Lipoprotein(a) levels and heart transplantation atherosclerosis

Surgery

Lipoprotein(a) levels and heart transplantation atherosclerosis Gene Chang, MD, David DeNofrio, MD, Shashank Desai, MD, Michael P. Kelley, MD, Daniel J. Rader, MD, Michael A. Acker, MD, and Evan Loh, MD Philadelphia, Pa.

Background Elevated serum lipoprotein(a) [Lp(a)] levels are associated with the development of native coronary atherosclerosis. The association between increased levels of Lp(a) and the development of accelerated cardiac allograft vasculopathy (ACAV) in patients who have undergone orthotopic heart transplantation has not been firmly established.

Methods and Results We studied 74 consecutive heart transplant recipients with at least 1 year survival to determine the relation between Lp(a) and the presence of ACAV. Recipient and donor clinical and laboratory parameters, including mean serum Lp(a) levels, were obtained. ACAV was defined angiographically as ≥30% stenosis in one or more epicardial arteries. ACAV 1 year after heart transplantation was angiographically present in 26 (35%) patients. Mean donor age (36 ± 13 years [ACAV (+)] vs 28 ± 10 years, [ACAV (–)]; p = 0.004) and mean serum triglyceride levels 6 months after transplantation (286 ± 275 mg/dl [ACAV (+)] vs 169 ± 85 mg/dl [ACAV (–)]; p = 0.025) were univariate predictors of ACAV. No significant difference in mean serum Lp(a) levels was observed (20 ± 19 mg/dl [ACAV (+)] vs 30 ± 30 mg/dl [ACAV (–)]; p = NS). Donor age was the single greatest independent predictor of ACAV by multivariate logistic regression ( p = 0.02).

Conclusions Lp(a) does not appear to be a risk factor for the development of ACAV 1 year after heart transplantation. Further studies are needed to define the influence of serum Lp(a) on the development of cardiovascular disease after orthotopic heart transplantation. (Am Heart J 1998;136:329-34.)

Accelerated cardiac allograft vasculopathy (ACAV) remains the major limitation of long-term survival in heart transplant recipients, with a reported angiographic incidence of approximately 20% at 1 year and 40% to 60% at 5 years after heart transplantation.1-3 The disease process results in progressive luminal narrowing of the epicardial coronary arteries and their intramyocardial branches, resulting in acute myocardial infarction, congestive heart failure, ventricular arrhythmias, and sudden cardiac death. Despite advances in immunosuppressive therapy, its incidence has not decreased.2,3 The pathogenesis of ACAV appears to be multifactorial. Proposed mechanisms include both immune-mediated3-5 and non-immune-mediated6-13 factors. Nonimmune-mediated factors implicated in the development of ACAV include recipient-donor sex mismatch,6 From the Cardiovascular Division, Department of Medicine, and the Cardiothoracic Surgery Division, Department of Surgery, University of Pennsylvania Health System. Submitted Sept. 12, 1997; accepted Feb. 10, 1998. Reprint requests: David DeNofrio, MD, Cardiovascular Division, 9 Founders Pavilion, Department of Medicine, University of Pennsylania Health System, Philadelphia, PA 19104-4024. Copyright © 1998 by Mosby, Inc. 002-8703/98/$5.00 + 0 4/1/89581

hyperlipidemia,7-9 obesity,9 cytomegalovirus (CMV) infection,10,11 and advanced donor age.12,13 Lipoprotein(a) [Lp(a)] is a macromolecular lipoprotein resembling low-density lipoprotein but also contains the glycoprotein apolipoprotein(a). Lp(a) has been demonstrated to have prothrombotic and proatherogenic properties,14,15 possibly caused in part by its structural homology to the plasma serine protease plasminogen. Elevated Lp(a) levels have been associated with acute coronary syndromes in both men and women.16,17 In addition to being associated with the development of native coronary atherosclerosis,15-19 elevated serum Lp(a) levels have also been associated with saphenous vein bypass graft atherosclerosis.20 Increased serum Lp(a) levels may be a risk factor for the development of ACAV in patients after orthotopic heart transplantation.21 However, the role of Lp(a) in the development of ACAV and its association with increased serum levels of other atherogenic substances has not been delineated. To further assess whether serum Lp(a) is associated with the development of ACAV, we examined the relation between donor and recipient clinical variables, including serum Lp(a) levels

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330 Chang et al.

Figure 1

Table I. Baseline recipient demographics of study transplantation group (n = 74) Age (yr) Race (white) Sex (male) Diabetes mellitus CMV (positive) Diagnosis Ischemic cardiomyopathy Idiopathic cardiomyopathy Other Cholesterol (mg/dl) Triglycerides (mg/dl) Serum Lp(a) (mg/dl) Ischemic time (min)

51.5 ± 12 89.2% 86.5% 10.8% 74.3% 51.4% 36.5% 12.1% 188.9 ± 46.2 171.8 ± 206.2 26.3 ± 26.6 145.4 ± 43.4

and the presence of angiographically defined ACAV in 74 consecutive heart transplant recipients at 1 year after orthotopic heart transplantation.

The first annual coronary angiogram for each patient was reviewed for the presence of ACAV, blinded to baseline demographic, clinical, and laboratory data [including Lp(a) values]. ACAV in the transplant recipient was prospectively defined as the presence of ≥30% stenosis in one or more epicardial coronary arteries in either a focal or a diffuse manner on coronary angiography. This definition for ACAV has been used in other similar studies.21

Methods

Statistics

Seventy-four consecutive patients at the Hospital of the University of Pennsylvania with a minimum of 1 year of survival after orthotopic heart transplantation were studied. Baseline recipient and donor demographics, including factors associated with the transplantation process (i.e., HLA mismatch, panel reactive antibody [PRA] screen, ischemic time), were obtained by retrospective chart review. Baseline and routine serial laboratory data, including fasting lipid profiles (total cholesterol and triglyceride levels), at the time of transplantation were also included. Serum Lp(a) values were obtained from each member of the study group and independently quantitated by using an immunoturbidometric assay.19 The median time after heart transplantation for serum Lp(a) level determinations was 26 months. All transplant recipients received standard triple-drug immunosuppression therapy with cyclosporine, azathioprine, and prednisone. No lymphocytolytic induction therapy was used. Cardiac rejection was graded according to the International Society for Heart and Lung Transplantation (ISHLT) grading system.22 The number of rejection episodes (ISHLT grade ≥3A) within the first year was recorded.

Chi-square analyses were performed on all discrete variables, and two-tailed t tests were performed on all continuous and ordinal variables. The nonparametric Mann-Whitney U test was used to compare means between variables that were not normally distributed [Lp(a) and triglycerides]. Multivariate analysis was conducted on all variables that reached statistical significance or showed a strong trend toward significance (p ≤ 0.15) with univariate analysis. Statistical significance was defined if the null hypothesis could be rejected at the p < 0.05 level.

Donor age and accelerated cardiac allograft vasculopathy.

Results Demographics and routine lipid profiles of patients with and those without ACAV Baseline demographics for the study patients are presented in Table I. Twenty-six patients (35%) demonstrated angiographic evidence of ACAV. Mean donor age (36 ± 13 years [ACAV (+)] vs 28 ± 10 years [ACAV (–)]; p = 0.004) and mean serum triglyceride levels at 6 months after transplantation (286 ± 275 mg/dl [ACAV (+)] vs 169 ± 85 mg/dl [ACAV (–)]; p = 0.025) were univariate predictors of ACAV (Figs. 1 and 2).

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Figure 2

Chang et al. 331

Figure 3

Total serum cholesterol levels (mg/dl) at baseline, 6 months, and 1 year after heart transplantation.

Mean triglyceride levels at 6 months after heart transplantation (mg/dl) and accelerated cardiac allograft vasculopathy.

No differences in serum cholesterol levels at baseline, 6 months after transplantation, or 1 year after transplantation were noted between patients with and those without ACAV (Fig. 3). A trend toward prolonged ischemic time in patients with ACAV was observed (157 ± 53 minutes [ACAV (+)] vs 140 ± 37 minutes [ACAV (–)]; p = 0.12). No statistically significant differences in recipient pretransplantation clinical characteristics were observed in patients with and those without ACAV (Table II).

Lp(a) and ACAV Mean Lp(a) levels (20 ± 19 mg/dl [ACAV (+)] vs 30 ± 30 mg/dl [ACAV (–)]; p = NS) did not differ between patients with and those without ACAV (Fig. 4). Because serum Lp(a) levels were not obtained at standardized times after transplantation, we subdivided the patients into two groups according to the median follow-up time since transplantation (26 months) to assess any potential interaction between serum Lp(a) values and the length of time after heart transplantation, with the end point of ACAV. No significant association was found between serum Lp(a) values and the presence of ACAV when patients were divided into short-term follow-up (<26 months after transplantation) and long-term follow-up (≥26 months after transplantation): 27.5 ± 28.6 versus 24.9 ± 24.6 mg/dl (p = NS).

Table II. Baseline clinical characteristics of patients with [ACAV (+)] and patients without [ACAV (–)] accelerated cardiac allograft vasculopathy ACAV (–) ACAV (+) p Value (n = 48) (n = 26) Recipient characteristics Age (yr) 52 ± 13 Race (white) 92% Sex (male) 92% Diagnosis ICM 56% IDCM 31% Other 12% PRA (positive) 4% Ischemic time (min) 140 ± 37 Rejection episodes 1.2 ± 1.4 Donor characteristics Age (yr) 28 ± 10 Race (white) 85% Sex (male) 67% Donor-recipient characteristics CMV mismatch 50% HLA matches (out of 6) 1.2 ± 1.0 HLA A match (≥1) 47% HLA B match (≥1) 23% HLA DR match (≥1) 42% Lipid profiles (mg/dl) Cholesterol, baseline 186 ± 46 Cholesterol, 6 months 239 ± 65 Cholesterol, 1 year 225 ± 63 Triglycerides, baseline 147 ± 73 Triglycerides, 6 months 169 ± 85 Triglycerides, 1 year 196 ± 129 Lp(a) 30 ± 30

51 ± 11 85% 77%

NS NS NS

42% 46% 12% 4% 157 ± 53 1.2 ± 1.2

NS NS NS NS

36 ± 13 88% 81%

0.004 NS NS

42% 1.4 ± 1.3 50% 35% 27%

NS NS NS NS NS

195 ± 47 251 ± 73 224 ± 59 217 ± 333 286 ± 275 220 ± 110 20 ± 19

NS NS NS NS 0.025 NS NS

ICM, ischemic cardiomyopathy; IDCM, idiopathic cardiomyopathy.

Multivariate analysis Advanced donor age (p = 0.023) was the only independent risk factor associated with the presence of

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Figure 4

Figure 5

Mean lipoprotein(a) levels and accelerated cardiac allograft vasculopathy.

angiographic ACAV at 1 year after orthotopic heart transplantation.

Discussion In this study, donor age and serum triglyceride levels 6 months after heart transplantation were univariate predictors of ACAV at 1 year after transplantation. Advanced donor age was the only independent predictor of ACAV (p = 0.023) at 1 year after transplantation. Serum Lp(a) levels, CMV status, CMV donor-recipient mismatch, degree of HLA mismatch (total, A, B, and DR), PRA status, and the number of rejection episodes noted within the first year after heart transplantation were not associated with the presence of ACAV. Recently, Barbir et al.21 reported elevated serum Lp(a) values to be an independent risk factor for the presence of ACAV. Despite similar baseline demographics, similar angiographic definitions, and a similar frequency of ACAV, we did not observe this association. The effect of time after heart transplantation on serum Lp(a) levels may partially explain the findings of our study. Serum Lp(a) levels were apparently though not definitively measured at the time of an annual angiographic evaluation in the study by Barbir et al.21 In contrast, the median time to determination of serum Lp(a) levels in our study was 26 months. Furthermore, unlike our study, the angiographic assessment was not blinded to clinical variables.

Frequency distribution of serum Lp(a) levels (mg/dl).

The effect of transplantation and immunosuppressive therapy, which affect serum lipid profiles, on serum Lp(a) levels is as yet undefined. Serum Lp(a) levels have been shown to both increase as well as decrease in kidney transplant recipients with cyclosporine therapy.23,24 Farmer et al.25 reported a significant decrease in serum Lp(a) levels 3 months after transplantation in 41 consecutive heart transplant recipients receiving cyclosporine therapy when compared with pretransplantation values. These apparent changes in Lp(a) values with time after transplantation could partially explain the discrepancy between our findings and those of Barbir et al.21 regarding an association of Lp(a) levels and cardiac allograft vasculopathy. Nevertheless, the frequency distribution of Lp(a) plasma concentrations in our study population (Fig. 5) reflected that described for the general population.19 Further studies regarding changes in serum Lp(a) levels with

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time and immunosuppressive therapy after transplantation are currently in progress to help clarify any potential interaction between Lp(a) levels and ACAV. Advanced donor age and hypertriglyceridemia have consistently been shown in numerous studies to be independent risk factors for the onset of ACAV.12,13 Consistent with our observations, Mehra et al.13 noted that advanced donor age, elevated total triglyceride levels, and a measure of rejection emerged as significant independent predictors for the development of ACAV as assessed by intravascular ultrasound. Furthermore, a correlation between the magnitude of hypertriglyceridemia and ACAV was observed, identifying a potential target for early intervention. Eich et al.8 identified hypercholesterolemia at 6 months after transplantation as a strong predictive marker for the onset of ACAV and early graft failure by the third year after transplantation. By contrast, neither hypercholesterolemia at baseline, 6 months after transplantation, nor 1 year after transplantation identified those patients likely to subsequently develop ACAV at 1 year in our study population (Table II). Whether or not hypercholesterolemia 6 months after heart transplantation accurately predicts the subsequent presence of angiographically detectable ACAV 3 years after transplantation cannot be assessed by our current data set.

Study limitations Baseline angiography of the cardiac allograft was not routinely performed in our patients, thereby limiting our ability to detect preexisting atherosclerosis in the donor as a potential confounder in our analysis. Further investigations with baseline angiographic studies to compare subsequent angiograms for the development of ACAV are clearly needed. In addition, our study did not standardize the use of medications such as diltiazem26,27 and pravastatin,28 which may influence the development of ACAV.

Conclusions In this study of heart transplant recipients surviving beyond 1 year after transplantation, serum Lp(a) levels were not associated with the presence of ACAV. Advanced donor age and serum triglyceride levels obtained 6 months after transplantation were univariate predictors for the presence of ACAV, and advanced donor age was the single independent predictor for the presence of ACAV. Prospective studies are needed to better define the role that serum Lp(a) values play in the development of ACAV 1 year after transplantation.

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