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Multimodal Framework of Left Heart-Pulmonary Vascular Remodeling Underlying Right Ventricular Failure in PH-HFpEF
Key result
RV dysfunction in PH-HFpEF is linked to an ~8-fold higher 1-year mortality or HF hospitalization risk.
- HR 8.2
- 95% CI 2.5-25.4
- n=48
Why the study?
Right ventricular dysfunction in PH-HFpEF causes adverse outcomes, but the mechanisms driving RV failure remain incompletely understood.
Key Points
- To establish a multimodal framework integrating vascular mechanics, 4-dimensional flow cardiac MRI, and myocardial transcriptomics to characterize the mechanisms underlying right ventricular failure in pulmonary hypertension with heart failure with preserved ejection fraction (PH-HFpEF).
- Evaluated a retrospective PH-HFpEF cohort (n=48) stratified by cardiac MRI right ventricular ejection fraction (<45% defining RV dysfunction, n=19; normal RV function, n=29) using clinical evaluation, echocardiography, cardiac MRI, and invasive cardiopulmonary exercise testing.
- Assessed prospective subsets with pulmonary vascular mechanics (impedance and wave intensity analysis, n=17), 4-dimensional flow cardiac MRI (n=15), and endomyocardial biopsy profiled with PacBio long-read RNA sequencing (n=10).
- Participants with RV dysfunction experienced significantly worse 1-year outcomes for mortality or first heart failure hospitalization (hazard ratio, 8.2 [95% CI, 2.5-25.4]; 2 deaths and 9 hospitalizations in the RV dysfunction group vs. 0 deaths and 3 hospitalizations in the normal RV group).
- RV dysfunction was characterized by impaired left ventricular longitudinal strain, increased proximal pulmonary arterial stiffness (characteristic impedance), elevated RV energy expenditure during exercise, and disturbed flow patterns on 4D flow cardiac MRI.
- Myocardial long-read RNA sequencing demonstrated upregulation of RNA metabolism pathways, significant downregulation of mitochondrial and oxidative phosphorylation pathways, and differential isoform usage in key cardiac genes in patients with RV dysfunction.
Study Design
Type
Cohort (n=48)
Structured PICO
P
Population
48 patients with pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF) who underwent comprehensive assessment including cardiac MRI.
C
Comparator
PH-HFpEF patients with normal RV function (RVEF ≥45%) and a pre-capillary PH comparison group.
O
Outcome
Composite of mortality or first heart failure hospitalization at 1 year.composite
Main Result
Hazard Ratio: 8.2 (95% CI 2.5–25.4)
In patients with PH-HFpEF, right ventricular dysfunction is associated with an 8-fold increased risk of death or heart failure hospitalization and is linked to increased pulmonary arterial stiffness and altered myocardial transcriptomics.
Limitations
- Modest sample size, particularly in the prospective and transcriptomic subsets
- Retrospective design of the primary cohort introduces potential selection bias
- Findings from pulmonary vascular mechanics and 4D flow MRI are based on small subsets and should be considered hypothesis-generating
- Transcriptomic analyses were performed in a limited number of myocardial biopsy samples
- Causal relationships between vascular remodeling, myocardial changes, and RV failure cannot be definitively established
- Modest sample size, particularly in the prospective and transcriptomic subsets, limiting statistical power.
- Retrospective design of the primary cohort introduces potential selection bias.
- Findings from pulmonary vascular mechanics and 4D flow MRI are based on small subsets and should be considered hypothesis-generating.
- Transcriptomic analyses were performed in a limited number of myocardial biopsy samples.
- Causal relationships between vascular remodeling, myocardial changes, and RV failure cannot be definitively established.
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
DBDr. Bradley Serwerinterventional cardiologist
“This study may signify a paradigm shift in our understanding of heart failure with preserved ejection fraction. Patients who concurrently develop pulmonary vascular remodeling and right ventricular dysfunction may represent a fundamentally distinct and significantly elevated risk group compared to those with standard uncomplicated heart failure with preserved ejection fraction. The main clinical message from this study is that heart failure with preserved ejection fraction should be viewed as a disease of the entire cardiopulmonary system, rather than simply a disease isolated to the left ventricle.”
“Many of the genes we identified are linked to mitochondrial function and cellular energy production, suggesting that disrupted energy metabolism may play an important role in HFpEF.”
“While these are early results, I think our study does a pretty good job of introducing this strong pipeline, which will translate into human precision clinical trials within a few years. We are deeply grateful to every patient who has chosen to take part in this research. Their generosity and the trust they place in us are creating knowledge that will benefit countless patients and families in the years to come.”
Implication
RV dysfunction flags high-risk PH-HFpEF; hypothesis-generating for pulmonary stiffness or mitochondrial targets before interventional trials.
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 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 understanding of left heart-pulmonary vascular remodeling in PH-HFpEF.
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Cite This Study
Raza et al. (2026) conducted a cohort in Pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF) (n=48). Right ventricular dysfunction (RVEF <45%) vs. Normal right ventricular function (RVEF ≥45%) was evaluated on 1-year outcomes (mortality or first heart failure hospitalization) (HR 8.2, 95% CI 2.5-25.4). Right ventricular dysfunction in PH-HFpEF was associated with an 8.2-fold increased risk of 1-year mortality or first heart failure hospitalization.