Independent APOE4 knock-in mouse models display reduced brain APOE protein, altered neuroinflammation, and simplification of dendritic spines.

APOE is an immunomodulator in the brain and the major genetic risk factor for late-onset Alzheimer's disease (AD). Targeted replacement APOE mice (APOE-TR) have been a useful tool to study the effects of APOE isoforms on brain neurochemistry and activity prior to and during AD. We use newly available APOE knock-in mice (JAX-APOE) to compare phenotypes associated with APOE4 across models. Similar to APOE4-TR mice, JAX-E4 mouse brains showed 27% lower levels of APOE protein compared with JAX-E3 (p < 0.001). We analyzed several neuroinflammatory molecules that have been associated with APOE genotype. SerpinA3 was much higher in APOE4-TR mice to APOE3-TR mice, but this effect was not seen in JAX-APOE mice. There were higher levels of IL-3 in JAX-E4 brains compared with JAX-E3, but other neuroinflammatory markers (IL6, TNFα) were not affected by APOE genotype. In terms of neuronal structure, basal dendritic spine density in the entorhinal cortex was 39% lower in JAX-E4 mice compared with JAX-E3 mice (p < 0.001), again similar to APOE-TR mice. One-week treatment with ibuprofen significantly increased dendritic spine density in the JAX-E4 mice, consistent with our previous finding in APOE-TR mice. Behaviorally, there was no effect of APOE genotype on Barnes Maze learning and memory in 6-month-old JAX-APOE mice. Overall, the experiments performed in JAX-APOE mice validated findings from APOE-TR mice, identifying particularly strong effects of APOE4 genotype on lower APOE protein levels and simplified neuron structure. These data demonstrate pathways that could promote susceptibility of APOE4 brains to AD pathological changes.

Survival in Patients With Nonischemic Cardiomyopathy With Preserved vs Reduced Ejection Fraction.

BACKGROUND: Prior studies suggest similar long-term mortality rates for patients with heart failure (HF) with preserved ejection fraction (HFpEF) vs reduced ejection fraction. However, although coronary heart disease (CHD) is associated with worse prognosis in HF, clinical outcomes are less well characterized for HF without CHD. We investigated the characteristics and 5-year mortality outcomes among patients with HF without significant CHD, stratified by EF. METHODS: Patients with clinical heart failure who underwent coronary angiography at Duke University Medical Center from 1996 through 2009 and had no significant CHD with EF ≤ 40% were compared with patients without significant CHD with EF > 40%. Survival was examined using Kaplan-Meier methods and multivariable Cox proportional hazards modeling. Analyses were repeated using EF ≥ 50%. RESULTS: Of 3154 patients with HF without significant CHD, 1530 (48.5%) had HFpEF (EF > 40%). These patients were older and more likely to have a Charlson Index ≥ 2 than patients with reduced EF. Patients with HFpEF had a lower risk of death than those with reduced EF (unadjusted hazard ratio [HR] 0.85; 95% confidence interval [CI] 0.74-0.99). From 1996 through 2009, the secular trend of death decreased among patients without CHD and with reduced EF (HR 0.92; 95% CI 0.88-0.97) but not among those with preserved EF (HR 0.99; 95% CI 0.93-1.05; P interaction 0.095). No finding was significant after multivariable risk adjustment. Results were consistent when defining preserved EF as EF ≥ 50%. CONCLUSIONS: Among patients without significant CHD, those with HFpEF had similar risks of 5-year mortality as patients with HF with reduced ejection fraction.

INTRODUCTION: Des études antérieures indiquent des taux de mortalité à long terme similaires entre les patients atteints d'insuffisance cardiaque (IC) avec fraction d'éjection (FE) préservée (ICFEP) vs les patients atteints d'IC avec FE réduite (ICFER). Toutefois, bien que la coronaropathie soit associée à un plus mauvais pronostic de l'IC, les résultats cliniques sont moins bien définis que ceux de l'IC sans coronaropathie. Nous avons examiné les caractéristiques et les résultats des patients atteints d'IC sans coronaropathie importante, stratifiés selon la FE, sur la mortalité dans les cinq ans. MÉTHODES: Nous avons comparé les patients montrant des signes cliniques d'IC qui avaient subi une angiographie coronarienne à la Duke University de 1996 à 2009 et n'avait pas de coronaropathie importante avec FE ≤ 40 % aux patients sans coronaropathie importante avec FE > 40 %. Nous avons examiné la survie à l'aide de la méthode de Kaplan-Meier et du modèle multivarié à risques proportionnels de Cox. Nous avons répété les analyses en fonction d'une FE ≥ 50 %. RÉSULTATS: Parmi les 3 154 patients atteints d'IC sans coronaropathie importante, 1 530 (48,5 %) avaient une ICFEP (FE > 40 %). Ces patients étaient plus âgés et plus susceptibles d'avoir un indice de Charlson ≥ 2 que les patients atteints d'ICFER. Les patients atteints d'ICFEP avaient un risque plus faible de mortalité que ceux atteints d'une ICFER (rapport de risque [RR] non ajusté 0,85; intervalle de confiance [IC] à 95 % 0,74-0,99). De 1996 à 2009, la tendance séculaire de la mortalité avait diminué chez les patients sans coronaropathie et qui avaient une FE réduite (RR 0,92; IC à 95 % 0,88-0,97), mais non chez ceux qui avaient une FE préservée (RR 0,99; IC à 95 % 0,93-1,05; valeur P de l'interaction 0,095). Aucun résultat n'était significatif après l'ajustement multivarié en fonction du risque. Les résultats étaient cohérents lorsque la FE préservée était définie par une FE ≥ 50 %. CONCLUSIONS: Chez les patients sans coronaropathie importante, ceux atteints d'une ICFEP avaient des risques similaires de mortalité dans les cinq ans aux patients atteints d'ICFER.

Clinical Effectiveness of Sacubitril/Valsartan Among Patients Hospitalized for Heart Failure With Reduced Ejection Fraction.

Background Sacubitril/Valsartan has been highly efficacious in randomized trials of heart failure with reduced ejection fraction (HFrEF). However, the effectiveness of sacubitril/valsartan in older patients hospitalized for HFrEF in real-world US practice is unclear. Methods and Results This study included Medicare beneficiaries age ≥65 years who were hospitalized for HFrEF ≤40% in the Get With The Guidelines-Heart Failure registry between October 2015 and December 2018, and eligible for sacubitril/valsartan. Associations between discharge prescription of sacubitril/valsartan and clinical outcomes were assessed after inverse probability of treatment weighting and adjustment for other HFrEF medications. Overall, 1551 (10.9%) patients were discharged on sacubitril/valsartan. Of those not prescribed sacubitril/valsartan, 7857 (62.0%) were prescribed an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker. Over 12-month follow-up, compared with a discharge prescription of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, sacubitril/valsartan was independently associated with lower all-cause mortality (adjusted hazard ratio [HR], 0.82; 95% CI, 0.72-0.94; P=0.004) but not all-cause hospitalization (adjusted HR, 0.97; 95% CI, 0.89-1.07; P=0.55) or heart failure hospitalization (adjusted HR, 1.04; 95% CI, 0.91-1.18; P=0.59). Patients prescribed sacubitril/valsartan versus those without a prescription had lower risk of all-cause mortality (adjusted HR, 0.69; 95% CI, 0.60-0.79; P<0.001), all-cause hospitalization (adjusted HR, 0.90; 95% CI, 0.82-0.98; P=0.02), but not heart failure hospitalization (adjusted HR, 0.94; 95% CI, 0.82-1.08; P=0.40). Conclusions Among patients hospitalized for HFrEF, prescription of sacubitril/valsartan at discharge was independently associated with reduced postdischarge mortality compared with angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, and reduced mortality and all-cause hospitalization compared with no sacubitril/valsartan. These findings support the use of sacubitril/valsartan to improve postdischarge outcomes among older patients hospitalized for HFrEF in routine US clinical practice.

Outcomes and cost among Medicare beneficiaries hospitalized for heart failure assigned to accountable care organizations.

Little is known about the impact of accountable care organizations (ACO) on hospitalized heart failure (HF) patients, a high-cost and high-risk population. OBJECTIVE: We linked Medicare fee-for-service claims from 2013 to 2015 with data from American Heart Association Get With The Guidelines-HF registry to compare HF care, post-discharge outcomes, and total annual Medicare spending by ACO status at discharge. METHODS: Using adjusted Cox models and accounting for competing risks of death, we compared all-cause mortality and readmission at 1 year by ACO status with reporting of hazard ratios (HR) and 99% confidence intervals (CI). RESULTS: The study included 45,259 HF patients from 300 hospitals, with 21.1% assigned to an ACO. Patient characteristics were similar between the two groups with a few exceptions. The ACO patients lived in geographic areas with higher median income ($54400 [IQR $48600-65900] vs $52300 [$45900-61200], P < .0001). Compliance with four HF-specific quality measures was modestly higher in the ACO group (80% vs 76%, P < .0001). In adjusted analysis, ACO status was associated with similar all-cause readmission (HR: 1.03; 99% CI: 0.99, 1.07) but lower risk of 1-year mortality (HR: 0.85; 99% CI: 0.85, 0.90) compared with non-ACO status. Median Medicare spending in the calendar year of hospitalization was similar (ACO $42,737 [IQR $23,011-72,667] vs non-ACO $42,586 [$22,896-72,518], P = 0.06). CONCLUSIONS: Among Medicare patients hospitalized for HF, participation in an ACO was associated with similar rates of all-cause readmission and no associated cost reductions compared with non-ACO status. There was a lower risk of 1-year mortality associated with ACO participation, which warrants further evaluation.

STIM1-Ca2+ signaling in coronary sinus cardiomyocytes contributes to interatrial conduction.

Pacemaker action potentials emerge from the sinoatrial node (SAN) and rapidly propagate through the atria to the AV node via preferential conduction pathways, including one associated with the coronary sinus. However, few distinguishing features of these tracts are known. Identifying specific molecular markers to distinguish among these conduction pathways will have important implications for understanding atrial conduction and atrial arrhythmogenesis. Using a Stim1 reporter mouse, we discovered stromal interaction molecule 1 (STIM1)-expressing coronary sinus cardiomyocytes (CSC)s in a tract from the SAN to the coronary sinus. Our studies here establish that STIM1 is a molecular marker of CSCs and we propose a role for STIM1-CSCs in interatrial conduction. Deletion of Stim1 from the CSCs slowed interatrial conduction and increased susceptibility to atrial arrhythmias. Store-operated Ca2+ currents (Isoc) in response to Ca2+ store depletion were markedly reduced in CSCs and their action potentials showed electrical remodeling. Our studies identify STIM1 as a molecular marker for a coronary sinus interatrial conduction pathway. We propose a role for SOCE in Ca2+ signaling of CSCs and implicate STIM1 in atrial arrhythmogenesis.

Daily Oscillation of the Excitation-Inhibition Balance in Visual Cortical Circuits.

A balance between synaptic excitation and inhibition (E/I balance) maintained within a narrow window is widely regarded to be crucial for cortical processing. In line with this idea, the E/I balance is reportedly comparable across neighboring neurons, behavioral states, and developmental stages and altered in many neurological disorders. Motivated by these ideas, we examined whether synaptic inhibition changes over the 24-h day to compensate for the well-documented sleep-dependent changes in synaptic excitation. We found that, in pyramidal cells of visual and prefrontal cortices and hippocampal CA1, synaptic inhibition also changes over the 24-h light/dark cycle but, surprisingly, in the opposite direction of synaptic excitation. Inhibition is upregulated in the visual cortex during the light phase in a sleep-dependent manner. In the visual cortex, these changes in the E/I balance occurred in feedback, but not feedforward, circuits. These observations open new and interesting questions on the function and regulation of the E/I balance.

International variation in characteristics and clinical outcomes of patients with type 2 diabetes and heart failure: Insights from TECOS.

International differences in management/outcomes among patients with type 2 diabetes and heart failure (HF) are not well characterized. We sought to evaluate geographic variation in treatment and outcomes among these patients. METHODS AND RESULTS: Among 14,671 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), those with HF at baseline and a documented ejection fraction (EF) (N = 1591; 10.8%) were categorized by enrollment region (North America, Latin America, Western Europe, Eastern Europe, and Asia Pacific). Cox models were used to examine the association between geographic region and the primary outcome of all-cause mortality (ACM) or hospitalization for HF (hHF) in addition to ACM alone. Analyses were stratified by those with EF <40% or EF ≥40%. The majority of participants with HF were enrolled in Eastern Europe (53%). Overall, 1,267 (79.6%) had EF ≥40%. ß-Blocker (83%) and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (86%) use was high across all regions in patients with EF <40%. During a median follow-up of 2.9 years, Eastern European participants had lower rates of ACM/hHF compared with North Americans (adjusted hazard ratio: 0.45; 95% CI: 0.32-0.64). These differences were seen only in the EF ≥40% subgroup and not the EF <40% subgroup. ACM was similar among Eastern European and North American participants (adjusted hazard ratio: 0.79; 95% CI: 0.44-1.45). CONCLUSIONS: Significant variation exists in the clinical features and outcomes of HF patients across regions in TECOS. Patients from Eastern Europe had lower risk-adjusted ACM/hHF than those in North America, driven by those with EF ≥40%. These data may inform the design of future international trials.

Relationship Between Hospital Characteristics and Early Adoption of Angiotensin-Receptor/Neprilysin Inhibitor Among Eligible Patients Hospitalized for Heart Failure.

Background The angiotensin-receptor/neprilysin inhibitor ( ARNI ) sacubitril/valsartan reduces hospitalization and mortality for patients with heart failure with reduced ejection fraction. However, adoption of ARNI into clinical practice has been slow. Factors influencing use of ARNI have not been fully elucidated. Using data from the Get With The Guidelines-Heart Failure registry, Hospital Compare, Dartmouth Atlas, and the American Hospital Association Survey, we sought to identify hospital characteristics associated with patient-level receipt of an ARNI prescription. Methods and Results We analyzed patients with heart failure with reduced ejection fraction who were eligible for ARNI prescription (ejection fraction≤40%, no contraindications) and hospitalized from October 1, 2015 through December 31, 2016. We used logistic regression to estimate the associations between hospital characteristics and patient ARNI prescription at hospital discharge, accounting for clustering of patients within hospitals using generalized estimating equation methods and adjusting for patient-level covariates. Of 16 674 eligible hospitalizations from 210 hospitals, 1020 patients (6.1%) were prescribed ARNI at discharge. The median hospital-level proportion of patients prescribed ARNI was 3.3% (Q1, Q3: 0%, 12.6%). After adjustment for patient-level covariates, for-profit hospitals had significantly higher odds of ARNI prescription compared with not-for-profit hospitals (odds ratio, 2.53; 95% CI , 1.05-6.10; P=0.04), and hospitals located in the Western United States had lower odds of ARNI prescription compared with those in the Northeast (odds ratio, 0.33; 95% CI , 0.13-0.84; P=0.02). Conclusions Relatively few hospital characteristics were associated with ARNI prescription at hospital discharge, in contrast to what has been observed in early adoption in other disease areas. Additional evaluation of barriers to implementing new evidence into heart failure practice is needed.

Relationship between changing patient-reported outcomes and subsequent clinical events in patients with chronic heart failure: insights from HF-ACTION.

AIMS: A 5-point change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) is commonly considered to be a clinically significant difference in health status in patients with heart failure. We evaluated how the magnitude of change relates to subsequent clinical outcomes. METHODS AND RESULTS: Using data from the HF-ACTION trial of exercise training in chronic heart failure (n = 2331), we used multivariable Cox regression with piecewise linear splines to examine the relationship between change in KCCQ overall summary score from baseline to 3 months (range 0-100; higher scores reflect better health status) and subsequent all-cause mortality/hospitalization. Among 2038 patients with KCCQ data at the 3-month visit, KCCQ scores increased from baseline by ≥5 points for 45%, scores decreased by ≥5 points for 23%, and scores changed by <5 points for the remaining 32% of patients. There was a non-linear relationship between change in KCCQ and outcomes. Worsening health status was associated with increased all-cause mortality/hospitalization (adjusted hazard ratio 1.07 per 5-point KCCQ decline; 95% confidence interval 1.03-1.12; P < 0.001). In contrast, improving health status, up to an 8-point increase in KCCQ, was associated with decreased all-cause mortality/hospitalization (adjusted hazard ratio 0.93 per 5-point increase; 95% confidence interval 0.90-0.97; P < 0.001). Additional improvements in health status beyond an 8-point increase in KCCQ was not associated with all-cause death or hospitalization (P = 0.42). CONCLUSION: In patients with heart failure, small changes in KCCQ are associated with changing future risk, but more research will be necessary to understand how different magnitudes of improving health status affect outcomes.

Use of Oral Anticoagulation in Eligible Patients Discharged With Heart Failure and Atrial Fibrillation.

BACKGROUND: Stroke prophylaxis in patients with atrial fibrillation (AF) and heart failure (HF) in the era of direct oral anticoagulants is not well characterized. Using data from American Heart Association Get With The Guidelines-AFIB, we sought to evaluate oral anticoagulation (OAC) use at discharge among AF patients with concomitant HF. METHODS AND RESULTS: AF patients with a diagnosis of HF hospitalized from January 2013 to March 2017 were included. We compared patient characteristics and use of OAC at discharge among patients with reduced (redundant ejection fraction [EF], EF≤40%), borderline (40%

Early impact of guideline publication on angiotensin-receptor neprilysin inhibitor use among patients hospitalized for heart failure.

BACKGROUND: On May 20, 2016, US professional organizations in cardiology published joint treatment guidelines recommending the use of angiotensin-receptor neprilysin inhibitor (ARNI) for eligible patients with heart failure with reduced ejection fraction (HFrEF). Using data from the Get With The Guidelines-Heart Failure registry, we evaluated the early impact of this update on temporal trends in ARNI prescription. METHODS: We analyzed patients with HFrEF who were eligible for ARNI prescription (EF ≤40%, no contraindications) and hospitalized from February 20, 2016, through August 19, 2016-allowing for 13weeks before and after guideline publication. We quantified trends in ARNI use associated with guidelines publication with an interrupted time-series design using logistic regression and accounting for correlations within hospitals using general estimating equation methods. RESULTS: Of 7,200 eligible patient hospitalizations, 51.9% were discharged in the period directly preceding publication of the guidelines, and 48.1% were discharged after. Odds ratios of ARNI prescription at discharge were significantly higher in the postguideline period compared with the preguideline period in adjusted models (adjusted odds ratio 1.29, 95% CI 1.06-1.57, P=.01). However, there was no significant interaction between observed and expected ARNI use after guideline publication (Pinteraction=.14). Results were consistent using a 6-month before and after time frame. CONCLUSIONS: The model suggested a small increase in ARNI use in HF patients being discharged from the hospital immediately after guideline release. However, the publication of national guidelines recommending ARNI use seemed to have little influence on the adoption of this evidence-based medication in the first 3 to 6months.

Home-Time After Discharge Among Patients Hospitalized With Heart Failure.

BACKGROUND: Surveys of patients with cardiovascular disease have suggested that "home-time"-being alive and out of any health care institution-is a prioritized outcome. This novel measure has not been studied among patients with heart failure (HF). OBJECTIVES: This study sought to characterize home-time following hospitalization for HF and assess its relationship with patient characteristics and traditionally reported clinical outcomes. METHODS: Using GWTG-HF (Get With The Guidelines-Heart Failure) registry data, patients discharged alive from an HF hospitalization between 2011 and 2014 and ≥65 years of age were identified. Using Medicare claims, post-discharge home-time over 30-day and 1-year follow-up was calculated for each patient as the number of days alive and spent outside of a hospital, skilled nursing facility (SNF), or rehabilitation facility. RESULTS: Among 59,736 patients, 57,992 (97.1%) and 42,153 (70.6%) had complete follow-up for home-time calculation through 30 days and 1 year, respectively. The mean home-time was 21.6 ± 11.7 days at 30 days and 243.9 ± 137.6 days at 1 year. Contributions to reduced home-time varied by follow-up period, with days spent in SNF being the largest contributor though 30 days and death being the largest contributor through 1 year. Over 1 year, 2,044 (4.8%) patients had no home-time following index hospitalization discharge, whereas 8,194 (19.4%) had 365 days of home-time. In regression models, several conditions were associated with substantially reduced home-time, including chronic obstructive pulmonary disease, renal insufficiency, and dementia. Through 1 year, home-time was highly correlated with time-to-event endpoints of death (tau = 0.72) and the composite of death or HF readmission (tau = 0.59). CONCLUSIONS: Home-time, which can be readily calculated from administrative claims data, is substantially reduced for many patients following hospitalization for HF and is highly correlated with traditional time-to-event mortality and hospitalization outcomes. Home-time represents a novel, easily measured, patient-centered endpoint that may reflect effectiveness of interventions in future HF studies.

Multinational and multiethnic variations in health-related quality of life in patients with chronic heart failure.

BACKGROUND: Assessing health-related quality of life (HRQoL) in patients with heart failure (HF) is an important goal of clinical care and HF research. We sought to investigate ethnic differences in perceived HRQoL and its association with mortality among patients with HF and left ventricular ejection fraction ≤35%, controlling for demographic characteristics and HF severity. METHODS AND RESULTS: We compared 5697 chronic HF patients of Indian (26%), white (23%), Chinese (17%), Japanese/Koreans (12%), black (12%), and Malay (10%) ethnicities from the HF-ACTION and ASIAN-HF multinational studies using the Kansas City Cardiomyopathy Questionnaire (KCCQ; range 0-100; higher scores reflect better health status). KCCQ scores were lowest in Malay (58±22) and Chinese (60±23), intermediate in black (64±21) and Indian (65±23), and highest in white (67±20) and Japanese or Korean patients (67±22) after adjusting for age, sex, educational status, HF severity, and risk factors. Self-efficacy, which measures confidence in the ability to manage symptoms, was lower in all Asian ethnicities (especially Japanese/Koreans [60±26], Malay [66±23], and Chinese [64±28]) compared to black (80±21) and white (82±19) patients, even after multivariable adjustment (P<.001). In all ethnicities, KCCQ strongly predicted 1-year mortality (HR 0.45, 95% CI 0.30-0.67 for highest vs lowest quintile of KCCQ; P for interaction by ethnicity .101). CONCLUSIONS: Overall, HRQoL is inversely and independently related to mortality in chronic HF but is not modified by ethnicity. Nevertheless, ethnic differences exist independent of HF severity and comorbidities. These data may have important implications for future global clinical HF trials that use patient-reported outcomes as endpoints.

Plasma acylcarnitines are associated with pulmonary hypertension.

Quantifying metabolic derangements in pulmonary hypertension (PH) by plasma metabolomics could identify biomarkers useful for diagnosis and treatment. The objective of this paper is to test the hypotheses that circulating metabolites are differentially expressed in PH patients compared with controls and among different hemodynamic subtypes of PH associated with left heart disease. We studied patients enrolled in the CATHGEN biorepository with PH (right heart catheterization mPAP ≥ 25 mmHg; n = 280). Of these, 133 met criteria for postcapillary PH, 82 for combined precapillary and postcapillary PH (CpcPH), and 65 for precapillary PH. Targeted profiling of 63 metabolites (acylcarnitines, amino acids, and ketones) was performed using tandem flow injection mass spectrometry. Multivariable linear regression was used to determine differences in metabolite factors derived from a principal components analysis between PH cases, PH subtypes, and non-PH controls. In adjusted models, the metabolite factor loaded with long-chain acylcarnitines was higher in all PH cases versus non-PH controls (P = 0.00008), but did not discriminate between CpcPH and postcapillary PH (P = 0.56). In analyses of subtypes, CpcPH patients had lower levels of factors loaded with urea cycle amino acids and short chain acylcarnitines as compared to controls (P = 0.002 and P = 0.01, respectively) and as compared to postcapillary PH (P = 0.04 and P = 0.02, respectively). Compared to controls, PH was strongly associated with greater concentrations of long-chain acylcarnitines. Postcapillary PH and CpcPH were weakly associated with distinct metabolomic profiles. These findings suggest the presence of unique metabolic abnormalities in subtypes of PH and may reflect underlying pathophysiology.

Early Adoption of Sacubitril/Valsartan for Patients With Heart Failure With Reduced Ejection Fraction: Insights From Get With the Guidelines-Heart Failure (GWTG-HF).

OBJECTIVES: The aim of this study was to assess the prevalence and variation in angiotensin receptor/neprilysin inhibitor (ARNI) prescription among a real-world population with heart failure with reduced ejection fraction (HFrEF). BACKGROUND: The U.S. Food and Drug Administration approved sacubitril/valsartan for patients with HFrEF in July 2015. Little is known about the early patterns of use of this novel therapy. METHODS: The study included patients discharged alive from hospitals in Get With the Guidelines-Heart Failure (GWTG-HF), a registry of hospitalized patients with heart failure, between July 2015 and June 2016 who had documentation of whether ARNIs were prescribed at discharge. Patient and hospital characteristics were compared among patients with HFrEF (ejection fraction ≤40%) with and without ARNI prescription at discharge, excluding those with documented contraindications to ARNIs. To evaluate hospital variation, hospitals with at least 10 eligible hospitalizations during the study period were assessed. RESULTS: Of 21,078 patients hospitalized with HFrEF during the study period, 495 (2.3%) were prescribed ARNIs at discharge. Patients prescribed ARNIs were younger (median age 65 years vs. 70 years; p < 0.001), had lower ejection fractions (median 23% vs. 25%; p < 0.001), and had higher use of aldosterone antagonists (45% vs. 31%; p < 0.001) at discharge. At the 241 participating hospitals with 10 or more eligible admissions, 125 (52%) reported no discharge prescriptions of ARNIs. CONCLUSIONS: Approximately 2.3% of patients hospitalized for HFrEF in a national registry were prescribed ARNI therapy in the first 12 months following Food and Drug Administration approval. Further study is needed to identify and overcome barriers to implementing new evidence into practice, such as ARNI use among eligible patients with HFrEF.

Exercise Training in Patients With Chronic Heart Failure and Atrial Fibrillation.

BACKGROUND: The safety and efficacy of aerobic exercise in heart failure (HF) patients with atrial fibrillation (AF) has not been well evaluated. OBJECTIVES: This study examined whether outcomes with exercise training in HF vary according to AF status. METHODS: HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) randomized 2,331 ambulatory HF patients with ejection fraction ≤35% to exercise training or usual care. We examined clinical characteristics and outcomes (mortality/hospitalization) by baseline AF status (past history of AF or AF on baseline electrocardiogram vs. no AF) using adjusted Cox models and explored an interaction with exercise training. We assessed post-randomization AF events diagnosed via hospitalizations for AF and reports of serious arrhythmia caused by AF. RESULTS: Of 2,292 patients with baseline rhythm data, 382 (17%) had AF, 1,602 (70%) had sinus rhythm, and 308 (13%) had "other" rhythm. Patients with AF were older and had lower peak Vo2. Over a median follow-up of 2.6 years, AF was associated with a 24% per year higher rate of mortality/hospitalization (hazard ratio [HR]: 1.53; 95% confidence interval [CI]: 1.34 to 1.74; p < 0.001) in unadjusted analysis; this did not remain significant after adjustment (HR: 1.15; 95% CI: 0.98 to 1.35; p = 0.09). There was no significant difference in AF event rates by randomized treatment assignment in the overall population or by baseline AF status (all p > 0.10). There was no interaction between AF and exercise training on measures of functional status or clinical outcomes (all p > 0.10). CONCLUSIONS: AF in patients with chronic HF was associated with older age, reduced exercise capacity at baseline, and a higher overall rate of clinical events, but not a differential response to exercise training for clinical outcomes or changes in exercise capacity. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437).