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Background Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA‐HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). Methods and Results A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5–20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site‐interpreted Valsalva left ventricular outflow tract gradient

Background Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. Methods and Results We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF enrolled in the PARAGON‐HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial using a modified aptamer proteomic assay. Baseline circulating protein concentrations significantly associated with the primary end point and the timing and occurrence of total heart failure hospitalization and cardiovascular death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared with published analyses in 2515 patients with heart failure with reduced ejection fraction from the PARADIGM‐HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity–Mortality in Patients With Chronic Heart Failure) clinical trials. We identified 288 proteins that were robustly associated with the risk of heart failure hospitalization and cardiovascular death in patients with HFpEF. The baseline proteins most strongly related to outcomes included B2M (β‐2 microglobulin), TIMP1 (tissue inhibitor of matrix metalloproteinase 1), SERPINA4 (serpin family A member 4), and SVEP1 (sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1). Overall, the protein–outcome associations in patients with HFpEF did not markedly differ as compared with patients with heart failure with reduced ejection fraction. A proteomic risk score derived in patients with HFpEF was not superior to a previous proteomic score derived in heart failure with reduced ejection fraction nor to clinical risk factors, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), or high‐sensitivity cardiac troponin. Conclusions Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis in the PARAGON‐HF proteomic substudy. Our results demonstrate substantial similarities among serum proteomic risk markers for heart failure hospitalization and cardiovascular death when comparing clinical trial participants with heart failure across the ejection fraction spectrum. Registration URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT01920711, NCT01035255, NCT00853658.

Background The sodium glucose cotransporter‐2 inhibitors are guideline‐recommended to treat heart failure across the spectrum of left ventricular ejection fraction; however, economic evaluations of adding sodium glucose cotransporter‐2 inhibitors to standard of care in chronic heart failure across a broad left ventricular ejection fraction range are lacking. Methods and Results We conducted a US‐based cost‐effectiveness analysis of dapagliflozin added to standard of care in a chronic heart failure population using pooled, participant data from the DAPA‐HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials. The 3‐state Markov model used estimates of transitional probabilities, effectiveness of dapagliflozin, and utilities from the pooled trials. Costs estimates were obtained from published sources, including published rebates in dapagliflozin cost. Adding dapagliflozin to standard of care was estimated to produce an additional 0.53 quality‐adjusted life years (QALYs) compared with standard of care alone. Incremental cost effectiveness ratios were $85 554/QALY when using the publicly reported full (undiscounted) Medicare cost ($515/month) and $40 081/QALY, at a published nearly 50% rebate ($263/month). The addition of dapagliflozin to standard of care would be of at least intermediate value (

Background Studies demonstrated sex differences in outcomes following acute myocardial infarction, with women more likely to develop heart failure (HF). Sacubitril/valsartan has been shown to reduce cardiovascular death and HF hospitalizations in patients with HF with reduced ejection fraction. Methods and Results A total of 5661 patients (1363 women [24%]) with acute myocardial infarction complicated by reduced left ventricular ejection fraction (≤40%), pulmonary congestion, or both and ≥1 of 8 risk‐augmenting factors were randomized to receive sacubitril/valsartan or ramipril. The primary outcome was cardiovascular death or incident HF. Baseline characteristics, clinical outcomes, and safety events were compared according to sex, a prespecified subgroup. Female participants were older and had more comorbidities. After multivariable adjustment, women and men were at similar risks for cardiovascular death or all‐cause death. Women were more likely to have first HF hospitalization (hazard ratio [HR], 1.34 [95% CI, 1.05–1.70]; P=0.02) and total HF hospitalizations (HR, 1.39 [95% CI, 1.05–1.84]; P=0.02). Sex did not significantly modify the treatment effect of sacubitril/valsartan compared with ramipril on the primary outcome (P for interaction=0.11). Conclusions In contemporary patients who presented with reduced left ventricular ejection fraction, pulmonary congestion, or both, following acute myocardial infarction, women had a higher incidence of HF during follow‐up. Sex did not modify the treatment effect of sacubitril/valsartan relative to ramipril. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02924727.

Background Whether coronary artery disease (CAD) is a significant risk factor for heart failure (HF) with preserved ejection fraction (HFpEF) is unclear. Methods and Results Among 9902 participants in the ARIC (Atherosclerosis Risk in Communities) study, we assessed the association of incident CAD with subsequent incident HFpEF (left ventricular ejection fraction [≥50%]) and HF with reduced ejection fraction (HFrEF; left ventricular ejection fraction 1 year post‐CAD event, adjusted incidence of HFrEF and HFpEF were similar (7.2 [95% CI, 5.2–10.0] and 6.7 [4.8–9.2] per 1000 person‐years, respectively) and CAD remained predictive of both (HFrEF: hazard ratio, 2.76 [95% CI, 1.99–3.84]; HFpEF: 1.85 [1.35–2.54]) after adjusting for demographics and common comorbidities. Among 4779 HF‐free participants at Visit 5 (2011–2013), the 490 with prevalent CAD had lower left ventricular ejection fraction and higher left ventricular mass index, E/e’, and left atrial volume index (all P

Background The contribution of atrial cardiopathy to dementia risk is uncharacterized. We aimed to evaluate the association of atrial cardiopathy with incident dementia and potential mediation by atrial fibrillation (AF) and stroke. Methods and Results We conducted a prospective cohort analysis of participants in the ARIC (Atherosclerosis Risk in Communities) study attending visit 5 (2011–2013). We used Cox regression to determine the association between atrial cardiopathy and risk of dementia. Structural equation modeling methods were used to determine potential mediation by AF and/or stroke. Atrial cardiopathy was defined if ≥1 of the following at visit 5: P‐wave terminal force >5000 mV·ms in ECG lead V1, NT‐proBNP (N‐terminal pro–brain natriuretic peptide) >250 pg/mL or left atrial volume index ≥34 mL/m2 by transthoracic echocardiography. We repeated our analysis necessitating ≥2 markers to define atrial cardiopathy. The prevalence of atrial cardiopathy was 34% in the 5078 participants (mean age 75 years, 59% female, 21% Black adults), with 763 participants developing dementia. Atrial cardiopathy was significantly associated with dementia (adjusted HR, 1.35 [95% CI, 1.16–1.58]), with strengthening of the effect estimate when necessitating ≥2 biomarkers (adjusted HR, 1.54 [95% CI, 1.25–1.89]). There was an increased risk of dementia among those with atrial cardiopathy when excluding those with AF (adjusted HR, 1.31 [95% CI, 1.12–1.55]) or stroke (adjusted HR, 1.28 [95% CI, 1.09–1.52]). The proportion of the effect mediated by AF was 4% (P=0.005), and 9% was mediated by stroke (P=0.048). Conclusions Atrial cardiopathy was significantly associated with an increased risk of dementia, with only a small percent mediation of the effect by AF or stroke.

Background Pulmonary and cardiac functions decline with age, but the associations of pulmonary dysfunction with cardiac function and heart failure (HF) risk in late life is not known. We aimed to determine the associations of percent predicted forced vital capacity (ppFVC) and the ratio of forced expired volume in 1 second (FEV1) to forced vital capacity (FVC; FEV1/FVC) with cardiac function and incident HF with preserved or reduced ejection fraction in late life. Methods and Results Among 3854 HF‐free participants in the ARIC (Atherosclerosis Risk in Communities) cohort study who underwent echocardiography and spirometry at the fifth study visit (2011–2013), associations of FEV1/FVC and ppFVC with echocardiographic measures, cardiac biomarkers, and risk of HF, HF with preserved ejection fraction, and HF with reduced ejection fraction were assessed. Multivariable linear and Cox regression models adjusted for demographics, body mass index, coronary disease, atrial fibrillation, hypertension, and diabetes. Mean age was 75±5 years, 40% were men, 19% were Black, and 61% were ever smokers. Mean FEV1/FVC was 72±8%, and ppFVC was 98±17%. In adjusted analyses, lower FEV1/FVC and ppFVC were associated with higher NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide; both P

Background Age‐related left atrial (LA) structural and functional abnormalities may be related to subclinical cerebral infarcts (SCIs) and stroke. We evaluated the association of 3‐dimensional echocardiographic LA contractility parameters with SCIs and stroke across the spectrum of tertiles of age increment in elderly patients with sinus rhythm, normal ejection fraction, and no history of atrial fibrillation. Methods and Results We enrolled 407 participants (mean age, 76±8 years; 40% men) from ARIC‐NCS (Atherosclerosis Risk in Communities Neurocognitive Study) undergoing a brain magnetic resonance imaging and 3‐dimensional echocardiographic examinations in 2011 to 2013. The sample was analyzed among age tertiles and subgroups: no cerebral magnetic resonance imaging–detectable infarcts (n=315), magnetic resonance imaging–diagnosed SCIs (n=58), and clinically diagnosed stroke (n=34). The frequency of SCIs significantly increased over age tertiles (P trend 0.023). LA global longitudinal strain—a 3‐dimensional echocardiographic index of LA reservoir function—and E/e’ divided by LA global longitudinal strain—an index of LA stiffness—worsened across age tertiles (P trend 0.014 and 0.001, respectively), and only in the categories of SCIs (P trend

Background Baseline and temporal changes in natriuretic peptide (NP) concentrations have strong prognostic value with regard to long‐term cardiovascular risk stratification. To increase the clinical utility of NP sampling for patient management, we wanted to assess the incremental predictive value of 2 serial NP measurements compared with a single measurement and provide absolute risk estimates for cardiovascular death or heart failure hospitalization (HFH) within 6 months based on 2 serial NP measurements. Methods and Results Consecutive NP samples obtained from 5393 patients with a recent coronary event and type 2 diabetes enrolled in the ELIXA (Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With Lixisenatide) trial were used to construct best logistic regression models with outcome of cardiovascular death or HFH (136 events). Absolute risk estimates of cardiovascular death or HFH within 6 months using either BNP (B‐type natriuretic peptide) or NT‐proBNP (N‐terminal pro‐BNP) serial measurements were depicted based on the concentrations of 2 serial NP measurements. During the 6‐month follow‐up periods, the incidence rate (±95% CIs) of cardiovascular death or HFH for patients was 14.0 (11.8‒16.6) per 1000 patient‐years. Risk prediction depended on NP concentrations from both prior and current sampling. NP sampling 6 months apart improved the predictive value and reclassification of patients compared with a single sample (AUROC [Area Under the Receiver Operating Characteristic curve]: BNP, P=0.003. NT‐proBNP, P

Background Whether cardiac structure and function abnormalities associated with dysglycemia are sufficient to explain the increased risk of death or heart failure (HF) remains unclear. Methods and Results We analyzed 6059 participants (mean age, 75±5 years; 58% women; and 22% Black individuals) who attended the ARIC (Atherosclerosis Risk in Communities) study visit 5 examination (2011–2013). Participants were categorized as no diabetes, pre‐diabetes, and diabetes (on the basis of medical history and glycated hemoglobin values). We assessed whether diabetes modified the association between echocardiographic measures of cardiac structure and function and the composite of all‐cause death or HF hospitalization and then estimated the extent to which the increased risk of the composite outcome associated with diabetes was explained by cardiac structure and function. Diabetes was prevalent in 33.5% of the subjects. Death or HF occurred in 1111 (18%) at a rate of 3.6 per 100 person‐years. Both measures of cardiac structure and function and diabetes status were significantly associated with worse prognosis after accounting for clinical confounders. While diabetes was consistently associated with a higher risk of events, it did not significantly modify the association between cardiac abnormalities and the risk of death or HF, except for subjects with higher left atrial volume who showed higher relative risk of events (P for interaction

Background Influenza infection may increase the risk of stroke and acute myocardial infarction (AMI). Whether influenza vaccination may reduce mortality in patients with hypertension is currently unknown. Methods and Results We performed a nationwide cohort study including all patients with hypertension in Denmark during 9 consecutive influenza seasons in the period 2007 to 2016 who were prescribed at least 2 different classes of antihypertensive medication (renin‐angiotensin system inhibitors, diuretics, calcium antagonists, or beta‐blockers). We excluded patients who were aged 100 years, had ischemic heart disease, heart failure, chronic obstructive lung disease, cancer, or cerebrovascular disease. The exposure to influenza vaccination was assessed before each influenza season. The end points were defined as death from all‐causes, from cardiovascular causes, or from stroke or AMI. For each influenza season, patients were followed from December 1 until April 1 the next year. We included a total of 608 452 patients. The median follow‐up was 5 seasons (interquartile range, 2–8 seasons) resulting in a total follow‐up time of 975 902 person‐years. Vaccine coverage ranged from 26% to 36% during the study seasons. During follow‐up 21 571 patients died of all‐causes (3.5%), 12 270 patients died of cardiovascular causes (2.0%), and 3846 patients died of AMI/stroke (0.6%). After adjusting for confounders, vaccination was significantly associated with reduced risks of all‐cause death (HR, 0.82; P

Background Depressive symptoms are associated with heightened risk of heart failure (HF), but their association with cardiac function and with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) in late life is unclear. We aimed to determine the prevalence of depression in HFpEF and in HFrEF in late life, and the association of depressive symptoms with cardiac function and incident HFpEF and HFrEF. Methods and Results We studied 6025 participants (age, 75.3±5.1 years; 59% women; 20% Black race) in the ARIC (Atherosclerosis Risk in Communities) study at visit 5 who underwent echocardiography and completed the Center for Epidemiologic Studies Depression Scale questionnaire. Among HF‐free participants (n=5086), associations of Center for Epidemiologic Studies Depression Scale score with echocardiography and incident adjudicated HFpEF and HFrEF were assessed using multivariable linear and Cox proportional hazards regression. Prevalent HFpEF, but not HFrEF, was associated with a higher prevalence of depression compared with HF‐free participants (P0.05). Over 5.5‐year follow‐up, higher Center for Epidemiologic Studies Depression Scale score was associated with heightened risk of incident HFpEF (hazard ratio [HR] [95% CI], 1.06 [1.04–1.12]; P=0.02), but not HFrEF (HR [95% CI], 1.02 [0.96–1.08]; P=0.54), independent of echocardiographic measures, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), troponin, and hs‐CRP (high‐sensitivity C‐reactive protein) (HR [95% CI], 1.06 [1.00–1.12]; P=0.04). Conclusions Worse depressive symptoms predict incident HFpEF in late life, independent of common comorbidities, cardiac structure and function, and prognostic biomarkers. Further studies are necessary to understand the mechanisms linking depression to risk of HFpEF.

Background Little is known about the impact of chronic obstructive pulmonary disease (COPD) in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We examined outcomes in patients with heart failure with preserved ejection fraction, according to COPD status, in the PARAGON‐HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and cardiovascular death. Of 4791 patients, 670 (14%) had COPD. Patients with COPD were more likely to be men (58% versus 47%; P

Background Black Americans have more atrial fibrillation risk factors but lower atrial fibrillation risk than White Americans. Left atrial (LA) enlargement and/or dysfunction, frequent atrial tachycardia (AT), and premature atrial contractions (PAC) are associated with increased atrial fibrillation risk. Racial differences in these factors may exist that could explain the difference in atrial fibrillation risk. Methods and Results We included 2133 ARIC (Atherosclerosis Risk in Communities) study participants (aged 74±4.5 years[mean±SD], 59% women, 27% Black participants) who had echocardiograms in 2011 to 2013 and wore the Zio XT Patch (a 2‐week continuous heart monitor) in 2016 to 2017. Linear regression was used to analyze (1) differences in AT/day or PAC/hour between Black and White participants, (2) differences in LA measures between Black and White participants, and (3) racial differences in the association of LA measures with AT or PAC frequency. Compared with White participants, Black participants had a higher prevalence of cardiovascular risk factors and disease, lower AT frequency, greater LA size, and lower LA function. After multivariable adjustments, Black participants had 37% (95% CI, 24%–47%) fewer AT runs/day than White participants. No difference in PAC between races was noted. Greater LA size and reduced LA function are associated with more AT and PAC runs; however, no race interaction was present. Conclusions Differences in LA measures are unlikely to explain the difference in atrial fibrillation risk between Black and White individuals. Despite more cardiovascular risk factors and greater atrial remodeling, Black participants have lower AT frequency than White participants. Future research is needed to elucidate the protective mechanisms that confer resilience to atrial arrhythmias in Black individuals.

Background Dyslipidemia is common in heart failure with preserved ejection fraction. Sacubitril/valsartan improves glycemic control and augments natriuretic peptide signaling, providing mechanisms by which sacubitril/valsartan may affect serum lipids. However, empiric data on these effects are lacking. Methods and Results We analyzed 4774 participants from PARAGON‐HF (Prospective Comparison of Angiotensin Receptor–Neprilysin Inhibitor With Angiotensin‐Receptor Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction) with available screening lipids. During follow‐up visits, we analyzed the treatment effect on lipid levels and assessed for interaction by baseline lipid levels. At the 16‐week visit, we adjusted these treatment effects for the change in several biomarkers (including hemoglobin A1c and urinary cyclic guanosine monophosphate/creatinine [a biomarker of natriuretic peptide activation]). The average age was 73±8 years, 52% were women, 43% had diabetes mellitus, and 64% were on statin therapy. Compared with valsartan, sacubitril/valsartan reduced triglycerides −5.0% (95% CI, −6.6% to −3.5%), increased high‐density lipoprotein cholesterol +2.6% (95% CI, +1.7% to +3.4%), and increased low‐density lipoprotein cholesterol +1.7% (95% CI, +0.4% to +3.0%). Sacubitril/valsartan reduced triglycerides most among those with elevated baseline levels (triglycerides≥200 mg/dL) (P‐interaction

Background Maximal left atrial (LA) volume is reported by most echocardiography laboratories and is associated with clinical outcomes in patients with heart failure (HF). Recent studies suggest that minimal LA volume may better reflect left ventricular filling pressure and may be more prognostic than maximal LA volume. This study assessed the prognostic value of indexed minimal LA volume (LAVImin) in patients with HF with preserved ejection fraction. Methods and Results We assessed the relationship of LAVImin with a primary composite end point of cardiovascular death, aborted cardiac death, or HF hospitalization in 347 patients with HF with preserved ejection fraction enrolled from the Americas region in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). We compared LAVImin with indexed maximal LA volume with respect to their prognostic values. In addition, we assessed if LA functional parameters provide additional prognostic information over LAVImin. During a median follow‐up of 2.5 years, 107 patients (31%) experienced a primary composite end point. LAVImin was associated with increased risk of a primary composite outcome (hazard ratio [HR], 1.35; 95% CI, 1.12–1.61) and HF hospitalization alone (HR, 1.42; 95% CI, 1.17–1.71) after adjusting for clinical confounders and ejection fraction. In contrast, indexed maximal LA volume was not related to the primary composite outcome, but related to HF alone (HR, 1.25; 95% CI, 1.02–1.54). In comparison with indexed maximal LA volume, LAVImin was significantly more prognostic for primary composite outcome (P for comparison=0.032). Both LA emptying fraction and LA strain were prognostic of primary outcome independent of LAVImin (all P

Background Chronic obstructive pulmonary disease (COPD) is a common comorbidity in heart failure with reduced ejection fraction, associated with undertreatment and worse outcomes. New treatments for heart failure with reduced ejection fraction may be particularly important in patients with concomitant COPD. Methods and Results We examined outcomes in 8399 patients with heart failure with reduced ejection fraction, according to COPD status, in the PARADIGM‐HF (Prospective Comparison of Angiotensin Receptor Blocker–Neprilysin Inhibitor With Angiotensin‐Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. Cox regression models were used to compare COPD versus non‐COPD subgroups and the effects of sacubitril/valsartan versus enalapril. Patients with COPD (n=1080, 12.9%) were older than patients without COPD (mean 67 versus 63 years; P

Background Atrial fibrillation (AF) is a risk factor for cognitive decline, possibly from silent brain infarction. Left atrial changes in structure or function (atrial cardiopathy) can lead to AF but may impact cognition independently. It is unknown if AF or atrial cardiopathy also acts on Alzheimer disease–specific mechanisms, such as deposition of β‐amyloid. Methods and Results A total of 316 dementia‐free participants from the ARIC (Atherosclerosis Risk in Communities) study underwent florbetapir positron emission tomography, electrocardiography, and 2‐dimensional echocardiography. Atrial cardiopathy was defined as ≥1: (1) left atrial volume index >34 mL/m2; (2) P‐wave terminal force >5000 µV×ms; and (3) serum NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) >250 pg/mL. Cross‐sectional associations between global cortical β‐amyloid (>1.2 standardized uptake value ratio) and adjudicated history of AF and atrial cardiopathy, each, were evaluated using multivariable logistic regression. Participants (mean age, 76 years) were 56% women and 42% Black individuals. Odds of elevated florbetapir standardized uptake value ratio were significantly increased among those with atrial cardiopathy (odds ratio, 1.81; 95% CI, 1.02–3.22) and doubled for those with enlarged left atrial volume index after adjustment for demographics/risk factors (95% CI, 1.04–4.61). There was no association between P‐wave terminal force or NT‐proBNP and elevated florbetapir standardized uptake value ratio, nor between AF and elevated standardized uptake value ratio. Conclusions Among healthy, nondemented community‐dwelling older individuals, we report an association between atrial cardiopathy, left atrial volume index, and elevated brain amyloid, by positron emission tomography, without a similar association in individuals with AF. Potential limitations include reverse causation and survival bias. Ongoing work will help determine if changes in cardiac structure and function precede or occur simultaneously with amyloid deposition.

Background Heart failure with preserved ejection fraction (HFpEF) accounts for half of heart failure hospitalizations, with limited data on predictors of mortality by sex and race. We evaluated for differences in predictors of all‐cause mortality by sex and race among hospitalized patients with HFpEF in the ARIC (Atherosclerosis Risk in Communities) Community Surveillance Study. Methods and Results Adjudicated HFpEF hospitalization events from 2005 to 2013 were analyzed from the ARIC Community Surveillance Study, comprising 4 US communities. Comparisons between clinical characteristics and mortality at 1 year were made by sex and race. Of 4335 adjudicated acute decompensated heart failure cases, 1892 cases (weighted n=8987) were categorized as HFpEF. Men had an increased risk of 1‐year mortality compared with women in adjusted analysis (hazard ratio [HR], 1.27; 95% CI, 1.06–1.52 [P=0.01]). Black participants had lower mortality compared with White participants in unadjusted and adjusted analyses (HR, 0.79; 95% CI, 0.64–0.97 [P=0.02]). Age, heart rate, worsening renal function, and low hemoglobin were associated with increased mortality in all subgroups. Higher body mass index was associated with improved survival in men, with borderline interaction by sex. Higher blood pressure was associated with improved survival among all groups, with significant interaction by race. Conclusions In a diverse HFpEF population, men had worse survival compared with women, and Black participants had improved survival compared with White participants. Age, heart rate, and worsening renal function were associated with increased mortality across all subgroups; high blood pressure was associated with decreased mortality with interaction by race. These insights into sex‐ and race‐based differences in predictors of mortality may help strategize targeted management of HFpEF.

Background NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) improves the discriminatory ability of risk‐prediction models in type 2 diabetes mellitus (T2DM) but is not yet used in clinical practice. We assessed the discriminatory strength of NT‐proBNP by itself for death and cardiovascular events in high‐risk patients with T2DM. Methods and Results Cox proportional hazards were used to create a base model formed by 20 variables. The discriminatory ability of the base model was compared with that of NT‐proBNP alone and with NT‐proBNP added, using C‐statistics. We studied 5509 patients (with complete data) of 8561 patients with T2DM and cardiovascular and/or chronic kidney disease who were enrolled in the ALTITUDE (Aliskiren in Type 2 Diabetes Using Cardiorenal Endpoints) trial. During a median 2.6‐year follow‐up period, 469 patients died and 768 had a cardiovascular composite outcome (cardiovascular death, resuscitated cardiac arrest, nonfatal myocardial infarction, stroke, or heart failure hospitalization). NT‐proBNP alone was as discriminatory as the base model for predicting death (C‐statistic, 0.745 versus 0.744, P=0.95) and the cardiovascular composite outcome (C‐statistic, 0.723 versus 0.731, P=0.37). When NT‐proBNP was added, it increased the predictive ability of the base model for death (C‐statistic, 0.779 versus 0.744, P

Background Circulating galectin‐3 levels provide prognostic information in patients with established heart failure (HF), but the associations between galectin‐3 levels and other incident cardiovascular events in asymptomatic individuals at midlife and when remeasured ≈15 years later are largely uncharacterized. Methods and Results Using multivariable Cox proportional hazards models, we identified associations between plasma galectin‐3 levels (hazard ratio [HR] per 1 SD increase in natural log galectin‐3) and incident coronary heart disease, ischemic stroke, HF hospitalization, and total mortality in ARIC (Atherosclerosis Risk in Communities) participants free of cardiovascular disease at ARIC visit 4 (1996–1998; n=9247) and at ARIC visit 5 (2011–2013; n=4829). Higher galectin‐3 level at visit 4 (median age 62) was independently associated with incident coronary heart disease (adjusted HR, 1.30; 95% CI, 1.06–1.60), ischemic stroke (HR, 1.42; 95% CI, 1.01–2.00), HF (HR, 1.44; 95% CI, 1.17–1.76), and mortality (HR, 1.56; 95% CI, 1.35–1.80). At visit 5 (median age, 74), higher galectin‐3 level was associated with incident HF (HR, 1.93; 95% CI, 1.15–3.24) and total mortality (HR, 1.70; 95% CI, 1.15–2.52), but not coronary heart disease or stoke. Individuals with the greatest increase in galectin‐3 levels from visit 4 to visit 5 were also at increased risk of incident HF and total mortality. Conclusions In a large, biracial community‐based cohort, galectin‐3 measured at midlife and older age was associated with increased risk of cardiovascular events. An increase in galectin‐3 levels over this period was also associated with increased risk.

Background Atrial fibrillation (AF) is associated with cognitive decline. Whether left atrial enlargement (LAE), a critical substrate for AF, is also associated is less well established. Therefore, we assessed the association of LAE and AF with cognitive decline in the ARIC‐NCS (Atherosclerosis Risk in Communities Neurocognitive Study). Methods and Results Participants (n=3391; mean age, 75±5 years; 59% women) underwent cognitive tests and 2‐dimensional echocardiograms at visit 5 (2011–2013) and follow‐up cognitive tests at visit 6 (2016–2017). LAE was defined as left atrium volume index ≥34 mL/m2. AF was ascertained using study ECGs and hospitalization discharge codes. We assessed the association of AF and LAE with (a) cognitive domain scores at visit 5 and (b) cognitive domain score changes between visit 5 and visit 6. At visit 5, compared with the reference group (without AF, normal left atrium), participants with LAE and AF had significantly lower global cognition (Z score, −0.24; 95% CI, −0.38 to −0.10), whereas participants with AF and without LAE and participants with LAE and without AF did not have lower global cognition. In longitudinal analysis, compared with the reference group, participants with AF but without LAE had significantly greater decline in global cognition (Z score, −0.13; 95% CI, −0.21 to −0.06). However, LAE, with or without AF, was not associated with greater cognitive decline. Conclusion Although LAE with AF was significantly associated with lower cognitive function in cross‐sectional analysis, LAE, with or without AF, was not associated with greater cognitive decline over 5 years, highlighting the importance of evaluating longitudinal cognitive function. Future studies should have longer follow‐up and evaluate left atrium function.

Background Associations between subtle changes in cardiac and cerebral structure and function are not well understood, with some studies suggesting that subclinical cardiac changes may be associated with markers of vascular brain insult. Methods and Results Data from the ARIC (Atherosclerosis Risk in Communities) Study (5th ARIC visit; 2011‐2013; N=1974) were used to explore relationships between abnormalities of cardiac structure/function and subclinical brain disease and to test specific associations between those cardiac and vascular brain changes that share a common mechanism. In adjusted models white matter hyperintensities were 0.66 cm3 greater (95% confidence interval [CI] 0.08‐1.25) for every 1‐mm increase in left ventricular LV wall thickness and 0.64 cm3 greater (95% CI 0.19‐1.08) for every 10 g/m2 increase in LV mass index, both markers of LV structure. Odds of brain infarction also increased with greater LV wall thickness (odds ratio 1.11, 95% CI 1.01‐1.23 per 1 mm) and larger LV mass (odds ratio 1.08, 95% CI 1.00‐1.17 per 10 g/m2). Higher ejection fraction (per 5%), a marker of systolic function, was significantly associated with decreased odds of overall infarct (odds ratio 0.85, 95% CI0.77‐0.95), but not with cortical infarction (odds ratio 0.92, 95% CI0.78‐1.08). Conclusions Among elderly participants in a large cohort study, subclinical markers of LV structure and LV systolic dysfunction were associated with increased odds of brain infarction and more white matter hyperintensities, independent of other vascular risk factors. This suggests end‐organ dysfunction occurs in the heart and brain in parallel, with further studies needed to determine causality.

BackgroundECG global electrical heterogeneity (GEH) is associated with sudden cardiac death. We hypothesized that a genome‐wide association study would identify genetic loci related to GEH. Methods and ResultsWe tested genotyped and imputed variants in black (N=3057) and white (N=10 769) participants in the ARIC (Atherosclerosis Risk in Communities) study and CHS (Cardiovascular Health Study). GEH (QRS‐T angle, sum absolute QRST integral, spatial ventricular gradient magnitude, elevation, azimuth) was measured on 12‐lead ECGs. Linear regression models were constructed with each GEH variable as an outcome, adjusted for age, sex, height, body mass index, study site, and principal components to account for ancestry. GWAS identified 10 loci that showed genome‐wide significant association with GEH in whites or joint ancestry. The strongest signal (rs7301677, near TBX3) was associated with QRS‐T angle (white standardized β+0.16 [95% CI 0.13–0.19]; P=1.5×10−26), spatial ventricular gradient elevation (+0.11 [0.08–0.14]; P=2.1×10−12), and spatial ventricular gradient magnitude (−0.12 [95% CI −0.15 to −0.09]; P=5.9×10−15). Altogether, GEH‐SNPs explained 1.1% to 1.6% of GEH variance. Loci on chromosomes 4 (near HMCN2), 5 (IGF1R), 11 (11p11.2 region cluster), and 7 (near ACTB) are novel ECG phenotype‐associated loci. Several loci significantly associated with gene expression in the left ventricle (HMCN2 locus—with HMCN2; IGF1R locus—with IGF1R), and atria (RP11‐481J2.2 locus—with expression of a long non‐coding RNA and NDRG4). ConclusionsWe identified 10 genetic loci associated with ECG GEH. Replication of GEH GWAS findings in independent cohorts is warranted. Further studies of GEH‐loci may uncover mechanisms of arrhythmogenic remodeling in response to cardiovascular risk factors.

BackgroundThe relationship between ideal cardiovascular health reflected in the cardiovascular health score (CVHS) and valvular heart disease is not known. The purpose of this study was to determine the association of CVHS attainment through midlife to late life with aortic stenosis prevalence and severity in late life. Methods and ResultsThe following 6 ideal cardiovascular health metrics were assessed in ARIC (Atherosclerosis Risk in Communities) Study participants at 5 examination visits between 1987 and 2013 (visits 1–4 in 1987–1998 and visit 5 in 2011–2013): smoking, body mass index, total cholesterol, blood pressure, physical activity, and blood glucose. Percentage attained CVHS was calculated in 6034 participants as the sum of CVHS at each visit/the maximum possible score. Aortic stenosis was assessed by echocardiography at visit 5 on the basis of the peak aortic valve velocity. Aortic stenosis was categorized sclerosis, mild stenosis, and moderate‐to‐severe stenosis. Mean age was 76±5 years, 42% were men, and 22% were black. Mean percentage attained CVHS was 63±14%, and the prevalence of aortic stenosis stages were 15.9% for sclerosis, 4.3% for mild stenosis, and 0.7% for moderate‐to‐severe stenosis. Worse percentage attained CVHS was associated with higher prevalence of aortic sclerosis (P

BackgroundNatriuretic peptides are recognized as important predictors of cardiovascular events in patients with heart failure, but less is known about their prognostic importance in patients with acute coronary syndrome. We sought to determine whether B‐type natriuretic peptide (BNP) and N‐terminal prohormone B‐type natriuretic peptide (NT‐proBNP) could enhance risk prediction of a broad range of cardiovascular outcomes in patients with acute coronary syndrome and type 2 diabetes mellitus. Methods and ResultsPatients with a recent acute coronary syndrome and type 2 diabetes mellitus were prospectively enrolled in the ELIXA trial (n=5525, follow‐up time 26 months). Best risk models were constructed from relevant baseline variables with and without BNP/NT‐proBNP. C statistics, Net Reclassification Index, and Integrated Discrimination Index were analyzed to estimate the value of adding BNP or NT‐proBNP to best risk models. Overall, BNP and NT‐proBNP were the most important predictors of all outcomes examined, irrespective of history of heart failure or any prior cardiovascular disease. BNP significantly improved C statistics when added to risk models for each outcome examined, the strongest increments being in death (0.77–0.82, P

BackgroundElevated B‐type natriuretic peptide (BNP) levels are associated with heart failure and increased mortality in the general population. We investigated rs198389, a functional variant in the promoter region of the BNP gene (NPPB), in patients from the Atherosclerosis Risk in Communities Study to investigate associations with N‐terminal pro‐BNP (NT‐proBNP) levels and outcomes. Methods and ResultsA total of 11 361 black and white patients with rs198389 genotyping attended visit 1 (aged 45–64 years; 1987–1989), with follow‐up visits occurring every 3 years (visit 2–visit 4, 1990–1999), followed by visit 5 (2011–2013). NT‐proBNP levels were measured at visits 2, 4, and 5. At visit 2, the GG genotype (frequency 18%) was associated with a 41% higher mean plasma level of NT‐proBNP compared with the AA genotype (frequency 34%), with intermediate values observed in AGs (P=4.2×10−52). The GG genotype was associated with reduced systolic blood pressure (−1.6 mm Hg, P=0.006), diastolic blood pressure (−1 mm Hg, P=0.003), antihypertension medication use (odds ratio, 0.85; 95% CI, 0.74–0.97 [P=0.02]), and hypertension (odds ratio, 0.81; 95% CI, 0.72–0.92 [P=0.002]) compared with the AA genotype with intermediate values in AGs. These relationships persisted throughout subsequent visits. After a median follow‐up of 23 years, there were 4031 deaths. With and without covariate adjustment, the GG genotype was associated with modestly lower mortality (hazard ratio, 0.86; 95% CI, 0.78–0.95), primarily reflective of cardiovascular death (hazard ratio, 0.75; 95% CI, 0.61–0.92), and increased residual lifespan of 8 months from 50 years of age (P=0.02) versus AAs. ConclusionsThe rs198389 G allele in the NPPB promoter is associated with elevated levels of NT‐proBNP throughout adult life, reduced blood pressure, hypertension and cardiovascular mortality, and increased lifespan.

BackgroundObesity is a risk factor for various subtypes of cardiovascular disease (CVD), including coronary heart disease (CHD), heart failure (HF), and stroke. Nevertheless, there are limited comparisons of the associations of obesity with each of these CVD subtypes, particularly regarding the extent to which they are unexplained by traditional CVD mediators. Methods and ResultsWe followed 13 730 participants in the Atherosclerosis Risk in Communities (ARIC) study who had a body mass index ≥18.5 and no CVD at baseline (visit 1, 1987–1989). We compared the association of higher body mass index with incident HF, CHD, and stroke before and after adjusting for traditional CVD mediators (including systolic blood pressure, diabetes mellitus, and lipid measures). Over a median follow‐up of 23 years, there were 2235 HF events, 1653 CHD events, and 986 strokes. After adjustment for demographics, smoking, physical activity, and alcohol intake, higher body mass index had the strongest association with incident HF among CVD subtypes, with hazard ratios for severe obesity (body mass index ≥35 versus normal weight) of 3.74 (95% CI 3.24–4.31) for HF, 2.00 (95% CI 1.67–2.40) for CHD, and 1.75 (95% CI 1.40–2.20) for stroke (P

BackgroundMost studies of risk assessment or stratification in patients with myocardial infarction (MI) have been static and fail to account for the evolving nature of clinical events and care processes. We sought to identify predictors of mortality, cardiovascular death or nonfatal MI, and cardiovascular death or nonfatal heart failure (HF) over time in patients with HF, left ventricular systolic dysfunction, or both post‐MI. Methods and ResultsUsing data from the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial, we developed models to estimate the association between patient characteristics and the likelihood of experiencing an event from the time of a follow‐up visit until the next visit. The intervals are: hospital arrival to discharge or 14 days, whichever occurs first; hospital discharge to 30 days; 30 days to 6 months; and 6 months to 3 years. Models were also developed to predict the entire 3‐year follow‐up period using baseline information. Multivariable Cox proportional hazards modeling was used throughout with Wald chi‐squares as the comparator of strength for each predictor. For the baseline model of overall mortality, the 3 strongest predictors were age (adjusted hazard ratio [HR], 1.35; 95% CI, 1.28–1.42; P

BackgroundAlthough clear evidence shows that chronic kidney disease is a predictor of cardiovascular events, death, and accelerated coronary artery disease (CAD) progression, it remains unknown whether CAD is a predictor of progression of chronic kidney disease to end‐stage renal disease. We sought to assess whether CAD adds prognostic information to established predictors of progression to dialysis in patients with chronic kidney disease, diabetes, and anemia. Methods and ResultsUsing the previously described Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) population, we compared baseline characteristics of patients with and without CAD. Cox proportional hazards models were used to assess the association between CAD and the outcomes of end‐stage renal disease and the composite of death or end‐stage renal disease. Of the 4038 patients, 1791 had a history of known CAD. These patients were older (mean age 70 versus 65 years, P

Background Natriuretic peptides promote natriuresis, diuresis, and vasodilation. Experimental deficiency of natriuretic peptides leads to hypertension (HTN) and cardiac hypertrophy, conditions more common among African Americans. Hospital‐based studies suggest that African Americans may have reduced circulating natriuretic peptides, as compared to Caucasians, but definitive data from community‐based cohorts are lacking. Methods and Results We examined plasma N‐terminal pro B‐type natriuretic peptide (NTproBNP) levels according to race in 9137 Atherosclerosis Risk in Communities (ARIC) Study participants (22% African American) without prevalent cardiovascular disease at visit 4 (1996–1998). Multivariable linear and logistic regression analyses were performed adjusting for clinical covariates. Among African Americans, percent European ancestry was determined from genetic ancestry informative markers and then examined in relation to NTproBNP levels in multivariable linear regression analysis. NTproBNP levels were significantly lower in African Americans (median, 43 pg/mL; interquartile range [IQR], 18, 88) than Caucasians (median, 68 pg/mL; IQR, 36, 124; P