Exercise Intolerance in Older Adults With Heart Failure With Preserved Ejection Fraction: JACC State-of-the-Art Review

Abstract

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.

Keywords: aging; exercise intolerance; heart failure with preserved ejection fraction; senescence; skeletal muscle.

Figure 1.. VO_2peak required for ADLs relative to average VO_2peak in HFpEF.

Among patients with HFpEF, the threshold of functional independence is 21% above the average peak VO2 (blue bar) of patients with HFpEF. Figure reproduced with permission from Nayor et al. JACC Heart Failure 2020.

Figure 2.. The multimorbidity model of exercise intolerance in HFpEF.

Accumulation of cardiac and non-cardiac co-morbidities coupled with aging contributes to systemic inflammation, endothelial dysfunction, global reduction in physiologic reserve, and exercise intolerance in patients with HFpEF.

Figure 3:. Contribution of cardiovascular maladaptations to exercise intolerance in HFpEF.

Patients with HFpEF have impairment in stroke volume reserve and chronotropic reserve, and increased afterload, all of which contribute to reduced forward flow. This “central limitation’ coupled with impairment peripheral vasodilation and reduced oxygen extraction contributes to lower peak exercise oxygen uptake.

Figure 4:. Microvascular function and sarcopenia.

Comparison of the thigh compartment fat and muscle composition in a control vs. HFpEF individual on MRI. HFpEF patients have greater intramuscular fat and reduced skeletal muscle mass. Impaired microcirculatory function leads to sarcopenia, which is magnified by the catabolic effects of inflammation, insulin resistance, and increased myostatin. AA=amino acids; FFA=free fatty acids; GH=growth hormone; IGF-1=insulin-like growth factor-1.

Figure 5:. Contribution of hallmarks of aging to HFpEF and exercise intolerance.

The hallmarks of aging refers to closely inter-related cellular and molecular processes implicated in aging and conserved across species which could serve as new therapeutic targets for many age-related chronic diseases and geriatric syndromes, including HFpEF.

Figure 6:. Proposed high priority extracardiac areas for future research in HFpEF.

Future research should focus on advancing the understanding of the pathophysiology of EI, development of novel approaches to pathophysiology-guided phenotypic classification of HFpEF, identification of novel targets for preventing and mitigating EI, and testing such interventions in animal and human studies.

Central Illustration:. Pathophysiology and outcomes in HFpEF.

Risk factors such as multimorbidity, aging, physical inactivity, and systemic inflammation lead to loss of capillarity, mitochondrial and endothelial dysfunction, and sarcopenia and result in downstream multi-organ dysfunction, frailty, and cardiac and skeletal muscle myopathy. This constellation of pathophysiologic abnormalities contributes to the clinical manifestation of HFpEF.