Abstract 419: Deep Sequencing Provides Evidence Of Mitochondrial Abnormalities In Right Ventricular Failure In Pulmonary Arterial Hypertension

Abstract

Introduction: Right ventricular (RV) function is a critical predictor of both morbidity and mortality in pulmonary arterial hypertension (PAH). In PAH patients present either with adaptive remodelling RV and compensatory RV hypertrophy (RVH), or maladaptive remodeling that rapidly deteriorates to RV failure (RVF). While the molecular mechanisms underlying RVF remain poorly understood, acquired mitochondrial abnormalities including impaired mitochondrial electron transport chain activity, altered metabolic substrate utilization, and aberrant mitochondrial dynamics likely play a crucial role. We assessed the role of mitochondria in RVF using an unbiased assessment of gene expression in the RV of rats with maladaptive vs adaptive RVH and PAH. Method and result: Male rats were treated with either sugen+hypoxia (SuHx) or Monocrotaline (MCT). We determined RV status using non-invasive echocardiography and right heart catheterisation. Compared to control (Ctrl; n=15) both MCT (n=8) and SuHx (n=5) rats displayed severe PAH with increased RVSP, mPAP, total pulmonary resistance (TPR) and decreased PA acceleration time (PAAT) (p<0.05). MCT rats developed RVF characterized by increased RV end diastolic volume (EDV), decreased CO, TAPSE and ventricular-arterial decoupling (decreased Emax/Ea ratio) (p<0.05). SuHx rats had adaptive RVH. RNAsequencing revealed 2,547 differentially regulated transcripts. Functional Annotation analysis revealed multiple enriched GOterms, the most significant of which described mitochondrion (GO: 0005739; p=1.6E-53 which describes 414 genes). Significant GOterms also include mitochondrial inner membrane (GO: 0005743; p=3.9E-20) and mitochondrial respiratory chain complex I (GO: 0005747 ; p=4.9E-10). We validated 15 key dysregulated mitochondrial genes in maladaptive RVH (MCT; n=7) compared to both adaptive RVH (SuHx; n=4) and Ctrl (n=12) by qPCR, Finally, we validated these findings in human samples from PAH patients with RVH compared to controls (n=5 per group; p<0.05). Conclusion: We combined haemodynamic investigation and transcriptomics to identify specific mitochondrial-metabolic gene expression signatures associated with RVF in two different preclinical models and in human samples.