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Circulation. 1996;93:1380-1387

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(Circulation. 1996;93:1380-1387.)
© 1996 American Heart Association, Inc.

Articles

Normalization of Abnormal Coronary Vasomotion by Calcium Antagonists in Patients With Hypertension

Jürgen Frielingsdorf, MD; Christian Seiler, MD; Philipp Kaufmann, MD; Giuseppe Vassalli, MD; Thomas Suter, MD; Otto M. Hess, MD

From Cardiology, University Hospital, Zürich, Switzerland.

Correspondence to O.M. Hess, MD, Cardiology, University Hospital, Rämistr 100, 8091 Zürich, Switzerland.


*    Abstract
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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 ({Delta}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


*    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


*    Methods
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 up arrowIntroduction
 *Methods
down arrowResults
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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 ({Delta}Ex, percent change compared with rest=100%) as well as after administration of sublingual nitroglycerin ({Delta}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.


*    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 1Down). 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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  		Table 1. Exercise-Induced Coronary Vasomotor Response in Normotensive and Hypertensive Patients With and Without Administration of Systemic Calcium Antagonists: Patient Characteristics

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 2Down). 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 2Down).


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  		Table 2. Exercise Data Before Angiography and Left Ventricular Values in Normotensive and Hypertensive Patients With and Without Administration of Systemic Calcium Antagonists During Angiography

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 3Down). 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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  		Table 3. Exercise-Induced Coronary Vasomotor Response in Normotensive and Hypertensive Patients With and Without Administration of Systemic Calcium Antagonists: Exercise and Hemodynamic Data

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 ({Delta}Ex, change in percent of control value) differed significantly between normotensive (+20±24%) and hypertensive (+1±9%) patients (P<.003) (Fig 1Down). 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 1Down). However, after administration of the calcium antagonist (group 2), coronary vasodilation in normotensive and hypertensive patients was preserved in both normal ({Delta}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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  		Figure 1. Luminal area change during exercise ({Delta}Ex, %) of normal and stenotic coronary arteries in hypertensive patients and normotensive control subjects. Values are mean±SEM.

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 2Down). 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 3Down and 4Down).



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  		Figure 2. Luminal area change of normal and stenotic coronary arteries after pretreatment with calcium antagonists before exercise ({Delta}Ca2+) and after administration of sublingual nitroglycerin at the end of exercise ({Delta}Ntg, %) in hypertensive patients and normotensive control subjects. Values are mean±SEM. There is no statistically significant difference between normotensive and hypertensive patients after administration of calcium antagonists (Ca2+) or after nitroglycerin (Ntg). Values are mean±SEM.



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  		Figure 3. Luminal area change in percent of resting cross-sectional area ({Delta}CSA) after treatment with calcium antagonists (Ca2+) and during exercise (Ex) as well as after 1.6 mg sublingual nitroglycerin (Ntg) in normotensive patients. The normal vessel shows normal behavior during exercise with or without Ca2+ treatment. However, the stenotic vessel shows an abnormal response (vasoconstriction) to exercise that is reversed after pretreatment with calcium channel blockers. There is an additive effect of Ca2+ and nitroglycerin on maximal vasodilation of the stenotic but not the normal vessel. Values are mean±SEM.



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  		Figure 4. Luminal area change in percent of resting cross-sectional area ({Delta}CSA) after treatment with calcium antagonists (Ca2+) and during exercise (Ex) as well as after 1.6 mg sublingual nitroglycerin (Ntg) in hypertensive patients. The reaction of the normal vessel to exercise is abnormal in hypertensive patients but is normalized after administration of Ca2+. The same response can be observed in the stenotic vessel, although the abnormal response to exercise is even more pronounced than in the normal vessel. Again, the vasoconstrictive response is eliminated by calcium channel blockers, and there is an additive effect between Ca2+ and nitroglycerin not only in the stenotic but also the normal vessel. Values are mean±SEM.


*    Discussion
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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 4Up). 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 1Up), 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.


*    References
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 *References
 

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