Transplant-mediated coronary artery disease (CAD) is the major limitation to long-term survival after cardiac transplantation, with a 5-year incidence of 40% to 60%.1 The pathogenesis of transplant-mediated CAD is poorly understood but may relate to endothelial cell injury resulting from hyperlipidemia, antiallograft immune responses, or ischemia and reperfusion. Transplant-mediated CAD is characterized by vascular smooth muscle cell proliferation with resulting neointimal hyperplasia, abnormal vascular remodeling, and luminal obstruction. Clinical manifestations include myocardial ischemia, heart failure, and sudden cardiac death.2 The HMG-CoA reductase inhibitors (statins) pravastatin and simvastatin have been shown to decrease transplant-mediated CAD.3,4 The pluripotent anti-inflammatory effects of statins may provide benefits beyond cholesterol reduction, thus making them attractive prophylactic agents to treat transplant-mediated CAD. This study evaluated the effect of atorvastatin on endothelial function and development of transplant-mediated CAD in the initial posttransplant year in patients with normal or mildly elevated baseline cholesterol levels.
Patients and methods
Twenty-five consecutive patients were enrolled in this prospective, randomized study within 1 month after cardiac transplantation. Exclusion criteria included statin therapy at the time of randomization, active infection, cardiac rejection, and a history of statin-associated sensitivity, liver dysfunction, or myositis. All patients received standard immunosuppression with cyclosporine, mycophenolate mofetil, and prednisone. Per institutional protocol, prednisone was tapered with the goal of having all patients steroid-free by 9 months posttransplant. Before discharge, an investigator who was blind to coronary and lipid data randomly assigned patients to atorvastatin 10 mg daily or usual therapy. To achieve a goal low-density lipoprotein (LDL) level of ± 100 mg/dL, atorvastatin doses were increased to 20 mg daily, if tolerated, at 2-month follow-up. No control patients were treated with other statins; niacin therapy was initiated when LDL levels were greater than 130 mg/dL, which occurred in four control patients.
Cardiac catheterization was performed within 1 month of transplantation (baseline) and at 1 year. Vasoactive medications were discontinued 48 hours before performing coronary vasoreactivity studies. Acetylcholine was administered sequentially at 10—8, 10–7, and 10–6 M. After each infusion, cineangio-
graphic images were obtained in identical views, and end-diastolic coronary artery maps were analyzed off line. Four arterial sites, each separated by more than 1 cm, were evaluated: one proximal, one distal, and two midcoronary artery segments, and changes in arterial diameter were averaged along the segment profile. A single mean and a pooled standard deviation for the segment at each infusion were obtained by averaging each measurement along the segment profile.
Intracoronary imaging of the most accessible artery was performed in segments measuring 2 mm or more in diameter using mechanized pullback from the dis-tal artery to the proximal origin. Ultrasound measurements were made within segments with the greatest intimal thickness, proximal, mid-, and distal coronary arteries.
The external elastic membrane area (external elastic membrane: representing total vessel cross-sectional area), luminal area, and intimal thickness were measured and used to calculate intimal and plaque areas. Percent area stenosis was
calculated as the sum of intimal
and medial areas divided by external elastic membrane area.
Differences between the groups were assessed using appropriate
unpaired and paired 2-tailed t-tests and the Fisher exact test. Changes in lipid levels were evaluated using analysis of variance. A 2-tailed P value below .05 was considered significant. All data are presented as mean ± SD or SEM.
Control and treatment groups were evenly matched for recipient and donor age and sex. There were no significant differences between the groups for cardiac risk factors, procedural factors, or transplant indication. The percentages of donor cytomegalovirus-positive serologies were similar in both groups (7 of 12 treatment patients versus 8 of 13 controls). No patient died or had any toxicity, clinical adverse effects, or biochemical abnormalities associated with statin use.
Baseline lipid levels were similar between groups (table 1). At 12 months, the total and LDL cholesterol levels were stable in the control group, while atorvastatin decreased both total cholesterol and LDL levels. There was no significant difference in cholesterol levels between the two groups at 12 months. In the control group, however, both the mean LDL and total cholesterol levels increased in the first 6 months, whereas no increase was noted in the atorvastatin group. There were significant differences (P < .05) for total and LDL cholesterol at 2 and 3 months, and the control group had a significantly higher total cholesterol level at 6 months (P = .002).
Epicardial vasomotor responses to acetylcholine are shown as percent change in coronary artery lumen diameter (figure). At baseline both groups showed vasoconstrictive responses at all acetylcholine concentrations. In the atorvastatin group, there was a relative vaso-
dilatory response at 1 year at the 10—8 and 10–7 M acetylcholine doses, while the control group demonstrated
significantly increased vasoconstriction at all acetylcholine concentrations between baseline and 1 year
(P = .02).
At baseline, there were no significant differences in intimal, medial, luminal, or external elastic membrane measurements (mean ± SEM). Over 12 months, the control group developed significant increases in mean neointima media area, maximal intimal thickness, and percent area stenosis (table 2). There was nonsignificant progression in these parameters in the atorvastatin group. The increases in maximal intimal thickness and percent area stenosis were significantly greater in the control groups (P < .05). While there was no intergroup difference in the number of lesions at baseline, the control group had significantly more lesions and a greater number of new or progressing lesions at
1 year (table 3).
The results of this prospective, randomized trial demonstrate that early use of atorvastatin maintained endothelial function and retarded development of transplant-mediated CAD in patients with normal or mildly elevated cholesterol levels. Atorvastatin also had a significant effect in decreasing the incidence of new lesions and progression of established lesions in the initial posttransplant year. Although the cholesterol reduction over 12 months was mild, atorvastatin eliminated the increase in cholesterol and LDL levels observed in the control group within the initial 3 months and a decline of high-density lipoprotein (HDL) over the study period.
Hyperlipidemia affects 60% to 80% of heart transplant recipients and may influence development of transplant-mediated CAD.5 As we observed, hyperlipidemia often de-velops within the first 3 months. Posttransplant hyperlipidemia has several risk factors, such as advanced age, pretransplant hyperlipidemia, and ischemic cardiomyopathy as a transplant indication.6 Increased baseline levels of oxidized LDL cholesterol have been shown to correlate with transplant-mediated CAD detected by angiography over 2 years.7 In a porcine model of cardiac transplantation, hypercholesterolemia had an additive effect on vascular cholesterol accumulation, resulting in increased endothelial dysfunction and intimal hyperplasia.8
Immunosuppressant drugs may contribute to hyperlipidemia. Corticosteroids are associated with the development and severity of posttransplant hyperlipidemia, and both cumulative and maintenance doses affect lipid levels.9 Cyclosporine, es-pecially the nonmicroemulsion formulation, is also associated with hyperlipidemia.10 Oxidized LDL and cyclosporine may act in a synergistic manner that potentiates endothelial dysfunction.11
Several comorbidities affect the degree of posttransplant hyperlipidemia. Obesity is independently associated with hyperlipidemia, and rapid weight increases after transplantation may elevate serum lipid levels.9 Corticosteroid dose is related to obesity, and combined with obesity, promotes hyperlipidemia and insulin resistance that may induce diabetes, endothelial dysfunction, and vascular disease. In this study, most patients demonstrated a decrease in serum cholesterol and LDL levels between 3 and 12 months when corticosteroid therapy was tapered.
Statins have been shown to improve endothelial function in native atherosclerotic lesions12 and reduce serum levels of highly sensitive C-reactive protein in hypercholesterolemic patients,13 to reduce intravascular matrix-metalloproteinase levels in hypercholesterolemia animal models,14 and to reduce intravascular monocyte chemoattractant protein-1 levels.15 While our findings suggest that the reduction in cholesterol levels, specifically LDL, by atorvastatin may have played a major role in reducing transplant-mediated CAD, the potent anti-inflammatory or immunosuppressant effects of statins may have also contributed to the protective effects on vascular function.
This study indicates that ator-vastatin ameliorates the initial 3-month increase in cholesterol and LDL levels and reduces endothelial dysfunction in the first year posttransplantation while reducing development of transplant-mediated CAD. These results support the hypothesis that early, aggressive statin therapy after cardiac transplantation is warranted regardless of cholesterol levels.