Molecular Signature of a Right Heart Failure Program in Chronic Severe Pulmonary Hypertension

Right heart failure is the cause of death of most patients with severe pulmonary arterial hypertensive (PAH) disorders, yet little is known about the cellular and molecular causes of right ventricular failure (RVF). We first showed a differential gene expression pattern between normal rat right and left ventricles, and postulated the existence of a molecular right heart failure program that distinguishes RVF from adaptive right ventricular hypertrophy (RVH), and that may differ in some respects from a left heart failure program. By means of microarrays and transcriptional sequencing strategies, we used two models of adaptive RVH to characterize a gene expression pattern reflective of growth and the maintenance of myocardial structure. Moreover, two models of RVF were associated with fibrosis, capillary rarefaction, the decreased expression of genes encoding the angiogenesis factors vascular endothelial growth factor, insulin-like growth factor 1, apelin, and angiopoeitin-1, and the increased expression of genes encodinga set of glycolytic enzymes. The treatment of established RVF with a beta-adrenergic receptor blocker reversed RVF, and partly reversed the molecular RVF program. We conclude that normal right and left ventricles demonstrate clearly discernable differences in the expression of mRNA and microRNA, and that RVH and RVF are characterized by distinct patterns of gene expression that relate to cell growth, angiogenesis, and energy metabolism.