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Am J Physiol Heart Circ Physiol 295: H2054–H2060, 2008.
First published September 12, 2008; doi:10.1152/ajpheart.91400.2007.
Increased diastolic time fraction as beneficial adjunct of ␣1-adrenergic
receptor blockade after percutaneous coronary intervention
Christina Kolyva,1 Bart-Jan Verhoeff,2 Jos A. E. Spaan,1 Jan J. Piek,2 and Maria Siebes1,2
Departments of 1Biomedical Engineering & Physics and 2Cardiology, Academic Medical Center, University of Amsterdam,
Amsterdam, The Netherlands
Submitted 4 December 2007; accepted in final form 11 September 2008
(DTF), decreases with increasing heart rate both in healthy
humans and in patients with coronary artery disease (4).
Notably, diastolic perfusion time, expressing the total amount
of diastole relative to that of systole per minute, was shown to
be closely related to stenosis severity at the onset of stressinduced myocardial ischemia in humans, whereas no such
correlation was found with heart rate at the ischemic threshold (7).
It has recently been reported that DTF also depends inversely on coronary pressure (24), which is an important
determinant of coronary perfusion since it influences microvascular resistance in the vasodilated coronary bed (14, 35).
We hypothesized that the reported improvement in coronary
blood flow and cardiac function with ␣-receptor blockade after
balloon angioplasty may be in part due to a concomitant
increase in the duration of diastole. Accordingly, the major aim
of this study was to assess the effect of ␣-adrenergic receptor
blockade after percutaneous coronary intervention (PCI) by
balloon angioplasty and stent placement on DTF.
METHODS
dysfunction and impaired coronary flow reserve after balloon angioplasty have been attributed to the stimulation of ␣-adrenergic pathways in the vessel
wall (9, 11, 12, 16), leading to vasoconstriction not only of the
manipulated coronary artery but also of a normal control vessel
(9, 20). These adverse effects could be diminished by prior or
subsequent ␣-receptor blockade (9, 11, 12, 20, 27).
Coronary flow occurs predominantly during diastole (19, 31)
and is therefore critically dependent on diastolic duration.
Animal studies have demonstrated that in the maximally dilated coronary bed the duration of diastole is an important
factor that limits subendocardial perfusion (1, 8). The relative
duration of diastole per heart cycle, diastolic time fraction
Study population. Eleven patients [9 males; age 60 years (SD 6)]
scheduled for elective coronary angioplasty were enrolled in this
study. All patients suffered from stable angina and had a single de
novo stenosis in the target vessel. Exclusion criteria were diffuse or
triple-vessel disease, left main coronary artery stenosis (⬎50%) or a
subtotal lesion in the vessel targeted for angioplasty, recent myocardial infarction (⬍6 wk), prior cardiac surgery, serious heart valve
abnormalities, hypertrophic cardiomyopathy, or visible collateral vessels. The local Medical Ethics Committee approved the study protocol, and all patients gave written informed consent.
Hemodynamic measurements. All data were acquired during cardiac catheterization using a right femoral artery approach. Aortic
pressure (Pa) was obtained via a 5F or 6F guiding catheter, which was
advanced into the coronary ostium. Distal intracoronary pressure (Pd)
and blood flow velocity distal to the target lesion were measured via
a novel 0.014-in dual-sensor guide wire (Volcano, Rancho Cordova,
CA) equipped with a Doppler sensor at the tip and a pressure sensor
3 cm proximal to the tip. The position of the wire was manipulated
until an optimum and stable velocity signal was obtained, and attention was paid to maintain sensor position for measurements taken at
different phases of the protocol. All signals were recorded on a
personal computer at a sampling rate of 120 Hz after 12-bit analogto-digital conversion for offline analysis.
Protocol. The patients continued their antianginal and antiplatelet
medication as clinically indicated and received 1 mg lorazepam before
cardiac catheterization. Heparin was administered at the beginning of
the procedure (5,000 –7,500 IU, intravenous bolus) followed by 0.1
Address for reprint requests and other correspondence: M. Siebes, Dept. of
Biomedical Engineering & Physics, Academic Medical Center, Meibergdreef
9, 1105 AZ Amsterdam, The Netherlands (e-mail: [email protected]).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
coronary circulation; angioplasty; microcirculation; diastole; ␣-adrenergic receptors
POSTISCHEMIC LEFT VENTRICULAR
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0363-6135/08 $8.00 Copyright © 2008 the American Physiological Society
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Kolyva C, Verhoeff BJ, Spaan JA, Piek JJ, Siebes M. Increased
diastolic time fraction as beneficial adjunct of ␣1-adrenergic receptor
blockade after percutaneous coronary intervention. Am J Physiol
Heart Circ Physiol 295: H2054 –H2060, 2008. First published September 12, 2008; doi:10.1152/ajpheart.91400.2007.—The effect of
␣1-receptor blockade with urapidil on coronary blood flow and left
ventricular function has been attributed to relief of diffuse coronary
vasoconstriction following percutaneous coronary intervention (PCI).
We hypothesized that an increase in diastolic time fraction (DTF)
contributes to the beneficial action of urapidil. In eleven patients with
a 63% (SD 13) diameter stenosis, ECG, aortic pressure (Pa) and distal
intracoronary pressure (Pd), and blood flow velocity were recorded at
baseline and throughout adenosine-induced hyperemia. Measurements were obtained before and after PCI and after subsequent
␣1-receptor blockade with urapidil (10 mg ic). DTF was determined
from the ECG and the Pa waveform. Functional parameters such as
coronary flow velocity reserve, fractional flow reserve, and an index
of hyperemic microvascular resistance (HMR) were assessed. Urapidil administration after PCI induced an upward shift in the DTF-heart
rate relationship, resulting in a 3.1% (SD 2.7) increase in hyperemic
DTF at a constant heart rate (P ⬍ 0.005) due to a shorter duration of
systole. Hyperemic Pa and Pd decreased, respectively, by 6.1% (SD
6.6; P ⬍ 0.05) and 5.7% (SD 5.8; P ⬍ 0.01) after ␣1-blockade.
Although epicardially measured functional parameters were on average not altered by ␣1-blockade due to concurrent changes in pressure
and heart rate, HMR decreased by urapidil in those patients where
coronary pressure remained constant. In conclusion, ␣1-receptor
blockade after PCI produced a modest but significant prolongation of
DTF at a given heart rate, thereby providing an adjunctive beneficial
mechanism for improving subendocardial perfusion, which critically
depends on DTF.
EFFECT OF URAPIDIL ON DIASTOLIC TIME FRACTION
interval yielded the duration of diastole, and DTF was calculated as
diastolic duration divided by the RR interval.
Mid-systolic and end-diastolic hemodynamic values were derived
during time intervals corresponding to the highest and lowest 10%,
respectively, of the distal pressure signal as illustrated in Fig. 1. Rate
pressure product (RPP), calculated as the product of heart rate and
systolic Pa, served as an estimate of oxygen consumption. Fractional
flow reserve (FFR) was determined as the ratio of Pd/Pa at maximal
hyperemia and coronary flow velocity reserve (CFVR) as hyperemic
divided by resting flow velocity. An index of average hyperemic
microvascular resistance (HMR) was computed as the ratio of distal
coronary pressure to flow velocity during maximal vasodilation
(30, 35).
Statistical analysis. All variables are expressed as means (SD).
Average per-beat data obtained at successive steps of the protocol
were compared using ANOVA with repeated measures, followed by
contrast analysis. Paired Student’s t-test was used to compare means
before and after ␣-receptor blockade. Linear regressions were obtained for DTF and heart rate data obtained after PCI. The slopes of
the regression lines obtained before and after urapidil administration
were compared using a t-test. Analysis of covariance was performed
to determine whether urapidil administration had a significant effect
on the DTF-heart rate relationship (SPSS, version 12.0).
To remove effects of acute changes in heart rate before ␣-blockade
and at maximum action of urapidil, representative values of DTF at
center heart rate (DTFC) were derived from the respective regression
lines at a common center heart rate halfway within the range of
recorded heart rates. Statistical significance was assumed at P ⬍ 0.05.
RESULTS
Fig. 1. Representative example of the hyperemic hemodynamic signals as a
function of time in a patient 15 min after stent placement. Starting from top, the
ECG, aortic pressure (Pa) and its first derivative (dPa/dt), coronary flow
velocity (CFV), and distal intracoronary pressure (Pd) are plotted. The vertical
solid lines show the position of the R-peak, and the dashed lines show the
position of the dicrotic notch used to determine systolic duration. The thick
tracings indicate those periods of the hemodynamic signals that were used to
derive mid-systolic and end-diastolic values.
AJP-Heart Circ Physiol • VOL
Clinical and angiographic features of the study population
are listed in Table 1. Two lesions were located in the right
coronary artery, six in the left anterior descending, and three in
the left circumflex coronary artery. Diameter stenosis ranged
from 43.0% to 86.8% before PCI. Treatment was successful
with a residual stenosis of 0% (SD 12). No patient had diabetes
mellitus, and all but one patient received ␤-blocking medication.
Hemodynamic effects of PCI and ␣1-receptor blockade.
Figure 2 compares average hemodynamic parameters at each
step of the protocol. PCI restored distal pressure and flow
velocity during maximal vasodilation (P ⬍ 0.005), as well as
functional parameters such as FFR and CFVR (both P ⬍
0.005) to levels obtained in the reference vessel, whereas Pa,
heart rate, and DTF remained constant. HMR decreased as
perfusion pressure increased with treatment (P ⬍ 0.05). Hemodynamic or functional parameters did not change in the
15-min period after stent placement (Table 2). Flow velocity at
rest remained constant throughout the protocol.
After ␣1-receptor blockade with urapidil, both hyperemic Pa
and distal coronary pressure decreased by 6.1% (SD 6.6; P ⬍
0.05) and 5.7% (SD 5.8; P ⬍ 0.01), respectively. Mid-systolic
and end-diastolic pressures followed the same pattern. RPP
during maximal hyperemia decreased by 5.9% (SD 7.3) after
urapidil administration (P ⬍ 0.05). These changes were similar
at resting conditions. On average, other hemodynamic and
functional parameters remained unchanged after ␣1-receptor
blockade.
DTF-heart rate relation before and after ␣1-receptor blockade. A significant inverse linear relation between DTF and
heart rate was present in all patients before (P ⬍ 0.005) and
after (P ⬍ 0.02) administration of urapidil, as shown in Fig. 3.
The DTF-heart rate relations at rest and during maximal
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mg intracoronary nitroglycerin to minimize vascular tone in the large
epicardial vessels.
Hemodynamic measurements were obtained at resting conditions
and during maximal hyperemia induced by 20 – 40 ␮g intracoronary
adenosine, first in an angiographically normal reference vessel and
then in the target vessel before and 3 min after PCI. The measurements were repeated 10 –15 min after stent placement, at a time when
maximal ␣1-adrenergic coronary vasoconstriction has been reported
(9, 20). Finally, data were acquired 5– 8 min following a 10-mg
intracoronary bolus of the selective ␣1-receptor antagonist urapidil,
when urapidil had reached its maximum effect (10, 12).
Data processing. Per-beat data analysis was performed using custom-made programs (Delphi, version 6.0; Borland Software). The
duration of each heart cycle was determined from the interval between
two consecutive R-peaks on the ECG. Systolic duration was defined
as the time interval between the ECG R-peak and closure of the aortic
valve as identified by the dicrotic notch in the Pa signal, corresponding
to the first local maximum of the first derivative of the Pa signal after
the ECG T-wave (Fig. 1). Subtracting the systolic from the RR
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EFFECT OF URAPIDIL ON DIASTOLIC TIME FRACTION
Hyperemic flow velocity increased after urapidil in this constant Pd group (not shown).
The reduction in HMR in these patients is therefore to a
large extent due to the blocking action of urapidil following
␣-receptor stimulation after PCI. The decrease in Pd after
urapidil in the other group essentially limited this effect and
resulted in an elevated HMR and a reduction in hyperemic flow
velocity by 21%.
Table 1. Clinical and angiographic characteristics
60 (SD 6)
9/2
0 (0%)
7 (64%)
4 (36%)
4 (36%)
4 (36%)
3 (27%)
2 (18%)
DISCUSSION
The key finding of the present study is that intracoronary
administration of the selective ␣1-receptor blocking agent ura-
3 (27%)
10 (91%)
10 (91%)
5 (45%)
9 (82%)
6 (55%)
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Age, yr
Sex, male/female
Coronary risk factors
Diabetes mellitus
Hyperlipidemia
Hypertension
Positive family history
Smoking
Prior myocardial infarction ⬎6 wk
Prior angioplasty in different vessel
Medication
ACE inhibitors
Aspirin
␤-blockers
Calcium antagonists
Lipid-lowering drugs
Nitrates
%Diameter stenosis
Before PCI
After PCI
Minimum lumen diameter, mm
Before PCI
After PCI
62.9 (SD 13.2)
0.0 (SD 11.7)
1.15 (SD 0.41)
3.08 (SD 0.42)
Values are means (SD) or n, number of patients(%). Percutaneous coronary
intervention (PCI) indicates balloon angioplasty and stent placement. ACE,
angiotensin-converting enzyme.
hyperemia shifted significantly upward after ␣1-blockade in
eight out of 11 patients (P ⬍ 0.001). Changes in the remaining
three patients showed a similar trend but did not reach significance.
This heart rate-independent shift was quantified by evaluating DTFC at respective center heart rates halfway within the
range of recorded heart rates. DTFC averaged over all patients
increased after urapidil by 3.1% (SD 2.7; P ⬍ 0.005) at
maximal hyperemia and by 3.8% (SD 3.1; P ⬍ 0.005) at rest.
The increase in DTFC was due to a decrease in systolic
duration at the center heart rate (P ⬍ 0.005). No significant
difference was found between corresponding DTFC values at
rest and during maximal hyperemia.
Acute changes in heart rate ranging from ⫺5 to 10 beats/min
(white arrow in Fig. 3) essentially prevented the urapidil effect
on the DTF-heart rate relation to be directly detectable from the
actually measured DTF values. Without the upward shift in the
DTF-heart rate relation, DTF at the actual heart rates after
urapidil would have decreased by 2.0%, whereas the measured
DTF increased by 1.7%, which can be attributed to a significant
decrease in systolic duration (P ⬍ 0.05; Table 2).
Effect of concurrent changes in coronary pressure on microvascular resistance at maximal vasodilation. Figure 4 illustrates individual changes in hyperemic Pd and DTF after
␣1-receptor blockade and related changes in HMR. Hyperemic
Pd is an important determinant of HMR, and to reveal an effect
of urapidil on HMR the data were separated into a group where
Pd before and after urapidil administration differed ⬍5% (F in
Fig. 4) and into a group where distal pressure after urapidil
administration was always lower than before (E in Fig. 4). No
systematic difference between these two Pd groups can be
noted in the relationship between DTF before and after urapidil. The constant Pd group revealed a decrease in HMR by
10.5% (SD 5.6), with a strong correlation between HMR
values before and after urapidil administration (r2 ⫽ 0.93).
AJP-Heart Circ Physiol • VOL
Fig. 2. Average hemodynamic parameters at each step of the procedure. All
measurements were obtained under hyperemic conditions unless otherwise
indicated. Pre, Before treatment; Stent, shortly after stent placement; Stent15,
15 min after stent placement; Ura, after urapidil administration; Ref, reference
vessel; FFR, fractional flow reserve; CFVR, coronary flow velocity reserve;
HMR, hyperemic microvascular resistance index; DTF, diastolic time fraction;
HR, heart rate; bpm, beats/min. Error bars represent SE. *P ⬍ 0.05; †P ⬍
0.005 compared with the previous step.
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EFFECT OF URAPIDIL ON DIASTOLIC TIME FRACTION
Table 2. Hemodynamic data before and after ␣1-blockade
Stent, 15 min
Urapidil
10
22.8 (SD 5.6)
17.0 (SD 6.9)
24.7 (SD 6.3)
62.9 (SD 14.0)
54.9 (SD 14.7)
69.7 (SD 13.9)
98 (SD 10)
136 (SD 21)
78 (SD 7)
92 (SD 11)
131 (SD 21)
70 (SD 9)
9,659 (SD 1,591)
0.93 (SD 0.05)
2.84 (SD 0.69)
1.52 (SD 0.40)
72 (SD 10)
0.85 (SD 0.11)
0.42 (SD 0.03)
0.43 (SD 0.10)
0.497 (SD 0.052)
11
22.7 (SD 11.0)
16.9 (SD 10.4)
25.5 (SD 12.2)
63.0 (SD 16.0)
54.0 (SD 18.1)
72.3 (SD 15.9)
101 (SD 12)
139 (SD 21)
80 (SD 10)
95 (SD 12)
134 (SD 18)
73 (SD 11)
10,092 (SD 1,964)
0.94 (SD 0.04)
3.05 (SD 0.97)
1.58 (SD 0.37)
73 (SD 12)
0.84 (SD 0.14)
0.42 (SD 0.04)
0.42 (SD 0.11)
0.497 (SD 0.047)
0.496 (SD 0.046)
11
22.3 (SD 12.3)
16.5 (SD 11.4)
25.6 (SD 14.0)
60.5 (SD 18.8)
49.6 (SD 22.2)
71.2 (SD 17.9)
95 (SD 10)*
128 (SD 15)†
76 (SD 8)*
89 (SD 10)†
123 (SD 14)†
69 (SD 9)*
9,434 (SD 1,538)*
0.94 (SD 0.04)
2.95 (SD 0.76)
1.60 (SD 0.49)
74 (SD 10)
0.83 (SD 0.13)
0.40 (SD 0.02)*
0.42 (SD 0.12)
0.505 (SD 0.050)
0.511 (SD 0.049)†
All values are means (SD) and represent hyperemic conditions unless otherwise indicated; n, number of patients. CFV, coronary flow velocity; Pa, aortic
pressure; Pd, distal pressure; RPP, rate pressure product; FFR, fractional flow reserve; CFVR, CFV reserve; HMR, hyperemic microvascular resistance index;
DTF, actual diastolic time fraction; DTFC, diastolic time fraction at center heart rate. *P ⬍ 0.05; †P ⬍ 0.01 compared with previous condition.
pidil after PCI induced an upward shift in the DTF-heart rate
relationship, which amounted to a 3.1% increase in DTFC
(range, 1.4% to 8.2%). For the subgroup in which coronary
pressure remained constant after the urapidil administration,
HMR was reduced by 10.5%.
Comparison with other studies on ␣1-blockade after angioplasty. Coronary resistance vessels receive autonomic innervation, and ␣1-adrenoreceptors are present in vessels with a
diameter ⬍300 ␮m (5, 16). Although ␣-adrenergic coronary
constrictor tone is negligible under resting conditions, it has
been shown to increase hyperemic coronary resistance in
normal coronary vessels (18, 23). Pathophysiological conditions such as atherosclerosis sensitize resistance vessels to the
constrictive effect of ␣-adrenergic receptors (2, 16). Previous
studies have furthermore demonstrated that ␣-adrenergic pathways in the vessel wall were acutely stimulated in patients who
underwent balloon angioplasty (9, 12, 20). Gregorini et al. (9,
11, 12) observed that ␣1-mediated vasoconstriction developed
over time (9, 11) and reached a maximum 15 min after
angioplasty, resulting in a blunted flow reserve compared with
shortly after the intervention (12).
Our results in terms of CFVR do not concur with these
earlier findings in that CFVR was restored to values equal to
the reference vessel after PCI and was not depressed 15 min
later or enhanced by the subsequent administration of urapidil.
These contrasting findings may be due to differences in adjunctive medication and initial outcomes of the PCI. Patients in
the former study were sedated with neuroleptic analgesia, and
CFVR was not improved by PCI (12). In addition, vasoactive
medication was not discontinued in the present study, and all
patients received an initial dose of intracoronary nitroglycerin,
which may have attenuated the vasoconstrictive effects of
PCI-induced ␣-receptor stimulation.
In terms of hyperemic coronary resistance, ␣1-receptor
blockade with doxazosin demonstrated a reduction not only in
AJP-Heart Circ Physiol • VOL
normal subjects (23) but also in patients 5 days after PCI (27).
Coronary resistance in these studies was derived from myocardial blood flow determined with PET and mean arterial
pressure obtained by cuff sphygmomanometry. In contrast, our
measurements only confirm a reducing effect of urapidil on
HMR in a group with minimal changes in coronary pressure.
Hence, when studying the drug-induced effect on HMR, one
has to be aware of altered mechanical conditions that have a
marked influence on HMR, and in this respect especially DTF
and coronary perfusion pressure are important, which were
shown to exert opposite effects on subendocardial conductance
(8). These possible mechanical pathways were not considered
in earlier studies on the effects of ␣1-receptor blockade.
Interaction of mechanisms affecting HMR. The vasodilatory
effect of urapidil on HMR has to be discerned from concurrent
changes in other major determinants of hyperemic coronary
resistance such as coronary pressure and DTF. Diastolic duration and perfusion pressure act in concert to alter microvascular
resistance of the maximally vasodilated bed (32). The distending effect of coronary pressure on resistance vessels at maximal vasodilation causes HMR to vary in a direction opposite to
a pressure change (14, 35). The compressive effects of heart
contraction on intramural vessels decrease when DTF is increased. Animal studies showed that the sensitivity of HMR for
DTF depends on coronary pressure (8). These studies also
demonstrated that the pressure dependence of HMR holds for
all layers in the myocardium, whereas the DTF effect is absent
in the subepicardium and increases toward the subendocardium. In our study, we were not able to measure transmural
differences of myocardial resistance and had to rely on the
lumped hyperemic resistance downstream from the epicardial
measurement location. Actual changes in DTF after urapidil
administration were rather small in the present study despite
the significant upward shift in the DTF-heart rate relation (see
Fig. 3). Variations in coronary pressure were relatively larger,
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n
Baseline CFV, cm/s
Systolic
Diastolic
Hyperemic CFV, cm/s
Systolic
Diastolic
Pa, mmHg
Systolic
Diastolic
Pd, mmHg
Systolic
Diastolic
RPP, beats 䡠 min⫺1 䡠 mmHg⫺1
FFR
CFVR
HMR, mmHg 䡠 s/cm
Heart rate, beats/min
RR interval, s
Systolic
Diastolic
DTF
DTFC
Stent
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EFFECT OF URAPIDIL ON DIASTOLIC TIME FRACTION
and its distending effect on dilated resistance vessels occurs
across all myocardial layers and, hence, the perfusion enhancing effect of ␣-receptor blockade could only be discerned in the
group with minimal coronary pressure changes. Similar effects
could have been present in previous studies on the effect of
␣-receptor blockade after PCI. However, in none of those
studies was intracoronary pressure and flow velocity measured
simultaneously, and the effect of changes in coronary pressure
on microvascular resistance could thus not be divorced from
that of ␣-blockade in this scenario.
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Fig. 3. Example of DTF-heart rate relations for a patient at rest (top) and
during maximal vasodilation (bottom) showing measurements in the target
vessel after percutaneous coronary intervention (balloon angioplasty and stent
placement) and after urapidil. Linear regressions were obtained for respective
data before and after urapidil administration. After ␣1-blockade, the DTF-heart
rate relation shifted upward (P ⬍ 0.001). Actual DTF did not change due to an
increase in heart rate after urapidil (white arrow). Representative values for
DTFC (dashed left arrows) were assessed at center heart rate (vertical line).
PTCA, percutaneous transluminal coronary angioplasty.
Potential mechanisms for DTF increase after ␣-blockade.
Pharmacological agents can have a significant effect on diastolic duration (3, 17). Urapidil is a selective ␣1-antagonist,
which has a central hypotensive effect without reflex tachycardia due to serotonergic activation (2, 6, 29). Urapidil has a
90-fold larger preference for ␣1- than for ␣2-receptors (6). To
some degree it causes presynaptic ␣2-blockade and thereby
␤-receptor stimulation and increased norepinephrine release
(13, 28), which shortens the duration of systole and could allow
for an increase in the duration of diastole at a given heart rate.
However, all but one patient received ␤-blocking medication,
which limits the effectiveness of this mechanism.
Merkus et al. (24) demonstrated in an animal study an
inverse nonlinear relation between DTF and intracoronary
perfusion pressure and flow, suggesting a possible protective
mechanism whereby DTF increases when coronary perfusion
is impaired distal to a stenosis. However, this regulatory
mechanism only takes action at perfusion pressure below
50 – 60 mmHg, whereas average distal pressure after PCI was
⬎90 mmHg in our study group.
From the effect of urapidil on DTFC it is clear that urapidil
influences the mechanical function of the heart. There is no
reference in the literature directly relating ␣-adrenoreceptors
and DTF. A possible link exists via stimulation of myocardial
␣1-adrenergic receptors, which has been shown to exert a
positive inotropic effect in a large number of species including
humans (21, 26) and is associated with a prolongation of
contraction (15, 22). Hence, ␣1-receptor blockade by urapidil
may counteract this prolongation and thereby increase DTF.
Interestingly, cardiac myocytes have been shown to release a
substance that stimulates the production of the potent vasoconstrictor endothelin-1 in coronary microvessels in response to
␣1-adrenergic stimulation, which is blocked by the administration of an ␣-adrenergic antagonist (33) and augmented by
decreased bioavailability of nitric oxide (25, 34), a hallmark of
endothelial dysfunction associated with atherosclerotic coronary artery disease. Regulation of DTF may be an additional
player in this scenario.
Methodological considerations. Because in the present study
heart rate in individual patients did not change spontaneously
by ⬎20 –25 beats/min throughout the protocol, we fitted the
DTF-heart rate relations by a linear rather than a curvilinear
relationship, which is obtained over a larger range of heart
rates, usually achieved by pacing (3, 4). Due to the pressure
dependence of DTF (24), we also did not use any measurements obtained in the presence of a stenosis for the DTF-heart
rate regression lines before ␣-blockade, to avoid mixing DTF
values obtained at substantially lower perfusion pressures.
We defined systole as the period between the ECG R-peak
and the dicrotic notch on the Pa signal. In that way systolic time
includes both the isovolumic contraction phase and the left
ventricular ejection period. It is possible that the beneficial
effect of urapidil is partly the result of improved relaxation
after the occurrence the dicrotic notch. However, although the
absolute magnitudes of DTF might have been different for a
different definition of systolic duration, it is unlikely that the
relative changes in DTF would have been affected (24).
Epicardial vessel dilation after urapidil could cause an increase in flow to be underestimated when assessed by flow
velocity. Coronary blood flow was not determined in the
present study since its estimation from angiographic vessel
EFFECT OF URAPIDIL ON DIASTOLIC TIME FRACTION
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dimensions and velocity is subject to simplifying assumptions
and prone to errors, especially for angiograms obtained during
adenosine-induced vasodilation. It also would have required
additional contrast injections and radiation exposure, which we
tried to limit in our study. All patients received intracoronary
nitroglycerin before stent placement to relax large vessel tone
and minimize active changes in vessel caliber. We therefore
consider epicardial vessel dilation unlikely in our study group,
in particular since observed hyperemic velocity changes were
opposite to changes in HMR after urapidil for both pressure
groups shown in Fig. 4.
Left ventricular pressure (LVP) was not measured, and a
possible effect of changes in end-diastolic LVP on coronary
hemodynamics could not be assessed. However, ␣1-adrenergic
stimulation has previously not been shown to alter end-diastolic LVP in humans (21), and changes induced by intracoronary urapidil administration are therefore rather unlikely.
Our choice for ␣1-receptor blockade was prompted by the
prominent vascular effect of this subtype observed in earlier
studies on PCI-induced vasoconstriction (12, 27) and the demonstrated cardiac myocyte-mediated effects upon ␣1-adrenergic stimulation (21, 26, 33). With the consideration of the
preferential sensitivity of coronary arterioles to ␣2-adrenergic
stimulation, it would certainly be interesting to extend the
investigation to ␣2-blocking agents.
The size of our study group was small, and although the
effect of ␣1-blockade on heart rate-independent DTFC was
significant, with a marked reduction in HMR in the constant
coronary pressure group, future studies using combined intracoronary pressure and flow velocity measurements should be
carried out in a larger population to confirm the urapidil-related
mechanisms and to further investigate potential implications
for functional parameters.
AJP-Heart Circ Physiol • VOL
Implications. Our data revealed interactive effects that occurred after ␣1-receptor blockade. Administration of urapidil
resulted in a significant elevation of the DTF-heart rate relationship, effectively prolonging diastolic perfusion time irrespective of heart rate. Additionally, coronary perfusion pressure, which has been shown to increase HMR in humans (34),
was reduced after urapidil. Animal microsphere studies have
shown a beneficial effect of prolonged DTF via an enhanced
subendocardial perfusion (1, 8). The observed increase in
DTFC in the present study, although small, may well be of
clinical importance, since microsphere studies of myocardial
perfusion (1) have shown that a 1% increase in DTF increases
subendocardial flow by 2.6% to 6.1%, which for the present
3.1% prolongation in DTFC translates to a potential 18.3%
increase in subendocardial perfusion. This effect would be on
top of the HMR-reducing effect of urapidil by pharmacological
pathways involving the relief of constricted resistance vessels.
Conclusion
We conclude that ␣1-receptor blockade after coronary angioplasty produced an upward shift in the DTF-heart rate
relationship, resulting in a modest but significant prolongation
of DTF at a given heart rate. This suggests a possible adjunctive mechanism to the well-established beneficial effect of
urapidil after PCI via an improvement in subendocardial perfusion, which is critically dependent on DTF.
ACKNOWLEDGMENTS
We acknowledge the skilled assistance of the clinical and nursing staff at
our cardiac catheterization laboratory. Present address for C. Kolyva: Brunel
Institute for Bioengineering, Brunel Univ. West London, Uxbridge, UK.
295 • NOVEMBER 2008 •
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Fig. 4. Individual patient data showing Pd, DTF, and HMR
before and after ␣1-receptor blockade. The solid gray line in
each graph is the identity line. Hyperemic Pd and DTF
remained essentially constant after urapidil in 6 patients (F),
who had a 10% lower HMR, attributed to the vasodilating
action of urapidil. In the other 5 patients (E), the decrease in
Pd caused a 14% increase in HMR. No systematic distinction between these 2 groups existed for DTF.
H2060
EFFECT OF URAPIDIL ON DIASTOLIC TIME FRACTION
GRANTS
This study was funded in part by the Netherlands Heart Foundation Grants
2000.090 and 2006B186.
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AJP-Heart Circ Physiol • VOL
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