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Exercise intolerance (EI) is the primary manifestation of chronic heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure among older individuals. The recent recognition that HFpEF is likely a systemic, multiorgan disorder that shares characteristics with other common, difficult-to-treat, aging-related disorders suggests that novel insights may be gained from combining knowledge and concepts from aging and cardiovascular disease disciplines. This state-of-the-art review is based on the outcomes of a National Institute of Aging-sponsored working group meeting on aging and EI in HFpEF. We discuss aging-related and extracardiac contributors to EI in HFpEF and provide the rationale for a transdisciplinary, "gero-centric" approach to advance our understanding of EI in HFpEF and identify promising new therapeutic targets. We also provide a framework for prioritizing future research, including developing a uniform, comprehensive approach to phenotypic characterization of HFpEF, elucidating key geroscience targets for treatment, and conducting proof-of-concept trials to modify these targets.

Aims Heart failure (HF) has a major impact on exercise tolerance that may (in part) be due to abnormalities in body and skeletal muscle composition. This systematic review and meta-analysis aims to assess how differences in whole-body and skeletal muscle composition between patients with HF and non-HF controls (CON) contribute to reduced peak oxygen uptake (VO2peak). Methods and results The PubMed database was searched from 1975 to May 2024 for eligible studies. Cross-sectional studies with measures of VO2peak, body composition, or muscle biopsies in HF and CON were considered. Out of 709 articles, 27 studies were included in this analysis. Compared with CON, VO2peak [weighted mean difference (WMD): −9.96 mL/kg/min, 95% confidence interval (CI): −11.71 to −8.21), total body lean mass (WMD: −1.63 kg, 95% CI: −3.05 to −0.21), leg lean mass (WMD: −1.38 kg, 95% CI: −2.18 to −0.59), thigh skeletal muscle area (WMD: −10.88 cm2 , 95% CI: −21.40 to −0.37), Type I fibres (WMD: −7.76%, 95% CI: −14.81 to −0.71), and capillary-to-fibre ratio (WMD: −0.27, 95% CI: −0.50 to −0.03) were significantly lower in HF. Total body fat mass (WMD: 3.34 kg, 95% CI: 0.35–6.34), leg fat mass (WMD: 1.37 kg, 95% CI: 0.37–2.37), and Type IIx fibres (WMD: 7.72%, 95% CI: 1.52–13.91) were significantly higher in HF compared with CON. Absolute VO2peak was significantly associated with total body and leg lean mass, thigh skeletal muscle area, and capillary-to-fibre ratio. Conclusion Individuals with HF display abnormalities in body and skeletal muscle composition including reduced lean mass, oxidative Type I fibres, and capillary-to-fibre ratio that negatively impact VO2peak. [ABSTRACT FROM AUTHOR]

In a 77-year-old former world-record-holding male marathoner (2:08:33.6), this study sought to investigate the impact of lifelong intensive endurance exercise on cardiac structure, function, and the trajectory of functional capacity (determined by maximal oxygen consumption, V̇ o 2max) throughout the adult lifespan. As a competitive runner, our athlete (DC) reported performing up to 150–300 miles/wk of moderate-to-vigorous exercise and sustained 10–15 h/wk of endurance exercise after retirement from competition. DC underwent maximal cardiopulmonary exercise testing in 1970 (aged 27 yr), 1991 (aged 49 yr), and 2020 (aged 77 yr) to determine V̇ o 2max. At his evaluation in 2020, DC also underwent comprehensive cardiac assessments including resting echocardiography, and resting and exercise cardiac magnetic resonance to quantify cardiac structure and function at rest and during peak supine exercise. DC's V̇ o 2max showed minimal change from 27 yr (69.7 mL/kg/min) to 49 yr (68.1 mL/kg/min), although it eventually declined by 36% by the age of 77 yr (43.6 mL/kg/min). DC's V̇ o 2max at 77 yr, was equivalent to the 50th percentile for healthy 20- to 29-yr-old males and 2.4 times the requirement for maintaining functional independence. This was partly due to marked ventricular dilatation (left-ventricular end-diastolic volume: 273 mL), which facilitates a large peak supine exercise stroke volume (200 mL) and cardiac output (22.2 L/min). However, at the age of 78 yr, DC developed palpitations and fatigue and was found to be in atrial fibrillation requiring ablation procedures to revert his heart to sinus rhythm. Overall, this life study of a world champion marathon runner exemplifies the substantial benefits and potential side effects of many decades of intense endurance exercise. NEW & NOTEWORTHY: This life study of a 77-yr-old former world champion marathon runner exemplifies the impact of lifelong high-volume endurance exercise on functional capacity (V̇ o 2max equivalent to a 20- to 29-yr-old), partly due to extreme ventricular remodeling that facilitates a large cardiac output during exercise despite reduced maximal heart rate. Although it is possible that this extreme remodeling may contribute to developing atrial fibrillation, the net benefits of extreme exercise throughout this athlete's lifespan favor increased health span and expected longevity. [ABSTRACT FROM AUTHOR]

BACKGROUND: We identified peripherally limited patients using cardiopulmonary exercise testing and measured skeletal muscle oxygen transport and utilization during invasive single leg exercise testing to identify the mechanisms of the peripheral limitation. METHODS: Forty-five patients with heart failure with preserved ejection fraction (70±7 years, 27 females) completed seated upright cardiopulmonary exercise testing and were defined as having a (1) peripheral limitation to exercise if cardiac output/oxygen consumption (VO2) was elevated (=6) or 5 to 6 with a stroke volume reserve >50% (n=31) or (2) a central limitation to exercise if cardiac output/VO2 slope was =5 or 5 to 6 with stroke volume reserve <50% (n=14). Single leg knee extension exercise was used to quantify peak leg blood flow (Doppler ultrasound), arterial-to-venous oxygen content difference (femoral venous catheter), leg VO2, and muscle oxygen diffusive conductance. In a subset of participants (n=36), phosphocreatine recovery time was measured by magnetic resonance spectroscopy to determine skeletal muscle oxidative capacity. RESULTS: Peak VO2 during cardiopulmonary exercise testing was not different between groups (central: 13.9±5.7 versus peripheral: 12.0±3.1 mL/min per kg; P=0.135); however, the peripheral group had a lower peak arterial-to-venous oxygen content difference (central: 13.5±2.0 versus peripheral: 11.1±1.6 mLO2/dL blood; P<0.001). During single leg knee extension, there was no difference in peak leg VO2 (P=0.306), but the peripherally limited group had greater blood flow/VO2 ratio (P=0.024), lower arterial-to-venous oxygen content difference (central: 12.3±2.5 versus peripheral: 10.3±2.2 mLO2/dL blood; P=0.013), and lower muscle oxygen diffusive conductance (P=0.021). A difference in magnetic resonance spectroscopy-derived phosphocreatine recovery time was not detected (P=0.199). CONCLUSIONS: Peripherally limited patients with heart failure with preserved ejection fraction identified by cardiopulmonary exercise testing have impairments in oxygen transport and utilization at the level of the skeletal muscle quantified by invasive knee extension exercise testing, which includes an increased blood flow/VO2 ratio and poor muscle diffusive capacity. [ABSTRACT FROM AUTHOR]