Cold ischemia contributes to the development of chronic rejection and mitochondrial injury after cardiac transplantation

Abstract

Summary Chronic rejection (CR) remains an unsolved hurdle for long‐term heart transplant survival. The effect of cold ischemia (CI) on progression of CR and the mechanisms resulting in functional deficit were investigated by studying gene expression, mitochondrial function, and enzymatic activity. Allogeneic (Lew→F344) and syngeneic (Lew→Lew) heart transplantations were performed with or without 10 h of CI. After evaluation of myocardial contraction, hearts were excised at 2, 10, 40, and 60 days for investigation of vasculopathy, gene expression, enzymatic activities, and mitochondrial respiration. Gene expression studies identified a gene cluster coding for subunits of the mitochondrial electron transport chain regulated in response to CI and CR. Myocardial performance, mitochondrial function, and mitochondrial marker enzyme activities declined in all allografts with time after transplantation. These declines were more rapid and severe in CI allografts (CR‐CI) and correlated well with progression of vasculopathy and fibrosis. Mitochondria related gene expression and mitochondrial function are substantially compromised with the progression of CR and show that CI impacts on progression, gene profile, and mitochondrial function of CR. Monitoring mitochondrial function and enzyme activity might allow for earlier detection of CR and cardiac allograft dysfunction.

The influence of ischemia and reperfusion time on outcome in heart transplantation

“…There were no significant differences in mean donor age between the groups in our study. Previous studies have shown an increased incidence of rejection and CAV, 1,5,27,28 primary graft dysfunction, higher morbidity, and increased mortality, especially in older donors with extended ischemic time 6,29‐31 . Yeen et al 14 states that it is an overall risk when exceeding 4 hours but suggest that it may be possible to safely increase the ischemic time to 5 hours with a careful selection of both donor and recipient.…”

Impact of Cold Ischemia on Mitochondrial Function in Porcine Hearts and Blood Vessels

“…Cardiovascular surgery exposes the heart itself and also various blood vessels to prolonged periods of warm and cold ischemia. Especially in the heart transplantation, prolonged ischemia leads to higher rates of primary organ failure resulting in worse overall outcome of heart transplant recipients [11,12]. The right ventricular function is primarily affected in cases of primary organ failure; it is significantly more severe and more frequent than the left ventricle.…”

Role of Mitogen-Activated Protein Kinases in Myocardial Ischemia-Reperfusion Injury during Heart Transplantation

“…Extended cold ischemic times during heart transplantation have been associated with increased risk of developing graft vasculopathy and failure both in animal models [17, 18] and in humans [19]. Moreover, prolonged times between donor brain death and organ retrieval have been associated with increased mortality in cardiac transplant recipients [20].…”