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Background: As patients with heart failure experience worsening of their condition, including acute decompensated heart failure, quality of life deteriorates. However, the trajectory of quality of life changes and their determinants in the context of the Rehabilitation Therapy in Older Acute Heart Failure Patients trial physical rehabilitation intervention are unknown. Methods: Patients ≥60 years old admitted for acute decompensated heart failure (n=349) were randomized to either attention control or intervention. Quality of life outcomes (Kansas City Cardiomyopathy Questionnaire; 12-Item Short-Form Health Survey) were measured at baseline (inpatient), 1 month, and 3 months. Intervention effects were assessed using linear mixed effects regression, including covariates to model the main effects of the intervention and timing of outcome assessments. Mediation analysis determined if changes in Kansas City Cardiomyopathy Questionnaire were due to improvement in physical function (short physical performance battery, 6-minute walk distance). Results: Baseline Kansas City Cardiomyopathy Questionnaire summary score was similarly poor in the intervention and control arms (40.2±20.6 versus 41.5±20.6). Although the intervention experienced nominally greater Kansas City Cardiomyopathy Questionnaire improvement than control at 1 month (64.7±1.9 versus 61.1±1.9, P =0.13), the difference was not statistically significant until 3 months (67.7±1.9 versus 60.8±1.9, P =0.004). Twelve-Item Short-Form Health Survey Physical and Mental Composite Scores increased in both arms at 1 month and continued improvement only in the intervention. The 3-month improvement in short physical performance battery score explained 64.1% of the improvement in Kansas City Cardiomyopathy Questionnaire ( P Conclusions: In older patients hospitalized for acute decompensated heart failure, quality of life improves in the first month after discharge. The quality of life benefit of a post-discharge physical rehabilitation intervention is detected early with large significant improvements at 3 months achieved primarily through improvement in short physical performance battery. Registration: URL: https://clinicaltrials.gov ; Unique identifier: NCT02196038.

The approved use of transcatheter aortic valve replacement (TAVR) for aortic stenosis has expanded substantially over time. However, gaps remain with respect to accurately delineating risk for poor clinical and patient-centered outcomes. Our objective was to develop prediction models for 30-day clinical and patient-centered outcomes after TAVR within a large, diverse community-based population.We identified all adults who underwent TAVR between 2013-2019 at Kaiser Permanente Northern California, an integrated healthcare delivery system, and were monitored for the following 30-day outcomes: all-cause death, improvement in quality of life, all-cause hospitalizations, all-cause emergency department (ED) visits, heart failure (HF)-related hospitalizations, and HF-related ED visits. We developed prediction models using gradient boosting machines using linked demographic, clinical and other data from the Society for Thoracic Surgeons (STS)/American College of Cardiology (ACC) TVT Registry and electronic health records. We evaluated model performance using area under the curve (AUC) for model discrimination and associated calibration plots. We also evaluated the association of individual predictors with outcomes using logistic regression for quality of life and Cox proportional hazards regression for all other outcomes.We identified 1,565 eligible patients who received TAVR. The risks of adverse 30-day post-TAVR outcomes ranged from 1.3% (HF hospitalizations) to 15.3% (all-cause ED visits). In models with the highest discrimination, discrimination was only moderate for death (AUC 0.60) and quality of life (AUC 0.62), but better for HF-related ED visits (AUC 0.76). Calibration also varied for different outcomes. Importantly, STS risk score only independently predicted death and all-cause hospitalization but no other outcomes. Older age also only independently predicted HF-related ED visits, and race/ethnicity was not significantly associated with any outcomes.Despite using a combination of detailed STS/ACC TVT Registry and electronic health record data, predicting short-term clinical and patient-centered outcomes after TAVR remains challenging. More work is needed to identify more accurate predictors for post-TAVR outcomes to support personalized clinical decision making and monitoring strategies.

Volitional physical activity level is predictive of a variety of health outcomes, but has not been examined in patients recently hospitalized for acute decompensated HF (ADHF).Ten to 14 days after index hospitalization for ADHF, 93 participants wore a wrist-mounted triaxial accelerometer (ActiGraph GT3X+) to objectively quantify sedentary behavior, light physical activity, and moderate-to-vigorous physical activity. Levels were compared to 2 groups of age-matched NHANES participants: healthy and chronic, stable HF. The relationship between physical activity levels and physical function [Short Physical Performance Battery (SPPB)], HF-specific quality-of-life (QOL) [Kansas City Cardiomyopathy Questionnaire (KCCQ)], and cognition [Montreal Cognitive Assessment (MOCA)] were examined.ADHF participants accumulated a median 1,008 (IQR 896, 1,109) minutes of sedentary time, 88 (57, 139) minutes of light physical activity, and 10 (6, 25) minutes of moderate-to-vigorous physical activity per day. Sedentary time, light physical activity, or moderate-to-vigorous activity did not differ by sex or EF subtype. ADHF participants spent only 9% of awake time nonsedentary, compared to 34% and 27% for healthy adults and adults with chronic, stable HF, respectively. Among ADHF participants, SPPB, KCCQ, and MOCA scores did not differ among quartiles of total physical activity.Older patients recently hospitalized for ADHF have very low levels of physical activity and high levels of sedentary time, both of which may be potential targets for interventions in this high-risk population. Physical activity level was not significantly associated with objectively measured physical function, QOL, or cognition, suggesting that this measure provides independent information regarding the patient experience of living with HF.NCT02196038, https://clinicaltrials.gov/ct2/show/NCT02196038.

Suboptimal adherence is a major limitation to achieving the benefits of exercise interventions, and our ability to predict and improve adherence is limited. The purpose of this analysis was to identify baseline clinical and demographic characteristics predicting exercise training adherence in the HF-ACTION study cohort.Adherence to exercise training, defined by the total duration of exercise performed (min/wk), was evaluated in 1159 participants randomized to the HF-ACTION exercise intervention. More than 50 clinical, demographic, and exercise testing variables were considered in developing a model of the min/wk end point for 1-3 mo (supervised training) and 10-12 mo (home-based training).In the multivariable model for 1-3 mo, younger age, lower income, more severe mitral regurgitation, shorter 6-min walk test distance, lower exercise capacity, and Black or African American race were associated with poorer exercise intervention adherence. No variable accounted for2% of the variance and the adjusted R2 for the final model was 0.14. Prediction of adherence was similarly limited for 10-12 mo.Clinical and demographic variables available at the initiation of exercise training provide very limited information for identifying patients with heart failure who are at risk for poor adherence to exercise interventions.

Cardiac rehabilitation (CR) programs are integral in the treatment of coronary heart disease (CHD). However, most programs do not incorporate structured, evidence-based obesity treatment, potentially limiting efficacy for the large number of CHD patients with overweight/obesity. This pilot study determined the feasibility of adding a behavioral weight loss intervention during standard CR.Adults aged ≥40 yr with CHD and overweight/obesity were randomized to 6 mo of CR alone or CR plus a behavioral weight loss program incorporating meal replacements and individual dietary counseling (CR + WL). Body weight, adiposity, cardiometabolic risk factors, self-efficacy for eating, and stages and processes of change for weight management (S-Weight, P-Weight) were assessed at baseline and during follow-up.Thirty-eight participants (64.5 ± 7.9 yr, 24% female, 16% Black/Hispanic) were enrolled over 18 mo. Retention was high, with 95% of participants completing the 6-mo follow-up visit. Participants attended ∼58% of the prescribed exercise sessions, and those in the CR + WL group attended 98% of the prescribed weight loss sessions. The CR + WL group lost significantly more weight than the CR group (6.4 ± 4.7% vs 1.2 ± 3.0%, P = .001), and there were significant treatment effects for total/regional adiposity, eating self-efficacy, and P-weight scores (all P values.05). Overall, greater weight loss was associated with improvements in self-efficacy ( P = .014) and P-weight scores for weight consequences evaluation ( P = .007) and weight management actions ( P = .04).A behavioral weight loss intervention during CR is feasible and safe, leading to greater weight and fat loss and related improvements in weight maintenance behaviors in overweight/obese adults with CHD.

Because heart failure with preserved ejection fraction (HFpEF) is closely linked to aging processes and disproportionately affects older adults, consideration of geriatric domains is paramount to ensure high-quality care to older adults with HFpEF. Multimorbidity, polypharmacy, cognitive impairment, depressive symptoms, frailty, falls, and social isolation each have important implications on quality of life and clinical events including hospitalization and mortality. There are multiple strategies to screen for these conditions. This narrative review underscores the importance of screening for multiple geriatric conditions, integrating these conditions into decision making, and addressing these conditions when caring for older adults with HFpEF.

To assess whether echocardiographic parameters of left ventricular (LV) structure and function relate to the long-term risk of incident end-stage kidney disease (ESKD).We conducted a prospective cohort study analyzing 2137 Black participants from the Jackson site of the Atherosclerosis Risk in Communities Study from January 1, 1993, through July 31, 2017. Echocardiographic parameters of LV structure and function were obtained from 1993 to 1995. The primary outcome incident ESKD was identified through the linkage to the United States Renal Data System. Cox proportional hazards models were used to estimate the hazard ratios (HRs) according to each echocardiographic parameter.There were 117 incident ESKD cases during a median follow-up of 22.2 (interquartile range, 15.0-23.3) years. Multivariable Cox models revealed that a higher LV mass index was significantly associated with the risk of ESKD (HR, 2.38; 95% CI, 1.21 to 4.68 for highest vs lowest quartile, P = 0.012). The HRs were significant and even higher for LV posterior wall thickness, with slightly higher HRs when their measures in end-systole (HR for highest vs lowest quartile, 4.38; 95% CI, 1.94 to 9.92, P0.001) vs end-diastole (HR, 3.50; 95% CI, 1.53 to 8.01, P = 0.003) were used. The associations were not significant for LV function parameters.In Black individuals residing in the community, echocardiographic parameters of LV structure, including LV wall thickness, were robustly associated with the risk of subsequently incident ESKD. These results have potential implications for novel prevention and management strategies for persons with abnormal LV structure.

Background: The SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated reductions in major cardiovascular disease events and mortality with an intensive systolic blood pressure (SBP) goal intervention. However, a detailed description of the blood pressure intervention, antihypertensive medication usage, blood pressure levels, and rates and predictors of blood pressure control has not been reported previously. Methods: Hypertensive participants (n=9361) 50 years and older with elevated cardiovascular disease risk were randomized 1:1 to SBP goal Results: Baseline blood pressure (median±interquartile range) was 138±19/78±16 mm Hg. For intensive group participants, percent at goal rose from 8.9% at baseline to 52.4% at 6 months and average antihypertensive medications rose from 2.2 to 2.7; SBP was Conclusions: These results may inform and help replicate the benefits of SPRINT in clinical practice. Registration: URL: http://www.clinicaltrials.gov ; Unique identifier: NCT01206062.

BACKGROUND: The endothelin receptor antagonist atrasentan reduced the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease (CKD) in the SONAR (Study of Diabetic Nephropathy with Atrasentan) trial, although with a numerically higher incidence of heart failure (HF) hospitalization.OBJECTIVES: The purpose of this study was to assess if early changes in B-type natriuretic peptide (BNP) and body weight during atrasentan treatment predict HF risk.METHODS: Participants with type 2 diabetes and CKD entered an open-label enrichment phase to assess response to atrasentan 0.75 mg/day. Participants without substantial fluid retention (>3 kg body weight increase or BNP increase to >300 pg/mL), were randomized to atrasentan 0.75 mg/day or placebo. Cox proportional hazards regression was used to assess the effects of atrasentan vs placebo on the prespecified safety outcome of HF hospitalizations.RESULTS: Among 3,668 patients, 73 (4.0%) participants in the atrasentan and 51 (2.8%) in the placebo group developed HF (HR: 1.39; 95% CI: 0.97-1.99; P = 0.072). In a multivariable analysis, HF risk was associated with higher baseline BNP (HR: 2.32; 95% CI: 1.81-2.97) and percent increase in BNP during response enrichment (HR: 1.46; 95% CI: 1.08-1.98). Body weight change was not associated with HF. Exclusion of patients with at least 25% BNP increase during enrichment attenuated the risk of HF with atrasentan (HR: 1.02; 95% CI: 0.66-1.56) while retaining nephroprotective effects (HR: 0.58; 95% CI: 0.44-0.78).CONCLUSIONS: In patients with type 2 diabetes and CKD, baseline BNP and early changes in BNP in response to atrasentan were associated with HF hospitalization, highlighting the importance of natriuretic peptide monitoring upon initiation of atrasentan treatment. (Study Of Diabetic Nephropathy With Atrasentan [SONAR]; NCT01858532).

Background: Patients with heart failure (HF) have a high burden of symptoms and physical limitations, regardless of ejection fraction (EF). Whether the benefits of SGLT2 (sodium-glucose cotransporter-2) inhibitors on these outcomes vary across the full range of EF remains unclear. Methods: Patient-level data were pooled from the DEFINE-HF trial (Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction) of 263 participants with reduced EF (≤40%), and PRESERVED-HF trial (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure) of 324 participants with preserved EF (≥45%). Both were randomized, double-blind 12-week trials of dapagliflozin versus placebo, recruiting participants with New York Heart Association class II or higher and elevated natriuretic peptides. The effect of dapagliflozin on the change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at 12 weeks was tested with ANCOVA adjusted for sex, baseline KCCQ, EF, atrial fibrillation, estimated glomerular filtration rate, and type 2 diabetes. Interaction of dapagliflozin effects on KCCQ-CSS by EF was assessed using EF both categorically and continuously with restricted cubic spline. Responder analyses, examining proportions of patients with deterioration, and clinically meaningful improvements in KCCQ-CSS were conducted using logistic regression. Results: Of 587 patients randomized (293 dapagliflozin, 294 placebo), EF was ≤40, >40-≤60, and >60% in 262 (45%), 199 (34%), and 126 (21%), respectively. Dapagliflozin improved KCCQ-CSS at 12 weeks (placebo-adjusted difference 5.0 points [95% CI, 2.6–7.5]; P P =0.01), >40 to ≤60 (4.9 points [95% CI, 0.8–9.0]; P =0.02) and >60% (6.8 points [95% CI, 1.5–12.1]; P =0.01; P interaction =0.79). Benefits of dapagliflozin on KCCQ-CSS were also consistent when analyzing EF continuously ( P interaction =0.94). In responder analyses, fewer dapagliflozin-treated patients had deterioration and more had small, moderate, and large KCCQ-CSS improvements versus placebo; these results were also consistent regardless of EF (all P interaction values nonsignificant). Conclusions: In patients with HF, dapagliflozin significantly improves symptoms and physical limitations after 12 weeks of treatment, with consistent and clinically meaningful benefits across the full range of EF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT02653482 and NCT03030235.

BACKGROUND: Health status outcomes, including symptoms, function, and quality of life, are worse for Black compared with White patients with heart failure. Sodium–glucose cotransporter 2 inhibitors (SGLT2is) reduce cardiovascular mortality and improve health status in patients with heart failure, but whether the health status benefit of SGLT2is is similar across races is not established. The objective of this study was to compare the treatment effect of SGLT2is (versus placebo) on health status for Black compared with White patients with heart failure. METHODS: We combined patient-level data from 3 randomized clinical trials of SGLT2is: DEFINE-HF (Dapagliflozin Effect on Symptoms and Biomarkers in Patients With Heart Failure; n=263), PRESERVED-HF (Dapagliflozin in Preserved Ejection Fraction Heart Failure; n=324), and CHIEF-HF (A Study on Impact of Canagliflozin on Health Status, Quality of Life, and Functional Status in Heart Failure; n=448). These 3 United States–based trials enrolled a substantial proportion of Black patients, and each used the Kansas City Cardiomyopathy Questionnaire (KCCQ) to measure health status at baseline and after 12 weeks of treatment. Among 1035 total participants, selecting self-identified Black and White patients with complete information yielded a final analytic cohort of 935 patients. The primary endpoint was KCCQ Clinical Summary score. Twelve-week change in KCCQ with SGLT2is versus placebo was compared between Black and White patients by testing the interaction between race and treatment using multivariable linear regression models adjusted for trial, baseline KCCQ (as a restricted cubic spline), race, and treatment. The data that support the findings of this study are available from the corresponding author upon reasonable request. RESULTS: Among 935 participants, 236 (25%) self-identified as Black, and 469 (50.2%) were treated with an SGLT2i. Treatment with an SGLT2i, compared with placebo, resulted in KCCQ Clinical Summary score improvements at 12 weeks of +4.0 points (95% CI, 1.7–6.3; P =0.0007) in White patients and +4.7 points (95% CI, 0.7–8.7; P =0.02) in Black patients, with no significant interaction by race and treatment ( P =0.76). Other KCCQ scales showed similar results. CONCLUSIONS: Treatment with an SGLT2i resulted in consistent and significant improvements in health status for both Black and White patients with heart failure.

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.

An academic career in aging research is filled with the incredible highs of important discoveries that improve the lives of older adults and repeated lows when papers and grants are rejected or studies are negative. To normalize the experience of setbacks and failures in aging research, we invited three senior investigators to share their journeys of persistence and resilience as they have navigated their research careers. This career development symposium was presented at the 2021 Annual Scientific Meeting of the American Geriatrics Society, which was held virtually. We aimed to connect researchers in aging, especially trainees and junior investigators, through personal stories of persistence and shared strategies to build resilience and respond to setbacks with a growth mindset.

Background Substantive previous work has shown that both gait speed and global cognition decline as people age. Rates of their decline, as opposed to cross-sectional measurements, could be more informative of future functional status and other clinical outcomes because they more accurately represent deteriorating systems. Additionally, understanding the sex and racial disparity in the speed of deterioration, if any, is also important as ethnic minorities are at an increased risk of mobility disability and dementia. Method Data from 2 large longitudinal intervention studies were integrated. Rates of decline were derived from individual-level measures of gait speed of 400-m walk and scores on the Modified Mini Mental State Examination (3MSE). We also assessed age-associated declines and accelerations in changes across the ages represented in the studies (age range 53–90). Results The mean rate of decline in 400-m gait speed across individuals was 0.03 m/s per year, and multivariable analysis showed a significant acceleration in decline of −0.0013 m/s/y2 (p < .001). Both race and sex moderated the rate of decline. For global cognition, the mean rate of decline was 0.05 of a point per year on the 3MSE scale, and acceleration in the rate of decline was significant (−0.017 point/y2, p < .001), but neither sex nor race moderated the decline. Conclusion Rate of decline in physical but not cognitive function appears moderated by sex and race. This finding, as well as rates and accelerations of decline estimated herein, could inform future intervention studies. Clinical Trials Registration Number NCT00017953 (Look AHEAD); NCT01410097 (Look AHEAD ancillary); NCT00116194 (LIFE).

Background : Heart failure with preserved ejection fraction (HFpEF) is the fastest growing form of HF and is associated with high morbidity and mortality. The primary chronic symptom in HFpEF is exercise intolerance, associated with reduced quality of life (QoL). Emerging evidence implicates left atrial (LA) dysfunction as an important pathophysiologic mechanism. Here we extend prior observations by relating LA dysfunction to peak oxygen uptake (peak VO2), physical function (distance walked in six minutes, 6MWD) and QoL (Kansas City Cardiomyopathy Questionnaire, KCCQ). Methods : We compared 75 older, obese, HFpEF patients to 53 healthy age-matched controls. LA strain was assessed by magnetic resonance cine imaging using feature tracking. LA function was defined according to its three distinct phases, with the LA serving as a reservoir during systole, as a conduit during early diastole, and as a booster pump at the end of diastole. LA stiffness index was calculated as the ratio of early mitral inflow velocity-to-early annular tissue velocity (E/e’, by Doppler ultrasound) and LA reservoir strain. Results : HFpEF had decreased reservoir strain (16.4±4.4% vs. 18.2±3.5%, p=0.018), lower conduit strain (7.7±3.3% vs. 9.1±3.4%, p=0.028), and increased stiffness index (0.86±0.39 vs. 0.53±0.18, p Conclusion : LA stiffness is independently associated with impaired exercise tolerance and QoL and may be an important therapeutic target in obese HFpEF. Registration : NCT00959660

Background: The majority of patients with heart failure with preserved ejection fraction (HFpEF) have the obesity phenotype, but no therapies specifically targeting obesity in HFpEF exist. Objectives: The aim of this study was to describe the design and baseline characteristics of 2 trials of semaglutide, a glucagon-like peptide-1 receptor agonist, in patients with the obesity HFpEF phenotype: STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF; NCT04788511) and STEP-HFpEF DM (Semaglutide Treatment Effect in People with obesity and HFpEF and type 2 diabetes; NCT04916470). Methods: Both STEP-HFpEF and STEP-HFpEF DM are international multicenter, double-blind, placebo-controlled trials that randomized adults with HFpEF and a body mass index ≥30 kg/m2 to once-weekly semaglutide at a dose of 2.4 mg or placebo. Participants were eligible if they had a left ventricular ejection fraction (LVEF) ≥45%; New York Heart Association (NYHA) functional class II to IV; a Kansas City Cardiomyopathy Questionnaire (KCCQ)–Clinical Summary Score (CSS)

Patients with heart failure and preserved ejection fraction (HFpEF) have a high burden of symptoms and functional limitations, and have a poor quality of life. By targeting cardiometabolic abmormalities, sodium glucose cotransporter 2 (SGLT2) inhibitors may improve these impairments. In this multicenter, randomized trial of patients with HFpEF (NCT03030235), we evaluated whether the SGLT2 inhibitor dapagliflozin improves the primary endpoint of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CS), a measure of heart failure-related health status, at 12 weeks after treatment initiation. Secondary endpoints included the 6-minute walk test (6MWT), KCCQ Overall Summary Score (KCCQ-OS), clinically meaningful changes in KCCQ-CS and -OS, and changes in weight, natriuretic peptides, glycated hemoglobin and systolic blood pressure. In total, 324 patients were randomized to dapagliflozin or placebo. Dapagliflozin improved KCCQ-CS (effect size, 5.8 points (95% confidence interval (CI) 2.3–9.2, P = 0.001), meeting the predefined primary endpoint, due to improvements in both KCCQ total symptom score (KCCQ-TS) (5.8 points (95% CI 2.0–9.6, P = 0.003)) and physical limitations scores (5.3 points (95% CI 0.7–10.0, P = 0.026)). Dapagliflozin also improved 6MWT (mean effect size of 20.1 m (95% CI 5.6–34.7, P = 0.007)), KCCQ-OS (4.5 points (95% CI 1.1–7.8, P = 0.009)), proportion of participants with 5-point or greater improvements in KCCQ-OS (odds ratio (OR) = 1.73 (95% CI 1.05–2.85, P = 0.03)) and reduced weight (mean effect size, 0.72 kg (95% CI 0.01–1.42, P = 0.046)). There were no significant differences in other secondary endpoints. Adverse events were similar between dapagliflozin and placebo (44 (27.2%) versus 38 (23.5%) patients, respectively). These results indicate that 12 weeks of dapagliflozin treatment significantly improved patient-reported symptoms, physical limitations and exercise function and was well tolerated in chronic HFpEF., In a multicenter, randomized trial, the SGLT2 inhibitor dapagliflozin improved the health status and exercise function of patients with heart failure with preserved ejection fraction (HFpEF), a condition for which effective treatments are lacking.

Background: Given the important role of cardiac injury and neurohormonal activation in the pathways leading from hypertension to heart failure and strong associations observed between hypertension and its sequelae on hs-cTnT (high-sensitivity cardiac troponin T) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, we hypothesized that intensive systolic blood pressure (SBP) lowering would decrease levels of hs-cTnT and NT-proBNP. Methods: hs-cTnT and NT-proBNP were measured at baseline and 1 year from stored specimens in SPRINT (Systolic Blood Pressure Intervention Trial). Changes in biomarkers were evaluated continuously on the log scale and according to categories (≥50% increase, ≥50% decrease, or Results: Randomization to intensive SBP lowering (versus standard SBP management) resulted in a 3% increase in hs-cTnT levels over 1-year follow-up (geometric mean ratio, 1.03 [95% CI, 1.01–1.04]) and a higher proportion of participants with ≥50% increase (odds ratio, 1.47 [95% CI, 1.13, 1.90]). In contrast, randomization to intensive SBP lowering led to a 10% decrease in NT-proBNP (geometric mean ratio, 0.90 [95% CI, 0.87–0.93]) and a lower probability of ≥50% increase in NT-proBNP (odds ratio, 0.57 [95% CI, 0.46–0.72]). The association of randomized treatment assignment on change in hs-cTnT was completely attenuated after accounting for changes in estimated glomerular filtration rate over follow-up, whereas the association of treatment with NT-proBNP was completely attenuated after adjusting for change in SBP. Increases in hs-cTnT and NT-proBNP from baseline to 1 year were associated with higher risk for heart failure and death, with no significant interactions by treatment assignment. Conclusions: Intensive SBP lowering increased hs-cTnT, mediated by the effect of SBP lowering on reduced kidney filtration. In contrast, intensive SBP lowering decreased NT-proBNP, a finding that was explained by the decrease in SBP. These findings highlight the importance of noncardiac factors influencing variation in cardiac biomarkers and raise questions about the potential role of hs-cTnT as a surrogate marker for heart failure or death in SBP-lowering studies.

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.

Background: We've shown that combined caloric restriction (CR) and aerobic exercise training (AT) improve peak exercise O 2 consumption (VO 2 peak); and quality-of-life (QOL) in older patients with obese heart failure with preserved ejection fraction (HFpEF). However, ~35% of weight lost during CR+AT was skeletal muscle (SM) mass. We examined whether addition of resistance training (RT) to CR+AT would reduce SM loss and further improve outcomes. Methods: Randomized, controlled, single-blind, 20-week trial of RT+CR+AT vs. CR+AT in 88 patients with chronic HFpEF and body mass index (BMI) ≥28 kg/m 2 . Outcomes at 20 weeks included: the primary outcome (VO2peak); MRI and dual X-ray absorptiometry; leg muscle strength and quality (leg strength ÷ leg SM area); Kansas City Cardiomyopathy Questionnaire (KCCQ). Results: 77 participants completed the trial. RT+CR+AT and CR+AT produced non-significant differences in weight loss: mean (95% CI): -8(-9,-7) versus -9(-11,-8) (p=0.21). RT+CR+AT and CR+AT had non-significantly differences in the reduction of body fat [-6.5(-7.2,-5.8) versus -7.4(-8.1,-6.7) kg] and SM [-2.1(-2.7,-1.5) versus -2.1(-2.7,-1.4) kg] (p=0.20 and 0.23, respectively). RT+CR+AT produced significantly greater increases in leg muscle strength [4.9(0.7,9.0) versus -1.1(-5.5,3.2) Nm, p=0.05] and leg muscle quality [0.07(0.03,0.11) versus 0.02(-0.02,0.06) Nm/cm2, p=0.04]. Both RT+CR+AT and CR+AT produced significant improvements in VO 2 peak [108(958,157) versus 80(30,130) ml/min; p=0.001 and 0.002, respectively], and KCCQ score [17(12,22) versus 23(17,28); p=0.001 for both], with no significant between-group differences. Both RT+CR+AT and CR+AT significantly reduced LV mass and arterial stiffness. There were no study-related serious adverse events. Conclusions: In older obese HFpEF patients, CR+AT produces large improvements in VO 2 peak and QOL. Adding RT to CR+AT increased leg strength and muscle quality without attenuating SM loss or further increasing VO2peak or QOL. Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02636439

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.

Background Older patients who are hospitalized for acute decompensated heart failure have high rates of physical frailty, poor quality of life, delayed recovery, and frequent rehospitaliza...

Background Lower exercise capacity, as measured by 6-minute walk distance (6MWD), is associated with incident heart failure (HF). Among those without HF, the associations of measures of cardiac function with 6MWD are unclear, and may provide insight regarding the risk of incident HF. Objectives The purpose of this study was to understand the relationships between cardiac function and exercise capacity. Methods This study evaluated the associations of cardiac mechanics with 6MWD in the sixth examination of the Multi-Ethnic Study of Atherosclerosis. Echocardiography (2-dimensional, Doppler, and speckle-tracking) was performed at rest and after passive leg raise to evaluate functional reserve after intravascular volume challenge. Results Of 2,096 participants without HF (mean age 73 years, 48% men, 58% non-White), individuals with lower (worse) left atrial (LA) reservoir strain were older and had higher blood pressure. Lower resting LA reservoir strain (β coefficient per SD decrease: −5.0; 95% confidence interval [CI]: −8.8 to −1.3 m; p = 0.009), inability to augment LA reservoir strain after passive leg raise (β coefficient per SD decrease: −5.8; 95% CI: −9.1 to −2.5 m; p Conclusions Among individuals without HF, worse biatrial function, lack of LA functional reserve, and worse LV diastolic function were associated with reduced submaximal exercise capacity. Therapies aimed to improve these functional domains may increase exercise capacity and prevent HF.

RATIONALE AND OBJECTIVE. While low estimated glomerular filtration rate (eGFR) is associated with cardiovascular disease (CVD) events and mortality, the clinical significance of variability in eGFR over time is uncertain. We aimed to evaluate the association between variability in eGFR and the risk of CVD events and all-cause mortality. STUDY DESIGN. Longitudinal analysis of clinical trial participants. SETTINGS AND PARTICIPANTS. 7,520 Systolic Blood Pressure Intervention Trial (SPRINT) participants aged ≥ 50 year with 1 or more CVD risk factors. PREDICTORS. eGFR variability, estimated by the coefficients of variation of eGFR measurements at the 6, 12, and 18-month study visits. OUTCOMES. SPRINT primary CVD composite outcome (myocardial infarction, acute coronary syndrome, stroke, heart failure, or CVD death) and all-cause mortality from month 18 to end of follow-up. ANALYTICAL APPROACH. Cox models evaluated associations between eGFR variability and CVD outcomes and all-cause mortality. Models were adjusted for demographics, randomization arm, CVD risk factors, albuminuria and month 18 eGFR. RESULTS. Mean age was 68±9 years, 65% were men, and 58% were white. The mean eGFR was 73±21 ml/min/1.73m(2) at 6 months. There were 370 CVD events and 154 deaths during a median follow-up of 2.4 years. Greater eGFR variability was associated with higher risk for all-cause mortality (hazard ratio (HR) per standard deviation (SD) greater variability, 1.29; 95% confidence interval (CI) 1.14 to 1.45) but not CVD events (HR 1.05; 95% CI 0.95 to 1.16) after adjusting for albuminuria at baseline, eGFR at month 18, and other CVD risk factors. Associations were similar when stratified by treatment arm and baseline CKD status, when accounting for concurrent systolic BP changes, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and diuretic medications during follow-up. LIMITATIONS. Persons with diabetes and proteinuria > 1 g/day were excluded. CONCLUSIONS. In trial participants at high risk for CVD with hypertension, greater eGFR variability was independently associated with all-cause mortality but not CVD events.

Background We assessed the prevalence and clinical characteristics of patients with acute decompensated heart failure (ADHF) who live alone and how they were different from patients who lived with someone else. Methods We analyzed patients in the REHAB-HF Trial. Patients were ≥60 years with preserved or reduced ejection fraction who were hospitalized with ADHF. Results Of 202 patients, 67 (33.2%) lived alone. Patients who lived alone had a mean age of 72.4±7.8 years, 64% (n=43) of whom were female, 52% (n=35) were non-white and had a mean 6.1±5.5 comorbidities. Patients living alone were largely similar in baseline characteristics, comorbid burden and prescribed medications to patients living with someone else. However, patients living alone were more likely to be female than patients living with someone else (63% [n=43] vs. 49% [n=66], p=0.04). Patients living alone had severe impairments in physical function and QoL. Cognitive dysfunction was present in 81% of those living alone. However, after adjusting for sex, no differences in physical function, depression, cognitive dysfunction or QoL were noted between patients who lived alone or those who lived with someone else. Conclusions In this diverse population of older ADHF patients, 33% lived alone (versus 26% in the general population). Those living alone were more often female, non-white, and had >6 comorbidities. Treatment strategies for older ADHF patients should consider the potential impact of social determinants.

Plasma exposure of the endothelin receptor antagonist atrasentan varies between individuals and is associated with nephroprotective effects and the risk of heart failure. We examined the influence of genetic polymorphisms on atrasentan plasma exposure and pharmacodynamic effects. We performed a substudy of the Study of Diabetic Nephropathy With Atrasentan (SONAR) trial which enrolled adults with type 2 diabetes and chronic kidney disease (estimated glomerular filtration rate: 25–75 mL/min/1.73 m2, and a urine albumin-to-creatinine ratio of 300–5,000 mg/g). Single nucleotide polymorphisms (SNPs) were determined for prespecified membrane transporters, metabolizing enzymes, and the endothelin-1 peptide. The associations among genotype, atrasentan plasma exposure, and the effect of atrasentan on the prespecified kidney and heart failure hospitalization (HHF) outcomes was assessed with Cox proportional hazards regression models. Of 3,668 patients randomized, 2,329 (63.5%) consented to genotype analysis. Two SNPs in the SLCO1B1 gene (rs4149056 and rs2306283), encoding the hepatic organic anion transporter 1B1 (OATP1B1), showed the strongest association with atrasentan plasma exposure. Based on their SLCO1B1 genotype, patients were classified into normal (atrasentan area under the plasma-concentration time curve from zero to infinity (AUC0−inf) 41.3 ng·h/mL) or slow (atrasentan AUC0−inf 49.7 ng·h/mL, P < 0.001) OATP1B1 transporter phenotypes. Among patients with a normal OATP1B1 phenotype, the hazard ratio (HR) with atrasentan for the primary kidney and HHF outcomes were 0.61 (95% confidence interval (CI): 0.45–0.81) and 1.35 (95% CI: 0.84–2.13), respectively. In the slow transporter phenotype, HRs for kidney and HHF outcomes were 1.95 (95% CI: 0.95–4.03, P-interaction normal phenotype = 0.004), and 4.18 (95% CI: 1.37–12.7, P-interaction normal phenotype = 0.060), respectively. OATP1B1 gene polymorphisms are associated with significant between-patient variability in atrasentan plasma exposure and long-term efficacy and safety.