Multimodal Framework of Left Heart–Pulmonary Vascular Remodeling Underlying Right Ventricular Failure in PH-HFpEF

Abstract

Background: Right ventricular (RV) dysfunction in pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF) leads to adverse outcomes, yet the mechanisms underlying RV failure remain incompletely defined. We aimed to develop a multimodal framework integrating vascular mechanics and myocardial transcriptomics for mechanistic understanding of RV dysfunction in PH-HFpEF. Methods: In a two-step study, a predominantly retrospective PH-HFpEF cohort (n=48) underwent comprehensive assessment with clinical, echocardiography, cardiac MRI (cMRI), and invasive cardiopulmonary exercise testing. Based on cMRI-derived RV ejection fraction <45%, PH-HFpEF cohort was stratified into normal RV function (n=29) and RV dysfunction (n=19). A prospective subset underwent pulmonary vascular mechanics (impedance and wave intensity analysis, n=17), 4D flow cMRI (n=15), and endomyocardial biopsy with long-read RNA sequencing (n=10). Results: PH-HFpEF participants with RV dysfunction had worse one-year outcomes (mortality or first heart failure hospitalization, HR=8.2, 95% CI 2.5-25.4) and exhibited multi-system limitations (abnormal cardiac reserve, pulmonary vascular and ventilatory function). Compared to normal RV subgroup, RV dysfunction subgroup had impaired left ventricular longitudinal strain on cMRI. Pulmonary vascular mechanics demonstrated increased proximal pulmonary arterial stiffness (characteristic impedance), increased RV energy expenditure, and abnormal distal vascular reflections with exercise, indicating segmental pulmonary vascular remodeling. 4D flow MRI revealed disturbed flow patterns and trends toward increased viscous energy loss across the left heart and pulmonary circulation. Global gene differences were minimal, likely reflecting the limited statistical power for detecting individual differentially expressed genes in this modest cohort; however, pathway analysis revealed upregulation of RNA metabolism and downregulation of mitochondrial pathways in the RV dysfunction subgroup. Long-read sequencing further identified selective isoform expression in key cardiac genes, highlighting differential regulation in PH-HFpEF with RV dysfunction. Conclusions: This integrative methodological framework of vessel-specific wave mechanics and myocardial transcriptomics advances mechanistic understanding of left heart-pulmonary vascular remodeling in PH-HFpEF.