Grant: Travel Awards - Institute Community Support

Background: Right ventricular failure (RVF) is an independent prognostic factor for pulmonary arterial hypertension (PAH) patients. Recent studies have demonstrated that a metabolic shift toward increased glycolysis over glucose oxidation (Warburg effect) in compensated RV hypertrophy (cRVH). While the pyruvate kinase muscle isozyme M2 (PKM2) regulates metabolism, it also promotes DNA damage repair which triggers inflammation. However, its role has never been studied in RVF. We hypothesized that, in addition to promoting the Warburg effect in cRVH, PKM2 accounts for sustained DNA damage repair activation, contributing to enhanced cardiac inflammation and decompensated RV hypertrophy (dRVH). Methods and Results: We found in human RV biopsies that PKM2/PKM1 ratio was upregulated in cRVH patients (Cardiac index >2.2, n=14) and dRVH patients (died of RVF, n=9), compared to control donors (n=14), and correlated with RV hypertrophy. Similar findings were found in three PH rat models (monocrotaline, PA banding and sugen-hypoxia). Interestingly, inflammation (CD68) and oxidative DNA damage (8-OxoDG, MTH1) were significantly increased in dRVH compared to cRVH despite similar PKM2/PKM1 ratios. Specifically, MTH1 (protein level) inversely correlated with cardiac output and positively correlated with RVEDP, ANP, BNP, hypertrophy and fibrosis (Masson trichrome staining); suggesting that MTH1 is a predictive factor of dRVH. Using rat neonate RV cardiomyocytes, we confirmed that endothelin 1 promotes PKM2 upregulation, ultimately leading to increased inflammation (NF-kB), oxidative DNA damage (8-OxoDG) and apoptosis (TUNEL) (All p<0.05). Conclusions: We demonstrated for the first time that PKM2 is critical for RVF and PKM2/inflammation/oxidative DNA damage signaling is implicated in the transition from cRVH to dRVH in RVF by impacting RV functions.