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ImportanceThe pathophysiology of exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF) remains incompletely understood. Multiple lines of evidence suggest that abnormal skeletal muscle metabolism is a key contributor, but the mechanisms underlying metabolic dysfunction remain unresolved.ObjectiveTo evaluate the associations of skeletal muscle mitochondrial function using respirometric analysis of biopsied muscle fiber bundles from patients with HFpEF with exercise performance.Design, Setting, and ParticipantsIn this cross-sectional study, muscle fiber bundles prepared from fresh vastus lateralis biopsies were analyzed by high-resolution respirometry to provide detailed analyses of mitochondrial oxidative phosphorylation, including maximal capacity and the individual contributions of complex I–linked and complex II-linked respiration. These bioenergetic data were compared between patients with stable chronic HFpEF older than 60 years and age-matched healthy control (HC) participants and analyzed for intergroup differences and associations with exercise performance. All participants were treated at a university referral center, were clinically stable, and were not undergoing regular exercise or diet programs. Data were collected from March 2016 to December 2017, and data were analyzed from November 2020 to May 2021.Main Outcomes and MeasuresSkeletal muscle mitochondrial function, including maximal capacity and respiration linked to complex I and complex II. Exercise performance was assessed by peak exercise oxygen consumption, 6-minute walk distance, and the Short Physical Performance Battery.ResultsOf 72 included patients, 50 (69%) were women, and the mean (SD) age was 69.6 (6.1) years. Skeletal muscle mitochondrial function measures were all markedly lower in skeletal muscle fibers obtained from patients with HFpEF compared with HCs, even when adjusting for age, sex, and body mass index. Maximal capacity was strongly and significantly correlated with peak exercise oxygen consumption (R = 0.69; P R = 0.70; P R = 0.46; P Conclusions and RelevanceIn this study, patients with HFpEF had marked abnormalities in skeletal muscle mitochondrial function. Severely reduced maximal capacity and complex I–linked and complex II–linked respiration were associated with exercise intolerance and represent promising therapeutic targets.

ObjectivesEvaluate neurocognitive health and its response to interventions in older, obese patients with heart failure with preserved ejection fraction (HFpEF).BackgroundNeurocognitive dysfunction may be an underrecognized feature of HFpEF that responds to weight-loss interventions.MethodsWe first compared detailed baseline cognitive testing (Uniform Data Set version 3 and Rey Auditory Verbal Learning Test [RAVLT]), and brain volumes and cerebral blood flow (CBF) from 3T magnetic resonance imaging between older patients with HFpEF (n=46) and healthy age-matched controls (HC; n=22). The HFpEF patients were then randomized to a 20-week caloric restriction (CR) intervention with either aerobic-only (CR+AT; n=23) or aerobic+resistance exercise training (CR+AT+RT; n=23), and repeated cognitive testing and neuroimaging post-intervention. Cognitive scores were normalized to national data and transformed toz-scores for global, memory, attention, executive function, visuospatial, and language fluency domains.ResultsCompared to HC, participants with HFpEF had significantly lower baseline global cognitive performance, and lower global, visuospatial processing and language fluency domainz-scores than normative means. Following the diet and exercise intervention, there were significant improvements in global (+0.6 [95% CI: 0.3, 0.8]) and category fluency (+0.2 [95% CI: −0.004, 0.3])z-scores, and in RAVLT immediate (+0.6 [95% CI: 0.1, 1.0] points) and delayed (0.9 [95% CI: 0.2, 1.6] points) recall. Only CR+AT+RT was associated with improved phonemic fluency z-score (+0.4 [95% CI: 0.1, 0.7]). There were no significant intervention effects on brain volumes or CBF.ConclusionsOlder, obese patients with chronic HFpEF have significant cognitive deficits that are ameliorated by diet and exercise interventions.

Intermediate endpoints are needed to evaluate the effect of interventions targeting the biology of aging in clinical trials. A working group identified five blood-based biomarkers that may serve such a purpose as an integrated index. We evaluated the responsiveness of the panel to caloric restriction or aerobic exercise in the context of a randomized clinical trial conducted in patients with heart failure with preserved ejection fraction (HFpEF) with obese phenotype who were predominantly female. Obese HFpEF is highly prevalent in women, and is a geriatric syndrome whose disease pathology is driven by non-cardiac factors and shared drivers of aging. We measured serum Interleukin-6, TNF-α-receptor-I, growth differentiating factor-15, cystatin C, and N-terminal pro-b-type natriuretic peptide at baseline and after 20 weeks in older participants with stable obese HFpEF participating in a randomized, controlled, 2 × 2 factorial trial of caloric restriction and/or aerobic exercise. We calculated a composite biomarker index, summing baseline quintile scores for each biomarker, and analyzed the effect of the interventions on the index and individual biomarkers and their associations with changes in physical performance. This post hoc analysis included 88 randomized participants (71 women [81%]). The mean ± SD age was 66.6 ± 5.3 years, and body mass index (BMI) was 39.3 ± 6.3 kg/m(2). Using mixed models, mean values of the biomarker index improved over 20 weeks with caloric restriction (− 0.82 [Formula: see text] 0.58 points, p = 0.05), but not with exercise (− 0.28 [Formula: see text] 0.59 points, p = [Formula: see text] ), with no evidence of an interaction effect of CR [Formula: see text] EX [Formula: see text] time (p = 0.80) with adjustment for age, gender, and BMI. At baseline, the biomarker index was inversely correlated with 6-min walk distance, scores on the short physical performance battery, treadmill test peak workload and exercise time to exhaustion (all [Formula: see text] (s) = between − 0.21 and − 0.24). A reduction in the biomarker index was also associated with increased 4-m usual walk speed ([Formula: see text] (s) = − 0.31). Among older patients with chronic obese HFpEF, caloric restriction improved a biomarker index designed to reflect biological aging. Moreover, the index was associated with physical performance and exercise tolerance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-021-00509-9.

OBJECTIVE Patients with type 2 diabetes are encouraged to lose weight, but excessive weight loss in older adults may be a marker of poor health and subsequent mortality. We examined weight change during the postintervention period of Look AHEAD, a randomized trial comparing intensive lifestyle intervention (ILI) with diabetes support and education (DSE) (control) in overweight/obese individuals with type 2 diabetes and sought to identify predictors of excessive postintervention weight loss and its association with mortality. RESEARCH DESIGN AND METHODS These secondary analyses compared postintervention weight change (year 8 to final visit; median 16 years) in ILI and DSE in 3,999 Look AHEAD participants. Using empirically derived trajectory categories, we compared four subgroups: weight gainers (n = 307), weight stable (n = 1,561), steady losers (n = 1,731), and steep losers (n = 380), on postintervention mortality, demographic variables, and health status at randomization and year 8. RESULTS Postintervention weight change averaged −3.7 ± 9.5%, with greater weight loss in the DSE than the ILI group. The steep weight loss trajectory subgroup lost on average 17.7 ± 6.6%; 30% of steep losers died during postintervention follow-up versus 10–18% in other trajectories (P < 0001). The following variables distinguished steep losers from weight stable: baseline, older, longer diabetes duration, higher BMI, and greater multimorbidity; intervention, randomization to control group and less weight loss in years 1–8; and year 8, higher prevalence of frailty, multimorbidity, and depressive symptoms and lower use of weight control strategies. CONCLUSIONS Steep weight loss postintervention was associated with increased risk of mortality. Older individuals with longer duration of diabetes and multimorbidity should be monitored for excessive unintentional weight loss.

COVID-19 public health recommendations have prohibited many older adults from attending in-person physical activity (PA) programs that improve physical function and promote functional independence. Most PA programs have shifted towards a video conference (VC) format, but this modality has been noted to “flatten” the social experience which is fundamental for lasting behavior change. Virtual reality (VR) is now designed for immersion and place-presence and may be better suited for instilling a feeling of social connection, which will likely improve physical function. The purpose of this study was to evaluate differences in physical function after a 4-week in-home VR or VC based PA intervention. Low-active adults (66.8±4.8 years) were randomized to VR (n=5) or VC (n=4) based PA counselling and instructed to find activities that were intrinsically motivating. VR participants were asked to select pre-approved available active games in addition to enjoyable real-world activities. ANCOVA models were used to explore group differences in six-minute walk distances across time. Results are reported using η^2 effect sizes based on the small sample size. After controlling for baseline values, the ANCOVA models revealed a moderate-to-large magnitude effect for distance traveled during the six-minute walk test (η^2=.10). Additionally, the VR group participants walked 42.63 meters further, which approaches a clinically meaningful difference. These promising early findings suggest there is value to exploring the impact of VR-delivered, group-mediated activity promotion on physical functioning in older adults. Future research should investigate aspects of VR that promote increased social connection and physical function in the older adult population.