Paradigm shift: from pulmonary vasodilation to cardiopulmonary dual-track therapy—a comprehensive review of pathophysiology and advances in pulmonary hypertension-associated right heart failure

Pulmonary arterial hypertension (PAH)-induced right heart failure (RHF) remains a major determinant of poor patient outcomes, driven by multifaceted pathophysiological mechanisms including impaired right ventricle-pulmonary artery coupling, metabolic reprogramming, mitochondrial dysfunction, chronic inflammation, and gut–lung axis disruption. Traditional therapies focusing solely on pulmonary vasodilation provide symptomatic relief but often fail to halt progressive right heart deterioration. Recent advances underscore a paradigm shift toward cardiopulmonary dual-track strategies that simultaneously reduce right ventricular afterload and directly protect or enhance right heart function. Novel agents such as Sotatercept—an activin signaling inhibitor—significantly reverse vascular remodeling and improve hemodynamics. Metabolic modulators (e.g., metformin), mitochondrial-targeted antioxidants (e.g., Elamipretide), and immunomodulators (e.g., tocilizumab) show promise in correcting bioenergetic deficits and inflammatory activation. Interventional approaches like percutaneous pulmonary artery denervation (PADN) and atrial septostomy serve as effective bridging options, while percutaneous right ventricular assist devices (pRVADs) and extracorporeal membrane oxygenation (ECMO) offer critical circulatory support in end-stage disease. Emerging therapies—including gene editing, cell-based treatments, and exosome technology—hold potential for targeted, personalized intervention. Despite these innovations, challenges persist such as variable treatment responses, long-term safety concerns, and translational inefficiencies. Future efforts should prioritize multi-omics-guided precision medicine, multidisciplinary care integration, and novel technologies like CRISPR/Cas9 to advance disease-modifying therapies and improve quality of life.