This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kofoed, K. F. Articles by Schelbert, H. R. Search for Related Content PubMed PubMed Citation Articles by Kofoed, K. F. Articles by Schelbert, H. R.

(Circulation. 1997;95:600-606.)
© 1997 American Heart Association, Inc.

Articles

Effects of Cardiac Allograft Vasculopathy on Myocardial Blood Flow, Vasodilatory Capacity, and Coronary Vasomotion

Klaus F. Kofoed, MD; Johannes Czernin, MD; Jay Johnson, MD; Jon Kobashigawa, MD; Michael E. Phelps, PhD; Hillel Laks, MD; Heinrich R. Schelbert, MD

the Division of Nuclear Medicine, Department of Molecular and Medical Pharmacology, Division of Cardiology (J.J., J.K.), and Cardiothoracic Surgery Department (H.L.), UCLA School of Medicine, and the Laboratory of Structural Biology & Molecular Medicine, University of California, Los Angeles.

Correspondence to Johannes Czernin, MD, Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA 90024-1721.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Coronary vasculopathy is the third leading cause of death 1 year after cardiac allograft transplantation. This study was designed to assess the hemodynamic effects of transplant vasculopathy on myocardial blood flow and vasomotion.

Methods and Results Thirty-two patients were studied 1 to 2 years after cardiac transplantation by use of positron emission tomography (n=32), intravascular ultrasound (n=26), coronary angiography (n=32), and endomyocardial biopsy (n=32). Twenty healthy individuals served as control subjects. Quantitative intravascular ultrasound was used to compute coronary lumen area, intimal thickness, and intimal index [Intima Area/(Intima+Lumen Area)]. Myocardial blood flow was quantified with the use of ¹³N-ammonia/positron emission tomography. Mean myocardial blood flow was higher in the transplant patients than in control subjects (0.94±0.26 versus 0.68±0.16 mL·min^-1·g^-1; P<.0005). Cold increased myocardial blood flow to 0.79±0.18 mL·min^-1·g^-1 in control subjects but not in patients (0.98±0.36 mL·g^-1·min^-1). Hyperemic myocardial blood flow was lower in patients than in control subjects (1.69±0.78 versus 2.30±0.32 mL·min^-1·g^-1; P<.05) and was inversely related to maximal intimal thickness and intimal index (all P<.05). The myocardial flow reserve was reduced in patients (1.82±0.55 versus 3.45±1.03; P<.0001).

Conclusions The degree of intimal thickening is correlated with abnormalities in coronary function in patients with diffuse cardiac allograft vasculopathy. The reduction in vasodilatory capacity and the abnormal blood flow response to cold suggest abnormalities in endothelium-dependent and -independent coronary vasodilation in transplant recipients.

Key Words: transplantation • ultrasonics • blood flow • tomography

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Cardiac allograft vasculopathy is the third leading cause of death and the leading cause of morbidity 1 year after transplantation.¹ Histopathologically, discrete intracellular endothelial changes and diffuse concentric intimal plaques have been described.² Such diffuse structural changes might alter coronary function. Conventional myocardial perfusion imaging fails to detect transplant vasculopathy.³ The clinical diagnosis of cardiac allograft vasculopathy has relied on coronary angiography,⁴ which is limited in detecting diffuse intimal thickening. Recently, IVUS has detected cardiac transplant vasculopathy accurately.^{5 6} Coronary angiography and IVUS are invasive procedures. In contrast, the evaluation of myocardial blood flow can now be accomplished noninvasively with ¹³N-ammonia and PET.^{7 8} Thus, the net effect of allograft vasculopathy on myocardial blood flow, vasomotion, and coronary vasodilatory capacity can be measured noninvasively in human transplant recipients. The present study in cardiac allograft recipients sought to relate structural coronary alterations as determined by IVUS to coronary circulatory function as quantified by PET.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Study Population
Thirty-two transplant recipients (26 males, 6 females; mean age, 55±8 years) were studied with PET at 12±1 (n=22) or 24±1 months (n=10) after cardiac transplantation. All had myocardial blood flow studies at rest and during cold pressor testing. Twenty-eight patients underwent a hyperemic blood flow study during intravenous dipyridamole. Four patients were excluded because of systolic hypotension of <100 mm Hg. In two patients, hyperemic blood flow could not be measured in the territory of the LAD because of patient mispositioning in the scanner. Coronary angiography (n=32), IVUS (n=26), and two-dimensional echocardiography (n=32) were performed as clinical follow-up tests within 4±6 and 11±9 weeks of the 1- or 2-year PET studies, respectively. Six patients did not undergo IVUS for logistical reasons. Twenty-one patients completed both the IVUS and PET study protocols. Indications for heart transplantation were cardiomyopathies of various origins. Three patients had undergone retransplantation because of progressive cardiac allograft vasculopathy. The age of the donor hearts was 31±14 years. At the time of the PET study, 12 patients (38%) had no history of allograft rejection by myocardial biopsy. Twenty patients (62%) had been rejection free for 43±36 weeks (range, 7 to 101 weeks). The severity of past rejections by myocardial biopsy ranged from 1B to 3A by ISHT classification.⁹ At the time of IVUS and PET, 20 patients (62%) were treated with triple-drug (cyclosporine, azathioprine, and prednisone), 10 (31%) with double-drug (azathioprine and cyclosporine), and 2 (6%) with single-drug (cyclosporine) immunosuppression. Lipid-lowering therapy consisted of pravastatin (n=15); empirical antihypertensive therapy consisted of calcium antagonists (n=9), diuretics (n=9), and ACE inhibitors (n=8); and antidiabetic treatment consisted of insulin (n=1) and oral antidiabetics (n=1). Twenty healthy volunteers, matched in age and sex to the heart donors, served as control subjects for the PET study. They were divided into two subgroups. Subgroup I (n=10; age, 35±18 years) was studied at rest and during cold pressor testing. Subgroup II (n=10; age, 35±13 years) was examined at rest and during dipyridamole-induced hyperemia. All participants signed an informed consent form approved by the UCLA Human Subject Protection Committee.

Study Protocol
Examples of a coronary angiogram, IVUS image, and PET polar map obtained in a transplant recipient are shown in Fig 1.

View larger version (59K): [in this window] [in a new window]   Figure 1. Coronary angiogram (left), intravascular sonogram (middle), and PET polar map (right) in a patient with intimal thickening as indicated by the arrow. Note that neither the angiogram nor the polar map revealed any significant abnormalities, whereas IVUS demonstrated significant intimal thickening. Quantitative PET revealed an attenuated hyperemic response with blood flow of 1.58 mL·g-1·min-1. Thus, neither coronary angiography nor relative 13N-ammonia PET imaging detected transplant vasculopathy. LCX indicates left circumflex coronary artery; RCA, right coronary artery.

IVUS
The angiographic extent and severity of coronary artery disease were assessed visually from standard views. A commercially available IVUS system (Cardiovascular Imaging Systems) was used to determine the degree of vasculopathy in the LAD. After intracoronary administration of nitroglycerin, a 0.018-in guidewire was introduced into the LAD. A 4.3F, 30-MHz IVUS catheter was advanced over the guidewire to a distal site of the LAD. Then, during a 30-second pullback, images were recorded continuously via super VHS videotape. From the video recording, 10 random end-diastolic images were converted (Media Grabber, Raster Ops) into a 640x480-pixel image matrix. The 10 images, corresponding to 10 sites of the LAD, were then analyzed with the use of computerized planimetry (NIH Image; version 1.55, public domain program). The circumference of the lumen border, internal elastic lamina, and intima and the maximal intimal thickness were manually traced. This method has been shown to be reproducible with a low interobserver variability of <13%¹⁰ and an excellent correlation between estimates of intimal thickness and those from histological samples (r=.93).¹¹ Total vessel area (mm²), lumen area (mm²), intimal area (mm), and maximal intimal thickness (mm) were computed. An intimal index was calculated as Intima Area/(Intima+Lumen Area). Estimates of total plaque burden were calculated in each patient as average maximal intimal thickness and intimal index of the 10 vascular sites. The average maximal intimal thickness was derived by averaging the maximal intimal thickness from the 10 sites.

Myocardial Biopsy
Four endomyocardial biopsies from the interventricular septum were graded according to the ISHT classification system.⁹

PET
Myocardial blood flow was measured at rest and during cold pressor testing in all 32 patients. Only 28 patients underwent pharmacological stress with dipyridamole. The dipyridamole study was always preceded by the cold pressor test. The Siemens/CTI 931/08-12 positron tomograph, which acquires 15 transaxial images simultaneously, was used.¹² All patients refrained from caffeine-containing food or beverages for 24 hours before the PET study.¹³ A 20-minute transmission image was acquired first to correct for photon attenuation. This was followed by the intravenous injection of 740 MBq ¹³N-ammonia while the dynamic imaging sequence started simultaneously. Forty-five minutes later, the cold pressor test was performed by immersing the patient's left hand in ice water for 105 seconds. ¹³N-ammonia (740 MBq) was injected 45 seconds after the start of the cold pressor test. At the time of the ¹³N-ammonia injection, the dynamic imaging sequence started and the cold pressor test was continued for 1 minute. Pharmacological vasodilation was induced by intravenous dipyridamole for 4 minutes (0.56 mg/kg). Four minutes after the end of the infusion, ¹³N-ammonia (740 MBq) was injected again while the serial image acquisition (12 frames of 10 seconds each, 2 frames of 30 seconds each, 1 frame of 60 seconds, and 1 frame of 15 minutes) was started. The rate-pressure product and mean arterial blood pressure were calculated from the two measurements during the first 2 minutes of the dynamic image acquisition.

Semiquantitative Image Analysis
The last frame of the transaxially acquired images was reoriented into six short-axis planes and assembled into polar maps that were compared with a reference database of healthy volunteers.¹⁴

Measurement of Blood Flow
Myocardial blood flow was measured in the territories of the LAD, the left circumflex artery, and the right coronary artery.¹⁵ Regions of interest were approximated to the three vascular territories on three short-axis images (one basilar, one midventricular, and one apical image). The same anatomic landmark (the insertion of the right ventricle into the intraventricular septum) was used in all studies to ensure identical regions of interest in all three flow studies. A small region of interest was centered in the left ventricular blood pool to derive the arterial input function.¹⁶ The regions were then copied to the first 120 seconds of the dynamic imaging sequence to obtain tissue time-activity curves. For each of the vascular territories, the three tissue curves (basilar, midventricular, and apical) were averaged and corrected for partial volume effects and physical decay.¹⁷ They were fitted with a previously validated two-compartment model that corrects for spillover of activity from blood pool into the left ventricular myocardium.¹⁸

Statistical Analysis
Mean values are given with SDs. The paired t test was used for comparisons within individuals. ANOVA was used to assess differences between groups. Correlations were sought by use of least-squares regression analysis. Probability levels of <.05 were considered statistically significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Two-dimensional Echocardiography
Minimal left ventricular hypertrophy was observed in one patient. All but one patient, who had diffuse mild left ventricular hypokinesis and an ejection fraction of 38%, had normal global left ventricular function.

Coronary Angiography
Two patients had a 60% ostial stenosis of the left circumflex coronary artery and a 70%, long, irregular stenosis in the middle portion of the right coronary artery, respectively.

IVUS
All 26 patients who underwent IVUS revealed some intimal thickening. The plaque burden (average maximal intimal thickness and intimal index of the 10 vascular sites) varied considerably between patients. Average maximal intimal thickness was 0.42±0.33 mm (range, 0.03 to 1.28 mm), and intimal index of the 10 vascular sites was 0.18±0.13 (range, 0.02 to 0.53).

Endomyocardial Biopsy
Four patients had evidence of mild allograft rejection classified as 1B (n=2) and 2A (n=2) by ISHT grading.⁹

PET
Hemodynamic Findings
Resting heart rate (86±12 versus 66±13 bpm; P<.0001), systolic blood pressure (126±18 versus 114±12 mm Hg; P<.01), diastolic blood pressure (79±11 versus 68±10 mm Hg; P<.001), and rate-pressure product (10 824±1892 versus 7424±1353; P<.0001) were higher in patients than in control subjects. The response to cold did not differ between the two groups. Heart rate, systolic blood pressure, diastolic blood pressure, and rate-pressure product increased by 7±6% and 14±19%, 19±10% and 18±16%, 17±12% and 18±15%, and 27±13% and 35±34% in patients and control subjects, respectively (all P=NS). The rate-pressure product during cold pressor testing was higher in patients than in control subjects (13 612±2219 versus 9615±2885; P<.0001). During intravenous dipyridamole, the heart rate increased less in the transplant recipients than in control subjects (15±8% versus 44±27%; P<.0001). Systolic blood pressure increased only in control subjects (9±9%; P<.005). Diastolic blood pressure remained unchanged in both groups. Mean aortic blood pressure was similar in patients and control subjects (90±13 versus 90±12 mm Hg; P=NS).

Semiquantitative Polar Map Analysis
Three patients (9%) had reduced regional myocardial ¹³N-ammonia uptake. Two had small, fixed defects at the interface between the territories of the left circumflex and the right coronary arteries. The remaining patient had a small, fixed defect in the left circumflex territory. The extent and severity of these defects were <10% below the normal reference values in all three patients who had no arteriographic evidence for atheroma. However, they had varying degrees of intimal thickening by IVUS. The two patients with angiographic evidence of mild coronary artery disease had normal polar maps at rest and during stress. Both patients were treated with calcium antagonists at the time of the study. No perfusion abnormalities were identified in the normal volunteers.^{19 20}

Myocardial Blood Flow at Rest
In the patients, regional myocardial blood flow averaged 0.95±0.25, 0.91±0.34, and 0.96±0.27 mL·g^-1·min^-1 in the territory of the LAD, the left circumflex artery, and the right coronary artery, respectively (P=NS). Mean myocardial blood flow was higher in the transplant patients than in control subjects (0.94±0.26 versus 0.68±0.16 mL·min^-1·g^-1; P<.0005) and correlated linearly with the rate-pressure product in both groups (r=.42, P<.05 and r=.60, P<.01, respectively). No differences in blood flow normalized to the rate-pressure product were observed.

Blood Flow Response to Cold
Myocardial blood flow did not increase in patients (0.94±0.26 versus 0.98±0.36 mL·min^-1·g^-1; P=NS) in response to cold and was unrelated to the rate-pressure product (r=.07; P=NS). In contrast, it increased in the control group from 0.64±0.13 to 0.79±0.18 mL·min^-1·g^-1 (P<.005) and remained significantly correlated to the rate-pressure product (r=.59; P<.05). Blood flow normalized to the rate-pressure product declined in patients (0.88±0.22 versus 0.74±0.28 mL·min^-1·g^-1; P<.005) but not in control subjects (0.90±0.13 versus 0.85±0.19 mL·min^-1·g^-1; P=NS).

Hyperemic Blood Flow and Flow Reserve
In transplant patients, dipyridamole-induced hyperemic blood flow averaged 1.79±0.84, 1.55±0.71, and 1.76±0.90 mL·g^-1·min^-1 in the three vascular territories (P=NS). Mean hyperemic blood flow (1.69±0.78 versus 2.30±0.32 mL·min^-1·g^-1; P<.05) and flow reserve (1.81±0.55 versus 3.45±1.03; P<.0001) were lower in patients than in control subjects.

Coronary Vascular Resistance
Minimal coronary vascular resistance²¹ during dipyridamole (mean arterial blood pressure/myocardial blood flow) was higher in patients than in control subjects (62±22 versus 40±9 mm Hg·mL^-1·min^-1·g^-1; P<.005). In patients, the abnormal response to cold was associated with a proportional impairment of vasodilatory capacity as evidenced by a linear correlation between coronary vascular resistance during cold and that during pharmacological vasodilation (r=.72; P<.0001; Fig 2).

View larger version (11K): [in this window] [in a new window]   Figure 2. Relation between coronary vascular resistance during cold (CVR-CPT; x axis) and that during dipyridamole (CVR-DIP; y axis). These parameters were correlated by y=0.37x+13. r=.72; SEE=0.069; P<.001.

Intimal Thickening, Myocardial Blood Flow, and Flow Reserve
Blood flow at rest and during cold pressor testing were unrelated to intimal thickness. In contrast, hyperemic blood flow was inversely related to average maximal intimal thickness (r=.49) and intimal index (r=.44; all P<.05). A stronger inverse correlation was found between myocardial flow reserve and average maximal intimal thickness (r=.61; SEE=0.3; P<.005; Fig 3) and intimal index (r=.52; SEE=0.79; P<.05).

View larger version (12K): [in this window] [in a new window]   Figure 3. Myocardial flow reserve (y axis) as a function of average maximal intimal thickness (mm; x axis) in the territory of the LAD. Increases in intimal thickness were associated with decreases in myocardial flow reserve. The relation was y=-1.03x+2.25. r=.62; SEE=0.3; P<.005.

Relation Between Blood Flow and Risk Factors for Transplant Vasculopathy
The quantitative blood flow measurements were unrelated to preexisting risk factors for coronary artery disease, including serum lipid levels, donor/recipient gender, gender match, and donor/recipient age at the time of transplantation. Previous studies²² suggested that prolonged cytomegalovirus infections might be associated with transplant vasculopathy. No relation between blood flow and cytomegalovirus status or the number or severity of previous rejections was observed. Resting and hyperemic blood flow in the four patients with mild allograft rejection did not differ from those in the remaining patients. The time from transplantation to PET was unrelated to the degree of intimal thickening, resting blood flow, hyperemic blood flow, or flow reserve (r=.06).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Intimal thickening is correlated with abnormalities in coronary function in transplant patients. The reduction in vasodilatory capacity is associated with an impairment in coronary vasomotion as evidenced by an abnormal blood flow response to cold. These findings suggest abnormalities in endothelium-dependent and -independent coronary vasodilation.

Semiquantitative Image Analysis
Because of the diffuse nature of intimal changes, conventional myocardial perfusion imaging fails to detect transplant vasculopathy reliably.³ Consistently, polar map analysis failed to detect allograft vasculopathy in the current study. Three patients had small, fixed perfusion defects in the posterolateral wall of the left ventricle despite normal angiographic findings. Regional heterogeneities in ¹³N-ammonia distribution, as previously observed in this segment in healthy volunteers, might account for this finding.¹⁴ Two of the 32 patients had angiographic evidence of mild coronary artery disease but normal PET polar map findings. However, the angiographic severity of the stenosis was determined only visually. In addition, the coronary vasomotor tone and thus the diameter of the coronary lumen might have changed between the time of angiography and PET. Thus, the physiological significance of these stenoses remains unknown. Both patients were treated with calcium antagonists at the time of the PET study, which might offer another explanation for why these lesions remained undetected.

Myocardial Blood Flow at Rest
Myocardial blood flow at rest is increased in rejection-free transplant recipients.^{23 24} The current study suggests that this increase is explained by the higher heart rates in patients than in control subjects, which might be accounted for by the absence of cholinergic stimuli in the denervated allografts.²⁵

In the patients, the relation between rate-pressure product and myocardial blood flow was rather poor, with a correlation coefficient of only .42. This is because the rate-pressure product does not take into account the variability in stroke volume and contractility. In addition, the various drug combinations used in the transplant recipients might have contributed to the substantial data scatter. Alternatively, abnormalities in the regulation of resting coronary vasomotor tone in these functionally denervated hearts might have altered the relation between myocardial blood flow and rate-pressure product.

Myocardial Blood Flow During Cold Pressor Testing
Cold activates the nervous system by inducing the release of catecholamines from terminal nerve endings and, more importantly in transplant recipients, the adrenal medulla.^{26 27} The subsequent stimulation of coronary ₂ (vasoconstriction) and ß₂ (vasodilation) as well as myocardial ß₁ receptors (indirect vasodilation) results in coronary vasodilation in individuals with preserved endothelial function. Accordingly, healthy control subjects showed increases in blood flow in response to cold, which remained significantly correlated to the rate-pressure product (r=.59; P<.05).The reduction or absence of endothelium-derived vasodilating compounds such as endothelium-derived relaxing factor–nitric oxide results in coronary vasoconstriction or reductions in blood flow in response to cold or exercise in patients at risk for or with documented coronary artery disease.^{26 27} Similar observations were made in transplant recipients in whom intracoronary acetylcholine^{28 29} or cold³⁰ induced a paradoxical coronary vasoconstriction. Endothelial dysfunction might account for this finding.² A low-level immunologic response to allogeneic endothelial cells might result in endothelial cell activation and production of growth factors. This promotes smooth muscle cell proliferation in the intima,^{31 32} which responds to increases in catecholamines with an increase in coronary vasomotor tone.³³ Consistently, myocardial blood flow failed to increase and was unrelated to the rate-pressure product during cold pressor testing in patients in the present study. (r=.07; P=NS).

Hyperemic Blood Flow and Flow Reserve
The effect of a single epicardial coronary artery stenosis on hyperemic blood flow and coronary flow reserve has been investigated extensively by Gould and coworkers,^{34 35} who observed in animal experimental studies a nonlinear relation between stenosis severity and near-maximal coronary blood flow. A similar relation was reported recently in humans with the use of quantitative PET.^{36 37} In the current study, average maximal intimal thickness and flow reserve were significantly correlated, yet there was considerable data scatter about the regression line (Fig 3). Moreover, the relation seemed strongly held by three data points on the extreme right of the scatterplot. Two of these three patients were studied 2 years after transplantation, none of them had bioptic evidence for recent rejection, all had normal left ventricular function at rest, and their drug therapy did not differ from the remainder of the study group. Thus, the severe intimal changes in these patients were likely to have accounted for their markedly reduced or even absent flow reserve.

Hyperemic blood flow and flow reserve were reduced in the current study population. This contradicts previous studies that described a normal hyperemic flow response in rejection-free cardiac allograft recipients using IVUS, intracoronary Doppler flow velocity measurements,³⁸ or PET.^{23 24 39} Anderson et al⁴⁰ studied 40 transplant recipients 1 to 8 years after cardiac transplantation. The coronary response to nitroglycerin tended to be attenuated in patients studied late after transplantation, who in turn had more severe intimal thickening. Similarly, Pinto et al⁴¹ used nitroglycerin to induce coronary hyperemia in 32 patients 3 weeks to 10 years after cardiac allograft transplantation and observed a normal hyperemic response in nonrejecting transplant recipients. The hyperemic response tended to be attenuated early (<3 weeks) but not late (>1 year) after transplantation.

Methodological differences as well as differences in the study populations might account for these discrepancies. Changes in coronary flow velocity in large epicardial coronary arteries cannot necessarily be equated to changes in the myocardial microcirculation.^{38 42} In addition, differences in the vasodilatory agents used might account for some of the conflicting results. For instance, nitroglycerin is a less potent coronary vasodilator than dipyridamole. Thus, the hyperemic stimulus might have been insufficient to uncover the hemodynamic significance of intimal changes in these other studies.

Chan et al³⁹ demonstrated a significant reduction in hyperemic blood flow during moderate allograft rejection, whereas the coronary vasodilatory capacity was close to normal in patients without rejection. In the current study, resting blood flow in patients with mild rejection averaged 1.05±0.34 mL·g^-1·min^-1, hyperemic blood flow ranged from 1.08 to 3.72 mL·g^-1·min^-1 and averaged 2.2±1.2 mL·g^-1·min^-1, and flow reserve averaged 1.95±0.76. Obviously, the number of patients with mild rejection in the current study was too small for a meaningful statistical comparison to patients without rejection. However, their myocardial blood flow did not appear to be different from that in patients without rejection. This might be explained by the different severity of allograft rejection, which was graded bioptically as moderate in the previous study³⁹ yet as mild in the current study. One major discrepancy between the previous and the current study was that the hyperemic response and flow reserve were abnormal in patients without rejection. Differences in the study populations might have accounted for these conflicting results. The previous rejection-free study group consisted of only six individuals, who were examined 2 to 4 months after transplantation. In contrast, in the current investigation, myocardial blood flow was studied 1 or 2 years after cardiac transplantation. Thus, transplant vasculopathy was likely to have been more prevalent and prominent in the current group, which in turn might account for their abnormal vasodilatory capacity even without evidence of allograft rejection.

The vasodilatory effect of dipyridamole has generally been considered endothelium independent. However, this hypothesis has been challenged by an animal experimental study that demonstrated that adenosine-induced increases in coronary blood flow could be abolished by inhibition of nitric oxide synthesis,⁴³ suggesting that the coronary response to adenosine may be modulated directly by altered nitric oxide production, release of nitric oxide,⁴⁴ or alterations in the cell-to-cell communication between endothelium and smooth muscle cells. However, a more recent animal experimental study⁴⁵ failed to demonstrate a significant association between adenosine-mediated hyperemia and inhibition of nitric oxide synthesis by N-nitro-L-arginine methyl ester. Thus, the reduced flow response to dipyridamole might result from basally increased vasomotor tone of the small arteries associated with a metabolic vasodilation of arterioles. The significant relation between coronary resistance during cold and that during dipyridamole might suggest a common defect affecting both endothelium-dependent and -independent coronary vasodilation in patients with transplant vasculopathy.

Study Limitations
The study group included four patients with mild allograft rejection and two with mild atheromatous coronary artery disease. These patients might have exhibited a different blood flow response to cold and dipyridamole than the remaining transplant recipients. However, quantitative analysis revealed no heterogeneities in regional blood flow. Although no statistical analysis could be performed because of the small sample size, these patients did not appear to respond differently to cold and dipyridamole than the rest of the study population.

As another limitation, the cold pressor test might not have evoked a stable hemodynamic response in all patients. However, systolic blood pressure and heart rate were measured in minute intervals and did not change significantly after the first minute of exposure to cold. Thus, significant hemodynamic changes were unlikely to have occurred during the first 2 minutes of the dynamic image acquisition.

The individual drug regimen might have affected myocardial blood flow and flow reserve. However, no differences in blood flow or flow reserve were noted between patients who were taking calcium antagonists or ACE inhibitors and those who were only receiving immunosuppressive treatment. Serum cholesterol levels were lower in patients with than in those without lipid-lowering therapy (160±38 versus 215±46 mg%; P<.05). However, lipid-lowering therapy and serum lipid levels were unrelated to resting or hyperemic blood flow.

Clinical Implications
Transplant vasculopathy alters myocardial blood flow and flow reserve. Abnormalities in myocardial blood flow and vasomotion as detected by PET might help to noninvasively identify cardiac allograft recipients with transplant vasculopathy. Quantitative PET might emerge as a useful tool to monitor the course of transplant vasculopathy and to noninvasively determine whether its progression can be halted or even reversed by short-term or long-term pharmacological interventions.

	Selected Abbreviations and Acronyms

 

ISHT = International Society of Heart Transplantation IVUS = intravascular ultrasound LAD = left anterior descending coronary artery PET = positron emission tomography

	Acknowledgments

 
This work was supported in part by the Director of the Office of Energy Research, Office of Health and Environmental Research, Washington, DC; by research grant No. HL-33177, National Institutes of Health, Bethesda, Md; and by an Investigative Group Award by the Greater Los Angeles Affiliate of the American Heart Association, Los Angeles, Calif. Dr Kofoed is a research fellow of the Danish Heart Foundation and the Danish Research Academy.

	Footnotes

 
The Laboratory of Structural Biology & Molecular Medicine is operated for the US Department of Energy by the University of California under contract No. DE-FC03-87ER60615.

Received March 5, 1996; revision received September 5, 1996; accepted September 9, 1996.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Gao SZ, Schroeder JS, Alderman EL, Hunt SA, Valantine HA, Wiederhold V, Stinson EB. Prevalence of accelerated coronary artery disease in heart transplant survivors: comparison of cyclosporine and azathioprine regimens. Circulation. 1989;80(pt 2):III-100-III-105.

2. Billingham ME. Histopathology of graft coronary disease. J Heart Lung Transplant. 1992;11(pt 2):S38-S44.

3. Smart F, Ballantyne C, Cocanougherand B. Insensitivity of noninvasive tests to detect coronary artery vasculopathy after heart transplant. Am J Cardiol. 1991;67:243-247.[Medline] [Order article via Infotrieve]

4. Miller LW, Schlant RC, Kobashigawa J, Kubo S, Renlund DG. 24th Bethesda Conference: cardiac transplantation—Task Force 5: complications. J Am Coll Cardiol. 1993;22:41-54.[Medline] [Order article via Infotrieve]

5. Ventura HO, Ramee SR, Jain A, White CJ, Collins TJ, Mesa JE, Murgo JP. Coronary artery imaging with intravascular ultrasound in patients following cardiac transplantation. Transplantation. 1992;53:216-219.[Medline] [Order article via Infotrieve]

6. St Goar F, Pinto FJ, Alderman EL, Valantine HA, Schroeder JS, Gao SZ, Stinson EB, Popp RL. Intracoronary ultrasound in cardiac transplant recipients: in vivo evidence of `angiographically silent' intimal thickening [see comments]. Circulation. 1992;85:979-987.[Abstract/Free Full Text]

7. Kuhle W, Porenta G, Huang S-C, Phelps ME, Schelbert H. Issues in the quantitation of reoriented cardiac PET images. J Nucl Med. 1992;33:1235-1242.[Abstract/Free Full Text]

8. Krivokapich J, Smith GT, Huang SC, Hoffman EJ, Ratib O, Phelps ME, Schelbert HR. ¹³N ammonia myocardial imaging at rest and with exercise in normal volunteers: quantification of absolute myocardial perfusion with dynamic positron emission tomography. Circulation. 1989;80:1328-1337.[Abstract/Free Full Text]

9. Billingham ME, Cary NR, Hammond ME, Kemnitz J, Marboe C, McCallister HA, Snovar DC, Winters GL, Zerbe A. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group—The International Society for Heart Transplantation. J Heart Transplant. 1990;9:587-593.[Medline] [Order article via Infotrieve]

10. Hausmann D, Lundkvist A, Friedrich G, Mullen W, Fitzgerald P, Yock P. Intracoronary ultrasound imaging: intraobserver and interobserver variability of morphometric measurements. Am Heart J. 1994;128:674-680.[Medline] [Order article via Infotrieve]

11. Potkin B, Bartorelli A, Gessert J, Neville R, Almagor Y, Roberts W, Leon M. Coronary artery imaging with intravascular high-frequency ultrasound. Circulation. 1990;81:1575-1585.[Abstract/Free Full Text]

12. Spinks TJ, Jones T, Gilardi MC, Heather JD. Physical performance of the latest generation of commercial positron scanner. Trans Nucl Sci. 1988;35:721-725.

13. Smits P, Lenders JW, Thien T. Caffeine and theophylline attenuate adenosine induced vasodilation in humans. Clin Pharmacol Ther. 1990;48:410-418.[Medline] [Order article via Infotrieve]

14. Porenta G, Kuhle W, Czernin J, Ratib O, Brunken R, Phelps ME, Schelbert H. Semiquantitative assessment of myocardial viability and perfusion utilizing polar map displays of cardiac PET images. J Nucl Med. 1992;33:1623-1631.[Abstract/Free Full Text]

15. Czernin J, Muller P, Chan S, Brunken R, Porenta G, Krivokapich J, Chen K, Chan A, Phelps ME, Schelbert H. Influence of age and hemodynamics on myocardial blood flow and flow reserve. Circulation. 1993;88:62-69.[Abstract/Free Full Text]

16. Weinberg IN, Huang SC, Hoffman EJ, Araujo L, Nienaber C, Grover-McKay M, Dahlbom M, Schelbert H. Validation of PET-acquired functions for cardiac studies. J Nucl Med. 1988;29:241-247.[Abstract/Free Full Text]

17. Gambhir SS, Schwaiger M, Huang SC, Krivokapich J, Schelbert HR, Nienaber CA, Phelps ME. Simple noninvasive quantification method for measuring myocardial glucose utilization in humans employing positron emission tomography and fluorine-18 deoxyglucose. J Nucl Med. 1989;30:359-366.[Abstract/Free Full Text]

18. Kuhle W, Porenta G, Huang SC, Buxton D, Gambhir S, Hansen H, Phelps ME, Schelbert H. Quantification of regional myocardial blood flow using ¹³N-ammonia and reoriented dynamic positron emission tomographic imaging. Circulation. 1992;86:1004-1017.[Abstract/Free Full Text]

19. Demer LL, Gould KL, Goldstein RA, Kirkeeide RL, Mullani NA, Smalling RW, Nishikawa A, Merhige ME. Assessment of coronary artery disease severity by positron emission tomography: comparison with quantitative arteriography in 193 patients. Circulation. 1989;79:825-835.[Abstract/Free Full Text]

20. Stewart R, Schwaiger M, Molina E, Popma J, Gacioch G, Kalus M, Squicciarini S, Al-Aouar Z, Schork A, Kuhl D. Comparison of rubidium-82 positron emission tomography and thallium-201 SPECT imaging for detection of coronary artery disease. Am J Cardiol. 1991;67:1303-1310.[Medline] [Order article via Infotrieve]

21. Marcus MR, Wilson RF, White CW. Methods of measurements of myocardial blood flow in patients: a critical review. Circulation. 1987;76:873-885.

22. Everett JR, Hershberger D, Norman D, Chou S, Ratkovec R, Cobanoglu A, Ott G, Hosenpud J. Prolonged cytomegalovirus infection with viremia is associated with cardiac allograft vasculopathy. J Heart Lung Transplant. 1992;11:S133-S137.[Medline] [Order article via Infotrieve]

23. Rechavia EL, Araujo L, De-Silva R, Kushwaha SS, Lammertsma AA, Jones T, Mitchell A, Maseri A, Yacoub MH. Dipyridamole vasodilator response after human orthotopic heart transplantation: quantification by oxygen-15-labeled water and positron emission tomography [see comments]. J Am Coll Cardiol. 1992;19:100-106.[Abstract]

24. Senneff MJ, Hartman J, Sobel BE, Geltman EM, Bergmann SR. Persistence of coronary vasodilator responsivity after cardiac transplantation. Am J Cardiol. 1993;71:333-338.[Medline] [Order article via Infotrieve]

25. Arrowood J, Goudreau E, Minisi A, Davis A, Mohanty P. Evidence against reinnervation of cardiac vagal afferents after human orthotopic cardiac transplantation. Circulation. 1995;92:402-408.[Abstract/Free Full Text]

26. Robertson DG, Johnson R, Robertson R, Nies A, Shand D, Oates J. Comparative assessment of stimuli that release neuronal and adrenomedullary catecholamines in man. Circulation. 1979;59:637-643.[Abstract/Free Full Text]

27. Nabel E, Ganz P, Gordon J, Alexander R, Selwyn A. Dilation of normal and constriction of atherosclerotic coronary arteries caused by the cold pressor test. Circulation. 1988;77:43-52.[Abstract/Free Full Text]

28. Treasure CB, Vita JA, Ganz P, Ryan TJ Jr, Schoen FJ, Vekshtein VI, Yeung AC, Mudge GH, Alexander WJ, Selwyn AP, Fish RD. Loss of the coronary microvascular response to acetylcholine in cardiac transplant patients. Circulation. 1992;86:1156-1164.[Abstract/Free Full Text]

29. Fish R, Nabel E, Selwyn AP. Responses of coronary arteries of transplant recipients to acetylcholine. J Clin Invest. 1988;81:21-31.

30. Benvenutti C, Aptecar E, Mazzucotelli J, Jouannot P, Loisance D, Nitneberg A. Coronary artery response to cold pressor test is impaired early after operation in transplant recipients. J Am Coll Cardiol. 1995;26:446-451.[Abstract]

31. Libby P, Tanaka H. The pathogenesis of coronary arteriosclerosis (`chronic rejection') in transplanted hearts. Clin Transplant. 1994;8:313-318.[Medline] [Order article via Infotrieve]

32. Hosenpud JD, Shipley GD, Wagner CR. Cardiac allograft vasculopathy: current concepts, recent developments, and future directions. J Heart Lung Transplant. 1992;11(pt 1):9-23.

33. Gilbert EM, Eiswirth CC, Mealey PC, Larrabee P, Herrick CM, Bristow MR. ß-Adrenergic supersensitivity of the transplanted human heart is presynaptic in origin. Circulation. 1989;79:344-349.[Abstract/Free Full Text]

34. Gould KL, Lipscomb K, Hamilton GW. Physiologic basis for assessing critical coronary stenosis: instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve. Am J Cardiol. 1974;33:87-94.[Medline] [Order article via Infotrieve]

35. Gould KL. Quantitative coronary arteriography and positron emission tomography. Circulation. 1988;78:237-245.[Free Full Text]

36. Uren NG, Melin JA, De Bruyne B, Wijns W, Baudhuin M, Camici PG. Relation between myocardial blood flow and the severity of coronary-artery stenosis. N Engl J Med. 1994;330:1782-1788.[Abstract/Free Full Text]

37. Di Carli M, Czernin J, Hoh CK, Gerbaudo VH, Brunken RC, Huang SC, Phelps ME, Schelbert HR. Relation among stenosis severity, myocardial blood flow, and flow reserve in patients with coronary artery disease. Circulation. 1994;91:1944-1951.[Abstract/Free Full Text]

38. McGinn AL, Wilson RF, Olivari MT, Homans MT, White CW. Coronary vasodilator reserve after human orthotopic cardiac transplantation. Circulation. 1988;78:1200-1209.[Abstract/Free Full Text]

39. Chan SY, Kobashigawa J, Stevenson LW, Brownfield E, Brunken RC, Schelbert HR. Myocardial blood flow at rest and during pharmacological vasodilation in cardiac transplants during and after successful treatment of rejection. Circulation. 1994;90:204-212.[Abstract/Free Full Text]

40. Anderson TJ, Meredith IT, Uehata A, Mudge GH, Selwyn AP, Ganz P, Yeung AC. Functional significance of intimal thickening as detected by intravascular ultrasound early and late after cardiac transplantation. Circulation. 1993;88:1093-1100.[Abstract/Free Full Text]

41. Pinto FJ, St Goar FG, Fischell TA, Stadius ML, Valantine HA, Alderman EL, Popp RL. Nitroglycerin-induced coronary vasodilation in cardiac transplant recipients: evaluation with in vivo intracoronary ultrasound. Circulation. 1992;85:69-77.[Abstract/Free Full Text]

42. Nitenberg A, Tavolaro O, Benvenuti C, Loisance D, Foult JM, Hittinger L, Castaigne A, Cachera JP, Vernant P. Recovery of a normal coronary vascular reserve after rejection therapy in acute human cardiac allograft rejection. Circulation. 1990;81:1312-1318.[Abstract/Free Full Text]

43. Parent R, Richard P, Lavallee M. Contribution of nitric oxide to dilation of resistance coronary vessels in conscious dogs. Am J Physiol. 1992;262:H10-H16.[Abstract/Free Full Text]

44. Balcells E, Suarez J, Rubio R. Implications of the coronary vascular endothelium as mediator of the vasodilatory and dromotropic actions of adenosine. J Mol Cell Cardiol. 1993;25:693-706.[Medline] [Order article via Infotrieve]

45. Jones CJH, Kuo L, Davies MJ, DeFily DV, Chillian WM. Role of nitric oxide in the coronary microvascular responses to adenosine and increased metabolic demand. Circulation. 1995;91:1807-1813.[Abstract/Free Full Text]

This article has been cited by other articles:

				G. Tellides and J. S. Pober Interferon-{gamma} Axis in Graft Arteriosclerosis Circ. Res., March 16, 2007; 100(5): 622 - 632. [Abstract] [Full Text] [PDF]

				E. Nygard, K. F. Kofoed, J. Freiberg, S. Holm, J. Aldershvile, K. Eliasen, and H. Kelbaek Effects of High Thoracic Epidural Analgesia on Myocardial Blood Flow in Patients With Ischemic Heart Disease Circulation, May 3, 2005; 111(17): 2165 - 2170. [Abstract] [Full Text] [PDF]

				O. M. Muehling, N. M. Wilke, P. Panse, M. Jerosch-Herold, B. V. Wilson, R. F. Wilson, and L. W. Miller Reduced myocardial perfusion reserve and transmural perfusiongradient in heart transplant arteriopathyassessed by magnetic resonance imaging J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1054 - 1060. [Abstract] [Full Text] [PDF]

				E. Tadamura, M. Mamede, S. Kubo, H. Toyoda, M. Yamamuro, H. Iida, N. Tamaki, K. Nishimura, M. Komeda, and J. Konishi The Effect of Nitroglycerin on Myocardial Blood Flow in Various Segments Characterized by Rest-Redistribution Thallium SPECT J. Nucl. Med., May 1, 2003; 44(5): 745 - 751. [Abstract] [Full Text] [PDF]

				J. Schwitter, T. DeMarco, S. Kneifel, G. K. von Schulthess, M. C. Jorg, H. Arheden, S. Ruhm, K. Stumpe, A. Buck, W. W. Parmley, et al. Magnetic Resonance-Based Assessment of Global Coronary Flow and Flow Reserve and Its Relation to Left Ventricular Functional Parameters : A Comparison With Positron Emission Tomography Circulation, June 13, 2000; 101(23): 2696 - 2702. [Abstract] [Full Text] [PDF]

				P. L. Skarsgard, X. Wang, P. McDonald, A. H. Lui, E. K. Lam, B. M. McManus, C. van Breemen, and I. Laher Profound Inhibition of Myogenic Tone in Rat Cardiac Allografts Is Due to eNOS- and iNOS-Based Nitric Oxide and an Intrinsic Defect in Vascular Smooth Muscle Contraction Circulation, March 21, 2000; 101(11): 1303 - 1310. [Abstract] [Full Text] [PDF]

				R. Campisi, J. Czernin, H. Schoder, J. W. Sayre, F. D. Marengo, M. E. Phelps, and H. R. Schelbert Effects of Long-term Smoking on Myocardial Blood Flow, Coronary Vasomotion, and Vasodilator Capacity Circulation, July 14, 1998; 98(2): 119 - 125. [Abstract] [Full Text] [PDF]

				S. E. Reis, V. Bhoopalam, K. A. Zell, P. J. Counihan, A. J. C. Smith, S. Pham, and S. Murali Conjugated Estrogens Acutely Abolish Abnormal Cold-Induced Coronary Vasoconstriction in Male Cardiac Allografts Circulation, January 13, 1998; 97(1): 23 - 25. [Abstract] [Full Text] [PDF]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kofoed, K. F. Articles by Schelbert, H. R. Search for Related Content PubMed PubMed Citation Articles by Kofoed, K. F. Articles by Schelbert, H. R.