(Circulation. 1996;93:1380-1387.)
© 1996 American Heart Association, Inc.
Articles |
Normalization of Abnormal Coronary Vasomotion by Calcium Antagonists in Patients With Hypertension
From Cardiology, University Hospital, Zürich, Switzerland.
Correspondence to O.M. Hess, MD, Cardiology, University Hospital, Rämistr 100, 8091 Zürich, Switzerland.
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Abstract |
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Background Endothelial dysfunction with a loss of endothelium-dependent vasodilation has been reported in patients with arterial hypertension. The purpose of the present study was to evaluate coronary vasomotor response to dynamic exercise in patients with coronary artery disease with and without arterial hypertension and to determine the effect of calcium antagonists on coronary vasomotion.
Methods and Results Cross-sectional areas of a normal
and a stenotic coronary vessel segment were examined in
79 patients with coronary artery disease at rest and during
supine bicycle exercise (Ex). Change in luminal area after acute
administration of a calcium antagonist (diltiazem or
nicardipine), during exercise, and after sublingual
nitroglycerin (percent change compared with rest=100%)
was assessed by biplane quantitative coronary arteriography.
Patients were divided into two groups: Group 1 (control) consisted of
48 patients without (normotensive subjects, n=30; hypertensive
subjects, n=18) and group 2 of 31 patients with (normotensive subjects,
n=15; hypertensive subjects, n=16) pretreatment with a calcium
antagonist immediately before exercise. The groups did not
differ with regard to clinical characteristics or
hemodynamic data measured during exercise. Mean aortic
pressure at rest, however, was significantly increased in hypertensive
patients compared with normotensive subjects in group 1 (103 mm Hg
versus 92 mm Hg, P<.01) and group 2 (110 mm Hg versus 98 mm
Hg, P<.025). In group 1, exercise-induced vasomotor
response was significantly different between normotensive and
hypertensive patients in normal (+20% versus +1%, P<.003)
and stenotic vessels (-5% versus -20%,
P<.025). However, in group 2 there was coronary
vasodilation in normotensive and hypertensive patients for both normal
(
Ex +23% versus +21%, P=NS) and stenotic vessel
segments (+24% versus +26%, P=NS).
Conclusions Abnormal coronary vasomotion during exercise can be observed in hypertensive patients with reduced vasodilator response in normal arteries and enhanced vasoconstrictor response in stenotic arteries. Calcium antagonists prevent the abnormal response of normal and stenotic coronary arteries to exercise in hypertensive patients and thus may compensate for endothelial dysfunction with reduced vasodilator response to exercise.
Key Words: arteries • hypertension • vasoconstriction • vasodilation • exercise
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Introduction |
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Arterial hypertension is associated with morphological and functional alterations of the endothelium, such as an increase in endothelial cell volume,1 an increased extracellular matrix,2 and an increase in vascular responsiveness to vasoconstrictor stimuli.3 In hypertensive animals, impairment of endothelium-dependent relaxation is probably due to a reduced release of endothelium-derived relaxing factors or nitric oxide.4 5 6 7 8 9 Similar data have been obtained with acetylcholine in hypertensive patients.10 11 12 13 14 15 16
Previous investigations17 18 19 20 21 studied the effect of calcium channel blockers on coronary vasomotion. This class of drugs prevents narrowing of stenotic coronary arteries and induces vasodilation in normal segments of diseased arteries. However, there are no reports on the effect of calcium antagonists on coronary vasomotion in hypertensive patients with coronary artery disease. Therefore, the present study was undertaken to determine coronary vasomotor response in hypertensive individuals with coronary artery disease and to evaluate the effect of acutely administered calcium antagonists in this subset of patients. Coronary vasomotion was examined under a physiological stimulus, eg, dynamic exercise, which reflects the natural behavior of the coronary vessels better than pharmacological interventions.22 23
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Methods |
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Study Population
Seventy-nine patients (75 men, 4 women) were included in the present analysis. Patients were divided into two groups: those who were and those who were not treated with calcium channel blockers before arteriography. No randomization was performed, but patients treated with calcium antagonists were studied on a prospective basis, whereas the control group was selected on a retrospective basis. The patient groups were subdivided according to the presence or absence of arterial hypertension. Group 1 consisted of 48 men (mean age, 54±8 years) with coronary artery disease but without pharmacological intervention (control group). Thirty patients in this group were normotensive, with a mean aortic pressure at rest of 92±14 mm Hg, and 18 were hypertensive, with a significantly increased mean aortic pressure of 103±15 mm Hg (P<.01). Group 2 consisted of 27 men and 4 women (mean age, 58±8 years) with coronary artery disease and pretreatment with calcium antagonists before coronary arteriography. Fifteen patients were normotensive, with a mean aortic pressure at rest of 98±9 mm Hg, and 16 were hypertensive, with a significantly increased mean aortic pressure of 110±12 mm Hg (P<.025). In both groups, a normal and a stenotic vessel segment were evaluated. The normal vessel segment did not show segmental stenosis or luminal irregularities. In all patients, upright bicycle exercise testing was performed the day before coronary arteriography.
Inclusion Criteria
Patients were selected from a group of patients undergoing
bicycle exercise during coronary arteriography on the basis of
the following criteria: (1) stable, exercise-induced angina
pectoris; (2) written informed consent to undergo the exercise study;
(3) qualitatively good biplane angiogram for quantitative evaluation;
(4) clearly visible coronary arteries with a normal and a
stenotic vessel segment (two different vessels) for
quantitative evaluation (in five patients, the right coronary
artery was used; in all others, the left coronary artery was
used); and (5) normal vessel segment chosen from a nonstenosed artery
and the stenotic vessel segment from a diseased vessel segment
with a localized stenosis of >50% (quantitatively assessed).
The stenosed vessel segments (culprit lesions) were chosen from the
proximal two thirds of the respective arteries.
Exclusion Criteria
Patients were excluded in the presence of unstable angina
pectoris, diffuse three-vessel disease, inability to perform
exercise angiography, recent myocardial infarction (<1 month), large
infarction with hypokinetic or akinetic regions, or renal or hepatic
disease.
Definition of Arterial Hypertension
Hypertension was defined as a history of high blood pressure
(diastolic pressure 
95 mm Hg and/or systolic
values 160 mm Hg) and sustained blood pressure elevation documented
during hospitalization in a drug-free period (drugs discontinued 24
hours before cardiac catheterization). Patients were
considered to have normal blood pressure if continuous blood pressure
readings showed diastolic values <90 mm Hg and
systolic values <140 mm Hg. Control blood pressure was
recorded at the time of cardiac catheterization.
Patients with secondary causes of hypertension and evidence of damage
to end organs were excluded.
Definition of Coronary Risk Factors
Hypercholesterolemia (>200 mg/dL),
cigarette smoking, family history (coronary artery disease in
one patient's parents or in a sibling <60 years old), obesity (body
mass index 28 kg/m2), and diabetes mellitus (five
patients with insulin-dependent diabetes mellitus) were evaluated
in the present analysis.
Cardiac Catheterization
Informed consent was obtained from all patients. Medication was
stopped at least 24 hours before cardiac
catheterization. Premedication consisted of 10 mg
chlordiazepoxide administered orally 1 hour before the procedure.
Aortic pressure was measured with an 8F Judkins catheter, and
pulmonary artery pressure was determined with a 6F pacing
catheter with a side hole for pressure measurements. Biplane left
ventricular angiography was performed in all patients,
followed by diagnostic coronary arteriography. An
interval of at least 10 minutes was allowed for dissipation of the
effect of the contrast material. Nonionic contrast material (Iopamiro
370: iopamidol 755.2 mg/mL, trometamol 1 mg/mL) was used for
quantitative coronary angiography to minimize hyperemic
reactions with transient changes in coronary blood flow.
Quantitative coronary angiography was performed in the right
and left anterior oblique projection, but in some patients
cranio-caudal angulation was necessary for proper visualization of
the stenotic segment. Cinefilm was used as a data carrier
(filming rate, 50 frames/s-1).
Study Protocol
At the end of diagnostic
catheterization, biplane coronary arteriography
was performed with the patient's feet attached to the bicycle
ergometer (Siemens-Elema AG, model 380B). Exercise was begun at 50 to
75 W and was increased every 2 minutes in increments of 25 to 50 W.
Coronary arteriography was done at the end of each exercise
level with patients holding their breath during injection of the
contrast medium. Arteriograms obtained at maximum exercise level were
used for analysis of coronary vasomotion. In group 1,
no vasoactive substances were administered before exercise. In group 2,
an equipotent dose of a calcium channel blocker was given before
exercise: In 17 patients, nicardipine 0.2 mg IC (a tenth
of the systemic dose) was injected over 30 seconds, and in 14 patients,
diltiazem 2 to 3 mg IC was administered over 4 to 5 minutes. The doses
were chosen according to previously established dose-response
curves that have indicated maximal vasodilation with these
doses.24 25 26 Immediately after administration of the
calcium channel blocker, a second angiogram was acquired. Then, bicycle
exercise was begun as described above. The exercise test was terminated
because of angina pectoris, fatigue, or ST-segment depression >0.2 mV.
At the end of the exercise test, nitroglycerin 1.6 mg
was administered sublingually. Biplane coronary arteriography
was repeated 5 minutes thereafter. There were no complications related
to the study protocol.
Quantitative Coronary Arteriography
Quantitative evaluation of biplane coronary arteriograms
was performed with a semiautomatic computer system, as described
previously.27 28 29 Interobserver variability for this system
is 4.1% and intraobserver variability is 2.1%.
Quantitative analysis was performed in a normal proximal vessel
segment of a coronary artery unaffected by luminal
irregularities or stenoses and in a stenotic vessel
segment. Measurement sites were selected on the basis of the following
criteria: (1) sufficient filling of the vessel with
radiographic contrast medium, (2) high-quality
end-diastolic cineframe without motion artifacts, (3)
straightness of the vessel segment to be analyzed, and (4)
biplane x-ray views. Angiograms were measured by observers blinded
with regard to the variables of interest as well as to the actual
study sequence (rest, exercise, or nitroglycerin).
Luminal area changes were determined during exercise (Ex, percent
change compared with rest=100%) as well as after administration of
sublingual nitroglycerin (Ntg, percent change
compared with rest=100%).
Statistical Analysis
Between-group comparisons with regard to clinical,
hemodynamic, and angiographic data were performed by
one-way ANOVA for continuous variables followed by
Scheffé's test if the probability value was significant
(P<.05). Fisher's exact test was used for categorical
variables. All values are expressed as mean±SD. In the figures,
values are expressed as mean±SEM.
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Results |
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Patient Characteristics
Gender distribution, age, functional classification according to the New York Heart Association, and body mass index were comparable in all groups (Table 1
). There was no difference among the
study groups with regard to patient history, frequency of angina
pectoris, or myocardial infarction. Hypertensive patients in the
control group had a lower total number of diseased coronary
arteries compared with all other groups (P<.03), but
normotensive as well as hypertensive patients showed the same
percentage (P=NS) of coronary artery disease of the
right and left arteries in group 1 (normotensive patients, 57% and
93%, respectively; hypertensive patients, 39% and 89%, respectively)
and group 2 (normotensive patients, 53% and 93%, respectively;
hypertensive patients, 50% and 100%, respectively).
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Risk factors for coronary artery disease were evenly distributed among the groups. Patients with hypertension and pretreatment with calcium antagonists smoked less than hypertensive patients in the control group (P<.02). Normotensive patients in group 2 showed less use of calcium channel blockers before hospitalization (P<.03).
Exercise and Hemodynamic Data
Exercise workload in the upright position was similar within
groups 1 and 2 but was slightly higher in hypertensive patients in the
control group compared with those treated with calcium
antagonists (143±33 versus 118±36 W, P<.04),
although percent workload (percent of the age-, sex-, and
height-corrected normal value) was not different among hypertensive
patients in the two groups (95±19 versus 87±21 W, P=NS)
(Table 2). The frequency of angina pectoris and
ST-segment depression during exercise did not differ among the
subgroups. Left ventricular end-diastolic
volume index, left ventricular ejection fraction, and left
ventricular mass were similarly distributed among the
subgroups (Table 2).
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In the supine position, exercise workload was lower than in the upright
position but was similar within groups 1 and 2 and slightly higher in
hypertensive patients in group 1 compared with those in group 2
(111±30 versus 88±25 W, P<.02), although percentage
workload was not different in the two groups (73±19% versus 65±16%,
P=NS) (Table 3). Changes in heart rate and
mean pulmonary artery pressure during exercise were comparable
in the subgroups. Mean aortic pressure increased significantly only in
patients without administration of calcium antagonists
(P<.001), whereas the increase was not significant in
patients pretreated with calcium channel blockers. All variables
returned to control levels after administration of sublingual
nitroglycerin. Mean aortic pressure at rest and during
exercise differed significantly between normotensive and hypertensive
patients in the control group (P<.01 for both exercise
levels). Mean aortic pressure during exercise did not differ between
normotensive and hypertensive patients in the group pretreated with
calcium antagonists.
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Coronary Angiographic Data
Angiographically normal vessels in the control group (group 1)
were similar in size in the two subgroups, but the increase in
coronary artery luminal area during exercise (Ex, change in
percent of control value) differed significantly between normotensive
(+20±24%) and hypertensive (+1±9%) patients (P<.003)
(Fig 1). Mean percent area stenosis (range, 58%
to 77%) and mean vessel size of the stenotic vessels were also
similar in the two subgroups, but there was a significant difference in
percent change of the coronary artery luminal area
(P<.025) between normotensive (-5±22%) and
hypertensive (-20±19%) patients during exercise (Fig 1).
However, after administration of the calcium antagonist
(group 2), coronary vasodilation in normotensive and
hypertensive patients was preserved in both normal (Ex, +23% versus
+21%; P=NS) and stenotic vessels (+24% versus
+26%; P=NS). Area stenosis in group 2 ranged from
60% to 99%.
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Administration of 1.6 mg sublingual nitroglycerin
at the end of exercise was associated with an increase in mean vessel
area in normotensive as well as hypertensive patients in group 1
(normal vessel: 35±25% versus 23±14%, P<.03;
stenotic vessel: 14±17% versus 15±20%, P=NS) and
group 2 (normal vessel: 39% versus 35%, P=NS;
stenotic vessel: 44% versus 36%, P=NS) (Fig 2). Between nitroglycerin and calcium
antagonists, there was an additive effect on maximal
vasodilation in normal and stenotic vessels of the hypertensive
patients but only in the stenotic vessels of the normotensive
patients (Figs 3 and 4).
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Discussion |
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Previous Studies
A number of pharmacological agents, such as serotonin, norepinephrine, vasopressin, papaverine, and primarily acetylcholine, have been used to evaluate the vasomotor response of epicardial coronary arteries in humans and in experimental animals. In most of these studies, hypertensive patients exhibited vasoconstriction of epicardial coronary arteries in response to intracoronary acetylcholine.30 31 Although endothelium-dependent vasodilation was impaired in microvessels of patients with hypertension in some studies,32 33 this was not observed in others.34 35 A recent investigation35 found impaired endothelium-mediated relaxation in patients with hypercholesterolemia and advanced age but not in individuals with arterial hypertension. Hence, endothelial dysfunction is not uniformly distributed and differs in different models and vascular beds.
The current study protocol used a different approach to induce endothelium-dependent vasodilation, namely, dynamic exercise. Although the physiological effects of exercise on vasomotion are probably more complex than those of pharmacological compounds, this stimulus for coronary vasomotion reflects the daily activities of the investigated patients better than pharmacological interventions. There were four important findings in the present study. First, hypertensive patients with angiographically documented coronary artery disease show a markedly blunted vasodilatory response of nonstenotic vessels compared with normotensive control subjects. Second, hypertensive patients elicit coronary vasoconstriction of stenotic vessel segments. Third, acutely administered calcium antagonists are able to prevent abnormal vasomotor response of normal and stenotic coronary arteries during exercise in hypertensive patients. Fourth, sublingual nitroglycerin and calcium channel blockers have an additive effect on coronary vasodilation.
Pathophysiological Mechanisms
Hypertension has a direct effect on the arteries that is
characterized by structural changes such as media
hypertrophy, increase in endothelial cell
volume, microvascular rarefaction, and an augmentation of the
extracellular matrix.1 2 36 37 These changes may lead to
impaired endothelium-dependent
relaxation.30 31 Recent human data indicate that
endothelial dysfunction occurs early in the development
of atherosclerosis.38 39 40 41 42 43 44 45 However,
angiography is not a sensitive method for detection of early
atherosclerosis. Thus, undetected
atherosclerosis in angiographically smooth vessels may
account for insufficient vasodilator response.29
In the present study, coronary vasodilation of the normal vessel was reduced in response to exercise, but the endothelium-independent dilator capacity after nitroglycerin was maintained in both hypertensive and normotensive patients. This suggests a preserved function of vascular smooth muscle but a primary defect of the endothelium-dependent regulation of the epicardial coronary arteries in hypertensive patients with coronary artery disease. A vasoconstrictive effect of exercise was observed in the stenotic coronary arteries of patients with hypertension that was not seen in normal arteries. The exact mechanism of this paradoxical vasoconstriction has not yet been elucidated46 47 48 49 but appears to be related to either endothelial dysfunction with attenuation of endothelium-dependent relaxation,50 an enhanced vasoconstriction during exercise due to circulating catecholamines, a Venturi mechanism with collapse of the normal vessel segment within the stenosis,51 and/or enhanced platelet aggregation with release of thromboxane A2 and serotonin.52
Effect of Calcium Channel Blockers
The present study is the first to demonstrate that in
hypertensive patients, the vasomotor response is impaired during
dynamic exercise but is maintained after administration of calcium
channel blockers. Pretreatment with calcium antagonists not
only prevents narrowing of the stenotic coronary
arteries during exercise but induces coronary vasodilation
instead of vasoconstriction at the site of the stenosis. The
exact mode of action of the calcium antagonists on
coronary vasomotion, however, is not clear. One possible
mechanism could be a direct action of these agents on
endothelial function by stimulating the release of the
endothelium-derived vasorelaxing
factor.53 54 Intracellular calcium also plays an important
role in the endothelin-induced contraction,55 56 which
can be attenuated by the application of calcium channel
blockers.57 Recently, LDL receptors were described in
platelets and were associated with the elevation of the calcium
concentration in these cells.58
Two different calcium antagonists were used in the present study, namely, a dihydropyridine (nicardipine) and a benzothiazepine-like substance (diltiazem). Differences among various calcium antagonists have been described with regard to contractility, peripheral vasodilator capacity, AV conduction, and cardioprotection. Dihydropyridines act mainly on the smooth vasculature and have a negative inotropic action with no effect on AV conduction, whereas benzothiazepine-like substances elicit a similar pharmacological action but show an effect on AV conduction. Vasomotor response to exercise was similarly affected by these two drugs, probably because of their strong vasodilator properties on the smooth vasculature. Thus, these two classes of calcium channel blockers have comparable effects on coronary vasomotion, since there were no statistical differences between the two substances with regard to exercise hemodynamics and changes in coronary luminal area.
Alterations of endothelial function are probably a
consequence rather than a cause of high blood pressure, and hence the
degree of endothelial dysfunction and its mechanism
change with increasing severity and duration of hypertension. In animal
models with antihypertensive treatment, reductions of blood pressure
are able to reverse endothelial dysfunction, although
the exact mechanism is not fully understood.54 59 An
interesting observation of the present study is that the
combination of both vasodilating drugs, nitroglycerin
and calcium channel blockers, leads to an additive effect, with maximal
vasodilation of the normal and stenotic coronary
arteries in hypertensive patients (Fig 4
). Apparently, no maximal
coronary vasodilation was achieved with administration of the
calcium antagonists alone, although the doses were chosen
to obtain maximal vasodilation according to previously established
dose-response curves.24 25 26 A similar additive effect
was reported in patients with coronary artery
disease.17 However, the exact mechanism is not clear but
might be related to the different mode of action of the two drugs:
Calcium channel blockers reduce calcium influx into the smooth muscle
cell, whereas nitroglycerin increases cGMP in the
vascular musculature, which not only regulates smooth muscle relaxation
but also has an inhibitory effect on endothelin
production.60 61
Study Limitations
The postulation of endothelial dysfunction remains
speculative, since no histological proof of the
presence or absence of an atherosclerotic lesion of the normal vessels
is available in the present study. However, all patients had
evidence of atherosclerosis, and thus a
disturbance of endothelial function is very
likely. Intraoperative echocardiographic studies and
intravascular ultrasound have demonstrated that in vivo
coronary atherosclerosis is far more extensive
than predicted by coronary arteriography.62
Patients in group 2 were studied after they received a calcium channel blocker, and thus it cannot be ruled out that the response to exercise was already normal before treating patients with this substance. However, from an ethical point of view, bicycle exercise cannot be repeated twice just for scientific purposes because this would have prolonged the research protocol for a considerable time period, and the second exercise test would have been of limited significance because of reduced exercise capacity and fatigue.
Only the acute effects of intracoronary calcium antagonists were studied, which precludes any firm statement on the long-term efficacy of the drugs. Although acute and chronic effects may be different (development of tolerance), it is not likely that these effects are different with regard to coronary vasomotion and endothelial function.
One-day washout of all medication may not be sufficient to achieve a drug-free interval. However, there was no difference in drug use in the four subgroups except for a lower incidence of calcium antagonists in normotensive patients in group 2, which may, if anything, have influenced our results in a negative way. Thus, previous antianginal and antihypertensive medication appears not to have an impact on coronary vasomotor response in the present study.
Although the study groups were similar (Table 1), there were some
slight differences with regard to the number of diseased vessels and
smoking habit. Since no randomization was performed and patients were
studied on a consecutive basis, these differences may have adversely
affected the results of the present study. However, if anything,
this fact would have attenuated but not enhanced the observed
differences.
Conclusions
The present study is the first to demonstrate a preserved
vasodilatory response of epicardial coronary arteries to
exercise with calcium channel blockers in hypertensive patients with
coronary atherosclerosis. The impaired
vasomotor response to exercise suggests a change in
endothelial function with an attenuated release of the
endothelium-derived relaxing factor.
Received August 23, 1995; revision received October 23, 1995; accepted October 29, 1995.
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