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.
The role of exercise training modality to attenuate left ventricular (LV) remodeling in heart failure patients with reduced ejection fraction (HFrEF) remains uncertain. The authors performed a ...systematic review and meta-analysis of published reports on exercise training (moderate-intensity continuous aerobic, high-intensity interval aerobic, and resistance exercise) and LV remodeling in clinically stable HFrEF patients.
We searched MEDLINE, Cochrane Central Registry of Controlled Trials, CINAHL, and PubMed (2007 to 2017) for randomized controlled trials of exercise training on resting LV ejection fraction (EF) and end-diastolic and end-systolic volumes in HFrEF patients.
18 trials reported LV ejection fraction (LVEF) data, while 8 and 7 trials reported LV end-diastolic and LV end-systolic volumes, respectively. Overall, moderate-intensity continuous training (MICT) significantly increased LVEF (weighted mean difference, WMD = 3.79%; 95% confidence interval, CI, 2.08 to 5.50%) with no change in LV volumes versus control. In trials ≥6 months duration, MICT significantly improved LVEF (WMD = 6.26%; 95% CI 4.39 to 8.13%) while shorter duration (<6 months) trials modestly increased LVEF (WMD = 2.33%; 95% CI 0.84 to 3.82%). High-intensity interval training (HIIT) significantly increased LVEF compared to control (WMD = 3.70%; 95% CI 1.63 to 5.77%) but was not different than MICT (WMD = 3.17%; 95% CI −0.87 to 7.22%). Resistance training performed alone or combined with aerobic training (MICT or HIIT) did not significantly change LVEF.
In clinically stable HFrEF patients, MICT is an effective therapy to attenuate LV remodeling with the greatest benefits occurring with long-term (≥6 months) training. HIIT performed for 2 to 3 months is superior to control, but not MICT, for improvement of LVEF.
Exercise intolerance is the primary chronic symptom in patients with heart failure and preserved ejection fraction (HFPEF), the most common form of heart failure in older persons, and can result from ...abnormalities in cardiac, vascular, and skeletal muscle, which can be further worsened by physical deconditioning. However, it is unknown whether skeletal muscle abnormalities contribute to exercise intolerance in HFPEF patients.
This study evaluated lean body mass, peak exercise oxygen consumption (VO2), and the short physical performance battery in 60 older (69 ± 7 years) HFPEF patients and 40 age-matched healthy controls.
In HFPEF versus healthy controls, peak percent total lean mass (60.1 ± 0.8% vs. 66.6 ± 1.0%, p < .0001) and leg lean mass (57.9 ± 0.9% vs. 63.7 ± 1.1%, p = .0001) were significantly reduced. Peak VO2 was severely reduced including when indexed to leg lean mass (79.3 ± 18.5 vs. 104.3 ± 20.4 ml/kg/min, p < .0001). Peak VO2 was correlated with percent total (r = .51) and leg lean mass (.52, both p < .0001). The slope of the relationship of peak VO2 with percent leg lean mass was markedly reduced in HFPEF (11 ± 5 ml/min) versus healthy controls (36 ± 5 ml/min; p < .001). Short physical performance battery was reduced (9.9 ± 1.4 vs. 11.3 ± 0.8) and correlated with peak VO2 and total and leg lean mass (all p < .001).
Older HFPEF patients have significantly reduced percent total and leg lean mass and physical functional performance compared with healthy controls. The markedly decreased peak VO2 indexed to lean body mass in HFPEF versus healthy controls suggests that abnormalities in skeletal muscle perfusion and/or metabolism contribute to the severe exercise intolerance in older HFPEF patients.
Heart failure （HF） with preserved ejection fraction （HFpEF） is the most common form of HF in older adults, and is increasing in preva- lence as the population ages. Furthermore, HFpEF is increasing ...out of proportion to HF with reduced EF （HFrEF）, and its prognosis is worsening while that of HFrEF is improving. Despite the importance of HFpEF, our understanding of its pathophysiology is incomplete, and optimal treatment remains largely undefined. A cardinal feature of HFpEF is reduced exercise tolerance, which correlates with symptoms as well as reduced quality of life. The traditional concepts of exercise limitations have focused on central dysfimction related to poor cardiac pump function. However, the mechanisms are not exclusive to the heart and lungs, and the understanding of the pathophysiology of this dis- ease has evolved. Substantial attention has focused on defining the central versus peripheral mechanisms underlying the reduced functional capacity and exercise tolerance among patients with HF. In fact, physical training can improve exercise tolerance via peripheral adaptive mechanisms even in the absence of favorable central hemodynamic function. In addition, the drug trials performed to date in HFpEF that have focused on influencing cardiovascular function have not improved exercise capacity. This suggests that peripheral limitations may play a significant role in HF limiting exercise tolerance, a hallmark feature of HFpEF.
Purpose of Review
To discuss the impact of deleterious changes in skeletal muscle morphology and function on exercise intolerance in patients with heart failure with reduced ejection fraction (HFrEF) ...and heart failure with preserved ejection fraction (HFpEF), as well as the utility of exercise training and the potential of novel treatment strategies to preserve or improve skeletal muscle morphology and function.
Recent Findings
Both HFrEF and HFpEF patients exhibit a reduction in percent of type I (oxidative) muscle fibers and oxidative enzymes coupled with abnormal mitochondrial respiration. These skeletal muscle abnormalities contribute to impaired oxidative metabolism with an earlier shift towards glycolytic metabolism during exercise that is strongly associated with exercise intolerance. In both HFrEF and HFpEF patients, peripheral “non-cardiac” factors are important determinants of the improvement in exercise tolerance following aerobic exercise training. Adjunctive strategies that include nutritional supplementation with amino acids and/or anabolic drugs to stimulate anabolic molecular pathways in skeletal muscle show great promise for improving exercise tolerance and treating heart failure-associated sarcopenia, but these efforts remain early in their evolution, with no immediate clinical applications.
Summary
There is consistent evidence that heart failure is associated with multiple skeletal muscle abnormalities which impair oxygen uptake and utilization and contribute greatly to exercise intolerance. Exercise training induces favorable adaptations in skeletal muscle morphology and function that contribute to improvements in exercise tolerance in patients with HFrEF. The contribution of skeletal muscle adaptations to improved exercise tolerance following exercise training in HFpEF remains unknown and warrants further investigation.
Abstract Objectives The aim of this study was to examine skeletal muscle mitochondria content, oxidative capacity, and the expression of key mitochondrial dynamics proteins in patients with heart ...failure with preserved ejection fraction (HFpEF), as well as to determine potential relationships with measures of exercise performance. Background Multiple lines of evidence indicate that severely reduced peak exercise oxygen uptake (peak VO2 ) in older patients with HFpEF is related to abnormal skeletal muscle oxygen utilization. Mitochondria are key regulators of skeletal muscle metabolism; however, little is known about how these organelles are affected in HFpEF. Methods Both vastus lateralis skeletal muscle citrate synthase activity and the expression of porin and regulators of mitochondrial fusion were examined in older patients with HFpEF (n = 20) and healthy, age-matched control subjects (n = 17). Results Compared with age-matched healthy control subjects, mitochondrial content assessed by porin expression was 46% lower (p = 0.01), citrate synthase activity was 29% lower (p = 0.01), and Mfn2 (mitofusin 2) expression was 54% lower (p <0.001) in patients with HFpEF. Expression of porin was significantly positively correlated with both peak VO2 and 6-min walk distance (r = 0.48, p = 0.003 and r = 0.33, p = 0.05, respectively). Expression of Mfn2 was also significantly positively correlated with both peak VO2 and 6-min walk distance (r = 0.40, p = 0.02 and r = 0.37, p = 0.03 respectively). Conclusions These findings suggest that skeletal muscle oxidative capacity, mitochondrial content, and mitochondrial fusion are abnormal in older patients with HFpEF and might contribute to their severe exercise intolerance.
Abstract
Bigaran, A, Howden, EJ, Foulkes, S, Janssens, K, Beaudry, R, Haykowsky, MJ, La Gerche, A, Fraser, SF, and Selig, SE. Prescribing exercise in early-stage breast cancer during chemotherapy: a ...simple periodized approach to align with the cyclic phases of chemotherapy.
J Strength Cond Res
36(10): 2934–2941, 2022—To evaluate whether a periodized aerobic and resistance training plan aligned to the anthracycline chemotherapy (AC) cycles would be well tolerated, feasible, and attenuate the decline in peak oxygen uptake (V̇
o
2
peak) in breast cancer (BC) patients. Twenty-eight women with early-stage BC treated with AC self-selected to undertake exercise training (EX 47 ± 9 years,
n
= 14) or usual care (53 ± 9 years,
n
= 14) for 12 weeks as part of a nonrandomized controlled trial. The periodized EX was aligned to the cyclic phases of AC, including AC taper and nontaper weeks. Outcome measures included cardiopulmonary exercise testing. Attendance and adherence variables (relative dose intensity RDI and volume load) were calculated to quantify the dose of EX completed relative to the amount of EX prescribed. The mean session attendance was 76% (range 46–88%). The mean ±
SD
prescribed and completed dose of aerobic training was 332.3 ± 48.7 MET h·wk
−1
and 380.6 ± 53.2 MET h·wk
−1
(
p
= 0.02), equating to a mean RDI of 89 ± 17%. For resistance training, the prescribed and completed cumulative dose was 128,264 ± 54,578 and 77,487 ± 26,108 kg (
p
< 0.001), equating to an RDI of 60 ± 11%. Adherence to the AC taper week RDI (52 ± 14%) for resistance training was significantly lower than the non-AC taper week (72 ± 8%,
p
= 0.02). The most frequent cause for EX interruption was hospitalization (35%), whereas AC-related illness was the most common cause for missed (57%) or modified EX sessions (64%). This periodized approach was mostly well tolerated for patients with BC. We speculate that a periodized approach may be both more palatable and useful, although this requires further investigation in a randomized controlled trial.
Because doxorubicin (DOX)-containing chemotherapy causes left ventricular (LV) dysfunction and remodeling that can progress to heart failure, strategies to alleviate DOX cardiotoxicity are necessary ...to improve health outcomes of patients surviving cancer. Although clinical evidence suggests that aerobic exercise training (ET) can prevent cardiotoxicity in patients undergoing DOX chemotherapy, the physiological mechanisms involved have not been extensively studied, nor is it known whether compounds such as resveratrol (RESV) have similar beneficial effects. With the use of a murine model of chronic DOX exposure, this study compared the efficacy of modest ET to RESV treatment on exercise performance, LV remodeling, and oxidative stress resistance. Mice were divided into four groups that received saline, DOX (8 mg/kg ip, one time per week), DOX + RESV (4 g/kg diet, ad libitum), and DOX + ET (45 min of treadmill exercise, 5 days/wk) for 8 wk. LV function and morphology were evaluated by in vivo echocardiography. DOX caused adverse LV remodeling that was partially attenuated by modest ET and completely prevented by RESV. These effects were paralleled by improvements in exercise performance. The cardioprotective properties of ET and RESV were associated with reduced levels of atrial natriuretic peptide and the lipid peroxidation by-product, 4-hydroxy-2-nonenal. In addition, ET and RESV increased the expression of cardiac sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a, superoxide dismutase, mitochondrial electron transport chain complexes, and mitofusin-1 and -2 in mice administered DOX. Compared with modest ET, RESV more effectively prevented DOX-induced LV remodeling and was associated with the reduction of DOX-induced oxidative stress. Our findings have important implications for protecting patients against DOX-associated cardiac injury.
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 (V̇o 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.
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, V̇o 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 V̇o 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 V̇o 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 V̇o 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 (V̇o 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.
The aim of this study was to determine the effect of exercise training and type of exercise (aerobic vs. strength vs. combined training) on left ventricular (LV) remodeling in heart failure (HF).
A ...number of randomized controlled trials have examined the effect of exercise training on LV remodeling in individuals with HF. However, the results of these trials have been inconclusive.
The authors searched MEDLINE (1966 to 2006), Cochrane Central Register of Controlled Trials (issue #3, 2006), CINAHL (1982 to 2006), EMBASE (1988 to 2006), PubMed (1966 to 2006), and reference lists of identified studies for randomized controlled trials examining the effects of exercise training on ejection fraction (EF), end-diastolic volume (EDV), and end-systolic volume (ESV) in clinically stable patients with HF. Primary study authors were also contacted if appropriate. Studies were selected and data were extracted independently by 2 reviewers. Weighted mean differences (WMD) were calculated using a random effects model.
Fourteen trials reported EF data (n = 812 patients). Seven trials reported both EDV and ESV data (n = 569). Aerobic training significantly improved EF (9 trials, 538 patients, WMD = 2.59%; 95% confidence interval CI 1.44% to 3.74%), EDV (371 patients; WMD = -11.49 ml; 95% CI -19.95 to -3.02 ml) and ESV (371 patients; WMD = -12.87 ml; 95% CI -17.80 to -7.93 ml). Combined aerobic and strength training was not associated with significant improvements in EF, EDV, or ESV.
Aerobic training reverses LV remodeling in clinically stable individuals with HF. This benefit was not confirmed with combined aerobic and strength training.
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