Multi-Organ Physiologic Deficits During Exercise Identify Clinical and Molecular Predisposition to Heart Failure with Preserved Ejection Fraction.
Isabela, L., K, S.L., E, P.T., Andrew, P., Phillip, L., Quanhu, S., Shilin, Z., Kaushik, A., Y, M.M., Takenori, I., P, C.L., Ilya, G., Joseph, C., C, L.J.A., S, P.W., D, T.K., Robert, G., S, R.S., Russell, T., . . . D, L.G. (2026). Multi-Organ Physiologic Deficits During Exercise Identify Clinical and Molecular Predisposition to Heart Failure with Preserved Ejection Fraction.. Circulation. https://doi.org/10.1161/CIRCULATIONAHA.125.077579
Isabela L, K SL, E PT, Andrew P, Phillip L, Quanhu S, et al. Multi-Organ Physiologic Deficits During Exercise Identify Clinical and Molecular Predisposition to Heart Failure with Preserved Ejection Fraction.. Circulation. 2026; doi: 10.1161/CIRCULATIONAHA.125.077579
Isabela L, K SL, E PT, et al. Multi-Organ Physiologic Deficits During Exercise Identify Clinical and Molecular Predisposition to Heart Failure with Preserved Ejection Fraction.[J]. Circulation. 2026. DOI: 10.1161/CIRCULATIONAHA.125.077579.
@article{isabela2026,
author = {Landsteiner Isabela and Stolze Lindsey K and Peterson Tess E and Perry Andrew and Lin Phillip and Sheng Quanhu and Zhao Shilin and Amancherla Kaushik and Mi Michael Y and Ikoma Takenori and Cohen Laura P and Giverts Ilya and Campain Joseph and Lima Joao A C and Post Wendy S and Taylor Kent D and Gerszten Robert and Rich Stephen S and Tracy Russell and Durda Peter and Wood Alexis C and Malhotra Rajeev and Rotter Jerome I and Clish Clary and Nayor Matthew and Gamazon Eric R and Shah Ravi V and Lewis Gregory D},
title = {Multi-Organ Physiologic Deficits During Exercise Identify Clinical and Molecular Predisposition to Heart Failure with Preserved Ejection Fraction.},
journal = {Circulation},
year = {2026},
doi = {10.1161/CIRCULATIONAHA.125.077579},
note = {PMID: 41944041},
}
TY - JOUR AU - Landsteiner Isabela AU - Stolze Lindsey K AU - Peterson Tess E AU - Perry Andrew AU - Lin Phillip AU - Sheng Quanhu AU - Zhao Shilin AU - Amancherla Kaushik AU - Mi Michael Y AU - Ikoma Takenori AU - Cohen Laura P AU - Giverts Ilya AU - Campain Joseph AU - Lima Joao A C AU - Post Wendy S AU - Taylor Kent D AU - Gerszten Robert AU - Rich Stephen S AU - Tracy Russell AU - Durda Peter AU - Wood Alexis C AU - Malhotra Rajeev AU - Rotter Jerome I AU - Clish Clary AU - Nayor Matthew AU - Gamazon Eric R AU - Shah Ravi V AU - Lewis Gregory D TI - Multi-Organ Physiologic Deficits During Exercise Identify Clinical and Molecular Predisposition to Heart Failure with Preserved Ejection Fraction. T2 - Circulation PY - 2026 DO - 10.1161/CIRCULATIONAHA.125.077579 AN - PMID:41944041 ER -
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/m2 ) 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.