New Multimodal Framework Targets Debilitating Form of Heart Failure

Heart failure with preserved ejection fraction (HFpEF) occurs when the left ventricle becomes stiff and thickened despite maintaining a normal ejection fraction. The condition is increasingly common with aging, hypertension, diabetes, and obesity and is associated with breathlessness, frequent hospitalizations, and increased mortality. More than 80% of patients also develop pulmonary hypertension, further worsening prognosis.

A team from the University of Wisconsin–Madison and the Morgridge Institute for Research reports advances in clinical characterization and mechanistic insight for PH‑HFpEF, published in Circulation: Heart Failure on August 24, 2026. The work introduces a framework that combines comprehensive cardiac testing with molecular profiling to better define prognosis and disease biology. The team describes an improved method to classify patients’ severity and identifies molecular pathways that may be amenable to future therapies.

The study evaluated 48 patients with PH‑HFpEF who had undergone invasive hemodynamic assessment and cardiac MRI. Of these, 29 had normal right ventricular (RV) function and 19 had RV dysfunction. Subsets received additional testing that included detailed pulmonary artery evaluation with catheterization, time‑resolved cardiac MRI measures of blood flow, and endomyocardial biopsies for genetic and molecular analyses.

RV dysfunction was associated with higher rates of mortality and hospitalization and outperformed other commonly used clinical measures for classifying HFpEF severity. The investigators also found that abnormalities originating in the left heart can increase stress on the RV, contributing to progressive dysfunction. Together, these findings support RV assessment as a central component of clinical evaluation in patients with PH-HFpEF.

Molecular analysis of biopsy tissue revealed reduced mitochondrial function along with increased RNA metabolism and transport as prominent features of PH-HFpEF. Using long-read RNA sequencing, the researchers also identified gene expression variants that differed between patients with and without RV dysfunction. One example, GATD3, showed a variant expressed at higher levels in patients with RV dysfunction, pointing to a potential target for further investigation.

The authors note that several HFpEF drug trials based on pulmonary vasodilation, including studies of sildenafil and oral levosimendan, have been unsuccessful, underscoring the need to move beyond one-size-fits-all treatment strategies. They plan larger studies to map patient-specific disease mechanisms and support more precise clinical trials. Ultimately, the researchers envision a workflow in which tissue-level molecular signals help guide selection of already approved therapies matched to each patient’s dominant disease mechanism.

Related Links
University of Wisconsin
Morgridge Institute for Research