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• Using one of the largest heart failure pragmatic trials (CONNECT-HF; (Care Optimization Through Patient and Hospital Engagement For HF), we assessed the completeness and validity of remote follow-up, integrating participant-reported via a centralized call center and site-reported approaches. • Both participant-reported via centralized call center- and site-reported approaches substantially missed hospitalization events. In contrast, both approaches demonstrated high and comparable adjudication rates for hospitalizations among the reported hospitalization events. • Our study highlighted that integrating both approaches remains essential to capture and validate effective clinical outcomes in the context of current pragmatic trials. Randomized controlled trials typically require study-specific visits, which can burden participants and sites. Remote follow-up, such as centralized call centers for participant-reported or site-reported, holds promise for reducing costs and enhancing the pragmatism of trials. In this secondary analysis of the CONNECT-HF (Care Optimization Through Patient and Hospital Engagement For HF) trial, we aimed to evaluate the completeness and validity of the remote follow-up process. The CONNECT-HF trial evaluated the effect of a post-discharge quality-improvement intervention for heart failure compared to usual care for up to 1 year. Suspected events were reported either by participants or by health care proxies through a centralized call center or by sites through medical-record queries. When potential hospitalization events were suspected, additional medical records were collected and adjudicated. Among 5942 potential hospitalizations, 18% were only participant-reported, 28% were reported by both participants and sites, and 50% were only site-reported. Concordance rates between the participant/site reports and adjudication for hospitalization were high: 87% participant-reported, 86% both, and 86% site-reported. Rates of adjudicated heart failure hospitalization events among adjudicated all-cause hospitalization were lower but also consistent: 45% participant-reported, 50% both, and 50% site-reported. Participant-only and site-only reports missed a substantial number of hospitalization events. We observed similar concordance between participant/site reports and adjudication for hospitalizations. Combining participant-reported and site-reported outcomes data is important to capture and validate hospitalizations effectively in pragmatic heart failure trials. Both approaches (centralized call center and site reports) substantially missed hospitalization events. However, both approaches demonstrated high and comparably adjudicated hospitalization rates among the reported potential hospitalization events. Integrating both approaches remains essential to capture and validate clinical outcomes effectively.   [ABSTRACT FROM AUTHOR]

Patients with obesity and advanced heart failure requiring left ventricular assist device (LVAD) support are more likely to experience LVAD complications and may be disproportionately Black and/or female when compared to patients without obesity. Among these patients, obesity may represent a barrier to transplant eligibility and a marker of inequity in heart transplantation and health outcomes in advanced heart failure. To better understand this issue at our institution, we examined our active LVAD cohort and found that almost one-third of all patients had severe obesity with BMI ≥ 35 kg/m2. Patients with LVADs and severe obesity were significantly younger and more likely to self-identify as Black, and numerically more likely to be female. Weight management in this group represents a vital area for improved equity in health outcomes and barriers to heart transplantation. NA. [ABSTRACT FROM AUTHOR]

Omecamtiv mecarbil improves outcomes in patients with heart failure and reduced ejection fraction (HFrEF). We examined the relationship between baseline troponin levels, change in troponin levels over time and the treatment effect of omecamtiv mecarbil in patients enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure (GALACTIC-HF) trial (NCT02929329). GALACTIC-HF was a double-blind, placebo-controlled trial that randomized 8256 patients with symptomatic HFrEF to omecamtiv mecarbil or placebo. High-sensitivity troponin I (cTnI) was measured serially at a core laboratory. We analyzed the relationship between both baseline cTnI and change in cTnI concentrations with clinical outcomes and the treatment effect of omecamtiv mecarbil. Higher baseline cTnI concentrations were associated with a risk of adverse outcomes (hazard ratio for the primary endpoint of time to first HF event or CV death = 1.30; 95% CI 1.28, 1.33; P < 0.001 per doubling of baseline cTnI). Although the incidence of safety outcomes was higher in patients with higher baseline cTnI, there was no difference between treatment groups. Treatment with omecamtiv mecarbil led to a modest increase in cTnI that was related to plasma concentrations of omecamtiv mecarbil, and it peaked at 6 weeks. An increase in troponin from baseline to week 6 was associated with an increased risk of the primary endpoint (P < 0.001), which was similar, regardless of treatment assignment (P value for interaction = 0.2). In a cohort of patients with HFrEF, baseline cTnI concentrations were strongly associated with adverse clinical outcomes. Although cTnI concentrations were higher in patients treated with omecamtiv mecarbil, we did not find a differential effect of omecamtiv mecarbil on either safety or efficacy based on baseline cTnI status or change in cTnI. [ABSTRACT FROM AUTHOR]

To assess tissue Doppler-derived mitral annular isovolumic contraction velocity (ICV) after starting sacubitril/valsartan (sac/val) for the treatment of heart failure with reduced ejection fraction (HFrEF) and left ventricular [LV] EF < 40%). ICV may inform load-independent systolic function; combining ICV and LVEF may improve assessment of LV contractility. Among 651 participants with HFrEF treated with sac/val, echocardiograms were performed at baseline, 6 and 12 months. Pretreatment median ICVs and LVEFs were used for classification to predict LV reverse remodeling, health status using the Kansas City Cardiomyopathy Questionnaire, and biomarker concentrations. The mean age was 64.6 ± 12.4 years, and 28% were women, baseline LVEF: 28.9% ± 6.9%. Compared to baseline, median ICV increased post sac/val therapy (4.6 [3.5, 6.1] vs 4.9 [3.6, 6.4]; P = 0.005). ICV added value to separate and combined models of biomarkers and clinical and echocardiographic variables for prediction of post-therapy EF recovery. Classification using baseline ICV/EF yielded relatively equal numbers in 4 groups based on low/high ICV or LVEF. Most deleterious results for remodeling, health status and biomarkers were found in patients with low ICV/low EF, whereas patients with high ICV/high EF had the best profiles; other groups were intermediate. Significant shifts toward better ICV/EF profiles were noted post sac/val treatment compared to baseline, with doubling of high ICV/high EF (241 [60%] vs 123 [31%]) and 78% reduction of low ICV/low EF (28 [7%] vs 125 [32%]). In HFrEF, ICV adds to the profiling of systolic function and represents an independent predictor of reverse cardiac remodeling after treatment with sac/val. ICV changes may be used for assessment of treatment responses. Study procedures, classifications and outcomes. [Display omitted] [ABSTRACT FROM AUTHOR]

In the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial, omecamtiv mecarbil, compared with placebo, reduced the risk of worsening heart failure (HF) events, or cardiovascular death in patients with HF and reduced ejection fraction. The primary aim of this prespecified analysis was to evaluate the safety and efficacy of omecamtiv mecarbil by randomization setting, that is, whether participants were enrolled as outpatients or inpatients. Patients were randomized either during a HF hospitalization or as an outpatient, within one year of a worsening HF event (hospitalization or emergency department visit). The primary outcome was a composite of worsening HF event (HF hospitalization or an urgent emergency department or clinic visit) or cardiovascular death. Of the 8232 patients analyzed, 2084 (25%) were hospitalized at randomization. Hospitalized patients had higher N-terminal prohormone of B-type natriuretic peptide concentrations, lower systolic blood pressure, reported more symptoms, and were less frequently treated with a renin–angiotensin system blocker or a beta-blocker than outpatients. The rate (per 100 person-years) of the primary outcome was higher in hospitalized patients (placebo group = 38.3/100 person-years) than in outpatients (23.1/100 person-years); adjusted hazard ratio 1.21 (95% confidence interval 1.12–1.31). The effect of omecamtiv mecarbil versus placebo on the primary outcome was similar in hospitalized patients (hazard ratio 0.89, 95% confidence interval 0.78–1.01) and outpatients (hazard ratio 0.94, 95% confidence interval 0.86–1.02) (interaction P =.51). Hospitalized patients with HF with reduced ejection fraction had a higher rate of the primary outcome than outpatients. Omecamtiv mecarbil decreased the risk of the primary outcome both when initiated in hospitalized patients and in outpatients. [ABSTRACT FROM AUTHOR]

Electronic health record (EHR)-based identification of heart failure with preserved ejection fraction (HFpEF) in the clinical setting may facilitate screening for clinical trials by improving the understanding of its epidemiology and outcomes; yet, previous data have yielded variable results. We sought to characterize groups identified with HFpEF by different EHR screening strategies and their associated long-term outcomes across a large and diverse population. We retrospectively analyzed 116,499 consecutive patients from an academic referral center who underwent echocardiography, and 9,263 patients who underwent echocardiography within 6 months of right heart catheterization (RHC), between 2008 and 2018. EHR-based screening strategies identified patients with HFpEF using 1) International Classification of Diseases (ICD)-9/10 codes, 2) H 2 FpEF score ≥6 and ejection fraction (EF) ≥50%, or 3) RHC wedge pressure ≥15 mmHg and EF ≥50%, when available. Primary outcomes were 1) cumulative incident heart failure hospitalization (HFH), and 2) death, over 10 years. There were 33,461 (29%) patients who met either ICD or H 2 FpEF-HFpEF definition, of whom 5,310 (16%) met both criteria. Compared to ICD-HFpEF, patients with H 2 FpEF-HFpEF were more likely older (median age 72 vs 67), White (78% vs 64%), and had atrial fibrillation (97% vs 41%). Among those also with RHC, 6,353 (69%) patients met any HFpEF criteria, of whom only 783 (12%) satisfied all three criteria. Female sex was more common among RHC-HFpEF (55%) compared to other methods (H 2 FpEF-HFpEF, 47%; ICD-HFpEF, 43%). Atrial fibrillation was substantially higher among HFpEF identified by the H 2 FpEF score (97%) compared to other methods (49% for ICD and 47% for RHC). Across HFpEF screening methods, 10-year cumulative incidence rates for HFH was 32% to 45% for echocardiography only and 43% to 52% for echocardiography and RHC populations; 10-year risk of death was 54% to 56% for echocardiography only and 52% to 57% for echocardiography and RHC populations. Different EHR-based HFpEF definitions identified cohorts with modest overlap and varying baseline characteristics. Yet, long-term risk for HFH and death were similarly high for cohorts identified among both populations undergoing echocardiography only or echocardiography and RHC. These data aid in identifying relevant subgroups in clinical trials of HFpEF. [ABSTRACT FROM AUTHOR]

• Heart failure events differ significantly in severity and clinical implications, potentially allowing for more nuanced understanding of treatment effects in heart failure clinical trials. • These data suggest that clinical trials in HF could rank the severity of HF events when assessing the treatment effects of novel therapeutics. Hospitalization due to heart failure (HFH) is a major source of morbidity, consumes significant economic resources and is a key endpoint in HF clinical trials. HFH events vary in severity and implications, but they are typically considered equivalent when analyzing clinical trial outcomes. We aimed to evaluate the frequency and severity of HF events, assess treatment effects and describe differences in outcomes by type of HF event in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction). VICTORIA compared vericiguat with placebo in patients with HF with reduced ejection fraction (< 45%) and a recent worsening HF event. All HFHs were prospectively adjudicated by an independent clinical events committee (CEC) whose members were blinded to treatment assignment. We evaluated the frequency and clinical impact of HF events by severity, categorized by highest intensity of HF treatment (urgent outpatient visit or hospitalization treated with oral diuretics, intravenous diuretics, intravenous vasodilators, intravenous inotropes, or mechanical support) and treatment effect by event categories. In VICTORIA, 2948 HF events occurred in 5050 enrolled patients. Overall total CEC HF events for vericiguat vs placebo were 43.9 vs 49.1 events/100 patient-years (P = 0.01). Hospitalization for intravenous diuretics was the most common type of HFH event (54%). HF event types differed markedly in their clinical implications for both in-hospital and post-discharge events. We observed no difference in the distribution of HF events between randomized treatment groups (P = 0.78). HF events in large global trials vary significantly in severity and clinical implications, which may have implications for more nuanced trial design and interpretation. ClinicalTrials.gov (NCT02861534) [Display omitted] [ABSTRACT FROM AUTHOR]

We sought to determine whether circulating modifiers of endothelial function are associated with cardiac structure and clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). We measured 25 proteins related to endothelial function in 99 patients from the GUIDE-IT study. Protein levels were evaluated for association with echocardiographic parameters and the incidence of all-cause death and hospitalization for heart failure (HHF). Higher concentrations of angiopoietin 2 (ANGPT2), vascular endothelial growth factor receptor 1 (VEGFR1) and hepatocyte growth factor (HGF) were significantly associated with worse function and larger ventricular volumes. Over time, decreases in ANGPT2 and, to a lesser extent, VEGFR1 and HGF, were associated with improvements in cardiac size and function. Individuals with higher concentrations of ANGPT2, VEGFR1 or HGF had increased risks for a composite of death and HHF in the following year (HR 2.76 (95% CI 1.73–4.40) per 2-fold change in ANGPT2; HR 1.76 (95% CI 1.11–2.79) for VEGFR1; and HR 4.04 (95% CI 2.19–7.44) for HGF). Proteins related to endothelial function associate with cardiac size, cardiac function and clinical outcomes in patients with HFrEF. These results support the concept that endothelial function may be an important contributor to the progression to and the recovery from HFrEF. Take-Home Visual Graphic: Changes in circulating angiokines are associated with reverse remodeling and outcomes in chronic heart failure. [Display omitted] [ABSTRACT FROM AUTHOR]

Natriuretic peptides, brain (B-type) natriuretic peptide (BNP) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) are globally and most often used for the diagnosis of heart failure (HF). In addition, they can have an important complementary role in the risk stratification of its prognosis. Since the development of angiotensin receptor neprilysin inhibitors (ARNIs), the use of natriuretic peptides as therapeutic agents has grown in importance. The present document is the result of the Trilateral Cooperation Project among the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America and the Japanese Heart Failure Society. It represents an expert consensus that aims to provide a comprehensive, up-to-date perspective on natriuretic peptides in the diagnosis and management of HF, with a focus on the following main issues: (1) history and basic research: discovery, production and cardiovascular protection; (2) diagnostic and prognostic biomarkers: acute HF, chronic HF, inclusion/endpoint in clinical trials, and natriuretic peptides-guided therapy; (3) therapeutic use: nesiritide (BNP), carperitide (ANP) and ARNIs; and (4) gaps in knowledge and future directions. [ABSTRACT FROM AUTHOR]

• Treatment with sacubitril/valsartan decreased the concentration of prognostically relevant biomarkers across heart failure duration groups. • Treatment with sacubitril/valsartan was associated with substantial improvement in health status across heart failure duration groups. • Treatment with sacubitril/valsartan reversed cardiac remodeling (marked by improved left ventricular ejection fraction, reduced left ventricular and/or left atrial volumes, improved myocardial relaxation, and decreased left ventricular mass index) across heart failure duration groups. Although sacubitril/valsartan (Sac/Val) is indicated for the treatment of heart failure with reduced ejection fraction (HFrEF), gaps in care continue to exist for those with newer onset HFrEF vs those with longer durations of disease. We categorized 794 persons with HFrEF (EF of ≤40%) according to a HF duration of less than 12 months, 12–24 months, 24–60 months, and more than> 60 months. After the initiation of Sac/Val, concentrations of N-terminal pro-B type natriuretic peptide, high sensitivity cardiac troponin T, and soluble ST2 were measured, and Kansas City Cardiomyopathy Questionnaire 23 scores were obtained serially from baseline to 12 months. The left ventricular ejection fraction was measured by echocardiography. Significant decreases in the concentrations of N-terminal pro-B type natriuretic peptide, high sensitivity cardiac troponin T, and soluble ST2 were observed regardless of HF duration (P <.001). Comparable gains in Kansas City Cardiomyopathy Questionnaire 23 scores were achieved in all HF duration categories. Moreover, consistent reverse cardiac remodeling in all HF duration categories occurred, with the absolute left ventricular ejection fraction improvement by 12 months across HF duration groups of 12.2%, 6.9%, 8.5%, and 8.6% for HF duration of less than 12 months, 12–24 months, 24–60 months, and more than 60 months, respectively. The initiation of Sac/Val decreases prognostic biomarkers, improves health status, and reverses cardiac remodeling processes, regardless of HF duration. We categorized 794 persons with heart failure owing to a low ejection fraction according to disease duration into 4 groups: less than 12 months, 12–24 months, 24–60 months, and more than 60 months. After the initiation of sacubitril/valsartan (Entresto), we found that regardless of the duration of heart failure significant improvements occurred in cardiac biomarkers, patients felt better with improved health status and on testing with cardiac ultrasound examination, improvement in heart size, and function occurred. These results suggest that, regardless of heart failure duration, patients with a reduced ejection fraction would benefit from use of sacubitril/valsartan for their care. Improvement in cardiac remodeling across all heart failure duration categories as evident by the increase in left ventricular ejection fraction and decrease in cardiac biomarker, left atrial volume index, and left ventricular end-systolic volume index during 12 months of treatment with sacubitril/valsartan. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Mobile health (mHealth) platforms can affect health behaviors but have not been rigorously tested in randomized trials.Objectives: We sought to evaluate the effectiveness of a pragmatic mHealth intervention in patients with heart failure (HF) and diabetes (DM).Methods: We conducted a multicenter randomized trial in 187 patients with both HF and DM to assess an mHealth intervention to improve physical activity and medication adherence compared to usual care. The primary endpoint was change in mean daily step count from baseline through 3 months. Other outcomes included medication adherence, health-related quality of life and metabolomic profiling.Results: The mHealth group had an increase in daily step count of 151 steps/day at 3 months, whereas the usual-care group had a decline of 162 steps/day (least squares mean between-group difference = 313 steps/day; 95% CI: 8 619; P = 0.044). Medication adherence, measured using the Voils Adherence Questionnaire, did not change from baseline to 3 months (LS-mean change -0.08 in mHealth vs -0.15 in usual care; P = 0.47). The mHealth group had an improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score compared to the usual-care group (LS-mean difference = 5.5 points, 95% CI: 1.4, 9.6; P = 0.009). Thirteen metabolites, primarily medium- and long-chain acylcarnitines, changed differently between treatment groups from baseline to 3 months (P < 0.05).Conclusions: In patients with HF and DM, a 3-month mHealth intervention significantly improved daily physical activity, health-related quality of life and metabolomic markers of cardiovascular health but not medication adherence.Condensed Abstract: Heart failure (HF) and diabetes (DM) have overlapping biological and behavioral risk factors. We conducted a multicenter randomized, clinical trial in 187 patients with both HF (regardless of ejection fraction) and DM to assess whether an mHealth intervention could improve physical activity and medication adherence. The mHealth group had an increase in mean daily step count and quality of life but not in medication adherence. Medium- and long-chain acylcarnitines changed differently in treatment groups from baseline to 3 months (P < 0.05). These data have important implications for designing effective lifestyle interventions in HF and DM. [ABSTRACT FROM AUTHOR]

Background: The role of blood volume (BV) expansion vs a change in vascular compliance in worsening heart failure (HF) remains under debate. We aimed to assess the relationship between BV and resting and stress hemodynamics in worsening HF and to further elucidate the significance of BV in cardiac decompensation.Methods and Results: Patients with worsening HF underwent radiolabeled indicator-dilution BV analysis and cardiac catheterization. Intravascular volumes and resting/stress hemodynamics were recorded. Provocative stress maneuvers included change in systolic blood pressure (ΔSBP) from lying to standing and Valsalva and intracardiac pressure changes with leg raise. Correlation between BV and invasive hemodynamics were assessed by linear regression. Of 27 patients with worsening HF, patients' characteristics included mean age 61 ± 12 years, 70% male, 19% Black, and mean ejection fraction 29% ± 15%. Of the patients, 13 (48%) had hypervolemia as measured by total BV, which weakly correlated with ΔSBP by position (R2 = 0.009) and Valsalva (R2 = 0.003) and with right atrial (R2 = 0.049) and pulmonary capillary wedge (R2 = 0.047) pressure changes during leg raise.Conclusions: In patients with worsening HF, BV mildly correlated with intracardiac pressures at rest. Provocative maneuvers intended to test vascular compliance did not correlate with BV, indicating that compliance may serve as a stand-alone metric in HF. [ABSTRACT FROM AUTHOR]

Background: Health system-level interventions to improve use of guideline-directed medical therapy (GDMT) often fail in the acute care setting. We sought to identify factors associated with high performance in adoption of GDMT among health systems in CONNECT-HF.Methods and Results: Site-level composite quality scores were calculated at discharge and last follow-up. Site performance was defined as the average change in score from baseline to last follow-up and analyzed by performance tertile using a mixed-effects model with baseline performance as a fixed effect and site as a random effect. Among 150 randomized sites, the mean 12-month improvement in GDMT was 1.8% (-26.4% to 60.0%). Achievement of 50% or more of the target dose for angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors, and beta-blockers at 12 months was modest, even at the highest performing sites (median 29.6% [23%, 41%] and 41.2% [29%, 50%]). Sites achieving higher GDMT scores had care teams that included social workers and pharmacists, as well as patients who were able to afford medications and access medication lists in the electronic health record.Conclusions: Substantial gaps in site-level use of GDMT were found, even among the highest performing sites. The failure of hospital-level interventions to improve quality metrics suggests that a team-based approach to care and improved patient access to medications are needed for postdischarge success. [ABSTRACT FROM AUTHOR]

Background: The GUIDE-IT trial was, a multicenter, randomized, parallel group, unblinded study that randomized patients to having heart failure therapy titrated to achieve an NT-proBNP <1000 pg/mL or to usual clinical care.Methods and Results: We performed pre-specified subgroup analysis to look for the race and ethnicity-based differences in clinical outcomes of patients who were able to achieve GDMT or target NT-proBNP concentration of ≤1000 pg/mL at 90 days of follow-up. There were 894 patients enrolled in GUIDE-IT study. Of these, 733 participants had available data on 90-day guideline directed triple therapy and 616 on NT-proBNP. 35% of the patients were Black and 6% were Hispanic. Black patients were younger, had more comorbidities, lower EF, and higher NYHA class compared with non-Black. Adjusting for 90-day NT-proBNP and important baseline covariates, Black patients were at a higher risk than non-Black patients for HF hospitalization [HR, 2.19; 95% CI, 1.51-3.17; p < 0.0001], but at a similar risk for mortality [HR, 0.85.; 95% CI, 0.44-1.66; p = 0.64]. Similar results were seen adjusting for 90-day GDMT [HF hospitalization: Black vs non-Black, HR: 1.97; 1.41-2.77, P < 0.0001; mortality: HR: 0.70; 0.39-1.26, p = 0.23]. There were no significant differences between Hispanic and non-Hispanic patients with respect to heart failure hospitalization, cardiovascular or all-cause mortality. Over the study period, Black and Hispanic patients experienced smaller changes in physical function and quality of life as measured by the Kansas City Cardiomyopathy Questionnaire overall score.Conclusion: Compared to non-Black patients, Black patients in GUIDE-IT study had a higher risk of heart failure hospitalization, but a comparable risk of mortality, despite improved use of GDMT and achievement of similar biomarker targets. [ABSTRACT FROM AUTHOR]

Background: Recent data suggest that patients with heart failure with reduced ejection fraction (HFrEF) and worsening heart failure (WHF) have potential for greater benefit from newer HF therapies. We investigated characteristics and outcomes of patients with HFrEF and WHF by severity of left ventricular dysfunction.Methods: We identified patients with chronic symptomatic HFrEF (left ventricular ejection fraction [LVEF] ≤35%) and evidence of WHF (emergency department visit or hospitalization for acute HF within 12 months of index echocardiogram) treated at Duke University between 1/2009 and 12/2018. Patients were stratified by LVEF≤25% or 26% to35%. Cox models were used to estimate cause-specific hazard ratios and 5-year event incidence of death and hospitalization across the range of LVEF.Results: Of 2823 patients with HFrEF and WHF, 1620 (57.4%) had an LVEF≤25% and 1203 (42.6%) had an LVEF 26% to35%. Compared to patients with LVEF 26% to35%, those with LVEF≤25% were younger and more commonly men with a lower cardiovascular comorbidity burden. Patients with LVEF≤25% were less commonly on beta blockers (85.9% vs 90.5%) but more commonly treated with mineralocorticoid receptor antagonists (49.3% vs 41.1%) and implantable defibrillators (41.3% vs 28.2%). Patients with LVEF≤25% had significantly higher hazards for death (HR 1.24 [95% CI 1.11 - 1.38]), all-cause hospitalization (HR 1.21 [95% CI 1.10 - 1.33]), and HF hospitalization (HR 1.25 [95% CI 1.1 - 1.38]) through 5-years.Conclusions: More than half of patients with chronic HFrEF and WHF have severe LV dysfunction. Important differences in comorbidities, HF therapies, and outcomes exist between those with LVEF≤25% and those with LVEF 26% to35%. [ABSTRACT FROM AUTHOR]

Background: It remains unclear why depression is associated with adverse outcomes in patients with heart failure (HF). We examine the relationship between depression and clinical outcomes among patients with HF with reduced ejection fraction managed with guideline-directed medical therapy (GDMT).Methods and Results: Using the GUIDE-IT trial, 894 patients with HF with reduced ejection fraction were stratified according to a history of depression, and Cox proportional hazards regression modeling was used to examine the association with outcomes. There were 140 patients (16%) in the overall cohort who had depression. They tended to be female (29% vs 46%, P < .001) and White (67% vs 53%, P = .002). There were no differences in GDMT rates at baseline or at 90 days; nor were there differences in target doses of these therapies achieved at 90 days (NS, all). amino-terminal pro-B-type natriuretic peptide levels at all time points were similar between the cohorts (P > .05, all). After adjustment, depression was associated with all-cause hospitalizations (hazard ratio, 1.42, 95% confidence interval 1.11-1.81, P < .01), cardiovascular death (hazard ratio, 1.69, 95% confidence interval 1.07-2.68, P = .025), and all-cause mortality (hazard ratio, 1.54, 95% confidence interval 1.03-2.32, P = .039).Conclusions: Depression impacts clinical outcomes in HF regardless of GDMT intensity and amino-terminal pro-B-type natriuretic peptide levels. This finding underscores the need for a focus on mental health in parallel to achievement of optimal GDMT in these patients.Trial Registration: NCT01685840, https://clinicaltrials.gov/ct2/show/NCT01685840. [ABSTRACT FROM AUTHOR]

Background: Decongestion is a primary goal during hospitalizations for decompensated heart failure (HF). However, data surrounding the preferred route and strategy of diuretic administration are limited with varying results in prior studies.Methods: This is a retrospective analysis using patients from ASCEND-HF with a stable diuretic strategy in the first 24 hours following randomization. Patients were divided into three groups: intravenous (IV) continuous, IV bolus and oral strategy. Baseline characteristics, in-hospital outcomes, 30-day composite cardiovascular mortality or HF rehospitalization and 180-day all-cause mortality were compared across groups. Inverse propensity weighted modeling was used for adjustment.Results: Among 5,738 patients with a stable diuretic regimen in the first 24 hours (80% of overall ASCEND trial), 3,944 (68.7%) patients received IV intermittent bolus administration of diuretics, 799 (13.9%) patients received IV continuous therapy and 995 (17.3%) patients with oral administration. Patients in the IV continuous group had a higher baseline creatinine (IV continuous 1.4 [1.1-1.7]; intermittent bolus 1.2 [1.0-1.6]; oral 1.2 [1.0-1.4] mg/dL; P <0.001) and high NTproBNP (IV continuous 5,216 [2,599-11,603]; intermittent bolus 4,944 [2,339-9,970]; oral 3,344 [1,570-7,077] pg/mL; P <0.001). There was no difference between IV continuous and intermittent bolus group in weight change, total urine output and change in renal function till 10 days/discharge (adjusted P >0.05 for all). There was no difference in 30 day mortality and HF readmission (adjusted OR 1.08 [95%CI: 0.74, 1.57]; P = 0.701) and 180 days mortality (adjusted OR 1.04 [95%CI: 0.75, 1.43]; P = 0.832).Conclusion: In a large cohort of patients with decompensated HF, there were no significant differences in diuretic-related in-hospital, or post-discharge outcomes between IV continuous and intermittent bolus administration. Tailoring appropriate diuretic strategy to different states of acute HF and congestion phenotypes needs to be further investigated. [ABSTRACT FROM AUTHOR]

Sacubitril/valsartan (S/V) treatment is associated with reverse cardiac remodeling and reductions in biomarkers reflecting ventricular wall stress and myocardial injury, such as NT-proBNP (N-terminal pro-B-type natriuretic peptide), hscTnT (high-sensitivity cardiac troponin T), and soluble suppressor of tumorigenicity 2 (sST2). How longitudinal changes in these biomarkers analyzed collectively are associated with cardiac remodeling in patients with heart failure with reduced ejection fraction treated with S/V is uncertain. METHODS: In a prospective study of S/V in patients with heart failure with reduced ejection fraction, this prespecified exploratory analysis included patients with serially collected biomarkers and echocardiographic measures of cardiac remodeling through 12 months of treatment. A multivariate latent growth curve model assessed associations between simultaneous changes in biomarkers and left ventricular ejection fraction and left atrial volume index. RESULTS: Seven hundred fifteen out of 794 total study participants were included (mean age 65 years, 73% male). Mean baseline left ventricular ejection fraction and left atrial volume index were 29% and 40 mL/m2, respectively. Adjusted geometric mean baseline concentrations for biomarkers included NT-proBNP of 649 pg/mL, hs-cTnT of 15.9 ng/L, and sST2 of 24.7 ng/mL. Following initiation of S/V, circulating concentrations of NT-proBNP, hs-cTnT, and sST2 significantly decreased within 30 days and remained significantly different than baseline at all subsequent timepoints. From baseline to month 12, decreases in adjusted biomarker concentrations averaged −27.9% (95% CI, −35.1% to −20.7%; P<0.001) for NT-proBNP; −6.7% (95% CI, −8.8% to −4.7%; P<0.001) for hs-cTnT; and −1.6% (95% CI, −2.9% to −0.4%; P<0.001) for sST2. NT-proBNP concentrations were predictive of later changes in hs-cTnT. The magnitude of reductions in NT-proBNP and hs-cTnT concentrations associated with improvements in left ventricular ejection fraction and left atrial volume index. There was no association between changes in sST2 and changes in other measures. CONCLUSIONS: Following initiation of S/V, NT-proBNP, hs-cTnT, and sST2 concentrations decreased significantly. Longitudinal changes in NT-proBNP and hs-cTnT together associated with left atrial and left ventricular reverse remodeling. [ABSTRACT FROM AUTHOR]

Background: The inflammatory cytokine IL-6 has been previously implicated in the pathophysiology of acute decompensated heart failure (HF). Prior observations in acute HF patients have suggested that IL-6 may be associated with outcomes and modulated by nesiritide. We aimed to evaluate the associations between serial IL-6 measurements, mortality and rehospitalization in acute HF.Methods and Results: We analyzed the associations between IL-6 in acute HF, readmission, and mortality (30 and 180 days) using a cohort of 883 hospitalized patients from the ASCEND-HF trial (nesiritide vs placebo). Plasma IL-6 was measured at randomization (baseline), 48-72 hours, and 30 days. The median IL-6 was highest at baseline (14.1 pg/mL) and decreased at subsequent time points (7.6 pg/mL at 30 days). In a univariable Cox regression analysis, the baseline IL-6 was associated with 30- and 180-day mortality (hazard ratio per log 1.74, 95% confidence interval 1.09-2.78, P = .021; hazard ratio 3.23, confidence interval 1.18-8.86, P = .022, respectively). However, there was no association after multivariable adjustment. IL-6 at 48-72 hours was found to be independently associated with 30-day mortality (hazard ratio 8.2, confidence interval 1.2-57.5, P= .03), but not 180-day mortality in multivariable analysis that included the ASCEND-HF risk model and amino terminal pro-B-type natriuretic peptide as covariates. In comparison with placebo, nesiritide therapy was not associated with differences in serial IL-6 levels.Conclusions: Although elevated IL-6 levels were associated with higher all-cause mortality in acute HF, no independent association with this outcome was identified at baseline or 30-day measurements. In contrast with prior reports, we did not observe any impact of nesiritide over placebo on serial IL-6 levels. [ABSTRACT FROM AUTHOR]

In this document, we propose a universal definition of heart failure (HF) as the following: HF is a clinical syndrome with symptoms and or signs caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and or objective evidence of pulmonary or systemic congestion. We propose revised stages of HF as: At-risk for HF (Stage A) , for patients at risk for HF but without current or prior symptoms or signs of HF and without structural or biomarkers evidence of heart disease. Pre-heart failure (Stage B) for patients without current or prior symptoms or signs of HF but evidence of structural heart disease or abnormal cardiac function, or elevated natriuretic peptide levels. HF (Stage C) for patients with current or prior symptoms and/or signs of HF caused by a structural and/or functional cardiac abnormality. Advanced HF (Stage D) for patients with severe symptoms and/ or signs of HF at rest, recurrent hospitalizations despite guideline-directed management and therapy (GDMT) , refractory or intolerant to GDMT, requiring advanced therapies such as consideration for transplant, mechanical circulatory support, or palliative care. Finally, we propose a new and revised classification of HF according to left ventricular ejection fraction (LVEF) . The classification includes HF with reduced EF (HFrEF) : HF with LVEF ≤ 40%; HF with mid-range EF (HFmrEF) : HF with LVEF 41-49%; HF with preserved EF (HFpEF) : HF with LVEF ≥ 50%; and HF with improved EF (HFimpEF) : HF with a baseline LVEF ≤ 40%, a ≥ 10 point increase from baseline LVEF, and a second measurement of LVEF > 40. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to identify the role of annexin A1 (AnxA1) as a congestion marker in acute heart failure (AHF) and to identify its putative role in predicting clinical outcomes.Background: AnxA1 is a protein that inhibits inflammation following ischemia-reperfusion injury in cardiorenal tissues. Because AHF is a state of tissue hypoperfusion, we hypothesized that plasma AnxA1 levels are altered in AHF.Methods: In the Renal Optimization Strategies Evaluation (ROSE) trial, patients hospitalized for AHF with kidney injury were randomized to receive dopamine, nesiritide, or placebo for 72 hours in addition to diuresis. In a subanalysis, plasma AnxA1 levels were measured at baseline and at 72 hours in 275 patients. Participants were divided into 3 tertiles based on their baseline AnxA1 levels.Results: The prevalence of peripheral edema 2+ increased with increasing AnxA1 levels (P < .007). Cystatin C, blood urea nitrogen, and kidney injury molecule-1 plasma levels were higher among participants in tertile 3 vs tertiles 1 or 2 (P< .05). Patients with a congestion score of 4 had a mean baseline AnxA1 level 8.63 units higher than those with a congestion score of 0 (P = .03). Patients in tertiles 2 and 3 were twice as likely to experience creatinine elevation as patients in tertile 1 (P = .03). Patients in tertiles 2 and 3 were at a higher risk of 60-day all-cause mortality or heart failure hospitalization and 180-day all-cause mortality (P < .05).Conclusions: Among patients hospitalized for AHF with impaired kidney function, elevated AnxA1 levels are associated with worse congestion, higher risk for further creatinine elevation, and higher rates of 60-day morbidity or all-cause mortality and 180-day all-cause mortality.Clinical Trial Registration: clinicaltrials.gov Identifier: NCT01132846. [ABSTRACT FROM AUTHOR]