Author + information
- Received February 12, 1996
- Revision received May 10, 1996
- Accepted May 14, 1996
- Published online October 1, 1996.
- JÜRGEN FRIELINGSDORF,
- PHILIPP KAUFMANN,
- CHRISTIAN SEILER,
- GIUSEPPE VASSALLI,
- THOMAS SUTER and
- OTTO M HESS*
- ↵*Address for correspondence: Dr. Otto M. Hess, Division of Cardiology, University Hospital, Rämistrasse 100, 8091 Zurich, Switzerland.
Objectives. This study sought to evaluate the effect of dynamic exercise on coronary vasomotion in hypertensive patients in the presence and absence of coronary artery disease.
Background. Endothelial dysfunction with abnormal coronary vasodilation in response to acetylcholine has been reported in patients with arterial hypertension.
Methods. Coronary artery dimensions of a normal and stenotic vessel segment were determined in 64 patients by biplane quantitative coronary arteriography at rest and during supine bicycle exercise. Patients were classified into two groups: 20 patients without evidence of coronary artery disease (10 normotensive, 10 hypertensive [group 1]) and 44 patients with coronary artery disease (26 normotensive, 18 hypertensive [group 2]). Both groups were comparable with regard to clinical characteristics, serum cholesterol levels, body mass index, exercise capacity and hemodynamic data.
Results. Mean aortic pressure was significantly higher in hypertensive than normotensive patients. Exercise-induced vasodilation of the normal vessel segment was similar in normotensive and hypertensive patients without coronary artery disease (group 1), namely, +19% versus +20%. However, in hypertensive patients with coronary artery disease, exercise-induced vasodilation was significantly less in both normal and stenotic vessel segments than in normotensive subjects (+1% vs. +20% for normal [p < 0.003] and −20% vs. −5% for stenotic vessels [p < 0.025]). Administration of 1.6 mg of sublingual nitroglycerin at the end of exercise led to a normalization of the vasodilator response in normotensive as well as hypertensive patients. However, this response became progressively abnormal in group 2 when coronary artery disease was present.
Conclusions. In the absence of coronary artery disease, the vasomotor response to exercise is normal in both normotensive and hypertensive patients. However, in hypertensive patients with coronary artery disease, an abnormal response of the coronary vessels can be observed, with a reduced vasodilator response to exercise in normal arteries but an enhanced vasoconstrictor response in stenotic arteries. This behavior of the epicardial vessels during exercise suggests the occurrence of endothelial dysfunction (i.e., functional defect) that is not evident in the absence of coronary artery disease. Nitroglycerin reverses impaired coronary vasodilation, but this effect is blunted in the presence of coronary artery disease (i.e., structural defect).
The endothelium plays an important role in the regulation of vascular smooth muscle tone by the release of relaxing and constricting factors. Endothelium-derived relaxing factor , which has been recently identified as nitric oxide , is a major determinant of vascular relaxation. However, the endothelium also releases vasoconstricting factors , but its exact role is still not yet clearly defined in humans. Arterial hypertension is associated with morphologic and functional alterations of the endothelium, such as increases in endothelial cell volume , extracellular matrix and vascular responsiveness to vasoconstrictor stimuli . In hypertensive animals, there is evidence that endothelium-dependent relaxation is impaired, probably due to a reduced release of endothelin-derived relaxing factor or nitric oxide [7–12]. In human studies, various pharmacologic agents, mainly acetylcholine, have been used to evaluate the response of the endothelium in hypertensive patients [13–26].
Depending on the presence or absence of atherosclerosis, the results of these studies have been somewhat controversial; some have reported the occurrence of endothelial dysfunction, others have not. Thus, the purpose of the present study was to evaluate coronary vasomotion in patients with essential hypertension and normal or diseased coronary arteries using exercise as a physiologic vasodilator stimulus. This study should help to define the role of the endothelium in the regulation of coronary vasomotor tone in normotensive and hypertensive patients during exercise.
Study patients. Sixty-four patients (61 men, 3 women) assigned to coronary arteriography were classified into two groups according to the presence or absence of coronary artery disease. The two groups were further classified into normotensive and hypertensive subjects. Group 1 included 17 men and 3 women (mean [±SD] age 50 ± 8 years) with normal coronary arteriographic findings. Ten patients in this group were normotensive, with a mean aortic pressure at rest of 90 ± 12 mm Hg, and 10 were hypertensive, with a significantly increased mean aortic pressure of 106 ± 16 mm Hg (p < 0.02). Group 2 included 44 men (mean age 53 ± 8 years) with angiographic evidence of coronary artery disease. In this group a normal vessel (group 2a) and a stenotic vessel segment (group 2b) were evaluated. Only patients with one- or two-vessel disease were included in group 2; an average of 1.8 ± 0.8 vessels/patient were involved. Twenty-six patients were normotensive, with a mean aortic pressure at rest of 92 ± 12 mm Hg, and 18 were hypertensive, with a significantly increased mean aortic pressure of 103 ± 15 mm Hg (p < 0.01). All patients performed upright bicycle exercise testing on the day before coronary arteriography.
Inclusion criteria. Study patients were selected from a cohort evaluated by quantitative coronary angiography on the basis of following criteria: 1) written informed consent to undergo the exercise study; 2) qualitatively good biplane angiogram for quantitative evaluation; 3) angiographically smooth coronary arteries in group 1 (lumenal irregularities were excluded) and patients with coronary artery disease with a normal as well as a stenotic vessel segment on the angiogram (group 2); 4) the normal vessel segment was 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 lesion) were chosen only from the proximal two thirds of the respective artery.
Exclusion criteria. Patients were excluded if they had severe or unstable angina pectoris, diffuse three-vessel disease, a recent myocardial infarction (<1 month), infarction with hypokinetic or akinetic myocardial regions, renal or hepatic disease or a history of diabetes mellitus.
Definition of arterial hypertension.Hypertension was defined as a history of high blood pressure (diastolic pressure ≥95 mm Hg or systolic pressure ≥160 mm Hg, or both) requiring long-term therapy and sustained blood pressure elevation documented during the hospital stay over a drug-free period (drugs discontinued 24 h 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. Patients with secondary causes of hypertension and evidence of damage to end-organs were excluded.
Definition of coronary risk factors. Coronary risk factors, such as hypercholesterolemia (>200 mg/100 ml), cigarette smoking, family history (coronary artery disease in one of the patient's parents or sibling <60 years old) and obesity (body mass index ≥28 kg/m2), were evaluated in the present analysis.
Cardiac catheterization. Medication was stopped at least 24 h before cardiac catheterization. Aortic pressure was measured with an 8F Judkins catheter inserted from the groin, 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.
Study protocol. Simultaneous biplane coronary arteriography was carried out in two orthogonal projections to guarantee optimal visualization of the stenotic lesions. A control arteriogram was acquired with the patient's feet attached to the bicycle ergometer (model 380 B, SiemensAlbis AG, Zurich, Switzerland). Exercise was begun at 50 to 75 W and was increased every 2 min in increments of 25 to 50 W. Coronary arteriography was carried out at the end of each exercise level with the patient holding his or her breath during injection of the contrast medium. Arteriograms at maximal exercise level were used for analysis of coronary vasomotion. The exercise test was terminated because of angina pectoris, fatigue or ST segment depression >0.2 mV. At the end of the exercise test, 1.6 mg of nitroglycerin was administered sublingually. Biplane coronary arteriography was repeated 5 min 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 that has been described previously [27–29]. Interobserver variability for this system is 4.1% and intraobserver variability 2.1%.
Quantitative analysis was performed in a proximal vessel segment of a normal coronary artery (group 1) or in an unaffected coronary artery without lumen changes as well as in a stenotic vessel segment (group 2). Measurement sites were selected on the basis of the following criteria: 1) sufficient filling of the vessel with radiographic contrast medium; 2) high quality late diastolic or end-diastolic cine frame without motion artifacts; 3) straightness of the vessel segment to be analyzed; and 4) biplane X-ray views. Angiograms were measured in blinded manner with regard to the variables of interest as well as the actual study sequence (rest, exercise or nitroglycerin). Lumen area changes were determined during exercise (percent change versus rest = 100%) as well as after administration of sublingual nitroglycerin.
Statistical analysis. Between-group comparisons with regard to clinical, hemodynamic and angiographic data were performed by one-way analysis of variance for continuous variables, followed by the Scheffé test if the probability value was significant (p < 0.05). The Fisher exact test was used for categoric variables. Results in text and tables are expressed as mean value ± SD and in figures as mean value ± SEM.
Patient characteristics. Gender distribution, body mass index, New York Heart Association functional classification and frequency of angina pectoris were comparable in the two groups (Table 1). However, normotensive patients without coronary artery disease were younger (p < 0.02) than normotensive subjects with coronary artery disease. In patients with coronary artery disease, normotensive subjects had a larger number of diseased coronary arteries than hypertensive subjects (p < 0.03). Coronary risk factors for coronary artery disease, especially cholesterol, were evenly distributed among the two groups. There was a trend (p < 0.06) to a slightly lesser use of anti-ischemic drugs in normotensive patients without than with coronary heart disease (Table 1).
Exercise and hemodynamic data. Exercise work load (absolute values as well as data in percent of age-, gender- and height-corrected normal values) in the upright position was similar in both groups, namely, 147 ± 39 W (96% of the normal value) in group 1 and 139 ± 27 W (91% of the normal value) in group 2. ST segment depression was 0.12 ± 0.09 mV in group 1 and 0.12 ± 0.13 mV in group 2. The frequency of angina pectoris during exercise did not differ between the two groups. Exercise work load was lower in the supine than the upright position but was similar in both study groups (Table 2), except for normotensive patients with coronary artery disease who performed less exercise than those without coronary artery disease (p < 0.03). Changes in heart rate and mean pulmonary artery pressure at rest, during exercise and after sublingual nitroglycerin administration were also comparable in the two groups. Heart rate, mean pulmonary artery pressure and mean aortic pressure increased significantly during bicycle exercise (p < 0.001 in both groups). These variables returned to baseline values after administration of sublingual nitroglycerin. Mean aortic pressure at rest differed significantly between normotensive and hypertensive patients without (p < 0.02) and with coronary heart disease (p < 0.01). Exercise-induced mean aortic pressure was higher in hypertensive patients with coronary heart disease than in normotensive subjects (p < 0.01). This difference was not significant between normotensive and hypertensive patients without coronary heart disease, probably due to the higher work load in normotensive subjects. Left ventricular function (end-diastolic volume, left ventricular ejection fraction) and left ventricular mass did not differ between the two groups and subgroups (Table 3).
Coronary angiographic data. In patients without coronary artery disease (group 1), normal vessels were similar in size, and the increase in lumen area was comparable during exercise (percent change during exercise in percent of control value) in normotensive (+19 ± 9%) and hypertensive (+20 ± 8%) patients (p = NS) (Fig. 1, left panel). When these data were compared with normal vessels in patients with coronary artery disease (group 2a), there was a significant difference in percent change of the coronary arteries during exercise (p < 0.003) between normotensive (+20 ± 25%) and hypertensive subjects (+1 ± 9%) (Fig. 1, middle panel). In contrast to normal segments, stenotic vessel segments (group 2b) showed exercise-induced vasoconstriction, with a significant difference (p < 0.025) between normotensive (− 5 ± 21%) and hypertensive (−20 ± 19%) patients (Fig. 1, right panel). Lumen area stenosis in group 2b ranged between 58% and 77% (mean 63 ± 19%).
Sublingual administration of 1.6 mg of nitroglycerin after exercise was associated with an increase in lumen area in normotensive as well as hypertensive patients (Fig. 1): +49 ± 24% and +38 ± 11%, respectively, in group 1 (p = NS); +30 ± 24% and +23 ± 14%, respectively, in group 2a (p = NS); and +16 ± 17% and +15 ± 21%, respectively, in group 2b (p = NS). Compared with the changes observed during exercise, vasodilation of all vessels was further enhanced after treatment with nitroglycerin, but the increase in lumen area was gradually smaller when the extent of coronary artery disease increased (Fig. 2); thus, vasodilation was less in group 2a than group 1 (p < 0.05 for normotensive subjects, p < 0.02 for hypertensive subjects) and less in group 2b than group 2a (p < 0.01 for normotensive subjects, p = NS for hypertensive subjects).
To our knowledge, the present study is the first to assess coronary vasomotion in normal subjects and patients with coronary artery disease in response to exercise and to evaluate the effect of hypertension on coronary vasomotor response. There were four important findings: 1) Coronary vasodilation was preserved in normotensive and hypertensive patients without any angiographic evidence of coronary artery disease. 2) Hypertensive patients with angiographically documented coronary artery disease show a blunted vasodilatory response of the “normal” vessel compared with that in normotensive control subjects. 3) Hypertensive patients elicited enhanced vasoconstriction of the stenotic vessel segment during exercise. 4) Maximal vasodilation after nitroglycerin tended to decrease in proportion to severity of disease, suggesting a structural abnormality of the vessel wall. Thus, abnormal coronary vasomotion was found during exercise in patients with hypertension and atherosclerosis. This finding implies that hypertension in conjunction with atherosclerosis has a detrimental effect on the function of the endothelium.
Previous studies. In hypertensive animals, endothelial dysfunction has been suggested to be responsible for the abnormal vasomotor response to pharmacologic stimuli. The underlying pathogenetic mechanism has been thought to be the diminished release of the endothelium-derived relaxing factor which has been identified as nitric oxide [7–12, 30, 31]. In these animal models, hypertension was found to be associated with an impaired relaxation to acetylcholine, adenosine diphosphate and thrombin in the large conductance arteries [8, 9, 12, 31, 32]and small resistance vessels [30, 33]. However, a more recent study could not confirm these findings.
In the forearm vasculature of patients with hypertension, a normal and an impaired vasodilator response of the resistance vessels to acetylcholine was reported [14–19]compared with that in normotensive subjects. The large coronary arteries of hypertensive patients exhibited vasoconstriction of epicardial coronary arteries mainly in response to intracoronary acetylcholine [20, 21]. However, another investigation showed that hypertension was not associated with coronary vasoconstriction after intracoronary acetylcholine. Although previous studies [23, 24]have found endothelium-dependent vasodilation to be impaired in microvessels of patients with hypertension, this finding has not been observed in other reports [25, 26]. A recent investigation described impaired endothelium-dependent relaxation in elderly patients with hypercholesterolemia but not in those with arterial hypertension. Hence, endothelial dysfunction is not uniformly distributed in the coronary and forearm vasculature and differs in different models and vascular beds.
Some coexisting factors may have influenced those results: 1) Small variations in the dose and rate of acetylcholine infusion may influence intraluminal concentration, which can convert vasodilation to vasoconstriction . Furthermore, a heterogenous vasomotor response to acetylcholine in different segments of the same vessel has been described . A different approach to induce coronary vasodilation was used in our study protocol, namely, dynamic exercise. Although the physiologic effects of exercise on vasomotion are probably more complex than that of pharmacologic compounds, this stimulus for coronary vasomotion reflects the daily activities of the study patients better than pharmacologic interventions. 2) Recent human data indicate that endothelial dysfunction occurs very early in the development of atherosclerosis [35, 37–43]. However, angiography is not a very sensitive method for detection of early atherosclerosis. Undetected atherosclerotic changes in angiographically smooth vessels may account for insufficient vasodilator response . The present study compared “normal” with stenosed vessels in patients with angiographically documented coronary artery disease and in vessels of patients with entirely smooth coronary arteries and showed a completely different vasomotor response in relation to the extent of coronary artery disease. 3) Cardiac hypertrophy may influence the reaction of coronary arteries to different vasoactive stimuli because of anatomic alterations in several segments of the coronary vasculature. It has been shown that the arterial media becomes thicker with left ventricular hypertrophy [5, 44], which probably augments vasoconstrictor effects in these arteries . In the present study, patients with significant ventricular hypertrophy were excluded to avoid any bias resulting from these influences. 4) There has been increasing emphasis in published reports on the functional impact of hypercholesterolemia on the vasculature [22, 26, 46]. Studies in humans have shown [22, 26]that hypercholesterolemia and other risk factors cause abnormal vasodilator responses, not only in patients with angiographically proved atherosclerosis but also in those with angiographically normal vessels. In the present study there were no major differences in cholesterol levels or in coronary risk factors other than arterial hypertension between the two groups.
Pathophysiologic mechanisms. Coronary vasodilation was found to be reduced in response to exercise in patients with hypertension and the presence of coronary artery disease (Fig. 1). However, endothelium-independent vasodilator capacity after nitroglycerin was maintained in hypertensive patients compared with that in normotensive subjects. This finding suggests a preserved function of the vascular smooth muscle but a primary defect of the endothelium-dependent regulation of the epicardial coronary arteries. The diminished response to sublingual nitroglycerin in patients with atherosclerotic changes supports the presence of structural abnormalities that are responsible for abnormal vasodilation, even in “normal” coronary arteries (Fig. 2). Intraoperative echocardiographic studies and intravascular ultrasound have demonstrated that in vivo coronary atherosclerosis is far more extensive than predicted by coronary arteriography. An enhanced vasoconstrictory effect to exercise was observed in the stenotic coronary arteries of patients with hypertension that was not seen in normal arteries. The exact mechanism of this paradoxic vasoconstriction has not yet been elucidated [48–51]but appears to be either related to the aforementioned endothelial dysfunction with attenuation of endothelium-dependent relaxation , an enhanced vasoconstriction during exercise due to circulating catecholamines, a Venturi mechanism with collapse of the atherosclerosis-free vessel wall within the stenosis or enhanced platelet aggregation with release of thromboxane A2 and serotonin , alone or in combination. The impact of each of these mechanisms on abnormal coronary vasomotion of the stenotic vessel segments is not clear and awaits further elucidation. These results raise the intriguing possibility that nitric oxide dysfunction may be mechanistically linked to the development of coronary artery disease. Patients with hypertension but a normal epicardial vasomotor response to the physiologic stress of dynamic exercise may not be at increased risk of coronary disease despite their hypertension, but this is purely hypothetical.
Study limitations. Because no histologic proof for the presence or absence of an atherosclerotic lesion of the normal vessels was available in our study, the interpretation of an exclusive change in endothelial function remains speculative in patients with normal epicardial coronary arteries. However, these patients had evidence of atherosclerosis elsewhere in the coronary system, suggesting that these normal vessels may represent the normal part of an otherwise atherosclerotic artery.
Normotensive patients in group 2 performed less in the supine exercise test (Table 2) than hypertensive patients in the same group as well as normotensive and hypertensive patients in the control group. This finding may be due to the more pronounced coronary artery disease in this subgroup (2.1 vessels diseased vs. 1.4 in the hypertensive subjects in group 2), which may lead to differences in the extent of exercise-induced vasodilation. However, this was not the case, as shown in Fig. 2 (left panel).
Another limitation is the lack of coronary blood flow measurements in the present study; thus, no firm conclusion as to the significance of coronary vasoconstriction can be made. However, in a previous study , coronary blood flow reserve was found to decrease during bicycle exercise but to increase after pharmacologic vasodilation with papaverine, suggesting that exercise-induced coronary vasoconstriction plays an important role during conditions of physiologic stress.
Conclusions. Exercise has a different effect on coronary dynamics in patients with coronary artery disease who also have hypertension. The impaired vasomotor response to exercise in hypertension suggests the occurrence of endothelial dysfunction with a reduced release of nitric oxide. Our findings of normal coronary vasomotion in hypertensive humans without coronary atherosclerosis do not argue against the presence of endothelial dysfunction but suggest a normal responsiveness of the coronary vascular bed to a physiologic stimulus such as bicycle exercise.
↵1 This study was supported by the Swiss National Science Foundation, Bern, Switzerland.
- Received February 12, 1996.
- Revision received May 10, 1996.
- Accepted May 14, 1996.
- THE AMERICAN COLLEGE OF CARDIOLOGY
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