Refined Heart Failure Stages Incorporating Cardiorespiratory Fitness Are Differentially Associated With Heart Failure Risk in the Community

Background Heart failure (HF) progresses through stages, from risk factors (stage A) to structural abnormalities, or elevated biomarkers (stage B), to clinical HF (stage C) as depicted by the American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines. Most individuals in stage B never develop clinical HF, highlighting the need for refined preclinical phenotyping. We hypothesized that refined HF stages incorporating cardiorespiratory fitness (CRF) would be differentially associated with HF risk. Methods This observational cohort study investigated FHS (Framingham Heart Study) participants who completed submaximal exercise testing (stage 2 of the Bruce protocol). CRF (peak oxygen uptake) was estimated on the basis of stage 2 heart rate, weight, age, sex, treadmill grade, and velocity. We evaluated the association of HF substages (categorized by CRF above versus below the sex‐specific median) with incident HF using Cox models adjusted for age and sex. Results Among 1683 individuals (55% women, age 58±8 years, estimated CRF 35.4±3.2 mL/kg per min in women and 40.1±4.2 mL/kg per min in men) 522 individuals (31%) were classified as no HF risk factors (“healthy”; stage H), 693 (41%) as stage A, and 468 (28%) as stage B at baseline. Over median follow‐up of 20 years, 99 HF events occurred. Stage B participants with low CRF had a >2.5‐fold higher HF risk (hazard ratio [HR], 2.75 [95% CI, 1.50–5.07]; P =0.001). Among stage B participants, every 1‐SD increase in CRF was associated with lower HF risk (HR, 0.57 [95% CI, 0.43–0.76]; P =0.0001). Conclusions Incorporating CRF into HF staging criteria may improve risk assessment and facilitate precision targeting of preventive therapies, especially among individuals classified as stage B.