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Background: Hyperhomocysteinemia is an independent risk factor for coronary disease and elevated plasma homocysteine levels have been documented in heart transplant recipients. The aim of this study was to test the hypothesis that homocysteine levels are associated with presence or absence of transplant coronary artery disease., Methods: Forty-three non-smoking adults were recruited, all of whom had received a heart transplant between 2 and 7 yr previously. All 43 had blood drawn for fasting homocysteine level on the day of presentation. All patients had undergone diagnostic coronary angiography within the past 6 months., Results: For all patients, the average fasting plasma homocysteine level was 17.0+/-SD 6.6 micromol/L with a range from 6.0 to 36.9 micromol/L. Twenty-six patients (60%) had fasting plasma homocysteine levels above 15.0 micromol/L. On the basis of arteriography, patients were categorized as those with angiographically normal (n=22) or abnormal (n=21) coronary arteries. There was no difference in the mean plasma homocysteine level comparing patients with angiographically normal (17.2+/-SD 7.0 micromol/L) to those with abnormal (16.8+/-SD 6.2 micromol/L) coronary arteries. Plasma homocysteine levels increased with increasing plasma creatinine levels (r=0.63, p<0.0001) and with decreasing vitamin B6 levels (r=-0.56, p<0.0001)., Conclusions: Mild hyperhomocysteinemia is a consistent finding among heart transplant recipients. This finding was not associated with transplant coronary artery disease in our patients. The combination of renal dysfunction and vitamin B6 deficiency may explain the unusual prevalence of hyperhomocysteinemia in heart transplant recipients.

Objectives: This study assessed the time of first appearance of angiographic graft coronary artery disease in relation to clinical and laboratory variables and clinical events in heart transplant recipients., Background: Graft coronary artery disease is the main factor limiting long-term survival after heart transplantation, and it is important to understand its natural history., Methods: One hundred thirty-nine consecutive patients who developed angiographic coronary artery disease after heart transplantation were classified according to early (< or = 2 years) versus late (> 2 years) posttransplantation initial detection of coronary artery disease. These subgroups were analyzed for differences in clinical and laboratory demographics, incidence of progression to ischemic events and incidence of antecedent cytomegalovirus infection., Results: The early-onset group (64 patients) had more rapid progression to ischemic events than the late-onset group (75 patients), with 59% of the late group and only 35% of the early group free from ischemic events by 5 years after initial detection (p = 0.02), but there were no significantly correlated clinical or laboratory predictors of ischemic events. The early group had a significantly higher incidence of antecedent cytomegalovirus infection., Conclusions: We conclude that 1) accelerated graft coronary artery disease develops at variable times after heart transplantation; 2) the early appearance of graft coronary artery disease may be a marker of intrinsically more aggressive disease; 3) cytomegalovirus infection is associated with earlier onset of graft coronary artery disease. Patients with early development of graft coronary artery disease should potentially be given priority for interventional strategies as they are developed.

The level of Antithrombin-III : antibody (ATIII : A), Antithrombin III: antigen (ATIII : Ag), protein C antigen (PC : Ag), Total protein S : antigen (TPS : Ag) and Free protein S : antigen (FPS : Ag) were determined in 46 cases of coronary heart disease (CHD) and 40 cases normal control with the thrombin gelplaque technique and the immunoelectrophoresis assay. The results showed: the level of the PC: Ag and TPS: Ag of Qi stagnation type of CHD were significantly higher than those in normal control group (P < 0.05), the level of the AIII: Ag, ATIII : Ag in blood stasis type of CHD were significantly less than those in control (P < 0.05). These suggested that the level of PC: Ag and TPS: Ag might be used as referential indices of the Qi stagnation type; the level of ATIII: A, ATIII : Ag might be used as those of blood stasis type in CHD.

Accelerated coronary artery disease (TxCAD) in the long term heart transplant patient remains the major limitation to long term survival, with approximately 50% of patients developing an angiographic event of TxCAD by five years post-transplant. This accelerated vasculopathic process is believed to be due to chronic immune injury to the endothelium with coronary intimal proliferation developing rapidly. Subsequent lipid deposition develops in these proliferated areas, leading to a diffuse progressive occlusive CAD which can be seen on serial coronary arteriography as a progressive luminal narrowing. Based on multiple annual studies demonstrating a protective effect of calcium blockers in diet- or injury-induced vascular disease in animals, the authors undertook a randomized trial of diltiazem versus no calcium blocker begun early after heart transplantation in 1986. Serial quantitative coronary arteriographic measurements have demonstrated no significant change in the diltiazem group versus a decrease in mean coronary lumen diameter, from 2.41 +/- 0.27 to 2.19 +/- 0.28 mm, in the no calcium blocker group. These differences persisted at two and three years of follow-up. Freedom from CAD based on qualitative angiographic data confirmed this protective effect of diltiazem. These observations are supported by other reported retrospective studies of calcium blockers post-heart transplantation and in non-TxCAD. Therefore, calcium blockers appear to prevent the early coronary intimal proliferation in response to chronic immune injury, as well as the later lipid deposition. The cardiac transplant patient may serve as a useful model for study of antiatherosclerotic agents in humans.

We postulated that transplant coronary artery disease with rapid progression to more than 50% stenosis within a 1-year interval may have a different prognosis from transplant coronary artery disease with a more indolent rate of progression. Annual coronary angiograms of 139 consecutive patients who underwent transplantation between January 1968 and February 1990 who survived at least 1 year after transplantation and in whom angiographically apparent transplant coronary artery disease developed were included in the study. Of this group, 45 patients progressed from a normal angiogram to the presence of 50% or greater stenosis in one or more major vessels within 1 year (fulminant group); 94 did not (indolent group). Mean posttransplantation follow-up time was 5.3 +/- 4.1 years for patients with fulminant progression of disease and 6.6 +/- 3.7 years for those with indolent progression. A highly significant difference was found in the time-related incidence of ischemic events (myocardial infarction, congestive heart failure, sudden death, and retransplantation) between the indolent and the fulminant groups after initial detection of transplant coronary artery disease. At 1, 3, and 5 years after initial detection of transplant coronary artery disease, 50%, 33%, and 16% of patients in the fulminant group and 89%, 70%, and 60% of patients in the indolent group were free of ischemic events (p < 0.0001). The fulminant group of patients had a mean of 2.9 +/- 1.5 rejection episodes, and the indolent group a mean of 2.3 +/- 1.4 episodes (p = 0.02) during the first year after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Conflicting data exist on the role of graft rejection as a risk factor for later development of accelerated graft coronary artery disease. We analyzed 126 consecutive heart transplant recipients treated with cyclosporine-based immunosuppressive regimens and devised an arbitrary method to incorporate the number, duration, and severity of myocardial rejection episodes during the first postoperative year, resulting in a rejection score for each patient. We then correlated the later incidence (mean follow-up, 4 years) of angiographic accelerated graft coronary artery disease with this rejection score and with its components: number, duration, and severity of rejection; number and duration of untreated rejection; and incidence and duration of delayed rejection therapy. Accelerated graft coronary artery disease developed in 60 patients (48%). The rejection score was 96.7 for patients in the "no accelerated graft coronary artery disease" group and 110.4 for those in the "accelerated graft coronary artery disease" group (p = NS). No significant difference was noted between patients with and without disease in any of the other seven rejection parameters analyzed, and no significant difference in time to occurrence of disease was noted between groups divided at the median rejection score. Donor age was older and fasting triglyceride blood level was higher in patients with accelerated graft coronary artery disease than in those without disease. All other clinical characteristics, including HLA mismatches, ischemic time, blood pressure, lipid profile, and drug therapy, did not differ between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Accelerated coronary artery disease is a major cause of late morbidity and mortality among heart-transplant recipients. Because calcium-channel blockers can suppress diet-induced atherosclerosis in laboratory animals, we assessed the efficacy of diltiazem in preventing coronary artery disease in transplanted hearts., Methods: Consecutive eligible cardiac-transplant recipients were randomly assigned to receive diltiazem (n = 52) or no calcium-channel blocker (n = 54). Coronary angiograms obtained early after cardiac transplantation and annually thereafter were used for the visual assessment of the extent of coronary artery disease. The average diameters of identical coronary artery segments were measured on the angiograms obtained at base line and at the first and second follow-up examinations., Results: In the 57 patients who had all three angiograms, the average coronary artery diameter (+/- SD) 0.27 decreased in the group that received no calcium-channel blocker from 2.41 +/- 0.27 mm at base line to 2.19 +/- 0.28 mm at one year, and to 2.22 +/- 0.26 mm at two years (P < 0.001 for both years). The average diameter in the diltiazem group changed little from the base-line value of 2.32 +/- 0.22 mm (2.32 +/- 0.27 mm at one year and 2.36 +/- 0.22 mm at two years). The average change in the diameter of the segment differed significantly between the two treatment groups (P < 0.001), and the estimated effect of treatment changed only negligibly after adjustment for other relevant clinical variables. New angiographic evidence of coronary artery disease developed in 14 patients not given calcium-channel blockers, as compared with 5 diltiazem-treated patients (P = 0.082). Coronary stenoses greater than 50 percent of the luminal diameter developed in seven patients not given calcium-channel blockers, as compared with two patients given diltiazem; death due to coronary artery disease or retransplantation occurred in five patients in the group that did not receive calcium-channel blockers and none of those who received diltiazem., Conclusions: Our preliminary results suggest that diltiazem can prevent the usual reduction in the diameter of the coronary artery in cardiac-transplant recipients, but further follow-up will be required to determine whether diltiazem can decrease the long-term incidence of symptomatic coronary artery disease.

Accelerated graft coronary artery disease (CAD) has become a major factor limiting survival among long-term heart transplant survivors. Currently 14%, 37%, and 50% of patients treated with triple therapy have angiographically apparent accelerated graft CAD at 1, 3, and 5 years after transplantation. Because cardiac allografts are denervated, transplant recipients generally do not experience angina pectoris. Therefore accelerated graft CAD may present as silent myocardial infarction, congestive heart failure, or ventricular arrhythmia leading to syncope or sudden death. Noninvasive tests for CAD have been insensitive for the detection of accelerated graft CAD because of the diffuse nature of the disease. Coronary arteriographic characteristics of accelerated graft CAD are a mixture of typical focal atherosclerotic lesions and unusual diffuse, concentric, and longitudinal narrowing prominent in middle to distal coronary vessels, with distal vessel obliteration and lack of collateral vessel formation. The presence and severity of accelerated graft CAD may be underestimated by routine angiography because of its diffuse and concentric nature. Quantitative arteriography has become an important technique to assess the progression of accelerated graft CAD. Intravascular ultrasound imaging can detect even earlier development of intimal thickening. CAD risk factor modification has had little impact on the overall incidence. We initiated a randomized study of diltiazem versus no calcium blocker to determine if this may prevent accelerated graft CAD. Patients have undergone early postoperative and annual quantitative coronary angiography since inception of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Accelerated coronary artery disease is a major cause of morbidity and mortality among cardiac transplant recipients. Ten patients who died or underwent retransplantation within 2 months of coronary angiography had direct correlation of angiographic (normal discrete lesions, diffuse concentric narrowing) with histologic appearance of coronary arteries. Of the 26 angiographically normal segments, 73% showed mild to moderate fibrous intimal thickening by light microscopy. The remainder had intermediate lesions or atheromatous plaques. Discrete stenoses usually corresponded to lipid-rich intermediate or atheromatous disease. In contrast, angiographically diffuse, concentrically narrowed lesions usually were areas of severe fibrous intimal thickening. Fresh or organizing thrombus was most often associated with discrete lesions and accounted for all complete occlusions. Histologic and angiographic comparisons of the degree of luminal narrowing showed generally good correlation for high grade stenoses. Lesions graded as having less than 25% diameter narrowing were often underestimated angiographically as compared with histologic determinations. Transplant coronary artery disease has a heterogeneous histologic and angiographic appearance, with angiographic underestimation of disease in some patients.

Accelerated coronary disease is a major factor limiting long-term survival in cardiac transplant recipients. Coronary angiography was obtained a mean of 5.1 weeks posttransplantation and annually thereafter. Replicate projections recorded after nitroglycerine administration were quantitated using computer-assisted edge detection. Five hundred and fifteen coronary segments in 25 patients having 1-year follow-up and 353 segments in 18 patients reaching 2-year follow-up were compared with baseline angiograms. Significant change was defined as +/- 0.10 mm, equal to 3.8% change in diameter based on three standard deviations obtained from estimation of measurement error. Mean coronary diameter fell from 2.44 +/- 0.26 mm at baseline to 2.21 +/- 0.34 mm (p less than 0.001) at 1-year follow-up. This rate of diameter decline was 20-fold more rapid during the initial posttransplantation year than the rate of change of visually normal segments in nontransplant patients with coronary atherosclerosis elsewhere. There was no significant drop in mean diameter between the first and second year in those patients who had second-year studies. Decrease in absolute diameter for vessels greater than 2.9 mm significantly exceeded diameter reduction for smaller vessels but did not differ when considered as a ratio of vessel diameter. In 21 of 25 patients, mean coronary diameter reduction exceeded the three-standard deviation threshold at their last angiogram, but only two of these patients had visually detectable transplant coronary disease.

Coronary artery morphologic features of 61 human cardiac allografts of short- and long-term survival were correlated with coexisting myocardial pathologic findings and cause of death. On the basis of distribution of coronary lesions, allografts were divided into two broad groups: those with fibrous or atherosclerotic lesions confined to the proximal region of epicardial arteries and those with diffuse necrotizing vasculitis or atherosclerosis of the entire coronary arterial system. Within the two groups, coronary artery morphologic features varied in a time-dependent fashion. Disease in the proximal region began as concentric fibrous intimal thickening, with atheromatous lesions observed after 1 year after transplantation. Five of 10 (50%) patients with atheromatous plaques in the proximal region of arteries died or underwent retransplantation because of coronary disease, as compared to only 1 of 29 (3%) patients with fibrous intimal thickening only in the proximal region. The earliest form of diffuse disease was a necrotizing vasculitis, which was invariably associated with acute myocardial rejection. Long-term survivors with diffuse disease showed severe fibrous or fibrofatty intimal lesions of the large and small epicardial and intramyocardial arteries. In some, diffuse disease may have resulted from healing of necrotizing vasculitis. Eight of nine (89%) long-term survivors with diffuse coronary artery disease died or required retransplantation because of coronary vascular disease. The coronary artery disease of human cardiac allografts is a heterogeneous phenomenon with variable distribution, morphologic features, severity, clinical significance, and, possibly, pathogenesis.

Rapid development of diffuse, occlusive coronary artery disease in the cardiac allograft has emerged as a major limiting factor for long-term survival after transplantation. Prior multivariate analyses have failed to identify any strong predictors of this disease. We retrospectively reviewed serial annual coronary angiograms to assess the prevalence of transplant coronary artery disease. A total of 103 patients treated initially with azathioprine-based therapy were compared with a later cohort of 78 patients for whom cyclosporine was the basis of immunosuppressive therapy. The percent of patients free of angiographically visible transplant coronary artery disease at 1 year was 89% for the azathioprine group versus 86% for the cyclosporine group. At 3 years, 74% of the azathioprine group versus 63% of the cyclosporine group were free of visible disease (p = NS). By the fifth postoperative year, 58% of azathioprine-treated and 50% of cyclosporine-treated patients were free of transplant coronary artery disease (p = NS). The mean number of rejection episodes in the first year after transplantation was 2.0 for cyclosporine patients versus 2.5 for azathioprine patients. The azathioprine and cyclosporine patients were compared with respect to a variety of baseline and clinical follow-up measurements that might influence the development of coronary artery disease. Patients in the cyclosporine group had higher blood pressure (135/94 versus 123/85 mm Hg, p less than 0.001) and were receiving lower maintenance prednisone doses. This study demonstrates that improved cyclosporine immunosuppression does not decrease the time-related prevalence of transplant coronary artery disease.

Accelerated coronary disease in the cardiac allograft (TxCAD) is a major complication affecting long-term survival of heart transplant patients. Since the transplanted heart remains denervated, the first sign of TxCAD may be silent myocardial infarction or sudden death. The prevalence of this disease has been unaltered since the advent of cyclosporine immunosuppression. Serial annual coronary arteriograms in 132 patients undergoing transplantation after 1979 at Stanford revealed 44 patients who developed TxCAD (33%). Multiple variables, including patient lipid profile, extent of donor and recipient tissue match, age of recipient and donor, number of rejection episodes, prednisone dose, and fasting blood sugar were examined in relation to occurrence of TxCAD. Donor age was greater among the 44 patients developing TxCAD that in the 88 patients who did not develop coronary artery disease (23.5 +/- 5.8 vs 21.3 +/- 5.7 years, p less than .05). The fasting plasma triglyceride level 1 year after transplantation was 236.0 +/- 246.3 mg% in the patients with TxCAD vs 170.1 +/- 108.2 mg% in those without TxCAD (p less than .05). No other indexes, including number of rejection episodes during first posttransplant year, number of HL-A mismatches, level of maintenance steroids, fasting blood sugar, and cholesterol subfractions identified patients who developed TxCAD. We conclude that TxCAD has limited correlation with the clinical and laboratory factors analyzed. Higher donor age and elevated plasma triglycerides may be significant predisposing factors for the development of TxCAD.

Development of accelerated coronary artery disease (CAD) in the cardiac allograft is one of the major causes of late graft failure in heart transplant recipients. At the Stanford University Medical Center 356 heart transplant procedures were performed in 329 patients by the end of January 1985. Eighty-nine of these patients developed evidence of transplant CAD. Twenty retransplant procedures, including 2 third transplants, were performed in 19 of the 89 patients because of transplant CAD. The graft survival rates after the second transplant were 55%, 25% and 10% after 1, 2 and 5 years, respectively. Nine of these retransplant patients currently survive, the longest for 5.5 years. To examine potential risk factors for development of severe transplant CAD, these 20 retransplant procedures were compared with 113 transplant recipients who had no evidence of transplant CAD on annual coronary arteriograms. An excess of rejection episodes (3 +/- 2 vs 2 +/- 1 episodes/patient, p = 0.02), elevated total cholesterol (266 +/- 78 vs 225 +/- 47 mg/dl, p = 0.002) and higher low-density lipoprotein levels (176 +/- 88 vs 137 +/- 46 mg/dl, p = 0.009) were noted in the transplant CAD retransplant group. Five of 11 retransplant recipients who survived greater than 1 year again developed transplant CAD. Characteristic morphologic features and rapid progression of CAD in the second graft were similar to those in the primary graft.(ABSTRACT TRUNCATED AT 250 WORDS)

Annual coronary arteriograms have been obtained from all heart transplant recipients at Stanford University Medical Center since 1969. Angiographic lesions in 81 transplant patients exhibiting coronary vascular disease were classified into three categories: type A, discrete or tubular stenoses; type B, diffuse concentric narrowing; and type C, narrowed irregular vessels with occluded branches. The 81 arteriograms showing transplant coronary vascular disease were contrasted with 32 from nontransplant patients with coronary artery disease analyzed in a similar fashion. The nontransplant angiograms showed 178 lesions, all of type A (discrete or tubular) morphology, 75% of which were located in primary epicardial coronary vessels and 25% in secondary branch vessels. In the patients with transplant coronary vascular disease, 349 (76%) of 461 lesions were type A: 57% in primary vessels, 42% in secondary branches and 1.4% in tertiary branches. Of the 112 type B and C lesions (diffuse narrowing, tapering and obliteration), 25% were in primary vessels, 44% in secondary vessels and 31% in tertiary branches (p less than 0.05 for patients with transplant coronary vascular disease versus patients with nontransplant coronary artery disease). Total vessel occlusion was found in proximal or middle vessel segments in 96% and distally in 4% of patients with "ordinary" coronary artery disease versus 49% distally in patients with transplant coronary disease (p less than 0.002). In the presence of total vessel occlusion, collateral vessels were poor or absent in 92% of transplant versus 7% of nontransplant patients with coronary disease (p less than 0.002). Therefore, coronary artery disease in transplant patients represents a mixture of typical atheromatous lesions and unique transplant-related progressive distal obliterative disease that occurs without collateral vessel development.