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Background: Benefit from cardiac resynchronization therapy (CRT) varies by QRS characteristics; individual randomized trials are underpowered to assess benefit for relatively small subgroups. Methods: The authors analyzed patient-level data from pivotal CRT trials (MIRACLE [Multicenter InSync Randomized Clinical Evaluation], MIRACLE-ICD [Multicenter InSync ICD Randomized Clinical Evaluation], MIRACLE-ICD II [Multicenter InSync ICD Randomized Clinical Evaluation II], REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction], RAFT [Resynchronization-Defibrillation for Ambulatory Heart Failure], BLOCK-HF [Biventricular Versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block], COMPANION [Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure], and MADIT-CRT [Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Therapy]) using Bayesian Hierarchical Weibull survival regression models to assess CRT benefit by QRS morphology (left bundle branch block [LBBB], n=4549; right bundle branch block [RBBB], n=691; and intraventricular conduction delay [IVCD], n=1024) and duration (with 150-ms partition). The continuous relationship between QRS duration and CRT benefit was also examined within subgroups defined by QRS morphology. The primary end point was time to heart failure hospitalization (HFH) or death; a secondary end point was time to all-cause death. Results: Of 6264 patients included, 25% were women, the median age was 66 [interquartile range, 58 to 73] years, and 61% received CRT (with or without an implantable cardioverter defibrillator). CRT was associated with an overall lower risk of HFH or death (hazard ratio [HR], 0.73 [credible interval (CrI), 0.65 to 0.84]), and in subgroups of patients with QRS ≥150 ms and either LBBB (HR, 0.56 [CrI, 0.48 to 0.66]) or IVCD (HR, 0.59 [CrI, 0.39 to 0.89]), but not RBBB (HR 0.97 [CrI, 0.68 to 1.34]; P interaction Conclusions: CRT is associated with reduced HFH or death in patients with QRS ≥150 ms and LBBB or IVCD, but not for those with RBBB. Aggregating RBBB and IVCD into a single “non-LBBB” category when selecting patients for CRT should be reconsidered. Registration: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT00271154, NCT00251251, NCT00267098, and NCT00180271.

International audience; Aims: Heart failure with reduced ejection fraction (HFrEF) remains associated with high morbidity and mortality, poor quality of life (QoL) and significant exercise limitation. Sympatho-vagal imbalance has been shown to predict adverse prognosis and symptoms in HFrEF, yet it has not been specifically targeted by any guideline-recommended device therapy to date. Barostim™, which directly addresses this imbalance, is the first Food and Drug Administration approved neuromodulation technology for HFrEF. We aimed to analyse all randomized trial evidence to evaluate the effect of baroreflex activation therapy (BAT) on heart failure symptoms, QoL and N-terminal pro-brain natriuretic peptide (NT-proBNP) in HFrEF.Methods and results: An individual patient data (IPD) meta-analysis was performed on all eligible trials that randomized HFrEF patients to BAT + guideline-directed medical therapy (GDMT) or GDMT alone (open label). Endpoints included 6-month changes in 6-min hall walk (6MHW) distance, Minnesota Living With Heart Failure (MLWHF) QoL score, NT-proBNP, and New York Heart Association (NYHA) class in all patients and three subgroups. A total of 554 randomized patients were included. In all patients, BAT provided significant improvement in 6MHW distance of 49 m (95% confidence interval [CI] 33, 64), MLWHF QoL of -13 points (95% CI -17, -10), and 3.4 higher odds of improving at least one NYHA class (95% CI 2.3, 4.9) when comparing from baseline to 6 months. These improvements were similar, or better, in patients who had baseline NT-proBNP

Up to 20% of patients in heart failure with reduced ejection fraction (HFrEF) trials are not taking diuretic agents at baseline, but little is known about them.The aim of this study was to examine outcomes in patients with HFrEF not taking diuretic medications and after diuretic medications are started.Patient characteristics and outcomes were compared between patients taking or not taking diuretic drugs at baseline in the ATMOSPHERE (Aliskiren Trial of Minimizing Outcomes for Patients With Heart Failure) and PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) trials combined. Patients starting diuretic medications were also compared with those remaining off diuretic drugs during follow-up. Symptoms (Kansas City Cardiomyopathy Questionnaire Clinical Summary Score [KCCQ-CSS]), hospitalization for worsening heart failure (HF), mortality, and kidney function (estimated glomerular filtration rate slope) were examined.At baseline, the 3,079 of 15,415 patients (20%) not taking diuretic medications had a less severe HF profile, less neurohumoral activation, and better kidney function. They were less likely to experience the primary outcome (hospitalization for HF or cardiovascular death) than patients taking diuretic agents (adjusted HR: 0.77; 95% CI: 0.74-0.80; P 0.001) and death of any cause. Commencement of a diuretic drug was associated with higher subsequent risk for death (adjusted HR: 2.05; 95% CI: 1.99-2.11; P 0.001) and greater decreases in KCCQ-CSS and estimated glomerular filtration rate. The 5 strongest predictors of initiation of diuretic medications were higher N-terminal pro-B-type natriuretic peptide, higher body mass index, older age, history of diabetes, and worse KCCQ-CSS. In PARADIGM-HF, fewer patients who were treated with sacubitril/valsartan commenced diuretic agents (OR: 0.72; 95% CI: 0.58-0.88; P = 0.002).Patients with HFrEF not taking diuretic medications and those who remained off them had better outcomes than patients treated with diuretic agents or who commenced them.

Cardiac resynchronization therapy (CRT) reduces mortality and improves outcomes in appropriately selected patients with heart failure (HF); however, response may vary.We sought to correlate 6-month CRT response assessed by clinical composite score (CCS) and left ventricular end-systolic volume index (LVESVi) with longer-term mortality and HF-related hospitalizations.Individual patient data from 5 prospective CRT studies-Multicenter InSync Randomized Clinical Evaluation (MIRACLE), Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE ICD), InSync III Marquis, predictors of response to cardiac resynchronization therapy (PROSPECT), and Adaptive CRT-were pooled. Classification of CRT response status using CCS and LVESVi were made at 6 months. Kaplan-Meier analyses were used to assess time to mortality. Cox proportional hazards regression models were used to compute hazard ratios (HRs) for the 3 levels of CRT response: improved, stabilized, and worsened. Adjusted models controlled for baseline factors known to influence both CRT response and mortality. HF-related hospitalization was compared between CRT response categories using incidence rate ratios.Among a total of 1603 patients, 1426 and 1165 were evaluated in the CCS and LVESVi outcome assessments, respectively. Mortality was significantly lower for patients in the improved (CCS: HR 0.22; 95% confidence interval [CI] 0.15-0.31; LVESVi: HR 0.40; 95% CI 0.27-0.60) and stabilized (CCS: HR 0.38; 95% CI 0.24-0.61; LVESVi: HR 0.41; 95% CI 0.25-0.68) groups than in the worsened group for both measures after adjusting for potential confounders.Patients with a worsened CRT response status have a high mortality rate and HF-related hospitalizations. Stabilized patients have a more favorable prognosis than do worsened patients and thus should not be considered CRT nonresponders.

Background: Heart failure (HF) patients with atrial fibrillation (AF) often have conduction system disorders, which may be worsened by β-blocker therapy.Objective: In a post hoc analysis we examined the prevalence of bradycardia and its association with adverse events (AEs) and failure to achieve target dose in the GENETIC-AF trial.Methods: Patients randomized to metoprolol (n = 125) or bucindolol (n = 131) entering 24-week efficacy follow-up and receiving study medication were evaluated. Bradycardia was defined as an electrocardiogram (ECG) heart rate (HR) Results: Mean HR in sinus rhythm (SR) was 62.6 ± 12.5 bpm for metoprolol and 68.3 ± 11.1 bpm for bucindolol (P < .0001), but in AF HRs were not different (87.5 bpm vs 89.7 bpm, respectively). Episodes per patient for bucindolol vs metoprolol were 0.82 vs 2.08 (P < .001) for bradycardia and 0.24 vs 0.57 for severe bradycardia (P < .001), with 98.9% of the episodes occurring in SR. Patients experiencing bradycardia had a 4.15-fold higher prevalence of study medication dose reduction (P Conclusion: In AF-prone HF patients bradycardia may limit the effectiveness of β blockers, and this property is agent-dependent.

BACKGROUND: As heart failure therapeutic care becomes increasingly complex, a composite medical therapy score could be useful to conveniently summarize background medical therapy. We applied the composite medical therapy score developed by the Heart Failure Collaboratory (HFC) to the Danish heart failure with reduced ejection fraction population to evaluate its external validation including assessing the distribution of the score and its association with survival. METHODS: In a retrospective nationwide cohort study, we identified all Danish heart failure with reduced ejection fraction patients alive on July 1, 2018, and assessed their treatment doses. Patients were excluded if they did not have at least 365 days for up-titration of medical therapy prior to identification. The HFC score (range 0–8) accounts for use and dosing of multiple therapies prescribed to each patient. Risk-adjusted association between the composite score and all-cause mortality was examined. RESULTS: In total, 26 779 patients (mean age 71.9 years; 32% women) were identified. At baseline, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker was used in 77%, β-blocker in 81%, mineralocorticoid receptor antagonist in 30%, angiotensin receptor-neprilysin inhibitor in 2%, and ivabradine in 2%. The median HFC score was 4. After multivariable adjustment, higher HFC scores were independently associated with lower mortality (≥median versus P P CONCLUSIONS: Nationwide assessment of therapeutic optimization in heart failure with reduced ejection fraction using the HFC score was feasible and the score was strongly and independently associated with survival.

Background Current treatment of fluid retention in heart failure (HF) relies primarily on diuretics. However, adequate decongestion is not achieved in many patients. Purpose To study the feasibility and short-term performance of a novel approach to remove fluids and sodium directly from the interstitial compartment by enhancing sweat rate. Methods We used a device designed to enhance fluid and salt loss via the eccrine sweat glands. Skin temperature in the lower body was increased to 35–38°, where the slope of the relationship between temperature and sweat production is linear. With this wearable device, the sweat evaporates instantaneously, thus avoiding the awareness of perspiration. The primary efficacy endpoint was the ability to increase skin temperature to the desired range without elevating the core temperature above normal range. A secondary efficacy endpoint was a clinically meaningful hourly sweat output, defined as ≥150 mL/h. The primary safety endpoint was any procedure-related adverse events. Results We studied 6 normal subjects and 10 HF patients with clinical evidence of congestion and median NT-proBNP of 602 pg/mL [interquartile range 427 to 1719 pg/mL]. Participants underwent 3 treatment sessions of up to 4h. Skin temperature increased to a median of 37.5°C (interquartile range 37.1–37.9°C) with the core temperature remaining unchanged. The median total weight loss during treatment was 219±67 g/h (Figure) with a range of 100–338 g/h. In 77% of cases, the average sweat rate was ≥150 mL/h. Systolic (P=0.25) and diastolic (P=0.48) blood pressure and heart rate (P=0.11) remained unchanged during the procedure. There were no significant changes in renal function and no procedure-related adverse events. Conclusion Enhancing sweat rate was safe and resulted in a clinically meaningful fluid removal and weight loss. Further evaluation of this concept is warranted. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): AquaPass Inc Weight loss due to sweat

Aims The impact of mitral valve geometry on outcomes after MitraClip treatment in secondary mitral regurgitation (MR) has not been examined. We therefore sought to evaluate the association between mitral valve geometry and outcomes of patients with heart failure (HF) and secondary MR treated with guideline-directed medical therapy (GDMT) and MitraClip. Methods and results Mitral valve geometry was assessed from the baseline echocardiograms in 614 patients from the COAPT trial. The primary endpoint for the present study was the composite of all-cause mortality or HF hospitalization (HFH) within 2 years. Effect of treatment arm (MitraClip plus maximally tolerated GDMT vs. GDMT alone) on outcomes according to baseline variables was assessed. Among 29 baseline mitral valve echocardiographic parameters, increasing anteroposterior mitral annular diameter was the only independent predictor of the composite endpoint of all-cause mortality or HFH [adjusted hazard ratio (aHR) per cm 1.49; P = 0.04]. The effective regurgitant orifice area (EROA) was independently associated with all-cause mortality alone (aHR per cm2 2.97; P = 0.04) but not with HFH, whereas increasing anteroposterior mitral annular diameter was independently associated with HFH alone (aHR per cm 1.85; P = 0.005) but not all-cause mortality. Other mitral valve morphologic parameters were unrelated to outcomes. MitraClip reduced HFH and mortality independent of anteroposterior mitral annular diameter and EROA (Pinteraction = 0.77 and 0.27, respectively). Conclusion In patients with HF and severe secondary MR, a large anteroposterior mitral annular diameter and greater EROA were the strongest echocardiographic predictors of HFH and death in patients treated with GDMT alone and with the MitraClip.

Cardiac resynchronization therapy is a well-established treatment of heart failure with reduced left ventricular ejection fraction and a wide QRS complex. Cardiac contractility modulation therapy is an emerging electrical treatment indicated for use in patients with symptomatic heart failure caused by moderate-to-severe systolic left ventricular dysfunction (left ventricular ejection fraction ranging from 25% to 45%), with no indication for cardiac resynchronization therapy. Cardiac contractility modulation therapy improves functional status, exercise capacity, quality of life, and possibly prevents hospital admissions in indicated patients. An algorithm for patient selection for these two forms of electrical therapy for heart failure is presented.

Objectives The aim of this study was to determine the prognostic impact of right ventricular (RV)–pulmonary arterial (PA) coupling in patients with heart failure (HF) with severe secondary mitral regurgitation (SMR) enrolled in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial. Background RV contractile function and PA pressures influence outcomes in patients with SMR, but the impact of RV-PA coupling in patients randomized to transcatheter edge-to-edge repair (TEER) vs guideline-directed medical therapy (GDMT) is unknown. Methods RV-PA coupling was assessed by the ratio of RV free wall longitudinal strain derived from speckle-tracking echocardiography and noninvasively measured RV systolic pressure. Advanced RV-PA uncoupling was defined as RV free wall longitudinal strain/RV systolic pressure ≤0.5%/mm Hg. The primary endpoint was a composite of all-cause mortality or HF hospitalization at 24-month follow-up. Results A total of 372 patients underwent speckle-tracking echocardiography, and 70.2% had advanced RV-PA uncoupling. By multivariable analysis, advanced RV-PA uncoupling was strongly associated with an increased risk for the primary 24-month endpoint of death or HF hospitalization (HR: 1.87; 95% CI: 1.31-2.66; P = 0.0005). A similar association was present for all-cause mortality alone (HR: 2.57; 95% CI: 1.54-4.29; P = 0.0003). The impact of RV-PA uncoupling was consistent in patients randomized to TEER and GDMT alone. Compared with GDMT alone, the addition of TEER improved 2-year outcomes in patients with (48.0% vs 74.8%; HR: 0.51; 95% CI: 0.37-0.71) and those without (28.8% vs 47.8%; HR: 0.51; 95% CI: 0.27-0.97) advanced RV-PA uncoupling (Pinteraction = 0.98). Conclusions In the COAPT trial, advanced RV dysfunction assessed by RV-PA uncoupling was a powerful predictor of 2-year adverse outcomes in patients with HF and SMR. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial]; NCT01626079 )

Objectives This study sought to understand the extent to which health status and exercise capacity are independently associated with long-term outcomes in patients with heart failure (HF) and secondary mitral regurgitation (MR). Background Secondary MR in patients with HF leads to impaired health status (Kansas City Cardiomyopathy Questionnaire Overall Summary Score [KCCQ-OS]) and exercise capacity (6-minute walk distance [6MWD]), both of which improve after transcatheter mitral valve repair (TMVr). Methods The study used data from the COAPT trial (N = 604) to examine the association of baseline KCCQ-OS and 6MWD with 2-year mortality and HF hospitalization, adjusting for treatment arm and patient factors. We also examined the association of change in KCCQ-OS and 6MWD from baseline to 1 month with risk of outcomes from 1 month to 2 years. Interactions of KCCQ-OS and 6MWD with treatment assignment were explored. Results Mean baseline KCCQ-OS was 53 ± 23 points, and 6MWD was 240 ± 125 meters. In models including both measures, greater baseline 6MWD (but not KCCQ-OS) was associated with reduced 2-year mortality (HR per 125 meters: 0.75, 95% CI: 0.61-0.92). When stratified by treatment group, both baseline KCCQ-OS and 6MWD were independently associated with HF hospitalization in patients treated with medical therapy, whereas only KCCQ-OS was associated with HF hospitalization in patients treated with TMVr. In separate analyses, 1-month improvements in KCCQ-OS and 6MWD were each associated with lower subsequent risk of mortality and HF hospitalization, independent of treatment group. Conclusions Among patients with HF and severe secondary MR, assessment of both health status and exercise capacity provide complementary prognostic information for patients with HF and severe secondary MR—both before and after TMVr. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial]; NCT01626079 )

Despite significant advances in drug‐based and device‐based therapies, heart failure remains a major and growing public health problem associated with substantial disability, frequent hospitalizations, and high economic costs. Keeping patients well and out of the hospital has become a major focus of heart failure disease management. Achieving and maintaining such stability in heart failure patients requires a holistic approach, which includes at least the management of the underlying heart disease, the management of comorbidities and the social and psychological aspects of the disease, and the management of haemodynamic/fluid status. In this regard, accurate assessment of elevated ventricular filling pressures or volume overload, that is, haemodynamic or pulmonary congestion, respectively, before the onset of worsening heart failure symptoms represents an important management strategy. Unfortunately, conventional methods for assessing congestion, such as physical examination and monitoring of symptoms and daily weights, are insensitive markers of worsening heart failure. Assessment tools that directly measure congestion, accurately and in absolute terms, provide more actionable information that enables the application of treatment algorithms designed to restore patient stability, in a variety of clinical settings. Two such assessment tools, implantable haemodynamic monitors and remote dielectric sensing (ReDS), meet the prerequisites for useful heart failure management tools, by providing accurate, absolute, and actionable measures of congestion, to guide patient management. This review focuses on the use of such technologies, across the spectrum of heart failure treatment settings. Clinical data are presented that support the broad use of pulmonary artery pressure‐guided and/or ReDS‐guided heart failure management in heart failure patients with reduced and preserved left ventricular ejection fraction.

Background : N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma concentrations are independent prognostic markers in patients with heart failure and reduced ejection fraction (HFrEF). Whether a differential risk association between NT-proBNP plasma concentrations and risk of cardiovascular (CV) vs non-CV adverse events exists is not well known. Objective : To assess if there is a differential proportional risk of CV vs non-CV adverse events by NT-proBNP plasma concentrations. Methods : In this post hoc combined analysis of PARADIGM-HF and ATMOSPHERE trials, proportion of CV vs non-CV mortality and hospitalizations were assessed by NT-proBNP levels ( 3000 pg/mL) at baseline using Cox regression adjusting for traditional risk factors. Results : A total of 14,737 patients with mean age of 62 ± 8 years (24% history of atrial fibrillation [AF]) were studied. For CV deaths, the event rates per 1000 patient-years steeply increased from 33.8 in the ≤400 pg/mL group to 142.3 in the ≥3000 pg/mL group, while the non-CV death event rates modestly increased from 9.0 to 22.7, respectively. Proportion of non-CV deaths decreased across the 5 NT-proBNP groups (21.1%, 18.4%, 17.9%, 17.4%, and 13.7% respectively). Similar trend was observed for non-CV hospitalizations (46.4%, 42.6%, 42.9%, 42.0%, and 36.9% respectively). These results remained similar when stratified according to the presence of AF at baseline and prior HF hospitalization within last 12 months. Conclusions : The absolute CV event rates per patient years of follow-up were greater and had higher stepwise increases than non-CV event rates across a broad range of NT-proBNP plasma concentrations indicating a differential risk of CV events at varying baseline NT-proBNP values. These results have implications for future design of clinical trials.

Background In the COAPT trial, transcatheter mitral valve repair with the MitraClip plus maximally tolerated guideline-directed medical therapy (GDMT) improved clinical outcomes compared with GDMT alone in symptomatic patients with heart failure (HF) and 3+ or 4+ secondary mitral regurgitation (SMR) due to left ventricular (LV) dysfunction. Aims In this COAPT substudy, we sought to evaluate two-year outcomes in HF patients with reduced LV ejection fraction (HFrEF; LVEF ≤40%) versus preserved LVEF (HFpEF; LVEF >40%) and in those with severe (LVEF ≤30%) versus moderate (LVEF >30%) LV dysfunction. Methods The principal effectiveness outcome was the two-year rate of death from any cause or HF hospitalisations (HFH). Subgroup analysis with interaction testing was performed according to baseline LVEF; 472 patients (82.1%) had HFrEF (mean LVEF 28.0%±6.2%; range 12% to 40%) and 103 (17.9%) had HFpEF (mean LVEF 46.6%±4.9%; range 41% to 65%), while 292 (50.7%) had severely depressed LVEF (LVEF ≤30%; mean LVEF 23.9%±3.8%) and 283 (49.3%) had moderately depressed LVEF (LVEF >30%; mean LVEF 39.0%±6.8%). Results The two-year rate of death or HFH was 56.7% in patients with HFrEF and 53.4% with HFpEF (HR 1.16, 95% CI: 0.86-1.57, p=0.32). MitraClip reduced the two-year rate of death or HFH in patients with HFrEF (HR 0.50, 95% CI: 0.39-0.65) and HFpEF (HR 0.60, 95% CI: 0.35-1.05), pint=0.55. MitraClip was consistently effective in reducing the individual endpoints of mortality and HFH, improving MR severity, quality of life, and six-minute walk distance in patients with HFrEF, HFpEF, LVEF ≤30%, and LVEF >30%. Conclusions In the COAPT trial, among patients with HF and 3+ or 4+ SMR who remained symptomatic despite maximally tolerated GDMT, the MitraClip was consistently effective in improving survival and health status in patients with severe and moderate LV dysfunction and those with preserved LVEF.

Background Sudden death (SD) and pump failure death (PFD) are the two leading causes of death in patients with heart failure and reduced ejection fraction (HFrEF). Objective Identifying patients at higher risk for mode-specific death would allow better targeting of individual patients for relevant device and other therapies. Methods We developed models in 7156 patients with HFrEF from the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, using Fine-Gray regressions counting other deaths as competing risks. The derived models were externally validated in the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure (ATMOSPHERE) trial. Results NYHA class and NT-proBNP were independent predictors for both modes of death. The SD model additionally included male sex, Asian or Black race, prior CABG or PCI, cancer history, MI history, treatment with LCZ696 vs. enalapril, QRS duration and ECG left ventricular hypertrophy. While LVEF, ischemic etiology, systolic blood pressure, HF duration, ECG bundle branch block, and serum albumin, chloride and creatinine were included in the PFD model. Model discrimination was good for SD and excellent for PFD with Harrell’s C of 0.67 and 0.78 after correction for optimism, respectively. The observed and predicted incidences were similar in each quartile of risk scores at 3 years in each model. The performance of both models remained robust in ATMOSPHERE. Conclusion We developed and validated models which separately predict SD and PFD in patients with HFrEF. These models may help clinicians and patients consider therapies targeted at these modes of death. Trial registration number PARADIGM-HF: ClinicalTrials.gov NCT01035255, ATMOSPHERE: ClinicalTrials.gov NCT00853658. Graphics abstract

BackgroundSystematically characterizing associations between circulating proteins and risk for subsequent clinical events may improve clinical risk prediction and shed light on unrecognized biological pathways in heart failure (HF). Large-scale assays measuring thousands of proteins now enable broad proteomic investigation in clinical trials.MethodsSerum levels of 4076 proteins were measured at baseline in the ATMOSPHERE (n=1258, 487 events over 6 years) and PARADIGM-HF (n=1257, 287 events over 4 years) trials of chronic HF with reduced ejection fraction using a modified aptamer-based proteomics assay. Proteins associated with the primary endpoint of HF hospitalization or cardiovascular death were identified in the ATMOSPHERE discovery cohort by Cox regression adjusted for age, sex, treatment arm, and anticoagulant use (false discovery rateResultsWe identified 377 serum proteins that were associated with the primary endpoint in ATMOSPHERE and replicated 167 in PARADIGM-HF. Prognostic proteins included known HF biomarkers such as Growth Differentiation Factor 15, NT-BNP, and Angiopoietin-2, and also a previously unrecognized HF biomarker: Sushi, Von Willebrand Factor Type A, EGF and Pentraxin Domain Containing 1 (SVEP1, HR 1.60 [95% CI 1.44-1.79] per standard deviation [SD], p=2×10−17). A 64-protein risk score derived in ATMOSPHERE predicted the primary endpoint in PARADIGM-HF with greater discrimination (C-statistic 0.70) than the MAGGIC clinical score (C-statistic 0.61), NT-proBNP (C-statistic 0.65), or both (C-statistic 0.66). Genetically controlled levels of BNP, WISP2, FSTL1, and CTSS were associated with the primary endpoint by Mendelian randomization.ConclusionsWe identified SVEP1, an extracellular matrix protein known to cause inflammation in vascular smooth muscle cells, as a new HF biomarker associated with risk of hospitalization or death. A 64-protein score improved risk discrimination compared with NT-proBNP and may assist in identifying high-risk patients.

Aims Patients with heart failure with reduced ejection fraction (HFrEF) are at significant risk of stroke. Anticoagulation reduces this risk in patients with and without atrial fibrillation (AF), but the risk-to-benefit balance in the latter group, overall, is not favourable. Identification of patients with HFrEF, without AF, at the highest risk of stroke may allow targeted and safer use of prophylactic anticoagulant therapy. Methods and results In a pooled patient-level cohort of the PARADIGM-HF, ATMOSPHERE, and DAPA-HF trials, a previously derived simple risk model for stroke, consisting of three variables (history of prior stroke, insulin-treated diabetes, and plasma N-terminal pro-B-type natriuretic peptide level), was validated. Of the 20 159 patients included, 12 751 patients did not have AF at baseline. Among patients without AF, 346 (2.7%) experienced a stroke over a median follow up of 2.0 years (rate 11.7 per 1000 patient-years). The risk for stroke increased with increasing risk score: fourth quintile hazard ratio (HR) 2.35 [95% confidence interval (CI) 1.60–3.45]; fifth quintile HR 3.73 (95% CI 2.58–5.38), with the first quintile as reference. For patients in the top quintile, the rate of stroke was 21.2 per 1000 patient-years, similar to participants with AF not receiving anticoagulation (20.1 per 1000 patient-years). Model discrimination was good with a C-index of 0.84 (0.75–0.91). Conclusion It is possible to identify a subset of HFrEF patients without AF with a stroke-risk equivalent to that of patients with AF who are not anticoagulated. In these patients, the risk-to-benefit balance might justify the use of prophylactic anticoagulation, but this hypothesis needs to be tested prospectively.

Aims This study aimed to assess the ability of a voice analysis application to discriminate between wet and dry states in chronic heart failure (CHF) patients undergoing regular scheduled haemodialysis treatment due to volume overload as a result of their chronic renal failure. Methods and results In this single‐centre, observational study, five patients with CHF, peripheral oedema of ≥2, and pulmonary congestion‐related dyspnoea, undergoing haemodialysis three times per week, recorded five sentences into a standard smartphone/tablet before and after haemodialysis. Recordings were provided that same noon/early evening and the next morning and evening. Patient weight was measured at the hospital before and after each haemodialysis session. Recordings were analysed by a smartphone application (app) algorithm, to compare speech measures (SMs) of utterances collected over time. On average, patients provided recordings throughout 25.8 ± 3.9 dialysis treatment cycles, resulting in a total of 472 recordings. Weight changes of 1.95 ± 0.64 kg were documented during cycles. Median baseline SM prior to dialysis was 0.87 ± 0.17, and rose to 1.07 ± 0.15 following the end of the dialysis session, at noon (P = 0.0355), and remained at a similar level until the following morning (P = 0.007). By the evening of the day following dialysis, SMs returned to baseline levels (0.88 ± 0.19). Changes in patient weight immediately after dialysis positively correlated with SM changes, with the strongest correlation measured the evening of the dialysis day [slope: −0.40 ± 0.15 (95% confidence interval: −0.71 to −0.10), P = 0.0096]. Conclusions The fluid‐controlled haemodialysis model demonstrated the ability of the app algorithm to identify cyclic changes in SMs, which reflected bodily fluid levels. The voice analysis platform bears considerable potential as a harbinger of impending fluid overload in a range of clinical scenarios, which will enhance monitoring and triage efforts, ultimately optimizing remote CHF management.

Objectives The authors sought to evaluate the association between mean mitral valve gradient (MVG) and clinical outcomes among patients who underwent MitraClip treatment for secondary mitral regurgitation (SMR) in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial. Background In the COAPT trial, patients with heart failure (HF) and severe SMR who remained symptomatic despite guideline-directed medical therapy had marked 2-year reductions in mortality and HF hospitalizations after treatment with MitraClip. Methods MitraClip-treated patients were divided into quartiles (Q) based on discharge echocardiographic MVG (n = 250). Endpoints including all-cause mortality, HF hospitalization, and health status measures at 2 years were compared between quartiles. Results Mean MVG after MitraClip was 2.1 ± 0.4 mm Hg, 3.0 ± 0.2 mm Hg, 4.2 ± 0.5 mm Hg, and 7.2 ± 2.0 mm Hg in Q1 (n = 63), Q2 (n = 61), Q3 (n = 62), and Q4 (n = 64), respectively. There was no difference across quartiles in the 2-year composite endpoint of all-cause mortality or HF hospitalization (43.2%, 49.2%, 40.6%, and 40.9%, respectively; p = 0.80), nor in improvements in New York Heart Association functional class, Kansas City Cardiomyopathy Questionnaire score, or 6-min walk time. Results were similar after adjustment for baseline clinical and echocardiographic characteristics, post-procedure MR grade, and number of clips (all-cause mortality or HF hospitalization Q4 [44.6%] vs. Q1 to Q3 [40.3%]; adjusted hazard ratio: 1.23, 95% confidence interval: 0.60 to 2.51; p = 0.57). Conclusions Among HF patients with severe SMR, higher MVGs on discharge did not adversely affect clinical outcomes following MitraClip. These findings suggest that in select patients with HF and SMR otherwise meeting the COAPT inclusion criteria, the benefits of MR reduction may outweigh the effects of mild-to-moderate mitral stenosis after MitraClip.

In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial, transcatheter mitral valve repair (TMVr) resulted in fewer heart failure hospitalizations (HFHs) and lower mortality at 24 months in patients with heart failure (HF) with mitral regurgitation (MR) secondary to left ventricular dysfunction compared with guideline-directed medical therapy (GDMT) alone.This study determined if these benefits persisted to 36 months and if control subjects who were allowed to cross over at 24 months derived similar benefit.This study randomized 614 patients with HF with moderate-to-severe or severe secondary MR, who remained symptomatic despite maximally tolerated GDMT, to TMVr plus GDMT versus GDMT alone. The primary effectiveness endpoint was all HFHs through 24-month follow-up. Patients have now been followed for 36 months.The annualized rates of HFHs per patient-year were 35.5% with TMVr and 68.8% with GDMT alone (hazard ratio [HR]: 0.49; 95% confidence interval [CI]: 0.37 to 0.63; p 0.001; number needed to treat (NNT) = 3.0; 95% CI: 2.4 to 4.0). Mortality occurred in 42.8% of the device group versus 55.5% of control group (HR: 0.67; 95% CI: 0.52 to 0.85; p = 0.001; NNT = 7.9; 95% CI: 4.6 to 26.1). Patients who underwent TMVr also had sustained 3-year improvements in MR severity, quality-of-life measures, and functional capacity. Among 58 patients assigned to GDMT alone who crossed over and were treated with TMVr, the subsequent composite rate of mortality or HFH was reduced compared with those who continued on GDMT alone (adjusted HR: 0.43; 95% CI: 0.24 to 0.78; p = 0.006).Among patients with HF and moderate-to-severe or severe secondary MR who remained symptomatic despite GDMT, TMVr was safe, provided a durable reduction in MR, reduced the rate of HFH, and improved survival, quality of life, and functional capacity compared with GDMT alone through 36 months. Surviving patients who crossed over to device treatment had a prognosis comparable to those originally assigned to transcatheter therapy. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation [COAPT]; NCT01626079).