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(Circulation. 1997;95:607-613.)
© 1997 American Heart Association, Inc.
Articles |
Reduced Coronary Flow Reserve During Exercise in Cardiac Transplant Recipients
the Department of Internal Medicine, Cardiology, and Department of Cardiovascular Surgery, University Hospital, Zurich, Switzerland.
Correspondence to Otto M. Hess, MD, Cardiology, Inselspital, 3010 Bern, Switzerland.
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Abstract |
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Background Coronary flow reserve (CFR) is reduced in a majority of patients after heart transplantation (HTx). Pharmacological interventions, however, provide only limited information on CFR under physiological conditions. Thus, CFR during exercise was evaluated in the present study.
Methods and Results Coronary angiography was performed at rest and during supine bicycle exercise in 35 patients early (2 to 3 months; n=10) or late (1 to 6 years; mean, 2.5 years; n=25) after HTx and in 8 controls (C). CFR was determined by parametric imaging after administration of 10 mg intracoronary papaverine, during exercise, and after 1.6 mg sublingual nitroglycerin. Epicardial coronary artery size was measured by quantitative coronary angiography. CFR after papaverine was normal early (3.6±0.5 versus C, 3.6±0.7; P=NS) and late (3.8±1.3; P=NS) after HTx. During exercise, CFR was normal early (3.1±0.6 versus C, 3.9±0.9; P=NS) but decreased late (2.3±0.6; P<.01) after HTx. The increase in coronary cross-sectional area during exercise was also diminished late after HTx (14±10% versus C, 22±10%; P<.05). Both exercise-induced CFR (r=-.39, P<.05) and coronary vasodilation (r=-.44, P<.01) were inversely correlated with time after HTx.
Conclusions CFR during exercise is normal early but reduced late after HTx, whereas CFR after papaverine administration is maintained. This difference between physiological and pharmacological vasodilation suggests progressive endothelial dysfunction after HTx.
Key Words: exercise • transplantation • endothelium
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Introduction |
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Graft coronary vasculopathy is the major cause of morbidity and mortality in long-term cardiac transplant survivors.1 2 3 4 The prevalence of angiographically detectable coronary lesions is
40% 5 years after heart transplantation.5 6 Immune-mediated processes,8 9 10 particularly the vascular type of acute allograft rejection,11 seem to play a crucial role in the pathogenesis of the disease. However, cytomegalovirus infection,12 13 14 time after transplantation,15 hypercholesterolemia,15 16 and a preoperative diagnosis of dilated cardiomyopathy17 have also been associated with an increased incidence of graft atherosclerosis. An abnormal vasodilator response of angiographically smooth coronary arteries and a decreased coronary flow reserve in response to the endothelium-dependent vasodilators acetylcholine18 19 20 21 22 23 24 and substance P25 have been reported in cardiac transplant recipients. In contrast, coronary vasodilation in response to endothelium-independent agents such as adenosine,21 22 23 papaverine,26 27 and dipyridamole22 28 29 was preserved, at least in the absence of graft atherosclerosis.26 These pharmacological stimuli, however, provide only limited information on the behavior of the coronary arteries under physiological conditions. Thus, the purpose of the present study was to evaluate the effect of dynamic exercise as a physiological vasodilator stimulus on coronary flow reserve both early and late after heart transplantation. |
Methods |
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Patients
Forty-three patients were included in the present study. Ten cardiac transplant recipients (age, 54±11 years; 9 men, 1 woman) were studied early (2 to 3 months) and 25 patients (age, 49±9 years; 24 men, 1 woman) late (2.5±1.5 years; range, 1 to 6 years) after transplantation. Seven transplant recipients underwent follow-up examination (paired comparison) 1 year after the initial evaluation (1.9±1.5 years after surgery). Eight healthy subjects (age, 42±12 years; P<.05 versus early, P=NS versus late after transplantation) served as controls (C group).
All transplant recipients were in New York Heart Association functional class I (n=7 in the early, n=20 in the late posttransplantation group) or II (n=3 and 5, respectively). Control subjects were catheterized because of atypical chest pain. All patients had normal coronary arteries and no signs of left ventricular hypertrophy. Acute allograft rejections were excluded by endomyocardial biopsy performed the day before coronary angiography. Medical therapy in the three groups is summarized in Table 1
. Cyclosporin A was withheld for at least 12 hours and all other medication for at least 24 hours before cardiac catheterization. Written informed consent was obtained from all patients. There were no complications related to the study protocol in any patient.
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Study Protocol
Biplane coronary angiography was performed at the end of diagnostic coronary angiography. A nonionic contrast material (8 mL; Jopamiro 370) was injected into the left coronary artery at a flow rate of 4 mL/s with an ECG-triggered power injector with a time delay of 1 second for acquisition of the mask. First, baseline coronary angiography was carried out; then 10 mg papaverine was injected over a period of 15 seconds into the left coronary artery, and 30 seconds later coronary angiography was repeated. An interval of 10 minutes was allowed for dissipation of the effects of the contrast medium before another coronary angiogram was acquired at rest with the patient's legs elevated and attached to the bicycle ergometer. Then, two levels of supine bicycle exercise were performed for 2 minutes each, and biplane coronary angiography was repeated immediately after each exercise level during breath holding. Finally, coronary angiograms were acquired 5 minutes after administration of 1.6 mg sublingual nitroglycerin. Aortic and pulmonary pressures were measured immediately before each angiogram. In the subgroup of patients undergoing follow-up coronary angiography after 1 year (paired comparison), the same exercise levels were selected for the two examinations. In the patients studied 2 to 3 months after surgery, two-dimensional intravascular ultrasound was performed according to our standard follow-up protocol after heart transplantation.
Parametric Imaging
Coronary flow measurements were carried out by parametric imaging30 31 32 with an image processing system developed at our institution. This system is based on a modified 35-mm film projector (model XR35, Vanguard Corp) and a high-resolution (2048x2048x12 bits) photodiode camera (Eikonixscan model 78/99, Eikonix Corp). After digitization, images were processed on a VAX 750 computer (Digital Equipment Corp) and stored, averaged, and subtracted on a DeAnza IP8500 image processing system (Gould Inc). Relative coronary blood flow was determined in two circular regions of interest (size, 249 pixels) in the myocardial perfusion zone of the left anterior descending and circumflex coronary arteries in the left anterior oblique projection. Eight to 11 end-diastolic frames (one per cardiac cycle) were digitized at baseline, after intracoronary papaverine injection, at rest with the patient's feet attached to the bicycle ergometer, during two levels of supine bicycle exercise, and after sublingual nitroglycerin administration. The end-diastolic image before contrast injection served as mask for image subtraction. The subtracted images were color coded (Fig 1), and peak contrast density as well as mean appearance time in the regions of interest were calculated from these perfusion images. Contrast density was determined in the four regions of interest as well as in four neighboring background regions; the contrast densities of the background regions were subtracted from the corresponding regions of interest. Mean appearance time was defined as the time interval from the beginning of the ECG-triggered injection to the time at which half of peak contrast density was reached. This system has been validated in an experimental model using radiolabeled microspheres and electromagnetic flow probes.32 Regional coronary blood flow (flow index, FI, s-1) was calculated as the ratio of peak contrast density (CD) divided by mean appearance time (AT): FI=CD/AT.
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Coronary flow reserve (CFR) was calculated as the flow index after papaverine or nitroglycerin administration as well as during exercise (hyperemia, h) divided by the flow index at baseline (b): CFR=(CDhxATb)/(AThxCDb).
Quantitative Coronary Angiography
Quantitative evaluation of the coronary angiograms was performed with a semiautomatic computer system.33 This system is based on a 35-mm film projector (Tagarno 35 CX), a slow-scan CCD camera (image digitation) developed at the Institute for Biomedical Engineering in Zurich, and a computer workstation (Apollo DN 3000) for image storage and processing. Contour detection was carried out with a geometric-densitometric edge-detection algorithm. The computer traced the coronary segments automatically and calculated their mean cross-sectional areas in two orthogonal projections using the isocenter technique for calibration purposes (Fig 2). The cross-sectional areas of proximal, intermediate, and distal segments of the left anterior descending and circumflex coronary arteries were measured in all patients (six coronary segments in each patient) over a length of 0.5 to 2 cm in two or three different end-diastolic cine frames, and values were averaged from these repeated measurements.
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Statistics
Comparisons between hemodynamic, angiographic, and flow data at rest, after papaverine administration, and during exercise were performed by a two-way ANOVA for repeated measures. When the test was significant, the Scheffe procedure was applied for determination of statistical differences. Comparisons between data in transplant recipients and controls were done with an unpaired Student's t test. A value of P<.05 was considered to be significant. The effect of time after transplantation and LDL cholesterol on coronary flow reserve was assessed by a linear regression analysis.
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Results |
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Angiographic Data
Angiographic evidence of coronary artery disease was found in one patient early and five patients late after transplantation (Table 1
). Endoluminal irregularities without hemodynamically relevant (>50%) stenoses were present in all these cases. Two-dimensional intravascular ultrasound, which was performed in all patients early after operation, showed intimal thickening in two patients, with calcifications of the media in one. Four patients had mild regional wall motion abnormalities, with an ejection fraction ranging between 45% and 55% in the late posttransplantation group. In all other patients, ejection fraction was normal (>56%) early (67±5%) and late (67±10%; P=NS versus C, 63±5%) after transplantation.
Hemodynamic Data
Physical working capacity was reduced early (79±11 versus C, 116±17 W; P<.05) but normal late (101±15 W; P=NS) after transplantation (Table 2). Resting heart rate was slightly although not significantly increased early as well as late after transplantation. However, heart rate at peak exercise was significantly reduced early but normal late after surgery. Mean aortic pressure at rest was normal early but increased late after transplantation, whereas it was normal in both groups during exercise. The rate-pressure product (heart ratexmean aortic pressure) was increased at rest (Fig 3) both early and late after surgery, whereas it was reduced during exercise early and normal late after transplantation. Mean pulmonary artery pressure was elevated at peak exercise in both patient groups.
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In the small subgroup of patients undergoing follow-up coronary angiography 1 year after the initial study (paired comparison), workload during supine bicycle exercise was 89±13 W on both occasions. No significant differences between the two examinations were found with respect to heart rate, mean aortic pressure, or the rate-pressure product at rest and during exercise.
Coronary Flow Reserve
Flow reserve after papaverine administration was normal early (3.60±0.54 versus C, 3.59±0.69; P=NS) and late (3.79±1.25; P=NS) after transplantation (Fig 4a). In contrast, flow reserve during exercise was normal early (3.08±0.63 versus C, 3.86±0.92; P=NS) but reduced late (2.32±0.57; P<.01) after surgery. No changes in coronary blood flow were observed after nitroglycerin administration (flow reserve, 0.95±0.34 and 0.95±0.19 early and late after transplantation, respectively; C, 0.97±0.10; P=NS). Flow reserve as a function of time after transplantation is shown in Fig 5a: Flow reserve after papaverine administration was maintained up to 6 years after surgery, whereas an inverse correlation (r=-.39, P<.05) between flow reserve during exercise and time after surgery was found. High LDL cholesterol was associated with a trend (r=-.35, P=.12) toward a reduced flow reserve during exercise. In the subgroup of patients undergoing follow-up coronary angiography 1 year after the initial examination (Fig 6), flow reserve remained unchanged after papaverine administration but was slightly decreased during exercise (2.09±0.62 versus baseline, 2.39±0.72; P=.06).
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Proximal Coronary Artery Vasomotion
Percent increase in epicardial coronary cross-sectional area at peak exercise was slightly reduced early (18±12% versus C, 22±10%; P=NS) but significantly decreased late (14±10%; P<.05) after transplantation (Fig 4b). Coronary vasoconstriction during exercise was seen in a single patient studied 5 years after transplantation. In contrast, proximal coronary vasodilation after papaverine infusion was normal both early (25±18% versus C, 28±21%; P=NS) and late (27±21%; P=NS) after transplantation. Vasodilation after nitroglycerin administration was also maintained early (38±12% versus C, 40±17%; P=NS) and late (32±19%; P=NS) after transplantation. Time after surgery (r=-.44, P<.01; Fig 5b) was inversely correlated with exercise-induced but not with nitroglycerin-induced vasodilation.
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Discussion |
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An abnormal response of the epicardial coronary arteries and a reduced coronary flow reserve after acetylcholine infusion have been reported in cardiac transplant recipients.21 22 23 24 Since acetylcholine-induced vasodilation is dependent on endothelial release of nitric oxide,34 these findings suggest that coronary endothelial dysfunction occurs after heart transplantation. This hypothesis is consistent with the observation that direct relaxants of the smooth vasculature21 22 23 26 27 28 29 are associated with a preserved flow reserve in cardiac transplant recipients. Pharmacological interventions, however, provide only limited information on the behavior of the coronary arteries under physiological conditions. Thus, a different approach was used in the present study to induce an increase in coronary flow, namely, dynamic exercise. Although the vasodilator effect of dynamic exercise is more complex than that of pharmacological agents, this hyperemic stimulus reflects the daily activities of the patients better than pharmacological interventions. Thus, we compared "physiological" coronary vasodilation during exercise with "pharmacological" vasodilation after papaverine or nitroglycerin administration in heart transplant recipients. The major findings of the present study were as follows. (1) Coronary flow reserve during exercise is slightly although not significantly impaired 2 to 3 months after surgery but shows a progressive deterioration over time, being markedly reduced late after transplantation. (2) Pharmacological flow reserve after papaverine administration is preserved up to 5 years after transplantation. (3) Coronary vasodilation of the epicardial arteries is reduced during exercise but normal after papaverine administration.
Physiological Versus Pharmacological Flow Reserve
The discrepancy between the reduced physiological and the preserved pharmacological flow reserve in cardiac transplant recipients may be due to several factors, such as (1) inadequate exercise performance, (2) changes in resting coronary flow, (3) neurohumoral dysregulation, (4) impaired left ventricular diastolic function, and (5) endothelial dysfunction. These factors, alone or in combination, may affect coronary flow reserve through the following mechanisms.
1. An inadequate exercise performance may be responsible for a decrease in flow reserve during exercise in the early postoperative phase despite normal left ventricular systolic function. The limited exercise tolerance can be accounted for by several factors, such as postoperative deconditioning and skeletal muscle atrophy, chronotropic incompetence of the denervated heart, increased filling pressures due to left ventricular diastolic dysfunction and the abnormal pressure-volume homeostasis, and abnormalities in peripheral oxygen transport or utilization.35 36 In the present study, however, physical working capacity was significantly reduced early but not late after transplantation, probably because of physical reconditioning and attenuation of chronotropic incompetence late after operation.37 38
2. An increase in resting coronary flow due to the increased rate-pressure product is associated with a reduced flow reserve, defined as the ratio of hyperemic to resting flow.39 An increase in coronary blood flow at rest in cardiac transplant recipients has been shown by positron emission tomography.40 Nevertheless, pharmacological flow reserve has been found to be normal in the present study as well as in others,21 22 23 26 28 29 suggesting that changes in resting flow are not of major importance for the decrease in flow reserve.
3. Neurohumoral dysregulation typically occurs in cardiac transplant recipients as a result of allograft denervation. Heart transplantation is accompanied by a loss of afferent neural information from cardiac mechanoreceptors, leading to an exaggerated neuroendocrine response to exercise. Plasma renin activity and atrial natriuretic peptide are elevated at rest and during exercise, and norepinephrine and vasopressin are also increased during exercise.41 Another consequence of cardiac denervation is chronotropic incompetence with a blunted increase in heart rate during exercise. However, physiological flow reserve was normal in the early postoperative period despite these factors, which therefore seem not to play a major role with respect to flow reserve.
4. Left ventricular diastolic dysfunction has been described in transplant recipients,42 which may lead to an abnormal increase in left ventricular filling pressure during exercise. However, elevated exercise filling pressures in heart transplant recipients may also result from other factors, including volume status (resting pulmonary wedge pressure) and preload reserve (change in left ventricular end-diastolic volume).35 An increase in filling pressure may lead to an augmentation of extravascular compressive forces, thus limiting the increase in coronary flow. In the present study, the increase in diastolic pulmonary artery pressure during exercise was larger in transplant recipients than in control subjects. However, this increase was similar in the early and late postoperative periods, suggesting that diastolic dysfunction alone cannot explain changes in flow reserve over time.
5. Endothelial dysfunction of the coronary arteries may occur after heart transplantation, as suggested by previous studies.18 19 20 21 22 23 24 Flow reserve after acetylcholine administration is frequently impaired in these patients21 22 23 24 but can be partially restored by infusion of L-arginine,24 the precursor of nitric oxide. The role of the intact endothelium for the maintenance of a normal vascular reactivity to dynamic exercise has recently been demonstrated in conscious dogs exercising before and after endothelial denudation of the coronary arteries.43 The denuded vessels showed an impaired vasodilation during exercise that was reversible when the vessels were allowed to recover from endothelial injury. Since exercise-dependent vasodilation is mediated by the release of nitric oxide, endothelial dysfunction of the coronary microvasculature is probably an important factor for the limited increase in coronary flow during exercise. The decreased vasodilation of the epicardial coronary arteries during exercise but not after papaverine administration also suggests endothelial dysfunction. Cyclosporine may play an important role in inducing endothelial dysfunction in patients who receive transplants, because this agent has been experimentally associated with abnormal vasomotion,44 45 a decreased endothelial release of prostacyclin,44 and arterial hypersensitivity to angiotensin II.46 This last factor may be important in cardiac transplant recipients because of the enhanced activation of the renin-angiotensin system during dynamic exercise in these patients.41
Long-term Changes in Coronary Flow Reserve
A progressive deterioration of coronary flow reserve during exercise was observed in transplant recipients (Fig 5). Physiological flow reserve was normal early after operation despite the reduced physical working capacity. However, flow reserve was significantly diminished 1 year after transplantation and continued to decrease thereafter. In the subgroup of transplant recipients studied on a prospective basis, a slight decrease (P=.06) in physiological but not pharmacological flow reserve was found. This is in agreement with previous data showing progressive deterioration of coronary flow reserve after acetylcholine but not after adenosine administration during the first 3 years after transplantation.23
Limitations of the Study
Relative but not absolute coronary blood flow was determined by parametric imaging; therefore, coronary flow reserve was used as a measure of myocardial perfusion. Previous validation studies in experimental animals32 have shown that this method can reliably detect changes in coronary flow >30%, which is certainly the case in the present study. Atrial pacing to keep heart rate constant during image acquisition has been said to be mandatory for parametric imaging; however, previous data from our laboratory47 have shown excellent reproducibility with regard to coronary flow reserve with and without atrial pacing.
Acetylcholine has not been used in the present study, for several reasons: a further prolongation of the study protocol would have not been acceptable for ethical reasons, and the additional information gained with acetylcholine would have been small, since exercise is a physiological vasodilator stimulus that depends largely on an intact endothelium. Flow reserve was directly correlated (r=.54, P<.05) with changes in epicardial coronary artery dimensions, indicating that flow and vessel size are closely interrelated.
In summary, our data show a progressive deterioration of exercise-induced coronary flow reserve after heart transplantation, whereas papaverine-induced flow reserve is maintained even several years after transplantation. The discrepancy between physiological (endothelium-dependent) and pharmacological (papaverine; endothelium-independent) coronary flow reserve suggests that endothelial dysfunction of the coronary arteries occurs progressively after heart transplantation.
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Acknowledgments |
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This study was supported by a grant from the Swiss National Science Foundation.
Received April 16, 1996; revision received September 11, 1996; accepted September 30, 1996.
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References |
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