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Background: Patterns and disparities in guideline-directed medical therapy (GDMT) uptake for heart failure with reduced ejection fraction (HFrEF) across rural vs urban regions are not well described., Objectives: This study aims to evaluate patterns, prognostic implications, and rural-urban differences in GDMT use among Medicare beneficiaries following new-onset HFrEF., Methods: Patients with a diagnosis of new-onset HFrEF in a 5% Medicare sample with available data for Part D medication use were identified from January 2015 through December 2020. The primary exposure was residence in rural vs urban zip codes. Optimal triple GDMT was defined as ≥50% of the target daily dose of beta-blockers, ≥50% of the target daily dose of angiotensin-converting enzyme inhibitors/angiotensin receptor blocker or any dose of sacubitril/valsartan, and any dose of mineralocorticoid receptor antagonist. The association between the achievement of optimal GDMT over time following new-onset HFrEF diagnosis and risk of all-cause mortality and subsequent HF hospitalization was also evaluated using adjusted Cox models. The association between living in rural vs urban location and time to optimal GDMT achievement over a 12-month follow-up was assessed using cumulative incidence curves and adjusted Fine-Gray subdistribution hazard models., Results: A total of 41,296 patients (age: 76.7 years; 15.0% Black; 27.6% rural) were included. Optimal GDMT use over the 12-month follow-up was low, with 22.5% initiated on any dose of triple GDMT and 9.1% on optimal GDMT doses. Optimal GDMT on follow-up was significantly associated with a lower risk of death (HR: 0.89 [95% CI: 0.85-0.94]; P < 0.001) and subsequent HF hospitalization (HR: 0.93 [95% CI: 0.87-0.98]; P = 0.02). Optimal GDMT use at 12 months was significantly lower among patients living in rural (vs urban) areas (8.4% vs 9.3%; P = 0.02). In adjusted analysis, living in rural (vs urban) locations was associated with a significantly lower probability of achieving optimal GDMT (HR: 0.92 [95% CI: 0.86-0.98]; P = 0.01 Differences in optimal GDMT use following HFrEF diagnosis accounted for 16% of excess mortality risk among patients living in rural (vs urban) areas., Conclusions: Use of optimal GDMT following new-onset HFrEF diagnosis is low, with substantially lower use noted among patients living in rural vs urban locations. Suboptimal GDMT use following new-onset HFrEF was associated with an increased risk of mortality and subsequent HF hospitalization., Competing Interests: Funding Support and Author Disclosures This study is supported by a National Institute of Minority Health and Disparities R01 grant (R01MD017529) and an American Heart Association grant (23DSG1154425) to Dr Pandey. Dr Keshvani has received grants from the National Heart, Lung, and Blood Institute (5T32HL125247-08) and consulting fees from Heart Test Laboratories and Tricog Health. Dr Khan has received consulting fees from Bayer. Dr Hsich is supported by grants from the National Heart, Lung, and Blood Institute (R01HL164405). Dr Fonarow has done consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Eli Lilly, Janssen, Medtronic, Merck, Novartis, and Pfizer. Dr Pandey has received research funding from the Texas Health Resources Clinical Scholarship, Gilead Sciences Research Scholar Program, Applied Therapeutics (investigator-initiated grant), and National Institute of Aging (GEMSSTAR grant 1R03AG067960-01); serves on the Advisory Board of Roche Diagnostics; has received grants from the National Institute on Aging (1R03AG067960-01), the National Institute on Minority Health and Disparities (R01MD017529), Applied Therapeutics, Gilead Sciences Research, and Myovista Research; has received consultant fees from Roche Diagnostics, Tricog Health, Pieces Technologies, Rivus, Palomarin Inc, Emmi Solutions; has received nonfinancial support from Pfizer and Merck; and has received Advisory Board fees from Lilly Inc, Cytokinetics, Alleviant Medical, Axon Therapies, and Bayer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 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.

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.

Background: Right heart catheterization-derived hemodynamic parameters have been associated with short-term prognosis., Hypothesis: Hemodynamic parameters will be associated with long-term prognosis., Methods: Retrospective cohort study from the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program included patients who underwent an index right heart catheterization between 2008 and 2016. Cox proportional hazard models were used to examine the association between stroke volume index and all-cause mortality., Results: For the final cohort of 37 209 patients, mean follow-up was 3.7 ± 2.5 years. All-cause mortality was 42.0% in the low (<35 cc/beat/m 2 ) compared with 33.2% in the normal stroke volume index group (≥35 cc/beat/m 2 ). In adjusted analysis, low stroke volume was significantly associated with higher mortality risk (HR (95% CI) 1.14 (1.10-1.18); P < .001) independent of clinical parameters. The area under the curve (AUC) for continuous measures of stroke volume index at predicting mortality in a Cox proportional hazard model was 0.56 at 3 years. When stroke volume index was combined with 14 clinical covariates, the AUC was 0.70 at 3 years. The addition of stroke volume index to these clinical covariates did not increase the discriminatory ability of the model at 1 year in a clinically meaningful way (integrated discrimination improvement index = 0.0021, 95% CI: 0.0010-0.0034)., Conclusions: The long-term prognostic value of right heart catheterization-derived stroke volume index appears to be marginal. While there was a weak association of low stroke volume index and excess mortality, inclusion of this parameter to a set of clinical covariates did not improve prognostic discrimination., (© 2020 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

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.)

Aims: Plasma volume expansion is clinically and prognostically relevant in individuals with heart failure. Prior cohorts either excluded or had limited representation of patients with heart failure with preserved ejection fraction (HFpEF). We aimed to examine the relationship between calculated plasma volume status (PVS) and outcomes in HFpEF., Methods and Results: We included enrollees from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT) with available haematocrit and weight data (n = 3414). Plasma volume was derived from the Hakim formula and compared to estimates of ideal plasma volume to generate a relative PVS. Multivariable Cox proportional hazards models tested the association of PVS with clinical outcomes. The median PVS was -11.9% (25th-75th percentile: -17.2% to -6.4%) and the majority (91.1%) had PVS consistent with relative volume contraction (PVS ≤ 0%) as opposed to volume expansion (8.9%, PVS > 0%). After multivariable adjustment, each 5% increment in PVS was associated with a ∼11%, 14%, and 12% higher risk for the primary composite endpoint, all-cause death, and heart failure hospitalization, respectively (P < 0.002 for all), but not cardiovascular death (P = 0.051). After additional adjustment for natriuretic peptides, PVS only remained associated with heart failure hospitalization (HR 1.10, 95% confidence interval 1.001-1.21, P = 0.047). There were no significant interactions between spironolactone use and the PVS-risk relationship for any endpoint (P > 0.1 for all)., Conclusion: Higher calculated estimates of PVS were independently associated with a higher risk of long-term clinical outcomes in HFpEF, and particularly, heart failure hospitalization., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Background: Older patients with heart failure with preserved ejection fraction have severe exercise intolerance. Vitamin D may play a role in cardiovascular and skeletal muscle function, and may therefore be implicated in exercise intolerance in heart failure with preserved ejection fraction. However, there are few data on vitamin D status and its relationship to exercise capacity in heart failure with preserved ejection fraction patients., Methods: Plasma 25-hydroxyvitamin D (25[OH]D) and exercise capacity (peak oxygen consumption, [VO 2 ], 6-minute walk distance) were measured in 112 older heart failure with preserved ejection fraction patients (mean ± SD age = 70 ± 8 years) and 37 healthy age-matched controls. General linear models were used to compare 25(OH)D between heart failure with preserved ejection fraction patients and healthy controls, and to determine the cross-sectional association between 25(OH)D and exercise capacity. The association between 25(OH)D and left ventricular function was evaluated secondarily in heart failure with preserved ejection fraction patients., Results: 25(OH)D concentrations were significantly lower in heart failure with preserved ejection fraction vs healthy controls (11.4 ± 0.6 ng/mL vs 19.1 ± 2.1 ng/mL; P = .001, adjusted for age, race, sex, body mass index, season). More than 90% of heart failure with preserved ejection fraction patients had 25(OH)D insufficiency (<20 ng/mL) and 30% had frank 25(OH)D deficiency (<10 ng/mL). In heart failure with preserved ejection fraction patients, but not healthy controls, 25(OH)D was significantly correlated with peak VO 2 (r = 0.26; P = 0.007) and 6-minute walk distance (r = 0.34; P < .001)., Conclusions: More than 90% of heart failure with preserved ejection fraction patients had 25(OH)D insufficiency, and 30% were frankly deficient. Lower 25(OH)D was associated with lower peak VO 2 and 6-minute walk distance in heart failure with preserved ejection fraction, suggesting that 25(OH)D insufficiency could contribute to exercise intolerance in this patient population. These findings provide the data and rationale for a future randomized trial designed to test the potential for vitamin D supplementation to improve exercise intolerance in heart failure with preserved ejection fraction., (Copyright © 2018. Published by Elsevier Inc.)

Heart failure with preserved ejection fraction (HFpEF) is common, increasing in prevalence, and refractory to available pharmacotherapies. Our understanding of HFpEF has evolved from a disorder of diastolic dysfunction to a constellation of physiologic impairments that lead to elevated left ventricular filling pressures and exercise intolerance. Accordingly, the therapeutic and preventive focus has shifted to identifying lifestyle factors that may have more pleotropic effects on the pathophysiologic mechanisms that define HFpEF. Recent studies have demonstrated that physical inactivity, low fitness, and obesity are potential modifiable targets for prevention as well as management of HFpEF. In this review, we have discussed the emerging epidemiological, mechanistic, and clinical evidence that support the role of these lifestyle factors as key determinants of development and progression of HFpEF. We also summarize the available evidence and major knowledge gaps with regard to developing exercise training and weight loss as unique and effective therapeutic strategies for management of HFpEF., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background The prognostic interrelationship between natriuretic peptide ( NP ) levels and body mass index ( BMI ) among patients with chronic stable heart failure with preserved ejection fraction is not well characterized. Methods and Results Participants from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial enrolled in the Americas meeting inclusion by the NP stratum were stratified into 4 data-derived categories by BMI and standardized NP -z score. Adjusted Cox-proportional models determined the independent association of BMI , NP -z score, and BMI / NP categories with composite primary end point, heart failure hospitalization, and all-cause mortality. The study population included 997 participants. There was a U-shaped relationship between BMI and NP with elevated NP levels noted at extremes of BMI distribution. There was also a U-shaped relationship between BMI and risk of adverse clinical outcomes with the lowest risk among patients approximating a BMI of 25 kg/m 2 . In contrast, higher NP levels were linearly associated with higher risk of adverse clinical outcomes. For BMI / NP -based categories, participants in the high BMI /high NP group had greater prevalence of cardiac structural and functional abnormalities and the highest risk of adverse clinical outcomes (hazard ratio for primary end point; 95% confidence interval: 2.29 [1.36-3.84] Reference: low BMI /low NP ). Conclusions There is a U-shaped association between BMI and NP levels among patients with chronic heart failure with preserved ejection fraction. Higher NP levels are independently associated with a higher risk of mortality across both high and low BMI strata. Among obese patients with heart failure with preserved ejection fraction, elevated NP levels identify a higher risk phenotype with a significantly increased incidence of both mortality and heart failure hospitalization.

Aims: Prior cohorts demonstrating the importance of serum chloride levels in heart failure either excluded or had partial representation of patients with heart failure with preserved ejection fraction (HFpEF). We aimed to examine the relationship between serum chloride concentration and outcomes in HFpEF., Methods and Results: We included participants from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT) who met the following criteria: met inclusion by the natriuretic peptide stratum, had recorded serum chloride levels, and were from the Americas (n = 942). Multivariable Cox proportional hazards models tested the association of serum chloride with clinical outcomes, and mixed effects modelling tested the association of spironolactone or loop diuretic on serial serum chloride levels. The median serum chloride level was 102 [25th-75th percentile 100-105 mmol/L (range 84-114 mmol/L)]. After multivariable adjustment, every standard deviation decrease in serum chloride (4.05 mmol/L) was associated with ∼50% increased risk for cardiovascular death [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.11-2.06, P = 0.008] and ∼30% increased risk for all-cause death (HR 1.29, 95% CI 1.02-1.62, P = 0.04), but not with the primary composite endpoint or heart failure hospitalization (P > 0.3 for both). There were no significant interactions between spironolactone use and the serum chloride-risk relationship (P > 0.1) for each endpoint. Spironolactone was not (P = 0.33) but loop diuretic use was associated with lower serial serum chloride levels (P < 0.001)., Conclusion: Lower serum chloride was independently associated with increased risk of cardiovascular and all-cause death in HFpEF. Loop diuretic use, but not spironolactone, lead to a decrease in serum chloride levels over time., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

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: The aim of this study was to compare the relative impairment in different exercise hemodynamic reserve parameters in patients with heart failure with preserved ejection fraction (HFpEF) and control patients using a study-level meta-analysis., Background: A cardinal manifestation of chronic HFpEF is severely decreased exercise capacity. Developing effective therapies for exercise intolerance in HFpEF requires optimal understanding of the factors underlying exercise intolerance., Methods: Data were included from 17 unique cohorts that measured peak oxygen uptake and hemodynamic or echocardiographic parameters during exercise in patients with HFpEF and control subjects in this meta-analysis. Standardized mean differences (SMDs) in the exercise reserve (exercise - resting) measures of hemodynamic or echocardiographic parameters between the HFpEF and control groups were pooled in a random-effects meta-analysis., Results: The pooled analysis included 910 patients with HFpEF and 476 control subjects. In pooled analysis, patients with HFpEF had significantly lower peak oxygen uptake (SMD: -2.13; 95% confidence interval [CI]: -2.68 to -1.57). Among hemodynamic exercise reserve parameters, the largest impairment was observed in chronotropic response reserve (change in heart rate from rest to peak exercise; SMD: -1.87; 95% CI: -2.44 to -1.29), followed by exaggerated increase in pulmonary capillary wedge pressure with exercise (SMD: 1.78; 95% CI: 1.46 to 2.09). Significant abnormalities were also observed in the arteriovenous oxygen difference reserve and stroke volume reserve between the HFpEF and control groups., Conclusions: The most consistent and severe hemodynamic reserve abnormalities observed in patients with HFpEF were impairment in chronotropic reserve and exaggerated increase in pulmonary capillary wedge pressure with exercise. These may be important targets for therapeutic strategies to improve exercise tolerance in patients with HFpEF., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Low cardiorespiratory fitness (CRF) and obesity are significant risk factors for heart failure (HF). However, given the inverse association between CRF and obesity, the independent contributions of low CRF and adiposity toward HF risk are not well established. We evaluated the association of CRF and measures of adiposity with left ventricular (LV) peak systolic strain-a subclinical measure of LV dysfunction-among the Dallas Heart Study phase II participants without cardiovascular disease who had CRF estimated using a submaximal treadmill test and LV systolic circumferential strain assessment by tissue-tagged cardiac magnetic resonance imaging. Peak midwall systolic circumferential strain (Ecc) was determined by harmonic phase imaging. Associations of CRF and adiposity measures with Ecc were determined using adjusted linear regression analysis. A total of 1,617 participants were included in the analysis. After adjustment for baseline risk factors, higher waist circumference (WC) and lower CRF were associated with higher Ecc (WC: β = 0.07; p = 0.01; CRF: β = -0.17; p = < 0.0001), whereas % body fat and body mass index were not associated with Ecc. The relationship between WC and Ecc was attenuated completely after additional adjustment for CRF. In contrast, the association between CRF and Ecc did not attenuate after additional adjustment for WC and other measures of LV structure and function (β = -0.18; p = < 0.0001). Taken together, our study findings suggest that lower CRF, but not measures of adiposity, is associated with greater impairment in LV strain independent of LV mass and ejection fraction., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: In the conventional paradigm of the progression of left ventricular hypertrophy, a thick-walled left ventricle (LV) ultimately transitions to a dilated cardiomyopathy. There are scant data in humans demonstrating whether this transition occurs commonly without an interval myocardial infarction., Methods and Results: Participants (n=1282) from the Dallas Heart Study underwent serial cardiac magnetic resonance ≈7 years apart. Those with interval cardiovascular events and a dilated LV (increased LV end-diastolic volume [EDV] indexed to body surface area) at baseline were excluded. Multivariable linear regression models tested the association of concentric hypertrophy (increased LV mass and LV mass/volume 0.67 ) with change in LVEDV. The study cohort had a median age of 44 years, 57% women, 43% black, and 11% (n=142) baseline concentric hypertrophy. The change in LVEDV in those with versus without concentric hypertrophy was 1 mL (-9 to 12) versus -2 mL (-11 to 7), respectively, P <0.01. In multivariable linear regression models, concentric hypertrophy was associated with larger follow-up LVEDV ( P ≤0.01). The progression to a dilated LV was uncommon (2%, n=25)., Conclusions: In the absence of interval myocardial infarction, concentric hypertrophy was associated with a small, but significantly greater, increase in LVEDV after 7-year follow-up. However, the degree of LV enlargement was minimal, and few participants developed a dilated LV. These data suggest that if concentric hypertrophy does progress to a dilated cardiomyopathy, such a transition would occur over a much longer timeframe (eg, decades) and perhaps less common than previously thought., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00344903., (© 2017 American Heart Association, Inc.)

Heart failure with preserved ejection fraction (HFpEF) is common, recalcitrant to treatment, and associated with poor outcomes. Diastolic dysfunction (DD) is an independent predictor of HFpEF risk, associated clinical manifestations, and long-term outcomes. However, the usefulness of diastolic function assessment is limited by the heterogeneity in the existing definitions of DD. In this issue of the Journal, Rasmussen-Torvik et al. (Am J Epidemiol. 2017;185(12):1221-1227) have highlighted this problem by evaluating the prevalence and concordance of 4 established definitions of DD in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. The authors demonstrate significant variability in prevalence of DD and its association with established risk factors across the different definitions. These findings suggest that the current 1-dimensional approach to HFpEF risk prediction based on noninvasive measures of diastolic function may not be optimal. Perhaps the future of HFpEF risk assessment lies in a multimodality approach that combines the relevant echocardiographic measures of diastolic function with blood-based biomarkers (such as N-terminal prohormone of brain natriuretic peptide (NT-proBNP)) and a measure of functional status (such as exercise capacity)., (© The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.)

Higher arterial stiffness is associated with increased risk of atherosclerotic events. However, its contribution toward risk of heart failure (HF) and its subtypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), independent of other risk factors is not well established. In this study, we included Health ABC study (Health, Aging, and Body Composition) participants without prevalent HF who had arterial stiffness measured as carotid-femoral pulse wave velocity (cf-PWV) at baseline (n=2290). Adjusted Cox-proportional hazards models were constructed to determine the association between continuous and data-derived categorical measures (tertiles) of cf-PWV and incidence of HF and its subtypes (HFpEF [ejection fraction >45%] and HFrEF [ejection fraction ≤45%]). We observed 390 HF events (162 HFpEF and 145 HFrEF events) over 11.4 years of follow-up. In adjusted analysis, higher cf-PWV was associated with greater risk of HF after adjustment for age, sex, ethnicity, mean arterial pressure, and heart rate (hazard ratio [95% confidence interval] for cf-PWV tertile 3 versus tertile 1 [ref] =1.35 [1.05-1.73]). However, this association was not significant after additional adjustment for other cardiovascular risk factors (hazard ratio [95% confidence interval], 1.14 [0.88-1.47]). cf-PWV velocity was also not associated with risk of HFpEF and HFrEF after adjustment for potential confounders (most adjusted hazard ratio [95% confidence interval] for cf-PWV tertile 3 versus tertile 1 [ref]: HFpEF, 1.06 [0.72-1.56]; HFrEF, 1.28 [0.83-1.97]). In conclusion, arterial stiffness, as measured by cf-PWV, is not independently associated with risk of HF or its subtypes after adjustment for traditional cardiovascular risk factors., (© 2016 American Heart Association, Inc.)

Importance: Elevated levels of cardiac troponins are associated with adverse clinical outcomes among patients with heart failure (HF) and reduced ejection fraction. However, the clinical significance of troponin elevation in the setting of decompensated HF with preserved ejection fraction (HFpEF) is not well established., Objective: To determine the clinical predictors of troponin elevation and its association with in-hospital and long-term outcomes among patients with decompensated HFpEF., Design, Setting, and Participants: Observational analysis of Get With The Guidelines-HF registry participants who were admitted for decompensated HFpEF (ejection fraction ≥50%) from January 2009 through December 2014 and who had quantitative or categorical (elevated vs normal based on institution's reference laboratory) measures of troponin level (troponin T or troponin I, as available)., Main Outcomes and Measures: In-hospital outcomes (mortality, length of stay, and discharge destination) and postdischarge outcomes (30-day mortality, 30-day readmission rate, 1-year mortality)., Results: We included 34 233 patients with HFpEF from 224 sites with measured troponin levels (33.4% men; median age, 79 years): 78.6% (n = 26 896) with troponin I and 21.4% (n = 7319) with troponin T measurements. Among these, 22.6% (n = 7732) had elevation in troponin levels. In adjusted analysis, higher serum creatinine level, black race, older age, and ischemic heart disease were associated with troponin elevation. Elevated troponin was associated with higher odds of in-hospital mortality (odds ratio [OR], 2.19; 95% CI, 1.88-2.56), greater length of stay (length of stay >4 days OR, 1.38; 95% CI, 1.29-1.47), and lower likelihood of discharge to home (OR, 0.65; 95% CI, 0.61-0.71) independent of other clinical predictors and measured confounders. Presence of elevated troponin I levels was also significantly associated with increased risk of 30-day mortality (hazard ratio [HR], 1.59; 95% CI, 1.42-1.80), 30-day all-cause readmission (HR, 1.12; 95% CI, 1.01-1.25), and 1-year mortality HR, 1.35; 95% CI, 1.26-1.45)., Conclusions and Relevance: Troponin elevation among patients with acutely decompensated HFpEF is associated with worse in-hospital and postdischarge outcomes, independent of other predictive variables. Future studies are needed to determine if measurement of troponin levels among patients with decompensated HFpEF may be useful for risk stratification.

Background: There has been an increasing interest in use of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure with preserved ejection fraction (HFPEF). However, a comprehensive evaluation of MRA effects on left ventricular (LV) structure and function in these patients is lacking. In this meta-analysis, we evaluated the effects of MRAs on LV structure and function among patients with diastolic dysfunction or HFPEF., Methods & Results: Randomized, controlled clinical trials evaluating the efficacy of MRAs in patients with diastolic dysfunction or HFPEF were included. The primary outcome was change in E/e', a specific measure of diastolic function. Secondary outcomes included changes in other measures of diastolic function, LV structure, surrogate markers for myocardial fibrosis (carboxy-terminal peptide of procollagen type I [PICP] and amino-terminal peptide of pro-collagen type-II [PIIINP]), blood pressure, and exercise tolerance. In the pooled analysis, MRA use was associated with significant reduction in E/e' (weighted mean difference [WMD] [95% confidence interval {CI}]: -1.68 [-2.03 to -1.33]; P<0.0001) and deceleration time (WMD [95% CI]: -12.0 ms [-23.3 to -0.7]; P=0.04) as compared with control, suggesting and improvement in diastolic function. Furthermore, blood pressure and levels of PIIINP and PICP were also significantly reduced with MRA therapy with no significant change in LV mass or dimensions., Conclusion: MRA therapy in patients with asymptomatic diastolic dysfunction or HFPEF is associated with significant improvement in diastolic function and markers of cardiac fibrosis without a significant change in LV mass or dimensions., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Heart failure (HF) with preserved ejection fraction (HFpEF) is common and recalcitrant to any medical therapy, highlighting the need for novel strategies focused on its prevention. Recent studies have shown that low cardiorespiratory fitness (CRF) in middle age identifies a subgroup of individuals at particularly high risk for HF, particularly HFpEF. These findings suggest that low CRF in middle age represents an upstream marker for late-life HFpEF. Furthermore, evidence from recent epidemiological studies suggests that low CRF associated risk for HFpEF appears to be modifiable with improvement in CRF. The primary objective of this review is to provide an overview of the potential mechanisms through which exercise training and improvement in CRF may protect against the transition from a low fit stage to clinical HFpEF among at-risk sedentary, middle-age adults., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Heart failure with preserved ejection fraction (HFPEF) is common and characterized by exercise intolerance and lack of proven effective therapies. Exercise training has been shown to be effective in improving cardiorespiratory fitness (CRF) in patients with systolic heart failure. In this meta-analysis, we aim to evaluate the effects of exercise training on CRF, quality of life, and diastolic function in patients with HFPEF., Methods and Results: Randomized controlled clinical trials that evaluated the efficacy of exercise training in patients with HFPEF were included in this meta-analysis. Primary outcome of the study was change in CRF (measured as change in peak oxygen uptake). Effect of exercise training on quality of life (estimated using Minnesota living with heart failure score), and left ventricular systolic and diastolic function was also assessed. The study included 276 patients who were enrolled in 6 randomized controlled trials. In the pooled data analysis, patients with HFPEF undergoing exercise training had significantly improved CRF (mL/kg per min; weighted mean difference, 2.72; 95% confidence interval, 1.79-3.65) and quality of life (weighted mean difference, -3.97; 95% confidence interval, -7.21 to -0.72) when compared with the control group. However, no significant change was observed in the systolic function (EF-weighted mean difference, 1.26; 95% confidence interval, -0.13% to 2.66%) or diastolic function (E/A-weighted mean difference, 0.08; 95% confidence interval, -0.01 to 0.16) with exercise training in patients with HFPEF., Conclusions: Exercise training in patients with HFPEF is associated with an improvement in CRF and quality of life without significant changes in left ventricular systolic or diastolic function., (© 2014 American Heart Association, Inc.)

The prevalence of heart failure (HF) and its subtype, HF with preserved ejection fraction (HFpEF), is on the rise due to aging of the population. HFpEF is convergence of several pathophysiological processes, which are not yet clearly identified. HFpEF is usually seen in association with systemic diseases, such as diabetes, hypertension, atrial fibrillation, sleep apnea, renal and pulmonary disease. The proportion of HF patients with HFpEF varies by patient demographics, study settings (cohort vs. clinical trial, outpatient clinics vs. hospitalised patients) and cut points used to define preserved function. There is an expanding body of literature about prevalence and prognostic significance of both cardiovascular and non-cardiovascular comorbidities in HFpEF patients. Current therapeutic approaches are targeted towards alleviating the symptoms, treating the associated comorbid conditions, and reducing recurrent hospital admissions. There is lack of evidence-based therapies that show a reduction in the mortality amongst HFpEF patients; however, an improvement in exercise tolerance and quality of life is seen with few interventions. In this review, we highlight the epidemiology and current treatment options for HFpEF.

AIMS: Sex differences in long-term outcomes following hospitalization for heart failure (HF) across ejection fraction (EF) subtypes are not well described. In this study, we evaluated the risk of mortality and rehospitalization among males and females across the spectrum of EF over 5 years of follow-up following an index HF hospitalization event. METHODS AND RESULTS: Patients hospitalized with HF between 1 January 2006 and 31 December 2014 from the American Heart Associations Get With The Guidelines-Heart Failure registry with available 5-year follow-up using Medicare Part A claims data were included. The association between sex and risk of mortality and readmission over a 5-year follow-up period for each HF subtype (HF with reduced EF [HFrEF, EF ≤40%], HF with mildly reduced EF [HFmrEF, EF 41-49%], and HF with preserved EF [HFpEF, EF >50%]) was assessed using adjusted Cox models. The effect modification by the HF subtype for the association between sex and outcomes was assessed by including multiplicative interaction terms in the models. A total of 155 670 patients (median age: 81 years, 53.4% female) were included. Over 5-year follow-up, males and females had comparably poor survival post-discharge; however, females (vs. males) had greater years of survival lost to HF compared with the median age- and sex-matched US population (HFpEF: 17.0 vs. 14.6 years; HFrEF: 17.3 vs. 15.1 years; HFmrEF: 17.7 vs. 14.6 years for age group 65-69 years). In adjusted analysis, females (vs. males) had a lower risk of 5-year mortality (adjusted hazard ratio [aHR] 0.89, 95% confidence interval [CI] 0.87-0.90, p

OBJECTIVES: In this study, we sought to evaluate the association of frailty with the use of optimal guideline-directed medical therapy (GDMT) and outcomes in heart failure with reduced ejection fraction (HFrEF). BACKGROUND: The burden of frailty in HFrEF is high, and the patterns of GDMT use according to frailty status have not been studied previously. METHODS: A post hoc analysis of patients with HFrEF enrolled in the GUIDE-IT (Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment in Heart Failure) trial was conducted. Frailty was assessed with the use of a frailty index (FI) using a 38-variable deficit model, and participants were categorized into 3 groups: class 1: nonfrail, FI 0.31). Multivariate-adjusted Cox models were used to study the association of frailty status with clinical outcomes. Use of optimal GDMT over time (beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and mineralocorticoid receptor antagonists) across frailty strata was assessed with the use of adjusted linear and logistic mixed-effect models. RESULTS: The study included 879 participants, of which 56.3% had high frailty burden (class 3 FI). A higher frailty burden was associated with a significantly higher risk of HF hospitalization or death in adjusted Cox models: high frailty vs nonfrail HR: 1.76, 95% CI: 1.20-2.58. On follow-up, participants with high frailty burden also had a significantly lower likelihood of achieving optimal GDMT: high frailty vs non-frail GDMT triple therapy use at study end: 17.7% vs 28.4%; P interaction, frailty class × time

Heart failure (HF) is a leading cause of morbidity. Strategies for preventing HF are paramount. Prevalent extracoronary calcification is associated with HF risk but less is known about progression of mitral annular (MAC) and aortic valve calcification (AVC) and HF risk. Progression of valvular calcification (VC) [interval change of >0 units/yr] was assessed by 2 cardiac computed tomography scans over a median of 2.4 years. We used Cox regression to determine the risk of adjudicated HF and linear mixed effects models to determine 10-year change in left ventricular (LV) parameters measured by cardiac magnetic resonance imaging associated with VC progression. We studied 5,591 MESA participants free of baseline cardiovascular disease. Mean ± SD age was 62 ± 10 years; 53% women; 83% had no VC progression, 15% progressed at 1 site (AVC or MAC) and 3% at both sites. There were 251 incident HF over 15 years. After adjusting for cardiovascular risk factors, the hazard ratios (95% confidence interval) of HF associated with VC progression at 1 and 2 sites were 1.62 (1.21 to 2.17) and 1.88 (1.14 to 3.09), respectively, compared with no progression (p-for-trend

BackgroundLower 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).ObjectivesThis study sought to quantify dose-response associations between LTPA, BMI, and the risk of different HF subtypes.MethodsIndividual-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 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/m2) was associated with a greater increase in risk of HFpEF than HFrEF.ConclusionsOur 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.