Abstract
Introduction: Although right ventricular failure (RVF) is associated with poor outcome following left ventricular assist device (LVAD) implantation, predictive factors of RVF have not been fully established. Epigenetic modification in cardiomyocytes has been recently shown to be related to progression of heart failure (HF). Hypothesis: We herein hypothesized that reduced histone modification including methylation/acethylation of cardiomyocytes in the RV would be associated with RVF after LVAD implantation. Methods: This study enrolled 22 patients who were diagnosed as having non-ischemic dilated cardiomyopathy (NIDCM) and underwent LVAD implantation for bridge-to-transplantation between 2012 and 2015. The RV biopsied prior to LVAD implantation were immunohistologically labeled for histone H3 lysine 9 tri-methylation (H3K9me3) and acethylation (H3K9ac) and scored ranging from 0 to 12 according to intensity and percentage of positively labelled cardiac cell nuclei. Results: Eight patients (40%) presented with RVF following LVAD implantation, which was defined as need of inotropic support for 30 days or more, nitric oxygen inhalation for 2 days or more, and/or exchange to bi-VAD support. Survival of the patients with and without RVF was 66% and 90%, respectively, at 2 years post-LVAD implantation (log rank=0.2). LV ejection fraction (p=0.7), right atrial pressure (RAP, p=0.4) or Michigan RVF score (p=0.5) was not different in the patients with and without RVF, whereas RV stroke work index (SWI) was modestly lower (6.4±2.5 vs 8.5±2.7 g·m/m2/beat, p=0.09) and percentage of fibrosis in the RV was significantly higher (61±16 vs 46±12%, p=0.02) in the patients with RVF. The score of H3K9me3 and H3K9ac were significantly lower in the patients with RVF (2.6±1.2 vs 5.1±2.8, p=0.028 and 5.8±2.3 vs 9.9±2.4, p<0.001, respectively). Furthermore, The score of H3K9ac was significantly correlated with RV systolic pressure and RV peak negative dp/dt (p=0.03 and p=0.02), and most powerful predictor of RVF by ROC analysis (AUC= 0.90). Conclusions: The epigenetical examination targeting H3K9 methylation and acetylation in NIDCM may promise exact predictor in RVF following LVAD implantation by the combination of histological or functional analysis.
Published Version
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