Raza F; University of Wisconsin-Madison. USA
Gregorich ZR; Freeman J; Moore B; et al
Circulation: Heart Failure. 19(10):e014620, 2026 Oct.
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 a
mechanistic understanding of RV dysfunction in PH-HFpEF.
METHODS: In a 2-step study, a predominantly retrospective PH-HFpEF cohort
(n=48) underwent comprehensive assessment with clinical evaluation,
echocardiography, cardiac magnetic resonance imaging (MRI), and invasive
cardiopulmonary exercise testing. Based on cardiac MRI-derived RV ejection
fraction <45%, the PH-HFpEF cohort was stratified into a normal RV
function group (n=29) and an RV dysfunction group (n=19). A prospective
subset underwent pulmonary vascular mechanics (impedance and wave
intensity analysis, n=17), 4-dimensional flow cardiac MRI (n=15), and
endomyocardial biopsy with long-read RNA sequencing (n=10).
RESULTS: PH-HFpEF participants with RV dysfunction had worse 1-year
outcomes (mortality or first heart failure hospitalization; hazard ratio,
8.2 [95% CI, 2.5-25.4]) and exhibited multisystem limitations (abnormal
cardiac reserve, pulmonary vascular, and ventilatory function). Compared
with the normal RV subgroup, the RV dysfunction subgroup had impaired left
ventricular longitudinal strain on cardiac MRI. 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. Four-dimensional 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 the mechanistic