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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 31 P 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.

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., (© 2024 European Society of Cardiology.)

Background: The optimal approach to identify individuals with diabetes who are at a high risk for developing heart failure (HF) to inform implementation of preventive therapies is unknown, especially in those without atherosclerotic cardiovascular disease (ASCVD)., Methods: Adults with diabetes and no HF at baseline from 7 community-based cohorts were included. Participants without ASCVD who were at high risk for developing HF were identified using 1-step screening strategies: risk score (WATCH-DM [Weight, Age, Hypertension, Creatinine, HDL-C, Diabetes Control, QRS Duration, MI, and CABG] ≥12), NT-proBNP (N-terminal pro-B-type natriuretic peptide ≥125 pg/mL), hs-cTn (high-sensitivity cardiac troponin T ≥14 ng/L; hs-cTnI ≥31 ng/L), and echocardiography-based diabetic cardiomyopathy (echo-DbCM; left atrial enlargement, left ventricular hypertrophy, or diastolic dysfunction). High-risk participants were also identified using 2-step screening strategies with a second test to identify residual risk among those deemed low risk by the first test: WATCH-DM/NT-proBNP, NT-proBNP/hs-cTn, NT-proBNP/echo-DbCM. Across screening strategies, the proportion of HF events identified, 5-year number needed to treat and number needed to screen to prevent 1 HF event with an SGLT2i (sodium-glucose cotransporter 2 inhibitor) among high-risk participants, and cost of screening were estimated., Results: The initial study cohort included 6293 participants (48.2% women), of whom 77.7% without prevalent ASCVD were evaluated with different HF screening strategies. At 5-year follow-up, 6.2% of participants without ASCVD developed incident HF. The 5-year number needed to treat to prevent 1 HF event with an SGLT2i among participants without ASCVD was 43 (95% CI, 29-72). In the cohort without ASCVD, high-risk participants identified using 1-step screening strategies had a low 5-year number needed to treat (22 for NT-proBNP to 37 for echo-DbCM). However, a substantial proportion of HF events occurred among participants identified as low risk using 1-step screening approaches (29% for echo-DbCM to 47% for hs-cTn). Two-step screening strategies captured most HF events (75-89%) in the high-risk subgroup with a comparable 5-year number needed to treat as the 1-step screening approaches (30-32). The 5-year number needed to screen to prevent 1 HF event was similar across 2-step screening strategies (45-61). However, the number of tests and associated costs were lowest for WATCH-DM/NT-proBNP ($1061) compared with other 2-step screening strategies (NT-proBNP/hs-cTn: $2894; NT-proBNP/echo-DbCM: $16 358)., Conclusions: Selective NT-proBNP testing based on the WATCH-DM score efficiently identified a high-risk primary prevention population with diabetes expected to derive marked absolute benefits from SGLT2i to prevent HF., Competing Interests: Disclosures Dr Patel has served as a consultant to Novo Nordisk. Dr Segar has received honoraria from Merck. Dr Klonoff has served as a consultant for Afon, Atropos Health, Better Therapeutics, Glucotrack, Lifecare, Novo, Samsung, and Thirdwayv. Dr Khan has received personal fees from Merck. Dr Lam has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as a consultant or on advisory boards/steering committees/executive committees for Actelion, Alleviant Medical, Allysta, Amgen, ANaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma, EchoNous, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research and Development, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, Us2.ai, and WebMD Global; and has served as cofounder and nonexecutive director of Us2.ai. Dr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; has received research grants and honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, PhaseBio, and Pfizer; has received honoraria from Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group; is a member of the scientific excellence committee of the EMPEROR-Reduced trial (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure With Reduced Ejection Fraction); has served as a national lead investigator of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and EMPEROR-Reduced trials; and is the president of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Dr Nasir is on the advisory board of Amgen, Novartis, and Novo Nordisk, and his research is partly supported by the Jerold B. Katz Academy of Translational Research. Dr Butler has served as a consultant for Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Daxor Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Roche, Secretome, Sequana, SQ Innovation, Tenex, and Vifor. Dr Vaduganathan is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (National Institutes of Health/National Center for Advancing Translational Sciences Award UL 1TR002541) and has served on advisory boards or has received research grant support from American Regent, Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Cytokinetics, and Relypsa. Dr Pandey has received research support from the National Institute on Aging GEMSSTAR Grant (1R03AG067960-01) and the National Institute on Minority Health and Disparities (R01MD017529). Dr Pandey has received grant funding (to the institution) from Applied Therapeutics, Gilead Sciences, Ultromics, Myovista, and Roche; has served as a consultant for and/or has received honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, Roche Diagnostics, Sarfez Therapeutics, Edwards Lifesciences, Merck, Bayer, Novo Nordisk, Alleviant, Axon Therapies; and has received nonfinancial support from Pfizer and Merck. Dr Pandey is also a consultant for Palomarin Inc with stocks compensation. The other authors report no conflicts.

Background: The contemporary burden and characteristics of coronary atherosclerosis, assessed using coronary computed tomography angiography (CCTA), is unknown among asymptomatic adults with diabetes and prediabetes in the United States. The pooled cohort equations and coronary artery calcium (CAC) score stratify atherosclerotic cardiovascular disease risk, but their association with CCTA findings across glycemic categories is not well established., Methods: Asymptomatic adults without atherosclerotic cardiovascular disease enrolled in the Miami Heart Study were included. Participants underwent CAC and CCTA testing and were classified into glycemic categories. Prevalence of coronary atherosclerosis (any plaque, noncalcified plaque, plaque with ≥1 high-risk feature, maximal stenosis ≥50%) assessed by CCTA was described across glycemic categories and further stratified by pooled cohort equations-estimated atherosclerotic cardiovascular disease risk and CAC score. Adjusted logistic regression was used to evaluate the associations between glycemic categories and coronary outcomes., Results: Among 2352 participants (49.5% women), the prevalence of euglycemia, prediabetes, and diabetes was 63%, 30%, and 7%, respectively. Coronary plaque was more commonly present across worsening glycemic categories (euglycemia, 43%; prediabetes, 58%; diabetes, 69%), and similar pattern was observed for other coronary outcomes. In adjusted analyses, compared with euglycemia, prediabetes and diabetes were each associated with higher odds of any coronary plaque (OR, 1.30 [95% CI, 1.05-1.60] and 1.75 [1.17-2.61], respectively), noncalcified plaque (OR, 1.47 [1.19-1.81] and 1.99 [1.38-2.87], respectively), and plaque with ≥1 high-risk feature (OR, 1.65 [1.14-2.39] and 2.53 [1.48-4.33], respectively). Diabetes was associated with stenosis ≥50% (OR, 3.01 [1.79-5.08]; reference=euglycemia). Among participants with diabetes and estimated atherosclerotic cardiovascular disease risk <5%, 46% had coronary plaque and 10% had stenosis ≥50%. Among participants with diabetes and CAC=0, 30% had coronary plaque and 3% had stenosis ≥50%., Conclusions: Among asymptomatic adults, worse glycemic status is associated with higher prevalence and extent of coronary atherosclerosis, high-risk plaque, and stenosis. In diabetes, CAC was more closely associated with CCTA findings and informative in a larger population than the pooled cohort equations., Competing Interests: Disclosures Dr Patel has received research support from the National Heart, Lung, and Blood Institute (R21HL169708); has served as a consultant to Novo Nordisk. Dr Blankstein receives research support from Amgen Inc and Novartis Inc and is a consultant to Caristo Diagnostics, Silence Therapeutics, and Roivant Sciences Inc. Dr Shapiro is on the advisory boards of Amgen, Novartis, and Novo Nordisk and is a consultant for Regeneron. Dr. Pandey has received research support from the National Institute on Aging GEMSSTAR Grant (1R03AG067960-01), the National Institute on Minority Health and Disparities (R01MD017529), and the National Institute of Heart, Lung, and Blood Institute (R21HL169708). Dr. Pandey has received grant funding (to the institution) from Applied Therapeutics, Gilead Sciences, Ultromics, Myovista, and Roche; has served as a consultant for and/or received honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, Roche Diagnostics, Sarfez Therapeutics, Edwards Lifesciences, Merck, Bayer, Novo Nordisk, Alleviant, Axon Therapies, and has received nonfinancial support from Pfizer and Merck. Dr. Pandey is also a consultant for Palomarin Inc. with stocks compensation. Dr Cury declares that he is a consultant to GE Healthcare, Covera Health, and Cleerly. Dr Nasir is on the advisory board of Amgen, Novartis, Novo Nordisk, and his research is partly supported by the Jerold B. Katz Academy of Translational Research. Dr Cainzos-Achirica and Dr Nasir are part of the steering committee of the PAK-SEHAT study, which is partly funded by Getz Pharma. The other authors report no conflicts.

Geroscience posits that cardiovascular disease (CVD) and other chronic diseases result from progressive erosion of the effectiveness of homeostatic mechanisms that oppose age-related accumulation of molecular damage. This hypothetical common root to chronic diseases explains why patients with CVD are often affected by multimorbidity and frailty and why older age negatively affects CVD prognosis and treatment response. Gerotherapeutics enhance resilience mechanisms that counter age-related molecular damage to prevent chronic diseases, frailty, and disability, thereby extending healthspan. Here, we describe the main resilience mechanisms of mammalian aging, with a focus on how they can affect CVD pathophysiology. We next present novel gerotherapeutic approaches, some of which are already used in management of CVD, and explore their potential to transform care and management of CVD. The geroscience paradigm is gaining traction broadly in medical specialties, with potential to mitigate premature aging, reduce health care disparities, and improve population healthspan., Competing Interests: Funding Support and Author Disclosures Dr Forman has received funding support from National Institute on Aging (NIA) 1R01 AG058883, R01 AG060499, U19AG065188, R01 AG073633, R01 AG077179, and P30AG024827; VA RR&D 1I21RX004409 and HSR&D1 I01 HX003518; and PCORI IHS-2021C3-24147. Dr Kuchel has received funding support from NIA P30 AG067988, U54 AG075941, R25AG073119, R33AG061456, R01AG058814, R01AG051647, and R01AG075271; NIAID U01 AI165452 and R01AI142086; and PCORI IHS-1502-27171. Dr Newman is cofounder and shareholder in BHB Therapeutics Ltd and Selah Therapeutics, Ltd, which develop products related to ketone bodies; and has received funding support from NIA R01 AG067333, NIA R01 AG068025, NIA R25AG073119, Longevity Impetus, Department of Defense PRMRP W81XWH2210867, and Buck institutional funds. Dr Kirkland has financial interest related to this research, including patents and pending patents covering senolytic drugs and their uses that are held by Mayo Clinic (this research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic conflict of interest policies); and has received funding support from NIH R37AG013925, R33AG061456, R01AG68048, R01AG 64165, and P01AG062413, the Connor Fund, Robert J. and Theresa W. Ryan Fund, and the Noaber Foundation. Dr Volpi has served on the Longeveron Scientific Advisory Board; has received funding from NIH P30 AG024832, R01 AG049611, R01 AG057732, and the Dairy Research Institute DMI 2859; has served as site PI for NIH R01AG078153, U19 AG062682, R01 AG0688, PCORI PCS-2017C1-6534, and Metro International Biotech, LLC; and has served as co-I for NIH UL1 TR001439, U01 AR071150, R01 AG064092. Dr Taffet has received honoraria from Boehringer Ingelheim and Novartis (Switzerland); holds intellectual property in Animatus Biosciences, and Uptodate; and has received funding support from NIA and is co-Investigator on R01AG068260, R01AG059599, and R01AG054131. Dr Barzilai has received funding from the NIA (P30AG038072) and the American Federation for Aging Research (Scientific Director). Dr Pandey has received honoraria from Applied Therapeutics, Roche, SC Pharmaceuticals, and Gilead Sciences; has served in advisory and consultant roles for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, Emmi Solutions, Axon Therapies, Sarfez Pharmaceuticals, Alleviant Medical, Palomarin Inc, Pieces Technologies, and Roche Diagnostics; has received nonfinancial support from Pfizer and Merck; and has received funding support from the NIA GEMSSTAR Grant (1R03AG067960-01), and the National Institute on Minority Health and Disparities (R01MD017529). Dr Kitzman has received honoraria as a consultant for Bayer, Merck, Corvia Medical, Boehringer Ingelheim, Ketyo, Rivus, Novo Nordisk, AstraZeneca, Pfizer, and Novartis; has received grant funding from Novartis, Bayer, Novo Nordisk, Rivus, Pfizer, and AstraZeneca; has stock ownership in Gilead Sciences; and has received funding support from the Kermit Glenn Phillips II Chair in Cardiovascular Medicine, and NIH grants U01AG076928, R01AG078153, R01AG045551, R01AG18915, P30AG021332, U24AG059624, and U01HL160272. Dr Libby is an unpaid consultant to or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Moderna, Novo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron; is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Eulicid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, TenSixteen Bio, Soley Thereapeutics, and XBiotech, Inc; his laboratory has received research funding in the last 2 years from Novartis, Novo Nordisk and Genentech; is on the Board of Directors of XBiotech, Inc; has a financial interest in Xbiotech, a company developing therapeutic human antibodies, in TenSixteen Bio, a company targeting somatic mosaicism and clonal hematopoiesis of indeterminate potential (CHIP) to discover and develop novel therapeutics to treat age-related diseases, and in Soley Therapeutics, a biotechnology company that is combining artificial intelligence with molecular and cellular response detection for discovering and developing new drugs, currently focusing on cancer therapeutics; his interests were reviewed and are managed by Brigham and Women's Hospital and Mass General Brigham in accordance with their conflict-of-interest policies; and receives funding support from the National Heart, Lung, and Blood Institute (1R01HL134892 and 1R01HL163099-01), the RRM Charitable Fund, and the Simard Fund. Dr Ferrucci has received funding support through the Intramural Research Program of the National Institute on Aging, NIH., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Social determinants of health are implicated in the geographic variation in cardiovascular diseases (CVDs). The social vulnerability index (SVI) is an estimate of a neighborhood's potential for deleterious outcomes when faced with natural disasters or disease outbreaks. We sought to investigate the association of the SVI with cardiovascular risk factors and the prevalence of coronary heart disease (CHD) in the United States at the census tract level. We linked census tract SVI with prevalence of census tract CVD risk factors (smoking, high cholesterol, diabetes, high blood pressure, low physical activity and obesity), and prevalence of CHD obtained from the behavioral risk factor surveillance system. We evaluated the association between SVI, its sub-scales, CVD risk factors and CHD prevalence using linear regression. Among 72,173 census tracts, prevalence of all cardiovascular risk factors increased linearly with SVI. A higher SVI was associated with a higher CHD prevalence (R 2  = 0.17, P < 0.0001). The relationship between SVI and CHD was stronger when accounting for census-tract median age (R 2  = 0.57, P < 0.0001). A multivariable linear regression model including 4 SVI themes separately explained considerably more variation in CHD prevalence than the composite SVI alone (50.0% vs 17.3%). Socioeconomic status and household composition and disability were the SVI themes most closely associated with cardiovascular risk factors and CHD prevalence. In the United States, social vulnerability can explain significant portion of geographic variation in CHD, and its risk factors. Neighborhoods with high social vulnerability are at disproportionately increased risk of CHD and its risk factors. Social determinants of health are implicated in the geographic variation in cardiovascular diseases (CVDs). We investigated the association of social vulnerability index (SVI) with cardiovascular risk factors and the prevalence of coronary heart disease (CHD) in the United States at the census tract level. We show that cardiovascular risk factors and CHD were more common with higher SVI. A multivariable linear regression model including 4 SVI themes separately explained considerably more variation in CHD prevalence than the composite SVI alone (50.0% vs 17.3%). Socioeconomic status and household composition and/or disability were the SVI themes most closely associated with cardiovascular risk factors and CHD prevalence., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The study aimed to assess the treatment effects of the two medications on cardiovascular and kidney outcomes in Asian compared with White patients with type 2 diabetes mellitus (T2DM)., Methods: MEDLINE, EMBASE, and CENTRAL were searched up to October 31, 2022. We included the trials that assessed the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus placebo in Asian and White patients with T2DM on major adverse cardiovascular events (MACE) and kidney outcomes. The Bucher method was used to perform an indirect comparison for estimating the differences in treatment effects of GLP-1 RA and SGLT2i between Asian versus White patients. Interaction tests were also performed for treatment-by-race to assess the potential effect modification by race., Results: We included 22 publications from 13 randomized trials. For MACE, there were no differences in treatment effects of GLP-1 RA (HR = 0.84, 95% CI: 0.68-1.04) or SGLT2i (HR = 0.90, 95% CI: 0.72-1.13) in Asian versus White patients. No differences in treatment effects of SGLT2i on kidney outcomes in Asian versus White patients were found (HR = 1.01, 95% CI: 0.75-1.36). There was no significant effect modification by race on cardiovascular and kidney outcomes., Conclusions: There were no significant differences in treatment effects of GLP-1 RA or SGLT2i for MACE between Asian and White patients with T2DM. Likewise, no significant differences in treatment effects of SGLT2i on kidney outcomes were found between Asian and White patients., Competing Interests: Declaration of competing interest All authors declare no competing interests., (Copyright © 2023 Research Trust of DiabetesIndia (DiabetesIndia) and National Diabetes Obesity and Cholesterol Foundation (N-DOC). Published by Elsevier Ltd. All rights reserved.)

Background: Racial disparities have been reported for breast cancer and cardiovascular disease (CVD) outcomes. The determinants of racial disparities in CVD outcomes are not yet fully understood. We aimed to examine the impact of individual and neighborhood-level social determinants of health (SDOH) on the racial disparities in major adverse cardiovascular events (MACE; consisting of heart failure, acute coronary syndrome, atrial fibrillation, and ischemic stroke) among female patients with breast cancer., Methods: This 10-year longitudinal retrospective study was based on a cancer informatics platform with electronic medical record supplementation. We included women aged ≥18 years diagnosed with breast cancer. SDOH were obtained from LexisNexis, and consisted of the domains of social and community context, neighborhood and built environment, education access and quality, and economic stability. Race-agnostic (overall data with race as a feature) and race-specific machine learning models were developed to account for and rank the SDOH impact in 2-year MACE., Results: We included 4,309 patients (765 non-Hispanic Black [NHB]; 3,321 non-Hispanic white). In the race-agnostic model (C-index, 0.79; 95% CI, 0.78-0.80), the 5 most important adverse SDOH variables were neighborhood median household income (SHapley Additive exPlanations [SHAP] score [SS], 0.07), neighborhood crime index (SS = 0.06), number of transportation properties in the household (SS = 0.05), neighborhood burglary index (SS = 0.04), and neighborhood median home values (SS = 0.03). Race was not significantly associated with MACE when adverse SDOH were included as covariates (adjusted subdistribution hazard ratio, 1.22; 95% CI, 0.91-1.64). NHB patients were more likely to have unfavorable SDOH conditions for 8 of the 10 most important SDOH variables for the MACE prediction., Conclusions: Neighborhood and built environment variables are the most important SDOH predictors for 2-year MACE, and NHB patients were more likely to have unfavorable SDOH conditions. This finding reinforces that race is a social construct.

Aims: Ketone bodies (KB) are an important alternative metabolic fuel source for the myocardium. Experimental and human investigations suggest that KB may have protective effects in patients with heart failure. This study aimed to examine the association between KB and cardiovascular outcomes and mortality in an ethnically diverse population free from cardiovascular disease (CVD)., Methods and Results: This analysis included 6796 participants (mean age 62 ± 10 years, 53% women) from the Multi-Ethnic Study of Atherosclerosis. Total KB was measured by nuclear magnetic resonance spectroscopy. Multivariable-adjusted Cox proportional hazard models were used to examine the association of total KB with cardiovascular outcomes. At a mean follow-up of 13.6 years, after adjusting for traditional CVD risk factors, increasing total KB was associated with a higher rate of hard CVD, defined as a composite of myocardial infarction, resuscitated cardiac arrest, stroke, and cardiovascular death, and all CVD (additionally included adjudicated angina) [hazard ratio, HR (95% confidence interval, CI): 1.54 (1.12-2.12) and 1.37 (1.04-1.80) per 10-fold increase in total KB, respectively]. Participants also experienced an 87% (95% CI: 1.17-2.97) increased rate of CVD mortality and an 81% (1.45-2.23) increased rate of all-cause mortality per 10-fold increase in total KB. Moreover, a higher rate of incident heart failure was observed with increasing total KB [1.68 (1.07-2.65), per 10-fold increase in total KB]., Conclusion: The study found that elevated endogenous KB in a healthy community-based population is associated with a higher rate of CVD and mortality. Ketone bodies could serve as a potential biomarker for cardiovascular risk assessment., Competing Interests: Conflict of interest statement F.R. reported receiving funding support from the National Heart, Lung, and Blood Institute, National Institutes of Health (1K01HL144607), Doris Duke Charitable Foundation, and the American Heart Association/Robert Wood Johnson Harold Amos Medical Faculty Development Program and consulting fees from Novartis, NovoNordisk, Amgen, and HealthPals. C.d.F. has received consulting fees from Abbott Diagnostics, FujiRebio, Ortho Diagnostics, Quidell, Roche Diagnostics, Siemens Healthineers, and a patent entitled ‘Methods for assessing differential risk for developing heart failure’ (patent number: PCT/US2015/029838). M.B. reported receiving funding support from the National Institutes of Health, the American Heart Association, the Food and Drug Administration, and NovoNordisk and consulting fees from Kowa. A.P. reported receiving funding support from the National Institute on Minority Health and Disparities (R01MD017529), National Institute on Aging GEMSSTAR Grant (1R03AG067960–01), Gilead Sciences, and has received consulting fees from Tricog Health Inc and Cytokinetics. M.V. has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, and Sanofi, speaker engagements with Novartis and Roche Diagnostics, and participates on clinical trial committees for studies sponsored by Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. M.D.S. reported receiving funding support from the National Institute Health, Amgen, Novartis, Regeneron and served on scientific advisory boards for Amgen, Novartis, Novo Nordisk, Esperion, Regeneron, Ionis. All other authors declare that they have no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: The burden of atherosclerotic cardiovascular disease (ASCVD) in the US is higher among Black and Hispanic vs White adults. Inclusion of race in guidance for statin indication may lead to decreased disparities in statin use., Objective: To evaluate prevalence of primary prevention statin use by race and ethnicity according to 10-year ASCVD risk., Design, Setting, and Participants: This serial, cross-sectional analysis performed in May 2022 used data from the National Health and Nutrition Examination Survey, a nationally representative sample of health status in the US, from 2013 to March 2020 (limited cycle due to the COVID-19 pandemic), to evaluate statin use for primary prevention of ASCVD and to estimate 10-year ASCVD risk. Participants aged 40 to 75 years without ASCVD, diabetes, low-density lipoprotein cholesterol levels 190 mg/dL or greater, and with data on medication use were included., Exposures: Self-identified race and ethnicity (Asian, Black, Hispanic, and White) and 10-year ASCVD risk category (5%-<7.5%, 7.5%-<20%, ≥20%)., Main Outcomes and Measures: Prevalence of statin use, defined as identification of statin use on pill bottle review., Results: A total of 3417 participants representing 39.4 million US adults after applying sampling weights (mean [SD] age, 61.8 [8.0] years; 1289 women [weighted percentage, 37.8%] and 2128 men [weighted percentage, 62.2%]; 329 Asian [weighted percentage, 4.2%], 1032 Black [weighted percentage, 12.7%], 786 Hispanic [weighted percentage, 10.1%], and 1270 White [weighted percentage, 73.0%]) were included. Compared with White participants, statin use was lower in Black and Hispanic participants and comparable among Asian participants in the overall cohort (Asian, 25.5%; Black, 20.0%; Hispanic, 15.4%; White, 27.9%) and within ASCVD risk strata. Within each race and ethnicity group, a graded increase in statin use was observed across increasing ASCVD risk strata. Statin use was low in the highest risk stratum overall with significantly lower rates of use among Black (23.8%; prevalence ratio [PR], 0.90; 95% CI, 0.82-0.98 vs White) and Hispanic participants (23.9%; PR, 0.90; 95% CI, 0.81-0.99 vs White). Among other factors, routine health care access and health insurance were significantly associated with higher statin use in Black, Hispanic, and White adults. Prevalence of statin use did not meaningfully change over time by race and ethnicity or by ASCVD risk stratum., Conclusions and Relevance: In this study, statin use for primary prevention of ASCVD was low among all race and ethnicity groups regardless of ASCVD risk, with the lowest use occurring among Black and Hispanic adults. Improvements in access to care may promote equitable use of primary prevention statins in Black and Hispanic adults.

Background: Among Black adults, high-sensitivity cardiac troponin I (hs-cTnI) is associated with heart failure (HF) risk. The association of longitudinal changes in hs-cTnI with risk of incident HF, HF with reduced and preserved ejection fraction (HFrEF and HFpEF, respectively), among Black adults is not well-established., Methods and Results: This study included Black participants from the Jackson Heart Study with available hs-cTnI data at visits 1 (2000-2004) and 2 (2005-2008) and no history of cardiovascular disease. Cox models were used to evaluate associations of categories of longitudinal change in hs-cTnI with incident HF risk. Among 2423 participants, 11.6% had incident elevation in hs-cTnI at visit 2, and 16.9% had stable or improved elevation (≤50% increase in hs-cTnI), and 4.0% had worsened hs-cTnI elevation (>50% increase). Over a median follow-up of 12.0 years, there were 139 incident HF hospitalizations (64 HFrEF, 58 HFpEF). Compared with participants without an elevated hs-cTnI, those with incident, stable or improved, or worsened hs-cTnI elevation had higher HF risk (adjusted hazard ratio 3.20 [95% confidence interval, 1.92-5.33]; adjusted hazard ratio 2.40, [95% confidence interval, 1.47-3.92]; and adjusted hazard ratio 8.10, [95% confidence interval, 4.74-13.83], respectively). Similar patterns of association were observed for risk of HFrEF and HFpEF., Conclusions: Among Black adults, an increase in hs-cTnI levels on follow-up was associated with a higher HF risk., Lay Summary: The present study included 2423 Black adults from the Jackson Heart Study with available biomarkers of cardiac injury and no history of cardiovascular disease at visits 1 and 2. The majority of participants did not have evidence of cardiac injury at both visits (67.5%), 11.6% had evidence of cardiac injury only on follow-up, 14.5% had stable elevations, 4.0% had worsened elevations, and 2.4% had improved elevations of cardiac injury biomarkers during follow-up. Compared with participants without evidence of cardiac injury, those with new, stable, and worsened levels of cardiac injury had a higher risk of developing heart failure., Tweet: Among Black adults, persistent or worsening subclinical myocardial injury is associated with an elevated risk of HF., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The majority of cardiovascular randomized controlled trials (RCTs) test interventions in selected patient populations under explicitly protocol-defined settings. Although these 'explanatory' trial designs optimize conditions to test the efficacy and safety of an intervention, they limit the generalizability of trial findings in broader clinical settings. The concept of 'pragmatism' in RCTs addresses this concern by providing counterbalance to the more idealized situation underpinning explanatory RCTs and optimizing effectiveness over efficacy. The central tenets of pragmatism in RCTs are to test interventions in routine clinical settings, with patients who are representative of broad clinical practice, and to reduce the burden on investigators and participants by minimizing the number of trial visits and the intensity of trial-based testing. Pragmatic evaluation of interventions is particularly important in cardiovascular diseases, where the risk of death among patients has remained fairly stable over the past few decades despite the development of new therapeutic interventions. Pragmatic RCTs can help to reveal the 'real-world' effectiveness of therapeutic interventions and elucidate barriers to their implementation. In this Review, we discuss the attributes of pragmatism in RCT design, conduct and interpretation as well as the general need for increased pragmatism in cardiovascular RCTs. We also summarize current challenges and potential solutions to the implementation of pragmatism in RCTs and highlight selected ongoing and completed cardiovascular RCTs with pragmatic trial designs., (© 2022. Springer Nature Limited.)

Background: Although diabetes increases heart failure (HF) risk, it is unclear how various dysglycemia markers (hemoglobin A 1C [HbA 1C ], fasting plasma glucose [FPG], homeostasis model assessment of insulin resistance, and fasting insulin) are associated with HF subtypes (HF with preserved ejection fraction [HFpEF] and HF with reduced ejection fraction [HFrEF]). We assessed the relation of markers of dysglycemia and risks of HFpEF and HFrEF., Methods and Results: We included 6688 adults without prevalent cardiovascular disease who attended the first MESA visit (2000-2002) and were followed for incident hospitalized HF (HFpEF or HFrEF). Association of glycemic markers and status (normoglycemia, prediabetes, diabetes) with HFpEF and HFrEF were evaluated using adjusted Cox models. Over a median follow-up of 14.9 years, there were 356 HF events (145 HFpEF, 173 HFrEF, and 38 indeterminate HF events). Diabetes status conferred higher risks of HFpEF (hazard ratio [HR] 1.85, 95% confidence interval [CI] 1.57-2.68) and HFrEF (HR 2.02, 95% CI 1.38-2.97) compared with normoglycemia. Higher levels of FPG (≥126 mg/dL) and HbA 1C (≥6.5%) were associated with similarly higher risks of HFpEF (HR for FPG 1.96, 95% CI 1.21-3.17; HR for HbA 1C 2.00, 95% CI 1.20-3.31) and HFrEF (HR for FPG 1.84, 95% CI 1.18-2.88; HR for HbA 1C 1.99, 95% CI 1.28-3.09) compared with reference values. Prediabetic range HbA 1C (5.7%-6.4%) or FPG (100%-125 mg/dL), homeostasis model assessment of insulin resistance, and fasting insulin were not significantly associated with HFpEF or HFrEF., Conclusions: Among community-dwelling individuals, HbA 1C and FPG in the diabetes range were each associated with higher risks of HFpEF and HFrEF, with similar magnitudes of their associations., Lay Abstract: Heart failure (HF) has 2 major subtypes (the heart's inability to pump or to fill up). Diabetes is known to increase HF risk, but its effects and that of markers of high glucose levels (fasting blood glucose and hemoglobin A 1C ) on the occurrence of HF subtypes remains unknown. Among 6688 adults without known cardiovascular disease followed for nearly 15 years, diabetes conferred significantly higher risks of both HF types, compared with those with normal blood glucose levels. Higher levels of fasting blood glucose and hemoglobin A 1C were similarly associated with higher risks of both types of HF., Competing Interests: Declaration of Competing Interest There are no potential conflict of interest relevant to this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Among individuals with atherosclerotic cardiovascular disease (ASCVD), type 2 diabetes mellitus (T2DM) is common and confers increased risk for morbidity and mortality. Differentiating risk is key to optimize efficiency of treatment selection. Our objective was to develop and validate a model to predict risk of major adverse cardiovascular events (MACE) comprising the first event of cardiovascular death, myocardial infarction (MI), or stroke for individuals with both T2DM and ASCVD., Methods: Using data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), we used Cox proportional hazards models to predict MACE among participants with T2DM and ASCVD. All baseline covariates collected in the trial were considered for inclusion, although some were excluded immediately because of large missingness or collinearity. A full model was developed using stepwise selection in each of 25 imputed datasets, and comprised candidate variables selected in 20 of the 25 datasets. A parsimonious model with a maximum of 10 degrees of freedom was created using Cox models with least absolute shrinkage and selection operator (LASSO), where the adjusted R-square was used as criterion for selection. The model was then externally validated among a cohort of participants with similar criteria in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial. Discrimination of both models was assessed using Harrell's C-index and model calibration by the Greenwood-Nam-D'Agostino statistic based on 4-year event rates., Results: Overall, 1491 (10.2%) of 14,671 participants in TECOS and 130 (9.3%) in the ACCORD validation cohort (n = 1404) had MACE over 3 years' median follow-up. The final model included 9 characteristics (prior stroke, age, chronic kidney disease, prior MI, sex, heart failure, insulin use, atrial fibrillation, and microvascular complications). The model had moderate discrimination in both the internal and external validation samples (C-index = 0.65 and 0.61, respectively). The model was well calibrated across the risk spectrum-from a cumulative MACE rate of 6% at 4 years in the lowest risk quintile to 26% in the highest risk quintile., Conclusion: Among patients with T2DM and prevalent ASCVD, this 9-factor risk model can quantify the risk of future ASCVD complications and inform decision making for treatments and intensity., (© 2022. The Author(s).)

Background: Supranormal ejection fraction by echocardiography in clinically referred patient populations has been associated with an increased risk of cardiovascular disease (CVD). The prognostic implication of supranormal left ventricular ejection fraction (LVEF)-assessed by cardiac magnetic resonance (CMR)-in healthy, community-dwelling individuals is unknown., Objectives: The purpose of this study is to investigate the prognostic implication of supranormal LVEF as assessed by CMR and its inter-relationship with stroke volume among community-dwelling adults without CVD., Methods: Participants from the MESA (Multi-Ethnic Study of Atherosclerosis) and DHS (Dallas Heart Study) cohorts free of CVD who underwent CMR with LVEF above the normal CMR cutoff (≥57%) were included. The association between cohort-specific LVEF categories and risk of clinically adjudicated major adverse cardiovascular events (MACE) was assessed using adjusted Cox models. Subgroup analysis was also performed to evaluate the association of LVEF and risk of MACE among individuals stratified by left ventricular stroke volume index., Results: The study included 4,703 participants from MESA and 2,287 from DHS with 727 and 151 MACE events, respectively. In adjusted Cox models, the risk of MACE was highest among individuals in LVEF Q4 (vs Q1) in both cohorts after accounting for potential confounders (MESA: HR = 1.27 [95% CI: 1.01-1.60], P = 0.04; DHS: HR = 1.72 [95% CI: 1.05-2.79], P = 0.03). A significant interaction was found between the continuous measures of LVEF and left ventricular stroke volume index (P interaction = 0.02) such that higher LVEF was significantly associated with an increased risk of MACE among individuals with low but not high stroke volume., Conclusions: Among community-dwelling adults without CVD, LVEF in the supranormal range is associated with a higher risk of adverse cardiovascular outcomes, particularly in those with lower stroke volume., Competing Interests: Funding Support and Author Disclosures The MESA study was supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute; and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). The Dallas Heart Study was supported by a grant from the Donald W. Reynolds Foundation and the National Center for Advancing Translational Sciences (UL1TR001105). Dr Segar has received nonfinancial support from Pfizer and Merck. Dr Pandey has received research support from the Texas Health Resources Clinical Scholarship, the Gilead Sciences Research Scholar Program, the National Institute of Aging GEMSSTAR Grant (1R03AG067960-01), and Applied Therapeutics; has served on the advisory board of Roche Diagnostics; serves as a consultant to Tricog Health, Rivus, and Lilly USA; and has received nonfinancial support from Pfizer and Merck. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Prior studies have reported improvements in population-level risk factor burden and cardiovascular disease (CVD) outcomes using polypills for CVD risk reduction. However, a comprehensive assessment of the impact of polypills on CVD outcomes, mortality, adherence, and side effects across different settings has not previously been reported. We performed a systematic review and meta-analysis of randomized controlled trials examining the association between polypill therapy and CVD outcomes published before February 2021. The primary outcome of interest was the risk of major adverse CVD events (MACE). Risk ratios for dichotomous outcomes were converted to log RR and pooled using a generic inverse variance weighted random-effects model. Data for continuous outcomes were pooled using random-effects modeling and presented as mean differences with 95% CIs. Eight studies representing 25,584 patients were included for analysis. In the overall pooled analysis, the use of polypills was associated with a non-significant reduction in the risk of MACE (RR: 0.85; 95% CI: 0.70-1.02) and significant reductions in the risk of all-cause mortality (RR: 0.90; 95% CI: 0.81-1.00). The reductions in the risk of MACE with polypill use varied by baseline risk and nature of the study population (primary prevention vs. secondary prevention), with the most significant risk reduction among lower-risk cohorts, including within primary prevention populations [RR 0.70 (0.62, 0.79)]. Among measures of CVD risk factors, modest but significant reductions were observed for systolic and diastolic blood pressure [systolic: mean difference 1.99 mmHg (95% CI: -3.07 to -0.91); diastolic: mean difference 1.30 mmHg (95% CI: -2.42 to -0.19), but not for levels of total or low-density lipoprotein-cholesterol. Use of the polypill strategy significantly improved drug adherence (RR: 1.31; 95% CI: 1.11-1.55) with no association between polypill use and rates of adverse events or drug discontinuation. The use of polypill formulations is associated with significant reductions in CVD risk factors and the risk of all-cause mortality and MACE, particularly in the low-risk and primary prevention population., Competing Interests: Declaration of Competing Interest Dr. Rao is supported by an instiutional training grant from the National Insitutes of Health (grant T-32HL125247-06). Dr. Greene has received research support from the Duke University Department of Medicine Chair’s Research Award, American Heart Association, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics, and Sanofi; has received speaker fees from Boehringer Ingelheim; and has served as a consultant for Amgen, Bayer, Bristol Myers Squibb, Merck, Sanofi, and Vifor. Dr. Pandey received grant funding outside the present study from Applied Therapeutics; has received honoraria outside of the present study as an advisor/consultant for Tricog Health Inc. and Lilly, USA, and has received nonfinancial support from Pfizer and Merck. Dr. Pandey is supported by the Gilead Sciences Research Scholar Program, the National Institute of Aging GEMSSTAR Grant (1R03AG067960–01), and grant support from Applied Therapeutics. Other authors have no relevant disclosures., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Current risk scores to estimate atherosclerotic cardiovascular disease (ASCVD) risk and allocate statins in at-risk persons have largely been developed in Western populations; their applicability in India is uncertain., Objective: To assess eligibility for primary prevention statin therapy using the 2018 U.S Multisociety Guideline and other contemporary cholesterol guidelines in patients presenting with ST-elevation myocardial infarction (STEMI) in the North India STEMI (NORIN-STEMI) registry., Methods: NORIN-STEMI registry prospectively enrolled 3,635 patients at 2 tertiary care centers in Delhi, India from January 2019 to February 2020. Pooled cohort risk equations were used to estimate ASCVD risk at presentation. Patients were evaluated for statin eligibility using the 2018 U.S Multisociety Guideline, United States Preventive Services Task Force (USPSTF), and National Cholesterol Education Program (NCEP) III cholesterol guidelines., Results: A total of 2,551 met the inclusion criteria. The median age was 54 years; 17% were women. The median ASCVD risk was 7.0%. At the time of MI, 54% of patients were eligible for primary prevention statin therapy by Multisociety Guideline, 46% by USPSTF, and 30% by NCEP III guidelines. These findings were applicable in both women and men. Compared with patients aged ≥50 years, those <50 years were less likely to be recommended statin therapy by all the three guidelines., Conclusion: A significant proportion of patients with STEMI in India did not meet the current guideline-based threshold for statin therapy for primary prevention. Novel risk stratification tools are needed to identify patients for primary prevention statin therapy in this population., (Copyright © 2021. Published by Elsevier Inc.)

Importance: Cardiovascular (CV) mortality has declined for more than 3 decades in the US. However, differences in declines among residents at a US county level are not well characterized., Objective: To identify unique county-level trajectories of CV mortality in the US during a 35-year study period and explore county-level factors that are associated with CV mortality trajectories., Design, Setting, and Participants: This longitudinal cross-sectional analysis of CV mortality trends used data from 3133 US counties from 1980 to 2014. County-level demographic, socioeconomic, environmental, and health-related risk factors were compiled. Data were analyzed from December 2019 to September 2021., Exposures: County-level characteristics, collected from 5 county-level data sets., Main Outcomes and Measures: Cardiovascular mortality data were obtained for 3133 US counties from 1980 to 2014 using age-standardized county-level mortality rates from the Global Burden of Disease study. The longitudinal K-means approach was used to identify 3 distinct clusters based on underlying mortality trajectory. Multinomial logistic regression models were constructed to evaluate associations between county characteristics and cluster membership., Results: Among 3133 US counties (median, 49.5% [IQR, 48.9%-50.5%] men; 30.7% [IQR, 27.1%-34.4%] older than 55 years; 9.9% [IQR, 4.5%-22.7%] racial minority group [individuals self-identifying as Black or African American, American Indian or Alaska Native, Asian, Native Hawaiian, Pacific Islander, other, or multiple races/ethnicities]), CV mortality declined by 45.5% overall and by 38.4% in high-mortality strata (694 counties), by 45.0% in intermediate-mortality strata (1382 counties), and by 48.3% in low-mortality strata (1057 counties). Counties with the highest mortality in 1980 continued to demonstrate the highest mortality in 2014. Trajectory groups were regionally distributed, with high-mortality trajectory counties focused in the South and in portions of Appalachia. Low- vs high-mortality groups varied significantly in demographic (racial minority group proportion, 7.6% [IQR, 4.1%-14.5%]) vs 23.9% [IQR, 6.5%-40.8%]) and socioeconomic characteristics such as high-school education (9.4% [IQR, 7.3%-12.6%] vs 20.1% [IQR, 16.1%-23.2%]), poverty rates (11.4% [IQR, 8.8%-14.6%] vs 20.6% [IQR, 17.1%-24.4%]), and violent crime rates (161.5 [IQR, 89.0-262.4] vs 272.8 [IQR, 155.3-431.3] per 100 000 population). In multinomial logistic regression, a model incorporating demographic, socioeconomic, environmental, and health characteristics accounted for 60% of the variance in the CV mortality trajectory (R2 = 0.60). Sociodemographic factors such as racial minority group proportion (odds ratio [OR], 1.70 [95% CI, 1.35-2.14]) and educational attainment (OR, 6.17 [95% CI, 4.55-8.36]) and health behaviors such as smoking (OR for high vs low, 2.04 [95% CI, 1.58-2.64]) and physical inactivity (OR, 3.74 [95% CI, 2.83-4.93]) were associated with the high-mortality trajectory., Conclusions and Relevance: Cardiovascular mortality declined in all subgroups during the 35-year study period; however, disparities remained unchanged during that time. Disparate trajectories were associated with social and behavioral risks. Health policy efforts across multiple domains, including structural and public health targets, may be needed to reduce existing county-level cardiovascular mortality disparities.

Purpose of Review: Current risk prediction tools do not include physical activity (PA) or cardiorespiratory fitness (CRF), despite their robust association with adverse cardiovascular disease (CVD) events and their potential as targets for preventive interventions., Recent Findings: PA and CRF are each associated with cardiovascular (CV) morbidity and mortality, independent of traditional risk factors. Improvement in CRF is associated with reduced risk of atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF). Risk prediction tools have been developed for ASCVD, and more recently for HF, to refine CVD risk assessment and inform CVD prevention strategies. Attempts have been made to incorporate PA and CRF into available CVD risk prediction models. Inclusion of PA and CRF into established CVD risk assessment models improves CVD risk prediction incremental to established CVD risk prediction tools, suggesting PA and CRF are markers of CVD risk and targets for CVD prevention., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: Low-density lipoprotein cholesterol (LDL-C)-lowering therapies are a cornerstone of prevention in atherosclerotic cardiovascular disease. With the introduction of generic formulations and the release of new therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, contemporary Medicare utilization of these therapies remains unknown., Objective: To determine trends in utilization and spending on brand-name and generic LDL-C-lowering therapies and to estimate potential savings if all Medicare beneficiaries were switched to available therapeutically equivalent generic formulations., Design, Setting, and Participants: This cross-sectional study analyzed prescription drug utilization and cost trend data from the Medicare Part D Prescription Drug Event data set from 2014 to 2018 for LDL-C-lowering therapies. A total of 11 LDL-C-lowering drugs with 25 formulations, including 16 brand-name and 9 generic formulations, were included. Data were collected and analyzed from October 2019 to June 2020., Main Outcomes and Measures: Number of Medicare Part D beneficiaries, annual spending, and spending per beneficiary for all formulations., Results: The total number of Medicare Part D beneficiaries ranged from 37 720 840 in 2014 to 44 249 461 in 2018. The number of Medicare beneficiaries taking LDL-C-lowering therapies increased by 23% (from 20.5 million in 2014 to 25.2 million in 2018), while the associated Medicare expenditure decreased by 46% (from $6.3 billion in 2014 to $3.3 billion in 2018). Lower expenditure was driven by greater uptake of generic statin and ezetimibe and a concurrent rapid decline in the use of their brand-name formulations. Medicare spent $9.6 billion on brand-name statins and ezetimibe and could have saved $2.1 billion and $0.4 billion, respectively, if brand-name formulations were switched to equivalent generic versions when available. The number of beneficiaries using PCSK9 inhibitors since their introduction in 2015 has been modest, although use has increased by 144% (from 25 569 in 2016 to 62 476 in 2018) and total spending has increased by 199% (from $164 million in 2016 to $491 million in 2018)., Conclusions and Relevance: Between 2014 and 2018, LDL-C-lowering therapies were used by 4.8 million more Medicare beneficiaries annually, with an associated $3.0 billion decline in Medicare spending. This cost reduction was driven by the rapid transition from brand-name formulations to lower-cost generic formulations of statins and ezetimibe. Use of PCSK9 inhibitions, although low, increased over time and could have broad implications on future Medicare spending.

Importance: Although kidney dysfunction and abnormalities in serum electrolyte levels are associated with poor clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF), the association of visit-to-visit variability in such laboratory measures with long-term outcomes is unclear., Objective: To evaluate the associations of visit-to-visit variability in indexes of kidney function (creatinine and blood urea nitrogen [BUN] levels) and serum electrolyte (sodium, chloride, and potassium) with the risk of adverse clinical outcomes among patients with chronic, stable HFpEF., Design, Setting, and Participants: This cohort analysis used data from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. All participants with 3 or more serial laboratory measurements who were event free within the first 4 months of enrollment were included. Data were analyzed from March 1, 2019, to January 31, 2020., Main Outcomes and Measures: Adjusted associations between indexes of variability in serum laboratory measurements during the first 4 months of follow-up and risk of the primary composite outcome (a composite of aborted cardiac arrest, hospitalization for heart failure, or cardiovascular death) and all-cause mortality were assessed using Cox proportional hazards regression models., Results: Of the 3445 patients enrolled in the TOPCAT trial (mean [SD] age, 68-69 [10] years; 49.7%-51.5% female), 2479 (BUN) to 3195 (potassium) were analyzed, depending on availability of serial measurements. Participants with higher laboratory variability in kidney function parameters were older, had more comorbidities, and had more severe symptoms of HFpEF. Higher visit-to-visit variability in BUN (hazard ratio [HR] per 1-SD higher average successive variability [ASV], 1.21; 95% CI, 1.10-1.33) and creatinine (HR per 1-SD higher ASV, 1.13; 95% CI, 1.04-1.22) were independently associated with a higher risk of the primary composite outcome as well as mortality independent of other baseline confounders, changes in kidney function, changes in medication dosages, and variability in other cardiometabolic parameters (systolic blood pressure and body mass index). The higher risk associated with greater variability in kidney function was consistent across subgroups of patients stratified by the presence of chronic kidney disease (CKD) at baseline (CKD: HR per 1-SD higher ASV, 1.39; 95% CI, 1.16-1.67 and no CKD: HR per 1-SD higher ASV, 1.13; 95% CI, 1.01-1.27), among placebo and spironolactone treatment arms separately (spironolactone arm: 1.30; 95% CI, 1.03-1.65 and placebo arm: HR per 1-SD higher ASV, 1.27; 95% CI, 1.04-1.56). Among serum electrolytes, variability in sodium and potassium measures were also significantly associated with a higher risk of primary composite events (sodium: HR per 1-SD higher ASV, 1.14; 95% CI, 1.01-1.30 and potassium: HR per 1-SD higher ASV, 1.21; 95% CI, 1.02-1.44)., Conclusions and Relevance: In HFpEF, visit-to-visit variability in laboratory indexes of kidney function and serum electrolytes is common and independently associated with worse long-term clinical outcomes.

Higher levels of physical activity (PA) and cardiorespiratory fitness (CRF) are associated with lower risk of incident cardiovascular disease (CVD). However, the relationship of aerobic PA and CRF with risk of atherosclerotic CVD outcomes and heart failure (HF) seem to be distinct. Furthermore, recent studies have raised concerns of potential toxicity associated with extreme levels of aerobic exercise, with higher levels of coronary artery calcium and incident atrial fibrillation noted among individuals with very high PA levels. In contrast, the relationship between PA levels and measures of left ventricular structure and function and risk of HF is more linear. Thus, personalizing exercise levels to optimal doses may be key to achieving beneficial outcomes and preventing adverse CVD events among high risk individuals. In this report, we provide a comprehensive review of the literature on the associations of aerobic PA and CRF levels with risk of adverse CVD outcomes and the preceding subclinical cardiac phenotypes to better characterize the optimal exercise dose needed to favorably modify CVD risk., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

Importance: Obesity is a global health challenge and a risk factor for atherosclerotic cardiovascular disease (ASVCD). Performance of the pooled cohort equations (PCE) for ASCVD risk by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is unknown., Objective: To assess performance of the PCE across clinical BMI categories., Design, Setting, and Participants: This cohort study used pooled individual-level data from 8 community-based, prospective, longitudinal cohort studies with 10-year ASCVD event follow-up from 1996 to 2016. We included all adults ages 40 to 79 years without baseline ASCVD or statin use, resulting in a sample size of 37 311 participants. Data were analyzed from August 2017 to July 2020., Exposures: Participant BMI category: underweight (<18.5), normal weight (18.5 to <25), overweight (25 to <30), mild obesity (30 to <35), and moderate to severe obesity (≥35)., Main Outcomes and Measures: Discrimination (Harrell C statistic) and calibration (Nam-D'Agostino χ2 goodness-of-fit test) of the PCE across BMI categories. Improvement in discrimination and net reclassification with addition of BMI, waist circumference, and high-sensitivity C-reactive protein (hsCRP) to the PCE., Results: Among 37 311 participants (mean [SD] age, 58.6 [11.8] years; 21 897 [58.7%] women), 380 604 person-years of follow-up were conducted. Mean (SD) baseline BMI was 29.0 (6.2), and 360 individuals (1.0%) were in the underweight category, 9937 individuals (26.6%) were in the normal weight category, 13 601 individuals (36.4%) were in the overweight category, 7783 individuals (20.9%) were in the mild obesity category, and 5630 individuals (15.1%) were in the moderate to severe obesity category. Median (interquartile range [IQR]) 10-year estimated ASCVD risk was 7.1% (2.5%-15.4%), and 3709 individuals (9.9%) developed ASCVD over a median (IQR) 10.8 [8.5-12.6] years. The PCE overestimated ASCVD risk in the overall cohort (estimated/observed [E/O] risk ratio, 1.22; 95% CI, 1.18-1.26) and across all BMI categories except the underweight category. Calibration was better near the clinical decision threshold in all BMI groups but worse among individuals with moderate or severe obesity (E/O risk ratio, 1.36; 95% CI, 1.25-1.47) and among those with the highest estimated ASCVD risk ≥20%. The PCE C statistic overall was 0.760 (95% CI, 0.753-0.767), with lower discrimination in the moderate or severe obesity group (C statistic, 0.742; 95% CI, 0.721-0.763) compared with the normal-range BMI group (C statistic, 0.785; 95% CI, 0.772-0.798). Waist circumference (hazard ratio, 1.07 per 1-SD increase; 95% CI, 1.03-1.11) and hsCRP (hazard ratio, 1.07 per 1-SD increase; 95% CI, 1.05-1.09), but not BMI, were associated with increased ASCVD risk when added to the PCE. However, these factors did not improve model performance (C statistic, 0.760; 95% CI, 0.753-0.767) with or without added metrics., Conclusions and Relevance: These findings suggest that the PCE had acceptable model discrimination and were well calibrated at clinical decision thresholds but overestimated risk of ASCVD for individuals in overweight and obese categories, particularly individuals with high estimated risk. Incorporation of the usual clinical measures of obesity did not improve risk estimation of the PCE. Future research is needed to determine whether incorporation of alternative high-risk obesity markers (eg, weight trajectory or measures of visceral or ectopic fat) into the PCE may improve risk prediction.

Aims: Thirty-day risk standardized readmission and mortality rates (RSRR, RSMR) are key determinants for hospital performance for cardiovascular conditions such as acute myocardial infarction (AMI) and heart failure (HF). We evaluated whether individual hospitals in the USA perform similarly for HF and AMI over time based on readmission and mortality metrics., Methods and Results: A total of 1950 hospitals in the USA with continuous participation in the Centers for Medicare and Medicaid Services (CMS) public reporting programme between 2010 and 2016 were identified. Latent mixture modelling was used to define performance trajectory groups. Overall, there were consistent declines in the RSMR (16.1-14.0%) and RSRR (20.3-16.6%) for AMI from 2010 to 2016. For HF, RSRR declined over time (25.1-21.7%), while there was a modest increase in RSMR (11.3-12.0%); parallel findings were observed across performance trajectory groups. The proportion of best performing centres for HF care that were also best performers for AMI care based on the 30-day RSMR and 30-day RSRR metric was 54% and 35%, respectively. Furthermore, the discordance rate between the best and worst performers for both conditions was low (<2% for both 30-day outcomes)., Conclusion: In the USA, despite variation in baseline hospital-level outcomes, hospitals had consistent longitudinal trajectories (worsening or improvement) across conditions and metrics. Hospitals identified as high performing were frequently similar across target conditions and over time, suggesting that performance may be driven by systems of care influencing different disease states in a comparable manner., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background Substantial heterogeneity exists in the cardiorespiratory fitness (CRF) change in response to exercise training, and its long-term prognostic implication is not well understood. We evaluated the association between the short-term supervised training-related changes in CRF and CRF levels 10 years later. Methods and Results STRRIDE (Studies of a Targeted Risk Reduction Intervention Through Defined Exercise) trial participants who were originally randomized to exercise training for 8 months and participated in the 10-year follow-up visit were included. CRF levels were measured at baseline, after training (8 months), and at 10-year follow-up as peak oxygen uptake (vo 2 , mL/kg per min) using the maximal treadmill test. Participants were stratified into low, moderate, and high CRF response groups according to the training regimen-specific tertiles of CRF change. The study included 80 participants (age: 52 years; 35% female). At 10-year follow-up, the high-response CRF group had the least decline in CRF compared with the moderate- and low-response CRF groups (-0.35 versus -2.20 and -4.25 mL/kg per minute, respectively; P =0.02). This result was largely related to the differential age-related changes in peak oxygen pulse across the 3 groups (0.58, -0.23, and -0.86 mL/beat, respectively; P =0.03) with no difference in the peak heart rate change. In adjusted linear regression analysis, high response was significantly associated with greater CRF at follow-up independent of other baseline characteristics (high versus low [reference] CRF response: standard β=0.25; P =0.004). Conclusions Greater CRF improvement in response to short-term training is associated with higher CRF levels 10 years later. Lack of CRF improvements in response to short-term training may identify individuals at risk for exaggerated CRF decline with aging.

Objective: To ascertain whether temporal and geographic interest in seeking cardiovascular disease (CVD) information online follows seasonal and geographic patterns similar to those observed in real-world data., Methods: We searched Google Trends for popular search terms relating to CVD. Relative search volumes (RSVs) were obtained for the period January 4, 2004, to April 19, 2014, for the United States and Australia. We compared average RSVs by month and season and used cosinor analysis to test for seasonal variation in RSVs. We also assessed correlations between state-level RSVs and CVD burden using an ecological correlational design., Results: RSVs were 15% higher in the United States and 45% higher in Australia for winter compared with summer (P<.001 for difference for both). In the United States, RSVs were 36% higher in February compared with August, while in Australia, RSVs were 75% higher in August compared with January. On cosinor analysis, we found a significant seasonal variability in RSVs, with winter peaks and summer troughs for both the United States and Australia (P<.001 for zero amplitude test for both). We found a significant correlation between state-level RSVs and mortality from CVD (r=0.62; P<.001), heart disease (r=0.58; P<.001), coronary heart disease (r=0.48; P<.001), heart failure (r=0.51; P<.001), and stroke (r=0.60; P<.001)., Conclusion: Google search query volumes related to CVD follow strong seasonal patterns with winter peaks and summer troughs. There is moderate to strong positive correlation between state-level search query volumes and burden of CVD mortality., (Copyright © 2018 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: The 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines include lower thresholds to define hypertension than previous guidelines. Little is known about the impact of these guideline changes in patients with or at high risk for cardiovascular disease., Methods: In this exploratory analysis using baseline blood pressure assessments in Systolic Blood Pressure Intervention Trial (SPRINT), we evaluated the prevalence and associated cardiovascular prognosis of patients newly reclassified with hypertension based on the 2017 ACC/AHA (systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥80 mm Hg) compared with the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) guidelines (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg). The primary endpoint was the composite of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or cardiovascular death., Results: In 4683 patients assigned to the standard treatment arm of SPRINT, 2328 (49.7%) met hypertension thresholds by JNC 7 guidelines, and another 1424 (30.4%) were newly reclassified as having hypertension based on the 2017 ACC/AHA guidelines. Over 3.3-year median follow-up, 319 patients experienced the primary endpoint (87 of whom were newly reclassified with hypertension based on the revised guidelines). Patients with hypertension based on prior guidelines compared with those newly identified with hypertension based on the new guidelines had similar risk of the primary endpoint (2.3 [95% confidence interval {CI}, 2.0-2.7] vs 2.0 [95% CI, 1.6-2.4] events per 100 patient-years; adjusted HR, 1.10 [95% CI, 0.84-1.44]; P = .48)., Conclusions: The 2017 ACC/AHA high blood pressure guidelines are expected to significantly increase the prevalence of patients with hypertension (perhaps to a greater extent in higher-risk patient cohorts compared with the general population) and identify greater numbers of patients who will ultimately experience adverse cardiovascular events., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Obesity increases a number of cardiovascular disease (CVD) risk factors, but patients with many types of CVD may have a better prognosis if classified as overweight or obese, a phenomenon known as the "obesity paradox". This paradoxical benefit of a medically unfavorable phenotype is particularly strong in the overweight and class I obesity, and less pronounced in the more severe or morbidly obese populations (class II-III and greater). Rather than an obesity paradox, it is possible that this phenomenon may represent a "lean paradox", in which individuals classified as normal weight or underweight may have a poorer prognosis with respect to CVD, as a result of a progressive catabolic state and lean mass loss. Cardiorespiratory fitness (CRF) is a fundamental part of this discussion. A greater CRF is associated with lower CVD risk, regardless of body mass index (BMI). Also, the assessment of body composition compartments (i.e., fat mass, fat-free mass, lean mass) and the presence of metabolic derangements may be better indicators of CVD risk than BMI alone. The focus of this review is to summarize the current evidence of the obesity paradox. Moreover, we discuss the utility and limitations of BMI for cardiometabolic risk stratification, in addition to concepts such as "metabolically healthy obesity" (MHO) and the "fat but fit" phenomenon, which describe patients who are diagnosed with obesity using BMI, but without major metabolic derangements and with greater CRF, respectively. Finally, we propose that obese patients presenting with an excess body fat, yet without metabolic abnormalities, should still be viewed as an "at risk" population, and as such should receive advice to change their lifestyle to improve their CRF and to prevent the development of impaired fasting glucose, diabetes mellitus and other CVD risk factors as a form of primary prevention., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Importance: Prior studies suggest that higher sedentary time is associated with a greater risk for cardiovascular disease (CVD). However, the quantitative, dose-response association between sedentary time and CVD risk is not known., Objective: To determine the categorical and quantitative dose-response association between sedentary time and CVD risk., Data Sources: Two independent investigators searched the MEDLINE and EMBASE databases for all studies published before July 6, 2015, that evaluated the association between sedentary time and incident CVD., Study Selection: Prospective cohort studies with participants 18 years or older that reported the association between sedentary time and incident CVD were included., Data Extraction and Synthesis: Two independent investigators performed the data extraction and collection using a standardized form. The study quality was assessed using the Newcastle-Ottawa Scale. The categorical dose-response association was evaluated by comparing the pooled hazard ratio (HR) for incident CVD associated with different levels of sedentary time (vs lowest sedentary time) across studies. The continuous dose-response association was assessed using random-effects generalized least squares spline models. Data were collected from April 5 to July 6, 2015., Main Outcomes and Measures: Incident CVD (coronary heart disease, including nonfatal myocardial infarction, stroke, and cardiovascular mortality)., Results: Nine prospective cohort studies with 720 425 unique participants (57.1% women; 42.9% men; mean age, 54.5 years) and 25 769 unique cardiovascular events and a median follow-up of 11 years were included. In categorical analyses, compared with the lowest sedentary time category (median, 2.5 h/d), participants in the highest sedentary time category (median, 12.5 h/d) had an increased risk for CVD (HR, 1.14; 95% CI, 1.09-1.19). However, no apparent risk associated with intermediate levels of sedentary time (HR for 7.5 h/d, 1.02; 95% CI, 0.96-1.08) was found. In continuous analyses, a nonlinear association between sedentary time and incident CVD was found (P for nonlinearity < .001), with an increased risk observed for more than 10 hours of sedentary time per day (pooled HR, 1.08; 95% CI, 1.00-1.14)., Conclusions and Relevance: The association between sedentary time and the risk for CVD is nonlinear with an increased risk only at very high levels. These findings could have implications for guideline recommendations regarding the risks related to sedentary behavior.

Lifetime risk estimation for cardiovascular disease (CVD) has been proposed as a useful strategy to improve risk communication in the primary prevention setting. However, the perception of lifetime risk for CVD is unknown. We included 2,998 subjects from the Dallas Heart Study. Lifetime risk for developing CVD was classified as high (≥39%) versus low (<39%) according to risk factor burden as described in our previously published algorithm. Perception of lifetime risk for myocardial infarction was assessed by way of a 5-point scale. Baseline characteristics were compared across levels of perceived lifetime risk. Multivariable logistic regression analyses were performed to determine the association of participant characteristics with level of perceived lifetime risk for CVD and with correctness of perceptions. Of the 2,998 participants, 64.8% (n = 1,942) were classified as having high predicted lifetime risk for CVD. There was significant discordance between perceived and predicted lifetime risk. After multivariable adjustment, family history of premature myocardial infarction, high self-reported stress, and low perceived health were all strongly associated with high perceived lifetime risk (odds ratio [OR] 2.37, 95% confidence interval [CI] 1.72 to 3.27; OR 2.17, 95% CI 1.66 to 2.83; and OR 2.71, 95% CI 2.09 to 3.53; respectively). However, the association between traditional CVD risk factors and high perceived lifetime risk was more modest. In conclusion, misperception of lifetime risk for CVD is common and frequently reflects the influence of factors other than traditional risk factor levels. These findings highlight the importance of effectively communicating the significance of traditional risk factors in determining the lifetime risk for CVD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

AimsThirty-day risk standardized readmission and mortality rates (RSRR, RSMR) are key determinants for hospital performance for cardiovascular conditions such as acute myocardial infarction (AMI) and heart failure (HF). We evaluated whether individual hospitals in the USA perform similarly for HF and AMI over time based on readmission and mortality metrics.Methods and resultsA total of 1950 hospitals in the USA with continuous participation in the Centers for Medicare and Medicaid Services (CMS) public reporting programme between 2010 and 2016 were identified. Latent mixture modelling was used to define performance trajectory groups. Overall, there were consistent declines in the RSMR (16.1-14.0%) and RSRR (20.3-16.6%) for AMI from 2010 to 2016. For HF, RSRR declined over time (25.1-21.7%), while there was a modest increase in RSMR (11.3-12.0%); parallel findings were observed across performance trajectory groups. The proportion of best performing centres for HF care that were also best performers for AMI care based on the 30-day RSMR and 30-day RSRR metric was 54% and 35%, respectively. Furthermore, the discordance rate between the best and worst performers for both conditions was low (

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. [ABSTRACT FROM AUTHOR]

Background: Lifetime risk of heart failure has been estimated to range from 20% to 46% in diverse sex and race groups. However, lifetime risk estimates for the 2 HF phenotypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), are not known.Methods: Participant-level data from 2 large prospective cohort studies, the CHS (Cardiovascular Health Study) and MESA (Multiethnic Study of Atherosclerosis), were pooled, excluding individuals with prevalent HF at baseline. Remaining lifetime risk estimates for HFpEF (EF ≥45%) and HFrEF (EF <45%) were determined at different index ages with the use of a modified Kaplan-Meier method with mortality and the other HF subtype as competing risks.Results: We included 12 417 participants >45 years of age (22.2% blacks, 44.8% men) who were followed up for median duration of 11.6 years with 2178 overall incident HF events with 561 HFrEF events and 726 HFpEF events. At the index age of 45 years, the lifetime risk for any HF through 90 years of age was higher in men than women (27.4% versus 23.8%). Among HF subtypes, the lifetime risk for HFrEF was higher in men than women (10.6% versus 5.8%). In contrast, the lifetime risk for HFpEF was similar in men and women. In race-stratified analyses, lifetime risk for overall HF was higher in nonblacks than blacks (25.9% versus 22.4%). Among HF subtypes, the lifetime risk for HFpEF was higher in nonblacks than blacks (11.2% versus 7.7%), whereas that for HFrEF was similar across the 2 groups. Among participants with antecedent myocardial infarction before HF diagnosis, the remaining lifetime risks for HFpEF and HFrEF were up to 2.5-fold and 4-fold higher, respectively, compared with those without antecedent myocardial infarction.Conclusions: Lifetime risks for HFpEF and HFrEF vary by sex, race, and history of antecedent myocardial infarction. These insights into the distribution of HF risk and its subtypes could inform the development of targeted strategies to improve population-level HF prevention and control. [ABSTRACT FROM AUTHOR]

Both obesity and atrial fibrillation (AF) are increasing in epidemic proportions, and both increase the prevalence of cardiovascular disease events. Obesity has adverse effects on cardiovascular hemodynamics and cardiac structure and function, and increases the prevalence of AF, partly related to electroanatomic remodeling in obese patients. However, numerous studies, including in AF, have demonstrated an obesity paradox, where overweight and obese patients with these disorders have a better prognosis than do leaner patients with the same degree of severity of cardiovascular disease/AF. In this paper, the authors discuss special issues regarding AF in obesity, as well as the evidence that despite the presence of an obesity paradox, there are benefits of weight loss, physical activity/exercise training, and increases in cardiorespiratory fitness on the prognosis of obese patients with AF. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The health benefits of exercise are well-recognized and are observed across multiple organ systems. These beneficial effects enhance overall resilience, healthspan and longevity. The molecular mechanisms that underlie the beneficial effects of exercise, however, remain poorly understood. Since the discovery in 2000 that muscle contraction releases IL-6, the number of exercise-associated signalling molecules that have been identified has multiplied. Exerkines are defined as signalling moieties released in response to acute and/or chronic exercise, which exert their effects through endocrine, paracrine and/or autocrine pathways. A multitude of organs, cells and tissues release these factors, including skeletal muscle (myokines), the heart (cardiokines), liver (hepatokines), white adipose tissue (adipokines), brown adipose tissue (baptokines) and neurons (neurokines). Exerkines have potential roles in improving cardiovascular, metabolic, immune and neurological health. As such, exerkines have potential for the treatment of cardiovascular disease, type 2 diabetes mellitus and obesity, and possibly in the facilitation of healthy ageing. This Review summarizes the importance and current state of exerkine research, prevailing challenges and future directions. [ABSTRACT FROM AUTHOR]

Background: Diabetes is associated with abnormalities in cardiac remodeling and high risk of heart failure (HF).Objectives: The purpose of this study was to evaluate the prevalence and prognostic implications of diabetes with cardiomyopathy (DbCM) among community-dwelling individuals.Methods: Adults without prevalent cardiovascular disease or HF were pooled from 3 cohort studies (ARIC [Atherosclerosis Risk In Communities], CHS [Cardiovascular Health Study], CRIC [Chronic Renal Insufficiency Cohort]). Among participants with diabetes, DbCM was defined using different definitions: 1) least restrictive: ≥1 echocardiographic abnormality (left atrial enlargement, left ventricle hypertrophy, diastolic dysfunction); 2) intermediate restrictive: ≥2 echocardiographic abnormalities; and 3) most restrictive: elevated N-terminal pro-B-type natriuretic peptide levels (>125 in normal/overweight or >100 pg/mL in obese) plus ≥2 echocardiographic abnormalities. Adjusted Fine-Gray models were used to evaluate the risk of HF.Results: Among individuals with diabetes (2,900 of 10,208 included), the prevalence of DbCM ranged from 67.0% to 11.7% in the least and most restrictive criteria, respectively. Higher fasting glucose, body mass index, and age as well as worse kidney function were associated with higher risk of DbCM. The 5-year incidence of HF among participants with DbCM ranged from 8.4%-12.8% in the least and most restrictive definitions, respectively. Compared with euglycemia, DbCM was significantly associated with higher risk of incident HF with the highest risk observed for the most restrictive definition of DbCM (HR: 2.55 [95% CI: 1.69-3.86]; least restrictive criteria HR: 1.99 [95% CI: 1.50-2.65]). A similar pattern of results was observed across cohort studies, across sex and race subgroups, and among participants without hypertension or obesity.Conclusions: Regardless of the criteria used to define cardiomyopathy, DbCM identifies a high-risk subgroup for developing HF. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) risk and the underlying risk factors vary by race. Traditional models for HF risk prediction treat race as a covariate in risk prediction and do not account for significant parameters such as cardiac biomarkers. Machine learning (ML) may offer advantages over traditional modeling techniques to develop race-specific HF risk prediction models and to elucidate important contributors of HF development across races.Methods: We performed a retrospective analysis of 4 large, community cohort studies (ARIC [Atherosclerosis Risk in Communities], DHS [Dallas Heart Study], JHS [Jackson Heart Study], and MESA [Multi-Ethnic Study of Atherosclerosis]) with adjudicated HF events. The study included participants who were >40 years of age and free of HF at baseline. Race-specific ML models for HF risk prediction were developed in the JHS cohort (for Black race-specific model) and White adults from ARIC (for White race-specific model). The models included 39 candidate variables across demographic, anthropometric, medical history, laboratory, and electrocardiographic domains. The ML models were externally validated and compared with prior established traditional and non-race-specific ML models in race-specific subgroups of the pooled MESA/DHS cohort and Black participants of ARIC. The Harrell C-index and Greenwood-Nam-D'Agostino χ2 tests were used to assess discrimination and calibration, respectively.Results: The ML models had excellent discrimination in the derivation cohorts for Black (n=4141 in JHS, C-index=0.88) and White (n=7858 in ARIC, C-index=0.89) participants. In the external validation cohorts, the race-specific ML model demonstrated adequate calibration and superior discrimination (Black individuals, C-index=0.80-0.83; White individuals, C-index=0.82) compared with established HF risk models or with non-race-specific ML models derived with race included as a covariate. Among the risk factors, natriuretic peptide levels were the most important predictor of HF risk across both races, followed by troponin levels in Black and ECG-based Cornell voltage in White individuals. Other key predictors of HF risk among Black individuals were glycemic parameters and socioeconomic factors. In contrast, prevalent cardiovascular disease and traditional cardiovascular risk factors were stronger predictors of HF risk in White adults.Conclusions: Race-specific and ML-based HF risk models that integrate clinical, laboratory, and biomarker data demonstrated superior performance compared with traditional HF risk and non-race-specific ML models. This approach identifies distinct race-specific contributors of HF. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: A malignant subphenotype of left ventricular hypertrophy (LVH) has been described, in which minimal elevations in cardiac biomarkers identify individuals with LVH at high risk for developing heart failure (HF). We tested the hypothesis that a higher prevalence of malignant LVH among blacks may contribute to racial disparities in HF risk. Methods: Participants (n=15 710) without prevalent cardiovascular disease were pooled from 3 population-based cohort studies, the ARIC Study (Atherosclerosis Risk in Communities), the DHS (Dallas Heart Study), and the MESA (Multi-Ethnic Study of Atherosclerosis). Participants were classified into 3 groups: those without ECG-LVH, those with ECG-LVH and normal biomarkers (hs-cTnT (high sensitivity cardiac troponin-T) <6 ng/L and NT-proBNP (N-terminal pro-B-type natriuretic peptide) <100 pg/mL), and those with ECG-LVH and abnormal levels of either biomarker (malignant LVH). The outcome was incident HF. Results: Over the 10-year follow-up period, HF occurred in 512 (3.3%) participants, with 5.2% in black men, 3.8% in white men, 3.2% in black women, and 2.2% in white women. The prevalence of malignant LVH was 3-fold higher among black men and women versus white men and women. Compared with participants without LVH, the adjusted hazard ratio for HF was 2.8 (95% CI, 2.1–3.5) in those with malignant LVH and 0.9 (95% CI, 0.6–1.5) in those with LVH and normal biomarkers, with similar findings in each race/sex subgroup. Mediation analyses indicated that 33% of excess hazard for HF among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant LVH in blacks. Of black men who developed HF, 30.8% had malignant LVH at baseline, with a corresponding population attributable fraction of 0.21. The proportion of HF cases occurring among those with malignant LVH, and the corresponding population attributable fraction, were intermediate and similar among black women and white men and lowest among white women. Conclusions: A higher prevalence of malignant LVH may in part explain the higher risk of HF among blacks versus whites. Strategies to prevent development or attenuate risk associated with malignant LVH should be investigated as a strategy to lower HF risk and mitigate racial disparities. [ABSTRACT FROM AUTHOR]