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Background: Sodium-glucose cotransporter-2 inhibitors are foundational therapy in patients with heart failure with reduced ejection fraction (HFrEF), but underlying mechanisms of benefit are not well defined. We sought to investigate the relationships between sodium-glucose cotransporter-2 inhibitor treatment, changes in metabolic pathways, and outcomes using targeted metabolomics. Methods: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) was a placebo-controlled trial of dapagliflozin in HFrEF. We performed targeted mass spectrometry profiling of 63 metabolites (45 acylcarnitines [markers of fatty acid oxidation], 15 amino acids, and 3 conventional metabolites) in plasma samples at randomization and 12 weeks. Using mixed models, we identified principal components analysis–defined metabolite clusters that changed differentially with treatment and examined the relationship between change in metabolite clusters and change in Kansas City Cardiomyopathy Questionnaire scores and NT-proBNP (N-terminal probrain natriuretic peptide). Models were adjusted for relevant clinical covariates and nominal P P Results: Among the 234 DEFINE-HF participants with targeted metabolomic data, the mean age was 62.0±11.1 years, 25% were women, 38% were Black, and mean ejection fraction was 27±8%. Dapagliflozin increased ketone-related and short-chain acylcarnitine as well as medium-chain acylcarnitine principal components analysis–defined metabolite clusters compared with placebo (nominal P =0.01, false discovery rate–adjusted P =0.08 for both clusters). However, ketosis (β-hydroxybutyrate levels >500 μmol/L) was achieved infrequently (3 [2.5%] in dapagliflozin arm versus 1 [0.9%] in placebo arm) and supraphysiologic levels were not observed. Increases in long-chain acylcarnitine, long-chain dicarboxylacylcarnitine, and aromatic amino acid metabolite clusters were associated with decreases in Kansas City Cardiomyopathy Questionnaire scores (ie, worse quality of life) and increases in NT-proBNP levels, without interaction by treatment group. Conclusions: In this study of targeted metabolomics in a placebo-controlled trial of sodium-glucose cotransporter-2 inhibitors in HFrEF, we observed effects of dapagliflozin on key metabolic pathways, supporting a role for altered ketone and fatty acid biology with sodium-glucose cotransporter-2 inhibitors in patients with HFrEF. Only physiologic levels of ketosis were observed. In addition, we identified several metabolic biomarkers associated with adverse HFrEF outcomes. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02653482.

Background: Loop diuretics are a primary therapy for the symptomatic treatment of heart failure (HF), but whether torsemide improves patient symptoms and quality of life better than furosemide remains unknown. As pre-specified secondary endpoints, the TRANSFORM-HF trial compared the effect of torsemide versus furosemide on patient-reported outcomes among patients with HF. Methods: TRANSFORM-HF was an open-label, pragmatic, randomized trial of 2,859 patients hospitalized for HF (regardless of ejection fraction) across 60 hospitals in the United States. Patients were randomized in a 1:1 ratio to a loop diuretic strategy of torsemide or furosemide with investigator-selected dosage. This report examined effects on pre-specified secondary endpoints, which included Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) (assessed as adjusted mean difference in change from baseline; range, 0-100 with 100 indicating best health status; clinically important difference, ≥5 points) and Patient Health Questionnaire-2 (PHQ-2) (range, 0-6; score ≥3 supporting evaluation for depression) over 12 months. Results: Baseline data were available for 2,787 (97.5%) patients for KCCQ-CSS and 2,624 (91.8%) patients for PHQ-2. Median baseline KCCQ-CSS was 42 (27-60) in the torsemide group and 40 (24-59) in the furosemide group. At 12-months, there was no significant difference between torsemide and furosemide in change from baseline in KCCQ-CSS (adjusted mean difference 0.06 [95% CI, -2.26 to 2.37]; P =0.96) or the proportion of patients with PHQ-2 score ≥3 (15.1% vs 13.2%: P =0.34). Results for KCCQ-CSS were similar at 1-month (adjusted mean difference 1.36 [95% CI, -0.64 to 3.36]; P =0.18) and 6-month follow-up (adjusted mean difference -0.37 [95% CI, -2.52 to 1.78]; P =0.73), and across subgroups by ejection fraction phenotype, New York Heart Association class at randomization, and loop diuretic agent prior to hospitalization. Irrespective of baseline KCCQ-CSS tertile, there was no significant difference between torsemide and furosemide on change in KCCQ-CSS, all-cause mortality, or all-cause hospitalization. Conclusions: Among patients discharged after hospitalization for HF, a strategy of torsemide compared with furosemide did not improve symptoms or quality of life over 12 months. The effects of torsemide and furosemide on patient-reported outcomes were similar regardless of ejection fraction, prior loop diuretic use, and baseline health status.

Background: Patients with heart failure (HF) have multiple coexisting comorbidities. The temporal trends in the burden of comorbidities and associated risk of mortality among patients with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) are not well established. Methods: HF-related hospitalizations were sampled by stratified design from 4 US areas in 2005 to 2014 by the community surveillance component of the ARIC study (Atherosclerosis Risk in Communities). Acute decompensated HF was classified by standardized physician review and a previously validated algorithm. An ejection fraction Results: A total of 5460 hospitalizations (24 937 weighted hospitalizations) classified as acute decompensated HF had available ejection fraction data (53% female, 68% white, 53% HFrEF, 47% HFpEF). The average number of comorbidities was higher for patients with HFpEF versus HFrEF, both for women (5.53 versus 4.94; P P P -trendP for interaction by HF type=0.02). The associated mortality risk per 1 higher comorbidity also increased significantly over time for patients with HFpEF and HFrEF, as well ( P for interaction with time=0.002 and 0.02, respectively) Conclusions: The burden of comorbidities among hospitalized patients with acute decompensated HFpEF and HFrEF has increased over time, as has its associated mortality risk. Higher burden of comorbidities is associated with higher risk of mortality, with a stronger association noted among patients with HFpEF versus HFrEF.

Background: EXSCEL (Exenatide Study of Cardiovascular Event Lowering) assessed the impact of once-weekly exenatide 2 mg versus placebo in patients with type 2 diabetes mellitus, while aiming for glycemic equipoise. Consequently, greater drop-in of open-label glucose-lowering medications occurred in the placebo group. Accordingly, we explored the potential effects of their unbalanced use on major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, and all-cause mortality (ACM), given that some of these agents are cardioprotective. Methods: Cox hazard models were performed by randomized treatment for drug classes where >5% open-label drop-in glucose-lowering medication occurred, and for glucagon-like peptide-1 receptor agonists (GLP-1 RAs; 3.0%) using three methodologies: drop-in visit right censoring, inverse probability for treatment weighting (IPTW), and applying drug class risk reductions. Results: Baseline glucose-lowering medications for the 14 752 EXSCEL participants (73.1% with previous cardiovascular disease) did not differ between treatment groups. During median 3.2 years follow-up, open-label drop-in occurred in 33.4% of participants, more frequently with placebo than exenatide (38.1% versus 28.8%), with metformin (6.1% versus 4.9%), sulfonylurea (8.7% versus 6.9%), dipeptidyl peptidase-4 inhibitors (10.6% versus 7.5%), SGLT-2i (10.3% versus 8.1%), GLP-1 RA (3.4% versus 2.4%), and insulin (13.8% versus 9.4%). The MACE effect size was not altered meaningfully by right censoring, but the favorable HR for exenatide became nominally significant in the sulfonylurea and any glucose-lowering medication groups, while the ACM HR and p-values were essentially unchanged. IPTW decreased the MACE HR from 0.91 ( P =0.061) to 0.85 ( P =0.008) and the ACM HR from 0.86 ( P =0.016) to 0.81 ( P =0.012). Application of literature-derived risk reductions showed no meaningful changes in MACE or ACM HRs or P values, although simulations of substantially greater use of drop-in cardioprotective glucose-lowering agents demonstrated blunting of signal detection. Conclusions: EXSCEL-observed HRs for MACE and ACM remained robust after right censoring or application of literature-derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by IPTW. Effects of open-label drop-in cardioprotective medications need to be considered carefully when designing, conducting, and analyzing cardiovascular outcome trials of glucose-lowering agents under the premise of glycemic equipoise. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01144338.

Introduction: Metabolic substrate utilization is central to metabolic disease. Metabolic pathways linking type 2 diabetes (T2D) to major adverse cardiac events (MACE) and heart failure (HF) remain poorly understood and T2D drug effects on metabolite biomarkers could improve biological understanding and support precision medicine approaches. Hypothesis: Circulating metabolites characterizing mitochondrial dysfunction are predictors for MACE and hospitalization for HF (hHF), and are improved with exenatide. Methods: We performed targeted mass-spectrometry profiling of 60 metabolites on baseline and 12-month plasma samples from 978 participants from EXSCEL, a randomized trial of the GLP-1 receptor agonist, exenatide. Principal components analysis (PCA) was used; resultant metabolite factors were analyzed with univariate and multivariable logistic regression (adjusted for history of HF, coronary artery disease, BMI, HbA 1c , eGFR, blood pressure) for association with MACE (CV death, non-fatal MI or stroke) and hHF. Results were validated in participants from TECOS, a randomized trial of the DPP-4 inhibitor sitagliptin. Metabolite changes by treatment arm were tested. Results: Of 12 PCA metabolite factors, two nominally associated with MACE in both univariate and multivariable models and two associated with hHF in univariate, but not multivariable models ( Table ). Individual metabolites remained associated with MACE in multivariable models and with hHF in univariate models. Similar results were seen in the TECOS validation cohort. Individual metabolites decreased to a greater extent in exenatide randomized individuals compared with placebo. Conclusions: Metabolites reporting on dysregulated mitochondrial fatty acid oxidation are increased in individuals with T2D who experience MACE. These biomarkers may improve CV risk prediction models, appear to be beneficially modified by exenatide, and highlight emerging risk mechanisms.

Background: Cigarette smoking has been associated with incident heart failure (HF), however the relationships with HF phenotypes have not been adequately investigated, particularly in African Americans. Methods and Results: Among 4129 African Americans participants in the Jackson Heart Study without a history of HF or coronary heart disease (CHD) at baseline, we investigated the relationships between baseline smoking status, smoking intensity (number of cigarettes/day) among current smokers, and smoking burden (pack years) among ever smokers and incident HF hospitalization. HF phenotypes were categorized either as HF with reduced ejection fraction (HFrEF: EF Conclusion: In this large community-based African American cohort, cigarette smoking (smoking status, smoking intensity, and smoking burden) was significantly associated with incident HFpEF, but not with HFrEF. Smoking cessation in African Americans who smoke may reduce risk for HFpEF in this high-risk population.

Introduction: Sacubitril/valsartan improves outcomes in patients with heart failure with reduced ejection fraction (HFrEF) compared to ACE inhibitors; however, comparative effectiveness data on post-discharge outcomes in renin-angiotensin system inhibitor (RASi)-naïve patients are limited. Methods: We analyzed Medicare beneficiaries age ≥65 years who were hospitalized for HFrEF in the Get With The Guidelines Heart Failure registry between 10/2015 and 6/2019, had Part D prescription coverage, and were not on RASi therapy 6 months prior to hospital admission. We examined associations between sacubitril/valsartan prescription at hospital discharge and outcomes at 30 days and 1 year after discharge using overlap weighted Cox proportional hazards models. The primary endpoint was “home-time”, defined as days alive and out of any healthcare institution. Secondary endpoints included mortality and rehospitalization. Results: Among 3,572 patients with HFrEF and naïve to RASi therapy, 290 (8.1%) were prescribed sacubitril/valsartan at hospital discharge. After adjusting for baseline patient characteristics, patients prescribed sacubitril/valsartan had greater home-time (parameter estimate [PEs] 27.0, 95%CI 12.4-41.6, p(Figure) Conclusions: In this contemporary, real-world population of RASi-naïve patients with HFrEF, initiation of sacubitril/valsartan at discharge was associated with greater home-time and improvements in overall survival similar to that seen in randomized trials. These findings support recent expert consensus recommendations endorsing a direct-to-sacubitril/valsartan therapeutic approach among RASi-naïve patients.

Introduction: Older patients with acute decompensated heart failure (ADHF) have severely impaired QOL. We recently reported that a novel physical rehab intervention improves QOL. Here we report trajectories of improvement and relationship to participation in a rehab intervention. Methods: Patients with ADHF, regardless of EF and ≥ 60 years old were randomized to either attention control (AC) or rehab intervention (RI). Participants completed the KCCQ, a disease-specific QOL instrument, and 12-Item Short-Form Health Survey (SF-12), a general QOL instrument composed of a mental and physical composite score, at baseline (inpatient), 1 month and 3 months. Effects of the intervention were assessed using linear mixed effects models including the main effect of intervention, follow-up visit, and interaction term with adjustment for EF category, age, and sex. Results: The REHAB-HF trial enrolled 349 patients with a mean age of 72.7±8.1 years, 52% women and 49% non-white. Baseline KCCQ scores were low for both arms (Figure 1). There was a substantial increase in KCCQ score at 1 month in both arms. However, in contrast to the AC participants who showed no further improvement, RI participants continued to experience an increase in QOL at 3 months creating a significant difference between arms (p< 0.01). Both SF-12 composite scores also increased in both arms at 1 month with continued improvement only in the RI arm; reaching significance for the mental composite at 1 month (50.8±1.1 vs. 46.9±1.1, p < 0.01) and at 3 months (52.7±1.1 vs. 48.2±1.1, p< 0.01). Conclusions: Older patients hospitalized with ADHF have severely impaired disease-specific and general QOL that improves soon after discharge. Patients receiving a novel physical rehabilitation intervention experienced an early benefit in terms of QOL that continued to improve throughout the 3 months trial period. Future studies will help determine if these benefits are sustained with longer term follow-up.

Background: Coronary artery disease (CAD) is a common cause of heart failure (HF). Whether the extent of coronary artery stenosis differs by HF type or prognosis for patients admitted with acute decompensated heart failure (ADHF) is uncertain. Methods: The Atherosclerosis Risk in Communities (ARIC) study conducted hospital surveillance of adjudicated HF in 4 US areas from 2005-2014. Medical histories were abstracted from the hospital record. Obstructive CAD was defined as > 49% stenosis in the left main coronary artery or >74% stenosis in the other major coronary arteries. Associations between obstructive CAD and 28-day mortality were analyzed separately for heart failure with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF), adjusting for age, race, sex, year of admission, and coronary revascularization procedures. All analyses were weighted by the inverse of the sampling probability. Results: A total of 5115 patients admitted with ADHF underwent coronary angiography during the hospital visit (mean age = 72, 45% women, 28% Black, 30% HFpEF). Obstructive CAD was more prevalent with HFrEF ( Figure 1 ), whether at the left main coronary artery (16% vs 12%), left anterior descending artery (50% vs 35%), left circumflex artery (42% vs 34%), right coronary artery (45% vs 34%), or multiple coronary vessels (47% vs 34%). A similar proportion of patients with obstructive CAD underwent revascularization, irrespective of HF type (HFrEF: 55%, HFpEF: 61%). After adjustments, obstructive CAD (in any vessel) was associated with higher 28-day mortality, both for HFrEF (OR: 3.21; CI: 1.91 - 5.97) and HFpEF (OR: 3.62; 95% CI: 1.43 - 9.18) with no significant interaction by HF type ( P -interaction = 0.9). Conclusion: Patients hospitalized with ADHF and coexisting obstructive CAD are at greater risk of short-term mortality, irrespective of the HF type, warranting the need for effective interventions as well as secondary preventive measures in this population.

Background: Risk for atherosclerotic cardiovascular disease was a novel consideration for antihypertensive medication initiation in the 2017 American College of Cardiology/American Heart Association Blood Pressure (BP) guideline. Whether biomarkers of chronic myocardial injury (high-sensitivity cardiac troponin T ≥6 ng/L] and stress (N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥100 pg/mL) can inform cardiovascular (CV) risk stratification and treatment decisions among adults with elevated BP and hypertension is unclear. Methods: Participant-level data from 3 cohort studies (Atherosclerosis Risk in Communities Study, Dallas Heart Study, and Multiethnic Study of Atherosclerosis) were pooled, excluding individuals with prevalent CV disease and those taking antihypertensive medication at baseline. Participants were analyzed according to BP treatment group from the 2017 American College of Cardiology/American Heart Association BP guideline and those with high BP (120 to 159/ Results: The study included 12 987 participants (mean age, 55 years; 55% women; 21.5% with elevated high-sensitivity cardiac troponin T; 17.7% with elevated NT-proBNP) with 825 incident CV events over 10-year follow-up. Participants with elevated BP or hypertension not recommended for antihypertensive medication with versus without either elevated high-sensitivity cardiac troponin T or NT-proBNP had a 10-year CV incidence rate of 11.0% and 4.6%, with a 10-year number needed to treat to prevent 1 event for intensive BP lowering of 36 and 85, respectively. Among participants with stage 1 or stage 2 hypertension recommended for antihypertensive medication with BP Conclusions: Elevations in high-sensitivity cardiac troponin T or NT-proBNP identify individuals with elevated BP or hypertension not currently recommended for antihypertensive medication who are at high risk for CV events. The presence of nonelevated biomarkers, even in the setting of stage 1 or stage 2 hypertension, was associated with lower risk. Incorporation of biomarkers into risk assessment algorithms may lead to more appropriate matching of intensive BP control with patient risk.

Background: Once-weekly exenatide (EQW) had a neutral effect on hospitalization for heart failure (HHF) in the EXSCEL study (Exenatide Study of Cardiovascular Event Lowering), with no differential treatment effect on major adverse cardiac events by baseline heart failure (HF) status. EQW’s effects on secondary end points based on HHF status have not been reported. The objective was to explore the effects of EQW on secondary end points in patients with and without baseline HF and test the effects of EQW on recurrent HHF events. Methods: The prespecified analysis of the randomized controlled EXSCEL trial, which enrolled patients with type 2 diabetes mellitus with and without additional cardiovascular disease, analyzed EQW effects on all-cause death, each major adverse cardiac event component, first HHF, and repeat HHF, by baseline HF status (regardless of ejection fraction). A subgroup analysis of the population stratified by preserved or reduced baseline ejection fraction was performed. Results: Of 14 752 EXSCEL participants, 2389 (16.2%) had HF at baseline. Compared with those without HF at baseline, patients with preexisting HF were older, and more likely to be male and white, with a higher burden of other cardiovascular diseases. Overall, those assigned to EQW had a lower incidence of all-cause death (hazard ratio [HR], 0.86 [95% CI, 0.77–0.97]) and the composite outcome of all-cause death or HHF (HR, 0.89 [95% CI, 0.80–0.99]). When stratified by presence or absence of baseline HF, there was no observed reduction in all-cause death with EQW with baseline HF (HR, 1.05 [95% CI, 0.85–1.29]), while the risk of mortality was reduced with EQW in the no-HF group (HR, 0.79 [95% CI, 0.68–0.92]) with an interaction P value of 0.031. The reduction in all-cause death or HHF seen with EQW in patients without baseline HF (HR, 0.81 [95% CI, 0.71–0.93]) was not seen in patients with baseline HF (HR, 1.07 [95% CI, 0.89–1.29]; interaction P =0.015). First, plus recurrent, HHF was reduced in the exenatide group versus placebo (HR, 0.82 [95% CI, 0.68–0.99]; P =0.038). Conclusions: In EXSCEL, the use of EQW in patients with or without HF was well tolerated, but benefits of EQW on reduction in all-cause death and first hospitalization for HF were attenuated in patients with baseline HF. Clinical Trial Registration: https://www.clinicaltrials.gov . Unique identifier: NCT01144338.

Background: Heart failure (HF) risk and the underlying risk factors vary by race. Traditional models for HF risk prediction treat race as a covariate in risk prediction and do not account for significant parameters such as cardiac biomarkers. Machine learning (ML) may offer advantages over traditional modeling techniques to develop race-specific HF risk prediction models and to elucidate important contributors of HF development across races. Methods: We performed a retrospective analysis of 4 large, community cohort studies (ARIC [Atherosclerosis Risk in Communities], DHS [Dallas Heart Study], JHS [Jackson Heart Study], and MESA [Multi-Ethnic Study of Atherosclerosis]) with adjudicated HF events. The study included participants who were >40 years of age and free of HF at baseline. Race-specific ML models for HF risk prediction were developed in the JHS cohort (for Black race–specific model) and White adults from ARIC (for White race–specific model). The models included 39 candidate variables across demographic, anthropometric, medical history, laboratory, and electrocardiographic domains. The ML models were externally validated and compared with prior established traditional and non–race-specific ML models in race-specific subgroups of the pooled MESA/DHS cohort and Black participants of ARIC. The Harrell C-index and Greenwood-Nam-D’Agostino χ 2 tests were used to assess discrimination and calibration, respectively. Results: The ML models had excellent discrimination in the derivation cohorts for Black (n=4141 in JHS, C-index=0.88) and White (n=7858 in ARIC, C-index=0.89) participants. In the external validation cohorts, the race-specific ML model demonstrated adequate calibration and superior discrimination (Black individuals, C-index=0.80–0.83; White individuals, C-index=0.82) compared with established HF risk models or with non–race-specific ML models derived with race included as a covariate. Among the risk factors, natriuretic peptide levels were the most important predictor of HF risk across both races, followed by troponin levels in Black and ECG-based Cornell voltage in White individuals. Other key predictors of HF risk among Black individuals were glycemic parameters and socioeconomic factors. In contrast, prevalent cardiovascular disease and traditional cardiovascular risk factors were stronger predictors of HF risk in White adults. Conclusions: Race-specific and ML-based HF risk models that integrate clinical, laboratory, and biomarker data demonstrated superior performance compared with traditional HF risk and non–race-specific ML models. This approach identifies distinct race-specific contributors of HF.

Background: Social determinants of health (SDH) are associated with cardiovascular disease outcomes, but the overall influence of SDH on end-stage heart failure has not been well-described. Methods: In the Palliative Care in Heart Failure (PAL-HF) study, 150 advanced HF patients were randomized to usual care or usual care plus palliative care intervention. In the present analysis, quality of life (QoL) metrics [Kansas City Cardiomyopathy Questionnaire (KCCQ) and Functional Assessment of Chronic Illness Therapy (FACIT) Palliative care (PAL)], anxiety and depression (Hospital Anxiety and Depression Scale; HADS Depression, HADS Anxiety) and clinical outcomes (mortality, rehospitalization) were examined based on SDH (marital status, employment status, economic security, education level). For statistical analyses, patients were grouped per independent variable of interest in dichotomous categories (partner vs. no partner, employed/retired vs. unemployed, patient-reported economic constraints vs. no constraints, education beyond high school (HS) vs. less than HS). Repeated measures models were used to compare QoL metrics between SDH groups and Cox models for clinical outcomes. Results: At 6-month follow-up, having a partner, being employed, education beyond HS, and having economic security were not associated with better QoL or anxiety/depression metrics in advanced HF patients. Unemployment and education less than HS were associated with increased 6-month rehospitalization (both p=0.03). SDH measures were not associated with mortality (all p>0.05) (Table). Conclusions: In this analysis of PAL-HF patients, SDH were not associated with improved QoL or anxiety/depression metrics over 6 months. However, being employed and education beyond HS were associated with reduced rehospitalization. Further studies accounting for SDH are needed to better determine how these factors should be incorporated into palliative care interventions in advanced HF.

Introduction: Elevation in the inflammatory marker high sensitivity C-reactive protein (hsCRP) is associated with worse outcomes in patients with heart failure (HF). We aimed to determine if baseline or trajectory of hsCRP levels over time predict incident HF hospitalization. Methods: Jackson Heart Study (JHS) participants’ (n=4203 African Americans) hsCRP levels were measured over 3 visits (visit 1: 2000 to 2004; visit 2: 2005 to 2008; visit 3: 2009 to 2013). We assessed the association of a single hsCRP level measurement at baseline (visit 1) with incident HF hospitalization using Cox proportional hazard models. Furthermore, we assessed the association of trajectory of hsCRP over repeated measurements (visit 1-3) with incident HF using a joint model, which incorporates estimated hsCRP from a linear mixed effects model into a Cox hazards model to predict incident HF hospitalization while incorporating trajectory of hsCRP over visits. All hazard ratios (HR) are presented as an increase in hsCRP by 1 standard deviation on a Log 2 scale. Results: At baseline, mean age of participants was 55±13 years, 63.4% were women, and mean hsCRP level was 0.5±0.7 mg/dl. Over a median follow-up of 12 years, 353 (8.4%) participants were hospitalized with incident HF. After adjustment for covariates, baseline hsCRP was not associated with increased risk of incident HF hospitalization (Table, p>0.05). However, increases in hsCRP levels on follow-up were associated with a significantly increased risk of incident HF hospitalization (Table, p Conclusions: While an elevated hsCRP level at one time point may not be associated with incident HF, the increasing trajectory of change in hsCRP over time is predictive of increased risk for incident HF hospitalization in African Americans. These data support the role of increased inflammatory status in the development of heart failure.

Introduction: People with type 2 diabetes mellitus (DM) have a large burden of cardiovascular (CV) morbidity and mortality, but the likelihood of these outcomes varies and existing risk calculators do not fully capture risk for individuals. Hypothesis: Circulating metabolites characterizing mitochondrial dysfunction may be novel predictors for CV outcomes. Methods: We performed targeted mass-spectrometry metabolite profiling (45 acylcarnitines, 15 amino acids) on baseline plasma samples from 568 cases (498 with major adverse cardiac events (MACE) and 131 with incident hospitalization for heart failure (hHF)) and 568 matched controls (without events) from the patients assigned to placebo in Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Matching was based on history of HF, coronary artery disease, BMI, hemoglobin A1C, creatinine, low-density lipoprotein cholesterol, fasting status and ejection fraction. Principal components analysis (PCA) was used for dimensionality reduction, and conditional logistic regression to determine association of PCA factors with MACE or hHF and for individual metabolites within significant factors (false discovery rate q Results: Of 12 PCA-derived metabolite factors, three were associated significantly with MACE or hHF; these factors were composed of: 1) short-chain dicarboxylacylcarnitines and long chain acylcarnitines (OR 1.50, q=0.03); 2) medium chain acylcarnitines (OR 1.28, q=0.001); 3) C5:1 and one medium-chain dicarboxylacylcarnitine (OR 1.17, q=0.03). Of these three factors, none were significantly associated with the individual components of MACE. Ten individual metabolites, including short- and medium-chain dicarboxylacylcarnitines and medium- and long-chain acylcarnitines, remained significantly associated with MACE (q Conclusions: Metabolites reporting on dysregulated mitochondrial fatty acid oxidation and endoplasmic reticulum stress are elevated in individuals with DM who progress to MACE and/or hHF. These biomarkers may improve CV risk prediction in DM patients and help highlight emerging risk mechanisms.

Introduction: Bedside evaluation of congestion remains important in both heart failure (HF) with reduced and preserved ejection fraction (HFrEF and HFpEF). Whether presence of physical exam findings have changed over time, or if prognosis of physical examination differs by HF type is uncertain. Methods: From 2005-2014, the Atherosclerosis Risk in Communities (ARIC) Study conducted hospital surveillance of acute decompensated heart failure (ADHF). Events were verified by physician review, and clinical data were abstracted from the medical record. We examined presence of 3 physical exam findings suggesting congestion: lower extremity edema, jugular venous distension, and pulmonary rales > 1/3 of the lung field. Analyses were weighted by sampling fractions. Results: Of 24,937 hospitalizations for ADHF (mean age 75 years, 53% women, 32% black), 47% were HFpEF. Presence of edema increased from 2005-2009 to 2010-2014, both for HFpEF (66% to 72%; P for annual trend = 0.002) and HFrEF (62% to 67%; P for annual trend = 0.009), while presence of rales and jugular distention remained stable. There were 2640 (11%) and 7766 (31%) deaths within 28 days and 1 year of hospitalization, respectively. Patients with HFpEF and all 3 physical exam signs had a greater risk of short- and long-term mortality ( Figure ). After adjustments for demographics and length of stay, there was a differential association between clinical signs and 28-day mortality by HF type ( P for interaction = 0.02). Presence of all 3 vs. Conclusion: The presence of edema on physical examination of patients with ADHF has increased in recent years, both for HFpEF and HFrEF. However, the prognostic utility of physical exam signs of congestion may differ by HF type.

Background: Lower serum vitamin D3 (VitD3) concentration has been associated with cardiovascular disease. However, the associations between serum VitD3 levels and left ventricular (LV) structure and function and heart failure with preserved ejection fraction (HFpEF) have not been well-characterized community. The prevalence of VitD3 deficiency is higher among African Americans than in other race/ethnicity groups. We hypothesized that serum VitD3 levels are associated with LV concentric remodeling and incident heart failure (HF) in African Americans. Methods and Results: Among 4872 African Americans in the Jackson Heart Study cohort, we investigated the relationships between serum VitD3 levels and LV structure and function, evaluated with echocardiography, and incident HF hospitalization, categorized either HF with reduced EF (HFrEF: EF Conclusion: In this community-based African American cohort, lower serum VitD3 levels were associated with LV concentric remodeling and incident HF, mainly HFpEF. Further investigation is required to examine whether the supplementation of VitD3 can prevent LV concentric remodeling and incident HFpEF in African Americans.

Introduction: To date, there are limited data on the potential role of proteomic biomarkers to predict future cardiovascular (CV) events among patients with type 2 diabetes mellitus (DM). Hypothesis: Specific protein biomarkers will be predictive of major adverse CV events (MACE) and incident heart failure hospitalization (HFH) among patients with DM. Methods: Using the Olink aptamer-based platform, we performed proteomic profiling (>700 proteins) on 440 paired cases and matched controls from placebo-assigned participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Cases were defined as having met the primary composite outcome of MACE or incident HFH and matched to controls on baseline prevalent heart failure, coronary artery disease, BMI, hemoglobin A1C, creatinine, low-density lipoprotein cholesterol, fasting status and ejection fraction. Conditional logistic regression was used to determine the association between log-transformed relative protein expression and incident MACE or HFH. False-discovery-rate (FDR) was used to adjust for multiple comparisons. Results: We identified three specific proteins that were significantly associated with prevalent MACE or HFH: METRNL, Notch 3, and ROR1 (OR 2.1, 1.6, 1.7 and q-value 0.01, 0.02, and 0.05 respectively) (Figure 1). METRNL, in particular, performed similarly to the established biomarker NT-proBNP (Figure 1). When MACE and HFH were analyzed separately, METRNL, in particular, remained strongly associated with both outcomes (OR 2.0, p Conclusions: Three novel protein biomarkers, in particular METRNL (a circulating adipokine that regulates insulin-sensitivity), may identify diabetic patients at high risk for subsequent HF and MACE. Additional studies are needed to replicate these findings and uncover the biologic mechanism linking adipokine signaling and heart failure.

Background: Several recent heart failure trials enrolled patients with heart failure with reduced ejection fraction (HFrEF) who had a worsening heart failure (WHF) event. Aim: To describe the characteristics and outcomes of patients with HFrEF and a WHF event at a large tertiary medical center. Methods: We identified patients 18-85 years of age with chronic symptomatic HFrEF (EF ≤35% and ≥2 HF encounters in the prior 18 months) treated at Duke University between Jan 2009-Dec 2018 through the Duke Echo Lab Database. A WHF event was defined as either a hospitalization or ED visit for HF in the prior 12 mos. A set of exclusion criteria [e.g., renal dysfunction, left ventricular assist device (LVAD), heart transplant] were applied to patients with a WHF event to generate a patient cohort similar to those enrolled in contemporary HF trials. We did not restrict the cohort based on BP or BNP levels since these vary over time. Baseline characteristics and outcomes including death and hospitalization were assessed. Results: Of 4846 unique patients with HFrEF, 3668 (76%) had a WHF event in the year prior to index echo. Sequentially, patients with GFR 2 (n=458), LVAD (n=291), or heart transplant (n=95) were excluded; 2824/4846 (58%) remained in the WHF study population. HFrEF patients with WHF were typically men (68%) with median age of 65 years (IQR 54, 73) and low EF (EF Conclusions: In patients with chronic HFrEF at Duke University, 76% had a WHF event in the past year and 58% met several of the key eligibility criteria of contemporary HF trials. Patients with recent WHF had a high burden of comorbidities and very high event rates.

Introduction: Patients with HF have multiple co-existing CV and non-CV comorbidities. The temporal trends in the burden of co-morbidities and associated risk of mortality among patients with acute decompensated HF (ADHF) is not well-established. Methods: HF related hospitalizations were captured in the ARIC surveillance cohort study across 4 US communities 2005 to 2014 using ICD-9 codes. HF hospitalizations were adjudicated using validated algorithm to identify ADHF with reduced ejection fraction (HFrEF, ejection fraction Results: Of the 22,805 hospitalizations sampled between 2005-2004, 8914 were classified as ADHF corresponding to 41,146 weighted hospitalizations for ADHF (53% HFrEF, 47% HFpEF). The burden of CV co-morbidities remained stable while that of and that of non-CV comorbidities increased significantly over time among patients with HFpEF and HFrEF. The overall burden of CV co-morbidities was not significantly associated with risk of mortality among patients with HFrEF and HFpEF. In contrast, greater burden of non-CV comorbidities was significantly associated with higher risk of in-hospital, 28-day, and 1-year mortality for both HFpEF and HFrEF. Among patients with HFrEF, the risk of mortality associated with higher burden of non-CV comorbidities did not change over time. In contrast, for HFpEF, there was a significant temporal decline in the non-CV burden associated risk of in-hospital mortality and an increase in the risk of 1-year mortality over time. Conclusion: The burden of non-CV co-morbidities among patients with ADHF has increased over time. Higher burden of non-CV comorbidities was associated with higher risk of mortality, with stable temporal associations in HFrEF and an increasing risk over time for 1-year mortality for HFpEF.

Introduction: Obesity is disproportionately prevalent in black populations and strongly associated with heart failure with preserved ejection fraction (HFpEF). An “obesity paradox” or lower mortality risk with obesity, has been reported in HFpEF populations. Whether racial differences exist in the temporal trends and outcomes of obesity is uncertain. Methods: Hospitalizations for acute decompensated heart failure (ADHF) were sampled from 2005-2014 by the ARIC Study Community Surveillance and classified by physician review. BMI was calculated using the admission height and weight. Associations between obesity and 1-year all-cause mortality were analyzed with multivariable Cox regression. Results: There were 10,147 weighted hospitalizations for ADHF with ejection fraction ≥50% (64% female, 74% white). Overall, black patients had a higher mean BMI than white patients (34 vs. 30 kg/m 2 ; P P P = 0.003 and P = 0.002) while remaining stable for black patients. Within BMI groups (18.5-24, 25-30, 30-35, 35-40, and ≥40 kg/m 2 ) a U-shaped mortality risk was observed, with the lowest risk among patients with a BMI of 30-35 kg/m 2 ( Figure ). When defining obesity by a BMI cutpoint ≥30 kg/m 2 , the “obesity paradox” was apparent in 2005-2009 for white obese vs. non-obese patients (HR = 0.58, 95% CI: 0.38 - 0.80), but attenuated by 2010-2014 (HR = 1.11; 95% CI: 0.80 - 1.48); P for interaction =0.006. Among black patients, there was no survival benefit for a BMI ≥30 kg/m 2 in 2005-2009 (HR = 1.15; 95% CI; 0.65 - 2.02) or 2010-2014 (HR = 1.06; 95% CI: 0.68 - 1.66). Conclusion: In this decade-long community surveillance of HFpEF patients hospitalized with ADHF, obesity and mean BMI were stable for black patients but steadily increased for white patients. A BMI ≥30 kg/m 2 was initially associated with better survival among white patients but the association dissipated as obesity and mean BMI increased over time.

With few notable exceptions, drug development for heart failure (HF) has become progressively more challenging, and there remain no definitively proven therapies for patients with acute HF or HF with preserved ejection fraction. Inspection of temporal trends suggests an increasing rate of disagreement between early-phase and phase III trial end points. Preliminary results from phase II HF trials are frequently promising, but increasingly followed by disappointing phase III results. Given this potential disconnect, it is reasonable to carefully re-evaluate the purpose, design, and execution of phase II HF trials, with particular attention directed toward the surrogate end points commonly used by these studies. In this review, we offer a critical reappraisal of the role of phase II HF trials and surrogate end points, highlighting challenges in their use and interpretation, lessons learned from past experiences, and specific strengths and weaknesses of various surrogate outcomes. We conclude by proposing a series of approaches that should be considered for the goal of optimizing the efficiency of HF drug development. This review is based on discussions between scientists, clinical trialists, industry and government sponsors, and regulators that took place at the Cardiovascular Clinical Trialists Forum in Washington, DC, on December 2, 2016.

Background: Cigarette smoking has been linked with several factors associated with cardiac dysfunction. We hypothesized that cigarette smoking is associated with left ventricular (LV) structure and function, and incident heart failure (HF) hospitalization. Methods: We investigated 4129 (never smoker n=2884, current smoker n=503, and former smoker n=742) black participants (mean age, 54 years; 63% women) without a history of HF or coronary heart disease at baseline in the Jackson Heart Study. We examined the relationships between cigarette smoking and LV structure and function by using cardiac magnetic resonance imaging among 1092 participants, cigarette smoking and brain natriuretic peptide levels among 3325 participants, and incident HF hospitalization among 3633 participants with complete data. Results: After adjustment for confounding factors, current smoking was associated with higher mean LV mass index and lower mean LV circumferential strain ( P P Conclusions: In blacks, cigarette smoking is an important risk factor for LV hypertrophy, systolic dysfunction, and incident HF hospitalization even after adjusting for effects on coronary heart disease.

Background: Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown. Methods: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HF patients with left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m 2 , and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of patients with ≥5-point increase in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire overall summary score, or a ≥20% decrease in NT-proBNP. Results: Patient characteristics reflected stable, chronic HF with reduced ejection fraction with high use of optimal medical therapy. There was no significant difference in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo (1133 pg/dL (95% CI 1036–1238) vs 1191 pg/dL (95% CI 1089–1304), P =0.43). For the second dual-primary outcome of a meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, 61.5% of dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted OR 1.8, 95% CI 1.03-3.06, nominal P =0.039). This was attributable to both higher proportions of patients with ≥5-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98–3.05), and ≥20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1–3.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (all P values for interaction=NS). Conclusions: In patients with heart failure and reduced ejection fraction, use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the proportion of patients experiencing clinically meaningful improvements in HF-related health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to patients without type 2 diabetes mellitus. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT 02653482.

Type 2 diabetes mellitus is a risk factor for incident heart failure and increases the risk of morbidity and mortality in patients with established disease. Secular trends in the prevalence of diabetes mellitus and heart failure forecast a growing burden of disease and underscore the need for effective therapeutic strategies. Recent clinical trials have demonstrated the shared pathophysiology between diabetes mellitus and heart failure, the synergistic effect of managing both conditions, and the potential for diabetes mellitus therapies to modulate the risk of heart failure outcomes. This scientific statement on diabetes mellitus and heart failure summarizes the epidemiology, pathophysiology, and impact of diabetes mellitus and its control on outcomes in heart failure; reviews the approach to pharmacological therapy and lifestyle modification in patients with diabetes mellitus and heart failure; highlights the value of multidisciplinary interventions to improve clinical outcomes in this population; and outlines priorities for future research.

The success or failure of multicenter clinical trials will remain dependent in large part on the engagement of the site principal investigator (PI). Site PIs play an important role in trial selection, site activation, and study execution, including the development and implementation of a strategy to maximize enrollment, optimize data quality, and ensure patient retention. It is notable that the legal, regulatory, financial, and workload burden for site PIs has grown considerably over time (Figure).1 In contrast, the benefits for serving as a site PI have become less evident. As a result, increasing dissatisfaction exists among physicians involved as site PIs in multicenter trials and there is less interest in trial participation. In this article, we outline current responsibilities and challenges faced by the site PI and propose new strategies to improve the engagement and recognition of site investigators moving forward. Figure. Legal and operational activities traditionally associated with site PIs1 and potential strategies to improve the engagement and recognition of site investigators. CME indicates continuing medical education; MOC, maintenance of certification; and PI, principal investigator. The roles and responsibilities of site PIs in a large clinical trial relative to those of the trial’s overall study leadership can be likened to the stage crew and principle actors in a theater production. The stage crew spends hours with set preparation and the logistics of production, which ultimately the actors will benefit from and receive recognition for. Similarly, the site PIs and their research team identify and recruit patients, conduct study procedures, complete necessary study documentation/reporting, and retain patients for outcomes assessments. However, the overall trial leadership most commonly reports the major trial results and receives national and international recognition. Specific examples of the workload of the clinical …

The state of medical care at the end of life in the United States was recently highlighted in the Institute of Medicine’s report titled Dying in America .1 However, this report focused mostly on cancer and did not address specific challenges faced by patients with heart disease, which continues to be the most common cause of death in the United States. This significant omission occurred because most research on end-of-life care has been conducted on cancer patients, and most care models, including hospice, have been designed to optimize care for that population. Therefore, unsurprisingly, patients with cancer continue to be overrepresented in hospice, whereas patients with heart disease are underrepresented (Figure). Figure. An analysis of Centers for Disease Control and Prevention data shows the relative proportions of the top 6 causes of death in the United States, both overall and in hospice. Advances in modern medicine have helped patients with cardiovascular disease live better and longer, but many suffer disproportionately when …

Introduction: Older patients with acute decompensated heart failure (ADHF) have impaired physical function (PF) and reduced quality of life (QOL). However, the relationship between impairments in PF and QOL are unknown but relevant to clinical practice and design of targeted intervention trials in this high-risk population. Methods: We assessed 202 consecutive patients hospitalized with ADHF in the multicenter Rehabilitation Therapy in Older Acute HF Patients (REHAB-HF) Trial. Standard measures of PF included the Short Physical Performance Battery (SPPB), a validated PF outcome measure in frail elderly, and 6-minute Walking Distance (6MWD). QOL was assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ). Pearson’s correlation statistics examined associations between PF and QOL. Stepwise regressions were performed to identify independent predictors of QOL including PF measures, demographics, and disease severity indicators (NYHA class, previous hospitalizations, duration of current hospitalization, and number of HF signs and symptoms). Results: Participants were 72±7.5 years, BMI 33.2±8.8 kg/m 2 , 54% women, 52% non-white, 52% with reduced ejection fraction, and 44% with previous hospitalizations within 6 months. Participants had marked deficits in PF (SPPB 6.0±2.5 units, 6MWD 185±99 meters) and low QOL (KCCQ Physical Limitation Score (PLS) 47.3±23.8). There were modest but highly significant correlations of QOL measures with SPPB, 6MWD, and number of HF symptoms and signs (Table). Using stepwise regressions, 6MWD and BMI were modest, significant independent predictors of QOL (partial r=0.18, p=0.012 and partial r=-0.27, p=0.0003, respectively), while SPPB, demographics, and HF severity indicators were not. Conclusion: In older, hospitalized ADHF patients, PF and QOL are both severely impaired, but are only modestly related. PF and QOL assess unique domains of impairment and provide complementary information for characterizing clinically meaningful patient-oriented outcomes in ADHF.

Introduction: African Americans are disproportionately affected by hypertension (HTN) and cardiovascular disease (CVD). Determining the population attributable risk (PAR) for CVD associated with HTN and prehypertension in African Americans can help inform policymakers and prioritize public health interventions. Methods: Among 3770 participants in the Jackson Heart Study without prevalent CVD, we used Cox-proportional hazard analysis adjusted for traditional CVD risk factors to determine the association of HTN and prehypertension with incident CVD and its components including coronary heart disease, heart failure, and stroke. The PAR was calculated as pd*(HR-1)/HR; where pd is the prevalence of the exposure and HR is the hazard ratio for the outcome associated with the exposure. HTN was defined as a systolic blood pressure (SBP) ≥140 mmHg, diastolic blood pressure (DBP) ≥90 mmHg, or self-reported antihypertensive medication use and prehypertension as SBP of 120 to 139 mmHg or DBP of 80 to 89 mmHg. Results: At baseline, 52.4% of the cohort had HTN and 77.1% had prehypertension or HTN. Over a median of 9.9 years follow-up, 349 (9.3%) participants developed CVD. The HR for CVD and PAR associated with HTN was 2.17 (95% CI 1.63, 2.89) and 0.28 (95% CI 0.20, 0.35), respectively (Table). The HR for CVD and PAR associated with HTN and prehypertension pooled together was 2.21 (95% CI 1.41, 3.47) and 0.42 (95% CI 0.25, 0.56), respectively. In the pooled group there were significant associations with incident coronary heart disease, heart failure, and stroke. Sex-specific sensitivity analysis demonstrated PAR for CVD associated with HTN and prehypertension was 0.40 (95% CI 0.07, 0.62) in men and 0.43 (95% CI 0.19, 0.61) in women. Conclusions: Approximately 40% of incident CVD is attributable to HTN and prehypertension among African Americans in the southeastern United States. Preventing HTN and prehypertension in this population is a major public health priority.

Heart failure with preserved ejection fraction (HFpEF) represents ≈50% of the overall heart failure (HF) population,1 yet relatively few prognostic markers are used in routine clinical practice. Clinicians commonly assess symptom severity, previous HF hospitalizations, natriuretic peptide levels, and comorbidity burden to characterize disease trajectory. Furthermore, without disease-modifying agents, the management of HFpEF is largely limited to the optimization of volume status and comorbid conditions.2 In contrast, for patients with HF with reduced EF, clinicians incorporate an array of data from clinical evaluation and diagnostic testing to risk-stratify patients, individualize guideline-based medication regimens, and determine optimal timing for implantable devices and advanced therapies. For instance, thresholds for echocardiographic and exercise testing parameters (eg, EF and maximal oxygen consumption) are central components of the decision-making process for defibrillator implantation and advanced therapies such as ventricular assist devices.2 An equivalent prognostic marker to EF has not been identified for HFpEF patients despite the similarly high event rate in comparison with HF with reduced EF cohorts.3,4 Article see p 402 Given that HFpEF patients have normal systolic function as quantified by EF, measures of diastolic dysfunction on echocardiography (eg, myocardial tissue relaxation and ventricular inflow patterns) have been used to characterize disease severity.5 However, these parameters have modest sensitivity and specificity.6,7 An alternative diagnostic measure that captures the underlying myocardial abnormality in HFpEF with superior fidelity would help with both diagnostic and prognostic dilemmas. For instance, such a test could help determine whether progressive dyspnea was due to worsening HF or whether another disease process (eg, lung disease) should be investigated. Moreover, if the parameter was shown to be modifiable with therapy and modulation translated into improved clinical outcomes, this would change the landscape of HFpEF care and clinical research. Such a biomarker …

Introduction: Despite concerns about sudden cardiac death (SCD) early after acute heart failure (AHF) hospitalization, the incidence of SCD and the factors and associated with its occurrence have not been well defined. We evaluated the incidence and predictors of SCD early after AHF hospitalization. Hypothesis: AHF is associated with SCD. Methods: ASCEND-HF included patients with AHF with any ejection fraction (EF). Clinical events including SCD, resuscitated SCD (RSCD), and sustained ventricular tachycardia/ventricular fibrillation (VT/VF) were adjudicated through 30 days. Patients could have more than one event. These three events were combined to form a new composite endpoint, and baseline characteristics associated with this composite were determined by logistic regression and stepwise selection. RSCD and VT/VF were used as time dependent variables in a Cox model to evaluate the association with 180-day all-cause mortality. Results: Among 7,011 patients with available date on SCD, RSCD, or VT/VF, median age was 67 years (IQR 56-76), median EF was 30% (IQR 20-37%), 9% had a history of VT, and 16% had an ICD. The 30-day event rates were 1.8% (n=121) for the composite, 0.6% for SCD (n=43), 0.4% for RSCD (n=24), and 0.9% for VT/VF (n=64). In the multivariable model, chronic obstructive pulmonary disease, history of VT, male sex, higher admission heart rate, and longer baseline QRS duration were associated with SCD, RSCD, or VT/VF (Table). The composite was independently associated with higher 180-day mortality (adjusted HR 6.6, 95% CI 4.8-9.1, p Conclusions: Patients admitted for AHF had relatively high rates of SCD, RSCD, or VT/VF within 30 days of follow-up, and RSCD or VT/VF were associated with higher 180-day mortality. Further studies are needed to evaluate ways to predict and therapies to prevent and treat tachyarrhythmias early after AHF hospitalization, including in those patients who may be eligible for an ICD after medical therapy has been optimized.

Background: Angina pectoris (AP) has different prognostic implications in various populations. Patients with diabetes mellitus (DM) may experience neuropathy such that AP may not be perceived in the setting of coronary artery disease (CAD). The association between the presence or absence of AP in DM patients with CAD is unknown. Methods: We analyzed DM patients with obstructive CAD who underwent coronary angiography at Duke University Medical Center from 2002 to 2011 and compared patients without AP to those with AP. DM and AP were defined based on physician-obtained past medical history at catheterization. Patients were categorized as no AP, atypical AP or typical AP within the 6 weeks prior. We assessed the association with subsequent cardiovascular (CV) death/CV hospitalization and all-cause mortality in patients with no or atypical AP relative to typical AP using multivariable Cox proportional hazards analysis. Results: In the Duke Databank, 5550 patients met criteria for inclusion and 1732 (31%) had no AP, 1075 (19%) had atypical AP and 2743 (50%) had typical AP. Those without AP more often had a prior MI and lower ejection fraction, but had similar HbA1c values compared to those with atypical AP or typical AP. Over a median follow-up of 5.4 years (IQR: 2.9-8.8), the lack of recent AP was associated with increased risk for outcomes (Table). Following adjustment, the lack of recent AP was independently associated with increased mortality compared to typical AP. Conclusions: In DM patients with CAD, the lack of AP was associated with increased mortality, but similar risk for CV events compared to patients with typical AP. Future studies are needed to assess whether these findings are related to increased severity of disease in those without AP or whether AP leads to differential management that improves survival.

Introduction: Despite the use of different definitions for worsening heart failure (WHF) in prior clinical trials and registries, an in-hospital WHF event has consistently been associated with worse patient outcomes. WHF is being considered as a potential endpoint to support drug approval. We combined patients from two acute HF trials conducted by the HF Network (ROSE-AHF and DOSE-AHF) to understand how different WHF definitions are associated with event rates. Methods: WHF was defined as persistent or worsening HF requiring rescue therapy including IV vasoactive agents, ultrafiltration, or mechanical support over 72 hours after randomization in ROSE and also included additional open label loop or thiazide diuretic in DOSE. We assessed the relationship between WHF and the composite endpoint (CE) of re-hospitalization, emergency room visits for HF and mortality through 60 days. We also assessed for a differential relationship of WHF from 0-24 hours, 24-48 hours and 48-72 hours post-randomization. Results: The overall incidence of WHF was 14.6% (24.1% in DOSE and 6.3% in ROSE). Patients who developed WHF had lower baseline systolic blood pressure, less peripheral edema and higher BUN. In the combined dataset, WHF was associated with an increase in the CE (hazard ratio [HR] 1.64; 95% confidence interval [CI] 1.11-2.42; p-value 0.01). However, the association between WHF and 60-day outcomes was significant in ROSE but not in DOSE (Table). The development of WHF between 48-72 hours compared with 0-24 hours or 24-48 hours was associated with improved outcomes ([HR] 0.48, 95% CI 0.27 - 0.88, p-value 0.02 and [HR] 0.45, 95% CI 0.26 - 0.78, p-value 0.004, respectively). Conclusions: A WHF definition that incorporated intensification of diuretics increased the event rate but was not associated with worse 60-day outcomes. The timing of a WHF event also had a differential association with outcomes. These data support the use of a standardized WHF definition in clinical trials.

Background: Angina pectoris (AP) is associated with worse outcomes in heart failure (HF) patients, but less is known about implications on health related quality of life (HRQoL) and functional capacity. Methods: We assessed HRQoL, functional capacity and outcomes in chronic HF patients with reduced EF in the HF-ACTION trial of usual care +/- exercise training based on whether patients had AP. AP was patient-reported based on recent symptoms or development during exercise testing. We assessed all-cause mortality/hospitalization in patients with AP vs. no AP using multivariable Cox proportional hazards regression. We assessed for an interaction between AP status and exercise training with respect to outcomes and the change in quality of life and functional capacity from baseline to 3 months. Results: In HF-ACTION, 406 (17%) patients had AP at baseline with 44% of these reporting ≥ class II symptoms. Patients with AP more often had ischemic etiology, but had similar EF, NT-proBNP and beta-blocker use. Baseline 6-minute walk distance and peak VO 2 were similar in both groups, but patients with AP had worse depressive symptoms and HRQoL. After risk adjustment, AP was associated with a 22% greater risk of all-cause mortality/hospitalization (Figure). There was evidence of an interaction between baseline AP and exercise training on change in peak VO 2 (P=0.019), but not for HRQoL or clinical outcomes. The median change in peak VO 2 with exercise training was 0.8 mL/kg/min with AP vs. 0.6 mL/kg/min without AP. Conclusion: AP was associated with worse HRQoL and more depressive symptoms. Despite a greater improvement in peak VO 2 with exercise training, patients with AP experienced more adverse events. Clinicians should consider routine assessment and management of AP in HF patients as well as the associated symptoms related to depression and implications on quality of life.

Introduction: The 2014 hypertension (HTN) guidelines liberalized blood pressure (BP) goals for people ≥60 years. Hypothesis: Increased systolic and diastolic blood pressure (SBP/DBP) will be associated with a higher risk of mortality and heart failure hospitalization (HFH) across all age groups. Methods: We used age-adjusted Kaplan-Meier estimates to calculate the cumulative incidence of mortality and HFH across SBP/DBP categories (Figure) among 5280 participants of the Jackson Heart Study (JHS), an exclusively black population. We used Cox proportional hazards models to investigate associations between baseline visit SBP/DBP and both mortality and HFH. Linearity of associations and differential effects by age were assessed. Results: Median age was 56 years (IQR: 46-65); 63% were female; median SBP was 125 mmHg (IQR: 114-137); and median DBP was 79 mmHg (IQR: 72-86). There were 520 deaths over 9 years and 340 HFHs over 7 years. The age-adjusted cumulative incidence of both mortality and HFH increased with SBP, while rates of both outcomes were similar by DBP (Figure). After multivariable adjustment, every 10 mmHg increase in SBP was associated with increased mortality (HR 1.12 95% CI [1.06, 1.17]; p Conclusions: In this JHS cohort, SBP was associated with both mortality and HFH, while DBP was inversely associated with mortality. Adults across all age groups were at increased risk of mortality as SBP increased. In the context of new HTN guidelines, these findings have important implications and should be considered when determining BP treatment goals in Black patients.

Introduction: Furosemide is the most commonly used loop diuretic in heart failure (HF) patients despite potential pharmacologic and anti-fibrotic benefits with torsemide. Hypothesis: We hypothesized that the comparative benefits of post-discharge use of torsemide would be superior to furosemide in a large acute HF trial. Methods: We investigated HF patients in ASCEND-HF who were discharged on either torsemide or furosemide. Given regional variation in torsemide use, we restricted analyses to the 6 countries with at least 20 patients on one of the diuretics and patients on torsemide. Using inverse probability weighting (IPW) to account for selection of diuretic, we assessed the relationship between diuretic at discharge with 30-day mortality or HF hospitalization, and 30- and 180-day mortality. Results: Of 7,141 patients in the trial, 3,282 patients were included in this analysis, of which, 88% (n=2,893) received furosemide and 12% (n=389) received torsemide. Torsemide-treated patients had lower blood pressure, and higher creatinine and BUN at baseline compared with furosemide-treated patients. On adjusted analysis, torsemide use was associated with a trend toward lower 30-day mortality or HF hospitalization (OR 0.62, 95% CI: 0.37-1.04; P=0.067). Torsemide was associated with similar 30-day mortality (OR 0.77, 95% CI: 0.28-2.09; P=0.60), and significantly reduced 180-day mortality (HR 0.56, 95% CI: 0.36-0.87; P=0.038) compared with furosemide (Figure). Conclusion: In this acute HF trial, a minority of patients received torsemide and commonly had indicators of higher risk. After risk-adjustment, torsemide was associated with lower risk of 180-day mortality. These data should be considered as hypothesis-generating and prospective, randomized comparative effectiveness trials are needed to investigate the optimal diuretic choice between torsemide vs. furosemide.

Background: Elevations of cardiac troponin are common in acute heart failure (AHF), but their clinical importance is uncertain. We examined the association between serial high-sensitivity troponin T (hs-cTnT) and outcomes in the RELAX-AHF study, a randomized trial of IV serelaxin in AHF. Methods: hs-cTnT (Roche Diagnostics) was measured at baseline and days 2, 5, and 14. Patients with clinical evidence of ACS were excluded by protocol. 1074 patients (93% of total cohort) with data available for both baseline and at least 1 follow-up hs-cTnT measurement were analyzed. We assessed the relationship between baseline hs-cTnT and peak change from baseline hs-cTnT with outcomes. Models were adjusted for other clinical variables and treatment assignment. Differential effect of serelaxin by troponin levels was assessed by interactions terms. Results: The median baseline troponin was 0.033 mcg/L, and 95% were above the 99 th upper reference limit (URL). Patients with elevated hs-cTnT were more likely to be men with ischemic heart disease, worse renal function, and higher natriuretic peptides. Both higher baseline hs-cTnT and greater peak hs-cTnT were associated with increased risk for adverse outcomes even after adjustment ( Table ). Treatment effect of serelaxin did not differ based on troponin status. Conclusion: Consistent with prior data, hs-cTnT was elevated above the 99% URL in the vast majority of AHF patients at baseline, and was associated with markers of disease severity. Both baseline and peak change from baseline hs-cTnT were associated with worse clinical outcomes, but relationships were generally strongest for 180-day CV mortality. Treatment effect of serelaxin did not differ based on troponin status.

Major advances in medicine have the curious property of simultaneously being the cause of both great excitement and great anxiety. Clinicians embrace the power of science to reduce human suffering and prolong life in ways that their forbearers could hardly have imagined. Patients, knowing little of the enormous theoretical and practical challenges to be surmounted in producing real medical breakthroughs, have been conditioned by the media to expect dramatic headlines in each morning's news reports as they sip their coffee. Healthcare payers and policy makers, reading those same reports, worry that consumers' enthusiasm for high-tech solutions to the chronic health problems of modern society is fueling a destructive growth rate in medical spending. Although cardiovascular medicine has no unique claim to technological innovation, the sheer number of patients affected with cardiovascular disease means that major technological advances addressing important clinical problems have measurable effects on the annual healthcare bill for the country. Over the last few decades, cardiovascular medicine has seen a series of remarkable, but expensive, therapeutic innovations evolve into guideline-endorsed standard care (eg, drug-eluting stents, implantable cardioverter-defibrillators, left ventricular assist devices). In each of these cases, the early dissemination phase of these technologies was marked by predictions that cardiovascular physicians, unable to restrain their enthusiasm for therapeutic novelty, would sink the national economy by adding billions of extra dollars to the already excessive annual healthcare bill. The apparent failure of such predictions to come true has left physicians increasingly inured to the voices of the Cassandras who make them. Administrative inefficiency and overuse of tests and therapies partially explain why the United States spends more than any other country on health care (17% of the gross domestic product at last accounting) but not why the spending continues to grow every year. Of the factors that account for the …