Advanced Molecular, Metabolic, and Imaging Approaches to Characterizing Right Ventricular Failure: A Scientific Statement From the American Heart Association

Right ventricular (RV) dysfunction is a key predictor of outcomes in pulmonary hypertension (PH), substantially contributing to illness and death. As PH progresses, increased pulmonary vascular resistance places chronic pressure overload on the right ventricle. Initially, the right ventricle adapts through hypertrophic remodeling, thickening the heart wall to maintain cardiac output. Over time, this adaptive phase shifts to maladaptive remodeling, marked by RV dilation, fibrosis, stiffness, and decoupling from the pulmonary artery, known as RV-pulmonary arterial uncoupling. This uncoupling reflects the inability of the right ventricle to sustain contractility against elevated afterload, ultimately leading to right heart failure, the primary cause of death in late-stage PH. Awareness of RV dysfunction has grown, extending beyond PH and pulmonary arterial hypertension to systemic conditions, such as heart failure with preserved ejection fraction, congenital heart disease, COVID-19, and complications of left ventricular assist device implantation. Research is increasingly focused on understanding the molecular and hemodynamic drivers of RV failure, including inflammation and altered cellular signaling. Innovations in imaging and biomarker discovery are improving the detection of maladaptive RV remodeling. Promising treatments, such as the activin signaling inhibitor sotatercept, may reduce pulmonary vascular resistance and support RV recovery. Further work is needed to enhance RV function and prevent failure. This review summarizes current knowledge on RV dysfunction in PH, emphasizing its mechanisms, clinical relevance, and therapeutic potential. Recognizing the right ventricle as a central therapeutic target may lead to more personalized, effective interventions and improved patient outcomes in PH and related conditions.