Multiorgan Physiological Deficits During Exercise Identify Clinical and Molecular Predisposition to Heart Failure With Preserved Ejection Fraction

Circulation, Volume 153, Issue 18, Page 1362-1384, May 5, 2026. BACKGROUND:Exercise unmasks limitations in multiorgan 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.METHODS:We used invasive cardiopulmonary exercise testing, metabolite profiling, and genomics to simultaneously characterize 7 exercise physiological deficits in patients with HFpEF: reduced exercise stroke volume and heart rate, steep pulmonary capillary wedge pressure/cardiac output 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 least absolute shrinkage and selection operator 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 heart failure in 6345 individuals in the MESA study (Multi-Ethnic Study of Atherosclerosis) with ≈20 years of follow-up. Last, we mapped deficit-implicated metabolites to tissue-specific genetic variation in ≈2 million individuals, including ≈153 000 with heart failure, leveraging the largest genome-wide association studies of HFpEF comorbidities (obesity, renal disease, diabetes) to evaluate shared metabolic mechanisms of HFpEF pathophysiology.RESULTS:Our invasive cardiopulmonary exercise testing HFpEF cohort (age, 61.7±14.1 years; 54% female; body mass index, 30.6±6.7 kg/m2) exhibited a broad range of compound cardiac and extracardiac exercise deficits.

Individuals with ≥5 exercise deficits had a nearly 4-fold higher hazard of incident cardiovascular event or mortality (hazard ratio, 3.90 [95% CI, 1.74–8.75];P<0.0001). The metabolite signature of exercise pulmonary capillary wedge pressure/cardiac output slope conferred a hazard ratio of 1.43 per 1-SD increment (95% CI, 1.20–1.71;P<0.001) for incident heart failure in MESA.

Addition of all invasive cardiopulmonary exercise testing 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 heart failure genome-wide association study (≈2 million) and shared with obesity, renal dysfunction, and diabetes, highlighting a lifelong shared predisposition to heart failure (including HFpEF) and its comorbidities.CONCLUSIONS: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.