Haptoglobin phenotype correlates with development of cardiac transplant vasculopathy

Objectives: The purpose of this study was to investigate the association between haptoglobin phenotypic variation and development of cardiac transplant vasculopathy. Background: The development of coronary vasculopathy determines long-term survival after cardiac transplantation. Serum haptoglobin levels are associated with non-transplant atherosclerosis. In addition, to free hemoglobin binding, haptoglobin influences free radical formation, prostaglandin synthesis and angiogenesis. Three phenotypes of haptoglobin exist in humans, which have both quantitative and qualitative differences. Methods: Coronary disease was diagnosed at post-transplant routine surveillance angiography. Hemoglobin (10%) was added to recipient plasma to form a haptoglobin-hemoglobin complex. Sample aliquots were applied to acid hemoglobin plates and electrophoretically separated. Phenotypes were recognized by comparing the electrophoretic pattern with that of established standards. Haptoglobin concentrations were measured using an immunoturbidimetric technique with polyethylene glycol (PEG)-enhanced precipitation. Results: Ninety-three patients were independently studied. Phenotype 1-1 was found in 20.4%, 2-1 in 41.9% and 2-2 in 37.6%. Haptoglobin levels were highest in 1-1 recipients (2.1 +/- 0.58 g/liter) compared with 1.78 +/- 0.88 g/liter and 1.3 +/- 0.81 g/liter in 2-1 and 2-2 individuals, respectively (p = 0.001). Haptoglobin phenotype was significantly related to the development of vasculopathy; recipients with a 2-1 phenotype were more likely to develop angiographic disease (p = 0.0084). No differences were found among the 3 groups according to univariate analysis. Multivariate analysis identified 3 risk factors for vasculopathy development: age of donor (hazard ratio 1.056 [95% confidence interval 1.02 to 1.094], p = 0.0023); pre-transplant recipient body mass index (hazard ratio 1.116 [95% confidence interval 1.015 to 1.23],p = 0.024), and haptoglobin phenotype (hazard ratio 2.725 [95% confidence interval 1.031 to 7.19], p = 0.012). Conclusions: Haptoglobin, through phenotype-dependent mechanisms, correlates with the development of coronary vasculopathy. This finding furthers our understanding of the disease, opens up new areas of research, and may lead to novel therapies. J Heart Lung Transplant 2004;23:43-49.