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Background: Patients waiting for heart transplant may be hospitalized for weeks to months before undergoing transplantation. This high-stress period is further complicated by restrictions of daily privileges including diet, rooming, access to the outdoors, and hygiene (eg, limited in ability to shower). However, there is a paucity of research on the experience of this waiting period. We sought to describe the inpatient experience among patients awaiting heart transplantation and to better understand the needs of inpatients waiting for heart transplant., Methods and Results: We conducted in-depth, semistructured phone interviews with a purposeful sample of patients who received a heart transplant in the past 10 years and waited in the hospital for at least 2 weeks before surgery. Using the prior literature, the lived experience of the lead author, and input from qualitative experts, we developed an interview guide. Interviews were recorded, transcribed, and analyzed in an iterative process until theoretical saturation was achieved. A 3-person coding team identified, discussed, and reconciled emergent themes. We conducted interviews with 15 patients. Overarching themes included food, hygiene, relationship with health care professionals, living environment, and stressors. Patients reported that strong bonds were formed between the patients and the staff, and the overwhelming majority only had positive comments about these relationships. However, many expressed negative comments about the experience of the food and limitations in personal hygiene. Other stressors included the unknown length of the waiting period, lack of communication about position on the transplant list, worry about family, and concerns that their life must be saved by the death of another. Many participants described that they would benefit from more interaction with recent heart transplant recipients., Conclusions: Hospitals and care units have the opportunity to make small changes that could greatly benefit the experience of waiting for a heart transplant, as well as the experience of hospitalization more generally., Competing Interests: Declaration of Competing Interest The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The prognostic utility of the oxygen uptake efficiency slope (OUES) in heart failure with reduced ejection fraction is uncertain. In this post hoc analysis of the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial (n = 2,074), we tested for associations of OUES and peak oxygen uptake (VO 2 ) with heart failure hospitalization or cardiovascular death in multivariable Cox regression models, adjusting for minute ventilation/carbon dioxide production (VE/VCO 2 ) slope and other important confounders. Harrell's C-statistics assessed the discriminatory performance of OUES and peak VO 2 . Lower OUES was associated with increased risk of the outcome (quartile 1 vs 4: hazard ratio 2.1 [1.5 to 2.9, p <0.001]). Peak VO 2 had greater discrimination than OUES in comparable models (e.g., C-statistic = 0.73 vs 0.70, p <0.001, respectively). In the subgroup with respiratory exchange ratio <1 (n = 358), peak VO 2 was associated with the outcome (p <0.001) but OUES was not (p = 0.96). In conclusion, whereas OUES was associated with clinical outcomes independently of VE/VCO 2 slope, its prognostic utility was inferior to that of peak VO 2 , even when measured at submaximal effort., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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.)

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.)

Background: Excess adiposity is a well-known risk factor for heart failure (HF). Fat accumulation in and around the peripheral skeletal muscle may further inform risk for HF., Objectives: The purpose of this study was to evaluate the association between intramuscular and intermuscular fat deposition and incident HF in a longitudinal cohort of community-dwelling older adults., Methods: The associations of intramuscular and intermuscular fat with incident HF were assessed using Cox models among 2,399 participants from the Health ABC (Health, Aging and Body Composition) study (70-79 years of age, 48% male, 40.2% Black) without baseline HF. Intramuscular fat was determined by bilateral thigh muscle density on computed tomography and intermuscular fat area was determined with computed tomography., Results: After a median follow-up of 12.2 years, there were 485 incident HF events. Higher sex-specific tertiles of intramuscular and intermuscular fat were each associated with HF risk. After multivariable adjustment for age, sex, race, education, blood pressure, fasting blood sugar, current smoking, prevalent coronary disease, and creatinine, higher intramuscular fat, but not intermuscular fat, was associated with higher risk for HF (HR: 1.34 [95% CI: 1.06-1.69]; P = 0.012, tertile 3 vs tertile 1). This association remained significant after additional adjustment for body mass index (HR: 1.32 [95% CI: 1.03-1.69]), total percent fat (HR: 1.33 [95% CI: 1.03-1.72]), visceral fat (HR: 1.30 [95% CI: 1.01-1.65]), and indexed thigh muscle strength (HR: 1.30 [95% CI: 1.03-1.64]). The association between higher intramuscular fat and HF appeared specific to higher risk of incident HF with reduced ejection fraction (HR: 1.53 [95% CI: 1.03-2.29]), but not with HF with preserved ejection fraction (HR: 1.28 [95% CI: 0.82-1.98])., Conclusions: Intramuscular, but not intermuscular, thigh muscle fat is independently associated with HF after adjustment for cardiometabolic risk factors and other measurements of adiposity., Competing Interests: Funding Support and Author Disclosures This research was supported by National Institute on Aging Contracts N01-AG-6-2101, N01-AG-6-2103,and N01-AG-6-2106; National Institute on Aging grant R01-AG028050; and National Institute of Nursing Research grant R01-NR012459. This research was funded in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. Dr Butler has served as a consultant for Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CVRx, G3 Pharmaceutical, Innolife, Janssen, LivaNova, Medtronic, Merck, Novartis, Novo Nordisk, Occlutech, Relypsa, Roche, and Vifor. Dr Neeland has received speaker and consultancy fees from Boehringer Ingelheim/Lilly Alliance, Merck, Nestle Health Sciences, and AMRA Medical; and grant support from Novo Nordisk. 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.)

Background: The V122I variant in transthyretin (TTR) is the most common amyloidogenic mutation worldwide. The aim of this study is to describe the cardiac phenotype and risk for adverse cardiovascular outcomes of young V122I TTR carriers in the general population., Methods and Results: TTR genotypes were extracted from whole-exome sequence data in participants of the Dallas Heart Study. Participants with African ancestry, available V122I TTR genotypes (N = 1818) and either cardiac magnetic resonance imaging (n = 1364) or long-term follow-up (n = 1532) were included. The prevalence of V122I TTR carriers (45 ± 10 years) was 3.2% (n/N = 59/1818). The V122I TTR carriers had higher baseline left ventricular wall thickness (8.52 ± 1.82 vs 8.21 ± 1.62 mm, adjusted P = .038) than noncarriers, but no differences in other cardiac magnetic resonance imaging measures (P > .05 for all). Although carrier status was not associated with amino terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline (P = .79), V122I TTR carriers had a greater increase in NT-proBNP on follow-up than noncarriers (median 28.5 pg/mL, interquartile range 11.4-104.1 pg/mL vs median 15.9 pg/mL, interquartile range 0.0-43.0 pg/mL, adjusted P = .018). V122I TTR carriers were at a higher adjusted risk of heart failure (hazard ratio 3.82, 95% confidence interval 1.80-8.13, P < .001), cardiovascular death (hazard ratio 2.65, 95% confidence interval 1.14-6.15, P = .023), and all-cause mortality (hazard ratio 1.95, 95% confidence interval 1.08-3.51, P = .026) in comparison with noncarriers., Conclusions: V122I TTR carrier status was associated with a greater increase in NT-proBNP, slightly greater left ventricular wall thickness, and a higher risk for heart failure, cardiovascular death, and all-cause mortality. These findings suggest the need to develop amyloidosis screening strategies for V122I TTR carriers., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: This study sought to evaluate the independent associations and interactions between high-sensitivity cardiac troponin I (hs-cTnI) and physical activity (PA) with risk of heart failure (HF) subtypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF)., Background: Black adults are at high risk for developing HF. Physical inactivity and subclinical myocardial injury, as assessed by hs-cTnI concentration, are independent risk factors for HF., Methods: Black adults from the Jackson Heart Study without prevalent HF who had hs-cTnI concentration and self-reported PA assessed at baseline were included. Adjusted Cox models were used to evaluate the independent and joint associations and interaction between hs-cTnI concentrations and PA with risk of HFpEF and HFrEF., Results: Among 3,959 participants, 25.1% had subclinical myocardial injury (hs-cTnI ≥4 and ≥6 ng/l in women and men, respectively), and 48.2% were inactive (moderate-to-vigorous PA = 0 min/week). Over 12.0 years of follow-up, 163 and 150 participants had an incident HFpEF and HFrEF event, respectively. In adjusted analysis, higher hs-cTnI concentration (per 1-U log increase) was associated with higher risk of HFpEF (hazard ratio [HR]: 1.47; 95% confidence interval [CI]: 1.25 to 1.72]) and HFrEF (HR: 1.57; 95% CI: 1.35 to 1.83]). In contrast, higher PA (per 1-U log increase) was associated with a lower risk of HFpEF (HR: 0.93; 95% CI: 0.88 to 0.99]) but not HFrEF. There was a significant interaction between hs-cTnI and PA for risk of HFpEF (p interaction = 0.04) such that inactive participants with subclinical myocardial injury were at higher risk of HFpEF but active participants were not., Conclusions: Among Black adults with subclinical myocardial injury, higher levels of PA were associated with attenuated risk of HFpEF., Competing Interests: Funding Support and Author Disclosures Supported by a Strategically Focused Research Network Grant for Prevention from the American Heart Association to University of Texas Southwestern Medical Center, Dallas, and Northwestern University School of Medicine, Chicago. Dr. Neeland is a consultant for Boehringer Ingelheim/Lilly Alliance and Merck. Dr. deFilippi has received grant support from Roche Diagnostics, Ortho Diagnostics, and Siemens Healthineers; is a consultant for Roche Diagnostics, Abbott Diagnostics, Ortho Clinical Diagnostics, Quidel, FujiRebio, and Siemen’s Health Care Diagnostics; has received royalty payments from UpToDate; co-owns a patent awarded to the University of Maryland (U.S. Patent Application: 15/309,754; Methods for Assessing Differential Risk for Developing Heart Failure); and has received an award, UL1TR003015, from the U.S. National Institutes of Health/Center for Advancing Translational Science. Dr. Seliger has received funding from Roche Diagnostics. Dr. Rodriguez has received research support from Amgen, the American Heart Association, and the National Health Lung and Blood Institute (2R01HL104199). Dr. de Lemos has received grant support from Roche Diagnostics and Abbott Diagnostics; is a consultant for Roche Diagnostics, Abbott Diagnostics, Ortho Clinical Diagnostics, Quidel Cardiovascular, and Siemen’s Health Care Diagnostics; and is a co-owner of a patent awarded to the University of Maryland (U.S. Patent Application: 15/309,754; Methods for Assessing Differential Risk for Developing Heart Failure). Dr. Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor, and Windtree Therapeutics. Dr. Berry has received a grant, 14SFRN20740000, from the American Heart Association prevention network and salary support from Abbott Diagnostics. Dr. Pandey has served on the advisory board of Roche Diagnostics; has received nonfinancial support from Pfizer and Merck; and has received research support from Texas Health Resources Clinical Scholarship, the Gilead Sciences Research Scholar Program, and the National Institute of Aging GEMSSTAR grant (1R03AG067960-01) and Applied Therapeutics., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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 χ 2 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.

Background Low cardiorespiratory fitness (CRF) and obesity are risk factors for heart failure but their associations with right ventricular (RV) systolic function and pulmonary artery systolic pressure (PASP) are not well understood. Methods and Results Participants in the CARDIA (Coronary Artery Risk Development in Young Adults) study who underwent maximal treadmill testing at baseline and had a follow-up echocardiographic examination at year 25 were included. A subset of participants had repeat CRF and body mass index (BMI) assessment at year 20. The associations of baseline and changes in CRF and BMI on follow-up (baseline to year 20) with RV systolic function parameters (tricuspid annular plane systolic excursion, RV Doppler systolic velocity of the lateral tricuspid annulus), and PASP were assessed using multivariable-adjusted linear regression models. The study included 3433 participants. In adjusted analysis, higher baseline BMI but not CRF was significantly associated with higher PASP. Among RV systolic function parameters, higher baseline CRF and BMI were significantly associated with higher tricuspid annular plane systolic excursion and RV systolic velocity of the lateral tricuspid annulus. In the subgroup of participants with follow-up assessment of CRF or BMI at year 20, less decline in CRF was associated with higher RV systolic velocity of the lateral tricuspid annulus and lower PASP, while greater increase in BMI was significantly associated with higher PASP in middle age. Conclusions Higher CRF in young adulthood and less decline in CRF over time are each significantly associated with better RV systolic function. Higher baseline BMI and greater age-related increases in BMI are each significantly associated with higher PASP in middle age. These findings provide insights into possible mechanisms through which low fitness and obesity may contribute toward risk of heart failure.

Aims: Non-alcoholic fatty liver disease leads to progressive liver fibrosis and appears to be a frequent co-morbid disease in heart failure with preserved ejection fraction (HFpEF). It is well known that liver fibrosis severity predicts future liver-related morbidity and mortality, but its impact on outcomes in patients with HFpEF remains unknown. This analysis aimed to describe the prevalence of liver fibrosis, as assessed using surrogate biomarkers, in patients with HFpEF and the association of such biomarkers in predicting clinical outcomes in these patients., Methods and Results: Patients with HFpEF from TOPCAT Americas were included in the analysis. The non-alcoholic fatty liver disease fibrosis score (NFS) and fibrosis-4 (FIB-4) scores were calculated using a combination of clinical characteristics and laboratory parameters. Risk of advanced fibrosis was classified as low, intermediate, and high. For the 1423 with sufficient data, we used Cox regression analysis to test the association between the risk of fibrosis severity and the combined primary endpoint of all cardiovascular death, aborted cardiac arrest, and hospitalization for heart failure. Advanced fibrosis, as determined by high fibrosis scores, was present in 37.57% by the NFS and 8.02% by the FIB-4. Higher risk of advanced hepatic fibrosis was associated with older age. In unadjusted models, the risk of advanced fibrosis was associated with the primary cardiovascular outcome [NFS high vs. low, hazard ratio (HR) 1.709 (95% confidence interval, CI 1.238-2.358, P = 0.0011) and FIB-4 high vs. low, HR 1.561 (95% CI 1.139-2.140, P = 0.0056)]. After multivariable adjustment, this association was diminished [NFS high vs. low, HR 1.349 (95% CI 0.938-1.939, P = 0.1064) and FIB-4 high vs. low, HR 1.415 (95% CI 0.995-2.010, P = 0.0531)]., Conclusions: Our study suggests that advanced liver fibrosis, as estimated by fibrosis risk scores, may not be uncommon in patients with HFpEF, and there appears to be a limited independent association between liver fibrosis risk scores and clinical outcomes related to heart failure events., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objectives: This study evaluated the application of a biomarker-based risk score to identify individuals with dysglycemia who are at high risk for incident heart failure (HF) and to inform allocation of effective preventive interventions., Background: Risk stratification tools to identify patients with diabetes and pre-diabetes at highest risk for HF are needed to inform cost-effective allocation of preventive therapies. Whether a biomarker score can meaningfully stratify HF risk is unknown., Methods: Participants free of cardiovascular disease from 3 cohort studies (ARIC [Atherosclerosis Risk In Communities], DHS [Dallas Heart Study], and MESA [Multi-Ethnic Study of Atherosclerosis]) were included. An integer-based biomarker score included high-sensitivity cardiac troponin T ≥6 ng/l, N-terminal pro-B-type natriuretic peptide ≥125 pg/ml, high-sensitivity C-reactive protein ≥3 mg/l, and left ventricular hypertrophy by electrocardiography, with 1 point for each abnormal parameter. The 5-year risk of HF was estimated among participants with diabetes and pre-diabetes across biomarker score groups (0 to 4)., Results: The primary analysis included 6,799 participants with dysglycemia (diabetes: 33.2%; pre-diabetes: 66.8%). The biomarker score demonstrated good discrimination and calibration for predicting 5- and 10-year HF risk among pre-diabetes and diabetes cohorts. The 5-year risk of HF among subjects with a biomarker score of ≤1 was low and comparable to participants with euglycemia (0.78%). The 5-year risk for HF increased in a graded fashion with an increasing biomarker score, with the highest risk noted among those with scores of ≥3 (diabetes: 12.0%; pre-diabetes: 7.8%). The estimated number of HF events that could be prevented using a sodium-glucose cotransporter-2 inhibitor per 1,000 treated subjects over 5 years was 11 for all subjects with diabetes and ranged from 4 in the biomarker score zero group to 44 in the biomarker score ≥3 group., Conclusions: Among adults with diabetes and pre-diabetes, a biomarker score can stratify HF risk and inform allocation of HF prevention therapies., Competing Interests: Funding Support and Author Disclosures Dr. Pandey was supported by the Texas Health Resources Clinical Scholarship, Gilead Sciences Research Scholar Program, and the National Institute of Aging GEMSSTAR Grant (1R03AG067960-01). The ARIC study is conducted as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN2 68201100006C, HHSN268201100007C, HHSN268201100008C, HHSN26820 1100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201 100012C). The Dallas Heart Study was funded by a grant from the Donald W. Reynolds Foundation. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (award number UL1TR001105) to the University of Texas Southwestern Medical Center. The Multi-Ethnic Study of Atherosclerosis was supported by the National Heart, Lung, and Blood Institute (R01 HL071739 and contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, and N01-C-95169). Dr. Vaduganathan has been supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (NIH/NCATS Award UL 1TR002541); and has served on advisory boards for Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Cytokinetics, and Relypsa. Dr. Pandey has served on the advisory board of Roche Diagnostics. Dr. Patel was supported by the National Heart, Lung, and Blood Institute T32 postdoctoral training grant (5T32HL125247-03). Dr. Kosiborod has received research grant support from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on advisory boards for Amgen, Applied Therapeutics, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Merck (Diabetes), Novo Nordisk, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca and honorarium from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr. de Lemos has received grant support from Roche Diagnostics and Abbott Diagnostics; and has received consulting fees from Roche Diagnostics, Abbott Diagnostics, Ortho Clinical Diagnostics, Siemen’s Health Care Diagnostics, Quidel Cardiovascular, Inc, Novo Nordisk, Amgen, Regeneron, Eli Lilly, and Esperion. Drs. DeFilippi and de Lemos hold a patent pending (U.S. Patent Number: 15/309,754) entitled: “Methods for Assessing Differential Risk for Developing Heart Failure.” Dr. McGuire has received personal fees for trial leadership from GlaxoSmithKline, Janssen, Lexicon, AstraZeneca, CSL Behring, Sanofi, Boehringer Ingelheim, Merck & Co, Pfizer, Novo Nordisk, Eisai Inc., Esperion, and Lilly USA; and has received personal consultancy fees from AstraZeneca, Lilly USA, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Metavant, Applied Therapeutics, Sanofi, and Afimmune. Dr. Everett has received personal consultancy fees from Amarin, Amgen, Gilead, FDA, Merck & Co., National Institute of Diabetes and Digestive and Kidney Diseases, and Roche Diagnostics outside the present work; and has received significant investigator-initiated grant funding from the National Institute of Heart, Lung, and Blood Institute outside the present work. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background Physical inactivity and low cardiorespiratory fitness (CRF) are associated with higher risk of heart failure. However, the independent contributions of objectively measured sedentary time, physical activity, and CRF toward left ventricular (LV) structure and function are not well established. Methods and Results We included 1368 participants from the DHS (Dallas Heart Study) (age, 49 years; 40% men) free of cardiovascular disease who had physical activity and sedentary time measured by accelerometer, CRF estimated from submaximal treadmill test, and cardiac magnetic resonance imaging performed using 3-T magnetic resonance imaging. A series of linear regression models were constructed to evaluate the associations of sedentary time, moderate physical activity, vigorous physical activity, and CRF with LV parameters after adjustment for established cardiovascular risk factors. We observed a modest correlation between CRF levels and objectively measured moderate (correlation coefficient, 0.17; P <0.001) and vigorous physical activity (correlation coefficient, 0.25; P <0.001) levels. In contrast, sedentary time was not associated with CRF. In adjusted analysis, both vigorous physical activity and higher CRF were significantly associated with greater stroke volume, LV mass, LV end-diastolic volume, and lower arterial elastance, independent of other confounders. Sedentary time and moderate physical activity levels were not associated with LV parameters. Conclusions Vigorous physical activity and CRF are significantly associated with cardiac structure and function parameters. Future studies are needed to determine if interventions aimed at improving CRF levels may favorably modify cardiac structure and function.

Aim: To identify distinct phenotypic subgroups in a highly-dimensional, mixed-data cohort of individuals with heart failure (HF) with preserved ejection fraction (HFpEF) using unsupervised clustering analysis., Methods and Results: The study included all Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) participants from the Americas (n = 1767). In the subset of participants with available echocardiographic data (derivation cohort, n = 654), we characterized three mutually exclusive phenogroups of HFpEF participants using penalized finite mixture model-based clustering analysis on 61 mixed-data phenotypic variables. Phenogroup 1 had higher burden of co-morbidities, natriuretic peptides, and abnormalities in left ventricular structure and function; phenogroup 2 had lower prevalence of cardiovascular and non-cardiac co-morbidities but higher burden of diastolic dysfunction; and phenogroup 3 had lower natriuretic peptide levels, intermediate co-morbidity burden, and the most favourable diastolic function profile. In adjusted Cox models, participants in phenogroup 1 (vs. phenogroup 3) had significantly higher risk for all adverse clinical events including the primary composite endpoint, all-cause mortality, and HF hospitalization. Phenogroup 2 (vs. phenogroup 3) was significantly associated with higher risk of HF hospitalization but a lower risk of atherosclerotic event (myocardial infarction, stroke, or cardiovascular death), and comparable risk of mortality. Similar patterns of association were also observed in the non-echocardiographic TOPCAT cohort (internal validation cohort, n = 1113) and an external cohort of patients with HFpEF [Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial cohort, n = 198], with the highest risk of adverse outcome noted in phenogroup 1 participants., Conclusions: Machine learning-based cluster analysis can identify phenogroups of patients with HFpEF with distinct clinical characteristics and long-term outcomes., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Aims: The relationship between resting stroke volume (SV) and prognostic markers in heart failure with preserved ejection fraction (HFpEF) is not well established. We evaluated the association of SV index (SVI) at rest with exercise capacity and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in stable patients with HFpEF., Methods and Results: Participants enrolled in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial with available data on SVI by the Doppler method were included in this analysis (n = 185). A low-flow state defined by resting SVI < 35 mL/m 2 was present in 37% of study participants. Multivariable adjusted linear regression analysis suggested that higher resting heart rate, higher body weight, prevalent atrial fibrillation, and smaller left ventricular (LV) end-diastolic dimension were each independently associated with lower SVI. Patients with low-flow HFpEF had lower systolic blood pressure and smaller LV end-diastolic dimension. In multivariable adjusted linear regression models, lower SVI was significantly associated with lower peak oxygen consumption (peak VO 2 ) and higher NT-proBNP levels at baseline, and greater decline in peak VO 2 at 6 month follow-up independent of other confounders. Resting LV ejection fraction was not associated with peak VO 2 and NT-proBNP levels., Conclusions: There is heterogeneity in the resting SVI distribution among patients with stable HFpEF, with more than one-third of patients identified with the low-flow HFpEF phenotype (SVI < 35 mL/m 2 ). Lower SVI was independently associated with lower peak VO 2 , higher NT-proBNP levels, and greater decline in peak VO 2 . These findings highlight the potential prognostic utility of SVI assessment in the management of patients with HFpEF., (© 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Importance: African Americans have a higher burden of heart failure (HF) risk factors and clinical HF than other racial/ethnic groups. However, the factors underlying the transition from at-risk to clinical HF in African Americans are not well understood., Objective: To evaluate the contributions of left ventricular hypertrophy (LVH) and subclinical myocardial injury as determined by abnormal high-sensitivity cardiac troponin-I (hs-cTnI) measurements toward HF risk among African Americans., Design, Setting, and Participants: This prospective, community-based cohort study was conducted between July 2016 and September 2018 and included African American participants from Jackson, Mississippi enrolled in the Jackson Heart Study without prevalent HF who had hs-cTnI measurements and an echocardiographic examination at baseline. Participants were stratified into categories based on the presence or absence of LVH and subclinical myocardial injury (category 1: hs-cTnI <4 ng/L in women and <6 ng/L in men; category 2: 4-10 ng/L in women and 6-12 ng/L in men; category 3: >10 ng/L in women and >12 ng/L in men)., Main Outcomes and Measures: Adjusted associations between LVH, subclinical myocardial injury, and the risk of incident HF hospitalization were assessed using Cox proportional hazards models., Results: The study included 3987 participants (2552 women [64%]; 240 (6.0%) with LVH; 1003 (25.1%) with myocardial injury) with 285 incident HF events over a median follow-up of 9.8 years (interquartile range, 8.9-10.6 years). In adjusted analyses, higher LV mass and subclinical myocardial injury were independently associated with the risk of HF with a significant interaction between the 2 (Pint < 0.001). The highest risk of HF was noted among individuals with both LVH and myocardial injury (absolute incidence, 35%; adjusted hazard ratio [aHR; vs no LVH and no myocardial injury], 5.35; 95% CI, 3.66-7.83). A significant interaction by sex was also observed. Men with LVH and subclinical myocardial injury had an almost 15-fold higher risk of HF (aHR, 14.62; 95% CI, 7.61-28.10) vs those with neither LVH nor injuries. By contrast, women with this phenotype had a nearly 4-fold higher risk of HF (aHR, 3.81; 95% CI, 2.40-6.85)., Conclusions and Relevance: The combination of LVH and subclinical myocardial injury identifies a malignant, preclinical HF phenotype in African Americans with a very high risk of HF, particularly among men. This finding could have implications for future screening strategies that are designed to prevent HF in the population.

Background: Obesity is highly prevalent among blacks and is associated with a greater risk of heart failure (HF). However, the contribution of regional adiposity depots such as visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue toward risk of HF in blacks is unknown., Methods and Results: We included 2602 participants (mean age: 59 years, 35% men) from the Jackson Heart Study without prevalent HF who underwent computed tomography quantification of VAT and subcutaneous adipose tissue during the second visit (2005-2009). The associations between different adiposity measures and HF were evaluated using adjusted Cox models. There were 122 incident HF events over a median follow-up of 7.1 years. Higher amounts of VAT were associated with greater risk of HF in age- and sex-adjusted analyses (hazard ratio [95% CI] per 1-SD higher VAT: 1.29 [1.09-1.52]). This association was attenuated and not significant after additional adjustment for traditional HF risk factors and body mass index. Overall obesity, represented by body mass index, was associated with higher risk of HF independent of risk factors and VAT (hazard ratio [95% CI] per 1-kg/m 2 higher body mass index: 1.06 [1.02-1.11]). Subcutaneous adipose tissue was not associated with risk of HF in adjusted analyses., Conclusions: In a community-dwelling black population, higher amounts of overall and visceral adiposity are associated with higher risk of HF. The association between VAT and HF risk in blacks may reflect differences in traditional HF risk factor burden. Future studies are needed to confirm this observation and clarify the independent role of different measures of adiposity on HF outcomes.

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., (© 2018 American Heart Association, Inc.)

Objectives: This study sought to evaluate the association between early-life cardiorespiratory fitness (CRF) and measures of left ventricular (LV) structure and function in midlife., Background: Low CRF in midlife is associated with a higher risk of heart failure. However, the unique contributions of early-life CRF toward measures of LV structure and function in middle age are not known., Methods: CARDIA (Coronary Artery Risk Development in Young Adults) study participants with a baseline maximal treadmill test and an echocardiogram at year 25 were included. Associations among baseline CRF, CRF change, and echocardiographic LV parameters (global longitudinal strain [GLS] and global circumferential strain, E/e') were assessed using multivariable linear regression., Results: The study included 3,433 participants. After adjustment for baseline demographic and clinical characteristics, lower baseline CRF was significantly associated with higher LV strain (standardized parameter estimate [Std β] = -0.06; p = 0.03 for GLS) and ratio of early transmitral flow velocity to early peak diastolic mitral annular velocity (E/e') (Std β = -0.10; p = 0.0001 for lateral E/e'), findings suggesting impaired contractility and elevated diastolic filling pressure in midlife. After additional adjustment for cumulative cardiovascular risk factor burden observed over the follow-up period, the association of CRF with LV strain attenuated substantially (p = 0.36), whereas the association with diastolic filling pressure remained significant (Std β = -0.05; p = 0.02 for lateral E/e'). In a subgroup of participants with repeat CRF tests at year 20, greater decline in CRF was significantly associated with increased abnormalities in GLS (Std β = -0.05; p = 0.02) and higher diastolic filling pressure (Std β = -0.06; p = 0.006 for lateral E/e') in middle age., Conclusions: CRF in young adulthood and CRF change were associated with measures of LV systolic function and diastolic filling pressure in middle age. Low CRF-associated abnormalities in systolic function were related to the associated higher cardiovascular risk factor burden. In contrast, the inverse association between CRF and LV diastolic filling pressure was independent of cardiovascular risk factor burden., (Copyright © 2017. Published by Elsevier Inc.)

Background: Lower leisure-time physical activity (LTPA) and higher body mass index (BMI) are independently associated with risk of heart failure (HF). However, it is unclear if this relationship is consistent for both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF)., Objectives: This study sought to quantify dose-response associations between LTPA, BMI, and the risk of different HF subtypes., Methods: Individual-level data from 3 cohort studies (WHI [Women's Health Initiative], MESA [Multi-Ethnic Study of Atherosclerosis], and CHS [Cardiovascular Health Study]) were pooled and participants were stratified into guideline-recommended categories of LTPA and BMI. Associations between LTPA, BMI, and risk of overall HF, HFpEF (ejection fraction ≥45%), and HFrEF (ejection fraction <45%) were assessed by using multivariable adjusted Cox models and restricted cubic splines., Results: The study included 51,451 participants with 3,180 HF events (1,252 HFpEF, 914 HFrEF, and 1,014 unclassified HF). In the adjusted analysis, there was a dose-dependent association between higher LTPA levels, lower BMI, and overall HF risk. Among HF subtypes, LTPA in any dose range was not associated with HFrEF risk. In contrast, lower levels of LTPA (<500 MET-min/week) were not associated with HFpEF risk, and dose-dependent associations with lower HFpEF risk were observed at higher levels. Compared with no LTPA, higher than twice the guideline-recommended minimum LTPA levels (>1,000 MET-min/week) were associated with an 19% lower risk of HFpEF (hazard ratio: 0.81; 95% confidence interval: 0.68 to 0.97). The dose-response relationship for BMI with HFpEF risk was also more consistent than with HFrEF risk, such that increasing BMI above the normal range (≥25 kg/m 2 ) was associated with a greater increase in risk of HFpEF than HFrEF., Conclusions: Our study findings show strong, dose-dependent associations between LTPA levels, BMI, and risk of overall HF. Among HF subtypes, higher LTPA levels and lower BMI were more consistently associated with lower risk of HFpEF compared with HFrEF., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: There is controversy regarding whether to report concentrations of high-sensitivity cardiac troponin T (hs-cTnT) to the limit of blank (LOB) (3 ng/L) or the limit of detection (LOD) (5 ng/L) of the assay in community-based cohorts. We hypothesized that hs-cTnT concentrations between the LOB and LOD would be associated with poorer cardiovascular outcomes compared to concentrations below the LOB., Methods: hs-cTnT was analyzed in a total of 10 723 participants from the Cardiovascular Health Study (CHS), Atherosclerosis Risk in Communities (ARIC) study, and Dallas Heart Study (DHS). Participants were divided into 2 groups, those with hs-cTnT concentrations below the limit of blank (LOB) (<3 ng/L) and those with hs-cTnT between the LOB and limit of detection (LOD) (3-4.99 ng/L). Cross-sectional associations with traditional cardiovascular risk factors and cardiac structural measurements, and longitudinal associations with long-term cardiovascular outcomes of incident heart failure and cardiovascular death, were determined., Results: Participants with hs-cTnT between the LOB and LOD for all 3 cohorts were older, more likely to be male, and have a higher burden of cardiovascular risk factors and structural pathology. A metaanalysis of the 3 cohorts showed participants with hs-cTnT between the LOB and LOD were at increased risk of new-onset heart failure (hazard ratio, 1.18; 95% CI, 1.02-1.38) and cardiovascular mortality (hazard ratio, 1.29; 95% CI, 1.06-1.57)., Conclusions: hs-cTnT concentrations between the LOB and LOD (3-4.99 ng/L) are associated with a higher prevalence of traditional risk factors, more cardiac pathology, and worse outcomes than concentrations below the LOB (<3 ng/L)., (© 2015 American Association for Clinical Chemistry.)

Background: Prior studies have reported an inverse association between physical activity (PA) and risk of heart failure (HF). However, a comprehensive assessment of the quantitative dose-response association between PA and HF risk has not been reported previously., Methods and Results: Prospective cohort studies with participants >18 years of age that reported association of baseline PA levels and incident HF were included. Categorical dose-response relationships between PA and HF risk were assessed with random-effects models. Generalized least-squares regression models were used to assess the quantitative relationship between PA (metabolic equivalent [MET]-min/wk) and HF risk across studies reporting quantitative PA estimates. Twelve prospective cohort studies with 20 203 HF events among 370 460 participants (53.5% women; median follow-up, 13 years) were included. The highest levels of PA were associated with significantly reduced risk of HF (pooled hazard ratio for highest versus lowest PA, 0.70; 95% confidence interval, 0.67-0.73). Compared with participants reporting no leisure-time PA, those who engaged in guideline-recommended minimum levels of PA (500 MET-min/wk; 2008 US federal guidelines) had modest reductions in HF risk (pooled hazard ratio, 0.90; 95% confidence interval, 0.87-0.92). In contrast, a substantial risk reduction was observed among individuals who engaged in PA at twice (hazard ratio for 1000 MET-min/wk, 0.81; 95% confidence interval, 0.77-0.86) and 4 times (hazard ratio for 2000 MET-min/wk, 0.65; 95% confidence interval, 0.58-0.73) the minimum guideline-recommended levels., Conclusions: There is an inverse dose-response relationship between PA and HF risk. Doses of PA in excess of the guideline-recommended minimum PA levels may be required for more substantial reductions in HF risk., (© 2015 American Heart Association, Inc.)

Background: Insertion of a left ventricular assist device (LVAD) is an accepted therapy for advanced heart failure patients. However, the effects on end-organ perfusion, including cerebral autoregulation, are unclear in the presence of reduced pulsatility. Therefore, the objective of this study was to determine whether cerebral autoregulation is impaired in patients with continuous-flow (CF) LVADs., Methods: Dynamic cerebral autoregulation was assessed in both time-domain (autoregulatory index) and frequency-domain (transfer function analysis) analyses in 9 CF-LVAD subjects, 5 pulsatile LVAD subjects and 10 healthy controls, by evaluating mean arterial pressure (MAP) and cerebral blood flow velocity (CBFV) during a sit-stand maneuver at 0.05 Hz (10-second sit, 10-second stand). The autoregulatory index was calculated as the percent change in mean CBFV per mm Hg change in MAP., Results: The magnitude of oscillation in MAP and CBFV was greater in subjects with pulsatile LVADs than either CF-LVADs or healthy controls (p = 0.065 for MAP, p = 0.004 for CBFV). The autoregulatory index and transfer function gain were similar among groups, indicating that dynamic cerebral autoregulation is preserved among patients with CF-LVADs., Conclusions: Cerebral blood flow in patients with CF-LVADs is comparable to that of healthy controls across a range of blood pressures. Patients with pulsatile devices have greater oscillations in MAP and CBFV. However, dynamic cerebral autoregulation is preserved among subjects with either type of device. Thus, the reduction in pulsatility afforded by CF-LVADs does not impair normal autoregulatory processes., (Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Multiple studies have demonstrated strong associations between cardiorespiratory fitness and lower cardiovascular disease mortality. In contrast, little is known about associations of fitness with nonfatal cardiovascular events., Methods and Results: Linking individual participant data from the Cooper Center Longitudinal Study with Medicare claims files, we studied 20642 participants (21% women) with fitness measured at the mean age of 49 years and who survived to receive Medicare coverage from 1999 to 2009. Fitness was categorized into age- and sex-specific quintiles (Q) according to Balke protocol treadmill time with Q1 as low fitness. Fitness was also estimated in metabolic equivalents according to treadmill time. Associations between midlife fitness and hospitalizations for heart failure and acute myocardial infarction after the age of 65 years were assessed by applying a proportional hazards model to the multivariate failure time data. After 133514 person-years of Medicare follow-up, we observed 1051 hospitalizations for heart failure and 832 hospitalizations for acute myocardial infarction. Compared with high fitness (Q4-5), low fitness (Q1) was associated with a higher rate of heart failure hospitalization (14.3% versus 4.2%) and hospitalization for myocardial infarction (9.7% versus 4.5%). After multivariable adjustment for baseline age, blood pressure, diabetes mellitus, body mass index, smoking status, and total cholesterol, a 1 unit greater fitness level in metabolic equivalents achieved in midlife was associated with ≈20% lower risk for heart failure hospitalization after the age of 65 years (men: hazard ratio [95% confidence intervals], 0.79 [0.75-0.83]; P<0.001 and women: 0.81 [0.68-0.96]; P=0.01) but just a 10% lower risk for acute myocardial infarction in men (0.91 [0.87-0.95]; P<0.001) and no association in women (0.97 [0.83-1.13]; P=0.68)., Conclusions: Fitness in healthy, middle-aged adults is more strongly associated with heart failure hospitalization than acute myocardial infarction outcomes decades later in older age.