Sex Disparities in Longitudinal Use and Intensification of Guideline-Directed Medical Therapy Among Patients With Newly Diagnosed Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Guideline-directed medical therapies (GDMTs) are the mainstay of treatment for heart failure with reduced ejection fraction (HFrEF), but they are underused. Whether sex differences exist in the initiation and intensification of GDMT for newly diagnosed HFrEF is not well established. METHODS: Patients with incident HFrEF were identified from the 2016 to 2020 Optum deidentified Clinformatics Data Mart Database, which is derived from a database of administrative health claims for members of large commercial and Medicare Advantage health plans. The primary outcome was the use of optimal GDMT within 12 months of HFrEF diagnosis. Consistent with the guideline recommendations during the time period of the study, optimal GDMT was defined as ≥50% of the target dose of evidence-based beta-blocker plus ≥50% of the target dose of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, or any dose of angiotensin receptor neprilysin inhibitor plus any dose of mineralocorticoid receptor antagonist. The probability of achieving optimal GDMT on follow-up and predictors of optimal GDMT were evaluated with time-to-event analysis with adjusted Cox proportional hazard models. RESULTS: The study cohort included 63 759 patients (mean age, 71.3 years; 15.2% non-Hispanic Black race; 56.6% male). Optimal GDMT use was achieved by 6.2% of patients at 12 months after diagnosis. Female (compared with male) patients with HFrEF had lower use across every GDMT class and lower use of optimal GDMT at each time point at follow-up. In an adjusted Cox model, female sex was associated with a 23% lower probability of achieving optimal GDMT after diagnosis (hazard ratio [HR], 0.77 [95% CI, 0.71-0.83]; P<0.001). The sex disparities in GDMT use after HFrEF diagnosis were most pronounced among patients with commercial insurance (females compared with males; HR, 0.66 [95% CI, 0.58-0.76]) compared with Medicare (HR, 0.85 [95% CI, 0.77-0.92]); Pinteraction sex×insurance status=0.005) and for younger patients (age <65 years: HR, 0.65 [95% CI, 0.58-0.74]) compared with older patients (age ≥65 years: HR, 87 [95% CI, 80-96]) Pinteraction sex×age=0.009). CONCLUSIONS: Overall use of optimal GDMT after HFrEF diagnosis was low, with significantly lower use among female (compared with male) patients. These findings highlight the need for implementation efforts directed at improving GDMT initiation and titration.

Effects of an Intervention to Improve Evidence-Based Care for People With Diabetes and Cardiovascular Disease Across Sex, Race, and Ethnicity Subgroups: Insights From the COORDINATE-Diabetes Trial.

BACKGROUND: Results from the COORDINATE-Diabetes trial (Coordinating Cardiology Clinics Randomized Trial of Interventions to Improve Outcomes - Diabetes) demonstrated that a multifaceted, clinic-based intervention increased prescription of evidence-based medical therapies to participants with type 2 diabetes and atherosclerotic cardiovascular disease. This secondary analysis assessed whether intervention success was consistent across sex, race, and ethnicity. METHODS: COORDINATE-Diabetes, a cluster randomized trial, recruited participants from 43 US cardiology clinics (20 randomized to intervention and 23 randomized to usual care). The primary outcome was the proportion of participants prescribed all 3 groups of evidence-based therapy (high-intensity statin, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and sodium-glucose cotransporter-2 inhibitor or glucagon-like peptide 1 receptor agonist) at last trial assessment (6 to 12 months). In this prespecified analysis, mixed-effects logistic regression models were used to assess the outcome by self-reported sex, race, and ethnicity in the intervention and usual care groups, with adjustment for baseline characteristics, medications, comorbidities, and site location. RESULTS: Among 1045 participants with type 2 diabetes and atherosclerotic cardiovascular disease, the median age was 70 years, 32% were female, 16% were Black, and 9% were Hispanic. At the last trial assessment, there was an absolute increase in the proportion of participants prescribed all 3 groups of evidence-based therapy in women (36% versus 15%), Black participants (41% versus 18%), and Hispanic participants (46% versus 18%) with the intervention compared with usual care, with consistent benefit across sex (male versus female; Pinteraction=0.44), race (Black versus White; Pinteraction=0.59), and ethnicity (Hispanic versus Non-Hispanic; Pinteraction= 0.78). CONCLUSIONS: The COORDINATE-Diabetes intervention successfully improved delivery of evidence-based care, regardless of sex, race, or ethnicity. Widespread dissemination of this intervention could improve equitable health care quality, particularly among women and minority communities who are frequently underrepresented in clinical trials. REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03936660.

MASLD and MASH at the crossroads of hepatology trials and cardiorenal metabolic trials.

Steatotic liver disease (SLD) is a worldwide public health problem, causing considerable morbidity and mortality. Patients with SLD are at increased risk for major adverse cardiovascular (CV) events, type 2 diabetes mellitus and chronic kidney disease. Conversely, patients with cardiometabolic conditions have a high prevalence of SLD. In addition to epidemiological evidence linking many of these conditions, there is evidence of shared pathophysiological processes. In December 2022, a unique multi-stakeholder, multi-specialty meeting, called MOSAIC (Metabolic multi Organ Science Accelerating Innovation in Clinical Trials) was convened to foster collaboration across metabolic, hepatology, nephrology and CV disorders. One of the goals of the meeting was to consider approaches to drug development that would speed regulatory approval of treatments for multiple disorders by combining liver and cardiorenal endpoints within a single study. Non-invasive tests, including biomarkers and imaging, are needed in hepatic and cardiorenal trials. They can be used as trial endpoints, to enrich trial populations, to diagnose and risk stratify patients and to assess treatment efficacy and safety. Although they are used in proof of concept and phase 2 trials, they are often not acceptable for regulatory approval of therapies. The challenge is defining the optimal combination of biomarkers, imaging and morbidity/mortality outcomes and ensuring that they are included in future trials while minimizing the burden on patients, trialists and trial sponsors. This paper provides an overview of some of the wide array of CV, liver and kidney measurements that were discussed at the MOSAIC meeting.

Association of disproportionate liver fat with markers of heart failure: The multi-ethnic study of atherosclerosis.

BACKGROUND: Metabolic dysfunction associated steatotic liver disease (MASLD) has been linked to heart failure with preserved ejection fraction (HFpEF). We sought to understand association between individuals with amounts of liver adiposity greater than would be predicted by their body mass index (BMI) in order to understand whether this disproportionate liver fat (DLF) represents a proxy of metabolic risk shared between liver and heart disease. METHODS: We studied 2,932 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) who received computed tomography (CT) measurements of hepatic attenuation. Quartiles of DLF were compared and multivariable linear regression was performed to evaluate the association of DLF with clinical, echocardiographic, and quality of life metrics. RESULTS: Compared to the lowest quartile of DLF, individuals in the highest quartile of DLF were more likely to be male (52.0% vs 47.1%, P < .001), less likely to be Black or African American (14.8 % vs 38.1% P < .001), have higher rates of dysglycemia (31.9% vs 16.6%, P < .001) and triglycerides (140 [98.0, 199.0] vs 99.0 [72.0, 144.0] mg/dL, P > .001). These individuals had lower global longitudinal strain (-0.13 [-0.25, -0.02], P = .02), stroke volumes (-1.05 [-1.76, -0.33], P < .01), lateral e' velocity (-0.10 [-0.18, -0.02], P = .02), and 6-minute walk distances (-4.25 [-7.62 to -0.88], P = .01). CONCLUSION: DLF is associated with abnormal metabolic profiles and ventricular functional changes known to be associated with HFpEF and may serve as an early metric to assess for those that may progress to clinical HFpEF.

Putting More Weight on Obesity Trials in Heart Failure.

PURPOSE OF REVIEW: To review ongoing and planned clinical trials of weight loss among individuals with or at high risk of heart failure. RECENT FINDINGS: Intentional weight loss via semaglutide among persons with heart failure and preserved ejection fraction and obesity significantly improves weight loss and health status as assessed by the KCCQ-CSS score and is associated with improvements in 6-min walk test. Ongoing and planned trials will explore the role of intentional weight loss with treatments such as semaglutide or tirzepatide for individuals with heart failure across the entire ejection fraction spectrum.

Role of exercise therapy and cardiac rehabilitation in heart failure.

Heart failure (HF) is a common cause of hospitalization and death, and the hallmark symptoms of HF, including dyspnea, fatigue, and exercise intolerance, contribute to poor patient quality of life (QoL). Cardiac rehabilitation (CR) is a comprehensive disease management program incorporating exercise training, cardiovascular risk factor management, and psychosocial support. CR has been demonstrated to effectively improve patient functional status and QoL among patients with HF. However, CR participation among patients with HF is poor. This review details the mechanisms of dyspnea and exercise intolerance among patients with HF, the physiologic and clinical improvements observed with CR, and the key components of a CR program for patients with HF. Furthermore, unmet needs and future strategies to improve patient participation and engagement in CR for HF are reviewed.

"Working me to life" - Longitudinal Perceptions from Adults with Heart Failure with Preserved Ejection Fraction Enrolled in an Exercise Training Clinical Trial.

AIMS: Adults with heart failure with preserved ejection fraction (HFpEF) responded more favorably to an exercise intervention compared to those with reduced ejection fraction. This study explores factors that contributed to this response focusing on the qualitative perceptions of adults with HFpEF enrolled in an exercise intervention. METHODS AND RESULTS: This qualitative descriptive study is a secondary analysis of longitudinal interviews collected at 3, 6, 12, and 18-months from participants with HFpEF enrolled in a randomized controlled trial testing an intervention to promote adherence to exercise. We included participants with at least 2 interviews. Interviews were examined across and within participants and time points using thematic analysis. Analyses included 67 interviews from 21 adults with HFpEF enrolled in the intervention arm. The sample was 52% (11/21) male and over 47% (10/21) non-White. Mean age at enrollment was 63.7 ± 9.9 years. We identified 4 major themes: 1. Overcoming negative attitudes, barriers, and injury, 2. Motivations to exercise, 3. Exercise - the panacea for HFpEF symptoms and quality of life, and 4. Advice for others with HFpEF. CONCLUSIONS: Our findings suggest that for many adults with HFpEF, initial hesitancy, fear, and negative attitudes about exercise can be overcome. Exercise coaching using social cognitive constructs, medical fitness center memberships, and heart rate self-monitoring are successful strategies of engaging adults with HFpEF in long-term unsupervised exercise training. REGISTRATION: This study is registered at ClinicalTrials.gov, NCT01658670.

Association of Beta-Blocker Use With Exercise Capacity in Participants With Heart Failure With Preserved Ejection Fraction: A Post Hoc Analysis of the RELAX Trial.

Patients with heart failure with preserved ejection fraction (HFpEF) often receive ß-blocker (BB) therapy for management of co-morbidities. However, the association of BB therapy with exercise capacity and health-related quality of life (HRQL) in HFpEF is not well-studied. In this post hoc analysis of the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF (RELAX) trial, which included patients with chronic stable HFpEF with peak exercise capacity assessment at baseline and at 12 and 24 weeks of follow-up, we evaluated the association of BB use with the measures of exercise capacity (peak exercise oxygen uptake), anaerobic threshold, and HRQL (Minnesota living with heart failure questionnaire). Separate linear mixed-effect models were constructed for each outcome with adjustment for treatment arm, demographics, medical history, left ventricular ejection fraction, and duration of heart failure. Of the 216 study participants (median age 69 years, 48.2% women), 76% reported BB use at baseline. Participants with (vs without) BB therapy were older (70 vs 63.5 years, p = 0.001) and had a higher prevalence of ischemic heart disease (44% vs 23%, p = 0.01). In the adjusted linear mixed model, BB use over time was not associated with peak exercise oxygen uptake (ß 95% confidence interval [CI] 0.2 (-0.31 to 0.7), p = 0.5) and 6-minute walk distance (ß 95% CI 14.69 [-14.25 to 43.63], p = 0.3). However, BB use was associated with a higher anaerobic threshold (ß 95% CI 0.32 (0.02 to 0.62), p = 0.036) and better HRQL (lower quality of life as assessed by Minnesota living with heart failure questionnaire score) (ß 95% CI -6.68 [-10.96 to -2.4], p = 0.002). Future trials are needed to better evaluate the effects of BB on exercise capacity in patients with chronic stable HFpEF.

Glucagon-like peptide-1 receptor agonist and sodium-glucose cotransporter 2 inhibitor use among adults with diabetes mellitus by cardiovascular-kidney disease risk: National Health and Nutrition Examination Surveys, 2015-2020.

Objective: Glucagon-like peptide-1 receptor agonists (GLP1-RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2Is) lower adverse cardiac and kidney events among high-risk patients with diabetes mellitus (DM) and are now guideline-recommended as first-line therapy alongside metformin. However, the adoption of these new treatments from 2015 to 2020 among the highest-risk adults with DM remains unclear. Methods: We performed a cross-sectional analysis of the National Health and Nutrition Examination Surveys (NHANES) 2015-2020 to estimate the use of GLP1-RAs and SGLT2Is among adults with DM overall and by level of cardiovascular and kidney risk (CKR). We defined high CKR by history of atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), heart failure, or age ≥55 years with at least 2 ASCVD risk factors (i.e., obesity, hypertension, hyperlipidemia, or current smoker). Results: Overall, 2,432 participants with DM (mean age 60.6 years, 46.8 % female, 58.8 % Non-Hispanic White) were included, of which 1,869 and 563 were with and without high CKR, respectively. Participants with vs. without high CKR were more likely to be older, have higher systolic blood pressure, lower estimated glomerular filtration rate, use oral antidiabetic agents, and have health insurance. Overall, the weighted prevalence of GLP1-RA or SGLT2I was 9.0 % (95 % confidence interval [CI] 6.9-11.0): 4.8 % (95 % CI 3.6-6.1) took GLP1-RAs, and 5.1 % (95 % CI 3.3-7.0) took SGLT2Is. Use of GLP1-RAs or SGLT2Is did not differ between participants with vs. without high CKR (adjusted prevalence ratio [aPR] 1.00; 95 % CI 0.98-1.02). Participants with ASCVD were more likely to be on a GLP1-RA or SGLT2I (aPR 1.28; 95 % CI 1.25-1.31), while adults with CKD were less likely (aPR 0.84; 95 % CI 0.82-0.86). Conclusion: Among US adults with DM, GLP1-RA and SGLT2I use was low regardless of CKR. Data since 2020 analyzing the utilization of GLP1-RAs and SGLT2Is among high-CKR patients with DM is needed to identify implementation strategies for increased utilization.

Peripheral artery disease, chronic kidney disease, and recurrent admissions for acute decompensated heart failure: The ARIC study.

BACKGROUND AND AIMS: Peripheral artery disease (PAD) has not only been associated with recurrent hospitalization for acute decompensated heart failure (ADHF) but is also associated with chronic kidney disease (CKD), a known risk factor for worse heart failure outcomes. The interaction of CKD with PAD in post-discharge ADHF outcomes is not well known. METHODS: Since 2005, hospitalizations for ADHF were sampled from 4 US regions by the Atherosclerosis Risk in Communities (ARIC) study and classified by physician review. We examined the adjusted association of PAD with 1-year ADHF readmissions, in patients with and without CKD (defined by glomerular filtration rate [GFR] ≤60 mL/min/1.73 m2 [stage 3a or worse]). RESULTS: From 2005 to 2018, there were 1049 index hospitalizations for patients with ADHF (mean age 77 years, 66 % white) with creatinine data, who were discharged alive. Of these, 155 (15 %) had PAD and 66 % had CKD. In comparison to those without PAD, patients with PAD had more comorbid conditions and higher 1-year ADHF readmission rates, irrespective of CKD status. After adjustment, PAD was associated with a greater risk of 1-year ADHF readmissions, both for patients with concomitant CKD (HR, 1.70; 95 % CI: 1.29-2.24) and those without CKD (HR, 1.97; 95 % CI: 1.14-3.40); p-interaction = 0.8. CONCLUSION: Among patients hospitalized with ADHF, those with concurrent PAD have more prevalent cardiovascular comorbidities and higher likelihood of 1-year ADHF readmission, irrespective of CKD status. Integrating a more holistic approach in management of patients with concomitant heart failure, PAD and CKD may be an important strategy to improve the prognosis in this vulnerable population.

Role of telemedicine in the management of obesity: State-of-the-art review.

Obesity is a worsening public health epidemic that remains challenging to manage. Obesity substantially increases the risk of cardiovascular diseases and presents a significant financial burden on the healthcare system. Digital health interventions, specifically telemedicine, may offer an attractive and viable solution for managing obesity. During the COVID-19 pandemic, the need for a safer alternative to in-person visits led to the increased popularity of telemedicine. Multiple studies have tested the efficacy of telemedicine modalities, including digital coaching via videoconferencing sessions, e-health monitoring using wearable devices, and asynchronous forms of communication such as online chatrooms with counselors. In this review, we discuss the available evidence for telemedicine interventions in managing obesity, review current challenges and barriers to using telemedicine, and outline future directions to optimize the management of patients with obesity using telemedicine.

Association of global longitudinal strain by feature tracking cardiac magnetic resonance imaging with adverse outcomes among community-dwelling adults without cardiovascular disease: The Dallas Heart Study.

AIM: Left ventricular (LV) global longitudinal strain (GLS) may detect subtle abnormalities in myocardial contractility among individuals with normal LV ejection fraction (LVEF). However, the prognostic implications of GLS among healthy, community-dwelling adults is not well-established. METHODS AND RESULTS: Overall, 2234 community-dwelling adults (56% women, 47% Black) with LVEF ≥50% without a history of cardiovascular disease (CVD) from the Dallas Heart Study who underwent cardiac magnetic resonance (CMR) with GLS assessed by feature tracking CMR (FT-CMR) were included. The association of GLS with the risk of incident major adverse cardiovascular events (MACE; composite of incident myocardial infarction, incident heart failure [HF], hospitalization for atrial fibrillation, coronary revascularization, and all-cause death), and incident HF or death were assessed with adjusted Cox proportional hazards models. A total of 309 participants (13.8%) had MACE during a median follow-up duration of 17 years. Participants with the worst GLS (Q4) were more likely male and of the Black race with a history of tobacco use and diabetes with lower LVEF, higher LV end-diastolic volume, and higher LV mass index. Cumulative incidence of MACE was higher among participants with worse (Q4 vs. Q1) GLS (20.4% vs. 9.0%). In multivariable-adjusted Cox models that included clinical characteristics, cardiac biomarkers and baseline LVEF, worse GLS (Q4 vs. Q1) was associated with a significantly higher risk of MACE (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.07-2.24, p = 0.02) and incident HF or death (HR 1.57, 95% CI 1.03-2.38, p = 0.04). CONCLUSIONS: Impaired LV GLS assessed by FT-CMR among adults free of cardiovascular disease is associated with a higher risk of incident MACE and incident HF or death independent of cardiovascular risk factors, cardiac biomarkers and LVEF.

Advanced Glycation Endproducts: A Marker of Long-term Exposure to Glycemia.

This article examines the importance of advanced glycation endproducts (AGEs) and summarizes the structure of AGEs, pathological changes associated with AGEs, the contribution of AGEs to metabolic memory, and the value of AGEs as a predictor of diabetic complications and cardiovascular disease in people with and without diabetes. As a practical focus, skin autofluorescence (SAF) is examined as an attractive approach for estimating AGE burden. The measurement of AGEs may be of significant value to specific individuals and groups, including Black and Hispanic/Latino Americans, as they appear to have higher concentrations of hemoglobin A1c (HbA1c) than would be predicted by other metrics of mean glycemia. We hypothesize that if the amount of glycation of HbA1c is greater than expected from measured glucose levels, and if AGEs are accumulating, then this accumulation of AGEs might account for the increased rate of complications of diabetes in populations with high rates of vascular disease and other complications. Thus, identifying and modifying the burden of AGEs based on measurement of AGEs by SAF may turn out to be a worthwhile metric to determine individuals who are at high risk for the complications of diabetes as well as others without diabetes at risk of vascular disease. We conclude that available evidence supports SAF as both a clinical measurement and as a means of evaluating interventions aimed at reducing the risks of vascular disease and diabetic complications.

Temporal trends and racial/ethnic- and sex-differences in LDL cholesterol control among US adults with self-reported atherosclerotic cardiovascular disease.

Objective: Current guidelines for secondary prevention of atherosclerotic cardiovascular disease (ASCVD) recommend targeting a low-density lipoprotein cholesterol (LDL-C) of < 70 mg/dL. However, temporal trends and racial/ethnic- and sex-differences in achievement of LDL-C targets are not well described. We assessed trends and racial/ethnic- and sex-differences in achievement of LDL-C < 70 mg/dL using data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2008 to 2017-March 2020. Methods: We combined NHANES cycles into 4 periods: 2005-2008, 2009-2012, 2013-2016, and 2017-March 2020 and included participants ≥ 40 years with self-reported ASCVD. We estimated LDL-C < 70 mg/dL prevalence over time and further stratified by sex and race/ethnicity. We used multivariable logistic regression adjusted for social determinants of health and clinical covariates to model LDL-C target attainment. Results: Among 1,826 NHANES participants representing 7,161,221 US adults with self-reported ASCVD (59.6% ≥ 65 years, 56.4% male, 74.8% White), LDL-C target attainment increased from 19.0% (95% CI, 15.3%-23.3%) in 2005-2008 to 26.3% (95% CI, 20.4%-33.1%) in 2017-March 2020 (P = 0.012 for trend). Achievement of LDL-C < 70 mg/dL significantly rose among men from19.5% (95% CI, 15.1%-24.8%) to 29.4% (95% CI, 20.7%-29.9%) without significant change in women (from 18.3% [95% CI, 13.6%-24.2%] to 22.5% [95% CI, 13.0%-35.9%]; P = 0.241 for trend). Improvement in LDL-C target attainment was similar among White, Black, and Hispanic individuals (∼5-7% increase) and was greatest among individuals of other (non-White, Hispanic, or Black) race/ethnicity (23.1% increase). In our multivariable analysis, comorbid diabetes and ages 65-75 and > 75 years were associated with LDL-C target attainment. Conclusion: LDL-C control modestly improved between 2005 and 2008 and 2017-March 2020; however, only ∼1/4 of individuals met guideline-directed LDL-C treatment targets by 2017-March 2020. Women had lower LDL-C control and lesser magnitude of improvement in LDL-C control than men, highlighting a need for targeted interventions to improve lipid-lowering therapy utilization in this population.

Association between dietary phosphate intake and skeletal muscle energetics in adults without cardiovascular disease.

Highly bioavailable inorganic phosphate (Pi) is present in large quantities in the typical Western diet and represents a large fraction of total phosphate intake. Dietary Pi excess induces exercise intolerance and skeletal muscle mitochondrial dysfunction in normal mice. However, the relevance of this to humans remains unknown. The study was conducted on 13 individuals without a history of cardiopulmonary disease (46% female, 15% Black participants) enrolled in the pilot-phase of the Dallas Heart and Mind Study. Total dietary phosphate was estimated from 24-h dietary recall (ASA24). Muscle ATP synthesis was measured at rest, and phosphocreatinine (PCr) dynamics was measured during plantar flexion exercise using 7-T 31P magnetic resonance (MR) spectroscopy in the calf muscle. Correlation was assessed between dietary phosphate intake normalized to total caloric intake, resting ATP synthesis, and PCr depletion during exercise. Higher dietary phosphate intake was associated with lower resting ATP synthesis (r = -0.62, P = 0.03), and with higher levels of PCr depletion during plantar flexion exercise relative to the resting period (r = -0.72; P = 0.004). These associations remain significant after adjustment for age and estimated glomerular filtration rate (both P < 0.05). High dietary phosphate intake was also associated with lower serum Klotho levels, and Klotho levels are in turn associated with PCr depletion and higher ADP accumulation post exercise. Our study suggests that higher dietary phosphate is associated with reduced skeletal muscle mitochondrial function at rest and exercise in humans providing new insight into potential mechanisms linking the Western diet to impaired energy metabolism.NEW & NOTEWORTHY This is the first translational research study directly demonstrating the adverse effects of dietary phosphate on muscle energy metabolism in humans. Importantly, our data show that dietary phosphate is associated with impaired muscle ATP synthesis at rest and during exercise, independent of age and renal function. This is a new biologic paradigm with significant clinical dietary implications.

National Variation in Hospital MTEER Outcomes and Correlation With TAVR Outcomes: STS/ACC TVT Registry Analysis.

BACKGROUND: A single, multitiered valve center designation has been proposed to publicly identify centers with expertise for all valve therapies. The correlation between transcatheter aortic valve replacement (TAVR) and mitral transcatheter edge-to-edge repair (MTEER) procedures is unknown. OBJECTIVES: The authors sought to examine the relationship between site-level volumes and outcomes for TAVR and MTEER. We further explored variability between sites for MTEER outcomes. METHODS: Using the STS/ACC TVT (Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy) national registry, TAVR and MTEER procedures at sites offering both therapies from 2013 to 2022 were examined. Sites were ranked into deciles of adjusted in-hospital and 30-day outcomes separately for TAVR and MTEER and compared. Stepwise, hierarchical multivariable models were constructed for MTEER outcomes, and the median OR was calculated. RESULTS: Between 2013 and 2022, 384,394 TAVRs and 53,274 MTEERs (median annualized volumes: 93.6 and 18.8, respectively) were performed across 453 U.S. sites. Annualized TAVR and MTEER volumes were moderately correlated (r = 0.48; P < 0.001). After adjustment, 14.3% of sites had the same decile rank for TAVR and MTEER 30-day composite outcome, 50.6% were within 2 decile ranks; 35% had more discordant outcomes for the 2 procedures (P = 0.0005). For MTEER procedures, the median OR for the 30-day composite outcome was 1.57 (95% CI: 1.51-1.64), indicating a 57% variability in outcome by site. CONCLUSIONS: There is modest correlation between hospital-level volumes for TAVR and MTEER but low interprocedural correlation of outcomes. For similar patients, site-level variability for mortality/morbidity following MTEER was high. Factors influencing outcomes and "centers of excellence" as a whole may differ for TAVR and MTEER.

Trends and Outcomes Associated With Bariatric Surgery and Pharmacotherapies With Weight Loss Effects Among Patients With Heart Failure and Obesity.

BACKGROUND: Utilization patterns of bariatric surgery among older patients with heart failure (HF), and the associations with cardiovascular outcomes, are not well known. METHODS: Medicare beneficiaries with HF and at least class II obesity from 2013 to 2020 were identified with Medicare Provider Analysis and Review 100% inpatient files and Medicare 5% outpatient files. Patients who underwent bariatric surgery were matched to controls in a 1:2 ratio (matched on exact age, sex, race, body mass index, HF encounter year, and HF hospitalization rate pre-surgery/matched period). In an exploratory analysis, patients prescribed pharmacotherapies with weight loss effects (semaglutide, liraglutide, naltrexone-bupropion, or orlistat) were identified and matched to controls with a similar strategy in addition to HF medical therapy data. Cox models evaluated associations between weight loss therapies (as a time-varying covariate) and mortality risk and HF hospitalization rate (calculated as the rate of HF hospitalizations following index HF encounter per 100 person-months) during follow-up. RESULTS: Of 298 101 patients with HF and body mass index ≥35 kg/m2, 2594 (0.9%) underwent bariatric surgery (45% men; mean age, 56.2 years; mean body mass index, 51.5 kg/m2). In propensity-matched analyses over a median follow-up of 4.7 years, bariatric surgery was associated with lower risk of all-cause mortality (HR, 0.55 [95% CI, 0.49-0.63]; P<0.001), greater reduction in HF hospitalization rate (rate ratio, 0.72 [95% CI, 0.67-0.77]; P<0.001), and lower atrial fibrillation risk (HR, 0.78 [95% CI, 0.65-0.93]; P=0.006). Use of pharmacotherapies with weight loss effects was low (4.8%), with 96.3% prescribed GLP-1 (glucagon-like peptide-1) agonists (semaglutide, 23.6%; liraglutide, 72.7%). In propensity-matched analysis over a median follow-up of 2.8 years, patients receiving pharmacotherapies with weight loss effects (versus matched controls) had a lower risk of all-cause mortality (HR, 0.82 [95% CI, 0.71-0.95]; P=0.007) and HF hospitalization rate (rate ratio, 0.87 [95% CI, 0.77-0.99]; P=0.04). CONCLUSIONS: Bariatric surgery and pharmacotherapies with weight loss effects are associated with a lower risk of adverse outcomes among older patients with HF and obesity; however, overall utilization remains low.

Associations Between Cardiac Function and Brain Health in Diverse Middle-Aged Adults: The Dallas Heart Study-2.

Background: Previous studies have linked cardiovascular risk factors during midlife to cognitive function in later life. However, few studies have looked at the association between cardiac function, brain structure, and cognitive function and even less have included diverse middle-aged populations. Objectives: The objective of this study was to determine associations between cardiac and brain structure and function in a multiethnic cohort of middle-aged adults. Methods: A cross-sectional study was conducted in participants of the Dallas Heart Study phase 2 (N = 1,919; 46% Black participants). Left ventricular (LV) mass, LV ejection fraction, LV concentricity, and peak systolic strain (LV Ecc) were assessed by cardiac magnetic resonance imaging. White matter hyperintensities (WMH) volume was measured by fluid attenuated inversion recovery magnetic resonance imaging. The Montreal Cognitive Assessment was used to measure cognitive functioning. Associations between cardiac and brain measures were determined using multivariable linear regression after adjusting for cardiovascular risk factors, education level, and physical activity. Results: LV ejection fraction was associated with total Montreal Cognitive Assessment score (ß = 0.06 [95% CI: 0.003-0.12], P = 0.042) and LV Ecc was associated with WMH volume (ß = 0.08 [95% CI: 0.01-0.14], P = 0.025) in the overall cohort without significant interaction by race/ethnicity. Higher LV mass and concentricity were associated with larger WMH volume in the overall cohort (ß = 0.13 [95% CI: 0.03-0.23], P = 0.008 and 0.10 [95% CI: 0.03-0.17], P = 0.005). These associations were more predominant in Black than White participants (ß = 0.17 [95% CI: 0.04-0.30] vs ß = -0.009 [95% CI: -0.16 to 0.14], P = 0.036 and ß = 0.22 [95% CI: 0.13-0.32] vs ß = -0.11 [95% CI: -0.21 to -0.01], P < 0.0001, for LV mass and concentricity, respectively). Conclusions: Subclinical cardiac dysfunction indicated by LVEF was associated with lower cognitive function. Moreover, LV mass and concentric remodeling were associated with higher WMH burden, particularly among Black individuals.

A novel controlled metabolic accelerator for the treatment of obesity-related heart failure with preserved ejection fraction: Rationale and design of the Phase 2a HuMAIN trial.

AIMS: Compared with those without obesity, patients with obesity-related heart failure with preserved ejection fraction (HFpEF) have worse symptoms, haemodynamics, and outcomes. Current weight loss strategies (diet, drug, and surgical) work through decreased energy intake rather than increased expenditure and cause significant loss of skeletal muscle mass in addition to adipose tissue. This may have adverse implications for patients with HFpEF, who already have reduced skeletal muscle mass and function and high rates of physical frailty. Mitochondrial uncoupling agents may have unique beneficial effects by producing weight loss via increased catabolism rather than reduced caloric intake, thereby causing loss of adipose tissue while sparing skeletal muscle. HU6 is a controlled metabolic accelerator that is metabolized to the mitochondrial uncoupling agent 2,4-dinotrophenol. HU6 selectively increases carbon oxidation from fat and glucose while also decreasing toxic reactive oxygen species (ROS) production. In addition to sparing skeletal muscle loss, HU6 may have other benefits relevant to obesity-related HFpEF, including reduced specific tissue depots contributing to HFpEF; improved glucose utilization; and reduction in systemic inflammation via both decreased ROS production from mitochondria and decreased cytokine elaboration from excess, dysfunctional adipose. METHODS: We describe the rationale and design of HuMAIN-HFpEF, a Phase 2a randomized, double-blind, placebo-controlled, dose-titration, parallel-group trial in patients with obesity-related HFpEF to evaluate the effects of HU6 on weight loss, body composition, exercise capacity, cardiac structure and function, metabolism, and inflammation, and identify optimal dosage for future Phase 3 trials. CONCLUSIONS: HuMAIN will test a promising novel agent for obesity-related HFpEF.

Effect of liraglutide on thigh muscle fat and muscle composition in adults with overweight or obesity: Results from a randomized clinical trial.

BACKGROUND: Excess muscle fat is observed in obesity and associated with greater burden of cardiovascular risk factors and higher risk of mortality. Liraglutide reduces total body weight and visceral fat but its effect on muscle fat and adverse muscle composition is unknown. METHODS: This is a pre-specified secondary analysis of a randomized, double-blind, placebo-controlled trial that examined the effects of liraglutide plus a lifestyle intervention on visceral adipose tissue and ectopic fat among adults without diabetes with body mass index ≥30 kg/m2 or ≥27 kg/m2 and metabolic syndrome. Participants were randomly assigned to a once-daily subcutaneous injection of liraglutide (target dose 3.0 mg) or matching placebo for 40 weeks. Body fat distribution and muscle composition was assessed by magnetic resonance imaging at baseline and 40-week follow-up. Muscle composition was described by the combination of thigh muscle fat and muscle volume. Treatment difference (95% confidence intervals [CI]) was calculated by least-square means adjusted for baseline thigh muscle fat. The association between changes in thigh muscle fat and changes in body weight were assessed using Spearman correlation coefficients. The effect of liraglutide versus placebo on adverse muscle composition, denoted by high thigh muscle fat and low thigh muscle volume, was explored. RESULTS: Among the 128 participants with follow-up imaging (92.2% women, 36.7% Black), median muscle fat at baseline was 7.8%. The mean percent change in thigh muscle fat over median follow-up of 36 weeks was -2.87% among participants randomized to liraglutide (n = 73) and 0.05% in the placebo group (absolute change: -0.23% vs. 0.01%). The estimated treatment difference adjusted for baseline thigh muscle fat was -0.24% (95% CI, -0.41 to -0.06, P-value 0.009). Longitudinal change in thigh muscle fat was significantly associated with change in body weight in the placebo group but not the liraglutide group. The proportion of participants with adverse muscle composition decreased from 11.0% to 8.2% over follow-up with liraglutide, but there was no change with placebo. CONCLUSIONS: In a cohort of predominantly women with overweight or obesity in the absence of diabetes, once-daily subcutaneous liraglutide was associated with a reduction in thigh muscle fat and adverse muscle composition compared with placebo. The contribution of muscle fat improvement to the cardiometabolic benefits of liraglutide requires further study.