(Circulation. 1995;91:2345-2352.)
© 1995 American Heart Association, Inc.
Articles |
Impaired Endothelium-Dependent Vasodilation of Coronary Resistance Vessels Is Associated With Exercise-Induced Myocardial Ischemia
From the Department of Internal Medicine, Division of Cardiology (A.M.Z., V.S., J.M.), and Department of Nuclear Medicine (T.K., E.M.), University of Freiburg (Germany).
Correspondence to Andreas M. Zeiher, MD, Department of Internal Medicine III, Division of Cardiology, University of Freiburg, Hugstetterstr 55, D-79106 Freiburg, Germany.
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Abstract |
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Background The release of endothelium-derived relaxing factors has been shown experimentally to be of pivotal importance for the maintenance of coronary blood flow during increased demand. In humans with coronary atherosclerosis, endothelial vasodilator dysfunction is not confined only to epicardial conductance vessels but may also extend into the coronary microcirculation. We therefore tested the hypothesis that endothelial vasodilator dysfunction of the coronary resistance vasculature is associated with myocardial ischemia during exercise in patients without hemodynamically significant epicardial artery stenoses.
Methods and Results Coronary vasodilator function was assessed by subselective infusion of the endothelium-dependent dilator acetylcholine (0.036 to 3.6 µg/mL) and the endothelium-independent dilator papaverine (7 mg). Coronary blood flow responses were evaluated by intracoronary Doppler flow velocity recordings and quantitative angiography. Exercise-induced myocardial perfusion was determined by 201Tl single photon emission computed tomographic imaging. Thirteen patients had exercise-induced myocardial perfusion defects suggestive of myocardial ischemia, whereas 14 patients had normal thallium imaging during exercise. In patients with exercise-induced thallium perfusion defects, coronary blood flow responses to acetylcholine were significantly (P<.005) blunted compared with patients with normal thallium imaging during exercise. In contrast, coronary blood flow reserve to the endothelium-independent smooth muscle relaxant papaverine was similar in the two groups. Patients with exercise-induced thallium perfusion defects exhibited a significantly (P<.005) reduced (23.9±9.0% [mean±SD]) endothelium-mediated coronary vasodilator capacity compared with patients with normal thallium testing (56.2±27.8%). Epicardial artery vasoreactivity to acetylcholine did not differ between the two groups.
Conclusions Impaired endothelium-dependent vasodilation of the coronary microcirculation is associated with exercise-induced myocardial ischemia in patients without hemodynamically significant epicardial artery lesions. Endothelial vasodilator dysfunction extending into the coronary microcirculation may thus contribute to the ischemic manifestations of coronary artery disease during times of increased myocardial demand.
Key Words: blood flow • atherosclerosis • endothelium • ischemia • acetylcholine
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Introduction |
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The endothelium plays a central role for circulatory homeostasis by synthesizing and metabolizing a number of vasoactive substances.1 Most notably, the production of an endothelium-derived relaxing factor (EDRF) by the endothelial cell layer in response to a variety of humoral and physical stimuli has been shown to be of pivotal importance for the regulation of coronary vascular tone and for the maintenance of coronary blood flow during increased metabolic demand.2 3 4
Previous studies have demonstrated that atherosclerosis of epicardial conductance vessels impairs the activity of EDRF,5 6 7 thereby altering the dynamic balance of neural and humoral factors acting on the vascular wall in favor of vasoconstriction,8 9 10 11 which may facilitate episodes of myocardial ischemia in the presence of epicardial artery stenoses.12 More importantly, however, we and others13 14 15 have shown that endothelial vasodilator dysfunction is not confined only to atherosclerotic epicardial conductance vessels but may also extend into the coronary resistance vasculature even in the absence of obstructive epicardial artery disease. Since in the absence of obstructive lesions within epicardial conductance vessels, coronary blood flow is regulated by the resistance vasculature,16 defective endothelium-mediated dilation of the resistance coronary arteries may contribute to an abnormal coronary blood flow regulation even in early stages of coronary atherosclerosis. Indeed, we could demonstrate a close correlation between the extent of endothelial vasodilator dysfunction of resistance vessels and the failure of coronary blood flow to increase during cold exposure,17 suggesting that endothelial function within resistance vessels may be important for the regulation of coronary blood flow during times of increased metabolic demand. The uncoupling of resistance vessel tone from metabolic factors may represent an important mechanism through which impaired endothelial function might contribute to the development of myocardial ischemia even in early stages of coronary atherosclerosis without obstructive lesions.
Therefore, the present study was designed to test the hypothesis that endothelial vasodilator dysfunction of the coronary resistance vasculature is associated with exercise-induced myocardial ischemia in patients without hemodynamically significant stenoses of their epicardial arteries.
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Methods |
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Patient Population
The study population included 27 prospectively studied patients who underwent both testing of coronary endothelium-mediated vasodilator functioning and exercise 201Tl perfusion imaging. The patients were classified into two groups according to the presence or absence of exercise-induced 201Tl perfusion defects in the territory of the left anterior descending coronary artery (LAD) (the vessel under study for assessing vasodilator function), suggestive of myocardial ischemia (see below). The individual patient characteristics are summarized in Table 1
. For inclusion into the study, the
LAD had to be either angiographically normal or minimally diseased,
with <30% luminal narrowing. Patients with unstable angina, recent
myocardial infarction, a clinical history suggestive of variant angina,
valvular heart disease, clinical evidence of heart failure, or diabetes
mellitus were excluded. No patient had angiographic or
echocardiographic evidence of left ventricular hypertrophy. All
patients demonstrated a normal left ventricular contraction pattern in
the anterior and septal left ventricular wall and a normal global
ejection fraction as assessed by biplane cineangiography. Left
ventricular end-diastolic pressure was within normal limits
(<12 mm Hg) in all patients. No patient had ECG evidence of a left
bundle branch block. In addition, patients with hypercholesterolemia
(serum cholesterol levels exceeding the 75th percentile adjusted for
age and sex) at the time of the study were excluded because previous
studies suggested that lipoproteins may induce a nonspecific inhibition
of endothelium-dependent relaxation by interfering with
the agonist-induced release of EDRF.18 19
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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.
Study Protocol
Assessment of Coronary Vasomotor
Responses
Vasoactive medications, including calcium channel blockers,
angiotensin-converting enzyme inhibitors, and long-acting nitrates,
were withheld at least 24 hours before cardiac catheterization. No
patient received ß-adrenergic blockers within 48 hours before the
study. A total of 14 patients were on aspirin therapy during the study.
Diagnostic left heart catheterization and coronary angiography were
performed by a standard percutaneous femoral approach. After completion
of the diagnostic catheterization, an additional 5000 U heparin was
given, and an 8F guiding catheter was introduced into the left main
coronary artery. In 22 patients, a 3F Monorail-Doppler catheter with a
20-MHz pulsed Doppler crystal was advanced into the LAD via a 0.014-in
guide wire, and in 5 patients, a 0.018-in Doppler-tipped guide wire
(Flowire) was used. The Doppler catheter was carefully positioned to
obtain a stable flow velocity signal. Before the Doppler catheter was
introduced into the guiding catheter, the flow velocity recordings were
referenced to zero and calibrated.
After stable baseline conditions were obtained, acetylcholine was selectively infused into the LAD via the Doppler catheter or via an additionally inserted 2.7F infusion catheter (for the Flowire studies) to assess endothelium-dependent increases in coronary blood flow. Increasing dosages of acetylcholine (0.036, 0.36, and 3.6 µg/mL) were infused at an infusion rate of 2 mL/min, lasting 3 minutes for each concentration. The lowest dose of acetylcholine, 0.036 mg/mL, corresponds to an estimated blood concentration in the coronary bed of 10-8 mol/L, assuming a blood flow of 80 mL/min.
Ten minutes after acetylcholine infusion, 7 mg papaverine was subselectively injected into the LAD via the Doppler catheter to assess endothelium-independent coronary flow reserve in the territory of the LAD in 21 patients. Previous studies20 have demonstrated that the dose of 7 mg papaverine subselectively infused into the LAD elicits a maximal increase in coronary blood flow without affecting global hemodynamic parameters.
Throughout the study, phasic and mean intracoronary blood flow velocity, heart rate, and aortic pressure (via the guiding catheter) were continuously measured. Serial hand injections of nonionic contrast material were performed during control, at the end of each acetylcholine-infusion period, at recontrol after acetylcholine infusion, and after subselective infusion of papaverine.
Quantitative Coronary Angiography
The method of quantitative
coronary angiography has been
described.9 13 20 In brief, with a
simultaneous biplane
multidirectional isocentric x-ray system (Siemens Bicor), the coronary
arteries under study were positioned near the isocenter, biplane
cineangiograms were recorded at a frame rate of 25 frames per second,
end-diastolic cine frames were videodigitized and stored in
the image analysis system (Mipron I, Kontron Electronics) in a
512x512 matrix with an eight-bit gray scale, and automatic contour
detection was performed by a previously described and validated method
using a geometric edge-differentiation
technique.9 20 21
The accuracy and precision of this technique as well as the
reproducibility of serial measurements under routine clinical
conditions have been established in previous
studies.9 20
Quantitative angiography of the epicardial artery was performed for two purposes: first, to determine the cross-sectional area of the artery immediately distal to the radiopaque tip of the Doppler catheter to convert the Doppler-derived flow velocity to an estimate of coronary arterial flow, and second, to exclude limitations of coronary artery flow due to epicardial coronary artery constriction in response to acetylcholine by measuring the most constricting epicardial artery segment distal to the tip of the Doppler catheter, as previously suggested by Treasure et al.22 To determine cross-sectional area of the artery, a 5- to 7-mm segment was measured immediately distal to the tip of the Doppler catheter. Whenever possible, measurements were performed in both views of the biplane images using the radiopaque tip of the Doppler catheter for identification of corresponding vessel segments, and the cross-sectional area of the vessel was calculated from both views, assuming an elliptical shape. Only single-plane analysis was performed for those coronary segments demonstrating overlapping with other parts of the coronary tree in one view; in those cases (8 of 27 patients, 30%), vessel cross-sectional area was calculated assuming a circular shape. Measurement of the most constricting artery segment was performed in a similar fashion. However, instead of calculating the mean diameter value, the minimal absolute diameter of the analyzed segment was identified in both views, and minimal cross-sectional area was calculated. Flow-limiting constriction was defined as >50% cross-sectional area reduction compared with preacetylcholine cross-sectional area of the identical segment.
Exercise 201Tl Single Photon Emission Computed
Tomographic Imaging
After an overnight fast, the patients underwent
thallium
scintigraphy while exercising on an electronically braked bicycle in
the supine position with a workload starting at 50 W and increasing by
25 W every 3 minutes. Exercise end points were exhaustion, development
of moderate-to-severe angina, serious arrhythmias, or exertional
hypertension. All cardiac and vasoactive medications were withdrawn at
least 12 hours before exercise testing. At peak exercise, 2 to 3 mCi
(70 to 105 MBq) 201Tl was administered intravenously, and
the patients continued to exercise for an additional 60 seconds.
Redistribution images were acquired 4 hours after exercise testing
while the patients were resting.
Studies were obtained with a large-field-of-view rotating gamma camera (Orbiter, Siemens) equipped with a low-energy, all-purpose collimator. A 20% window centered on the 70-keV photo peak and a second 15% energy window centered on the 167-keV photo peak of 201Tl were used. Thirty projections (40 seconds per projection) were obtained over a semicircular 180° arc from a 45° right anterior oblique to the left posterior oblique position. All projection images were stored on magnetic disk with a 64x64x16-bit matrix.
Data processing was performed by means of a back-projection algorithm using a Butterworth filter order of 5 with a cutoff frequency of 40% Nyquist and 1-2-1 prereconstruction filtering (Siemens). No attenuation or scatter correction was used. Short-axis, vertical, and horizontal long-axis tomograms were extracted from the filtered transaxial tomograms. All tomograms were reconstructed at one pixel per slice.
Image Interpretation
Interpretation of the
short-axis, vertical, and horizontal
long-axis tomograms was performed by consensus of two experienced
investigators unaware of the clinical history, coronary angiography,
and the results of vasomotor testing. Uptake of radiotracer was scored
as proposed23 by a 5-point scoring system: 0, normal; 1,
equivocal; 2, moderate; 3, severe reduction; and 4, absence of
radioisotope uptake. To ascertain that the location of
201Tl perfusion corresponded to the vessel undergoing
vasomotor testing, the anteroseptal, anterior, and anterolateral
segments of the left ventricle were assigned to the LAD. Thus, the
segments analyzed for exercise-induced 201Tl perfusion did
reflect the perfusion territory of the LAD. A perfusion defect was
defined as a score >2 in two or more contiguous segments during
exercise with complete redistribution at rest.
Data Analysis
For estimation of directional changes in
coronary blood flow, a
coronary flow index was calculated by multiplying the mean
Doppler-derived blood flow velocity with the computed cross-sectional
area of the vessel segment immediately distal to the tip of the Doppler
catheter. Since 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 due to 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
unless otherwise stated.
Statistical comparisons were made by ANOVA followed by the
Student-Newman-Keuls test. Dichotomous variables were compared by
2 test. Statistical significance was assumed if a
null hypothesis could be rejected at the .05 probability level.
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Results |
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Clinical Characteristics
Table 1
summarizes
the clinical characteristics of the
patients. Fourteen patients had normal exercise thallium tests, whereas
in 13 patients, exercise thallium testing revealed perfusion defects
suggestive of myocardial ischemia in the territory of the LAD. Fig
1 illustrates an example of an exercise-induced
201Tl perfusion defect as well as the coronary vasomotor
response to acetylcholine in an individual patient. Clinical
characteristics such as sex, total serum cholesterol levels, smoking
status, and history of arterial hypertension requiring antihypertensive
therapy were comparable between patients with and without
exercise-induced perfusion defects (Table 1). However, the
patients
with exercise-induced 201Tl perfusion abnormalities were
slightly but significantly (P<.05) older. As shown in Table
2, heart rate and blood pressure as well as maximum
exercise workload did not differ during exercise 201Tl
testing. Eight patients experienced anginalike chest pain during
exercise, of whom 3 (36%) also had thallium perfusion defects.
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Coronary Vasomotor Responses
No significant changes in mean
aortic pressure or heart rate
occurred during subselective infusion of acetylcholine or papaverine.
Baseline values for epicardial artery luminal area (7.85±4.3
mm2 for group 1 and 6.1±3.0 mm2 for group 2)
and coronary blood flow indexes (76.8±60.3 kHz · mm2
for group 1 and 64.7±70.3 kHz · mm2 for group 2) were
similar in the two groups of patients.
The administration of
acetylcholine produced a modest
dose-dependent decrease in epicardial artery luminal area. No patient
had vasoconstriction exceeding 50% luminal area reduction in the most
constricting segment of the LAD at the highest dose of acetylcholine
used. Fig 2 illustrates that the epicardial artery
vasomotor response to acetylcholine did not differ significantly
between the two groups. At the highest dose of acetylcholine used,
epicardial artery luminal area reduction was -11.5±13.7% in the
patients with normal exercise thallium tests and -25.5±23.0% in
the
patients with exercise-induced thallium perfusion defects
(P=.07). In contrast, as illustrated in Fig 3,
the dose-dependent increase in coronary blood flow in
response to acetylcholine was significantly blunted in the patients
with exercise-induced thallium perfusion defects. These data
demonstrate that despite similar vasoconstrictor responses of the
epicardial conductance vessels, acetylcholine-induced dilation of the
coronary resistance vasculature was impaired in the patients with
exercise-induced thallium perfusion defects.
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At the same time, the
responses to the smooth muscle relaxant
papaverine did not differ between the two groups (Fig 3),
indicating
comparable endothelium-independent vasodilator capacity
of the coronary microvasculature. Thus, when the maximum coronary blood
flow response to the endothelium-dependent dilator
acetylcholine was expressed as percentage of the blood flow response to
papaverine, patients with exercise-induced thallium perfusion defects
exhibited a significantly lower endothelium-mediated
vasodilator capacity, 23.9±9.0%, compared with patients with normal
thallium testing, with 56.2±27.8% (P<.005). These data
indicate that endothelium-dependent vasodilation of the
coronary microvasculature was selectively impaired in the patients with
exercise-induced 201Tl perfusion defects suggestive of
myocardial ischemia.
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Discussion |
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The most important finding of the present study was that patients without hemodynamically significant epicardial artery stenoses but with exercise-induced myocardial ischemia exhibited a marked attenuation of the increase in coronary blood flow evoked by the endothelium-dependent vasodilator acetylcholine, whereas coronary blood flow responses to the endothelium-independent vascular smooth muscle relaxant papaverine were not affected. These findings suggest that endothelium-dependent dilation of the coronary resistance vasculature was impaired in the patients with exercise-induced myocardial ischemia compared with the patients without myocardial perfusion defects during exercise.
Previous studies assessing coronary blood flow responses to intracoronary acetylcholine have demonstrated blunted responses suggestive of defective endothelium-dependent vasodilation in some patients with angina and normal coronary arteries.24 25 Very recently, Egashira et al26 provided evidence for impaired dilation of resistance coronary arteries in a highly selected group of patients with syndrome X, defined as anginalike chest pain, positive exercise ECG, and angiographically normal coronary arteries. The present study is the first to demonstrate that impaired endothelium-dependent regulation of coronary blood flow may translate into myocardial ischemia during times of increased myocardial demand. The presence of inducible myocardial ischemia during increased myocardial demand was assessed by thallium perfusion imaging during exercise testing rather than exercise ECG, which has been shown not to be very specific in patients without obstructive coronary lesions.27 The results of the present study extend previous observations that endothelial vasodilator dysfunction correlates with the failure of coronary blood flow to increase during cold exposure17 and during pacing,14 24 such that endothelial vasodilator dysfunction of the coronary resistance vasculature appears to be associated with exercise-induced myocardial perfusion defects indicative of inducible myocardial ischemia.
The present study also differs significantly from previous reports by another important aspect: we purposely included patients with conditions such as hypertension and early atherosclerosis, since these factors have been shown to be associated with impaired endothelial vasodilator function.13 15 28 29 Importantly, the patients with exercise-induced myocardial perfusion defects were significantly older than those with normal thallium perfusion scans during exercise. We have previously shown that advanced age is a significant independent predictor of impaired endothelium-dependent dilation of the coronary resistance vasculature irrespective of the presence or absence of epicardial artery atherosclerosis.28 Thus, impaired endothelial resistance vessel dilation associated with advanced age may indeed contribute to exercise-induced myocardial ischemia in the elderly. Interestingly, Nabel et al14 also reported a blunted coronary blood flow response to atrial pacing in elderly patients with non–flow-limiting epicardial atherosclerosis.
In contrast, in keeping with our previous reports,17 28 the patients with exercise-induced ischemia did not differ from those with normal exercise thallium tests with respect to the presence or absence of a history of arterial hypertension. These findings seem surprising, given the fact that patients with arterial hypertension frequently exhibit signs and symptoms of myocardial ischemia even in the absence of epicardial artery lesions.30 However, to exclude potentially confounding effects of left ventricular hypertrophy on coronary blood flow, all patients of the present study had normal left ventricular mass indexes as assessed by cineventriculography or echocardiography. Thus, hypertension per se does not appear to contribute to the development of exercise-induced myocardial perfusion defects via an impaired endothelium-dependent relaxation of the coronary resistance vasculature. A lack of an effect of hypertension has also been previously reported by Quyyumi et al,24 who compared coronary blood flow responses to atrial pacing and acetylcholine in patients with microvascular angina.
The responses of the large epicardial conductance vessels did not differ significantly between patients with and without exercise-induced myocardial ischemia, although there was a tendency toward an increased constrictor response in the patients with myocardial perfusion defects. In line with previous studies,13 31 32 the epicardial artery vasomotor response to acetylcholine was characterized by a moderate dose-dependent constriction in our patients, who had either angiographically visible atherosclerosis or risk factors for atherosclerosis, suggesting a loss of endothelium-dependent dilation in the epicardial conductance vessels. However, no patient had angiographic narrowing >50% at the highest dose of acetylcholine, indicating that the attenuated response of coronary blood flow to acetylcholine did not result from excessive vasoconstriction of the large epicardial conductance vessels. Whether the tendency toward an increased epicardial artery constrictor response in the patients with exercise-induced myocardial perfusion defects was secondary to the blunted blood flow increases with resultant reduced flow-dependent dilation or primarily indicative of a more severe endothelial vasodilator dysfunction cannot be differentiated in the present study.
A limitation of the present study is that we did not perform coronary angiography during exercise to document the extent of exercise-induced epicardial artery constriction. It is conceivable that exercise might have induced more significant epicardial artery constriction than the highest dose of acetylcholine, thereby attenuating coronary blood flow responses during increased myocardial demand. However, Gordon et al10 previously showed that in atherosclerotic epicardial arteries, the vasoconstrictor response to 10-6 mol/L acetylcholine significantly exceeded the extent of vasoconstriction in response to supine bicycle exercise testing. Thus, it is unlikely that excessive epicardial artery constriction during exercise limited coronary blood flow in the patients with exercise-induced myocardial ischemia.
Although it has been repeatedly demonstrated that, in humans, the most important vasodilator action of acetylcholine is mediated through the release of EDRF,33 34 35 we cannot exclude the possibility that acetylcholine might cause the concomitant release of endothelium-derived constricting factors36 or even exert exaggerated direct smooth muscle vasoconstriction.37 In addition, studies in the intact human coronary circulation do not allow us to differentiate whether the impaired acetylcholine-mediated vascular relaxation is due to an abnormal production or destruction of EDRF, to abnormalities of endothelial cell membrane receptor–second messenger interactions, or even to a nonspecifically reduced sensitivity of vascular smooth muscle cells to relax. Although papaverine is a potent smooth muscle relaxant to assess maximal vasodilator capacity of the coronary circulation, it does not act via the same mechanisms as nitrovasodilators, including EDRF. However, nitroglycerin has minimal effects on small coronary resistance vessels,38 and nitroprusside in intracoronary doses necessary to maximize coronary blood flow in humans profoundly affects systemic hemodynamics, thereby preventing interpretation of its effect on coronary vascular resistance. Thus, we cannot exclude the possibility that in the patients with exercise-induced myocardial perfusion abnormalities, the effects of acetylcholine are reduced because of an impaired guanylate cyclase activity of vascular smooth muscle or because of a reduced sensitivity of vascular smooth muscle cells in response to nonspecific vasodilator stimulation. Nevertheless, even if vascular smooth muscle relaxation were altered in patients with stress perfusion abnormalities, the net effect of EDRF activity released from the endothelium on stimulation would be a diminished relaxation of vascular smooth muscle. Thus, our conclusion of an impaired acetylcholine-induced vasodilator capacity of the coronary microvasculature with all its implications would still be valid.
Thus, a blunted coronary blood flow response to acetylcholine despite preserved vasodilator capacity to the smooth muscle relaxant papaverine does not necessarily indicate decreased production or release of EDRF/nitric oxide. However, regardless of the mechanisms involved, an impaired acetylcholine-mediated vasodilator capacity of the coronary resistance vasculature detected during diagnostic coronary angiography identifies patients likely to have inducible myocardial perfusion defects during exercise even in the absence of hemodynamically significant epicardial artery stenoses. Further studies are needed to address the underlying mechanisms of the blunted coronary blood flow response to acetylcholine in these patients.
In conclusion, our results indicate that patients with exercise-induced myocardial ischemia with atherosclerosis and without flow-limiting epicardial artery stenosis have associated impaired acetylcholine-induced vasodilation of coronary resistance vessels, suggestive of microvascular endothelial vasodilator dysfunction. Thus, endothelial vasodilator dysfunction extending into the coronary resistance vasculature appears to contribute to the ischemic manifestations of coronary artery disease during times of increased demand.
Received September 6, 1994; revision received November 10, 1994; accepted November 26, 1994.
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