Multimodal Characterization of High-risk PH-HFpEF phenogroup with Right Ventricular Dysfunction: Vascular Mechanics and Myocardial Transcriptomics

Background: Pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF) is a highly heterogeneous disease associated with right ventricular (RV) failure and adverse outcomes. Current diagnostic tools inadequately characterize pulmonary vascular disease and RV dysfunction, limiting treatment precision. We hypothesized that deep phenotyping-including invasive hemodynamics, advanced imaging, and myocardial transcriptomics-would identify high-risk PH-HFpEF phenotypes with distinct clinical, physiologic, and molecular characteristics. Methods: 42 PH-HFpEF participants (and 25 pre-capillary PH participants, as a comparison group) underwent clinical evaluation, echocardiography, cardiac MRI (cMRI), and invasive cardiopulmonary exercise testing (iCPET). K-means clustering considering clinical, iCPET, and cMRI data stratified participants into distinct clusters (phenogroups). A subset underwent further characterization by invasive pulmonary vascular mechanics (n=17 PH-HFpEF, n=5 pre-capillary PH) and 4D flow cMRI (n=10 PH-HFpEF, n=5 pre-capillary PH). Endomyocardial biopsies from 10 PH-HFpEF participants were analyzed using long-read RNA-sequencing for differential gene and transcript expression. Results: gene, encoding the giant sarcomeric protein titin, may be particularly relevant to elevated myocardial stiffness, which worsens vascular remodeling and precipitates RV dysfunction and failure. Conclusions: In PH-HFpEF, unsupervised clustering using deep physiologic and imaging data identified a high-risk group with impaired RV function and unique transcriptomic profiles. Our findings suggest that proximal and distal pulmonary vascular remodeling, as well as differences in titin isoform expression, may underlie RV failure in this phenogroup. This comprehensive approach provides a framework for mechanistically driven precision medicine strategies in PH-HFpEF. Clinical perspectives: 2.These findings offer a framework for more refined patient classification beyond traditional PVR-based methods, which may improve identification of high-risk individuals who require closer monitoring or targeted therapy.The integrative approach highlights titin isoform imbalance and vessel-specific stiffness as potential therapeutic targets, supporting the development of biology-informed, phenotype-specific interventions for PH-HFpEF with RV dysfunction.