Restoring the Cardiopulmonary Unit: A Coupling‐Centric Review of Pharmacotherapy in Pulmonary Vascular Disease

The clinical trajectory of pulmonary vascular disease (PVD) is governed by the functional and molecular integration of the right ventricle (RV) and pulmonary vasculature-the cardiopulmonary unit. Right ventricular-pulmonary arterial (RV-PA) coupling (Ees/Ea) is the principal determinant of survival. This review synthesizes contemporary pathophysiology and therapeutics through the lens of RV-PA coupling, reflecting the recognition of active heart-lung crosstalk. Advancing beyond traditional reviews, this article (1) formalizes a phenotype-guided treatment algorithm based on coupling derangement, (2) integrates emerging concepts of molecular crosstalk mediated by extracellular vesicles, and (3) positions sotatercept as a "coupling drug" targeting both components of the cardiopulmonary unit. We detail maladaptive pathways-including metabolic reprogramming, inflammation, fibrosis, and sex hormone signaling-that degrade RV contractility (Ees) under chronic pressure overload. The pharmacotherapeutic landscape is critically evaluated: from established vasodilators that indirectly support the RV by reducing afterload (Ea) to transformative disease-modifying agents like sotatercept that reverse vascular remodeling and the emerging frontier of direct RV-targeted therapies. We argue that the future of PVD management lies in a precision-based strategy using deep phenotyping to classify patients by dominant coupling derangements and matching them with mechanism-based therapies. The paradigm must shift beyond symptomatic vasodilation toward regimens explicitly designed to restore the physiological balance of the cardiopulmonary unit, carefully distinguishing between validated standards of care and investigational approaches.