Fig. 1

During RV pressure overload, elevated transmural wall pressures and reduced coronary perfusion results in ischemia and, in turn, increased production of reactive oxygen species (ROS). The ensuing direct and indirect inhibition of HIF1α leads to reduced angiogenesis via the downregulation of the VEGF axis. Imbalances between matrix metalloproteinase and tissue inhibitor metalloproteinases result in myocardial fibrosis. Alterations in pyruvate dehydrogenase kinase-related signaling drive a shift towards increased anaerobic glycolysis and glutaminolysis, further aggravating oxidative stress. Inhibited intracellular calcium release from sarcoplasmic reticulum stores via perturbed RyR2 and SERCA function contribute to contractile dysfunction in RV cardiomyocytes