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The burgeoning population of older adults is intrinsically prone to cardiovascular disease (CVD) in a context of multimorbidity and geriatric syndromes. Risks include high susceptibility to functional decline, with many older adults tipping towards patterns of sedentary behavior and to downstream effects of frailty, falls, disability, poor quality of life, as well as increased morbidity and mortality even if the incident CVD was treated perfectly. While physical activity has been shown to moderate these patterns both as primary or secondary preventive medical care, the majority of older adults fail to meet physical activity recommendations. Clinicians of all specialities, including CVD medicine, can benefit from greater proficiency in functional assessments for their older adults, as well as from insights how to initiate effective functional enhancing approaches even in older adults who may be frail, deconditioned, and medically complex. Pertinent functional assessments include traditional cardiovascular metrics of cardiorespiratory fitness, as well as strength and balance. This review summarizes the components of a wide‐ranging functional assessment that can be used to enhance care for older adults with CVD, as well as interventions to improve physical function.

Fatty acid transport from blood vessels to skeletal muscle, across endothelial cells, is regulated by the branched chain amino acid metabolite 3-hydroxy-isobutyrate. This finding provides a mechanistic explanation for the link between high levels of branched chain amino acids and diabetes. Epidemiological and experimental data implicate branched-chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms that underlie this link remain unclear 1 , 2 , 3 . Insulin resistance in skeletal muscle stems from the excess accumulation of lipid species 4 , a process that requires blood-borne lipids to initially traverse the blood vessel wall. How this trans-endothelial transport occurs and how it is regulated are not well understood. Here we leveraged PPARGC1a (also known as PGC-1α; encoded by Ppargc1a ), a transcriptional coactivator that regulates broad programs of fatty acid consumption, to identify 3-hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a new paracrine regulator of trans-endothelial fatty acid transport. We found that 3-HIB is secreted from muscle cells, activates endothelial fatty acid transport, stimulates muscle fatty acid uptake in vivo and promotes lipid accumulation in muscle, leading to insulin resistance in mice. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the ability of PGC-1α to promote endothelial fatty acid uptake. 3-HIB levels are elevated in muscle from db/db mice with diabetes and from human subjects with diabetes, as compared to those without diabetes. These data unveil a mechanism in which the metabolite 3-HIB, by regulating the trans-endothelial flux of fatty acids, links the regulation of fatty acid flux to BCAA catabolism, providing a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes.

Non-invasive cardiac imaging allows detection of cardiac amyloidosis (CA) in patients with aortic stenosis (AS). Our objective was to estimate the prevalence of clinically suspected CA in patients with moderate and severe AS referred for cardiovascular magnetic resonance (CMR) in age and gender categories, and assess associations between AS-CA and all-cause mortality. We retrospectively identified consecutive AS patients defined by echocardiography referred for further CMR assessment of valvular, myocardial, and aortic disease. CMR identified CA based on typical late-gadolinium enhancement (LGE) patterns, and ancillary clinical evaluation identified suspected CA. Survival analysis with the Log rank test and Cox regression compared associations between CA and mortality. There were 113 patients (median age 74 years, Q1-Q3: 62–82 years), 96 (85%) with severe AS. Suspected CA was present in 9 patients (8%) all > 80 years. Among those over the median age of 74 years, the prevalence of CA was 9/57 (16%), and excluding women, the prevalence was 8/25 (32%). Low-flow, low-gradient physiology was very common in CA (7/9 patients or 78%). Over a median follow-up of 18 months, 40 deaths (35%) occurred. Mortality in AS + CA patients was higher than AS alone (56% vs. 20% at 1-year, log rank 15.0, P < 0.0001). Adjusting for aortic valve replacement modeled as a time-dependent covariate, Society of Thoracic Surgery predicted risk of mortality, left ventricular ejection fraction, CA remained associated with all-cause mortality (HR = 2.92, 95% CI = 1.09–7.86, P = 0.03). Suspected CA appears prevalent among older male patients with AS, especially with low flow, low gradient AS, and associates with all-cause mortality. The importance of screening for CA in older AS patients and optimal treatment strategies in those with CA warrant further investigation, especially in the era of transcatheter aortic valve implantation.

To determine the impact of cardiorespiratory fitness (FIT) on survival in relation to the obesity paradox in patients with systolic heart failure (HF). We studied 2066 patients with systolic HF (body mass index [BMI] ≥18.5 kg/m2) between April 1, 1993 and May 11, 2011 (with 1784 [86%] tested after January 31, 2000) from a multicenter cardiopulmonary exercise testing database who were followed for up to 5 years (mean ± SD, 25.0±17.5 months) to determine the impact of FIT (peak oxygen consumption <14 vs ≥14 mL O2 ∙ kg−1 ∙ min−1) on the obesity paradox. There were 212 deaths during follow-up (annual mortality, 4.5%). In patients with low FIT, annual mortality was 8.2% compared with 2.8% in those with high FIT (P<.001). After adjusting for age and sex, BMI was a significant predictor of survival in the low FIT subgroup when expressed as a continuous (P=.03) and dichotomous (<25.0 vs ≥25.0 kg/m2) (P=.01) variable. Continuous and dichotomous BMI expressions were not significant predictors of survival in the overall and high FIT groups after adjusting for age and sex. In patients with low FIT, progressively worse survival was noted with BMI of 30.0 or greater, 25.0 to 29.9, and 18.5 to 24.9 (log-rank, 11.7; P=.003), whereas there was no obesity paradox noted in those with high FIT (log-rank, 1.72; P=.42). These results indicate that FIT modifies the relationship between BMI and survival. Thus, assessing the obesity paradox in systolic HF may be misleading unless FIT is considered.

Background Muscle loss is prevalent in chronic obstructive pulmonary disease (COPD). Prior studies evaluating musculoskeletal dysfunction in COPD have focused on individuals with baseline low muscle mass. Currently, there is limited data evaluating clinical characteristics and outcomes associated with progression to incident low muscle mass in a tobacco-exposed cohort of individuals with baseline normal muscle mass. Methods We evaluated 246 participants from a single-center longitudinal tobacco-exposed cohort with serial spirometry, thoracic imaging, dual energy x-ray absorptiometry (DXA) measurements, walk testing, and plasma adipokine measurements. DXA-derived fat free mass index (FFMI) and appendicular skeletal mass index (ASMI) were used as surrogates for muscle mass. Participants with incident low muscle mass (LM) at follow-up were characterized by FFMI < 18.4 kg/m 2 in males and < 15.4 kg/m 2 in females and/or ASMI < 7.25 kg/m 2 in males and < 5.67 kg/m 2 in females. Results Twenty-five (10%) participants progressed to incident low muscle mass at follow-up. At baseline, the LM subgroup had greater active smoking prevalence (60% v. 38%, p  = 0.04), lower FFMI (17.8 ± 1.7 kg/m 2 v. 19.7 ± 2.9 kg/m 2 , p  = 0.002), lower ASMI (7.3 ± 0.9 kg/m 2 v. 8.2 ± 1.2 kg/m 2 , p  = 0.0003), and lower plasma leptin (14.9 ± 10.1 ng/mL v. 24.0 ± 20.9 ng/mL, p  = 0.04). At follow-up, the LM subgroup had higher COPD prevalence (68% v. 43%, p  = 0.02), lower FEV 1 /FVC (0.63 ± 0.12 v. 0.69 ± 0.12, p  = 0.02), lower %DLco (66.5 ± 15.9% v. 73.9 ± 16.8%, p  = 0.03), and higher annual rate of FFMI decline (-0.17 kg/m 2 /year v. -0.04 kg/m 2 /year, p  = 0.006). There were no differences in age, gender distribution, pack years smoking history, or walk distance. Conclusions We identified a subgroup of tobacco-exposed individuals with normal baseline muscle mass who progressed to incident DXA-derived low muscle mass. This subgroup demonstrated synchronous lung disease and persistently low circulating leptin levels. Our study suggests the importance of assessing for muscle loss in conjunction with lung function decline when evaluating individuals with tobacco exposure.

Background Despite growing evidence on benefits of increased physical activity in hemodialysis (HD) patients and safety of intra-dialytic exercise, it is not part of standard clinical care, resulting in a missed opportunity to improve clinical outcomes in these patients. To develop a successful exercise program for HD patients, it is critical to understand patients’, staff and nephrologists’ knowledge, barriers, motivators and preferences for patient exercise. Methods In-depth interviews were conducted with a purposive sample of HD patients, staff and nephrologists from 4 dialysis units. The data collection, analysis and interpretation followed Criteria for Reporting Qualitative Research guidelines. Using grounded theory, emergent themes were identified, discussed and organized into major themes and subthemes. Results We interviewed 16 in-center HD patients (mean age 60 years, 50% females, 63% blacks), 14 dialysis staff members (6 nurses, 3 technicians, 2 dietitians, 1 social worker, 2 unit administrators) and 6 nephrologists (50% females, 50% in private practice). Although majority of the participants viewed exercise as beneficial for overall health, most patients failed to recognize potential mental health benefits. Most commonly reported barriers to exercise were dialysis-related fatigue, comorbid health conditions and lack of motivation. Specifically for intra-dialytic exercise, participants expressed concern over safety and type of exercise, impact on staff workload and resistance to changing dialysis routine. One of the most important motivators identified was support from friends, family and health care providers. Specific recommendations for an intra-dialytic exercise program included building a culture of exercise in the dialysis unit, and providing an individualized engaging program that incorporates education and incentives for exercising. Conclusion Patients, staff and nephrologists perceive a number of barriers to exercise, some of which may be modifiable. Participants desired an individualized intra-dialytic exercise program which incorporates education and motivation, and they provided a number of recommendations that should be considered when implementing such a program.

Purpose of ReviewTo 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 FindingsBoth 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.SummaryThere 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.

Background Peripheral artery disease (PAD) affects over 230 million people worldwide and is due to systemic atherosclerosis with etiology linked to chronic inflammation, hypertension, and smoking status. PAD is associated with walking impairment and mobility loss as well as a high prevalence of coronary and cerebrovascular disease. Intermittent claudication (IC) is the classic presenting symptom for PAD, although many patients are asymptomatic or have atypical presentations. Few effective medical therapies are available, while surgical and exercise therapies lack durability. Metformin, the most frequently prescribed oral medication for Type 2 diabetes, has salient anti-inflammatory and promitochondrial properties. We hypothesize that metformin will improve function, retard the progression of PAD, and improve systemic inflammation and mitochondrial function in non-diabetic patients with IC. Methods 200 non-diabetic Veterans with IC will be randomized 1:1 to 180-day treatment with metformin extended release (1000 mg/day) or placebo to evaluate the effect of metformin on functional status, PAD progression, cardiovascular disease events, and systemic inflammation. The primary outcome is 180-day maximum walking distance on the 6-min walk test (6MWT). Secondary outcomes include additional assessments of functional status (cardiopulmonary exercise testing, grip strength, Walking Impairment Questionnaires), health related quality of life (SF-36, VascuQoL), macro- and micro-vascular assessment of lower extremity blood flow (ankle brachial indices, pulse volume recording, EndoPAT), cardiovascular events (amputations, interventions, major adverse cardiac events, all-cause mortality), and measures of systemic inflammation. All outcomes will be assessed at baseline, 90 and 180 days of study drug exposure, and 180 days following cessation of study drug. We will evaluate the primary outcome with linear mixed-effects model analysis with covariate adjustment for baseline 6MWT, age, baseline ankle brachial indices, and smoking status following an intention to treat protocol. Discussion MOBILE IC is uniquely suited to evaluate the use of metformin to improve both systematic inflammatory responses, cellular energetics, and functional outcomes in patients with PAD and IC. Trial Registration : The prospective MOBILE IC trial was publicly registered (NCT05132439) November 24, 2021.

Aerobic exercise training in the heart failure (HF) population is supported by an extensive body of literature. The clinically accepted model for exercise prescription is currently moderate-intensity-aerobic continuous training (MI-ACT). Documented benefits from the literature include improvements in various aspects of physiologic function, aerobic exercise capacity and quality of life while the impact on morbidity and mortality is promising but requires further investigation. Recently, however, a body of evidence has begun to emerge demonstrating high-intensity-aerobic interval training (HI-AIT) can be performed safely with impressive improvements in physiology, functional capacity and quality of life. These initial findings have led some to question the long-standing clinical approach to aerobic exercise training in patients with HF (i.e., MI-ACT), implying it should perhaps be replaced with a HI-AIT model. This is a potentially controversial paradigm shift given the potential increase in adverse event risk associated with exercising at higher intensities, particularly in the HF population where the likelihood of an untoward episode is already at a heightened state relative to the apparently healthy population. The present review therefore addresses key issues related to HI-AIT in the HF population and makes recommendations for future research and current clinical practice.

Given the burden of cardiovascular disease (CVD), increasing the prevalence of healthy lifestyle choices is a global imperative. Currently, cardiac rehabilitation programs are a primary way that modifiable risk factors are addressed in the secondary prevention setting after a cardiovascular (CV) event/diagnosis. Even so, there is wide consensus that primary prevention of CVD is an effective and worthwhile pursuit. Moreover, continual engagement with individuals who have already been diagnosed as having CVD would be beneficial. Implementing health and wellness programs in the workplace allows for the opportunity to continually engage a group of individuals with the intent of effecting a positive and sustainable change in lifestyle choices. Current evidence indicates that health and wellness programs in the workplace provide numerous benefits with respect to altering CV risk factor profiles in apparently healthy individuals and in those at high risk for or already diagnosed as having CVD. This review presents the current body of evidence demonstrating the efficacy of worksite health and wellness programs and discusses key considerations for the development and implementation of such programs, whose primary intent is to reduce the incidence and prevalence of CVD and to prevent subsequent CV events. Supporting evidence for this review was obtained from PubMed, with no date limitations, using the following search terms: worksite health and wellness, employee health and wellness, employee health risk assessments, and return on investment. The choice of references to include in this review was based on study quality and relevance.