Multi-organ physiologic deficits during exercise identify clinical and molecular predisposition to heart failure with preserved ejection fraction

Authors: LANDSTEINER, ISABELA - Massachusetts General Hospital; STOLZE, LINDSEY - Vanderbilt University Medical Center; PETERSON, TESS - University Of Minnesota; PERRY, ANDREW - Vanderbilt University Medical Center; LIN, PHILLIP - Vanderbilt University Medical Center; SHENG, QUANHU - Vanderbilt University Medical Center; ZHAO, SHILIN - Vanderbilt University Medical Center; AMANCHERLA, KAUSHIK - Vanderbilt University Medical Center; MI, MICHAEL - Beth Israel Deaconess Medical Center; IKOMA, TAKENORI - Massachusetts General Hospital; COHEN, LAURA - Massachusetts General Hospital; GIVERTS, ILYA - Massachusetts General Hospital; CAMPAIN, JOSEPH - Massachusetts General Hospital; LIMA, JOAO - Johns Hopkins University School Of Medicine; POST, WENDY - Johns Hopkins University School Of Medicine; TAYLOR, KENT - Harbor-Ucla Medical Center; GERSZTEN, ROBERT - Beth Israel Deaconess Medical Center; RICH, STEPHEN - University Of Virginia School Of Medicine; TRACY, RUSSELL - University Of Vermont; DURDA, PETER - University Of Vermont; WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); MALHOTRA, RAJEEV - Massachusetts General Hospital; ROTTER, JEROME - Harbor-Ucla Medical Center; CLISH, CLARY - Broad Institute Of Mit/harvard; NAYOR, MATTHEW - Boston University Medical School; GAMAZON, ERIC - Vanderbilt University Medical Center; SHAH, RAVI - Vanderbilt University Medical Center; LEWIS, GREGORY - Massachusetts General Hospital

Submitted to: Circulation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/6/2026
Publication Date: 5/5/2026
Citation: Landsteiner, I., Stolze, L.K., Peterson, T.E., Perry, A., Lin, P., Sheng, Q., Zhao, S., Amancherla, K., Mi, M.Y., Ikoma, T., Cohen, L.P., Giverts, I., Campain, J., Lima, J.A., Post, W.S., Taylor, K.D., Gerszten, R., Rich, S.S., Tracy, R., Durda, P., Wood, A.C., Malhotra, R., Rotter, J.I., Clish, C., Nayor, M., Gamazon, E.R., Shah, R.V., Lewis, G.D. 2026. Multi-organ physiologic deficits during exercise identify clinical and molecular predisposition to heart failure with preserved ejection fraction. Circulation. 153(18):1362-1384. https://doi.org/10.1161/CIRCULATIONAHA.125.077579.
DOI: https://doi.org/10.1161/CIRCULATIONAHA.125.077579

Interpretive Summary: Heart failure with preserved ejection fraction (HFpEF) is a common and complex condition, but it is not well explained by heart function alone. This study examined how multiple body systems—such as the heart, lungs, blood vessels, and muscles—respond during exercise in people with HFpEF. Using detailed exercise testing in over 800 patients, researchers identified seven types of physiological problems that often occur together and found that having more of these deficits greatly increased the risk of hospitalization or death. They then linked these exercise-related problems to patterns of metabolites in the blood and showed that these patterns predicted future heart failure in a large, community-based population followed for nearly 20 years. The study also connected these metabolic patterns to genetic pathways shared with conditions like obesity, kidney disease, and diabetes. Overall, the findings show that HFpEF is a whole-body disease involving multiple organs and biological systems, not just the heart. This work is important for clinicians, researchers, and policymakers because it supports more precise ways to identify high-risk individuals and points to new targets for prevention and treatment.

Technical Abstract: Exercise unmasks limitations in multi-organ system reserve capacity characteristic of heart failure with preserved ejection fraction (HFpEF). However, the metabolic and genetic underpinnings of exercise deficits, and their cumulative contribution to HFpEF severity and prognosis, remain incompletely understood. We used invasive cardiopulmonary exercise testing (iCPET), metabolite profiling, and genomics to simultaneously characterize seven exercise physiologic deficits in HFpEF patients: reduced exercise stroke volume and heart rate, steep pulmonary capillary wedge pressure/cardiac output (PCWP/CO) slope, elevated pulmonary vascular resistance, pulmonary mechanical limitation to exercise, impaired peripheral oxygen extraction, and obesity-related exaggerated metabolic cost of initiating exercise. We first mapped the distribution, functional, and prognostic significance of these exercise deficits. We then applied LASSO regression to identify metabolite signatures of each exercise deficit, and measured the relation of these signatures with clinical-demographic features, cardiac magnetic resonance imaging, and incident HF in 6345 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) study with ˜20-year follow-up. Finally, we mapped deficit-implicated metabolites to tissue-specific genetic variation in ˜2M individuals with HF, and in the largest genome-wide association study (GWAS) studies of HFpEF comorbidities (obesity, renal disease, diabetes) to evaluate shared metabolic mechanisms of HFpEF pathophysiology. Our iCPET HFpEF cohort (61.7+/-14.1 years, 54% female, BMI 30.6+/-6.7 kg/m**2 ) exhibited a broad range of compound cardiac and extra-cardiac exercise deficits. Individuals with >=5 exercise deficits had a nearly 4-fold higher hazard of incident cardiovascular event or mortality (HR 3.90, 95% CI 1.74-8.75, P<0.0001). The metabolite signature of exercise PCWP/CO slope conferred a HR of 1.43 per SD increment, 95% CI 1.20-1.71, P<0.001 for incident HF in MESA. Addition of all iCPET deficit metabolic signatures in a single model yielded ˜20% continuous net reclassification improvement over traditional HFpEF risk factors. Genes implicated by the exercise deficit metabolome were enriched in the HF GWAS (˜2M) and shared with obesity, renal dysfunction, and diabetes, highlighting a lifelong shared predisposition to HF (including HFpEF) and its comorbidities. Organ-specific responses to exercise and their circulating metabolite signatures are strongly linked to HFpEF development and prognosis. These results offer a paradigm for parsing HFpEF subphenotypes and prioritizing metabolic mechanisms of HFpEF.