Heart failure (HF) is prevalent in the elderly and exceeds 10% in those older than 85 years [1]. Over 75% of HF cases involve older adults [2]. At least half of these cases involve HF with preserved ejection fraction (HFpEF) [3]. Regardless of left ventricular ejection fraction (LVEF), a hallmark feature of HF is exercise intolerance, as demonstrated by a reduction in peak oxygen consumption (V̇O2) with exercise [4]. Elderly patients are also most vulnerable to complications associated with HF. Patients with a low peak V̇O2 are at an increased risk for mortality.

This review presents a focused update of the cardiovascular and peripheral processes leading to exercise intolerance in older HF patients.

Peak oxygen consumption (V̇O2) is considered the “gold standard” for measuring aerobic performance. It is a product of cardiac output (CO), the central component, and the arterio-venous oxygenation difference (A-V̇O2 diff), the peripheral component, as described by the Fick equations below,

Equations:

(1)$$\begin{array}{c}\hfill VO2=CO\times AV{O}_2\text{ diff,}\hfill \\ \hfill VO2=SV\times HR\times AV{O}_2\text{ diff,}\hfill \\ \hfill VO2=EDV\times LVEF\times HR\times {\mathrm{AVO}}_2\text{ diff,}\hfill \end{array}$$

V̇O2, peak oxygen consumption; CO, cardiac output; EDV, end-diastolic volume; LVEF, left ventricular ejection fraction; AV$O_2$, arteriovenous oxygen difference; SV, stroke volume; HR, heart rate.

Mechanisms that alter any of the variables of the equations may affect aerobic performance. Peak V̇O2 is measured by cardiopulmonary exercise testing (CPET) to evaluate functional capacity. The examination is usually performed with a cycle ergometer or a treadmill. The patient’s heart rate and blood pressure and electrocardiogram (ECG) are continuously recorded while expired gasses (i.e., oxygen and carbon dioxide) are analyzed. Measurements are obtained at rest, throughout exercise, and during recovery. The V̇O2 is plotted as a function of time and correlates with the patient’s work [5]. Fig. 1 demonstrates a sample plot of V̇O2 and other exercise variables versus time. Both central and peripheral determinants are responsible for a blunted peak V̇O2 with exercise in the elderly HF population by affecting one or more of the parameters in the equations. The processes involving each variable are described below.

Fig. 1.

Example of a cardiopulmonary exercise test (CPET) report. Oxygen consumption (VO2) per kilogram of body weight (left) and volume of expired air (VE) (right) are plotted over time in minutes. BTPS, body temperature; pressure; saturated water vapor; FEO2%, Concentration of oxygen in exhaled gasses; FECO2%, Concentration of carbon dioxide in exhaled gasses; HR, heart rate; RER, Respiratory exchange ratio; Tm Grd, treadmill grade; Tm Spd, treadmill speed.

Heart failure with reduced ejection fraction (HFrEF) is defined by a reduction in the LVEF below 40%, and HFpEF by an LVEF $\ge$45% or 50% in association with the classic HF symptoms of dyspnea, fatigue, and exercise intolerance. The elderly are already at risk for an age-related reduction in maximal exercise capacity due to the processes mentioned in the previous section. Heart failure (regardless of LVEF) is an independent risk factor for further exercise intolerance as measured by a reduction in peak V̇O2 compared to healthy age peers [30].

In one study, older patients with HF (mean age: 70 years) demonstrated a blunted peak V̇O2 during upright cycle ergometry: (HFrEF: 13.1 mL/kg/min, HFpEF: 14.2 mL/kg/min) compared to similarly aged healthy controls: 19.9 mL/kg/min [31]. A subgroup analysis of the participants in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study demonstrated that age is the strongest predictor of peak V̇O2 in HFrEF patients [32]. This study showed a reduction of peak V̇O2 by approximately 1 mL/kg/min for every 7-year increase in the age above 40 years.

Lower peak V̇O2 is a potent risk factor for adverse outcomes in older HF patients similar to younger cohorts. A 2015 large multi-center prospective study evaluating 990 elderly ($\ge$70 years old) patients with HFrEF determined that higher peak V̇O2 was predictive of reduced risk of cardiovascular death or urgent heart transplant (hazard ratio: 0.97, p = 0.0016) [33]. This study demonstrated a graded reduction in median peak V̇O2 in mL/kg/min with each decade of life: 50 years: 17.1 mL/kg/min, 50 to 60 years: 14.8 mL/kg/m, 60 to 70 years: 13.9 mL/kg/min, and $\ge$70: 12.5 mL/kg/min. A peak V̇O2 less than 14 mL/kg/min in HFrEF patients is commonly used as a major criterion for cardiac transplantation referral [34].

Compared to patients with HFrEF, patients with HFpEF tend to be older, more often female, and have more comorbidities, such as obesity, diabetes mellitus, and hypertension [35]. Blunted exercise tolerance and impaired peak V̇O2 are also characteristic features of HFpEF patients. Haykowsky and colleagues [36] compared the peak V̇O2 of 60 older HFpEF patients (mean age: 70 years) undergoing CPET to age-matched healthy control subjects (N: 40, mean age: 69 years). They demonstrated a significantly reduced peak V̇O2 in the HFpEF patients compared to control subjects (cycle ergometer peak V̇O2: 14.6 vs. 22.9 mL/kg/min, respectively) [36]. Multiple studies have corroborated these results [15, 16, 37, 17]. Although studies relating mortality to exercise intolerance in elderly HFpEF patients are less common than in HFrEF, data in younger patients with HFpEF indicate that peak V̇O2 is similarly predictive of mortality [38]. A study by Yan and colleagues demonstrated that increased minute ventilation to carbon dioxide production (VE/VCO2) slope, a marker of excessive ventilation for work performed, was more predictive of mortality compared to peak V̇O2 alone in 224 older patients (mean age 69 years) with HFpEF [39]; however, more studies are needed to validate these results.

Peak V̇O2 is reduced with exercise in HF patients secondary to derangements in multiple central (i.e., heart rate, contractility, ventricular relaxation) and peripheral (i.e., skeletal muscle volume/function, metabolism, vasodilator reserve) parameters. The following sections will review these mechanisms in detail. Table 1 delineates the mechanisms for changes in aerobic capacity in older HF patients. The similarity of these changes to those related to aging per se is striking, providing a “double dose” via their superimposition on the aging changes.

A reduction in peak CO between 27% and 58% is notable in patients with HF compared to healthy individuals of similar age [40]. Understanding the mechanisms leading to impaired CO, the product of heart rate and stroke volume, is key in recognizing the central processes leading to blunted peak V̇O2 response with exercise.

Several significant peripheral structural, functional, and metabolic abnormalities lead to exercise intolerance in patients with HF [43, 51]. The elderly are more susceptible to these effects for the following reasons: reduced skeletal muscle mass, alterations in peripheral muscle composition and function, increased sedentary lifestyle, more comorbidities (i.e., arthritis, diabetes, hypertension), and impairments to metabolism [30]. Several recent trials in the elderly demonstrate significant peripheral alterations in patients with both HFrEF and HFpEF and are described below.

Most studies in contemporary literature on exercise intolerance in older HF populations are limited by their small sample sizes. There is also a significant under-representation of women and non-Whites in existing studies. As a result, it is difficult to generalize the conclusions of these studies to many older subgroups. There is also little homogeneity in the methodology and parameters studied across different clinical studies. For example, one study used near-infrared spectroscopy to study mitochondrial oxidative capacity [15], while another employed ${}^{31}$phosphorous magnetic resonance spectroscopy [63]. These two parameters are surrogates of oxidative capacity but are not necessarily congruent. There are also variations in exercise type, duration, and intensity across studies that further limit the generalizability of data.

Another important limitation to the existing literature is the effect of comorbidities common to older HF patients on aerobic exercise capacity. Comorbidities such as chronic renal disease, pulmonary disorders, diabetes, peripheral vascular disease, atrial arrhythmias, endocrinopathies, neurological disorders, and musculoskeletal disease affect exercise tolerance via complex pathways. Thus, the mechanisms for exercise intolerance described in this review likely vary in their importance based on a given patient’s comorbidities. Patients should therefore be evaluated in the context of their specific disease profiles.

This review does not discuss impairments in pulmonary mechanics and biochemical processes seen with both aging and HF. Both topics are also important for a global understanding of exercise intolerance in the elderly HF population but are outside the scope of the manuscript. Combined cardiopulmonary studies are needed to assess the degree to which these factors contribute to exercise intolerance in older HF patients. Finally, the role of exercise training in ameliorating the contributors to exercise intolerance in older HF patients is not addressed.

Heart failure is a common disorder in the elderly, leading to significant exercise intolerance. There are multiple mechanisms leading to exercise intolerance in elderly HF patients, including those due to age per se superimposed on those secondary to HF. Impairments in central parameters leading to reduced CO, including blunted heart rate, stroke volume, and blood flow distribution, are critical pathways for exercise intolerance. The elderly HF patient is also susceptible to peripheral contributors to exercise intolerance, including skeletal muscle architecture changes (i.e., increased fat mass and decreased muscle mass) as well as impaired muscle metabolism, and peripheral hypoperfusion. More clinical studies are needed in widely representative older HF populations to elucidate further these mechanisms of exercise intolerance and the role of exercise training in their treatment.

The content of this manuscript is solely the responsibility of the authors and does not necessarily reflect the official views of the National Heart, Lung, and Blood Institute, National Institutes of Health, or the United States Department of Health and Human Services.

NVS is the primary author who performed the literature review and manuscript preparation. MT assisted with literature review, edits, and revisions of text. JF was the senior author who assisted with the literature review, edits, and revisions of the text.

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This research received no external funding.

The authors declare no conflict of interest. Jerome L. Fleg is serving as Editor-in-Chief and Guest Editor of this journal. We declare that Jerome L. Fleg had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Giuseppe Boriani.