortality rate goes up to 60 to 100%.3 The causes of renal
failure are: pre-existing undetected renal artery
arteriosclerosis, peri-operative low cardiac output,
hypotension, hypoperfusion, hypothermia, exogenous
nephrotoxins (aminoglycosides, diuretics, contrast media),
and endogenous nephrotoxins (free plasma hemoglobin,
Letter-to-Editors.p65
262
myoglobin, free radicals, proinflammatory cytokines,
activation of the complement, coagulation, fibrinolytic and
kallikrein cascade). Radiocontrast agent administration less
than 48 hours before surgery is an independent
preoperative predictor of renal dysfunction.4
Percutaneous transluminal coronary angioplasty
(PTCA) has been associated with unfavorable acute and
long-term effects in patients with renal failure possibly
because of the presence of more complex lesions with
diffuse disease and extensive calcification, smaller diameter
vessels, high incidence of diabetes mellitus, multivessel
disease and increased prothrombotic risk.5,6 An emergency
CABG for failed angioplasty As such, entails a high
mortality7 especially in patients with renal impairment.
As outlined by Narang et al1 the cardiologist is in the
unique position of preventing CIN following the principles
they have mentioned. Care of these high risk patients in
whom emergent surgery is indicated because of unstable
hemodynamics after PCI or unfavorable coronary anatomy
mandates the development of innovative techniques and
strategies to minimize the deleterious effects of surgery to
reduce morbidity and mortality. Quite often because of the
exigency of the situation the cardiac team may be unaware
that CIN has developed until after the surgery is over. While
there are no clear cut guidelines for the optimum
management of such high risk patients in whom surgery
cannot be delayed, based on experience and previous
reports the following measures are suggested.
An off pump procedure using previously described
techniques8,9 is employed in majority of cases. This not only
maintains pulsatile flow (the beating heart is still the best
model of pulsatile perfusion but also avoids exposure to an
extracorporeal circuit and so a reduction in inflammatory
cytokine response. It maintains normothermia and
decreases the need for inotropes. Off pump surgery reduces
the likelihood of acute renal failure in patients with normal
renal function and also in those with pre-operative
nondialysis-dependent renal insufficiency undergoing
CABG.3
Other preventive measures to avoid a further
deterioration in renal function with CPB are: Keeping
optimum perfusion pressure; avoidance of all nephrotoxic
drugs; maintenance of adequate hydration and filling
pressures, optimal hemodynamics and cardiac output
guided by a pulmonary artery thermodilution catheter or
a continuous cardiac output catheter; use of mannitol,
frusemide and dopamine – efficacy unproven; prophylactic
perioperative hemodialysis;10 a low threshold for starting
hemodialysis post-operatively relying on clinical sense and
a combination of the following indications—a rising serum
9/29/2004, 5:16 PM
Indian Heart J 2004; 56: 258–263
creatinine and/or serum potassium level—without a fixed
cut off point, deterioration of oxygenation and a rise in
pulmonary artery pressures.
The goal of improved patient outcome warrants further
joint efforts of the cardiovascular surgeon, cardiologist,
cardiac anesthetist, intervention, and nephrologist.
References
1. Narang R, Sakhare M, Bahl VK. Contrast-induced nephropathy.
Indian Heart J 2004; 56: 13–20
2. Stallwood MI, Grayson AD, Mills K, Scawn ND. Acute renal failure
in coronary artery bypass surgery: independent effect of
cardiopulmonary bypass. Ann Thorac Surg 2004; 77: 968–972
3. Ascione R, Nason G, Al-Ruzzeh S, Ko C, Ciulli F, Angelini GD.
Coronary revascularization with or without cardiopulmonary
bypass in patients with preoperative nondialysis-dependent renal
insufficiency. Ann Thorac Surg 2001; 72: 2020–2055
4. Provenchere S, Plantefeve G, Hufnagel G, Vicaut E, De Vaumas C,
Lecharny JB et al. Renal dysfunction after cardiac surgery with
normothermic cardiopulmonary bypass: incidence, risk factors and
effect on clinical outcome. Anesth Analg 2003; 96: 1258-1264
5. Elsner D. How to diagnose and treat coronary artery disease in the
uraemic patient : an update. Nephrol Dial Transplant 2001; 16:
1103–1108
Letters to the Editor 263
6. Herzog CA, Ma JZ, Collins AJ. Comparative survival of dialysis
patients in the United States after coronary angioplasty, coronary
artery stenting, and coronary artery bypass surgery and impact of
diabetes. Circulation 2002; 106: 2207–2211
7. Lazar HL, Jacobs AK, Aldea GS, Shapira OM, Lancaster D, Shemin
RJ. Factors influencing mortality after emergency coronary artery
bypass grafting for failed percutaneous transluminal coronary
angioplasty. Ann Thorac Surg 1997; 64: 1747–1752
8. Bedi HS, Suri A, Kalkat MS, Sengar B, Chawla R, Sharma VP. Global
myocardial revascularisation without cardiopulmonary bypass
using innovative techniques for myocardial stabilisation and
perfusion. Ann Thorac Surg 2000; 69: 156–164
9. Bedi HS. Beating heart coronary artery bypass with continuous
perfusion through the coronary sinus. In: Salerno TA, Ricci M (eds).
Myocardial Protection 2004. Blackwell Publishing , New York. 1
52–159 pp
10. Durmaz I, Yagdi T, Calkavur T, Mahmudov R, Apaydin AZ, Posacioglu
H, et al. Prophylactic dialysis in patients with renal dysfunction
undergoing on-pump coronary bypass surgery. Ann Thorac Surg
2003; 75: 859–864
Harinder S Bedi, Raman P Singh,
Bhupender Sengar, Gaurav Sachdeva
Departments of Cardio-Vascular Surgery, Anesthesia and
Nephrology, Sigma New Life Heart Institute,
Ludhiana
Academy of Cardiology at Mumbai: International and Indian Fellowships
Academy of Cardiology at Mumbai invites applications for above fellowships (one each) beginning January
2005 from eligible candidates. Applications along with detailed curriculum vitae and two letters of support
from seniors in the profession should be sent to Academy of Cardiology, 102 Kirti Manor, S.V. Road,
Santacruz (W), Mumbai - 400 054 by October 15, 2004.
Eligibility : D.M. or D.N.B (Cardiology) from recognized centers and age 35 years or below. The fellowship will
provide funding for training in interventional/non-invasive cardiology in prestigious centers up to one year.
The interviews for selection will be conducted by Academy.
Letter-to-Editors.p65
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9/29/2004, 5:16 PM
264 Selected
Summaries
Selected
Summaries
Indian Heart J 2004; 56: 264–267
Enoxaparin versus Unfractionated Heparin in High-Risk Patients with Non-ST Segment
Elevation Acute Coronary Syndromes Managed with an Intended Early Invasive Strategy
The Synergy Trial Investigators. JAMA 2004; 292: 45-54
Summary
The Superior Yield of the New strategy of Enoxaparin,
Revascularization and Glycoprotien IIb/IIIa Inhibitors
(SYNERGY) trial was a prospective, randomized, open label
trial, enrolling 9978 high-risk acute coronary syndrome
(ACS) patients from 467 centers. It aimed at demonstrating
efficacy and safety of enoxaparin compared to
unfractionated heparin (UFH) in a group of patients with
high risk ACS, due for early invasive/interventional therapy.
Inclusion criteria included patients with ACS presenting
within 24 hours of onset of ischemic chest pain and at least
two of the following risk factors : age >60 years, elevated
troponin or CPK levels, and ST segment changes on ECG.
Overall, there was no difference in the baseline
characteristics between the two groups. Average age was
68 years. Most were male and most were asymptomatic
(87%) at the time of enrollment. Time from onset of pain
to enrollment was about 15 hours. Overall 92% of patients
underwent coronary angiography, within mean of 21
hours after randomization; 47% underwent PCI and
surgical revascularization was performed in 19% patients.
More than half were administered Gp IIb/IIIa antagonists
during procedure, but interestingly only two-third patients
received thienopyridines. The primary end point of allcause mortality and non-fatal myocardial infarction (MI)
during the first 30 days occurred in 14% patients in
enoxaparin arm versus 14.5% in UFH arm demonstrating
that while enoxaparin was not superior to UFH, it was also
not inferior. On the other hand bleeding complications were
significantly increased in enoxaparin group (9.1% v. 7.6%,
p=0.08). However, major bleeding was not increased in
enoxaparin group (2.7% v. 2.2%, p= 0.08) with no increase
in need for blood transfusion (17% v. 16%, p= 0.16). The
increased bleeding risk in enoxaparin arm could be pinned
down to excess bleeding related to coronary artery bypass
grafting (CABG)-related events. Three-fourth of the patients
in SYNERGY trial had received pre-randomization
antithrombins and 12% patients in enoxaparin arm and
4% patients in UFH arm underwent post-randomization
crossover. When cofounders (pre-randomization or postrandomization crossovers) were excluded, enoxaparin was
associated with reduction in hazard for primary end point
(0.82%) and no increase in TIMI bleeding hazard (1.06).
Comments
Several large randomized clinical trials of ACS have
demonstrated superior efficacy of enoxaparin over UFH,
without increased risk of bleeding. Superiority of enoxaparin
IHJ-Selected Sum.p65
264
over UFH may be due to several limitations of the later; a
narrow therapeutic window, poorly predictable kinetics,
paradoxical platelet activation and most importantly,
inability to inhibit clot-bound thrombin. In this context
enoxaparin, by virtue of higher anti-factor Xa/anti-IIa
factor ratio does away with most of these limitations.
Further, because of convenience of use, enoxaparin therapy
becomes even more attractive. With the availability of new
interventional devices and pharmacological adjuncts
particularly Gp IIb/IIIa antagonists, there is a need to
redefine the role of enoxaparin in patients of ACS due for
invasive management. The inability to monitor the activity
of enoxaparin during the PCI procedure leaves many
interventional cardiologists feeling out of control, with
some justification to it. Indeed, in a study Montalescot et
al. have reported underanticoagulation (anti Xa levels <0.5
IU/ml) in 8% patients contributing to a markedly increased
risk of death plus non-fatal MI at the end of 30 days in
these patients. This has led to a widespread strategy of
discontinuation of enoxaparin prior to PCI and replacing
it with UFH intra-procedure. In this context SYNERGY trial
shows that enoxaparin was not superior to UFH in highrisk patients of ACS due for invasive strategy. There could
be several reasons for it. Firstly, in SYNERGY trial patients
were not only given heparin, but also other potent
antithrombotics like thienopyridines and particularly Gp
IIb/IIIa antagonists and more importantly they underwent
PCI, so the benefit of enoxaparin over UFH could not get
manifest as much as it would have been otherwise.
Secondly, the time to PCI after randomization was just 22
hours (after which ischemic events anyway markedly
decrease) i.e. there was not enough time for enoxaparin to
show its benefit over UFH in contrast to older studies. But
most likely reason for this lack of efficacy seems to be the
trial design, which led to a lot of pre-randomization and
post-randomization issues. More than 75% patients were
on antithrombotics prior to randomization and nearly 10%
underwent post-randomization crossover. It was in these
patients that efficacy of enoxaparin was not manifest. In
those patients where post-randomization crossover
occurred compared to where it did not, the primary end
point was 18.5% versus 13.9%. Moreover there was a
higher risk of bleeding too in these patients (requirement
for blood transfusion more than doubled, 31.5% v.15.2%).
Another major limitation of the study, beside trial design,
is its open label nature, perhaps resulting in some physician
bias in reporting. All in all, the results of SYNERGY trial do
not support use of enoxaparin in patients of high-risk ACS
patients undergoing invasive management other than
convenience of usage.
9/29/2004, 5:15 PM
Indian Heart J 2004; 56: 264–267
Selected Summaries 265
A Randomized Trial of Rescue Angioplasty versus a Conservative Approach for Failed
Fibrinolysis in ST Segment Elevation Myocardial Infarction
Andrew GC Sutton et al. The MERLIN Trial. J Am Coll Cardiol 2004; 44: 287-296
Summary
Comments
The Middlesbrough Early Revascularization to Limit
INfarction (MERLIN) trial was a randomized, multicentric
trial based in UK which compared the strategy of
emergency invasive intervention (rescue angioplasty) with
conservative treatment in patients with failed thrombolysis.
The trial enrolled 307 patients with ST elevation myocardial infarction (STEMI) who had failed to respond to
thrombolytic therapy and had presented within 10 hours
of onset of symptoms. Failed thrombolysis was defined as
failure of ST segment elevation to have resolved in the worst
lead by 50% as compared with pre-treatment ECG or
absence of accelerated idioventricular rhythm, 60 min after
the institution of thrombolysis. Streptokinase was the
primary thrombolytic agent used in 95% patients. Overall,
the baseline characteristics were similar in both the groups.
In the rescue angioplasty arm, the mean time from onset
of chest pain to coronary angiography (CART) was about
5½ hours. Angioplasty was attempted mostly in patients
who had less than TIMI 3 flow (82/88 patients) but also in
some patients who had TIMI 3 flow but significant residual
stenosis (19/61 patients). Overall, about two-third patients
in rescue arm underwent angioplasty and 85% (130/153)
patients achieved TIMI 3 flow. Four patients did not undergo CART, 5 patients were considered unsuitable for
percutaneous coronary intervention (PCI) and 5 patients
had failed PCI. Half of the patients received stents but
glycoprotein (Gp) IIb/IIIa antagonists were used in only 5
(3.3%) patients. The primary end point of all-cause
mortality was similar in the rescue and conservative groups
(9.8% v. 11%, p=0.7). However, the composite secondary
end point of death, infarction, stroke, congestive heart
failure (CHF) and clinically driven subsequent revascularization within 30 days was lower in rescue group
(37.3% v.. 50%, p=0.02) primarily due to lesser rate of
subsequent revascularization (6.5% v. 20.1%, p<0.01).
Furthermore, reinfarctions and CHF were also less common
in the rescue group (7.2% v. 10.4%, p=0.03 and 24.2% v.
29.2% respectively, p=0.3) but not statistically significant.
On the other hand, strokes and need for blood transfusions
were more common in the rescue group (4.6% v. 0.6%,
p=0.03 and 11.1% v. 1.3%, p<0.001). There was no
difference in left ventricular (LV) function assessment at
30 days between 2 arms. Regional wall motion abnormality
(RWMI) was 1.52 in the rescue group versus 1.58 in
conservative group. The only univariate predictor of allcause mortality by 30 days was anterior MI. Multivariate
logistic regression analysis revealed that predictors for
composite secondary end points were anterior MI, female
gender and conservative treatment.
Several small studies, most of them observational ones,
have reported the utility of rescue angioplasty in patients
with failed thrombolysis. In RESCUE study, 151 patients
with acute anterior MI and TIMI grade 0/1 flow showed a
reduction in composite end point of death or CHF at 30
days favoring the rescue angioplasty arm (6.4% v. 16.6%,
p<0.05). In a subsequent large meta-analysis (n=2433),
Ellis et al. demonstrated a high success rate in angioplasty
arm with favorable results persisting beyond 1 year in
patients with moderate/large MI. One-year survival was
92% for rescue arm versus 87% for conservative arm
(p=0.001). On the other hand, TAMI I trial demonstrated
that immediate angioplasty for TIMI grade 2 flow was not
beneficial probably because of highly thrombogenic milieu
engendered by potent plasminogen activators via the
thrombin liberated from dissolved occlusive clot. MERLIN
study is unique in several respects. Firstly, streptokinase was
the thrombolytic agent (v. tpa in most other studies) used
in majority of patients. Secondly, failed thrombolysis was
defined only on ECG parameters with no consideration for
ischemic pain. Thirdly, it included all types of MI (and not
just higher risk patients with anterior MI) and finally, the
mortality was extremely high in both the arms, to the tune
of 10% in comparison to conventional angioplasty/
thrombolysis trials (2-5%). This trial showed that though
there was an improvement in combined end points of
death/re-infarction/stroke/subsequent reinfarction/CHF
(RR 12.7%), there was no improvement in primary end
point of all-cause mortality at 30 days. Furthermore, the
small improvement in combined end point itself was driven
almost entirely by lesser rates of subsequent
revascularizations in rescue arm (RR 13.6%), implying the
futility of the primary procedure itself. In other words, there
was no benefit of angioplasty in rescue arm, which anyway
could be offered on elective basis if required, saving on the
cost and logistics of the procedure. Additionally, there was
an increased risk of developing disabling strokes and more
requirement of blood transfusion in rescue group. However,
the present study had several limitations. It was
underpowered for assessment of all-cause mortality.
Secondly, the high mortality in both the arms was
surprising and at variance with all other trials. Whether it
was a chance matter, or related to choice of thrombolytic
i.e. streptokinase, is unclear. The failure of ST segment to
settle despite patent IRA may itself reflect a high-risk
situation probably indicating reperfusion injury,
hemorrhagic infarction or microvascular obstruction.
IHJ-Selected Sum.p65
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9/29/2004, 5:15 PM
Indian Heart J 2004; 56: 264–267
266 Selected Summaries
Drug- Induced Atrioventricular Block: Prognosis
after Discontinuation of the Culprit Drug
David Seltzer et al. J Am Coll Cardiol 2004; 44: 105-108
Summary
This study from Israel deals with a common yet clinically
important condition of atrioventricular (AV) block. Its aim
was to find out whether β-blockers or calcium channel
blockers merely unmask the presence of serious AV
conduction problems or are themselves the cause of AV
block. The authors analyzed the clinical course and
definitive management of 169 consecutive patients with
second or third degree AV block. The patients were excluded
if their AV block was secondary to acute myocardial
infarction, vasovagal syncope, digitalis toxicity or
radiofrequency ablation. The patients treated with class I
and class III antiarrythmic drugs were also excluded. The
level of block (nodal or infranodal) was defined by electrocardiographic criteria; no electrophysiological study was
done. Of the 169 patients enrolled, 92 (54%) patients
(mean age 78±9 years) were either on β-blockers (n=62)
or were receiving non-dihydropyridine calcium channel
antagonists - verapamil or diltiazem or receiving both
groups of medicines (n=13). The rest of the 77 patients
(mean age 78±8.5 years) out of the 169 enrolled, were not
on any incriminating drug therapy. The patients were
classified under drug-related AV block—if the block
resolved upon discontinuing the offending drug and did not
recur in the three weeks follow-up period. AV blocks that
resolved within 48 hours but recurred in the subsequent
three weeks follow-up period were classified as not caused
by drugs. The baseline clinical and electrocardiographic
characteristics including the level of block were similar in
patients with AV block related to drugs and in the group
not receiving such drugs. The culprit drug was discontinued
in 79 (86%) of the 92 patients, 32 (41%) of whom
experienced spontaneous resolution of AV block within 48
hours. In comparison, only 18 (23%) patients, who had
not received such medication, experienced spontaneous
resolution (p=0.014). However, there was a relapse of the
AV block (within the following 3 weeks) in 56% of the 32
patients who had experienced spontaneous resolution in
their drug-related blocks. Spontaneous relapse of AV block
also was seen in 38% patients who originally had block in
absence of any drug therapy. The presence of ECG
characteristics suggesting AV block at level of AV node
during drug therapy was found to be a poor predictor of
causation. Therefore the authors concluded that drugrelated AV block ‘truly caused by the drugs’ occurred only
in 15% of patients presenting with AV block while receiving
β-blockers, or calcium channel blockers (diltiazem and
IHJ-Selected Sum.p65
266
verapamil). The other important observation was that the
majority would persist with the block despite the
discontinuation of medication. More ominously, there is a
strong likelihood of recurrence of the block, even if it
resolves initially, when the medications are discontinued.
Comments
The AHA/ACC guidelines for permanent pacing have listed
as class III, with level of evidence B— the AV block expected
to resolve and unlikely to recur (e.g. drug toxicity)—thereby
recommending that for drug-induced AV block, a
pacemaker implantation by evidence and/or general
agreement, is not indicated. Based on the guidelines the
general management worldwide is to discontinue the
culprit drugs while patients are being monitored in the
hospital. However, the present study consisting mainly of
elderly patients with structural heart disease indicates that
AV block will most likely persist despite discontinuation of
the implicated drug therapy. There was resolution of AV
block shortly after drug discontinuation in 41% of cases.
However, 23% of AV blocks also resolved in those who had
not received medications. And there was a 56% recurrence
of AV block after its resolution following drug discontinuation in the short follow-up of three weeks. All this points
toward the suspicion that there was underlying AV
conduction disease in the first place and that the drugs—βblockers and calcium channel blockers merely unmask the
disorder. Improvement in AV block upon cessation of culprit
drugs may be coincidental and is often transient.
The study has limitations in being restricted mainly to
the elderly (mean age around 78 years) with infranodal
conduction disease. Also, no electrophysiological studies
were performed to ascertain the site of block. The dosage
relation to the occurrence of AV block with the β-blockers
and calcium channel blockers also was not determined
because of the less number of patients. However, this study
has important implications for clinicians in the
management protocol for drug-related AV block. It suggests
that the course of such patients despite discontinuation of
the culprit medication is not benign as made out by existing
ACC/AHA guidelines. Chances of improvement are not
certain and the recurrence of blocks despite early
improvement makes it important to carefully monitor these
patients. An electrophysiology test at this stage may
probably help in the decision to implant a permanent
pacemaker, that would eventually be required by a majority,
as shown in this study.
9/29/2004, 5:15 PM
Indian Heart J 2004; 56: 264–267
Selected Summaries 267
Randomized, Double-Blind, Placebo-Controlled Trial of Oral Sirolimus
for Restenosis Prevention in Patients with In-Stent Restenosis
Jorg Hausleiter et al. OSIRIS trial. Circulation 2004; 110: 790-795
Summary
Several trials including the RAVEL study and the subsequently
published series of SIRIUS trials have demonstrated the efficacy
of sirolimus-eluting stents in reducing the restenosis rates in
de novo coronary artery lesions. However, their role in
managing in-stent restenosis (ISR) has not been evaluated in
clinical trials. Sirolimus is a macrolide immunosuppressant
that inhibits proliferation of smooth muscle cells and thus
decreases the restenosis rate after angioplasty. Oral sirolimus
has also been shown to slow the accelerated arteriopathy
following cardiac transplant. The Oral Sirolimus to Inhibit
Recurrent In-stent Stenosis (OSIRIS), a randomized, double
blind, placebo-controlled trial was conducted with the objective
of evaluating the efficacy of oral sirolimus treatment with two
different dosing regimens for prevention of restenosis in
patients with ISR. 300 patients who had either angina or
exercise-induced ischemia in the presence of angiographically
significant ISR were randomized to either of the three
treatment arms – placebo, usual dose or high dose sirolimus
groups. Exclusion criteria were: acute coronary disease,
presence of severe infections or significant renal failure. All
patients were pre-treated with oral sirolimus for 2 days prior
to angioplasty. In the high-dose group, 24 mg was given over
3 days compared with 8 mg in the usual dose group. After the
percutaneous coronary intervention (PCI), a maintenance
dose of 2 mg/day was given for 1week (day 4 to 10) in both
the arms. Blood levels were determined on day three i.e. the
day of the procedure. The primary end point was angiographic
stenosis defined as diameter stenosis of >50%. Secondary end
points were the combined incidence of death and myocardial
infarction and target vessel revascularization (TVR) during 1year follow-up.
Repeat angiography was performed in 88.4% of patients at
a median time interval of 206 days. Angiographic restenosis
rate was reduced by 48% in the high-dose sirolimus group with
a restenosis rate of 22.1% (p=0.005). The placebo group had
a restenosis rate of 42.2% and the usual dose sirolimus group
had angiographic restenosis rate of 38.6%. The minimal
lumen diameter was highest (1.66±0.62 mm) in the high-dose
group (1.37±0.69 mm in the usual dose group and 1.53±0.61
in the placebo group). A significant correlation between the
sirolimus blood level on the day of PCI with the late lumen
loss was observed at follow-up (p<0.001). There was a
significant reduction in the white blood cell and thrombocyte
count; however there were no clinical consequences of either
leukopenia or thrombocytopenia. At 1-year clinical follow-up,
because of restenosis TVR was necessary in 25.5% of placebo
IHJ-Selected Sum.p65
267
group, 24.2% in the usual dose group and in 15.2% of the
high-dose group (p <0.08). The combined rate of death or
myocardial infarction (MI) at 1 year was 1%, 3% and 2%
respectively in the three groups.
Comments
Sirolimus has antiinflammatory and antiproliferative
properties besides being an effective immunosuppressant.
Sirolimus-eluting stents have found widespread acceptance
after several randomized trials demonstrated lower rates of
restenosis. However, the high cost of coated stents is a big
deterrent especially in the third world countries such as ours.
Moreover, as of now sirolimus-eluting stents have not been
approved for use in many conditions, with little data of its use
in situations such as chronic total occlusion and for in-stent
restenosis. Hence alternative means to prevent restenosis are
still being investigated. Brachytherapy was a promising means
toward decreasing ISR. However, disappointingly the early
benefit seen with brachytherapy is lost later on, as seen in
studies with longer follow-up. This study is the first randomized
trial with oral sirolimus that assessed the benefit of its shortterm administration in prevention of restenosis. Two previous
non-randomised trials have addressed this issue. In the study
by Brara et al, there was no clinical benefit achieved in 22 cases
of ISR. In the ORAR trial, a trend toward lower restenosis rates
was observed following coronary stenting in de novo lesions.
The explanation for the remarkable benefit seen in the present
study may be the administration of loading dose of sirolimus
2 days prior to intervention, unlike in the 2 previous studies
mentioned. Moreover, the maximum benefit was seen with
higher dose of sirolimus, than in the previous studies. This had
decreased the restenosis rate by 48% whereas the usual dose
showed a decrease of only 9% from that observed with placebo.
The importance of the loading dose was further confirmed by
a significant correlation between the sirolimus blood levels on
the day of the intervention and the late lumen loss.
This study also showed that the drug was well tolerated as
compared with previous studies probably because only short
duration (10 days) of therapy was used. The clustering of 5
patients in the 2 sirolimus groups who died during the followup period is also of some concern in this trial, although it
appears that oral sirolimus was not the cause of these deaths.
This being the first randomized trial with oral sirolimus, further
trials with longer follow-up are obviously needed addressing
the issue of optimal dosage, safety profile and duration of
treatment.
9/29/2004, 5:15 PM
Calendar of Conferences/CSI Executive Committee
October 10, 2004, 4th Mid Term Conference on
Preventive Cardiology, CSI, Uttar Pradesh Chapter, Jhansi
Contact: Dr Praveen Jain
Lifeline Hospital
Kanpur Road, Jhansi 284 128 UP
Tel: 0517 - 232 0183, 283 983
Fax: 0517- 232 0553
e-mail: [email protected]
Indian Heart J 2004; 56: 268
Cardiological Society of India
Executive Committee (2003-2004)
President
R J Manjuran, Kottayam
President Elect
P C Manoria, Bhopal
October 31 - November 3, 2004, 6th Asia - Pacific
Congress of Cardiovascular and Interventional
Radiology, New Delhi
Contact: Dr Sanjiv Sharma, Convener
Department of Cardiac Radiology
All India Institute of Medical Sciences
New Delhi 110 029
Tel: 2659 4759
Fax: 011-2658 8663, 2658 8641
e-mail: [email protected];[email protected]
Honorary Editor
V K Bahl, New Delhi
December 2-5, 2004, 56th Annual Conference of the
Cardiological Society of India, Bangalore
Contact: Dr CN Manjunath, Organising Secretary
#40, 4th Floor, Lakshmi Complex
Opposite Vasi Vilas Hospital
KR Road, Bangalore 560002
Fax: 91-080-6704483
Tel: 9844006659
e-mail: [email protected]
or
Dr PC Manoria, President-Elect
E-5/103, Arera Colony, Bhopal 462016
Tel: 9827074602
Fax: 91-0755-2532405
e-mail: [email protected]
Treasurer
S S Chatterjee, Kolkata
February 18-20, 2005, International Summit on
CAD and Cardiovascular Interventions, Mumbai
Contact: Dr Satyavan Sharma
Bombay Hospital and MRC
Room No. 104, 1st Floor MRC
12, New Marine Lines
Mumbai 400 020
Tel: 91 22 2205 4532
e-mail: [email protected] and
[email protected]
February 24-27, 2005, 2nd World Congress of Interventional Cardiology, Mumbai
Contact: Dr Lekha Adik Pathak
Memdil, Linking Road
Santacruz (W), Mumbai 400 034
Tel: 91 22 26490262
e-mail: [email protected]
Cal of Conference.p65
268
Vice Presidents
M K Das, Kolkata
A K Banerjee, Kolkata
J C Mohan, New Delhi
Honorary General Secretary
P S Banerjee, Kolkata
Honorary Joint Secretary
A George Koshy, Thiruvananthapuram
Sharad Kumar Parashar, Hoshangabad
Members
Kajal Ganguly, Kolkata
Satyendra Tewari, Lucknow
Santanu Guha, Kolkata
S B Gupta, Mumbai
Rakesh Gupta, Delhi
Suman Bhandari, New Delhi
Vidhut Kumar Jain, Indore
S K Parashar, New Delhi
K Venugopal, Calicut
Shirish Hiremath, Pune
A K Khan, Kolkata
P K Deb, Kolkata
H K Chopra, New Delhi
H M Mardikar, Nagpur
Shubhendu Banerjea, Kolkata
Binoda Nand Jha, Muzaffarpur
K Sarat Chandra, Hyderabad
Bikash Kumar Chatterjee, Kolkata
K K H Siddique, Kolkata
Lekha Pathak, Mumbai
Charanjit Singh, Pune
Immediate Past President
D S Gambhir, Noida
9/29/2004, 5:17 PM