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In this review we examine the complex interactions between lipoprotein metabolism, immunosuppressive drug therapy, and inflammation and the potential benefits of lipid-lowering drug therapy after heart transplantation. The newer formulations of cyclosporine, Neoral (Novartis Pharmaceuticals; Basle, Switzerland), and other newer agents such as tacrolimus may have advantages in regard to lipid metabolism as compared with traditional triple-drug immunosuppression. Lipoprotein levels may influence both the toxicity and efficacy of cyclosporine. Dyslipidemia may adversely influence inflammation and rejection in the allograft. Two recent clinical trials have shown that lipid-lowering therapy with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor alone or in combination with low-density lipoprotein apheresis may confer significant benefits toward preventing transplant coronary artery disease.

Hyperlipidemia occurs frequently after heart transplantation, and accelerated coronary artery disease remains the major cause of morbidity and mortality in patients who survive more than 1 year after heart transplantation. However, the risks and benefits of lipid-lowering therapy after heart transplantation remain poorly defined, and national guidelines for lipid-lowering drug therapy do not specifically address treatment of dyslipidemia in transplant recipients. Since the initial reports in the 1980s of rhabdomyolysis in heart transplant patients receiving high-dosage lovastatin, results of 11 post-transplantation series that used lovastatin, simvastatin, or pravastatin at lower dosages as drug monotherapy have been published. These studies have shown an overall 1% incidence of rhabdomyolysis, defined as creatine kinase > 10 times the upper limit of normal plus muscle symptoms. One randomized, controlled prospective trial has investigated the effects of lipid-lowering pharmacotherapy on patient outcome in cardiac transplant recipients. At 1-year follow-up in this nonblinded, single-center trial, patients treated with pravastatin (20 or 40 mg/day) initiated within 2 weeks of transplantation had a significant reduction in mortality rate and a significantly lower incidence of transplant arteriopathy. A number of important issues remain unanswered regarding treatment guidelines in patients with hyperlipidemia after heart transplantation. In January 1995 we began the Heart Transplant Lipid Registry, with 12 participant centers, to gather data prospectively on the efficacy and safety of lipid-lowering drugs in the treatment of dyslipidemia after heart transplantation.

The development of accelerated coronary artery disease after heart transplantation remains the limiting factor for long-term survival. The most widely accepted hypothesis to explain the development of this vascular lesion is chronic immunologic injury to the vessel wall, which leads to recruitment of monocytes and lymphocytes into the intima and to subsequent neointimal proliferation. In this report, we describe a case of accelerated coronary artery disease that led to allograft failure and repeat heart transplantation 3 years after the initial procedure. Pathologic examination showed striking intimal proliferation with abundant expression of intercellular adhesion molecule-1 in both endothelial cells and cells deep within the intima. Cardiac myocytes also stained for intercellular adhesion molecule-1, with the most intense staining noted in intercalated disks, whereas staining for E-selectin was restricted to endothelial cells. These findings are similar to those we observed in a canine model of transplant arteriopathy and highlight the need for further studies to examine whether inhibitors of endothelial cell adhesion molecules or their leukocyte ligands can successfully ameliorate transplant vasculopathy.

Background: Intercellular adhesion molecule-1 (ICAM-1, CD54) is a cell adhesion molecule that interacts with the leukocyte beta 2 integrins, lymphocyte function-associated antigen-1, and macrophage antigen-1. ICAM-1 is postulated to play a key role in several cell-cell interactions that are important in allograft rejection, including antigen presentation, transendothelial migration of leukocytes, and leukocyte-medicated myocyte injury., Methods and Results: Mice homozygous for a gene-targeted mutation of ICAM-1 were used in two different cardiac transplant models to further define the role of ICAM-1 in the process of allograft rejection. In the first model, hearts from newborn mice were implanted in the ear pinnae of H-2-incompatible recipients. In the second model, intra-abdominal transplantation by direct vascular anastomosis was performed. Time to rejection was defined by the loss of pulsatile activity assessed by visual inspection in the ear model or by cessation of palpable cardiac impulse in the abdominal model. Allograft survival did not differ significantly between control groups that express normal levels of ICAM-1 and those groups using ICAM-1-deficient mutants as either donors or recipients. Histological examination of rejection of both normal and mutant (ICAM-1-deficient) cardiac allografts revealed similar patterns of infiltration of mononuclear and granulocytic leukocytes and myocyte necrosis. Immunostaining with anti-ICAM-1 antibodies showed ICAM-1-positive infiltrating cells in both mutant (ICAM-1-deficient) and normal allografts, with the graft endothelium negative for ICAM-1 staining in the mutant allografts., Conclusions: The absence of surface expression of ICAM-1 in the donor allograft or recipient is insufficient to produce a significant impact on cardiac allograft survival. This study highlights the need to understand more precisely the mechanism of action whereby monoclonal antibodies to ICAM-1 prolong cardiac allograft survival before new therapeutic strategies based on gene transfer technology or small molecule inhibitors are developed. Mutant mice with targeted mutations in cell adhesion molecules provide powerful tools to study the complex role that cell adhesion molecules play in the cellular interactions between donor graft tissue and the recipient that culminate in graft rejection.

Noninvasive methods to assess immune activation would be helpful in optimizing therapy after heart transplantation to reduce rejection (acute and chronic) and complications caused by excessive immunosuppressive therapy. Intercellular adhesion molecule 1 has been shown to play an important role in T-cell activation and allograft rejection. A soluble form of intercellular adhesion molecule 1 has been discovered to be circulating in plasma. To test the hypothesis that increased levels of circulating intercellular adhesion molecule 1 may have prognostic value as a marker of immune activation, we examined whether levels of circulating intercellular adhesion molecule 1 during the early postoperative period correlated with endomyocardial biopsy scores, soluble interleukin-2 receptor levels, human leukocyte antigen mismatch, and survival. For the first 3 weeks after surgery, serum was obtained once weekly on the same day as endomyocardial biopsy samples from 52 patients who survived more than 30 days after heart transplantation. A sandwich enzyme-linked immunosorbent assay was used to measure circulating intercellular adhesion molecule 1 and soluble interleukin-2 receptor. Increased circulating intercellular adhesion molecule 1 levels did not correlate with endomyocardial biopsy scores but were associated with greater mismatch at the human leukocyte antigen-B and -DR loci (p = 0.02). A significant correlation was found (p = 0.002) between circulating intercellular adhesion molecule 1 levels and soluble interleukin-2 receptor, albeit with a low r value of 0.27. Survival was reduced in patients with high levels of circulating intercellular adhesion molecule 1 (p = 0.006) or soluble interleukin-2 receptor (p = 0.001) with the greatest reduction in survival when both were elevated.(ABSTRACT TRUNCATED AT 250 WORDS)

A multidisciplinary team approach with focused objectives characterizes research at Baylor College of Medicine into the causes, prevention, and treatment of atherosclerotic disease. Current clinical activities range from programs to modify lifestyle for the primary prevention of coronary artery disease to a large, angiographically monitored lipid-lowering trial. In basic research, much attention has been focused on the plasma lipoproteins and their roles in atherogenesis. The current review highlights recent advances in ongoing basic research involving 1) apolipoprotein (apo) B, whose form apo B-100 serves as a ligand for the low-density lipoprotein receptor; 2) lipoprotein[a], elevated plasma levels of which are predictive of atherosclerotic disease; and 3) transplantation arteriopathy, which impedes long-term survival of cardiac transplant recipients.

Mean plasma lipid values in 100 patients who survived greater than 3 months after heart transplantation increased significantly at 3 months over pretransplantation values: total cholesterol from 168 +/- 7 to 234 +/- 7 mg/dl, low density lipoprotein (LDL) cholesterol from 111 +/- 6 to 148 +/- 6 mg/dl, high density lipoprotein (HDL) cholesterol from 34 +/- 1 to 47 +/- 1 mg/dl and triglycerides from 107 +/- 6 to 195 +/- 10 mg/dl. There were no significant increases after this time. The LDL cholesterol values reamined greater than or equal to 130 mg/dl in 64% of patients and triglyceride values remained greater than or equal to 200 mg/dl in 41% of patients 6 months after postoperative dietary instructions. Beginning in 1985, select patients whose total cholesterol values remained greater than 300 mg/dl despite 6 months of dietary intervention were treated with lovastatin given alone in a high dose (40 to 80 mg/day) or in combination with another hypolipidemic agent. Four of the five patients so treated developed rhabdomyolysis; two of the four had acute renal failure. Beginning in 1988, a second protocol--lovastatin at 20 mg/day as monotherapy--was used in patients who despite dietary intervention had total cholesterol greater than 240 mg/dl (mean follow-up 13 months). In the 15 patients so treated, mean total cholesterol decreased from 299 +/- 10 mg/dl before treatment with lovastatin to 235 +/- 9 mg/dl during treatment (21% reduction, p less than 0.001) and mean LDL cholesterol was reduced from a baseline value of 190 +/- 10 to 132 +/- 12 mg/dl during treatment (31% reduction, p less than 0.001). In this study, lovastatin at a dose of less than or equal to 20 mg/day as monotherapy was a well tolerated, effective treatment for hyperlipidemia after heart transplantation. It did not result in rhabdomyolysis and required no alteration in immunosuppressive therapy. However, the dose should not exceed 20 mg/day and combination therapy with either gemfibrozil or nicotinic acid should be avoided, even if the target LDL cholesterol value is not reached.

Although lipoprotein changes after cardiac transplantation have been documented, the effects of transplantation and subsequent immunosuppressive therapy (particularly the combination of prednisone, azathioprine and cyclosporine) on apolipoprotein levels and lipoprotein(a) have not been reported. Fasting cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, apolipoprotein A-1 and B-100 and lipoprotein(a) were evaluated in 69 consecutive patients during the waiting period before cardiac transplantation. There were 28 deaths before donor organ identification and 41 patients received a cardiac allograft. The lipoprotein levels of transplant recipients were again assayed 3 months postoperatively. Mean (+/- SEM) values increased for total plasma cholesterol (from 180 +/- 8 to 228 +/- 8 mg/dl, p less than or equal to 0.001), triglycerides (from 126 +/- 11 to 207 +/- 14 mg/dl; p less than or equal to 0.001), HDL cholesterol (from 39 +/- 2 to 49 +/- 3 mg/dl; p less than or equal to 0.002) and LDL cholesterol (from 119 +/- 7 to 138 +/- 7 mg/dl; p less than 0.02). Apolipoprotein A-1 and B-100 also increased, but lipoprotein(a) decreased from 11.7 +/- 1.7 to 6.8 +/- 1.1 mg/dl; p less than or equal to 0.0001) after transplantation. Although total cholesterol, triglycerides, LDL cholesterol, apolipoprotein A-1 and B-100 increased dramatically after cardiac transplantation, so did HDL cholesterol, thereby keeping the LDL/HDL cholesterol ratio constant. The surprising decrease in lipoprotein(a) after cardiac transplantation suggests that metabolism of lipoprotein(a) is independent of LDL cholesterol and that immunosuppressive drugs either decrease the synthesis or increase catabolism of lipoprotein(a).

Obstructive coronary artery vasculopathy can be a major problem after cardiac transplant. The use of noninvasive tests to detect coronary artery vasculopathy was studied in 73 consecutive patients after heart transplant. Angiographically or autopsy-proved coronary artery disease was noted in 19 consecutive patients (26%) followed prospectively for 2.5 +/- 1.3 years (mean +/- standard deviation). Patients underwent yearly surveillance echocardiographic, rest/exercise-gated wall motion, oral dipyridamole thallium, ambulatory electrocardiographic monitor and angiographic studies. Positive test results were defined by decrease in ejection fraction, wall motion abnormality, failure to increase ejection fraction, lack of systolic blood pressure increase, and ischemic ST changes at maximal exercise (or on ambulatory monitor). Wall motion abnormalities and depressed ejection fraction on echocardiography were also abnormal studies as were fixed or reversible perfusion defects on thallium scan. Angiograms were considered positive when 50% luminal narrowing was observed and autopsy coronary artery vasculopathy was defined as cross-sectional coronary obstruction greater than or equal to 70%. No procedure that was examined proved to be a sensitive noninvasive detector of heart transplant coronary artery vasculopathy. All except ambulatory electrocardiographic monitoring had positive predictive values less than 50%. Interestingly, of the techniques evaluated, echocardiography was most sensitive (53%). The poor predictive ability of noninvasive testing in this population may be due to the fact that these tests are designed to detect effects of ischemia rather than coronary obstruction alone. Use of these particular noninvasive modalities routinely after heart transplant to detect coronary artery vasculopathy should be reconsidered because of their low sensitivity and predictive value when used as a surveillance screen.