Genetic Determinants of Allograft Hypertrophy- A Human Myocardial Biopsy Study

Abstract

Background Cardiac Allograft Hypertrophy (CAH) assessed by left ventricular mass (LVM) on imaging at 1 year has been validated as an early predictor of mortality and vasculopathy. The biology of such changes could be starting much earlier in the life of the graft and reflect the beginning of a continuum of remodeling of the transplanted heart that finally leads to chronic rejection and graft failure. However, definitive mechanisms and predictors have not been established. Therefore, we aimed to study the molecular mechanisms of CAH characterized by abnormal echo mass in heart transplant patients. We hypothesized there is a specific genetic signature in the myocardium that can predict the morphological mechanisms of CAH. Methods We used data from our heart transplant biopsy repository where consented patients agree for an extra biopsy and blood to be stored for research during their protocol visits. Biopsies are stored at -80C in RNA later. We used samples from 6 month time-point in a small cohort of randomly selected patients and performed full gene expression profiling using Ilumina Beadarray Microarray Technology. Additionally, clinical and echocardiogram parameters were collected at the same time-point. LVM index and relative wall thickness at 6m from transplant were used to define CAH according to ASE Guidelines. Results A total of 16 patients were included in the analysis. 5 patients had normal LV geometry, 8 had concentric remodeling and 3 concentric hypertrophy (CH). Patients in the abnormal group were significantly older than the patients in the normal group (53.4 vs 60.7 years, respectively, p=0.0478) while there were no other statistically significant differences in the rest of the baseline and clinical parameters. Gene expression data showed a distinct signature on the heatmap for CH (Figure 1). There were 40 genes that were differentially expressed in CH group compared to the rest. Conclusion Only 31% of the patients have a normal echo LVM by 6 months and there is a distinct genetic signature for CH suggesting that there is a specific biological change occurring in the heart as early as 6 months that contribute to hypertrophy. We hope to elicit the biological basis of these changes so as to create therapeutic interventions to temper these changes and promote longevity of grafts.