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

Area of Science:

• Cardiology
• Pulmonary Hypertension
• Heart Failure

Background:

• Pulmonary hypertension with heart failure with preserved ejection fraction (PH-HFpEF) is a complex condition with significant right ventricular (RV) dysfunction and poor outcomes.
• Current diagnostic methods fail to adequately characterize pulmonary vascular disease and RV dysfunction, hindering precise treatment strategies.

Purpose of the Study:

• To identify distinct high-risk PH-HFpEF phenotypes using deep phenotyping, including invasive hemodynamics, advanced imaging, and myocardial transcriptomics.
• To characterize the clinical, physiological, and molecular differences between these phenotypes.

Main Methods:

• 42 PH-HFpEF participants underwent clinical evaluation, echocardiography, cardiac MRI (cMRI), and invasive cardiopulmonary exercise testing (iCPET).
• K-means clustering integrated clinical, iCPET, and cMRI data to stratify participants into phenogroups.
• A subset underwent further characterization with invasive pulmonary vascular mechanics, 4D flow cMRI, and endomyocardial biopsies analyzed by long-read RNA-sequencing.

Main Results:

• Clustering identified two PH-HFpEF phenogroups with significantly different one-year outcomes (HR=11.96).
• The high-risk group showed greater LV mass, reduced RV ejection fraction, worse exercise-induced PH, impaired gas exchange, and higher pulmonary artery stiffness.
• Transcriptomic analysis revealed differences in RNA processing, translational control, mitochondrial function, and differential transcript usage of the TTN gene in the high-risk group.

Conclusions:

• Unsupervised clustering of deep physiologic and imaging data identified a high-risk PH-HFpEF group with impaired RV function and unique transcriptomic profiles.
• Findings suggest pulmonary vascular remodeling and titin isoform expression contribute to RV failure in this phenogroup.
• This comprehensive approach provides a framework for mechanistically driven precision medicine in PH-HFpEF.