Donor Myocardial HIF‐1α Is an Independent Predictor of Cardiac Allograft Dysfunction: A 7‐Year Prospective, Exploratory Study

Abstract

Knowledge on interplay between the cardiac molecular response to transplantation-induced stress and primary graft dysfunction (PGD) is limited. A cDNA array identified HIF-1, EGR-1, NAB-2, VEGF-A and uPA as mediators of cardiac tissue response to transplantationinduced stress. mRNA expression of these molecules was measured in left ventricular biopsies from 200 donors before and after aortic cross-clamping and at 10-, 30-and 60-min reperfusion by real-time RT-PCR. HIF-1a expression at two time points was significantly associated with PGD, as shown by univariate analysis, receiver operating characteristic curve and multivariate logistic regression. At a cut-off level of 200 arbitrary units, HIF-1a after aortic cross-clamping in donors (78% sensitivity, 83% specificity) and at 10-min reperfusion (85% sensitivity, 83% specificity) identified PGD. HIF-1a demonstrates the potential to be a predictive marker for PGD; however, as multiple factors were tested at different time points, prospective evaluation is clearly necessary to confirm this observation.

Clinical relevance of complement-fixing antibodies in cardiac transplantation

“…Primary graft failure (PGF) is the most common cause of death in the first 30 days after heart transplantation [41]. PGF is a poorly understood entity, but is significantly associated with hypoxic injury of the donor heart [42], making it likely that ischemia-reperfusion injury is an important causative factor.…”

Levosimendan: A New Therapeutic Option in the Treatment of Primary Graft Dysfunction After Heart Transplantation

“…1 Several theories have been proposed to explain the onset of PGD, including prolonged ischemia time, donor condition, size mismatch, and recently, the hypoxia-inducible factor 1-␣ graft levels. 2,3 The therapeutic options in patients diagnosed with PGD are limited to pharmacologic support with catecholamines and phosphodiesterase inhibitors or mechanical support. Pharmacologic therapy with catecholamines presents substantial limitations both in the short-term and the long-term treatment of acute heart failure because they are associated with elevated myocardial oxygen consumption, arrhythmogenesis, and regional hypoperfusion leading to organ damage.…”

Cardiomyocyte-targeted HIF-1α gene therapy inhibits cardiomyocyte apoptosis and cardiac allograft vasculopathy in the rat

“…In human donor hearts before organ procurement and 10 minutes after reperfusion of cardiac allografts, increased HIF-1␣ mRNA levels are linked with primary graft dysfunction. 10 Although HIF-1␣ protein is mainly regulated at the post-translational level by tissue hypoxia, 20 basal HIF-1␣ mRNA is controlled by nuclear factor-kappaB (NF-B), a major transcription factor responsible for gene regulation during both the innate and adaptive immune responses. Furthermore, during inflammation, HIF-1␣ mRNA and protein expression are regulated by inflammatory cytokines such as IL-1␤ and TNF-␣ via the NF-Bmediated pathway.…”

“…[6][7][8][9] HIF-1␣ is upregulated in donor hearts with primary graft dysfunction, but the functional role of HIF-1 in organ transplantation remains unclear. 10 The present study is the first to characterize the kinetics of HIF-1␣ during both acute rejection and development of CAV. Furthermore, we examined the functional role of HIF-1␣ by adeno-associated virus (AAV)-mediated cardiomyocyte-targeted gene delivery of the stabilized form of HIF-1␣.…”