Physical Activity Is Positively Associated with Episodic Memory in Aging.

Aging is associated with performance reductions in executive function and episodic memory, although there is substantial individual variability in cognition among older adults. One factor that may be positively associated with cognition in aging is physical activity. To date, few studies have objectively assessed physical activity in young and older adults, and examined whether physical activity is differentially associated with cognition in aging. Young (n=29, age 18-31 years) and older adults (n=31, ages 55-82 years) completed standardized neuropsychological testing to assess executive function and episodic memory capacities. An experimental face-name relational memory task was administered to augment assessment of episodic memory. Physical activity (total step count and step rate) was objectively assessed using an accelerometer, and hierarchical regressions were used to evaluate relationships between cognition and physical activity. Older adults performed more poorly on tasks of executive function and episodic memory. Physical activity was positively associated with a composite measure of visual episodic memory and face-name memory accuracy in older adults. Physical activity associations with cognition were independent of sedentary behavior, which was negatively correlated with memory performance. Physical activity was not associated with cognitive performance in younger adults. Physical activity is positively associated with episodic memory performance in aging. The relationship appears to be strongest for face-name relational memory and visual episodic memory, likely attributable to the fact that these tasks make strong demands on the hippocampus. The results suggest that physical activity relates to cognition in older, but not younger adults.

Analysis of skeletal muscle gene expression patterns and the impact of functional capacity in patients with systolic heart failure.

BACKGROUND: Declining physical function is common among systolic heart failure (HF) patients and heralds poor clinical outcomes. We hypothesized that coordinated shifts in expression of ubiquitin-mediated atrophy-promoting genes are associated with muscle atrophy and contribute to decreased physical function. METHODS: Systolic HF patients (left ventricular ejection fraction [LVEF] ≤40%) underwent skeletal muscle biopsies (nondominant vastus lateralis) and comprehensive physical assessments. Skeletal muscle gene expression was assessed with the use of real-time polymerase chain reaction. Aerobic function was assessed with the use of cardiopulmonary exercise and 6-minute walk tests. Strength capacity was assessed with the use of pneumatic leg press (maximum strength and power). Serologic inflammatory markers also were assessed. RESULTS: 54 male patients (66.6 ± 10.0 years) were studied: 24 systolic HF patients (mean LVEF 28.9 ± 7.8%) and 30 age-matched control subjects. Aerobic and strength parameters were diminished in HF versus control. FoxO1 and FoxO3 were increased in HF versus control (7.9 ± 6.2 vs 5.0 ± 3.5, 6.5 ± 4.3 vs 4.3 ± 2.8 relative units, respectively; P ≤ .05 in both). However, atrogin-1 and MuRF-1 were similar in both groups. PGC-1α was also increased in HF (7.9 ± 5.4 vs. 5.3 ± 3.6 relative units; P < .05). Muscle levels of insulin-like growth factor (IGF) 1 as well as serum levels of tumor necrosis factor α, C-reactive protein, interleukin (IL) 1ß, and IL-6 were similar in HF and control. CONCLUSION: Expression of the atrophy-promoting genes FoxO1 and FoxO3 were increased in skeletal muscle in systolic HF compared with control, but other atrophy gene expression patterns (atrogin-1 and MuRF-1), as well as growth promoting patterns (IGF-1), were similar. PGC-1α, a gene critical in enhancing mitochondrial function and moderating FoxO activity, may play an important counterregulatory role to offset ubiquitin pathway-mediated functional decrements.

Modified Application of Cardiac Rehabilitation in Older Adults (MACRO) Trial: Protocol changes in a pragmatic multi-site randomized controlled trial in response to the COVID-19 pandemic.

BACKGROUND: Older adults are at higher risk for cardiovascular disease and functional decline, often leading to deterioration and dependency. Cardiac rehabilitation (CR) provides opportunity to improve clinical and functional recovery, yet participation in CR decreases with age. Modified Application of CR in Older Adults (MACRO) is a National Institute on Aging (NIA)-funded pragmatic trial that responds to this gap by aiming to increase enrollment of older adults into CR and improving functional outcomes. This article describes the methodology and novel features of the MACRO trial. METHODS: Randomized, controlled trial of a coaching intervention (MACRO-I) vs. usual care for older adults (age ≥ 70 years) eligible for CR after an incident cardiac hospitalization. MACRO-I incorporates innovations including holistic risk assessments, flexible CR format (i.e., helping patients to select a CR design that aligns with their personal risks and preferences), motivational prompts, nutritional emphasis, facilitated deprescription, enhanced education, and home visits. Key modifications were necessitated by the COVID-19 pandemic, including switching from a performance-based primary endpoint (Short Physical Performance Battery) to a patient-reported measure (Activity Measure for Post-Acute Care Computerized Adaptive Testing). Changes prompted by COVID-19 maintain the original intent of the trial and provide key methodologic advantages. CONCLUSIONS: MACRO is exploring a novel individualized coaching intervention to better enable older patients to participate in CR. Due to COVID-19 many aspects of the MACRO protocol required modification, but the primary objective of the trial is maintained and the updated protocol will more effectively achieve the original goals of the study.

Differences in Comorbid Conditions Among Older Adult Participants in Cardiac Rehabilitation.

PURPOSE: Most older adults eligible for cardiac rehabilitation (CR) do not participate or participate with low frequency, although it is a standard of care for patients with cardiovascular disease (CVD). Identifying the barriers to older adult participation is key in improving CR efficacy. METHODS: A range of patient characteristics was analyzed in relation to on-site frequency of participation in a CR program by older adult patients. These characteristics included demographics and indications for referral, as well as CVD and non-CVD diagnoses. The prevalence of these characteristics was compared among three patient cohorts, ranging from high contact frequency to minimal contact frequency of on-site participation in CR. RESULTS: Among the three participation frequency cohorts, no differences were noted in demographic factors, indications for referral, or CVD diagnoses. However, patients with hearing impairment (OR = 4.15: 95% CI, 1.32-13.08) or visual impairment (OR = 4.11: 95% CI, 1.46-11.59) at time of enrollment were more likely to be found in the minimal contact cohorts than the moderate or high contact frequency cohorts. CONCLUSIONS: Whereas differences in CVD had little bearing on frequency of CR participation in older patients, differences in hearing and visual impairment varied significantly. Patients with hearing and vision impairments attended less frequently. Sensory impairment has previously been demonstrated to impact health care utilization by older adults, but is rarely considered in the treatment of CVD or CR. As sensory impairments are extremely prevalent among geriatric patients, further study of these potential barriers to care might open possibilities for older adult participation in CR.

Cardiac Rehabilitation Is Associated With Improved Physical Function in Frail Older Adults With Cardiovascular Disease.

PURPOSE: Frailty is highly prevalent among older adults with cardiovascular disease (CVD) and is associated with greater than 2-fold risk for morbidity and mortality, independent of age and comorbidities. Many candidates are not referred to cardiac rehabilitation (CR) under the assumption that they are too frail to benefit. We hypothesized that CR is associated with similar benefits for frail adults as for intermediate-frail and nonfrail adults. METHODS: Retrospective analysis of CVD patients who completed a phase II CR program. Patients classified as frail by meeting ≥2 frailty criteria and intermediate-frail by meeting 1 criterion, including 6-min walk distance (6MWD) <300 m, gait speed ≤0.65 m/sec or 0.76 m/sec normalized to height and sex, tandem stand <10 sec, Timed Up & Go (TUG) <15 sec, and weak hand grip strength per Fried criteria. Changes within and between groups were compared before and after completion of CR. RESULTS: We evaluated 243 patients; 75 were classified as frail, 70 as intermediate-frail, and 98 as nonfrail. Each group improved in all measures of frailty except for tandem stand. There were no significant differences in pre- to post-CR measures for 6MWD, gait speed, tandem stand, or hand grip strength between groups. Frail patients showed greater improvement in TUG than the other groups (P = .007). CONCLUSION: Among frail patients, CR was associated with improvements in multiple domains of physical function. Gains achieved by frail adults were similar to or greater than those achieved by intermediate-frail and nonfrail patients. These data provide strong rationale for referring all eligible patients to CR, including frail patients. Those who are most physically impaired may derive gains that have proportionally greater ramifications.

Enhancing Functional Risk Stratification in Contemporary Cardiac Rehabilitation: RESPONDING TO PATIENTS WHO ARE INCREASINGLY OLDER AND MORE PHYSICALLY IMPAIRED.

PURPOSE: Current American Association of Cardiovascular and Pulmonary Rehabilitation guidelines rely primarily on cardiovascular disease (CVD)-centered metrics to stratify risk and guide care. Yet, contemporary CVD patients are often older and are more likely to have risks attributable to rudimentary functional impairments that can have disproportionate bearing on management and prognosis. In this study, we stratified risk using novel indices of physical function as well as traditional indices of CVD in patients enrolling in phase II cardiac rehabilitation (CR). We hypothesized that risk stratification (RS) using functional criteria would be nonconcordant with CVD RS in a significant number of patients, thus inferring the conceptual value of CR management priorities that are better tailored for distinctive functional risks in many patients. METHODS: This was a retrospective analysis of a comprehensive quality improvement database with 489 patients. Risk stratification using novel functional indices (ie, gait speed, Timed Up and Go, hand grip, sit to stand, tandem stand, and a 6-min walk test) was compared with RS using traditional CVD criteria. RESULTS: Using functional RS, 97 patients were determined to be high risk versus 235 at low risk. Using CVD RS in the same cohort, 227 patients had high risk versus 161 who had low risk. Functional RS was consistent with CVD RS only 42.9% of the time. CONCLUSION: Functional RS and CVD RS varied in the same patients. Enhanced assessment of functional risks adds important prognostic refinement and greater potential to tailor exercise therapy, nutrition, and other CR caregiving priorities.

Effects of Home-Based Cardiac Rehabilitation on Time to Enrollment and Functional Status in Patients With Ischemic Heart Disease.

Background Cardiac rehabilitation is an established performance measure for adults with ischemic heart disease, but patient participation is remarkably low. Home-based cardiac rehabilitation (HBCR) may be more practical and feasible, but evidence regarding its efficacy is limited. We sought to compare the effects of HBCR versus facility-based cardiac rehabilitation (FBCR) on functional status in patients with ischemic heart disease. Methods and Results This was a pragmatic trial of 237 selected patients with a recent ischemic heart disease event, who enrolled in HBCR or FBCR between August 2015 and September 2017. The primary outcome was 3-month change in distance completed on a 6-minute walk test. Secondary outcomes included rehospitalization as well as patient-reported physical activity, quality of life, and self-efficacy. Characteristics of the 116 patients enrolled in FBCR and 121 enrolled in HBCR were similar, except the mean time from index event to enrollment was shorter for HBCR (25 versus 77 days; P<0.001). As compared with patients undergoing FBCR, those in HBCR achieved greater 3-month gains in 6-minute walk test distance (+95 versus +41 m; P<0.001). After adjusting for demographics, comorbid conditions, and indication, the mean change in 6-minute walk test distance remained significantly greater for patients enrolled in HBCR (+101 versus +40 m; P<0.001). HBCR participants reported greater improvements in quality of life and physical activity but less improvement in exercise self-efficacy. There were no deaths or cardiovascular hospitalizations. Conclusions Patients enrolled in HBCR achieved greater 3-month functional gains than those enrolled in FBCR. Our data suggest that HBCR may safely derive equivalent benefits in exercise capacity and overall program efficacy in selected patients. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT02105246.

Self-Efficacy for Adoption and Maintenance of Exercise Among Fibromyalgia Patients: A Pilot Study.

Objective. While multimodal treatment approaches for fibromyalgia (FM), incorporating exercise, have been found most effective, information about factors associated with exercise adoption and maintenance is lacking. Design, Setting, and Methods. Women veterans with FM (N = 19) completed an anonymous Internet survey measuring FM impact (FI), adoption of exercise behavior, and self-efficacy for exercise. Using classifications of behavior specified by the transtheoretical model, the self-efficacy of participants classified in the action or maintenance (AM) stages was compared with those in earlier stages (precontemplation through preparation) of exercise readiness. Multivariate analysis of variance analyses examined differences in FI domains by stage of change. Analysis of covariance examined whether exercise self-efficacy differed by stage of change while controlling for FI. Results. Higher levels of self-efficacy were detected among participants in the AM stages. Participants in the AM stages also reported higher levels of FI symptoms. After controlling for FI, self-efficacy did not differ significantly between the 2 groups; however the effect size was large (η2 = .11). Conclusions. Findings of this pilot study suggest a role for self-efficacy in exercise adoption and maintenance, even in the setting of higher FM symptoms. Replication of this study with a larger sample size is warranted.

Rapid Transition to Telehealth Group Exercise and Functional Assessments in Response to COVID-19.

Exercise is critical for health maintenance in late life. The COVID-19 shelter in place and social distancing orders resulted in wide-scale interruptions of exercise therapies, placing older adults at risk for the consequences of decreased mobilization. The purpose of this paper is to describe rapid transition of the Gerofit facility-based group exercise program to telehealth delivery. This Gerofit-to-Home (GTH) program continued with group-based synchronous exercise classes that ranged from 1 to 24 Veterans per class and 1 to 9 classes offered per week in the different locations. Three hundred and eight of 1149 (27%) Veterans active in the Gerofit facility-based programs made the transition to the telehealth delivered classes. Participants' physical performance testing continued remotely as scheduled with comparisons between most recent facility-based and remote testing suggesting that participants retained physical function. Detailed protocols for remote physical performance testing and sample exercise routines are described. Translation to remote delivery of exercise programs for older adults could mitigate negative health effects.

A Qualitative Study of Participation in Cardiac Rehabilitation Programs in an Integrated Health Care System.

INTRODUCTION: Despite strong incentives to use cardiac rehabilitation (CR), patient participation is low in the Veterans Health Administration (VHA). This is paradoxical given that VHA is an integrated health care system that offers a range of CR programs which should logically reduce barriers to access to CR participation. The purpose of this study was to better understand the contextual factors that influence patient participation in CR and how patients consider factors together when making decisions about CR participation. MATERIALS AND METHODS: Using a qualitative study design we examined patient and provider perceptions of CR across six VHA medical centers with high- and low-enrollment rates between December 2014 and October 2015. We conducted semistructured interviews with CR eligible patients who had both enrolled and not enrolled in CR (n = 16), cardiology providers who could refer patients to CR and CR staff who provided CR services (n = 15). Data were analyzed using grounded thematic techniques. RESULTS: We identified program and patient-specific factors related to CR participation. The four program factors were: program responsiveness to patient needs, CR schedule, specialized CR program equipment, and the CR program social environment. Program factors were primarily discussed by individuals associated with sites that had high CR enrollment rates. The patient-specific factor that promoted participation was patient perceptions of CR benefits. Disincentives to participation included competing conditions or obligations, logistical/cost challenges, convenience, and fear of exercise. CR participation entailed a complex process in which patients balanced factors that reinforced patient perceptions that CR was beneficial against factors that acted as disincentives to participation. CONCLUSIONS: CR participation was influenced by both program and patient factors. Patients weighed factors that fostered perceptions that CR was beneficial against factors that served as disincentives to CR participation when considering CR participation. High-enrollment sites may be better at countering disincentives to participate and/or improve patient perceptions of CR. Actionable ways to improve CR participation include encouraging providers to strongly and frequently endorse CR, educating patients about the importance and benefits of CR, emphasizing how exercises are individualized, supervised and monitored, educating patients about how CR is safe and effective, how CR offers peer support, and structuring CR programs to be responsive to patient needs in terms of duration, frequency, schedule, and location.

Factors Associated With Utilization of Cardiac Rehabilitation Among Patients With Ischemic Heart Disease in the Veterans Health Administration: A QUALITATIVE STUDY.

BACKGROUND: Cardiac rehabilitation (CR) programs reduce morbidity and mortality in patients with ischemic heart disease but are vastly underutilized in the United States, including the Veterans Health Administration (VA) Healthcare System. Numerous barriers affecting utilization have been identified in other health care systems, but the specific factors affecting Veterans are unknown. We sought to identify barriers and facilitators associated with utilization of CR in VA facilities. METHODS: We performed a qualitative study of 56 VA patients, providers, and CR program managers at 30 VA facilities across the United States. We conducted semistructured interviews with key informants to explore their attitudes and knowledge toward CR. Interviews were conducted until thematic saturation occurred. Analyses using grounded theory to identify key themes were conducted using the qualitative data analysis package ATLAS.ti. RESULTS: We identified 6 themes as barriers and 5 as facilitators. The most common barriers to participation in CR were patient transportation issues (68%), lack of patient willingness to participate (41%), and no access to a nearby VA hospital with a CR program (30%). The most common facilitators were involvement of a dedicated provider or "clinical champion" (50%), provider knowledge of or experience with CR (48%), and patient desire for additional medical support (32%). CONCLUSIONS: Our findings suggest that addressing access issues and educating and activating providers on CR may increase utilization of CR programs. Targeting these specific factors may improve utilization of CR programs.

Potential neurobiological benefits of exercise in chronic pain and posttraumatic stress disorder: Pilot study.

This pilot study assessed the effects of cardiopulmonary exercise testing and cardiorespiratory fitness on plasma neuropeptide Y (NPY), allopregnanolone and pregnanolone (ALLO), cortisol, and dehydroepiandrosterone (DHEA), and their association with pain sensitivity. Medication-free trauma-exposed participants were either healthy (n = 7) or experiencing comorbid chronic pain/posttraumatic stress disorder (PTSD) (n = 5). Peak oxygen consumption (VO2) during exercise testing was used to characterize cardiorespiratory fitness. Peak VO2 correlated with baseline and peak NPY levels (r = 0.66, p < 0.05 and r = 0.69, p < 0.05, respectively), as well as exercise-induced changes in ALLO (r = 0.89, p < 0.001) and peak ALLO levels (r = 0.71, p < 0.01). NPY levels at the peak of exercise correlated with pain threshold 30 min after exercise (r = 0.65, p < 0.05), while exercise-induced increases in ALLO correlated with pain tolerance 30 min after exercise (r = 0.64, p < 0.05). In contrast, exercise-induced changes in cortisol and DHEA levels were inversely correlated with pain tolerance after exercise (r = -0.69, p < 0.05 and r = -0.58, p < 0.05, respectively). These data suggest that cardiorespiratory fitness is associated with higher plasma NPY levels and increased ALLO responses to exercise, which in turn relate to pain sensitivity. Future work will examine whether progressive exercise training increases cardiorespiratory fitness in association with increases in NPY and ALLO and reductions in pain sensitivity in chronic pain patients with PTSD.

Utility and efficacy of a smartphone application to enhance the learning and behavior goals of traditional cardiac rehabilitation: a feasibility study.

PURPOSE: Most eligible patients do not participate in traditional clinic-based cardiac rehabilitation (CR) despite well-established benefits. Novel approaches to overcome logistic obstacles and increase efficiencies of learning, behavior modification, and exercise surveillance may increase CR participation. In an observational study, the feasibility and utility of a mobile smartphone application for CR, Heart Coach (HC), were assessed as part of standard care. Ultimately, innovative CR models incorporating HC may facilitate better CR usage and value. METHODS: Twenty-six patients enrolled in CR installed HC. Over the next 30 days, they were prompted by HC to complete a daily "task list" that included medications, walking, education (text and videos), and surveys. Cardiac rehabilitation providers monitored each patient's progress through a HC-based Web dashboard and also sent them personalized feedback and support. Completion of the tasks and feedback (qualitative and quantitative) from patients and clinicians were tracked. RESULTS: Patients engaged with HC 90% of days during the study period, with uniformly favorable impact on compliance and adherence. Eighty-three percent of patients reported a positive/very positive HC experience. Providers reported that HC enhanced their provision of therapy by improving communication, clinical insight, patient participation, and program efficiency. CONCLUSIONS: Integrating a mobile care delivery platform into CR was feasible, safe, and agreeable to patients and clinicians. It enhanced patient perceptions of CR care and physician perceptions of the CR caregiving process. Mobile-enabled technologies hold promise to extend the quality and reach of CR, and to better achieve contemporary accountable care goals.

Dynamic assessment of ventilatory efficiency during recovery from peak exercise to enhance cardiopulmonary exercise testing.

BACKGROUND: While cardiopulmonary exercise testing (CPX) assessment is generally regarded as an optimal means to assess functional capacity in heart failure (HF) patients, strength parameters are omitted. CPX indices collected in recovery may provide additional insight regarding function, including strength. DESIGN AND METHODS: We performed a cross-sectional controlled study. Systolic HF patients (aged ≥ 50 years) and age-matched controls were assessed using CPX and strength evaluations. Standard CPX indices were assessed during exercise (peak oxygen consumption [VO2], first ventilatory threshold [1stVT], and ventilatory efficiency [VE/VCO2 slope]) as well as indices at 1-minute recovery (1 min VO2, 1 min VE/VCO2, and 1 min heart rate recovery [HRR]) and differences between peak and 1-minute recovery (ΔVO2 and ΔVE/VCO2). Lower extremity strength was evaluated using the 1-repetition maximum (1RM) and power. RESULTS: Seventy adults (31 HF; 39 controls), mean age 66.2 ± 9.7 years were evaluated. Peak VO2 (15.4 ± 4.2 versus 23.4 ± 6.6 mlO2·kg(-1)·min(-1), p < 0.0001) and 1stVT (10.9 ± 2.1 versus 14.4 ± 4.0 mlO2·kg(-1)·min(-1), p < 0.0001) were diminished in HF versus controls and VE/VCO2 slope was increased (42.3 ± 12.2 versus 35.4 ± 8.3, p < 0.01). HF patients had reduced 1 minVO2 (13.1 ± 2.9 versus 16.3 ± 3.7 mlO2·kg(-1)·min(-1), p < 0.0001), 1 min HRR (6.7 ± 11.4 versus 12.4 ± 7.6 beats, p < 0.02), and ΔVO2 (2.43 ± 2.3 versus 7.3 ± 5.0 mlO2·kg(-1)·min(-1), p < 0.0001) as well as increased 1 min VE/VCO2 (37 ± 7.5 versus 31.5 ± 4.4, p < 0.001) and ΔVE/VCO2 (1.17 ± 3.0 versus -0.5 ± 1.3, p < 0.0001). Strength parameters were relatively lower in HF. While CPX exercise parameters correlated with strength, stronger correlations were observed between CPX recovery parameters and strength. CONCLUSIONS: CPX recovery indices corroborate disease-specific aerobic differences and distinguish differences in strength. Recovery ventilatory efficiency enhances CPX's value as a comprehensive physical function tool.

Adiposity facilitates increased strength capacity in heart failure patients with reduced ejection fraction.

BACKGROUND: Obesity is associated with relatively improved prognosis among heart failure (HF) patients. Mechanisms explaining this so-called "obesity paradox" have been unclear. We hypothesized that increased adiposity may contribute to increased strength capacity, and may thereby facilitate clinical benefits. METHODS AND RESULTS: In a controlled, cross-sectional study, adults aged ≥ 50 years with HF with reduced ejection fraction (HFREF) (LVEF ≤ 40%) were compared to age matched controls. Body composition was determined by dual-energy X-ray absorptiometry (DXA). Aerobic (cardiopulmonary exercise testing), maximum strength (one repetition maximum [1RM]), and power (submaximal resistance/time) were assessed. 70 adults (31 HFREF, 39 controls; mean age 66.2 ± 9.6 years) were studied. Peak oxygen consumption (VO2) (15.4 ± 4.2 vs. 23.4 ± 6.6 ml O2 · kg(-1) · min(-1), p<0.0001), 1RM (154.8 ± 52.0 vs. 195.3 ± 56.8 kg, p<0.01) and power (226.4 ± 99.2 vs. 313.3 ± 130.6, p<0.01) were lower in HFREF vs. controls. 1 RM correlated with total fat (r=0.56, p<0.01), leg fat (r=0.45, p<0.05) and arm fat (r=0.39, p<0.05) in HFREF. Moreover, among HFREF patients with a high (≥ 30 kg/m(2)) body mass index (BMI), 1RM and fat mass were significantly greater than those with lower (<30 kg/m(2)) BMIs. Correlations between 1 RM and total fat (r=0.65, p<0.05) and leg fat (r=0.64, p<0.05) were particularly notable in the high BMI subgroup. CONCLUSION: Increased adiposity correlates with relatively greater strength in HFREF patients which may explain some of the clinical benefits that result from obesity.

Expression of the irisin precursor FNDC5 in skeletal muscle correlates with aerobic exercise performance in patients with heart failure.

BACKGROUND: Exercise-induced increase in peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression has been shown to increase the expression of the fibronectin type III domain containing 5 (FNDC5) gene and thereby its product, irisin, in mice. Given that exercise intolerance is a hallmark characteristic of heart failure (HF), and because PGC-1α and irisin promote exercise benefits in animals, we hypothesized that expression of these genes relates to aerobic performance in patients with HF. METHODS AND RESULTS: Systolic HF (left ventricular ejection fraction ≤40%) patients underwent cardiopulmonary exercise testing to evaluate aerobic performance. High versus low aerobic performance was assessed using oxygen consumption (peak Vo(2) [>14 versus ≤14 mL O(2)·kg(-1)·min(-1)]) and ventilatory efficiency (VE/Vco(2) slope [<34 versus ≥34]). Muscle biopsies of the vastus lateralis and real-time polymerase chain reaction were used to quantify muscle gene expression. Twenty-four patients were studied. FNDC5 (5.7±3.5 versus 3.1±1.2, P<0.05) and PGC-1α (9.9±5.9 versus 4.5±1.9, P<0.01) gene expressions were greater in the high-peak Vo(2) group; correlation between FNDC5 and PGC-1α was significant (r=0.56, P<0.05) only in the high-peak Vo(2) group. Similarly, FNDC5 and PGC-1α gene expression was greater in the high-performance group based on lower VE/Vco(2) slopes (5.8±3.6 versus 3.3±1.4, P<0.05 and 9.7±6 versus 5.3±3.4, P<0.05); FNDC5 also correlated with PGC-1α (r=0.55, P<0.05) only in the low VE/Vco(2) slope group. CONCLUSIONS: This is the first study to show that FNDC5 expression relates to functional capacity in a human HF population. Lower FNDC5 expression may underlie reduced aerobic performance in HF patients.