We studied the effects of cytomegalovirus (CMV) infection on 301 cardiac transplant recipients who were treated during the cyclosporine era of immunosuppression (1980 to the present). These patients received varying combinations of cyclosporine, azathioprine, prednisone, rabbit antithymocyte globulin, and OKT3 as their immunosuppressive therapy. Two hundred ten patients were free of CMV infection (non-CMV group). During the same period CMV infection developed in 91 patients, as manifested by a fourfold IgG serologic titer rise, demonstration of CMV inclusion bodies in tissue, or positive cultures for the virus (CMV group). The rate of graft rejection was significantly higher in the CMV group. Graft atherosclerosis was significantly more severe in the CMV group as judged by angiographic criteria or by pathologic study. Patient survival rates were significantly lower in the CMV group. Death caused by graft atherosclerosis was significantly more common among patients in the CMV group. Finally, the graft loss rate (from either death or retransplantation for atherosclerosis) was significantly greater in the CMV group. These data demonstrate that CMV infection in cardiac transplant recipients is associated with more frequent rejection, graft atherosclerosis, and death.

The shape of the coronary arterial pressure-flow relationship results from the interaction of a number of poorly understood physiological factors. Experiments in which coronary inflow and outflow pressures were coupled so that driving pressure was held constant showed that changes in inflow or outflow pressures altered coronary blood flow: coronary vascular resistance varied inversely with changes inflow pressure below 50 mm Hg and with changes in outflow pressure below 80 mm Hg. The magnitude of the influence of inflow pressure on resistance also depended on the fixed level of outflow pressure, the influence being large when the outflow pressure was low, and small when it was high. Inflow and outflow pressures, then, are two physiological factors which are determinants of the shape of the pressure-flow relationship, and their interaction contributes to the degree of curvature found in a particular relationship. These findings suggest that the use of linear regression in the interpretation of pressure-flow relationships results in poor estimation of resistance and zero-flow pressure. Other experiments measuring regional coronary blood flow using radionuclide-labeled microspheres resulted in the same inverse relationship between inflow pressure and resistance, regardless of mural depth, indicating that inflow pressure may influence resistance by distending vessels, rather than by causing sequential cessation of perfusion in successive transmural layers.

SUMMARY. When steady state pressure-flow relations are studied in the circumflex coronary artery, pressure gradients develop between it and other branches of the left coronary artery. To assess the effects of these pressure gradients, we compared the pressure axis intercept and shape of steady state circumflex pressure-flow relations in the presence and absence of gradients after autoregulation was abolished, both in the beating heart and during long diastoles in dogs. We used peripheral coronary pressures and radionuclide-labeled microspheres to assess arterial collateral flow. In the beating heart, interarterial pressure gradients reduced the curvature at low circumflex pressures, and overestimated the mean pressure axis intercept by 7.8 mm Hg (P < 0.05). The results were similar for the pressure-flow relations derived during long diastoles. This overesrimation exaggerates the difference between the pressure axis intercept and coronary sinus pressure. The peripheral coronary pressure and microsphere results indicate that these effects are mediated largely by arterial collateral flow. {Circ Res 56: 11-19, 1985) CORONARY arterial pressure-flow relations have been used to investigate the physical forces that regulate coronary blood flow (Cross et al., 1961;Downey and Kirk, 1975;Bellamy, 1978). The pressure axis intercept of these relations has been interpreted as the downstream pressure opposing forward flow in the coronary circulation; however, this pressure has greatly exceeded the coronary sinus pressure, which traditionally has been assumed to be the downstream pressure. The shape of these relations, found to be linear by some (Dole and Bishop, 1982;Eng et al., 1982) but curvilinear by others (L'Abbate et al., 1980;Klocke et al., 1981), is thought to convey information about the conductance of the coronary circulation. Because of this variability of the pressure axis intercept and the shape of coronary arterial pressure-flow relations, the physiological significance of both remains uncertain.One factor that might account for this variability is the specific coronary artery in which the pressureflow relation is obtained. In our laboratory, we have consistently found that the pressure axis intercept of a steady state circumflex pressure-flow relation (Verrier et al., 1980;Vlahakes et al., 1982) is much higher than that in a steady state left main coronary arterial pressure-flow relation (Rouleau et al., 1979;Uhlig et al., 1984). A possible explanation for the higher pressure axis intercept of the circumflex pressure-flow relation may be that when circumflex pressure is selectively lowered below that in the other branches of the left coronary artery, interarterial pressure gradients occur and are accompanied by collateral flow that is not measured by the upstream flow transducer. This error in measurement could underestimate total circumflex flow and thus overestimate the pressure axis intercept. Whether these pressure gradients also affect the shape of a circumflex pressure-flow relation is unknown.To assess...

The role of cardiac interstitial adenosine as an important metabolite in coronary autoregulation has not been established. We therefore measured steady-state cardiac interstitial adenosine concentration at a high and a low coronary inflow pressure using an epicardial diffusion well in anesthetized dogs. Although coronary resistance for the high and low pressure points showed highly significant differences (P less than 0.001), adenosine averaged 302 +/- 98 and 286 +/- 91 (SD) pmol/ml for the high and low pressure points, respectively (P greater than 0.20). Cardiac interstitial adenosine concentration was then measured with and without an intracoronary infusion of adenosine deaminase catalytic subunit. Adenosine averaged 28 +/- 21 (SD) pmol/ml during the infusion compared with 281 +/- 68 during control conditions (P less than 0.001). Finally, pressure-flow relations were obtained with and without the adenosine deaminase infusion, and there was no loss of autoregulation in the pressure of adenosine deaminase. These findings indicate that intracoronary adenosine deaminase markedly reduces interstitial adenosine concentration, that cardiac interstitial adenosine concentration remains constant during autoregulation, and that the coronary bed autoregulates normally when interstitial adenosine is reduced to levels close to zero. We conclude that cardiac interstitial adenosine concentration is not an important component in coronary autoregulation.

To investigate transmural variations in coronary flow reserve, we studied 20 anesthetized dogs with a Gregg cannula in the left main coronary artery. In 11 dogs, radionuclide-labeled microspheres were injected over a range of perfusion pressures in the control state and during maximal coronary vasodilation produced with chromonar or adenosine. In another nine dogs, control, reactive hyperemic, and adenosine-vasodilated flows were compared at the same perfusion pressures. Adenosine dilated vessels more than did reactive hyperemia, which in turn vasodilated more than did hypoperfusion. Adenosine or chromonar vasodilated more than did hypoperfusion alone in all layers of the heart at perfusion pressures as low as 30 mmHg (P less than 0.05). This effect was greatest in the subepicardium and least in the subendocardium and varied with perfusion pressure (P less than 0.05). Subendocardial-to-subepicardial flow ratios declined with diminishing perfusion pressure despite the fact that flow reserve was present in all layers. We conclude that exhaustion of flow reserve is not the mechanism by which subendocardial ischemia occurs.

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To determine the effects of chronic myocardial infarction on beta-adrenergic properties of canine myocardium, the hearts of nine mongrel dogs were studied 3 weeks after acute myocardial infarction. Infarction was produced by ligating the left anterior descending coronary artery in five dogs and the circumflex artery in four dogs. The heart was divided into normal and infarct zones (either anterior or posterior, depending on the vessel ligated) and marginal zones (septal and lateral), each zone being subdivided into epicardial and endocardial portions. Myocardial blood flow (microsphere technique) was markedly reduced in the infarct zone. In eight endocardial infarct samples after left anterior descending ligation, the maximal number (+/- SD) of binding sites assessed by 125I-iodocyanopindolol was 3.9 +/- 1.9 pmol/mg deoxyribonucleic acid (DNA) and was reduced from normal endocardial values (9.7 +/- 9.4 pmol/mg DNA, p less than 0.05). The dissociation constant (Kd), which is a measure of the affinity of the iodinated antagonist for the receptor, did not differ (304 +/- 222 versus 338 +/- 219 pM, p = NS). In the epicardium, the maximal number of beta-adrenergic receptors was also reduced (p less than 0.05), without a change in Kd. In the lateral and septal zones neither the maximal number of binding sites nor Kd values differed from those of normal endocardium. In nine endocardial infarct zones, (-)-isoproterenol-stimulated adenylate cyclase activity was reduced compared with control (34,870 +/- 29,430 versus 88,660 +/- 63,640 pmol/mg DNA/30 minutes, p less than 0.01), but the ratio of (-)-isoproterenol-stimulated to maximal (sodium fluoride-stimulated) adenylate cyclase activity was unchanged between normal and infarct zones.(ABSTRACT TRUNCATED AT 250 WORDS)

Summary: The advent of effective immunosuppression has made cardiac transplantation a viable treatment option for end‐stage cardiac failure, with marked improvement noted in patient survival expectation in the past decades. However, rejection episodes and infectious complications continue to be of concern in the posttransplant period. A third clinical entity, graft atherosclerosis affecting the coronary arteries, has emerged as another source of significant morbidity and mortality in patients undergoing cardiac transplantation. An early analysis of clinical and laboratory correlates of graft atherosclerosis identified only advanced donor age and elevated plasma levels of triglycerides at 1 year posttransplantation as possible risk factors for the occurrence of coronary vascular disease in the posttransplant period. However, it should be noted that at all other time periods examined, triglyceride levels were not significantly different and that the same held true for virtually all other laboratory determinations. The possible involvement of cytomegalovirus (CMV) in graft atherosclerosis was suggested by clinical observations in renal transplant patients showing that CMV was associated with rejection episodes and with the development of glomerulopathy. An extensive study of 387 cardiac allograft recipients has provided evidence that patients infected with CMV posttransplant are at greater risk for development of graft atherosclerosis and that they die more frequently because of graft atherosclerosis. The precise role played by CMV in the pathogenesis of graft atherosclerosis has yet to be defined. It has been postulated that CMV may facilitate the development of graft atherosclerosis by mediating endothelial/medial cell hyperplasia, by causing direct damage to endothelial cells, by modifying blood vessel wall cell surface antigens, or by inducing cross‐reacting antibodies to sequences of human and CMV genomes. Investigations of these mechanisms to more clearly delineate the role of CMV in the development of graft atherosclerosis are ongoing.