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(Circulation. 1995;92:1094-1100.)
© 1995 American Heart Association, Inc.

Articles

Long-term Cigarette Smoking Impairs Endothelium-Dependent Coronary Arterial Vasodilator Function

Andreas M. Zeiher, MD; Volker Schächinger, MD; Jan Minners, BSC

From the Department of Internal Medicine IV, Division of Cardiology, Johann Wolfgang Goethe-University, Frankfurt, Germany.

Correspondence to Andreas M. Zeiher, MD, Department of Internal Medicine IV, Division of Cardiology, Johann Wolfgang Goethe-University Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.

	Abstract

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Background Smoking is a primary risk factor for coronary and peripheral vascular disease. Because the endothelium is a principal target for the effects of risk factors early in the pathogenesis of atherosclerosis, we investigated whether long-term smoking is associated with impaired endothelial vasodilator function of epicardial conductance vessels regardless of the presence or absence of atherosclerotic lesions.

Methods and Results Using quantitative coronary angiography, we measured epicardial artery diameter at baseline, after maximal increases in coronary blood flow that caused flow-mediated dilation (which is strictly endothelium dependent), and after intracoronary injection of nitroglycerin (an endothelium-independent dilator) in 96 patients. Endothelium-dependent, flow-mediated dilation was significantly (P<.0001) blunted in smokers (n=46) compared with nonsmokers (n=50). The ratio of flow-dependent dilation to nitroglycerin-induced dilation was significantly (P<.001) lower in smokers (0.34±0.32) compared with nonsmokers (0.59±0.23), indicating that the blunted dilator response to increased blood flow was out of proportion to the mildly impaired dilator response to nitroglycerin in smokers. In the presence of angiographically visible atherosclerosis, flow-dependent dilation was essentially absent (3.0±6.5%) in smokers. Multivariate analysis revealed that luminal irregularities by angiography (P<.0001) and smoking (P<.001) were the only variables to be independently associated with a reduced flow-dependent dilator response of epicardial arteries. Intracoronary ultrasound demonstrated that flow-dependent dilation progressively decreased with increasing atherosclerotic plaque load (r=-.82, P<.0001; n=24). However, over the entire range of wall thickening, segments from smokers exhibited a significantly (P<.01) impaired flow-dependent dilator response compared with those of nonsmokers.

Conclusions Long-term cigarette smoking is associated with impaired endothelium-dependent coronary vasodilation regardless of the presence or absence of coronary atherosclerotic lesions.

Key Words: smoking • coronary disease • endothelium • endothelium-derived factors • ultrasonics

	Introduction

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Smoking is a primary risk factor for coronary and peripheral vascular disease.¹ Most notably, smoking has been shown to be associated with impaired coronary blood flow responses during increased myocardial demand^{2 3} and might thereby contribute to myocardial ischemia in patients with coronary artery disease.⁴

The endothelium not only plays a pivotal role for the regulation of vascular tone⁵ but also is the principal target for the effects of risk factors early in the pathogenesis of atherosclerosis.⁶ Impaired coronary endothelial vasodilator function is well established in patients with overt atherosclerotic lesions⁷ or even with risk factors for coronary artery disease.^{8 9} Indeed, impaired endothelium-dependent dilation has been shown to be present in the brachial artery of long-term smokers.¹⁰ In contrast, in the coronary circulation, Vita et al⁸ failed to demonstrate an association between smoking and endothelial vasodilator dysfunction. Importantly, the human coronary vasculature differs from the brachial artery so that epicardial conductance vessels are primary targets for the development of atherosclerotic lesions, whereas overt atherosclerosis does not develop in the brachial artery. Because coronary endothelial vasodilator dysfunction worsens progressively with atherosclerotic lesion formation,⁹ the presence of atherosclerotic wall thickening may obscure potential adverse effects of long-term cigarette smoking on endothelium-dependent vasodilator function of coronary arteries.

Therefore, we investigated whether long-term smoking is associated with impaired endothelial vasodilator function of epicardial conductance vessels regardless of the presence or absence of atherosclerotic lesions. Because coronary angiography does not adequately reflect the extent of atherosclerosis, especially in early stages of the disease, we used intracoronary ultrasound in a subset of patients to quantify the extent of local atherosclerotic plaque load in the coronary arterial segment under study.

	Methods

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Patient Population
The study population included 96 patients undergoing routine diagnostic cardiac catheterization. Prerequisite for inclusion in the study was the absence of hemodynamically significant (>30%) stenosis in the left anterior descending coronary artery (the vessel under study). In addition, in the 24 patients undergoing intracoronary ultrasound examination, the proximal part of the left anterior descending coronary artery had to be at least 3 mm in diameter to accommodate the ultrasound catheter without flow restriction. The Table summarizes the clinical characteristics of the patients. Hypertension was defined as a history of hypertension for >2 years that required the initiation of antihypertensive therapy by the primary physician. Hypercholesterolemia was defined as fasting total serum cholesterol values exceeding the 75th percentile adjusted for age and sex. Long-term smoking was defined as at least 2 pack-years of cigarette smoking immediately before the study. However, all smokers refrained from smoking for at least 4 hours before examination. Nonsmokers had to be life-long nonsmokers. If there were uncertainties about a history of smoking, patients were not included in the study. Patients with unstable angina, recent myocardial infarction, a clinical history suggestive of variant angina, valvular heart disease, clinical evidence of heart failure, and diabetes mellitus were excluded. The epicardial artery vasomotor response of 38 of these patients was reported previously.⁹ Written informed consent was obtained from all patients before the study. The study protocol was approved by the Ethical Committee of the University of Freiburg.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics and Measurements

Study Protocol
Vasoactive medications, including calcium channel blockers, angiotensin-converting enzyme inhibitors, and long-acting nitrates, were withheld at least 24 hours before cardiac catheterization. Diagnostic catheterization and coronary angiography of the left side of the heart were performed by a standard percutaneous femoral approach. After completion of the diagnostic catheterization, an additional 5000 U heparin was given intravenously, and an 8F guiding catheter was introduced into the left main coronary artery. In 88 patients, a 3F Monorail Doppler catheter (Schneider) was advanced into the proximal part of the left anterior descending artery through a 0.014-in guide wire. In the remaining 8 patients, a 0.018-in Doppler wire (Flowire, Cardiometrics) was used to measure intracoronary flow velocities.

After stable baseline conditions were obtained, 7 mg papaverine was selectively infused into the left anterior descending artery through the Doppler catheter or through an additional 2.7F infusion catheter, when the Doppler wire was used, to maximally increase blood flow in the territory of the left anterior descending artery. Previous studies^{9 11} demonstrated that the dose of 7 mg of papaverine, subselectively infused into the left anterior descending artery, elicits a maximal increase in coronary blood flow without affecting global hemodynamic parameters. Eighty seconds after papaverine induced an increase in blood flow, a coronary angiogram was obtained to measure the diameter of the proximal segment of the artery exposed to increased blood flow but not directly to papaverine itself. Reflux of papaverine into the proximal artery segment was excluded by power injection of contrast material through the Doppler or infusion catheter.

After return to baseline 5 minutes later, 0.25 mg nitroglycerin was injected into the left main stem through the guiding catheter to assess endothelium-independent vasodilator capacity of the epicardial artery. As in previous studies,^{9 11} intracoronary infusion of papaverine and nitroglycerin in the doses used did not significantly affect the systemic hemodynamic parameters of heart rate and blood pressure.

Throughout the study, heart rate and aortic pressure (through the guiding catheter) were measured continuously. Serial hand injections of nonionic contrast material were performed during control, 80 seconds after papaverine infusion, and after the injection of nitroglycerin. In the 24 patients undergoing intracoronary ultrasound examination, the guide wire was reintroduced into the left anterior descending coronary artery to perform the intracoronary ultrasound examination following the angiogram after the nitroglycerin injection.

Intracoronary Ultrasound Examination
Intracoronary ultrasound examination was performed by use of a mechanical system with a 30-MHz ultrasound transducer enclosed within an acoustic housing on the tip of a 4.3F flexible, rapid exchange catheter (CVIS). Images were acquired at 30 frames per second and recorded on super VHS videotape for subsequent off-line analysis.

The ultrasound catheter was advanced over the 0.014-in guide wire into the midportion of the left anterior descending coronary artery. Thereafter, the ultrasound catheter was slowly retracted under combined intermittent fluoroscopic and continuous ultrasound guidance. Ultrasonic visualization of the takeoff of side branches was used to identify the precise position of the ultrasound transducer, and the ultrasound technician documented the positions to relate ultrasound images to angiographic segments during off-line analysis. Special care was taken to maneuver the ultrasound catheter to as central and coaxial a position in the proximal part of the coronary artery as feasible, primarily by catheter rotation and guide wire movement. Ultrasound gain settings were individually adjusted for optimal visualization of the lumen-intima interface and the outer boundary of the vessel wall by the highly echo-reflective adventitial layer.

Quantitative Coronary Angiography
The method of quantitative coronary angiography was described previously.^{9 11 12} In brief, with simultaneous biplane x-ray systems (Siemens), the coronary arteries under study were positioned near the isocenter, biplane cineangiograms were recorded at a frame rate of 25 frames per second, and end-diastolic cine frames were videodigitized and stored in the image analysis system (Mipron I, Kontron Electronics) in a 512x512 matrix with an 8-bit gray scale. With the 12-cm field of view, the resulting pixel density was 7.3 pixels per millimeter. Automatic contour detection was performed by a previously described and validated method with a geometric edge differentiation technique,^{9 12} and the exact radiological magnification factor of the measured segment was calculated to scale the data from pixels to millimeters.¹³ The accuracy and precision of this technique and the reproducibility of serial measurements under routine clinical conditions were established in previous studies.^{11 12}

Quantitative measurements were performed in a 5-mm-long straight segment of the proximal left anterior descending artery. The length of the segment was chosen to be 5 mm to minimize measurement errors for serial measurements and to obtain an average diameter value in those segments with luminal irregularities. The segments had to be clearly defined in between the takeoff of two side branches, which were used to identify the corresponding ultrasound images. The arterial segments used for quantitative angiographic measurements were selected and analyzed by an observer (J.M.) who was unaware of the ultrasound appearance of the coronary artery. Whenever possible, measurements were performed in both views of the biplane images, with the takeoff of side branches used as anatomic landmarks for identification of corresponding vessel segments, and the vessel cross-sectional area was calculated from both views with the assumption of an elliptical shape. Only single-plane analysis was performed for those coronary segments demonstrating overlap with other parts of the coronary tree in one view.

Ultrasound Image Analysis
Ultrasound image analysis was performed by an independent observer (V.S.) who was unaware of the angiographic measurements. On the basis of the protocol obtained during the examination at the time of cardiac catheterization, ultrasound images were selected by a review of the video recordings and identification of the takeoff of the side branches defining the vessel segment that was selected for quantitative angiography. Because the angiographic measurements were averaged along a 5-mm-long segment and intracoronary ultrasound provided a number of cross-sectional images along the entire length of the angiographically analyzed segment, the ultrasound video recordings of the defined vessel segment were carefully reviewed to select images for quantitative analysis. Because the majority of the selected vessel segments were angiographically smooth and because tapered and curved segments were excluded, the ultrasound images did not demonstrate significant differences in luminal area or wall thickness along the length of an individual 5-mm-long segment used for angiographic analysis. Therefore, when no major qualitative differences in arterial wall thickness along the length of the selected segment could be detected during review of the video recordings, only a single ultrasound image was used for quantitative analysis. However, when a review of the video recordings revealed variations in wall thickness along the length of the selected segment, at least two or more ultrasound frames were analyzed, and a mean value was calculated for the derived parameters. Ultrasound images with extensive fibrotic or calcific deposits that obscured the details of the subjacent arterial wall were excluded from the analysis. The selected high-quality videotaped ultrasound sequences were digitized into a 512x512x8-bit matrix with an image processing computer (Kontron) capable of digitization and storage of a series of 62 images, permitting at least two complete cardiac cycles to be digitized for each analyzed sequence. Review of the dynamic imaging sequence was used routinely to facilitate measurements in the frame with optimal delineation of the blood-intima border because a continuous border was not always visible along the entire circumference in an individual frame. The acoustic interface between the lumen and the intimal leading edge was manually traced to obtain the lumen cross-sectional area by planimetry, and total arterial area was obtained by planimetry by tracing the leading edge of the adventitia. Absolute wall area was calculated as total arterial area minus luminal area.^{14 15} Adjustment for magnification was performed by use of a distance scale automatically recorded within each ultrasound image. To normalize for different vessel sizes, relative wall area was calculated as absolute wall area divided by total arterial area multiplied by 100, thus representing the atherosclerotic "plaque load" of an individual segment.

The values for intraobserver and interobserver variability of ultrasound measurements were previously established to range from 3.3% to 5.8%.¹⁶

Assessment of Coronary Blood Flow
For estimation of directional changes in coronary blood flow as the stimulus for flow-dependent vasodilation, a coronary flow index was calculated by multiplying the mean Doppler-derived blood flow velocity by the computed cross-sectional area of the vessel segment measured immediately distal to the tip of the Doppler catheter, as previously described.⁹ Because the injection of contrast material into the coronary circulation resulted in the typical biphasic response of coronary blood flow velocity with an initial decrease followed by an increase in flow velocity resulting the hyperemic effects of the contrast material, the mean blood flow velocity immediately before the contrast injection was used for estimation of coronary blood flow.

Statistical Analysis
All data are expressed as mean±SD. Statistical comparisons were made by ANOVA followed by the Student-Newman-Keuls test. Multivariate analysis using multiple stepwise regression techniques was performed to examine potential interactions among age, sex, total serum cholesterol level, smoking, a history of hypertension, and the angiographic appearance of the vessel segment on flow-dependent dilation. Linear regression analysis was used to compare flow-dependent dilation with relative arterial wall area. To assess the effects of smoking on the relation between relative wall area and vasomotor responses to increased blood flow, regression models were fitted according to the method of Liang and Zeger¹⁷ by use of the SAS-MACRO GEE. Statistical significance was assumed if a null hypothesis could be rejected at P=.05.

	Results

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Clinical Characteristics and Measurements
The Table summarizes the clinical characteristics, such as age, sex, total serum cholesterol levels, HDL serum cholesterol levels, arterial pressure, and the angiographic appearance of the vessel segment under study, as well as baseline cross-sectional area of the vessel segments. There were no significant differences between smokers and nonsmokers with respect to any of these variables.

Flow-Mediated Dilation
Mean papaverine-induced increases in coronary blood flow indices were similar in smokers and nonsmokers (see the Table). However, despite an identical stimulus of increased blood flow, flow-dependent dilation was significantly (P<.0001) blunted in smokers compared with nonsmokers (Fig 1). Dilation in response to nitroglycerin was also significantly (P<.01) reduced in smokers compared with nonsmokers (Fig 1). There was a significant positive correlation between flow-dependent and nitroglycerin-induced dilation (r=.66, P<.0001; n=96). However, the slopes of the regression lines were significantly (P<.01) different in smokers (0.5) compared with nonsmokers (0.29). Accordingly, the ratio of flow-dependent dilation to nitroglycerin-induced dilation was significantly (P<.001) lower in smokers (0.34±0.32) compared with nonsmokers (0.59±0.23), indicating that the blunted dilator response to increased blood flow was out of proportion to the mildly impaired dilator response to nitroglycerin in the smokers. Within the relatively narrow range (4.5 to 25 mm²) of cross-sectional areas of the vessel segments studied, there was no relation between baseline cross-sectional area of the vessel segment and either flow-dependent or nitroglycerin-induced dilation.

View larger version (16K): [in this window] [in a new window]   Figure 1. Plots showing flow-dependent dilation (top) and nitroglycerin (NTG)-induced dilation (bottom) in smokers (n=46) and nonsmokers (n=50).

When the vessel segments were divided into normal and irregular segments according to their angiographic appearance, the significant differences in flow-dependent dilation were well preserved in both groups for smokers and nonsmokers (Fig 2), indicating that, even in the presence of angiographically visible atherosclerosis, smoking was associated with a significantly blunted flow-dependent vasodilator response. Importantly, flow-dependent dilation was essentially absent (3.0±6.5%) in angiographically irregular segments of smokers.

View larger version (17K): [in this window] [in a new window]   Figure 2. Plot showing flow-dependent dilation of angiographizhycally normal () and angiographically irregular segments () in smokers and nonsmokers.

The significant difference between flow-dependent dilation was also preserved, when only female patients were analyzed, with 10.0±9.6% in female smokers (n=10) compared with 20.3±7.1% in female nonsmokers (n=16, P=.005).

Univariate analysis also revealed a significantly (P<.05) reduced flow-dependent dilation in patients with hypercholesterolemia, whereas flow-dependent dilation did not differ with respect to age, sex, and the presence or absence of a history of hypertension. However, when a multivariate analysis was performed to account for potential interactions of different risk factors, luminal irregularities by angiography (P<.0001) and smoking (P<.001) were the only variables to be independently associated with a reduced flow-dependent dilator response of epicardial arteries. Moreover, there was no relation between total serum cholesterol levels and flow-dependent dilation in smokers or nonsmokers.

Flow-Dependent Dilation and Atherosclerotic Plaque Load
Fig 3 illustrates two examples of the extent of flow-dependent dilation and vessel wall architecture as assessed by intracoronary ultrasound in a patient with an angiographically normal segment and in a patient with an irregular segment, respectively. Fig 4 demonstrates the relation between the magnitude of flow-dependent dilation and the extent of atherosclerotic plaque load in all 24 patients undergoing intracoronary ultrasound examination. Flow-dependent dilation decreased progressively with increasing plaque load expressed as percent wall area and was essentially absent when atherosclerotic plaque load made up >50% of the total arterial area. However, although there was a fairly close inverse relation between flow-dependent dilation and atherosclerotic plaque load, vessel segments from smokers (n=11) exhibited a significantly (P<.01) impaired flow-dependent dilator response compared with nonsmokers (n=13) over the entire range of atherosclerotic wall thickening (Fig 4). Thus, smoking appears to contribute independently to impaired flow-dependent dilation in addition to local atherosclerotic plaque load in epicardial arteries.

View larger version (64K): [in this window] [in a new window]   Figure 3. Coronary angiograms at control (CTL), during flow-dependent dilation (FDD), and after 0.25 mg nitroglycerin (NTG) and corresponding wall architecture as assessed by intracoronary ultrasound (ICUS) in angiographically normal (A) and angiographically irregular (B) segments. Inset, Percent luminal area changes of the analyzed vessel segments. Note the significant atherosclerotic wall thickening resulting from an eccentric plaque in panel B associated with abolished FDD despite preserved NTG-induced dilation. Small white arrow denotes site of papaverine infusion.

View larger version (12K): [in this window] [in a new window]   Figure 4. Plot showing relation between ultrasound-derived local atherosclerotic plaque load expressed as relative wall area in percent and flow-dependent epicardial artery dilation (FDD) in smokers (n=11, ) and nonsmokers (n=13, ). There is a significant (P<.01) difference between the regression lines for segments of smokers (y=-0.55x+29.5, r=-.86, P<.0001) and nonsmokers (y=-1.0x+56.5, r=-.93, P<.0001), respectively.

	Discussion

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The present study demonstrates that long-term cigarette smoking is associated with impaired endothelium-dependent coronary vasodilation regardless of the presence or absence of atherosclerotic wall thickening. These findings extend previous observations obtained in the brachial artery to coronary arteries, suggesting that smoking is associated with a generalized endothelial vasodilator dysfunction. Most importantly, even in the presence of atherosclerotic wall thickening, smokers exhibited further impairment in flow-dependent coronary arterial dilation indicative of an additive adverse effect on endothelium-dependent coronary vasodilator function.

Vasodilation in response to increased blood flow in conductance vessels was shown to be strictly dependent on an intact, normally functioning endothelium^{18 19} and is mediated by the signal of shear stress on the endothelial cell layer²⁰ to release vasoactive factors like endothelium-derived relaxing factor (EDRF), believed to be nitric oxide or a related compound,^{21 22} and prostacyclin.²³ The endothelial cell layer thus represents a mechanotransducer that senses local blood flow and converts signals of increased shear stress into vessel wall relaxation, thereby optimizing tissue perfusion according to metabolic needs.²⁴ We^{9 11} and others^{25 26} showed previously that flow-dependent dilation is impaired in epicardial conductance vessels with angiographic evidence of atherosclerosis. The present study extends these findings by demonstrating an inverse relation between endothelium-dependent coronary vasodilation and the extent of local atherosclerotic wall thickening as quantified by intravascular ultrasound. The progressive impairment in flow-dependent dilation with increased atherosclerotic plaque load suggests that endothelial vasodilator dysfunction merely reflects the severity of the atherosclerotic disease process. However, at any given extent of atherosclerotic wall thickening, flow-dependent coronary dilation was significantly blunted in long-term smokers compared with nonsmokers. Thus, in addition to increased wall thickness caused by the atherosclerotic plaque load itself, smoking appears to contribute independently to impairment in endothelium-dependent, flow-mediated coronary vasodilation, suggesting that additional functional mechanisms are involved.

The mechanisms of smoking-associated endothelial damage are not established, but a number of factors may contribute to the impairment of the functional integrity of the endothelium. Nicotine has been reported to produce structural damage in aortic endothelial cells of animals.^{27 28} Smoking is associated with a direct toxic effect on human endothelial cells^{29 30} and reduces endothelial prostacyclin production.³¹ More importantly, a very recent study demonstrated that cigarette smoke extract impairs endothelium-dependent dilation of porcine coronary arteries by superoxide anion–mediated degradation of EDRF.³² Increased production of superoxide anions, which rapidly inactivate EDRF,³³ is a characteristic feature of experimental models of atherosclerosis^{34 35} and importantly contributes to the impairment of endothelium-dependent vascular relaxation.³⁶ Smokers appear to be particularly susceptible to the activity of oxygen free radicals, and plasma indexes of lipid peroxidation are increased in smokers.³⁷ Thus, free radicals generated by long-term smoking may deleteriously affect coronary endothelial vasodilator function in addition to the atherosclerotic plaque load itself and may, at least in part, be responsible for the blunted flow-dependent dilation observed at any given extent of atherosclerotic wall thickening in the smokers of the present study. Importantly, free radicals have also been shown experimentally to impair vasodilation in response to nitroglycerin,³⁶ although to a lesser extent than endogenously released EDRF. The results of the present study that demonstrate an impaired coronary arterial dilator response to nitroglycerin in smokers are compatible with these experimental observations and provide further support for a potential role of free radicals generated by long-term smoking in mediating epicardial artery vasodilator dysfunction in humans.

Epidemiological studies have demonstrated an inverse relation between cigarette smoking and plasma levels of HDLs.³⁸ Elevated high-density cholesterol serum levels exert a beneficial effect on abnormal coronary vascular reactivity by ameliorating vasoconstriction in response to both the endothelium-dependent dilator acetylcholine and sympathetic activation in early atherosclerosis.¹⁶ In the present study, however, HDL levels did not differ significantly between smokers and nonsmokers. Thus, the observed differences in flow-dependent coronary dilation cannot be attributed to different lipoprotein profiles in smoking and nonsmoking patients.

Flow-mediated dilation represents the primary mechanism by which the epicardial vessels respond to stimuli such as exercise or sympathetic activation that increase myocardial work and oxygen demand. Impaired endothelial vasodilator function not only uncouples vascular tone from metabolic demand but also alters the dynamic balance of neural and humoral factors acting on the vascular wall in favor of vasoconstriction.^{9 39 40 41 42 43} Impaired vasodilation is the predominant mechanism underlying inappropriate coronary vasoconstriction in atherosclerosis and may facilitate episodes of myocardial ischemia in the presence of epicardial artery stenosis.⁴⁴ The present study demonstrates that long-term smoking independently contributes to this fundamental functional disturbance associated with the development of coronary atherosclerosis. Therefore, these findings suggest that smoking may play an important causative role in the ischemic manifestations of coronary artery disease. Moreover, in combination with increased platelet aggregation,²⁹ increased fibrinogen levels,⁴⁵ and decreased plasminogen levels,⁴⁶ the endothelial vasodilator dysfunction associated with long-term smoking also very likely promotes acute ischemic events in patients with established coronary artery disease in addition to the well-known acute effects of cigarette smoking on coronary vascular tone.²

Received December 6, 1994; revision received March 15, 1995; accepted March 19, 1995.

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