Journal: JACC Heart Fail

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<div><h4>The End of Endomyocardial Biopsy?: A Practical Guide for Noninvasive Heart Transplant Rejection Surveillance.</h4><i>Holzhauser L, DeFilippis EM, Nikolova A, Byku M, ... Khush KK, Vest AR</i><br /><AbstractText>Noninvasive heart transplant rejection surveillance using gene expression profiling (GEP) to monitor immune activation is widely used among heart transplant programs. With the new development of donor-derived cell-free DNA (dd-cfDNA) assays, more programs are transitioning to a predominantly noninvasive rejection surveillance protocol with a reduced frequency of endomyocardial biopsies. As a result, many practical questions arise that potentially delay implementation of these valuable new tools. The purpose of this review is to provide practical guidance for clinicians transitioning toward a less invasive acute rejection monitoring protocol after heart transplantation, and to answer 10 common questions about the GEP and dd-cfDNA assays. Evidence supporting GEP and dd-cfDNA testing is reviewed, as well as guidance on test interpretation and future directions.</AbstractText><br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 11 Jan 2023; epub ahead of print</small></div>
Holzhauser L, DeFilippis EM, Nikolova A, Byku M, ... Khush KK, Vest AR
JACC Heart Fail: 11 Jan 2023; epub ahead of print | PMID: 36682960
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<div><h4>Blood Pressure and Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: DELIVER.</h4><i>Selvaraj S, Vaduganathan M, Claggett BL, Miao ZM, ... McMurray JJV, Solomon SD</i><br /><b>Background</b><br />Optimizing systolic blood pressure (SBP) in heart failure (HF) with preserved ejection fraction carries a Class I recommendation but with limited evidence. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have antihypertensive effects across cardiovascular disease.<br /><b>Objectives</b><br />The authors examined the interplay between SBP and treatment effects of dapagliflozin on SBP and cardiovascular outcomes.<br /><b>Methods</b><br />The authors analyzed 6,263 DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) participants and related baseline and mean achieved SBP categories (<120, 120-129, 130-139, ≥140 mm Hg) to the primary outcome (cardiovascular death or worsening HF), secondary outcomes, and safety events. They analyzed whether the blood pressure-lowering effects of dapagliflozin accounted for its treatment effects by adjusting for the change in SBP from baseline to 1 month.<br /><b>Results</b><br />The average age was 72 ± 10 years and 44% were women. SBP <120 mm Hg was associated with higher HF and mortality events, although amputation and stroke risk increased with higher SBP. Dapagliflozin reduced SBP by 1.8 (95% CI: 1.1-2.5) mm Hg compared with placebo at 1 month. The treatment effect of dapagliflozin on the primary outcome and Kansas City Cardiomyopathy Questionnaire total symptom score was consistent across SBP (interaction P = 0.15 and P = 0.98, respectively). Adverse events between arms were similar across SBP categories. The treatment effect was not accounted for by reducing blood pressure.<br /><b>Conclusions</b><br />In DELIVER, risk by SBP was augmented in the lowest and highest categories and varied by endpoint examined. Dapagliflozin modestly decreased SBP compared with placebo. Dapagliflozin was similarly efficacious and safe across the range of baseline SBP. The beneficial effects of dapagliflozin were not accounted for the changes in SBP. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).<br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jan 2023; 11:76-89</small></div>
Selvaraj S, Vaduganathan M, Claggett BL, Miao ZM, ... McMurray JJV, Solomon SD
JACC Heart Fail: 01 Jan 2023; 11:76-89 | PMID: 36599553
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<div><h4>Race and Socioeconomic Bias in Pediatric Cardiac Transplantation.</h4><i>Amdani S, Conway J, Kleinmahon J, Auerbach S, ... Kirklin JK, Asante-Korang A</i><br /><b>Background</b><br />To date, no studies evaluated implicit bias among clinicians caring for children with advanced heart failure.<br /><b>Objectives</b><br />This study aims to evaluate implicit racial and socioeconomic bias among pediatric heart transplant clinicians.<br /><b>Methods</b><br />A cross-sectional survey of transplant clinicians from the Pediatric Heart Transplant Society was conducted between June and August 2021. The survey consisted of demographic questions along with explicit and validated race and socioeconomic status (SES) implicit association tests (IATs). Implicit and explicit biases among survey group members were studied and associations were tested between implicit and explicit measures.<br /><b>Results</b><br />Of 500 members, 91 (18.2%) individuals completed the race IAT and 70 (14%) completed the SES IAT. Race IAT scores indicated moderate levels of implicit bias (mean = 0.33, d = 0.76; P < 0.001; ie, preference for White individuals). SES IAT scores indicated strong implicit bias (mean = 0.52, d = 1.53; P < 0.001; ie, preference for people from upper SES). There were weak levels of explicit race and wealth bias. There was a strong level of explicit education bias (mean = 5.22, d = 1.19; P < 0.001; ie, preference for educated people). There were nonsignificant correlations between the race and the SES IAT and explicit measures (P > 0.05 for all).<br /><b>Conclusions</b><br />As observed across other health care disciplines, among a group of pediatric heart transplant clinicians, there is an implicit preference for individuals who are White and from higher SES, and an explicit preference for educated people. Future studies should evaluate how implicit biases affect clinician behavior and assess the impact of efforts to reduce such biases.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jan 2023; 11:19-26</small></div>
Amdani S, Conway J, Kleinmahon J, Auerbach S, ... Kirklin JK, Asante-Korang A
JACC Heart Fail: 01 Jan 2023; 11:19-26 | PMID: 36599545
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<div><h4>Comparison of Demographic, Clinical, Biochemical, and Imaging Findings in Hypertrophic Cardiomyopathy Prognosis: A Network Meta-Analysis.</h4><i>Georgiopoulos G, Figliozzi S, Pateras K, Nicoli F, ... Masci PG, Olivotto I</i><br /><b>Background</b><br />Despite hypertrophic cardiomyopathy (HCM) being the most common inherited heart disease and conferring increased risk for heart failure (HF) and sudden cardiac death (SCD), risk assessment in HCM patients is still largely unresolved.<br /><b>Objectives</b><br />This study aims to synthesize and compare the prognostic impact of demographic, clinical, biochemical, and imaging findings in patients with HCM.<br /><b>Methods</b><br />The authors searched PubMed, Embase, and Cochrane Library for studies published from 1955 to November 2020, and the endpoints were: 1) all-cause death; 2) an arrhythmic endpoint including SCD, sustained ventricular tachycardia, ventricular fibrillation, or aborted SCD; and 3) a composite endpoint including (1) or (2) plus hospitalization for HF or cardiac transplantation. The authors performed a pairwise meta-analysis obtaining the pooled estimate separately for the association between baseline variables and study endpoints. A random-effects network meta-analysis was subsequently used to comparatively assess the prognostic value of outcome associates.<br /><b>Results</b><br />A total of 112 studies with 58,732 HCM patients were included. Among others, increased brain natriuretic peptide/N-terminal pro-B-type natriuretic peptide, late gadolinium enhancement (LGE), positive genotype, impaired global longitudinal strain, and presence of apical aneurysm conferred increased risk for the composite endpoint. At network meta-analysis, LGE showed the highest prognostic value for all endpoints and was superior to all other associates except New York Heart Association functional class >class II. A multiparametric imaging-based model was superior in predicting the composite endpoint compared to a prespecified model based on conventional risk factors.<br /><b>Conclusions</b><br />This network meta-analysis supports the development of multiparametric risk prediction algorithms, including advanced imaging markers additively to conventional risk factors, for refined risk stratification in HCM. (Long-term prognosis of hypertrophic cardiomyopathy according to genetic, clinical, biochemical and imaging findings: a systemic review and meta-analysis; CRD42020185219).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jan 2023; 11:30-41</small></div>
Georgiopoulos G, Figliozzi S, Pateras K, Nicoli F, ... Masci PG, Olivotto I
JACC Heart Fail: 01 Jan 2023; 11:30-41 | PMID: 36599547
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<div><h4>Prediction of Left Ventricular Ejection Fraction Change Following Treatment With Sacubitril/Valsartan.</h4><i>Mohebi R, Liu Y, Felker GM, Prescott MF, ... Solomon SD, Januzzi JL</i><br /><b>Background</b><br />Sacubitril/valsartan (Sac/Val) improves left ventricular ejection fraction (LVEF) in heart failure (HF) with reduced ejection fraction regardless of previous treatments. Improvements in LVEF may change eligibility for primary implantable cardioverter-defibrillator (ICD) placement. Awaiting LVEF improvement may expose patients to potential risks for arrhythmic complications.<br /><b>Objectives</b><br />The authors sought to develop a model predicting LVEF change after Sac/Val therapy.<br /><b>Methods</b><br />A total of 416 persons with HF and LVEF of <35% were included in this analysis. Following initiation of Sac/Val, echocardiographic parameters were measured serially for 1 year. A machine learning algorithm was implemented to develop a risk model for predicting the persistence of LVEF of <35% after 1 year and was validated in a separate group of study participants.<br /><b>Results</b><br />Baseline LVEF, left ventricular mass index, HF duration, age, N-terminal pro-B-type natriuretic peptide concentration at baseline and change by day 14, and body mass index were the most significant factors for identifying lack of LVEF improvement to ≥35% after 1 year. In the training and validation cohorts, the areas under the model curve for predicting lack of LVEF improvement were 0.92 and 0.86, respectively. Three categories of likelihood for LVEF of <35% after 1 year of Sac/Val treatment were developed based on the model predictions: 3.8%, 30.1%, and 83.7%. During follow-up, arrhythmia event rates were 0.9%, 2.9%, and 6.7% in these groups, respectively.<br /><b>Conclusions</b><br />Many persons with HF with reduced ejection fraction eligible for ICD insertion experience an increase in LVEF to ≥35% after treatment with Sac/Val. Early identification of those less likely to improve their LVEF might allow for more refined selection of primary ICD candidates. (Effects of Sacubitril/Valsartan Therapy on biomarkers, Myocardial Remodeling, and Outcomes [PROVE-HF]; NCT02887183).<br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jan 2023; 11:44-54</small></div>
Mohebi R, Liu Y, Felker GM, Prescott MF, ... Solomon SD, Januzzi JL
JACC Heart Fail: 01 Jan 2023; 11:44-54 | PMID: 36599549
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<div><h4>Prediction of Left Ventricular Reverse Remodeling and Outcomes by Circulating Collagen-Derived Peptides.</h4><i>Ravassa S, Lupón J, López B, Codina P, ... Bayés-Genís A, González A</i><br /><b>Background</b><br />Myocardial fibrosis may increase vulnerability to poor prognosis in patients with heart failure (HF), even in those patients exhibiting left ventricular reverse remodeling (LVRR) after guideline-based therapies.<br /><b>Objectives</b><br />This study sought to characterize fibrosis at baseline in patients with HF with left ventricular ejection fraction (LVEF) <50% by determining serum collagen type I-derived peptides (procollagen type I C-terminal propeptide [PICP] and ratio of collagen type I C-terminal telopeptide to matrix metalloproteinase-1) and to evaluate their association with LVRR and prognosis.<br /><b>Methods</b><br />Peptides were determined in 1,034 patients with HF at baseline. One-year echocardiography was available in 665 patients. Associations of peptides with 1-year changes in echocardiographic variables were analyzed by multivariable linear mixed models. LVEF was considered improved if it increased by ≥15% or to ≥50% or if it increased by ≥10% to >40% in patients with LVEF ≤40%. Cardiovascular death and HF-related outcomes were analyzed in all patients randomized to derivation (n = 648) and validation (n = 386) cohorts.<br /><b>Results</b><br />Continuous associations with echocardiographic changes were observed only for PICP. Compared with high-PICP (≥108.1 ng/mL) patients, low-PICP (<108.1 ng/mL) patients exhibited enhanced LVRR and a lower risk of HF-related outcomes (P ≤ 0.018), with women and nonischemic patients with HF showing a stronger LVEF increase (interaction P ≤ 0.010). LVEF increase was associated with a better prognosis, particularly in low-PICP patients (interaction P ≤ 0.029). Only patients with both low PICP and improved LVEF exhibited a better clinical evolution than patients with nonimproved LVEF (P < 0.001).<br /><b>Conclusions</b><br />Phenotyping with PICP, a peptide associated with myocardial fibrosis, may be useful to differentiate patients with HF who are more likely to experience clinical myocardial recovery from those with partial myocardial improvement.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jan 2023; 11:58-72</small></div>
Ravassa S, Lupón J, López B, Codina P, ... Bayés-Genís A, González A
JACC Heart Fail: 01 Jan 2023; 11:58-72 | PMID: 36599551
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<div><h4>Negative Predictive Value and Prognostic Associations of Rb-82 PET/CT with Myocardial Blood Flow in CAV.</h4><i>Abadie BQ, Chan N, Sharalaya Z, Bhat P, ... Cremer PC, Jaber WA</i><br /><b>Background</b><br />Invasive coronary angiography (ICA) is the traditional screening modality for cardiac allograft vasculopathy (CAV). Positron emission tomography/computed tomography (PET/CT) scan with myocardial blood flow (MBF) quantification has emerged as a potential noninvasive alternative.<br /><b>Objectives</b><br />The aim of the study was to validate the diagnostic and prognostic value of a previously published algorithm for diagnosing CAV via PET/CT scans with MBF in a larger population. The study also sought to assess the downstream use of ICA when using PET/CT scanning as a screening modality.<br /><b>Methods</b><br />Patients with heart transplantation without prior revascularization who underwent PET/CT scans with MBF were identified retrospectively. The accuracy of the algorithm was assessed in patients who underwent PET/CT scanning within 1 year of ICA. The prognostic value was assessed via a composite outcome of heart failure hospitalization, myocardial infarction, retransplantation, and all-cause mortality.<br /><b>Results</b><br />A total of 88 patients for the diagnostic portion and 401 patients for the prognostic portion were included. PET CAV 0 had high negative predictive value for moderate to severe CAV (97%) and PET CAV 2/3 had a high positive predictive value for moderate to severe CAV (68%) by ICA. The cohort was followed for a median of 1.2 (IQR: 1.0-1.8) years with 46 patients having an adverse event. The annualized event rates were 6.9%, 9.3%, and 30.8% for PET CAV 0, 1, and 2/3, respectively (P < 0.001).<br /><b>Conclusions</b><br />An algorithm using PET/CT scanning with MBF demonstrates high a negative predictive value for CAV. PET CAV 2/3 is associated with a higher risk of adverse events and need for revascularization. PET/CT scanning with MBF is a reasonable alternative to ICA for screening for CAV.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 20 Dec 2022; epub ahead of print</small></div>
Abadie BQ, Chan N, Sharalaya Z, Bhat P, ... Cremer PC, Jaber WA
JACC Heart Fail: 20 Dec 2022; epub ahead of print | PMID: 36639302
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<div><h4>Functional and Symptomatic Clinical Trial Endpoints: The HFC-ARC Scientific Expert Panel.</h4><i>Psotka MA, Abraham WT, Fiuzat M, Filippatos G, ... Anker SD, O\'Connor CM</i><br /><AbstractText>The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and the Academic Research Consortium (ARC) composed of patients, academic investigators from the United States and Europe, the U.S. Food and Drug Administration, the National Institutes of Health, payers, and industry. Members discussed the measure, remote capture, and clinical utility of functional and quality-of-life endpoints for use in clinical trials of heart failure and cardiovascular therapeutics, with the goal of improving the efficiency of heart failure and cardiovascular clinical research, evidence generation, and thereby patient quality of life, functional status, and survival. Assessments of patient-reported outcomes and maximal and submaximal exercise tolerance are standardized and validated, but actigraphy remains inconsistent as a potential endpoint. This paper details those discussions and consensus recommendations.</AbstractText><br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Dec 2022; 10:889-901</small></div>
Psotka MA, Abraham WT, Fiuzat M, Filippatos G, ... Anker SD, O'Connor CM
JACC Heart Fail: 01 Dec 2022; 10:889-901 | PMID: 36456063
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<div><h4>Hemodynamically-Guided Management of Heart Failure Across the Ejection Fraction Spectrum: The GUIDE-HF Trial.</h4><i>Zile MR, Mehra MR, Ducharme A, Sears SF, ... Costanzo MR, Lindenfeld J</i><br /><b>Background</b><br />Hemodynamically-guided management using an implanted pulmonary artery pressure sensor is indicated to reduce heart failure (HF) hospitalizations in patients with New York Heart Association (NYHA) functional class II-III with a prior HF hospitalization or those with elevated natriuretic peptides.<br /><b>Objectives</b><br />The authors sought to evaluate the effect of left ventricular ejection fraction (EF) on treatment outcomes in the GUIDE-HF (Hemodynamic-GUIDEd management of Heart Failure) randomized trial.<br /><b>Methods</b><br />The GUIDE-HF randomized arm included 1,000 NYHA functional class II-IV patients (with HF hospitalization within the prior 12 months or elevated natriuretic peptides adjusted for EF and body mass index) implanted with a pulmonary artery pressure sensor, randomized 1:1 to a hemodynamically-guided management group (treatment) or a control group (control). The primary endpoint was the composite of HF hospitalizations, urgent HF visits, and all-cause mortality at 12 months. The authors assessed outcomes by EF in guideline-defined subgroups ≤40%, 41%-49%, and ≥50%, within the trial specified pre-COVID-19 period cohort.<br /><b>Results</b><br />There were 177 primary events (0.553/patient-year) in the treatment group and 224 events (0.682/patient-year) in the control group (HR: 0.81 [95% CI: 0.66-1.00]; P = 0.049); HF hospitalization was lower in the treatment vs control group (HR: 0.72 [95% CI: 0.57-0.92]; P = 0.0072). Within each EF subgroup, primary endpoint and HF hospitalization rates were lower in the treatment group (HR <1.0 across the EF spectrum). Event rate reduction by EF in the treatment groups was correlated with reduction in pulmonary artery pressures and medication changes.<br /><b>Conclusions</b><br />Hemodynamically-guided HF management decreases HF-related endpoints across the EF spectrum in an expanded patient population of patients with HF. (Hemodynamic-GUIDEd Management of Heart Failure [GUIDE-HF]; NCT03387813).<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Dec 2022; 10:931-944</small></div>
Zile MR, Mehra MR, Ducharme A, Sears SF, ... Costanzo MR, Lindenfeld J
JACC Heart Fail: 01 Dec 2022; 10:931-944 | PMID: 36456066
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<div><h4>Prediction of Survival After Implantation of a Fully Magnetically Levitated Left Ventricular Assist Device.</h4><i>Mehra MR, Nayak A, Morris AA, Lanfear DE, ... Chuang J, Estep JD</i><br /><b>Background</b><br />Clinical trials inform on average efficacy, but individualized risk assessments for outcome prediction are important in guiding treatment implementation.<br /><b>Objectives</b><br />The authors developed and validated a patient-specific risk score to predict survival at 1 and 2 years after HeartMate 3 (HM3) left ventricular assist device (LVAD) implantation.<br /><b>Methods</b><br />The MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) trial includes 2,200 HM3 LVAD patients in the pivotal trial and Continued Access Protocol study (2014-2018). The authors randomly assigned all patients to a derivation cohort (n = 1,540) or validation cohort (n = 660). Univariate mortality predictors were screened for potential model inclusion, stepwise selection was used to build the multivariable Cox proportional hazards regression model, and performance (discrimination and calibration) was evaluated.<br /><b>Results</b><br />Age, prior cardiac surgery (coronary artery bypass grafting [CABG] or valve procedure), lower serum sodium, higher blood urea nitrogen (BUN), small left ventricular size, and right atrial pressure-to-pulmonary capillary wedge pressure (RAP/PCWP) ratio >0.6 were significant risk factors for mortality. Receiver-operating characteristic (ROC) analysis in the validation cohort demonstrated an area under the curve (AUC) of 0.76 (95% CI: 0.70-0.81) at 1 year and 0.71 (95% CI: 0.66-0.77) at 2 years. Calibration between predicted and observed survival of the risk quintiles was high, with Pearson correlation coefficients of 0.986 and 0.994 at 1 and 2 years, respectively. Patients were successfully stratified into tertiles with higher-than-average, average, and lower-than-average survival, and observed mortality risk increased by 2-fold from one tertile to the next.<br /><b>Conclusions</b><br />A practical, easy-to-use HM3 Survival Risk Score with 6 components was developed to accurately predict 1- and 2-year survival after HM3 LVAD implantation. The survival risk score can be used to provide individual survival estimates to facilitate shared decision making when considering HM3 LVAD therapy. (MOMENTUM 3 Trial Portfolio; NCT02224755, NCT02892955).<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Dec 2022; 10:948-959</small></div>
Mehra MR, Nayak A, Morris AA, Lanfear DE, ... Chuang J, Estep JD
JACC Heart Fail: 01 Dec 2022; 10:948-959 | PMID: 36456068
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<div><h4>Safety of Right and Left Ventricular Endomyocardial Biopsy in Heart Transplantation and Cardiomyopathy Patients.</h4><i>Bermpeis K, Esposito G, Gallinoro E, Paolisso P, ... Bartunek J, Vanderheyden M</i><br /><b>Background</b><br />Endomyocardial biopsy (EMB) facilitates a histopathologic diagnosis with unique prognostic and therapeutic implications in both native and donor hearts. It is a relatively safe procedure, with an overall complication rate ranging from <1% to 6% depending on the experience of the operator, the clinical status of the patient, the presence or absence of left bundle branch block, the access site, and the site of procurement (right ventricular [RV] vs left ventricular [LV] approach).<br /><b>Objectives</b><br />This study aimed to assess the incidence of procedure-related complications in a real-world population. EMBs were performed either for surveillance of rejection episodes after heart transplantation or for diagnosis of etiology of cardiomyopathy.<br /><b>Methods</b><br />The authors retrospectively analyzed 1,368 biopsies obtained in 561 consecutive patients between May 2011 and May 2021. Patients were stratified according to the underlying heart disease, sex, age, access site, body mass index, and RV vs LV approach.<br /><b>Results</b><br />The analysis revealed an overall complication rate of 4.1%. Serious life-threatening cardiac complications occurred in <1% of EMBs, with tamponade necessitating pericardiocentesis in 0.2% and urgent cardiac surgery in 0.1% of the procedures. Minor complications occurred in 3.3% of the overall population and were more often encountered during LV EMBs (3.9%) and when the native heart was sampled (5.3%).<br /><b>Conclusions</b><br />In experienced hands, LV and RV EMB for heart transplantation rejection surveillance and cardiomyopathy diagnosis is a safe procedure with low risk of complications. Older, female patients and those undergoing native heart EMB were more prone to complications following EMB.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Dec 2022; 10:963-973</small></div>
Bermpeis K, Esposito G, Gallinoro E, Paolisso P, ... Bartunek J, Vanderheyden M
JACC Heart Fail: 01 Dec 2022; 10:963-973 | PMID: 36456070
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<div><h4>Age Differences in Effects of Sacubitril/Valsartan on Cardiac Remodeling, Biomarkers, and Health Status.</h4><i>Murphy SP, Ward JH, Piña IL, Felker GM, ... Solomon SD, Januzzi JL</i><br /><b>Background</b><br />Sacubitril/valsartan (Sac/Val) improves outcomes in patients with heart failure with reduced ejection fraction (HFrEF).<br /><b>Objectives</b><br />In this study, the authors sought to explore age differences in effects of Sac/Val on biomarkers, Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores and cardiac remodeling.<br /><b>Methods</b><br />After initiation and titration of Sac/Val, concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-cTnT), and soluble suppressor of tumorigenicity 2 (sST2) were measured and KCCQ-23 scores obtained from baseline to 12 months. Left ventricular ejection fraction (LVEF), and indexed left ventricular end-systolic (LVESVi) and indexed left ventricular end-diastolic (LVEDVi) and left atrial volume index (LAVi) volumes were measured with the use of echocardiography. Safety end points were assessed. Age-stratified analysis was performed for groups aged <65, 65-74, and ≥75 years.<br /><b>Results</b><br />Among 794 participants with HFrEF (mean age 65.1 years, 28.5% women), compared with patients aged <65 years (n = 369), 65-74 years (n = 237), and those aged ≥75 years (n = 188), had similar reductions in hs-cTnT and sST2, but less NT-proBNP reduction (-45.6% vs -40.2% vs -30.5%, respectively; P = 0.02). Gains in KCCQ-23 were smaller (+11.8 vs +11.4 vs +6.0 points; P = 0.03) in patients aged ≥75 years, although similar proportions of each age group achieved ≥10-point and ≥20-point increases in KCCQ-23 by month 12. Improvements in LVEF, LVEDVi, LVESVi, and LAVi were similar among age groups. Incidence of safety end points was also similar.<br /><b>Conclusions</b><br />Sac/Val resulted in significant improvements in prognostic biomarkers and measures of cardiac remodeling and health status from baseline to month 12 across age categories. Older study participants showed somewhat blunted reduction in NT-proBNP and less improvement in KCCQ-23 overall summary scores. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling, and Outcomes [PROVE-HF]; NCT02887183).<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Dec 2022; 10:976-988</small></div>
Murphy SP, Ward JH, Piña IL, Felker GM, ... Solomon SD, Januzzi JL
JACC Heart Fail: 01 Dec 2022; 10:976-988 | PMID: 36456072
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<div><h4>Plasma Amyloid-β in Relation to Cardiac Function and Risk of Heart Failure in General Population.</h4><i>Zhu F, Wolters FJ, Yaqub A, Leening MJG, ... Ikram MA, Kavousi M</i><br /><b>Background</b><br />Amyloid-β (Aβ) may be related to cardiac function. However, there are limited data on the association of plasma Aβ with cardiac function and risk of heart failure (HF) in the general population.<br /><b>Objectives</b><br />This study sought to determine the associations of plasma amyloid-β40 (Aβ40) and amyloid-β42 (Aβ42) with echocardiographic measurements of cardiac dysfunction and with incident HF in the general population.<br /><b>Methods</b><br />The study included 4,156 participants of the population-based Rotterdam Study (mean age: 71.4 years; 57.1% women), who had plasma Aβ samples collected between 2002 and 2005 and had no established dementia and HF at baseline. Multivariable linear regression models were used to explore the cross-sectional association of plasma Aβ with echocardiographic measures. Participants were followed up until December 2016. Cox proportional hazards models were used to assess the association of Aβ levels with incident HF. Models were adjusted for cardiovascular risk factors.<br /><b>Results</b><br />A per 1-SD increase in log-transformed plasma Aβ40 was associated with a 0.39% (95% CI: -0.68 to -0.10) lower left ventricular ejection fraction and a 0.70 g/m<sup>2</sup> (95% CI: 0.06-1.34) larger left ventricular mass indexed by body surface area. Aβ42 was not significantly associated with echocardiographic measures cross-sectionally. During follow-up (median: 10.2 years), 472 incident HF cases were identified. A per 1-SD increase in log-transformed Aβ40 was associated with a 32% greater risk of HF (HR: 1.32; 95% CI: 1.15-1.51), and the association was significant in men, but not in women. Higher plasma Aβ42 levels were associated with an increased risk of HF (HR: 1.12; 95% CI: 1.02-1.24), although the association was attenuated after further adjustment for concomitant Aβ40 (HR: 1.03; 95% CI: 0.92-1.16).<br /><b>Conclusions</b><br />Higher levels of Aβ40 were associated with worse cardiac function and higher risk of new onset HF in the general population, in particular among men.<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 09 Nov 2022; epub ahead of print</small></div>
Zhu F, Wolters FJ, Yaqub A, Leening MJG, ... Ikram MA, Kavousi M
JACC Heart Fail: 09 Nov 2022; epub ahead of print | PMID: 36372727
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<div><h4>Potential Interactions When Prescribing SGLT2 Inhibitors and Intravenous Iron in Combination in Heart Failure.</h4><i>Packer M</i><br /><AbstractText>In patients with heart failure, sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to decrease hepcidin and ferritin and increase transferrin receptor protein, changes that are typically indicative of worsening absolute iron deficiency, as would be seen with poor dietary intake or gastrointestinal bleeding, neither of which is provoked by SGLT2 inhibitors. Therefore, 2 alternative conceptual frameworks may explain the observed pattern of changes in iron homeostasis proteins. According to the \"cytosolic iron depletion hypothesis,\" the effect of SGLT2 inhibitors to decrease hepcidin and ferritin and increase transferrin receptor is related to a decline in cytosolic Fe<sup>2+</sup> that occurs after drug-induced erythropoietin-related increase in iron use. Erythropoietin-mimetics (eg, darbepoietin) elicit this type of iron-deficiency pattern of response, and it is typically accompanied by erythropoietin resistance that is alleviated by intravenous iron supplementation. In contrast, according to the \"cytosolic iron repletion hypothesis,\" the effect of SGLT2 inhibitors to decrease hepcidin and ferritin and increase transferrin receptor represents a direct action of these drugs: 1) to reverse inflammation-related increases in hepcidin and ferritin, and, thus, alleviate functional blocks on iron utilization; and 2) to increase in sirtuin-1 signaling, which suppresses hepcidin, accelerates the degradation of ferritin, and up-regulates transferrin receptor protein. Through either or both mechanisms, direct suppression of hepcidin and ferritin would be expected to increase cytosolic Fe<sup>2+</sup>, thus allowing an unattenuated erythrocytic response to erythropoietin without the need for intravenous iron supplementation. The totality of clinical evidence supports the \"cytosolic iron repletion hypothesis\" because SGLT2 inhibitors elicit a full and sustained erythrocytosis in response to erythropoietin, even in overtly iron-deficient patients and in the absence of intravenous iron therapy. Therefore, the emergence of an iron-deficiency pattern of response during SGLT2 inhibition does not reflect worsening iron stores that are in need of replenishment, but instead, represents potential alleviation of a state of inflammation-related functional iron deficiency that is commonly seen in patients with chronic heart failure. Treatment with intravenous iron may be unnecessary and theoretically deleterious.</AbstractText><br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 05 Nov 2022; epub ahead of print</small></div>
Packer M
JACC Heart Fail: 05 Nov 2022; epub ahead of print | PMID: 36396554
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<div><h4>Retinal Microvasculature: A Potential Window Into Heart Failure Prevention.</h4><i>Chaikijurajai T, Ehlers JP, Tang WHW</i><br /><AbstractText>Endothelial dysfunction and microvascular disease have been shown to play an important role in the development and progression of heart failure (HF). Retinal imaging provides a unique opportunity to noninvasively assess vascular structure and function, vessel features, and microcirculation within the retina. Accumulating evidence suggests that retinal vessel caliber, microvascular features, and vascular characteristics extracted from various imaging modalities are associated with alterations in left ventricular structure and function in stage B HF, as well as incident development of symptomatic HF in the general population. Moreover, dynamic retinal vessel analysis has been shown to differentiate HF patients based on their phenotypes. Given the increasing availability of rapid image acquisition devices (eg, nonmydriatic widefield systems and smartphone-based retinal cameras) and the integration of artificial intelligence-based interrogation/assessment techniques, retinal imaging is a promising noninvasive tool, in conjunction with cardiac imaging and biomarkers, to prevent HF and risk stratify those at risk of developing HF. This review focuses on the current evidence on retinal microvasculature changes, and potential clinical relevance and promising utility of retinal imaging in HF.</AbstractText><br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Nov 2022; 10:785-791</small></div>
Chaikijurajai T, Ehlers JP, Tang WHW
JACC Heart Fail: 01 Nov 2022; 10:785-791 | PMID: 36328644
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<div><h4>Family Screening in Dilated Cardiomyopathy: Prevalence, Incidence, and Potential for Limiting Follow-Up.</h4><i>Vissing CR, Espersen K, Mills HL, Bartels ED, ... Christensen AH, Bundgaard H</i><br /><b>Background</b><br />According to patterns of inheritance and incomplete penetrance, fewer than half of relatives to dilated cardiomyopathy probands will develop disease.<br /><b>Objectives</b><br />The purpose of this study was to investigate the prevalence and incidence, and to identify predictors of developing familial dilated cardiomyopathy (FDC) in relatives participating in family screening.<br /><b>Methods</b><br />The study was a retrospective, longitudinal cohort study of families screened and followed from 2006 to 2020 at a regional assembly of clinics for inherited cardiomyopathies.<br /><b>Results</b><br />In total, 211 families (563 relatives, 50% women) were included. At baseline, 124 relatives (22%) were diagnosed with FDC. Genetic sequencing identified the etiology in 37% of screened families and classified 101 (18%) relatives as unaffected carriers (n = 43) or noncarriers (ie, not at risk of FDC [n = 58]). The combined clinical and genetic baseline yield was 30%. During follow-up (2,313 person-years, median 5.0 years), 45 developed FDC (incidence rate of 2.0% per person-year; 95% CI: 1.4%-2.8%), increasing the overall yield to 34%. The incidence rate of FDC was high in relatives with baseline abnormalities on electrocardiogram or echocardiography compared with relatives with normal findings (4.7% vs 0.4% per person-year; HR: 12.9; P < 0.001). In total, baseline screening identified 326 (58%) relatives to be at low risk of FDC.<br /><b>Conclusions</b><br />Family screening identified a genetic predisposition to or overt FDC in 1 of 3 relatives at baseline. Genetic and clinical screening was normal in more than half of relatives, and these relatives had a low risk of developing FDC during follow-up. Thus, baseline screening identified a large proportion, in whom follow-up may safely be reduced, allowing focused follow-up of relatives at risk.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Nov 2022; 10:792-803</small></div>
Vissing CR, Espersen K, Mills HL, Bartels ED, ... Christensen AH, Bundgaard H
JACC Heart Fail: 01 Nov 2022; 10:792-803 | PMID: 36328645
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<div><h4>Trends in Ischemic Evaluation in New-Onset Heart Failure Without Known Coronary Artery Disease.</h4><i>Andersson C, Schou M, Boden WE, Schwartz B, ... Gislason GH, Torp-Pedersen C</i><br /><b>Background</b><br />Guidelines recommend consideration of an ischemic evaluation (Class IIa-IIb) in new-onset heart failure (HF), but it is not well-known how often this is performed and leads to revascularization.<br /><b>Objectives</b><br />The authors investigated temporal trends in ischemic evaluation and revascularization within 90 days of HF onset in Denmark 2008-2018.<br /><b>Methods</b><br />From the Danish nationwide administrative registries, diagnostic tests and revascularizations within 90 days were identified among patients with new-onset HF between 2008 and 2018, alive 90 days after diagnosis.<br /><b>Results</b><br />Of 61,475 patients (mean age: 72.6 ± 13.8 years, 46% women), 12,503 (20%) underwent an ischemic evaluation, of whom 10,547 (84%) underwent invasive coronary angiography, and 1,956 (16%) underwent an initial noninvasive test, most frequently coronary computed tomographic angiography (n = 1,813, 93%). Of those who were initially referred for coronary computed tomographic angiography, 374 (21%) had a subsequent invasive coronary angiogram undertaken. Among individuals undergoing ischemic testing, percutaneous coronary intervention and coronary artery bypass graft surgery were performed in 1,354 (11%) and 619 (5%), respectively, corresponding to 2.2% and 1.0% of the entire sample. Between 2008 and 2018, the number of patients referred for ischemic evaluations increased, adjusted OR for 1.07 (95% CI: 1.06-1.07) per year high, and was greater among older versus younger individuals (OR: 1.01 [95% CI: 0.99-1.03], OR: 1.04 [95% CI: 1.03-1.06], OR: 1.06 [95% CI: 1.05-1.07], OR: 1.11 [95% CI: 1.09-1.12], and OR: 1.14 [95% CI: 1.10-1.18] per year increase for age group <50, 51-60, 61-75, 76-85, and >85 years, respectively, P for interaction <0.0001).<br /><b>Conclusions</b><br />In clinical practice, few patients with new-onset HF are referred for an ischemic evaluation and a minority undergo revascularization. Studies are needed to establish the appropriateness of this practice.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Nov 2022; 10:807-815</small></div>
Andersson C, Schou M, Boden WE, Schwartz B, ... Gislason GH, Torp-Pedersen C
JACC Heart Fail: 01 Nov 2022; 10:807-815 | PMID: 36328647
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<div><h4>Risks of Depression and Suicide After Diagnosis With Heart Failure: A National Cohort Study.</h4><i>Crump C, Sundquist J, Kendler KS, Sieh W, Edwards AC, Sundquist K</i><br /><b>Background</b><br />Heart failure (HF) has been associated with psychosocial distress, but other long-term mental health sequelae are unclear.<br /><b>Objectives</b><br />In this study, the authors sought to determine risks of major depression and suicide, susceptible time periods, and sex-specific differences after HF diagnosis in a large population-based cohort.<br /><b>Methods</b><br />A national cohort study was conducted of all 154,572 persons diagnosed with HF at ages 18-75 years during 2002-2017 in Sweden and 1,545,720 age- and sex-matched population-based control subjects who were followed up for major depression and suicide ascertained from nationwide inpatient, outpatient, and death records through 2018. Poisson regression was used to compute incidence rate ratios (IRRs) while adjusting for sociodemographic factors and comorbidities.<br /><b>Results</b><br />HF was associated with increased risks of major depression and death by suicide in both men and women, with highest risks in the first 3 months, then declining to modest risks at ≥12 months after HF diagnosis. Within 3 months after HF diagnosis, adjusted IRRs for new-onset major depression were 3.34 (95% CI: 3.04-3.68) in men and 2.78 (95% CI: 2.51-3.09) in women, and for suicide death were 4.47 (95% CI: 2.62-7.62) in men and 2.82 (95% CI: 1.11-7.12) in women. These risks were elevated regardless of age at HF diagnosis. HF was associated with significantly more depression cases in women (P < 0.001).<br /><b>Conclusions</b><br />In this large national cohort, HF was associated with substantially increased risks of depression and suicide in men and women, with highest risks occurring within 3 months after HF diagnosis. Men and women with HF need timely detection and treatment of depression and suicidality.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Nov 2022; 10:819-827</small></div>
Crump C, Sundquist J, Kendler KS, Sieh W, Edwards AC, Sundquist K
JACC Heart Fail: 01 Nov 2022; 10:819-827 | PMID: 36328649
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<div><h4>Posterior Wall Thickness Associates With Survival Following Septal Myectomy for Obstructive Hypertrophic Cardiomyopathy.</h4><i>Sun D, Schaff HV, Nishimura RA, Geske JB, ... Ducharme MT, Ommen SR</i><br /><b>Background</b><br />The left ventricular (LV) posterior wall thickness (PWT) is a predictor of sudden cardiac death in pediatric patients with hypertrophic cardiomyopathy (HCM), but the prognostic importance of PWT in adults has not been examined.<br /><b>Objectives</b><br />The goal of this study was to evaluate the association of LV PWT with late survival in adult patients undergoing septal myectomy for obstructive HCM.<br /><b>Methods</b><br />This single-center study reviewed 2,418 patients who underwent transaortic septal myectomy for obstructive HCM.<br /><b>Results</b><br />The median preoperative PWT was 13 (IQR: 11-15) mm. Patients with PWT >13 mm tended to have systemic hypertension (55.4% vs 49.1%; P = 0.002) and a larger body mass index (median: 30.8 [IQR: 27.1-35.1] kg/m<sup>2</sup> vs 29.6 [IQR: 26.1-33.9] kg/m<sup>2</sup>; P < 0.001). Preoperatively, PWT >13 mm was associated with increased septal thickness (median: 21 [IQR: 18-24] mm vs 19 [IQR: 17-22] mm; P < 0.001), greater maximum instantaneous left ventricular outflow tract (LVOT) gradient at rest (median: 67 [IQR: 36-96] mm Hg vs 47 [IQR: 19-79] mm Hg), and increased likelihood of moderate or greater mitral valve regurgitation (54.3% vs 47.3%; P = 0.001). However, PWT was not related to the severity of limitations measured by New York Heart Association functional class (P = 0.674). After adjusting for baseline covariates, greater PWT was an independent risk factor for late mortality after septal myectomy (P = 0.003).<br /><b>Conclusions</b><br />PWT is a newly identified predictor of reduced long-term survival after septal myectomy that is independent of septal thickness and severity of LVOT gradient. Future studies are warranted to investigate the mechanisms underlying the association and the potential usefulness of PWT in patient management.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Nov 2022; 10:831-837</small></div>
Sun D, Schaff HV, Nishimura RA, Geske JB, ... Ducharme MT, Ommen SR
JACC Heart Fail: 01 Nov 2022; 10:831-837 | PMID: 36328651
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<div><h4>Steroidal MRA Across the Spectrum of Renal Function: A Pooled Analysis of RCTs.</h4><i>Ferreira JP, Pitt B, McMurray JJV, Pocock SJ, ... Zannad F, Rossignol P</i><br /><b>Background</b><br />Mineralocorticoid receptor antagonists (MRAs) are underused in patients with kidney dysfunction, and their efficacy among patients with chronic kidney disease (CKD) is uncertain.<br /><b>Objectives</b><br />The goal of this study was to analyze the efficacy and safety of steroidal MRAs across the spectrum of estimated glomerular filtration rates (eGFRs) in randomized controlled trials. The study included patients with heart failure (HF) or myocardial infarction and advanced CKD who participated in the RALES (Randomized Aldactone Evaluation Study), EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) in the Americas, and EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study) trials.<br /><b>Methods</b><br />This study used individual patient data meta-analysis using Cox models stratified by trial with treatment-by-eGFR interaction terms. eGFR was recalculated by using the Chronic Kidney Disease Epidemiology Collaboration creatinine formula.<br /><b>Results</b><br />A total of 12,700 patients were included, of whom 331 (2.6%) had an eGFR ≤30 mL/min/1.73 m<sup>2</sup> (mean eGFR: 26.8 ± 3.2 mL/min/1.73 m<sup>2</sup>). Patients with advanced CKD had higher annualized event rates for all studied outcomes: placebo event rate for the composite of cardiovascular death or HF hospitalization was ∼3-fold higher in patients with eGFR ≤30 compared with those with eGFR >90 mL/min/1.73 m<sup>2</sup>: 41.6 vs 14.6 events per 100 person-years. MRAs (vs placebo) reduced the composite of cardiovascular death or HF hospitalization, but the effect was attenuated as eGFR decreased: the corresponding HRs by eGFR categories were: HR for >90 mL/min/1.73 m<sup>2</sup>: 0.62 (95% CI: 0.49-0.78); HR for 61-90 mL/min/1.73 m<sup>2</sup>: 0.69 (95% CI: 0.61-0.77); HR for 46-60 mL/min/1.73 m<sup>2</sup>: 0.84 (95% CI: 0.74-0.95); HR for 31-45 mL/min/1.73 m<sup>2</sup>: 0.79 (95% CI: 0.68-0.91); and HR for ≤30 mL/min/1.73 m<sup>2</sup>: 0.96 (95% CI: 0.70-1.32) (treatment-by-eGFR interaction P for trend = 0.033). Investigator-reported hyperkalemia and worsening renal function were more frequent (2- to 3-fold) among MRA users, and hyperkalemia was more frequent as eGFR decreased (treatment-by-eGFR interaction P for trend = 0.002).<br /><b>Conclusions</b><br />Steroidal MRAs reduced HF hospitalizations and mortality across a wide range of eGFR. However, declining benefit and worsening safety may limit their use in patients with lower eGFR, particularly those with levels ≤30 mL/min/1.73 m<sup>2</sup>.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Nov 2022; 10:842-850</small></div>
Ferreira JP, Pitt B, McMurray JJV, Pocock SJ, ... Zannad F, Rossignol P
JACC Heart Fail: 01 Nov 2022; 10:842-850 | PMID: 36328653
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<div><h4>Trends in Heart Failure-Related Mortality Among Older Adults in the United States From 1999-2019.</h4><i>Siddiqi TJ, Khan Minhas AM, Greene SJ, Van Spall HGC, ... Butler J, Khan MS</i><br /><b>Background</b><br />The U.S. population is aging with concurrent increases in heart failure (HF) burden. However, HF-related mortality trends among adults ≥75 years have not been investigated.<br /><b>Objectives</b><br />The purpose of this study was to assess the trends and regional differences in HF-related mortality among older adults in the United States.<br /><b>Methods</b><br />Death certificates from the CDC WONDER (Centers for Disease Control and Prevention Wide-Ranging OnLine Data for Epidemiologic Research) database were examined from 1999 to 2019 for HF-related mortality in adults ≥75 years of age. Age-adjusted mortality rates (AAMRs) per 10,000 persons and annual percent change (APC) were calculated and stratified by year, sex, race/ethnicity, and geographic region.<br /><b>Results</b><br />Between 1999 and 2019, 5,014,919 HF-related deaths occurred among adults ≥75 years. The AAMR declined from 141.0 in 1999 to 108.3 in 2012 (APC: -2.1; 95% CI: -2.4 to -1.9), after which it increased to 121.3 in 2019 (APC: 1.7; 95% CI: 1.2-2.2). Men had consistently higher AAMR than women from 1999 (AAMR men: 158.3 vs women: 131.0) to 2019 (AAMR men: 141.1 vs women: 107.8). Non-Hispanic (NH) White adults had the highest overall AAMR (127.2), followed by NH Black (108.7), NH American Indian/Alaska Native (102.0), Hispanic or Latino (78.0), and NH Asian or Pacific Islander adults (57.1) AAMR also varied substantially by region (overall AAMR: Midwest 133.9; South: 119.2; West: 116.3; Northeast: 113.5), and nonmetropolitan areas had higher HF-related AAMR (147.0) than metropolitan areas (115.2). States in the top 90th percentile of HF-related AAMR were Mississippi, Oklahoma, West Virginia, Oregon, and Indiana, which had approximately double the AAMRs compared with states that fell into the lower 10th percentile.<br /><b>Conclusions</b><br />Following a period of steady decline, HF-related mortality in U.S. adults ≥75 years has increased since 2012. The highest AAMRs were observed among White adults and men, and among patients living in the Midwestern and nonmetropolitan United States. Targeted strategies are needed to prevent and treat HF among older adults to curb increasing levels of HF-related mortality.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Nov 2022; 10:851-859</small></div>
Siddiqi TJ, Khan Minhas AM, Greene SJ, Van Spall HGC, ... Butler J, Khan MS
JACC Heart Fail: 01 Nov 2022; 10:851-859 | PMID: 36328654
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<div><h4>Finerenone and Heart Failure Outcomes by Kidney Function/Albuminuria in Chronic Kidney Disease and Diabetes.</h4><i>Filippatos G, Anker SD, Pitt B, Rossing P, ... Ruilope LM, Agarwal R</i><br /><b>Background</b><br />In patients with type 2 diabetes (T2D), risks of cardiovascular mortality and heart failure (HF) increase with decreasing kidney function (estimated glomerular filtration rate [eGFR]) and increasing albuminuria (urine albumin-to-creatinine ratio [UACR]). Finerenone, a selective, nonsteroidal mineralocorticoid receptor antagonist, improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and T2D in FIDELITY (Finerenone in Chronic Kidney Disease and Type 2 Diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial Programme Analysis).<br /><b>Objectives</b><br />This study sought to evaluate the effects of finerenone on HF outcomes by eGFR and/or UACR categories.<br /><b>Methods</b><br />FIDELITY included 13,026 patients with T2D and CKD (UACR 30-5,000 mg/g and eGFR ≥25 mL/min/1.73 m<sup>2</sup>) randomized to finerenone or placebo. Time-to-event outcomes were first hospitalization for heart failure (HHF), cardiovascular death or first HHF, recurrent HHF, and cardiovascular death or recurrent HHF, analyzed in subgroups by baseline eGFR (<60 and ≥60 mL/min/1.73 m<sup>2</sup>) and/or UACR (<300 and ≥300 mg/g).<br /><b>Results</b><br />Compared with placebo, finerenone significantly reduced risk of first HHF (HR: 0.78 [95% CI: 0.66-0.92]; P = 0.003), cardiovascular death or first HHF (HR: 0.83 [95% CI: 0.74-0.93]; P = 0.002), recurrent HHF (HR: 0.79 [95% CI: 0.64-0.96]; P = 0.021), and cardiovascular death or recurrent HHF (HR: 0.82 [95% CI: 0.72-0.95]; P = 0.006). The risk of outcomes increased across baseline eGFR and UACR categories; lowest incidences were seen in patients with an eGFR ≥60 mL/min/1.73 m<sup>2</sup> and a UACR <300 mg/g. Finerenone improved HF outcomes irrespective of baseline eGFR and/or UACR categories (all P interaction values >0.10).<br /><b>Conclusions</b><br />Compared with placebo, finerenone improved HF-related outcomes in patients with CKD and T2D, with consistent benefits across eGFR and/or UACR categories. (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease [FIDELIO-DKD], NCT02540993; Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Chronic Kidney Disease [FIGARO-DKD], NCT02545049).<br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 01 Nov 2022; 10:860-870</small></div>
Filippatos G, Anker SD, Pitt B, Rossing P, ... Ruilope LM, Agarwal R
JACC Heart Fail: 01 Nov 2022; 10:860-870 | PMID: 36328655
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<div><h4>Treatment Differences in Medical Therapy for Heart Failure With Reduced Ejection Fraction Between Sociodemographic Groups.</h4><i>Witting C, Zheng J, Tisdale RL, Shannon E, ... Heidenreich P, Sandhu A</i><br /><b>Background</b><br />There are sociodemographic disparities in outcomes of heart failure with reduced ejection fraction (HFrEF), but disparities in guideline-directed medical therapy (GDMT) remain poorly characterized.<br /><b>Objectives</b><br />This study aimed to analyze GDMT treatment rates in eligible patients with recently diagnosed HFrEF, and to determine how rates vary by sociodemographic characteristics.<br /><b>Methods</b><br />This retrospective cohort study included patients diagnosed with HFrEF at Veterans Affairs (VA) hospitals from 2013 to 2019. The authors analyzed GDMT treatment rates and doses, excluding patients with contraindications. Therapies of interest were evidence-based beta-blockers (BBs), renin-angiotensin system inhibitors (RASIs), angiotensin receptor-neprilysin inhibitors (ARNIs), and mineralocorticoid antagonists (MRAs). The authors compared adjusted treatment rates by race and ethnicity, neighborhood social vulnerability, rurality, distance to medical care, and sex.<br /><b>Results</b><br />The cohort comprised 126,670 VA patients with recently diagnosed HFrEF. The study found that racial and ethnic minorities had similar or higher treatment rates than White patients. Patients residing in socially vulnerable neighborhoods had 3.4% lower ARNI (95% CI: 1.9%-5.0%) treatment rates. Patients residing farther from specialty care had similar rates of GDMT therapy overall, but were less likely to be taking at least 50% of the target doses of either BBs (4.0% less likely; 95% CI: 3.1%-5.0%) or RASIs (5.0% less likely; 95% CI: 4.1%-6.0%) compared with those closer to care.<br /><b>Conclusions</b><br />Among VA patients with recently diagnosed HFrEF, the authors did not find that racial and ethnic minority patients were less likely to receive GDMT. However, appropriate dose up-titration may occur less frequently in more remote patients.<br /><br />Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 26 Oct 2022; epub ahead of print</small></div>
Witting C, Zheng J, Tisdale RL, Shannon E, ... Heidenreich P, Sandhu A
JACC Heart Fail: 26 Oct 2022; epub ahead of print | PMID: 36647925
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<div><h4>IGFBP-7 and Outcomes in Heart Failure With Reduced Ejection Fraction: Findings From DAPA-HF.</h4><i>Adamson C, Welsh P, Docherty KF, de Boer RA, ... McMurray JJV, Jhund PS</i><br /><b>Background</b><br />Insulin-like growth factor-binding protein-7 (IGFBP-7) has been proposed as a potential prognostic biomarker in heart failure (HF), but the association between elevation in IGFBP-7 and HF outcomes in ambulant patients with heart failure with reduced ejection fraction (HFrEF) is unknown.<br /><b>Objectives</b><br />The authors addressed this question in a post hoc analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial.<br /><b>Methods</b><br />The primary outcome was a composite of cardiovascular death or a worsening HF event. The risk of adverse outcome was compared across tertiles of IGFBP-7 concentration by means of Cox proportional hazard models adjusted for N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT). The efficacy of randomized treatment across IGFBP-7 tertiles was assessed. Change in IGFBP-7 at 12 months was compared with the use of geometric means.<br /><b>Results</b><br />A total of 3,158 patients had IGFBP-7 measured at baseline, and 2,493 had a repeated measure at 12 months. Patients in the highest tertile of IGFBP-7 had evidence of more advanced HFrEF. The adjusted HR for the primary endpoint in tertile 3, compared with tertile 1, was 1.48 (95% CI: 1.17-1.88). There was no modification of the benefit of dapagliflozin by baseline IGFBP-7 (P interaction = 0.34). Dapagliflozin did not change IGFBP-7 levels over 1 year (P = 0.34).<br /><b>Conclusions</b><br />Higher IGFBP-7 in patients with HFrEF was associated with worse clinical profile and an increased risk of adverse clinical outcomes. IGFBP-7 provided prognostic information incremental to clinical variables, NT-proBNP, and hsTnT. The benefit of dapagliflozin was not modulated by IGFBP-7 level. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 20 Oct 2022; epub ahead of print</small></div>
Adamson C, Welsh P, Docherty KF, de Boer RA, ... McMurray JJV, Jhund PS
JACC Heart Fail: 20 Oct 2022; epub ahead of print | PMID: 36592046
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<div><h4>Clinical Presentation and In-Hospital Trajectory of Heart Failure Cardiogenic Shock.</h4><i>Hernandez-Montfort J, Kanwar M, Sinha SS, Garan AR, ... Burkhoff D, Kapur NK</i><br /><b>Background</b><br />HF-CS remains an understudied distinct clinical entity.<br /><b>Objectives</b><br />We sought to profile a large cohort of patients with heart failure related cardiogenic shock (HF-CS) focused on practical application of the SCAI staging system to define baseline and maximal shock severity, in-hospital management with AMCS support, and clinical outcomes.<br /><b>Methods</b><br />The Cardiogenic Shock Working Group (CSWG) registry includes patients with CS, regardless of etiology, from 17 clinical sites enrolled between 2016-2020. Patients with HF-CS (non-AMI) were analyzed and classified based on clinical presentation, outcomes at discharge and shock severity defined by SCAI stages.<br /><b>Results</b><br />A total of 1,767 patients with HF-CS were included, of which 349 (19.8%) had de novo HF-CS (DNHF-CS). Patients were more likely to present in SCAI Stage C or D and achieve maximum SCAI stage D. Patients with DNHF-CS were more likely to experience in-hospital death, in- and out of hospital cardiac arrest (IHCA or OHCA), and escalated more rapidly to a maximum achieved SCAI stage, compared to patients with acute on chronic HF-CS (ACHF-CS). IHCA was associated with greater in-hospital death regardless of clinical presentation (de novo: 63% vs 21%; ACHF 65% vs 17%; both p<0.001). Forty-five percent of HF-CS patients were exposed to at least one acute mechanical circulatory support (AMCS) device throughout hospitalization.<br /><b>Conclusions</b><br />In a large contemporary HF-CS cohort, we identified a greater incidence of in-hospital death, cardiac arrest, and more rapid escalation to maximum SCAI Stage severity among DNHF-CS. AMCS use in HF-CS was common with significant heterogeneity among device type.<br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 19 Oct 2022; epub ahead of print</small></div>
Hernandez-Montfort J, Kanwar M, Sinha SS, Garan AR, ... Burkhoff D, Kapur NK
JACC Heart Fail: 19 Oct 2022; epub ahead of print | PMID: 36342421
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<div><h4>Acute Myocarditis Associated With Desmosomal Gene Variants.</h4><i>Ammirati E, Raimondi F, Piriou N, Sardo Infirri L, ... Camici PG, Cooper LT</i><br /><b>Background</b><br />The risk of adverse cardiovascular events in patients with acute myocarditis (AM) and desmosomal gene variants (DGV) remains unknown.<br /><b>Objectives</b><br />The purpose of this study was to ascertain the risk of death, ventricular arrhythmias, recurrent myocarditis, and heart failure (main endpoint) in patients with AM and pathogenic or likely pathogenetic DGV.<br /><b>Methods</b><br />In a retrospective international study from 23 hospitals, 97 patients were included: 36 with AM and DGV (DGV[+]), 25 with AM and negative gene testing (DGV[-]), and 36 with AM without genetics testing. All patients had troponin elevation plus findings consistent with AM on histology or at cardiac magnetic resonance (CMR). In 86 patients, CMR changes in function and structure were re-assessed at follow-up.<br /><b>Results</b><br />In the DGV(+) AM group (88.9% DSP variants), median age was 24 years, 91.7% presented with chest pain, and median left ventricular ejection fraction (LVEF) was 56% on CMR (P = NS vs the other 2 groups). Kaplan-Meier curves demonstrated a higher risk of the main endpoint in DGV(+) AM compared with DGV(-) and without genetics testing patients (62.3% vs 17.5% vs 5.3% at 5 years, respectively; P < 0.0001), driven by myocarditis recurrence and ventricular arrhythmias. At follow-up CMR, a higher number of late gadolinium enhanced segments was found in DGV(+) AM.<br /><b>Conclusions</b><br />Patients with AM and evidence of DGV have a higher incidence of adverse cardiovascular events compared with patients with AM without DGV. Further prospective studies are needed to ascertain if genetic testing might improve risk stratification of patients with AM who are considered at low risk.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Oct 2022; 10:714-727</small></div>
Ammirati E, Raimondi F, Piriou N, Sardo Infirri L, ... Camici PG, Cooper LT
JACC Heart Fail: 01 Oct 2022; 10:714-727 | PMID: 36175056
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<div><h4>Periodontal Status, C-Reactive Protein, NT-proBNP, and Incident Heart Failure: The ARIC Study.</h4><i>Molinsky RL, Yuzefpolskaya M, Norby FL, Yu B, ... Colombo PC, Demmer RT</i><br /><b>Background</b><br />Periodontal disease (PD), resulting from inflammatory host response to dysbiotic subgingival microbiota, has been linked to cardiovascular disease; however, its relationship to heart failure (HF) and its subtypes (heart failure with reduced ejection fraction [HFrEF] and heart failure with preserved ejection fraction [HFpEF]) is unexplored.<br /><b>Objectives</b><br />The authors hypothesize that the presence of PD is associated with increased risk of incident HF, HFpEF, and HFrEF.<br /><b>Methods</b><br />A total of 6,707 participants (mean age 63 ± 6 years) of the ARIC (Atherosclerosis Risk In Communities) study with full-mouth periodontal examination at visit 4 (1996-1998) and longitudinal follow-up for any incident HF (visit 4 to 2018), or incident HFpEF and HFrEF (2005-2018) were included. Periodontal status was classified as follows: healthy, PD (as per Periodontal Profile Classification [PPC]), or edentulous. Multivariable-adjusted Cox proportional hazards models were used to calculate HRs and 95% CIs for the association between PPC levels and incident HF, HFpEF, or HFrEF. Additionally, biomarkers of inflammation (C-reactive protein [CRP]) and congestion (N-terminal brain natriuretic peptide [NT-proBNP]) were assessed.<br /><b>Results</b><br />In total, 1,178 incident HF cases occurred (350 HFpEF, 319 HFrEF, and 509 HF of unknown type) over a median of 13 years. Of these cases, 59% had PD, whereas 18% were edentulous. PD was associated with an increased risk for HFpEF (HR: 1.35 [95% CI: 0.98-1.86]) and significantly increased risk for HFrEF (HR: 1.69 [95% CI: 1.18-2.43]), as was edentulism: HFpEF (HR: 2.00 [95% CI: 1.37-2.93]), HFrEF (HR: 2.19 [95% CI: 1.43-3.36]). Edentulism was associated with unfavorable change in CRP and NT-proBNP, whereas PD was associated only with CRP.<br /><b>Conclusions</b><br />Periodontal status was associated with incident HF, HFpEF, and HFrEF, as well as unfavorable changes in CRP and NT-proBNP.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Oct 2022; 10:731-741</small></div>
Molinsky RL, Yuzefpolskaya M, Norby FL, Yu B, ... Colombo PC, Demmer RT
JACC Heart Fail: 01 Oct 2022; 10:731-741 | PMID: 36175058
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<div><h4>Transvenous Right Greater Splanchnic Nerve Ablation in Heart Failure and Preserved Ejection Fraction: First-in-Human Study.</h4><i>Fudim M, Zirakashvili T, Shaburishvili N, Shaishmelashvili G, ... Shaburishvili T, Shah SJ</i><br /><b>Background</b><br />Ablation of the right-sided greater splanchnic nerve (GSN) can reduce excessive splanchnic vasoconstriction, potentially improving the handling of volume shifts in patients with heart failure with preserved ejection fraction (HFpEF).<br /><b>Objectives</b><br />The purpose of this study was to assess a novel catheter procedure of right-sided GSN ablation to treat HFpEF: splanchnic ablation for volume management.<br /><b>Methods</b><br />This trial included 11 HFpEF patients (8 women, age 70 ± 8 years) with New York Heart Association functional class II or III symptoms, ejection fraction ≥50%, and elevated pulmonary capillary wedge pressure at rest or with exercise. After splanchnic ablation for volume management, follow-up at 1, 3, 6, and 12 months included 6-minute walk test, Kansas City Cardiomyopathy Questionnaire (KCCQ), and echocardiography.<br /><b>Results</b><br />There were no device-related adverse cardiac events or clinical sequelae following right GSN ablation through 12 months. Patients experienced clinical improvements by 1 month that were sustained through 12 months. KCCQ score improved from baseline median 48 (IQR: 35-52) to 65 (IQR: 58-77) at 1 month and 80 (IQR: 77-88) at 12 months (P < 0.05). The 6-minute walk test distance increased from baseline 292 ± 82 m to 341 ± 88 m at 1 month and 359 ± 75 m at 12 months (P < 0.05). The NT-proBNP decreased from a baseline mean of 1,292 ± 1,186 pg/mL to 1,202 ± 797 pg/mL (P = 0.585) at 1 month, to 472 ± 226 pg/mL (P = 0.028) at 6 months, and to 379 ± 165 pg/mL (P = 0.039) at 12 months.<br /><b>Conclusions</b><br />In this open-label, single-arm feasibility study, right-sided GSN ablation was safe and improved mostly subjective clinical metrics in patients with HFpEF over 12 months. (Endovascular GSN Ablation in Subjects With HFpEF; NCT04287946).<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Oct 2022; 10:744-752</small></div>
Fudim M, Zirakashvili T, Shaburishvili N, Shaishmelashvili G, ... Shaburishvili T, Shah SJ
JACC Heart Fail: 01 Oct 2022; 10:744-752 | PMID: 36175060
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<div><h4>Bereavement and Prognosis in Heart Failure: A Swedish Cohort Study.</h4><i>Chen H, Wei D, Janszky I, Dahlström U, Rostila M, László KD</i><br /><b>Background</b><br />The role of stress in the prognosis of heart failure (HF) is unclear. This study investigated whether the death of a close family member, a severe source of stress, is associated with mortality in HF.<br /><b>Objectives</b><br />This study assessed whether the death of a close family member is associated with mortality in HF.<br /><b>Methods</b><br />Patients from the Swedish Heart Failure Registry during 2000-2018 and/or in the Swedish Patient Register with a primary diagnosis of HF during 1987-2018 (N = 490,527) were included in this study. Information was obtained on death of family members (children, partner, grandchildren, siblings, and parents), mortality, sociodemographic variables, and health-related factors from several population-based registers. The association between bereavement and mortality was analyzed by using Poisson regression.<br /><b>Results</b><br />Loss of a family member was associated with an increased risk of dying (adjusted relative risk: 1.29; 95% CI: 1.27-1.30). The association was present not only in case of the family member\'s cardiovascular deaths and other natural deaths but also in case of unnatural deaths. The risk was higher for 2 losses than for 1 loss and highest in the first week after the loss. The association between bereavement and an increased mortality risk was observed for the death of a child, spouse/partner, grandchild, and sibling but not of a parent.<br /><b>Conclusions</b><br />Death of a family member was associated with an increased risk of mortality among patients with HF. Further studies are needed to investigate whether less severe sources of stress can also contribute to poor prognosis in HF and to explore the mechanisms underlying this association.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Oct 2022; 10:753-764</small></div>
Chen H, Wei D, Janszky I, Dahlström U, Rostila M, László KD
JACC Heart Fail: 01 Oct 2022; 10:753-764 | PMID: 36175061
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<div><h4>A Standardized and Regionalized Network of Care for Cardiogenic Shock.</h4><i>Tehrani BN, Sherwood MW, Rosner C, Truesdell AG, ... O\'Connor CM, Batchelor WB</i><br /><b>Background</b><br />The benefits of standardized care for cardiogenic shock (CS) across regional care networks are poorly understood.<br /><b>Objectives</b><br />The authors compared the management and outcomes of CS patients initially presenting to hub versus spoke hospitals within a regional care network.<br /><b>Methods</b><br />The authors stratified consecutive patients enrolled in their CS registry (January 2017 to December 2019) by presentation to a spoke versus the hub hospital. The primary endpoint was 30-day mortality. Secondary endpoints included bleeding, stroke, or major adverse cardiovascular and cerebrovascular events.<br /><b>Results</b><br />Of 520 CS patients, 286 (55%) initially presented to 34 spoke hospitals. No difference in mean age (62 years vs 61 years; P = 0.38), sex (25% vs 32% women; P = 0.10), and race (54% vs 52% white; P = 0.82) between spoke and hub patients was noted. Spoke patients more often presented with acute myocardial infarction (50% vs 32%; P < 0.01), received vasopressors (74% vs 66%; P = 0.04), and intra-aortic balloon pumps (88% vs 37%; P < 0.01). Hub patients were more often supported with percutaneous ventricular assist devices (44% vs 11%; P < 0.01) and veno-arterial extracorporeal membrane oxygenation (13% vs 0%; P < 0.01). Initial presentation to a spoke was not associated with increased risk-adjusted 30-day mortality (adjusted OR: 0.87 [95% CI: 0.49-1.55]; P = 0.64), bleeding (adjusted OR: 0.89 [95% CI: 0.49-1.62]; P = 0.70), stroke (adjusted OR: 0.74 [95% CI: 0.31-1.75]; P = 0.49), or major adverse cardiovascular and cerebrovascular events (adjusted OR 0.83 [95% CI: 0.50-1.35]; P = 0.44).<br /><b>Conclusions</b><br />Spoke and hub patients experienced similar short-term outcomes within a regionalized CS network. The optimal strategy to promote standardized care and improved outcomes across regional CS networks merits further investigation.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Oct 2022; 10:768-781</small></div>
Tehrani BN, Sherwood MW, Rosner C, Truesdell AG, ... O'Connor CM, Batchelor WB
JACC Heart Fail: 01 Oct 2022; 10:768-781 | PMID: 36175063
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<div><h4>Heart Failure Drug Treatment-Inertia, Titration, and Discontinuation: A Multinational Observational Study (EVOLUTION HF).</h4><i>Savarese G, Kishi T, Vardeny O, Adamsson Eryd S, ... Thuresson M, Bozkurt B</i><br /><b>Background</b><br />Guidelines recommend early initiation of multiple guideline-directed medical therapies (GDMTs) to reduce mortality/rehospitalization in patients with heart failure and reduced ejection fraction. Understanding GDMT use is critical to improving clinical practice.<br /><b>Objectives</b><br />This study sought to describe GDMT use in Japan, Sweden, and the United States in contemporary real-world settings.<br /><b>Methods</b><br />EVOLUTION HF (Utilization of Dapagliflozin and Other Guideline Directed Medical Therapies in Heart Failure Patients: A Multinational Observational Study Based on Secondary Data) is an observational cohort study using routine-care databases. Patients initiating any GDMT within 12 months of a hospitalization for heart failure (hHF) discharge were included. Dapagliflozin (the only sodium-glucose cotransporter-2 inhibitor approved at study onset), sacubitril/valsartan, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) were considered separately. Doses and discontinuation were assessed in the 12 months following initiation. Target dose was defined as ≥100% of the guideline-recommended dose.<br /><b>Results</b><br />Overall, 266,589 patients were included. Mean times from hHF to GDMT initiation were longer for novel GDMTs (dapagliflozin or sacubitril/valsartan) than for other GDMTs: 39 and 44 vs 12 to 13 days (Japan), 44 and 33 vs 22 to 31 days (Sweden), and 33 and 19 vs 18 to 24 days (United States). Pooled across countries, proportions of patients who discontinued therapy (not including switches from ACE inhibitor or ARB to sacubitril/valsartan) within 12 months were 23.5% (dapagliflozin), 26.4% (sacubitril/valsartan), 38.4% (ACE inhibitors), 33.4% (ARBs), 25.2% (beta-blockers), and 42.2% (MRAs). Corresponding target dose achievements were 75.7%, 28.2%, 20.1%, 6.7%, 7.2%, and 5.1%, respectively.<br /><b>Conclusions</b><br />Initiation of novel GDMTs is delayed compared with other GDMTs. Few patients received target doses of GDMTs requiring uptitration. Persistence was higher for dapagliflozin than other GDMTs.<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 07 Sep 2022; epub ahead of print</small></div>
Savarese G, Kishi T, Vardeny O, Adamsson Eryd S, ... Thuresson M, Bozkurt B
JACC Heart Fail: 07 Sep 2022; epub ahead of print | PMID: 36202739
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<div><h4>Contemporary Applications of Machine Learning for Device Therapy in Heart Failure.</h4><i>Gautam N, Ghanta SN, Clausen A, Saluja P, ... Fudim M, Al\'Aref SJ</i><br /><AbstractText>Despite a better understanding of the underlying pathogenesis of heart failure (HF), pharmacotherapy, surgical, and percutaneous interventions do not prevent disease progression in all patients, and a significant proportion of patients end up requiring advanced therapies. Machine learning (ML) is gaining wider acceptance in cardiovascular medicine because of its ability to incorporate large, complex, and multidimensional data and to potentially facilitate the creation of predictive models not constrained by many of the limitations of traditional statistical approaches. With the coexistence of \"big data\" and novel advanced analytic techniques using ML, there is ever-increasing research into applying ML in the context of HF with the goal of improving patient outcomes. Through this review, the authors describe the basics of ML and summarize the existing published reports regarding contemporary applications of ML in device therapy for HF while highlighting the limitations to widespread implementation and its future promises.</AbstractText><br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Sep 2022; 10:603-622</small></div>
Gautam N, Ghanta SN, Clausen A, Saluja P, ... Fudim M, Al'Aref SJ
JACC Heart Fail: 01 Sep 2022; 10:603-622 | PMID: 36049812
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<div><h4>Pathophysiologic Processes and Novel Biomarkers Associated With Congestion in Heart Failure.</h4><i>Pandhi P, Ter Maaten JM, Anker SD, Ng LL, ... Voors AA, Sama IE</i><br /><b>Background</b><br />Congestion is the main driver behind symptoms of heart failure (HF), but pathophysiology related to congestion remains poorly understood.<br /><b>Objectives</b><br />Using pathway and differential expression analyses, the authors aim to identify biological processes and biomarkers associated with congestion in HF.<br /><b>Methods</b><br />A congestion score (sum of jugular venous pressure, orthopnea, and peripheral edema) was calculated in 1,245 BIOSTAT-CHF patients with acute or worsening HF. Patients with a score ranking in the bottom or top categories of congestion were deemed noncongested (n = 408) and severely congested (n = 142), respectively. Plasma concentrations of 363 unique proteins (Olink Proteomics Multiplex CVD-II, CVD-III, Immune Response and Oncology II panels) were compared between noncongested and severely congested patients. Results were validated in an independent validation cohort of 1,342 HF patients (436 noncongested and 232 severely congested).<br /><b>Results</b><br />Differential protein expression analysis showed 107/363 up-regulated and 6/363 down-regulated proteins in patients with congestion compared with those without. FGF-23, FGF-21, CA-125, soluble ST2, GDF-15, FABP4, IL-6, and BNP were the strongest up-regulated proteins (fold change [FC] >1.30, false discovery rate [FDR], P < 0.05). KITLG, EGF, and PON3 were the strongest down-regulated proteins (FC <-1.30, FDR P < 0.05). Pathways most prominently involved in congestion were related to inflammation, endothelial activation, and response to mechanical stimulus. The validation cohort yielded similar findings.<br /><b>Conclusions</b><br />Severe congestion in HF is mainly associated with inflammation, endothelial activation, and mechanical stress. Whether these pathways play a causal role in the onset or progression of congestion remains to be established. The identified biomarkers may become useful for diagnosing and monitoring congestion status.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Sep 2022; 10:623-632</small></div>
Pandhi P, Ter Maaten JM, Anker SD, Ng LL, ... Voors AA, Sama IE
JACC Heart Fail: 01 Sep 2022; 10:623-632 | PMID: 36049813
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<div><h4>Electronic Health Record-Based Deep Learning Prediction of Death or Severe Decompensation in Heart Failure Patients.</h4><i>McGilvray MMO, Heaton J, Guo A, Masood MF, ... Pasque MK, Foraker R</i><br /><b>Background</b><br />Surgical mechanical ventricular assistance and cardiac replacement therapies, although life-saving in many heart failure (HF) patients, remain high-risk. Despite this, the difficulty in timely identification of medical therapy nonresponders and the dire consequences of nonresponse have fueled early, less selective surgical referral. Patients who would have ultimately responded to medical therapy are therefore subjected to the risk and life disruption of surgical therapy.<br /><b>Objectives</b><br />The purpose of this study was to develop deep learning models based upon commonly-available electronic health record (EHR) variables to assist clinicians in the timely and accurate identification of HF medical therapy nonresponders.<br /><b>Methods</b><br />The study cohort consisted of all patients (age 18 to 90 years) admitted to a single tertiary care institution from January 2009 through December 2018, with International Classification of Disease HF diagnostic coding. Ensemble deep learning models employing time-series and densely-connected networks were developed from standard EHR data. The positive class included all observations resulting in severe progression (death from any cause or referral for HF surgical intervention) within 1 year.<br /><b>Results</b><br />A total of 79,850 distinct admissions from 52,265 HF patients met observation criteria and contributed >350 million EHR datapoints for model training, validation, and testing. A total of 20% of model observations fit positive class criteria. The model C-statistic was 0.91.<br /><b>Conclusions</b><br />The demonstrated accuracy of EHR-based deep learning model prediction of 1-year all-cause death or referral for HF surgical therapy supports clinical relevance. EHR-based deep learning models have considerable potential to assist HF clinicians in improving the application of advanced HF surgical therapy in medical therapy nonresponders.<br /><br />Copyright © 2022 American College of Cardiology Foundation. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Sep 2022; 10:637-647</small></div>
McGilvray MMO, Heaton J, Guo A, Masood MF, ... Pasque MK, Foraker R
JACC Heart Fail: 01 Sep 2022; 10:637-647 | PMID: 36049815
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<div><h4>Chemoreflex and Baroreflex Sensitivity Hold a Strong Prognostic Value in Chronic Heart Failure.</h4><i>Giannoni A, Gentile F, Buoncristiani F, Borrelli C, ... Emdin M, Passino C</i><br /><b>Background</b><br />Novel treatments targeting in baroreflex sensitivity (BRS) and chemoreflex sensitivity (CRS) heart failure (HF) are grounded on small prognostic studies, partly performed in the pre-beta-blockade era.<br /><b>Objectives</b><br />This study assesses the clinical/prognostic significance of BRS and CRS in a large cohort of patients with chronic HF on modern treatments.<br /><b>Methods</b><br />Outpatients with chronic HF with either reduced (≤40%) or mildly reduced left ventricular ejection fraction (LVEF) (41% to 49%) underwent BRS (SD method) and CRS to hypoxia and hypercapnia (rebreathing technique) assessment and were followed up for a composite endpoint of cardiac death, implantable cardioverter-defibrillator shock, or HF hospitalization.<br /><b>Results</b><br />A total of 425 patients were enrolled (65 ± 12 years of age, LVEF 32% [IQR: 25%-38%], 94% on beta blockers). Patients with decreased BRS (n = 96 of 267, 36%) had lower exercise tolerance and heart rate variability (P < 0.05), whereas those with increased CRS to both hypoxia and hypercapnia (n = 74 of 369, 20%) had higher plasma norepinephrine and central apneas across the 24-hour period (P < 0.01). During a median 50-month follow-up (IQR: 24-94 months), the primary endpoint occurred more often in patients with decreased BRS (log-rank: 11.64; P = 0.001), mainly for increased cardiac deaths/implantable cardioverter-defibrillator shocks, and in those with increased CRS (log-rank: 34.81; P < 0.001), mainly for increased HF hospitalizations. Patients with both abnormal BRS and CRS showed the worst outcome. Reduced BRS (HR: 2.76 [95% CI: 1.36-5.63]; P = 0.005) and increased CRS (HR: 2.91 [95% CI: 1.34-6.31]; P = 0.007) were independently associated with the primary outcome and increased risk stratification when added to standard HF prognosticators (P < 0.05).<br /><b>Conclusions</b><br />In subjects with HF on modern treatment, abnormal BRS and CRS are frequently observed. BRS and CRS elicit autonomic imbalance, exercise limitation, unstable ventilation, and predict adverse outcomes.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Sep 2022; 10:662-676</small></div>
Giannoni A, Gentile F, Buoncristiani F, Borrelli C, ... Emdin M, Passino C
JACC Heart Fail: 01 Sep 2022; 10:662-676 | PMID: 36049816
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<div><h4>Sequential Evaluation of NT-proBNP in Heart Failure: Insights Into Clinical Outcomes and Efficacy of Vericiguat.</h4><i>Armstrong PW, Zheng Y, Troughton RW, Lund LH, ... Ezekowitz JA, VICTORIA Study Group</i><br /><b>Background</b><br />The effect of vericiguat on sequential N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and influence of this relationship on clinical outcomes is unknown.<br /><b>Objectives</b><br />This study assessed the relationship between changes in NT-proBNP and the primary outcome (cardiovascular death or heart failure hospitalization); evaluated the effect of vericiguat on changes in NT-proBNP; and explored the association between the efficacy of vericiguat and changes in NT-proBNP.<br /><b>Methods</b><br />NT-proBNP was measured at randomization and at 16, 32, 48, and 96 weeks in 4,805 of 5,050 patients. The association between NT-proBNP change at week 16 and the primary outcome was assessed. The relationship between changes in NT-proBNP and the primary outcome according to treatment group was assessed by using joint modeling and mediation analysis.<br /><b>Results</b><br />A significant and sustained decline in NT-proBNP levels was seen in both treatment groups. After week 16, NT-proBNP levels decreased more with vericiguat vs placebo (any reduction: odds ratio [OR]: 1.45 [95% CI: 1.28-1.65]; P < 0.001; ≥50% reduction: OR: 1.27 [95% CI: 1.10-1.47]; P = 0.001) and were less likely to increase (≥20% increase: OR: 0.68 [95% CI: 0.59-0.78]; P < 0.001; ≥50% increase: OR: 0.70 [95% CI: 0.59-0.82]; P < 0.001). The treatment effect related to serial NT-proBNP on the primary composite outcome was HR: 0.96 (95% CI: 0.95-0.99) at week 16, which increased to HR: 0.90 (95% CI: 0.85-0.96) at week 48; the average extent of mediation of the composite outcome related to NT-proBNP was 45%.<br /><b>Conclusions</b><br />In patients with worsening HFrEF, vericiguat significantly decreased NT-proBNP levels compared with placebo. This change appeared associated with a modest relative improvement in the primary outcome of cardiovascular death or heart failure hospitalization. (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534).<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Sep 2022; 10:677-688</small></div>
Armstrong PW, Zheng Y, Troughton RW, Lund LH, ... Ezekowitz JA, VICTORIA Study Group
JACC Heart Fail: 01 Sep 2022; 10:677-688 | PMID: 36049817
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<div><h4>Influence of NT-proBNP on Efficacy of Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction.</h4><i>Myhre PL, Vaduganathan M, Claggett BL, Miao ZM, ... McMurray JJV, Solomon SD</i><br /><b>Background</b><br />N-terminal pro-B-type natriuretic peptide (NT-proBNP) is used for diagnostic and prognostic evaluation in heart failure (HF). Previous clinical trials in heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF) have shown potential heterogeneity in the treatment response by baseline NT-proBNP levels.<br /><b>Objectives</b><br />To assess the treatment effect of dapagliflozin across baseline levels of NT-proBNP among patients with HFmrEF or HFpEF.<br /><b>Methods</b><br />This was a post hoc analysis from DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure), a randomized, placebo-controlled trial of dapagliflozin in patients with HFmrEF or HFpEF. Elevated NT-proBNP was part of the inclusion criteria (≥300 ng/L for non-atrial fibrillation or flutter [AFF]; ≥600 ng/L for AFF). Baseline NT-proBNP was categorized in quartiles and additionally analyzed continuously. The primary composite outcome was cardiovascular death or worsening HF events.<br /><b>Results</b><br />Among the 6,262 included patients (mean 71.7 years and 3,516 [56%] men), the median (Q1-Q3) baseline concentration of NT-proBNP was 716 (469-1,280) ng/L and 1,399 (962-2,212) ng/L for non-AFF and AFF, respectively. Higher NT-proBNP levels were linearly associated with a greater risk of the primary outcome (adjusted HR for log<sub>2</sub>NTpro-BNP was 1.53 [1.46, 1.62] and Q4 vs Q1: 3.46 [95%CI 2.48-4.22]; P < 0.001), with consistent results regardless of AFF status. The clinical benefit of dapagliflozin was present irrespective of baseline NT-proBNP concentration (P for interaction = 0.40 by quartiles and = 0.19 continuously for the primary outcome) and the absolute risk reduction was, therefore, greater with higher NT-proBNP concentrations. The effect on health status and safety of dapagliflozin was similarly consistent across NT-proBNP quartiles.<br /><b>Conclusions</b><br />Dapagliflozin is safe and improves outcomes irrespective of baseline NT-proBNP concentrations in HFmrEF or HFpEF, with the greatest absolute benefit likely seen in patients with higher NT-proBNP concentrations. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).<br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 27 Aug 2022; epub ahead of print</small></div>
Myhre PL, Vaduganathan M, Claggett BL, Miao ZM, ... McMurray JJV, Solomon SD
JACC Heart Fail: 27 Aug 2022; epub ahead of print | PMID: 36114137
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<div><h4>Obesity Status and Physical Rehabilitation in Older Patients Hospitalized With Acute HF: Insights From REHAB-HF.</h4><i>Peters AE, Kitzman DW, Chen H, Nelson MB, ... Whellan DJ, Mentz RJ</i><br /><b>Background</b><br />In the REHAB-HF trial, a novel, early, transitional, multidomain rehabilitation intervention improved physical function, frailty, quality of life (QOL), and depression in older patients hospitalized for acute decompensated heart failure (ADHF), but the potential impact of baseline obesity on this intervention has not been studied.<br /><b>Objectives</b><br />This study assessed for treatment interactions by body mass index (BMI) subgroups for a novel rehabilitation intervention in ADHF.<br /><b>Methods</b><br />Three-month outcomes including Short Physical Performance Battery (SPPB) (primary outcome), 6-minute walk distance (6MWD), and Kansas City Cardiomyopathy Questionnaire (KCCQ) were assessed by baseline BMI (≥30 kg/m<sup>2</sup> vs <30 kg/m<sup>2</sup>). Six-month end points included all-cause rehospitalization and death. All analyses were adjusted for age, sex, clinical site, and ejection fraction category, and 3-month outcomes were also adjusted for baseline measure. The prespecified significance level for treatment interaction by BMI category was P ≤ 0.10.<br /><b>Results</b><br />Of 349 trial participants, 204 (58%) had BMI ≥30 kg/m<sup>2</sup> and 145 (42%) <30 kg/m<sup>2</sup>. Compared with patients with BMI <30 kg/m<sup>2</sup>, participants with BMI ≥30 kg/m<sup>2</sup> were younger (age 71 ± 7 years vs 75 ± 9 years), more frequently women (57% vs 46%), and had significantly worse baseline physical function and QOL. Although interaction P values for 3-month outcomes by BMI were not significant (interaction P > 0.15 for overall measures), adjusted SPPB effect sizes were nominally larger for participants with BMI ≥30 kg/m<sup>2</sup> compared with those with BMI <30 kg/m<sup>2</sup>: +1.7 (95% CI: 0.8-2.7) vs +1.1 (95% CI: -0.1 to 2.2). This difference in SPPB effect size was due largely to improvements in the balance component of the SPPB for participants with BMI ≥30 kg/m<sup>2</sup>: +0.6 (95% CI: 0.2-1.0) vs 0.0 (-0.6 to 0.5) for those with BMI <30 kg/m<sup>2</sup> (interaction P = 0.02). In contrast, adjusted 6MWD and KCCQ effect sizes were smaller for participants with BMI ≥30 kg/m<sup>2</sup> compared with those with BMI <30 kg/m<sup>2</sup>: +21 meters (-17 to 59) vs +53 meters (6-100), and +5.0 (-4 to 14) vs +11 (-0.5 to 22), respectively. There was no significant interaction by BMI for 6-month clinical outcomes (all interaction P > 0.3).<br /><b>Conclusions</b><br />Older patients with ADHF benefit from the rehabilitation therapy regardless of BMI. Benefits for patients with obesity may be more evident in the multidomain measure of physical function (SPPB), compared with the 6MWD or KCCQ, which may be driven, in part, by the unique aspects of the novel rehabilitation intervention. (A Trial of Rehabilitation Therapy in Older Acute Heart Failure Patients [REHAB-HF]; NCT02196038).<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 17 Aug 2022; epub ahead of print</small></div>
Peters AE, Kitzman DW, Chen H, Nelson MB, ... Whellan DJ, Mentz RJ
JACC Heart Fail: 17 Aug 2022; epub ahead of print | PMID: 36164731
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<div><h4>Smoking Cessation Reduces the Risk of Heart Failure: A Nationwide Cohort Study.</h4><i>Yoo JE, Jeong SM, Yeo Y, Jung W, ... Park KW, Shin DW</i><br /><b>Background</b><br />There is a lack of data for the incidence of heart failure (HF) according to changes in smoking behaviors.<br /><b>Objectives</b><br />The authors aimed to investigate the effects of smoking behavior change on development of HF.<br /><b>Methods</b><br />In this population-based, retrospective cohort study using the Korean National Health Insurance System database, the authors identified 778,608 current smokers who participated in a health screening program in 2009 and in a follow-up screening in 2011. Participants were categorized into quitters, reducers I (≥50% reduction) and II (<50% reduction), sustainers, and increasers.<br /><b>Results</b><br />During a median follow-up of 6.3 years, there were 23,329 HF events (4.8 per 1,000 person-years). Compared with sustainers, the risk of HF was increased among increasers (adjusted hazard ratio [aHR]: 1.06; 95% CI: 1.02-1.10). By contrast, quitters had a reduced risk for HF (aHR: 0.86; 95% CI: 0.83-0.90). Even heavy smokers who quit smoking had a lower risk for HF than those who sustained heavy smoking (aHR: 0.90; 95% CI: 0.85-0.95). In reducers, the risk of HF was not reduced but rather increased slightly (≥50% reduction, aHR: 1.06; 95% CI: 1.01-1.11; <50% reduction, aHR: 1.04; 95% CI: 1.00-1.08).<br /><b>Conclusions</b><br />Current smokers who increased their smoking amount were associated with a higher risk for HF development compared to sustainers, whereas self-reported smoking cessation was associated with a lower risk of HF. There was no benefit from reduction in smoking amount. Self-reported smoking cessation should be reinforced whenever possible to prevent HF.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 12 Aug 2022; epub ahead of print</small></div>
Yoo JE, Jeong SM, Yeo Y, Jung W, ... Park KW, Shin DW
JACC Heart Fail: 12 Aug 2022; epub ahead of print | PMID: 36647926
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<div><h4>Angiotensinogen: More Than Its Downstream Products: Evidence From Population Studies and Novel Therapeutics.</h4><i>Kahlon T, Carlisle S, Otero Mostacero D, Williams N, Trainor P, DeFilippis AP</i><br /><AbstractText>The renin-angiotensin-aldosterone system (RAAS) is a well-defined pathway playing a key role in maintaining circulatory homeostasis. Abnormal activation of RAAS contributes to development of cardiovascular disease, including heart failure, cardiac hypertrophy, hypertension, and atherosclerosis. Although several key RAAS enzymes and peptide hormones have been thoroughly investigated, the role of angiotensinogen-the precursor substrate of the RAAS pathway-remains less understood. The study of angiotensinogen single-nucleotide polymorphisms (SNPs) has provided insight into associations between angiotensinogen and hypertension, congestive heart failure, and atherosclerotic cardiovascular disease. Targeted drug therapy of RAAS has dramatically improved clinical outcomes for patients with heart failure, myocardial infarction, and hypertension. However, all such therapeutics block RAAS components downstream of angiotensinogen and elicit compensatory pathways that limit their therapeutic efficacy as monotherapy. Upstream RAAS targeting by an angiotensinogen inhibitor has the potential to be more efficacious in patients with suboptimal RAAS inhibition and has a better safety profile than multiagent RAAS blockade. Newly developed therapeutics that target angiotensinogen through antisense oligonucleotides or silencer RNA technologies are providing a novel perspective into the pathobiology of angiotensinogen and show promise as the next frontier in the treatment of cardiovascular disease.</AbstractText><br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 04 Aug 2022; epub ahead of print</small></div>
Kahlon T, Carlisle S, Otero Mostacero D, Williams N, Trainor P, DeFilippis AP
JACC Heart Fail: 04 Aug 2022; epub ahead of print | PMID: 35963818
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<div><h4>Validation of the Kansas City Cardiomyopathy Questionnaire in Symptomatic Obstructive Hypertrophic Cardiomyopathy.</h4><i>Nassif M, Fine JT, Dolan C, Reaney M, ... Gosch K, Spertus JA</i><br /><b>Background</b><br />The primary goal for treating patients with obstructive hypertrophic cardiomyopathy (oHCM) is to improve their symptoms, function, and quality of life. Although the Kansas City Cardiomyopathy Questionnaire (KCCQ) is a valid, reliable, and sensitive measure for other etiologies of heart failure, its appropriateness for patients with oHCM is unknown.<br /><b>Objectives</b><br />The purpose of this study was to establish the interpretability, validity, reliability, and responsiveness of the KCCQ in patients with oHCM.<br /><b>Methods</b><br />Cognitive debriefing of the KCCQ was performed in 26 patients with oHCM. The validity, reliability, responsiveness, and interpretability of the KCCQ were tested in 196 participants from the EXPLORER-HCM trial by comparing each scale with relevant comparators, describing the internal reliability and the mean change in stable patients, and comparing the mean change in patients who reported different degrees of clinical change using a patient-reported global impression of change (PGIC).<br /><b>Results</b><br />All KCCQ domains demonstrated strong correlations with external standards of symptoms, function, social limitation, and quality of life, including a recently designed instrument measuring symptoms not captured by the KCCQ (P < 0.0001 for all). Mean changes in stable patients were nonsignificant, ranging from 0.21 to 2.3 points (P > 0.30 for all), with high intraclass correlation coefficients. The mean changes in patients with small, moderate, and large clinical changes were consistent with the 5-, 10-, and 20-point mean differences observed in other etiologies of heart failure.<br /><b>Conclusions</b><br />The KCCQ is well understood by patients with oHCM and has strong evidence of good psychometric performance. It can not only serve as a relevant endpoint in clinical trials of oHCM therapy, but may also prove useful in the clinical care of patients with oHCM. (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy [EXPLORER-HCM]; NCT03470545).<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Aug 2022; 10:531-539</small></div>
Nassif M, Fine JT, Dolan C, Reaney M, ... Gosch K, Spertus JA
JACC Heart Fail: 01 Aug 2022; 10:531-539 | PMID: 35902155
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<div><h4>Effects of Dapagliflozin According to the Heart Failure Collaboratory Medical Therapy Score: Insights From DAPA-HF.</h4><i>Butt JH, Dewan P, DeFilippis EM, Biering-Sørensen T, ... Fiuzat M, McMurray JJV</i><br /><b>Background</b><br />The Heart Failure Collaboratory (HFC) has developed a score integrating classes and doses of guideline-directed medical therapies prescribed for patients with heart failure (HF) and reduced ejection fraction. One potential use of this score is to test whether new treatments demonstrate incremental benefits, even in patients receiving comprehensive guideline-directed medical therapy.<br /><b>Objectives</b><br />The authors investigated the efficacy of dapagliflozin according to a modified HFC score in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial.<br /><b>Methods</b><br />In DAPA-HF, 4,744 patients with HF and reduced ejection fraction were randomized to dapagliflozin or placebo. The modified HFC score accounted for race and electrocardiogram rhythm and rate, with a maximum possible score of 100%. The primary outcome was the composite of worsening HF or cardiovascular death.<br /><b>Results</b><br />The median modified HFC score was 50% (IQR: 27.5%-62.5%; range 0%-100%). Compared with the lowest tertile, the highest tertile of the treatment score was associated with a lower risk of worsening HF or cardiovascular death (tertile 1, reference; tertile 2, HR: 0.97 [95% CI: 0.82-1.14]; tertile 3, HR: 0.83 [95% CI: 0.70-0.99]). Dapagliflozin reduced the risk of worsening HF or cardiovascular death, irrespective of treatment score (the HRs for dapagliflozin vs placebo from tertile 1 to 3 were: 0.76 [95% CI: 0.61-0.94], 0.76 [95% CI: 0.60-0.97], and 0.71 [95% CI: 0.55-0.90]), respectively; P<sub>interaction</sub> = 0.89). Consistent benefits were observed for HF hospitalization, cardiovascular death, all-cause mortality, and improvement in the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TTS).<br /><b>Conclusions</b><br />Dapagliflozin, compared with placebo, improved all outcomes examined, regardless of the modified HFC score. This score can be easily calculated in clinical trials and used to evaluate the incremental effects of new treatments. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Aug 2022; 10:543-555</small></div>
Butt JH, Dewan P, DeFilippis EM, Biering-Sørensen T, ... Fiuzat M, McMurray JJV
JACC Heart Fail: 01 Aug 2022; 10:543-555 | PMID: 35902157
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<div><h4>Sodium-Glucose Co-Transporter-2 Inhibitors and Cardiac Outcomes Among Patients Treated With Anthracyclines.</h4><i>Gongora CA, Drobni ZD, Quinaglia Araujo Costa Silva T, Zafar A, ... Nohria A, Neilan TG</i><br /><b>Background</b><br />Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve outcomes among patients with established heart failure. Despite supportive basic science studies, there are no data on the value of SGLT2 inhibitors among patients treated with anthracyclines.<br /><b>Objectives</b><br />This study sought to test the cardiac efficacy and overall safety of SGLT2 inhibitors in patients treated with anthracyclines.<br /><b>Methods</b><br />This study identified 3,033 patients with diabetes mellitus (DM) and cancer who were treated with anthracyclines. Cases were patients with cancer and DM who were on SGLT2 inhibitor therapy during anthracycline treatment (n = 32). Control participants (n = 96) were patients with cancer and DM who were also treated with anthracyclines, but were not on an SGLT2 inhibitor. The primary cardiac outcome was a composite of cardiac events (heart failure incidence, heart failure admissions, new cardiomyopathy [>10% decline in ejection fraction to <53%], and clinically significant arrhythmias). The primary safety outcome was overall mortality.<br /><b>Results</b><br />Age, sex, ethnicity, cancer type, cancer stage, and other cardiac risk factors were similar between groups. There were 20 cardiac events over a median follow-up period of 1.5 years. The cardiac event incidence was lower among case patients in comparison to control participants (3% vs 20%; P = 0.025). Case patients also experienced lower overall mortality when compared with control participants (9% vs 43%; P < 0.001) and a lower composite of sepsis and neutropenic fever (16% vs 40%; P = 0.013).<br /><b>Conclusions</b><br />SGLT2 inhibitors were associated with lower rate of cardiac events among patients with cancer and DM who were treated with anthracyclines. Additionally, SGLT2 inhibitors appeared to be safe. These data support the conducting of a randomized clinical trial testing SGLT2 inhibitors in patients at high cardiac risk treated with anthracyclines.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Aug 2022; 10:559-567</small></div>
Gongora CA, Drobni ZD, Quinaglia Araujo Costa Silva T, Zafar A, ... Nohria A, Neilan TG
JACC Heart Fail: 01 Aug 2022; 10:559-567 | PMID: 35902159
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<div><h4>Expenditure on Heart Failure in the United States: The Medical Expenditure Panel Survey 2009-2018.</h4><i>Bhatnagar R, Fonarow GC, Heidenreich PA, Ziaeian B</i><br /><b>Background</b><br />With rising United States health care expenditure, estimating current spending for patients with heart failure (HF) informs the value of preventative health interventions.<br /><b>Objectives</b><br />The purpose of this study was to estimate current health care expenditure growth for patients with HF in the United States.<br /><b>Methods</b><br />The authors pooled MEPS (Medical Expenditure Panel Survey) data from 2009-2018 to calculate total HF-related expenditure across clinical settings in the United States. A 2-part model adjusted for demographics, comorbidities, and year was used to estimate annual mean and incremental expenditures associated with HF.<br /><b>Results</b><br />In the United States, an average of $28,950 (2018 inflation-adjusted dollars) is spent per year for health care-related expenditure for individuals with HF compared with $5,727 for individuals without HF. After adjusting for demographics and comorbidities, a diagnosis of HF was associated with $3,594 in annual incremental expenditure compared with those without HF. HF-related expenditure increased from $26,864 annual per person in 2009-2010 to $32,955 in 2017-2018, representing a 23% rise over 10 years. In comparison, expenditure on myocardial infarction, type 2 diabetes mellitus, and cancer grew by 16%, 28%, and 16%, respectively. Most of the cost was related to hospitalization: $12,569 per year. Outpatient office-based care and prescription medications saw the greatest growth in cost over the period, 41% and 24%, respectively. Estimated incremental national expenditure for HF per year was $22.3 billion; total annual expenditure for adults with HF was $179.5 billion.<br /><b>Conclusions</b><br />HF is a costly condition for which expenditure is growing faster than that of other chronic conditions.<br /><br />Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 01 Aug 2022; 10:571-580</small></div>
Bhatnagar R, Fonarow GC, Heidenreich PA, Ziaeian B
JACC Heart Fail: 01 Aug 2022; 10:571-580 | PMID: 35902161
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<div><h4>Supranormal Left Ventricular Ejection Fraction, Stroke Volume, and Cardiovascular Risk: Findings From Population-Based Cohort Studies.</h4><i>Shah S, Segar MW, Kondamudi N, Ayers C, ... Longstreth WT, Pandey A</i><br /><b>Background</b><br />Supranormal ejection fraction by echocardiography in clinically referred patient populations has been associated with an increased risk of cardiovascular disease (CVD). The prognostic implication of supranormal left ventricular ejection fraction (LVEF)-assessed by cardiac magnetic resonance (CMR)-in healthy, community-dwelling individuals is unknown.<br /><b>Objectives</b><br />The purpose of this study is to investigate the prognostic implication of supranormal LVEF as assessed by CMR and its inter-relationship with stroke volume among community-dwelling adults without CVD.<br /><b>Methods</b><br />Participants from the MESA (Multi-Ethnic Study of Atherosclerosis) and DHS (Dallas Heart Study) cohorts free of CVD who underwent CMR with LVEF above the normal CMR cutoff (≥57%) were included. The association between cohort-specific LVEF categories and risk of clinically adjudicated major adverse cardiovascular events (MACE) was assessed using adjusted Cox models. Subgroup analysis was also performed to evaluate the association of LVEF and risk of MACE among individuals stratified by left ventricular stroke volume index.<br /><b>Results</b><br />The study included 4,703 participants from MESA and 2,287 from DHS with 727 and 151 MACE events, respectively. In adjusted Cox models, the risk of MACE was highest among individuals in LVEF Q4 (vs Q1) in both cohorts after accounting for potential confounders (MESA: HR = 1.27 [95% CI: 1.01-1.60], P = 0.04; DHS: HR = 1.72 [95% CI: 1.05-2.79], P = 0.03). A significant interaction was found between the continuous measures of LVEF and left ventricular stroke volume index (P interaction = 0.02) such that higher LVEF was significantly associated with an increased risk of MACE among individuals with low but not high stroke volume.<br /><b>Conclusions</b><br />Among community-dwelling adults without CVD, LVEF in the supranormal range is associated with a higher risk of adverse cardiovascular outcomes, particularly in those with lower stroke volume.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Aug 2022; 10:583-594</small></div>
Shah S, Segar MW, Kondamudi N, Ayers C, ... Longstreth WT, Pandey A
JACC Heart Fail: 01 Aug 2022; 10:583-594 | PMID: 35902163
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<div><h4>Tolerability of Sacubitril/Valsartan in Patients With Advanced Heart Failure: Analysis of the LIFE Trial Run-In.</h4><i>Vader JM, Givertz MM, Starling RC, McNulty SE, ... Mann DL, LIFE Investigators</i><br /><b>Background</b><br />The LIFE (LCZ696 In Hospitalized Advanced Heart FailurE) trial, which evaluated sacubitril/valsartan in patients with advanced heart failure (HF) with reduced ejection fraction and recent New York Heart Association functional class IV symptomatology, did not require tolerance to a renin angiotensin system antagonist before initiating sacubitril/valsartan, thus affording an opportunity to study the tolerability of sacubitril/valsartan in advanced HF with reduced ejection fraction.<br /><b>Objectives</b><br />The goal of this analysis of the LIFE trial is to characterize the tolerability of initiating sacubitril/valsartan in patients with chronic advanced HF with reduced ejection fraction.<br /><b>Methods</b><br />In the LIFE trial, 445 subjects with advanced HF entered an unblinded run-in period of 3-7 days with sacubitril/valsartan 24/26 mg twice a day. The authors compared characteristics of subjects completing and failing run-in, performed multivariable analysis of clinical parameters associated with run-in failure, and developed a predictive model for short-term intolerance to sacubitril/valsartan.<br /><b>Results</b><br />Of 445 subjects entering run-in, 73 (18%) were intolerant of sacubitril/valsartan. Reasons for intolerance included systolic blood pressure <90 mm Hg (59%), symptoms of hypotension/dizziness with systolic blood pressure >90 mm Hg (19%), and renal dysfunction (creatinine >2.0 mg/dL) (12%). Multivariable predictors of intolerance included lower mean arterial pressure, lower serum chloride, presence of an implantable cardioverter-defibrillator and/or cardiac resynchronization device, moderate or greater mitral regurgitation, nonuse of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker at the screening visit, and use of insulin at screening. Subjects with 4 or more predictors had a 48.9% probability of sacubitril/valsartan intolerance.<br /><b>Conclusions</b><br />Intolerance to low doses of sacubitril/valsartan is common in patients with advanced chronic HF with reduced ejection fraction and may be predicted by the presence of certain risk factors. (EntrestoTM [LCZ696] in Advanced Heart Failure [LIFE Study] [HFN-LIFE] NCT02816736).<br /><br />Copyright © 2022 American College of Cardiology Foundation. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jul 2022; 10:449-456</small></div>
Vader JM, Givertz MM, Starling RC, McNulty SE, ... Mann DL, LIFE Investigators
JACC Heart Fail: 01 Jul 2022; 10:449-456 | PMID: 35772853
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<div><h4>Happy Heart Syndrome: Frequency, Characteristics, and Outcome of Takotsubo Syndrome Triggered by Positive Life Events.</h4><i>Stiermaier T, Walliser A, El-Battrawy I, Pätz T, ... Santoro F, Eitel I</i><br /><b>Background</b><br />The association with a preceding stressor is a characteristic feature of takotsubo syndrome (TTS). Negative emotions before TTS are common and led to the popular term \"broken heart syndrome.\" In contrast, pleasant triggers (\"happy heart syndrome\") are rare and are scarcely investigated.<br /><b>Objectives</b><br />The authors analyzed the frequency, clinical characteristics, and prognostic implications of positive emotional stressors in the multicenter GEIST (GErman-Italian-Spanish Takotsubo) Registry.<br /><b>Methods</b><br />Patients enrolled in the registry were categorized according to their stressors. This analysis compared patients with pleasant emotional events with patients with negative emotional events.<br /><b>Results</b><br />Of 2,482 patients in the registry, 910 patients (36.7%) exhibited an emotional trigger consisting of 873 \"broken hearts\" (95.9%) and 37 \"happy hearts\" (4.1%). Consequently, the prevalence of pleasant emotional triggers was 1.5% of all TTS cases. Compared with patients with TTS with negative preceding events, patients with happy heart syndrome were more frequently male (18.9% vs 5.0%; P < 0.01) and had a higher prevalence of atypical ballooning patterns (27.0% vs 12.5%; P = 0.01), particularly midventricular ballooning. In-hospital complications, including death, pulmonary edema, cardiogenic shock, or stroke (8.1% vs 12.3%; P = 0.45), and long-term mortality rates (2.7% vs 8.8%; P = 0.20) were similar in \"happy hearts\" and \"broken hearts.\"<br /><b>Conclusions</b><br />Happy heart syndrome is a rare type of TTS characterized by a higher prevalence of male patients and atypical, nonapical ballooning compared with patients with negative emotional stressors. Despite similar short- and long-term outcomes in our study, additional data are needed to explore whether numerically lower event rates in \"happy hearts\" would be statistically significant in a larger sample size. (GErman-Italian-Spanish Takotsubo Registry [GEIST Registry]; NCT04361994).<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jul 2022; 10:459-466</small></div>
Stiermaier T, Walliser A, El-Battrawy I, Pätz T, ... Santoro F, Eitel I
JACC Heart Fail: 01 Jul 2022; 10:459-466 | PMID: 35772855
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<div><h4>Hospitalization Patterns and Impact of a Magnetically-Levitated Left Ventricular Assist Device in the MOMENTUM 3 Trial.</h4><i>Vidula H, Takeda K, Estep JD, Silvestry SC, ... Dirckx N, Mehra MR</i><br /><b>Background</b><br />In the MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) pivotal trial, the HeartMate 3 (HM3) fully magnetically levitated left ventricular assist device (LVAD) demonstrated superiority over the axial-flow HeartMate II (HMII) LVAD. The patterns and predictors of hospitalizations with the HM3 LVAD have not been characterized.<br /><b>Objectives</b><br />This study sought to determine causes, predictors, and impact of hospitalizations during LVAD support.<br /><b>Methods</b><br />Patients discharged after LVAD implantation were analyzed. In the pivotal trial, 485 recipients of HM3 were compared with 471 recipients of HMII. The pivotal trial HM3 group was also compared to 949 recipients of HM3 in the postapproval phase within the trial portfolio. Predictors of cause-specific rehospitalization were analyzed.<br /><b>Results</b><br />The rates of rehospitalization were lower with HM3 LVAD than with HMII LVAD in the pivotal trial (225.7 vs 246.4 events per 100 patient-years; P < 0.05). Overall, rehospitalization rates and duration were similar in the HM3 postapproval phase and pivotal trial but prolonged hospitalizations (>7 days) were less frequent (rate ratio: 0.90 [95% CI: 0.80-0.98]; P < 0.05). In HM3 recipients, the most frequent causes of rehospitalization included infection, heart failure (HF)-related events, and bleeding. First rehospitalization caused by HF-related event versus other causes was associated with reduced survival (HR: 2.2 [95% CI: 1.3-3.9]; P = 0.0014). Male sex, non-White race, presence of cardiac resynchronization therapy/implantable cardioverter-defibrillator, obesity, higher right atrial pressure, smaller LV size, longer duration of index hospitalization, and lower estimated glomerular filtration rate at index discharge predicted HF hospitalizations.<br /><b>Conclusions</b><br />Contemporary support with the HM3 fully magnetically levitated LVAD is associated with a lower hospitalization burden than with prior pumps; however, rehospitalizations for infection, HF, and bleeding remain important challenges for progress in the patient journey. (MOMENTUM 3 IDE Clinical Study, NCT02224755; MOMENTUM 3 Continued Access Protocol [MOMENTUM 3 CAP], NCT02892955).<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jul 2022; 10:470-481</small></div>
Vidula H, Takeda K, Estep JD, Silvestry SC, ... Dirckx N, Mehra MR
JACC Heart Fail: 01 Jul 2022; 10:470-481 | PMID: 35772857
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<div><h4>Association Between Thigh Muscle Fat Infiltration and Incident Heart Failure: The Health ABC Study.</h4><i>Huynh K, Ayers C, Butler J, Neeland I, ... Barton G, Berry JD</i><br /><b>Background</b><br />Excess adiposity is a well-known risk factor for heart failure (HF). Fat accumulation in and around the peripheral skeletal muscle may further inform risk for HF.<br /><b>Objectives</b><br />The purpose of this study was to evaluate the association between intramuscular and intermuscular fat deposition and incident HF in a longitudinal cohort of community-dwelling older adults.<br /><b>Methods</b><br />The associations of intramuscular and intermuscular fat with incident HF were assessed using Cox models among 2,399 participants from the Health ABC (Health, Aging and Body Composition) study (70-79 years of age, 48% male, 40.2% Black) without baseline HF. Intramuscular fat was determined by bilateral thigh muscle density on computed tomography and intermuscular fat area was determined with computed tomography.<br /><b>Results</b><br />After a median follow-up of 12.2 years, there were 485 incident HF events. Higher sex-specific tertiles of intramuscular and intermuscular fat were each associated with HF risk. After multivariable adjustment for age, sex, race, education, blood pressure, fasting blood sugar, current smoking, prevalent coronary disease, and creatinine, higher intramuscular fat, but not intermuscular fat, was associated with higher risk for HF (HR: 1.34 [95% CI: 1.06-1.69]; P = 0.012, tertile 3 vs tertile 1). This association remained significant after additional adjustment for body mass index (HR: 1.32 [95% CI: 1.03-1.69]), total percent fat (HR: 1.33 [95% CI: 1.03-1.72]), visceral fat (HR: 1.30 [95% CI: 1.01-1.65]), and indexed thigh muscle strength (HR: 1.30 [95% CI: 1.03-1.64]). The association between higher intramuscular fat and HF appeared specific to higher risk of incident HF with reduced ejection fraction (HR: 1.53 [95% CI: 1.03-2.29]), but not with HF with preserved ejection fraction (HR: 1.28 [95% CI: 0.82-1.98]).<br /><b>Conclusions</b><br />Intramuscular, but not intermuscular, thigh muscle fat is independently associated with HF after adjustment for cardiometabolic risk factors and other measurements of adiposity.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jul 2022; 10:485-493</small></div>
Huynh K, Ayers C, Butler J, Neeland I, ... Barton G, Berry JD
JACC Heart Fail: 01 Jul 2022; 10:485-493 | PMID: 35772859
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<div><h4>Increase in BNP in Response to Endothelin-Receptor Antagonist Atrasentan Is Associated With Incident Heart Failure.</h4><i>Smeijer JD, Koomen J, Kohan DE, McMurray JJV, ... de Zeeuw D, Heerspink HJL</i><br /><b>Background</b><br />The endothelin receptor antagonist atrasentan reduced the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease (CKD) in the SONAR (Study of Diabetic Nephropathy with Atrasentan) trial, although with a numerically higher incidence of heart failure (HF) hospitalization.<br /><b>Objectives</b><br />The purpose of this study was to assess if early changes in B-type natriuretic peptide (BNP) and body weight during atrasentan treatment predict HF risk.<br /><b>Methods</b><br />Participants with type 2 diabetes and CKD entered an open-label enrichment phase to assess response to atrasentan 0.75 mg/day. Participants without substantial fluid retention (>3 kg body weight increase or BNP increase to >300 pg/mL), were randomized to atrasentan 0.75 mg/day or placebo. Cox proportional hazards regression was used to assess the effects of atrasentan vs placebo on the prespecified safety outcome of HF hospitalizations.<br /><b>Results</b><br />Among 3,668 patients, 73 (4.0%) participants in the atrasentan and 51 (2.8%) in the placebo group developed HF (HR: 1.39; 95% CI: 0.97-1.99; P = 0.072). In a multivariable analysis, HF risk was associated with higher baseline BNP (HR: 2.32; 95% CI: 1.81-2.97) and percent increase in BNP during response enrichment (HR: 1.46; 95% CI: 1.08-1.98). Body weight change was not associated with HF. Exclusion of patients with at least 25% BNP increase during enrichment attenuated the risk of HF with atrasentan (HR: 1.02; 95% CI: 0.66-1.56) while retaining nephroprotective effects (HR: 0.58; 95% CI: 0.44-0.78).<br /><b>Conclusions</b><br />In patients with type 2 diabetes and CKD, baseline BNP and early changes in BNP in response to atrasentan were associated with HF hospitalization, highlighting the importance of natriuretic peptide monitoring upon initiation of atrasentan treatment. (Study Of Diabetic Nephropathy With Atrasentan [SONAR]; NCT01858532).<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jul 2022; 10:498-507</small></div>
Smeijer JD, Koomen J, Kohan DE, McMurray JJV, ... de Zeeuw D, Heerspink HJL
JACC Heart Fail: 01 Jul 2022; 10:498-507 | PMID: 35772861
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<div><h4>Minimally Clinically Important Difference in Health Status Scores in Patients With HFrEF vs HFpEF.</h4><i>Butler J, Shahzeb Khan M, Lindenfeld J, Abraham WT, ... Ponikowski P, Anker SD</i><br /><b>Objectives</b><br />The purpose of this study was to estimate meaningful thresholds for improvement or deterioration in the Kansas City Cardiomyopathy Questionnaire (KCCQ)-Total Symptom Score (TSS) in patients with heart failure with reduced ejection fraction (HFrEF) versus heart failure with preserved ejection fraction (HFpEF).<br /><b>Background</b><br />Differences in clinically important thresholds in patient-reported outcomes measures such as the KCCQ remain less well established in patients with HFpEF vs HFrEF.<br /><b>Methods</b><br />This secondary analysis of EMPERIAL program used anchor- and distribution-based approaches to estimate thresholds for improvement or deterioration in the KCCQ-TSS using Patient Global Impression of Severity (PGIS) as the primary anchor. Mean change in KCCQ-TSS from baseline to week 12 was calculated for each PGIS.<br /><b>Results</b><br />A total of 312 HFrEF and 315 HFpEF patients were enrolled. At week 12, mean ± SD changes in KCCQ-TSS corresponding to PGIS changes of \"any improvement,\" \"1-category improvement,\" and \"1-category deterioration\" were 13 ± 17, 12 ± 17, -3 ± 16 points in HFrEF, and 15 ± 18, 13 ± 17, -7 ± 18 points in HFpEF. Threshold for meaningful within-patient change in KCCQ-TSS was ≥9 points in HFrEF and ≥7 points in HFpEF patients. Sensitivity and specificity of ≥9 points/ ≥7 points change was 0.65 and 0.70 for HFrEF and 0.64 and 0.66 for HFpEF. Cumulative distribution function curves of KCCQ-TSS change from baseline to week 12 showed a shift to higher scores in both HFrEF and HFpEF patients.<br /><b>Conclusions</b><br />In the EMPERIAL program, a change in KCCQ-TSS of ≥9 points in HFrEF and ≥7 points in HFpEF represents the minimal clinically important difference for improvement, confirming the broad range of 5-10 points as meaningful thresholds.<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 08 Jun 2022; epub ahead of print</small></div>
Butler J, Shahzeb Khan M, Lindenfeld J, Abraham WT, ... Ponikowski P, Anker SD
JACC Heart Fail: 08 Jun 2022; epub ahead of print | PMID: 35780032
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<div><h4>Prognostic Value of Time in Blood Pressure Target Range Among Patients With Heart Failure.</h4><i>Chen K, Li C, Cornelius V, Yu D, ... Chen T, Jiang Z</i><br /><b>Background</b><br />Blood pressure (BP) is a continuous and dynamic measure. However, standard BP control metrics may not reflect the variability in BP over time.<br /><b>Objectives</b><br />This study assessed the prognostic value of time in BP target range among hypertensive patients with heart failure (HF).<br /><b>Methods</b><br />The authors performed a post hoc analysis of data from the TOPCAT (Treatment of Preserved Cardiac Function HF with an Aldosterone Antagonist) trial and the BEST (Beta-Blocker Evaluation of Survival Trial). Time in target range (TTR) for each patient was calculated using linear interpolation across the study period with the target range of systolic BP between 120 and 130 mm Hg.<br /><b>Results</b><br />A total of 4,789 hypertensive patients (n = 1,654 from BEST and n = 3,135 from TOPCAT) were included. The cumulative incidences of primary endpoint (ie, cardiovascular death or HF hospitalization) were highest among the top quartile of TTR with a dose-dependent manner across quartiles (P<sub>trend</sub> <0.005). The top quartile of TTR was significantly associated with a lower risk of primary outcome using adjusted Cox regression model (HR: 0.71; 95% CI: 0.60-0.82), cardiovascular mortality (HR: 0.68; 95% CI: 0.55-0.84), HF hospitalization (HR: 0.70; 95% CI: 0.58-0.85), all-cause mortality (HR: 0.69; 95% CI: 0.58-0.83), and any hospitalization (HR: 0.76; 95% CI: 0.67-0.85). Further analyses using restricted cubic spline indicated a linear relationship between TTR and primary outcome. Similar patterns were observed in the individual trial. Sensitivity analyses generated consistent results while redefining target range as 110 to 130 mm Hg for systolic BP or 70 to 80 mm Hg for diastolic BP.<br /><b>Conclusions</b><br />TTR could independently predict major adverse cardiovascular events in hypertensive patients with HF.<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jun 2022; 10:369-379</small></div>
Chen K, Li C, Cornelius V, Yu D, ... Chen T, Jiang Z
JACC Heart Fail: 01 Jun 2022; 10:369-379 | PMID: 35654521
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<div><h4>Apparent Treatment-Resistant Hypertension Across the Spectrum of Heart Failure Phenotypes in the Swedish HF Registry.</h4><i>Jackson AM, Benson L, Savarese G, Hage C, ... McMurray JJV, Lund LH</i><br /><b>Background</b><br />Hypertension is common in patients with heart failure (HF), but less is known about resistant hypertension.<br /><b>Objectives</b><br />This study sought to investigate apparent treatment-resistant hypertension (aTRH) in patients with HF in the SwedeHF (Swedish Heart Failure Registry), across the spectrum of HF phenotypes (heart failure with reduced ejection fraction [HFrEF], heart failure with mildly reduced ejection fraction [HFmrEF], and heart failure with preserved ejection fraction [HFpEF]).<br /><b>Methods</b><br />aTRH was defined as systolic blood pressure ≥140 mm Hg (≥135 mm Hg in diabetes) despite treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or sacubitril-valsartan, as well as a calcium-channel blocker and a diuretic; non-treatment-resistant hypertension (TRH) was defined as systolic blood pressure above these thresholds but not on the 3-drug combination; and normal blood pressure was defined as under these thresholds. In each left ventricular ejection fraction (LVEF) category, patient factors associated with aTRH and non-TRH and outcomes (HF hospitalization and cardiovascular death composite, its components, and all-cause death) according to hypertension category were examined.<br /><b>Results</b><br />Among 46,597 patients, aTRH was present in 2,693 (10%), 1,514 (14%), and 1,450 (17%) patients with HFrEF, HFmrEF, and HFpEF, respectively. Older age, obesity, diabetes, and kidney disease were associated with a greater likelihood of aTRH and non-TRH (vs normal blood pressure). Associations were generally similar irrespective of LVEF category. Compared with normal blood pressure, aTRH was associated with a lower adjusted risk of the composite outcome in HFrEF and HFmrEF (HR: 0.79 [95% CI: 0.74-0.85] and HR: 0.86 [95% CI: 0.77-0.96]) but not in HFpEF (HR: 0.93 [95% CI: 0.84-1.04]).<br /><b>Conclusions</b><br />aTRH was most common in HFpEF and least common in HFrEF. Associated patient characteristics were similar irrespective of LVEF category. aTRH (vs normal blood pressure) was associated with a lower risk of first HF hospitalization or cardiovascular death in HFrEF and HFmrEF but not in HFpEF.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jun 2022; 10:380-392</small></div>
Jackson AM, Benson L, Savarese G, Hage C, ... McMurray JJV, Lund LH
JACC Heart Fail: 01 Jun 2022; 10:380-392 | PMID: 35654522
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<div><h4>Early Blood Pressure Variables Associated With Improved Outcomes in VA-ECLS: The ELSO Registry Analysis.</h4><i>Rali AS, Ranka S, Butcher A, Shah Z, ... Lindenfeld J, Zalawadiya SK</i><br /><b>Background</b><br />As utilization of veno-arterial extracorporeal life support (VA-ECLS) in treatment of cardiogenic shock (CS) continues to expand, clinical variables that guide clinicians in early recognition of myocardial recovery and therefore, improved survival, after VA-ECLS are critical. There remains a paucity of literature on early postinitiation blood pressure measurements that predict improved outcomes.<br /><b>Objectives</b><br />The objective of this study is to help identify early blood pressure variables associated with improved outcomes in VA-ECLS.<br /><b>Methods</b><br />The authors queried the ELSO (Extracorporeal Life Support Organization) registry for cardiogenic shock patients treated with VA-ECLS or venovenous arterial ECLS between 2009 and 2020. Their inclusion criteria included treatment with VA-ECLS or venovenous arterial ECLS; absence of pre-existing durable right, left, or biventricular assist devices; no pre-ECLS cardiac arrest; and no surgical or percutaneously placed left ventricular venting devices during their ECLS runs. Their primary outcome of interest was the survival to discharge during index hospitalization.<br /><b>Results</b><br />A total of 2,400 CS patients met the authors\' inclusion criteria and had complete documentation of blood pressures. Actual mortality during index hospitalization in their cohort was 49.5% and survivors were younger and more likely to be Caucasian, intubated for >30 hours pre-ECLS initiation, and had a favorable baseline SAVE (Survival After Veno-arterial ECMO) score (P < 0.05 for all). Multivariable regression analyses adjusting for SAVE score, age, ECLS flow at 4 hours, and race showed that every 10-mm Hg increase in baseline systolic blood pressure (HR: 0.92 [95% CI: 0.89-0.95]; P < 0.001), and baseline pulse pressure (HR: 0.88 [95% CI: 0.84-0.91]; P < 0.001) at 24 hours was associated with a statistically significant reduction in mortality.<br /><b>Conclusions</b><br />Early (within 24 hours) improvements in pulse pressure and systolic blood pressure from baseline are associated with improved survival to discharge among CS patients treated with VA-ECLS.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jun 2022; 10:397-403</small></div>
Rali AS, Ranka S, Butcher A, Shah Z, ... Lindenfeld J, Zalawadiya SK
JACC Heart Fail: 01 Jun 2022; 10:397-403 | PMID: 35654524
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<div><h4>Acute Decompensated Heart Failure in the Setting of Acute Coronary Syndrome.</h4><i>Harrington J, Jones WS, Udell JA, Hannan K, ... Butler J, Hernandez AF</i><br /><AbstractText>Acute coronary syndrome (ACS) is frequently complicated by evidence of heart failure (HF). Those at highest risk for acute decompensated HF in the setting of ACS (ACS-HF) are older, female, and have preexisting heart disease, type 2 diabetes mellitus, hypertension, and/or kidney disease. The presence of ACS-HF is strongly associated with higher mortality and more frequent readmissions, especially for HF. Low implementation of guideline-directed medical therapy has further complicated the clinical care of this high-risk population. Improved utilization of current therapies, coupled with further investigation of strategies to manage ACS-HF, is desperately needed to improve outcomes in this vulnerable population, and the results of currently ongoing or recently concluded ACS-HF studies in this population are of great interest. In this review, we explore the pathophysiology, epidemiology, risk factors, and outcomes for patients with ACS-HF, and describe both existing evidence for management of this challenging condition and areas requiring further research.</AbstractText><br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jun 2022; 10:404-414</small></div>
Harrington J, Jones WS, Udell JA, Hannan K, ... Butler J, Hernandez AF
JACC Heart Fail: 01 Jun 2022; 10:404-414 | PMID: 35654525
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<div><h4>Clinical Outcomes Related to Background Diuretic Use and New Diuretic Initiation in Patients With HFrEF.</h4><i>Curtain JP, Campbell RT, Petrie MC, Jackson AM, ... Jhund PS, McMurray JJV</i><br /><b>Background</b><br />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.<br /><b>Objectives</b><br />The aim of this study was to examine outcomes in patients with HFrEF not taking diuretic medications and after diuretic medications are started.<br /><b>Methods</b><br />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.<br /><b>Results</b><br />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).<br /><b>Conclusions</b><br />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.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jun 2022; 10:415-427</small></div>
Curtain JP, Campbell RT, Petrie MC, Jackson AM, ... Jhund PS, McMurray JJV
JACC Heart Fail: 01 Jun 2022; 10:415-427 | PMID: 35654526
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<div><h4>Prognostic Implications of N-terminal Pro-B Type Natriuretic Peptide and High-Sensitivity Cardiac Troponin T in EMPEROR-Preserved.</h4><i>Januzzi JL, Butler J, Zannad F, Filippatos G, ... Anker SD, EMPEROR-Preserved Trial Study Group</i><br /><b>Background</b><br />N-terminal pro-B type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) are associated with disease severity and outcomes among patients with heart failure with preserved ejection fraction (HFpEF).<br /><b>Objectives</b><br />We evaluated associations between both biomarkers and clinical outcomes in the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) Trial.<br /><b>Methods</b><br />Of 5988 study participants, 5986 (99.9%) and 5825 (97.3%) had available baseline NT-proBNP and hs-cTnT; post-baseline NT-proBNP was also available. Baseline characteristics were expressed by biomarker quartiles. The effect of empagliflozin on cardiovascular death/HF hospitalization, the individual components, total HF hospitalizations, slope of decline of estimated glomerular filtration rate (eGFR) and a composite renal endpoint was examined across biomarker quartiles. Change in NT-proBNP across study visits as a function of treatment assignment was also assessed.<br /><b>Results</b><br />Higher baseline NT-proBNP and hs-cTnT concentrations were associated with more comorbidities and worse HF severity. Incidence rates for cardiac and renal outcomes were 2-5-fold higher among those in the highest vs lowest NT-proBNP or hs-cTnT quartiles. Empagliflozin consistently reduced the risk for cardiovascular events and reduced slope of eGFR decline across NT-proBNP or hs-cTnT quartiles. Empagliflozin treatment modestly lowered NT-proBNP; by 100 weeks the adjusted mean difference in NT-proBNP from placebo was 7%. Increase in NT-proBNP from baseline to 12-weeks was strongly associated with risk of CV death/HF hospitalization.<br /><b>Conclusions</b><br />The benefit of empagliflozin on cardiac outcomes and decline of eGFR is preserved across the wide range of baseline NT-proBNP and hs-cTnT evaluated. Empagliflozin modestly reduces NT-proBNP in HFpEF.<br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 25 May 2022; epub ahead of print</small></div>
Januzzi JL, Butler J, Zannad F, Filippatos G, ... Anker SD, EMPEROR-Preserved Trial Study Group
JACC Heart Fail: 25 May 2022; epub ahead of print | PMID: 35670067
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<div><h4>Covariate Adjustment in Cardiovascular Randomized Controlled Trials: Its Value, Current Practice, and Need for Improvement.</h4><i>Pirondini L, Gregson J, Owen R, Collier T, Pocock S</i><br /><AbstractText>In randomized controlled trials, patient characteristics are expected to be well balanced between treatment groups; however, adjustment for characteristics that are prognostic can still be beneficial with a modest gain in statistical power. Nevertheless, previous reviews show that many trials use unadjusted analyses. In this article, we review current practice regarding covariate adjustment in cardiovascular trials among all 84 randomized controlled trials relating to cardiovascular disease published in the New England Journal of Medicine, The Lancet, and the Journal of the American Medical Association during 2019. We identify trials in which use of covariate adjustment led to a change in the trial conclusions. By using these trials as case studies, along with data from the CHARM trial and simulation studies, we demonstrate some of the potential benefits and pitfalls of covariate adjustment. We discuss some of the complexities of using covariate adjustment, including how many covariates to choose, how covariates should be modeled, how to handle missing data for baseline covariates, and how adjusted analyses are viewed by regulators. We conclude that contemporary cardiovascular trials do not make best use of covariate adjustment and that more frequent use could lead to improvements in the efficiency of future trials.</AbstractText><br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 May 2022; 10:297-305</small></div>
Pirondini L, Gregson J, Owen R, Collier T, Pocock S
JACC Heart Fail: 01 May 2022; 10:297-305 | PMID: 35483791
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<div><h4>Relationship of Dapagliflozin With Serum Sodium: Findings From the DAPA-HF Trial.</h4><i>Yeoh SE, Docherty KF, Jhund PS, Petrie MC, ... Solomon SD, McMurray JJV</i><br /><b>Objectives</b><br />This study aimed to assess the prognostic importance of hyponatremia and the effects of dapagliflozin on serum sodium in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial.<br /><b>Background</b><br />Hyponatremia is common and prognostically important in hospitalized patients with heart failure with reduced ejection fraction, but its prevalence and importance in ambulatory patients are uncertain.<br /><b>Methods</b><br />We calculated the incidence of the primary outcome (cardiovascular death or worsening heart failure) and secondary outcomes according to sodium category (≤135 and >135 mmol/L). Additionally, we assessed: 1) whether baseline serum sodium modified the treatment effect of dapagliflozin; and 2) the effect of dapagliflozin on serum sodium.<br /><b>Results</b><br />Of 4,740 participants with a baseline measurement, 398 (8.4%) had sodium ≤135 mmol/L. Participants with hyponatremia were more likely to have diabetes, be treated with diuretics, and have lower systolic blood pressure, left ventricular ejection fraction, and estimated glomerular filtration rate. Hyponatremia was associated with worse outcomes even after adjustment for predictive variables (adjusted HRs for the primary outcome 1.50 [95% CI: 1.23-1.84] and all-cause death 1.59 [95% CI: 1.26-2.01]). The benefits of dapagliflozin were similar in patients with and without hyponatremia (HR for primary endpoint: 0.83 [95% CI: 0.57-1.19] and 0.73 [95% CI: 0.63-0.84], respectively, P for interaction = 0.54; HR for all-cause death: 0.85 [95% CI: 0.56-1.29] and 0.83 [95% CI: 0.70-0.98], respectively, P for interaction = 0.96). Between baseline and day 14, more patients on dapagliflozin developed hyponatremia (11.3% vs 9.4%; P = 0.04); thereafter, this pattern reversed and at 12 months fewer patients on dapagliflozin had hyponatremia (4.6% vs 6.7%; P = 0.003).<br /><b>Conclusions</b><br />Baseline serum sodium concentration was prognostically important, but did not modify the benefits of dapagliflozin on morbidity and mortality in heart failure with reduced ejection fraction. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]: NCT03036124).<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 May 2022; 10:306-318</small></div>
Yeoh SE, Docherty KF, Jhund PS, Petrie MC, ... Solomon SD, McMurray JJV
JACC Heart Fail: 01 May 2022; 10:306-318 | PMID: 35483792
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<div><h4>Time Spent Engaging in Health Care Among Patients With Left Ventricular Assist Devices.</h4><i>Chuzi S, Ahmad FS, Wu T, Argaw S, ... Allen LA, Tibrewala A</i><br /><b>Objectives</b><br />This study aims to examine a novel patient-centered metric of time spent engaging in left ventricular assist device (LVAD)-related clinical care outside the home.<br /><b>Background</b><br />Although LVAD implantation can improve survival and functional capacity in patients with advanced heart failure, this may occur at the expense of significant time spent engaging in LVAD-related health care activities.<br /><b>Methods</b><br />The authors retrospectively assessed consecutive patients at a single center who received a continuous-flow LVAD between May 9, 2008, and December 31, 2019, and queried health care encounters after implantation, including all inpatient encounters and LVAD-related ambulatory encounters. Patient-level time metrics were determined, including the total number of days with any health care encounter, and the total estimated time spent receiving care. The primary outcome was the proportion (%) of days alive with an LVAD spent engaged in at least 1 health care encounter. The secondary outcome was the proportion (%) of total time alive with an LVAD spent receiving care.<br /><b>Results</b><br />Among 373 patients, the median number of days alive with LVAD was 390 (IQR: 158-840 days). Patients had a median number of 88 (IQR: 45-161) days with ≥1 health care encounter, accounting for 23.2% (IQR: 16.3%-32.4%) of their days alive with an LVAD. A median 6.0% (IQR: 2.1%-14.1%) and 15.0% (IQR: 10.7%-20.0%) of total days alive were spent in inpatient and ambulatory encounters, respectively. Patients spent a median of 592 (IQR: 197-1,257) hours receiving care, accounting for 5.6% (IQR: 2.2%-12.7%) of their total time alive with an LVAD.<br /><b>Conclusions</b><br />LVAD patients spent more than 1 of every 5 days engaging in health care. Our findings may inform strategies to improve efficiency of postdischarge care delivery and expectations for post-treatment care.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 May 2022; 10:321-332</small></div>
Chuzi S, Ahmad FS, Wu T, Argaw S, ... Allen LA, Tibrewala A
JACC Heart Fail: 01 May 2022; 10:321-332 | PMID: 35483794
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<div><h4>Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial.</h4><i>Cikes M, Planinc I, Claggett B, Cunningham J, ... McMurray JJV, Solomon SD</i><br /><b>Objectives</b><br />In this study, the authors sought to assess the relationship between AFF and outcomes, the treatment response to sacubitril/valsartan and first-detected AFF in patients with HFpEF enrolled in the PARAGON-HF trial.<br /><b>Background</b><br />Atrial fibrillation and flutter (AFF) are common in heart failure with preserved ejection fraction (HFpEF) and increase the risk of adverse outcomes.<br /><b>Methods</b><br />A total of 4,776 patients formed 3 groups: those with AFF according to electrocardiography (ECG) at enrollment (n = 1,552; 33%), those with history of AFF but without AFF on ECG at enrollment (n = 1,005; 21%), and those without history of AFF or AFF on ECG at enrollment (n = 2,219, 46%). We assessed outcomes, treatment response to sacubitril/valsartan in each group, and the risk associated with first-detected AFF in patients without any known AFF. The primary outcome was a composite of total heart failure hospitalizations and cardiovascular death.<br /><b>Results</b><br />History of AFF and AFF at enrollment were associated with higher risk of the primary outcome (risk ratio [RR]: 1.36 [95% CI: 1.12-1.65] and RR: 1.31 [1.11-1.54], respectively), than no AFF. Neither history of AFF nor AFF at enrollment modified the treatment effect of sacubitril/valsartan. Post randomization AFF occurred in 12% of patients without previous AFF and was associated with 2.8-fold higher risk of the primary outcome, but it was not influenced by sacubitril/valsartan.<br /><b>Conclusions</b><br />History of AFF and AFF on ECG at enrollment were associated with a higher risk of the primary outcome. First-detected AFF was not influenced by sacubitril/valsartan, yet it was associated with increased risk of all subsequent outcomes and may represent a potential target for future HFpEF trials. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 May 2022; 10:336-346</small></div>
Cikes M, Planinc I, Claggett B, Cunningham J, ... McMurray JJV, Solomon SD
JACC Heart Fail: 01 May 2022; 10:336-346 | PMID: 35483796
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<div><h4>Trends in HF Hospitalizations Among Young Adults in the United States From 2004 to 2018.</h4><i>Jain V, Minhas AMK, Khan SU, Greene SJ, ... Butler J, Khan MS</i><br /><b>Objectives</b><br />The aim of this study was to assess trends in heart failure (HF) hospitalizations among young adults.<br /><b>Background</b><br />Data are limited regarding clinical characteristics and outcomes of young adults hospitalized for HF.<br /><b>Methods</b><br />The National Inpatient Sample database was analyzed to identify adults aged 18 to 45 years who were hospitalized for HF between 2004 and 2018.<br /><b>Results</b><br />In total, 767,180 weighted hospitalizations for HF in young adults were identified, equivalent to 4.32 (95% CI: 4.31-4.33) per 10,000 person-years. Overall HF hospitalizations per 10,000 U.S. population of young adults decreased from 2.43 in 2004 to 1.82 in 2012, followed by an increase to 2.51 in 2018. Black adults (50.1%) had a significantly higher proportion of HF hospitalizations compared with White (31.9%) and Hispanic adults (12.2%) throughout the study period. Nearly half of patients (45.8%) lived in zip codes in the lowest quartile of national household income. Overall, in-hospital mortality was 1.3%, which decreased over time; this trend was consistent by sex and race. The overall mean LOS (5.2 days) remained stable over time, while the mean inflation-adjusted cost increased from $12,449 in 2004 to $16,786 in 2018, with significant overall differences by race and sex.<br /><b>Conclusions</b><br />This longitudinal examination of U.S. clinical practice revealed that HF hospitalizations among young adults have increased since 2013. Approximately half of these patients are Black and reside in zip codes in the lowest quartile of national household income. Temporal trends showed decreased in-hospital mortality, stable adjusted lengths of stay, and increased inflation-adjusted costs, with significant racial differences in hospitalization rates.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 May 2022; 10:350-362</small></div>
Jain V, Minhas AMK, Khan SU, Greene SJ, ... Butler J, Khan MS
JACC Heart Fail: 01 May 2022; 10:350-362 | PMID: 35483798
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<div><h4>Spirituality in Patients With Heart Failure.</h4><i>Tobin RS, Cosiano MF, O\'Connor CM, Fiuzat M, ... Steinhauser KE, Mentz RJ</i><br /><AbstractText>With advances in heart failure (HF) treatment, patients are living longer, putting further emphasis on quality of life (QOL) and the role of palliative care principles in their care. Spirituality is a core domain of palliative care, best defined as a dynamic, multidimensional aspect of oneself for which 1 dimension is that of finding meaning and purpose. There are substantial data describing the role of spirituality in patients with cancer but a relative paucity of studies in HF. In this review article, we explore the current knowledge of spirituality in patients with HF; describe associations among spirituality, QOL, and HF outcomes; and propose clinical applications and future directions regarding spiritual care in this population. Studies suggest that spirituality serves as a potential target for palliative care interventions to improve QOL, caregiver support, and patient outcomes including rehospitalization and mortality. We suggest the development of a spirituality-screening tool, similar to the Patient Health Questionnaire-2 used to screen for depression, to identify patients with HF at risk for spiritual distress. Novel tools are soon to be validated by members of our group. Given spirituality in HF remains less well studied compared with other patient populations, further controlled trials and uniform measures of spirituality are needed to understand its impact better.</AbstractText><br /><br />Copyright © 2022 American College of Cardiology Foundation. All rights reserved.<br /><br /><small>JACC Heart Fail: 31 Mar 2022; 10:217-226</small></div>
Tobin RS, Cosiano MF, O'Connor CM, Fiuzat M, ... Steinhauser KE, Mentz RJ
JACC Heart Fail: 31 Mar 2022; 10:217-226 | PMID: 35361439
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<div><h4>Diabetes Mellitus, Race, and Effects of Omega-3 Fatty Acids on Incidence of Heart Failure Hospitalization.</h4><i>Djoussé L, Cook NR, Kim E, Walter J, ... Gaziano JM, Manson JE</i><br /><b>Objectives</b><br />The primary aim was to evaluate whether prevalent type 2 diabetes (T2D) modifies the effects of omega-3 supplementation on heart failure (HF) hospitalization. The secondary aim was to examine if race modifies the effects of omega-3 supplements on HF risk.<br /><b>Background</b><br />It is unclear whether race and T2D modify the effects of omega-3 supplementation on the incidence of HF.<br /><b>Methods</b><br />In this ancillary study of the parent VITAL (Vitamin D and Omega-3 Trial)-a completed randomized trial testing the efficacy of vitamin D and omega-3 fatty acids on cardiovascular diseases and cancer, we assessed the role of T2D and race on the effects of omega-3 supplements on the incidence of HF hospitalization (adjudicated by a review of medical records and supplemented with a query of Centers for Medicare and Medicaid Services data).<br /><b>Results</b><br />When omega-3 supplements were compared with placebo, the HR for first HF hospitalization was 0.69 (95% CI: 0.50-0.95) in participants with prevalent T2D and 1.09 (95% CI: 0.88-1.34) in those without T2D (P for interaction = 0.019). Furthermore, prevalent T2D modified the effects of omega-3 fatty acids on the incidence of recurrent HF hospitalization (HR: 0.53; 95% CI: 0.41-0.69 in participants with prevalent T2D vs HR: 1.07; 95% CI: 0.89-1.28 in those without T2D; P interaction <0.0001). In our secondary analysis, omega-3 supplementation reduced recurrent HF hospitalization only in Black participants (P interaction race × omega-3 = 0.0497).<br /><b>Conclusions</b><br />Our data show beneficial effects of omega-3 fatty acid supplements on incidence of HF hospitalization in participants with T2D but not in those without T2D, and such benefit appeared to be stronger in Black participants with T2D. (Intervention With Vitamin D and Omega-3 Supplements and Incident Heart Failure; NCT02271230; Vitamin D and Omega-3 Trial [VITAL]; NCT01169259 [parent study]).<br /><br />Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 31 Mar 2022; 10:227-234</small></div>
Djoussé L, Cook NR, Kim E, Walter J, ... Gaziano JM, Manson JE
JACC Heart Fail: 31 Mar 2022; 10:227-234 | PMID: 35361440
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<div><h4>1 Year HIIT and Omega-3 Fatty Acids to Improve Cardiometabolic Risk in Stage-A Heart Failure.</h4><i>Hearon CM, Dias KA, MacNamara JP, Hieda M, ... Levine BD, Sarma S</i><br /><b>Objectives</b><br />This study aims to determine whether 1 year of high-intensity interval training (HIIT) and omega-3 fatty acid (n-3 FA) supplementation would improve fitness, cardiovascular structure/function, and body composition in obese middle-aged adults at high-risk of heart failure (HF) (stage A).<br /><b>Background</b><br />It is unclear if intensive lifestyle interventions begun in stage A HF can improve key cardiovascular and metabolic risk factors.<br /><b>Methods</b><br />High-risk obese adults (n = 80; age 40 to 55 years; N-terminal pro-B-type natriuretic peptide >40 pg/mL or high-sensitivity cardiac troponin T >0.6 pg/mL; visceral fat >2 kg) were randomized to 1 year of HIIT exercise or attention control, with n-3 FA (1.6 g/daily omega-3-acid ethyl esters) or placebo supplementation (olive oil 1.6 g daily). Outcome variables were exercise capacity quantified as peak oxygen uptake (V.O<sub>2</sub>), left ventricular (LV) mass, LV volume, myocardial triglyceride content (magnetic resonance spectroscopy), arterial stiffness/function (central pulsed-wave velocity; augmentation index), and body composition (dual x-ray absorptiometry scan).<br /><b>Results</b><br />Fifty-six volunteers completed the intervention. There was no detectible effect of HIIT on visceral fat or myocardial triglyceride content despite a reduction in total adiposity (Δ: -2.63 kg, 95% CI: -4.08 to -0.46, P = 0.018). HIIT improved exercise capacity by ∼24% (ΔV.O<sub>2</sub>: 4.46 mL/kg per minute, 95% CI: 3.18 to 5.56; P < 0.0001), increased LV mass (Δ: 9.40 g, 95% CI: 4.36 to 14.44; P < 0.001), and volume (Δ: 12.33 mL, 95 % CI: 5.61 to 19.05; P < 0.001) and reduced augmentation index (Δ: -4.81%, 95% CI: -8.63 to -0.98; P = 0.009). There was no independent or interaction effect of n-3 FA on any outcome.<br /><b>Conclusions</b><br />One-year HIIT improved exercise capacity, cardiovascular structure/function, and adiposity in stage A HF with no independent or additive effect of n-3 FA administration. (Improving Metabolic Health in Patients With Diastolic Dysfunction [MTG]; NCT03448185).<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 31 Mar 2022; 10:238-249</small></div>
Hearon CM, Dias KA, MacNamara JP, Hieda M, ... Levine BD, Sarma S
JACC Heart Fail: 31 Mar 2022; 10:238-249 | PMID: 35361442
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<div><h4>Depressive Symptoms and Incident Heart Failure Risk in the Southern Community Cohort Study.</h4><i>Dixon DD, Xu M, Akwo EA, Nair D, ... Lipworth L, Gupta DK</i><br /><b>Objectives</b><br />This study aims to examine whether greater frequency of depressive symptoms associates with increased risk of incident heart failure (HF).<br /><b>Background</b><br />Depressive symptoms associate with adverse prognosis in patients with prevalent HF. Their association with incident HF is less studied, particularly in low-income and minority individuals.<br /><b>Methods</b><br />We studied 23,937 Black or White Southern Community Cohort Study participants (median age: 53 years, 70% Black, 64% women) enrolled between 2002 and 2009, without prevalent HF, receiving Centers for Medicare and Medicaid Services coverage. Cox models adjusted for traditional HF risk factors, socioeconomic and behavioral factors, social support, and antidepressant medications were used to quantify the association between depressive symptoms assessed at enrollment via the Center for Epidemiologic Studies Depression Scale (CESD-10) and incident HF ascertained from Centers for Medicare and Medicaid Services International Classification of Diseases-9th Revision (ICD-9) (code: 428.x) and ICD-10 (codes: I50, I110) codes through December 31, 2016.<br /><b>Results</b><br />The median CESD-10 score was 9 (IQR: 5 to 13). Over a median 11-year follow-up, 6,081 (25%) participants developed HF. The strongest correlates of CESD-10 score were antidepressant medication use, age, and socioeconomic factors, rather than traditional HF risk factors. Greater frequency of depressive symptoms associated with increased incident HF risk (per 8-U higher CESD-10 HR: 1.04; 95% CI: 1.00 to 1.09; P = 0.038) without variation by race or sex. The association between depressive symptoms and incident HF varied by antidepressant use (interaction-P = 0.03) with increased risk among individuals not taking antidepressants.<br /><b>Conclusions</b><br />In this high-risk, low-income, cohort of predominantly Black participants, greater frequency of depressive symptoms significantly associates with higher risk of incident HF.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 31 Mar 2022; 10:254-262</small></div>
Dixon DD, Xu M, Akwo EA, Nair D, ... Lipworth L, Gupta DK
JACC Heart Fail: 31 Mar 2022; 10:254-262 | PMID: 35361444
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<div><h4>Frailty, Guideline-Directed Medical Therapy, and Outcomes in HFrEF: From the GUIDE-IT Trial.</h4><i>Khan MS, Segar MW, Usman MS, Singh S, ... Butler J, Pandey A</i><br /><b>Objectives</b><br />In this study, we sought to evaluate the association of frailty with the use of optimal guideline-directed medical therapy (GDMT) and outcomes in heart failure with reduced ejection fraction (HFrEF).<br /><b>Background</b><br />The burden of frailty in HFrEF is high, and the patterns of GDMT use according to frailty status have not been studied previously.<br /><b>Methods</b><br />A post hoc analysis of patients with HFrEF enrolled in the GUIDE-IT (Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment in Heart Failure) trial was conducted. Frailty was assessed with the use of a frailty index (FI) using a 38-variable deficit model, and participants were categorized into 3 groups: class 1: nonfrail, FI <0.21); class 2: intermediate frailty, FI 0.21-0.31), and class 3: high frailty, FI >0.31). Multivariate-adjusted Cox models were used to study the association of frailty status with clinical outcomes. Use of optimal GDMT over time (beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and mineralocorticoid receptor antagonists) across frailty strata was assessed with the use of adjusted linear and logistic mixed-effect models.<br /><b>Results</b><br />The study included 879 participants, of which 56.3% had high frailty burden (class 3 FI). A higher frailty burden was associated with a significantly higher risk of HF hospitalization or death in adjusted Cox models: high frailty vs nonfrail HR: 1.76, 95% CI: 1.20-2.58. On follow-up, participants with high frailty burden also had a significantly lower likelihood of achieving optimal GDMT: high frailty vs non-frail GDMT triple therapy use at study end: 17.7% vs 28.4%; P interaction, frailty class × time <0.001.<br /><b>Conclusions</b><br />Patients with HFrEF with a high burden of frailty have a significantly higher risk for adverse clinical outcomes and are less likely to be initiated and up-titrated on an optimal GDMT regimen.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 31 Mar 2022; 10:266-275</small></div>
Khan MS, Segar MW, Usman MS, Singh S, ... Butler J, Pandey A
JACC Heart Fail: 31 Mar 2022; 10:266-275 | PMID: 35361446
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<div><h4>Exercise Blood Pressure in Heart Failure With Preserved and Reduced Ejection Fraction.</h4><i>Namasivayam M, Lau ES, Zern EK, Schoenike MW, ... Malhotra R, Lewis GD</i><br /><b>Objectives</b><br />This study aimed to evaluate hemodynamic correlates of inducible blood pressure (BP) pulsatility with exercise in heart failure with preserved ejection fraction (HFpEF), to identify relationships to outcomes, and to compare this with heart failure with reduced ejection fraction (HFrEF).<br /><b>Background</b><br />In HFpEF, determinants and consequences of exercise BP pulsatility are not well understood.<br /><b>Methods</b><br />We measured exercise BP in 146 patients with HFpEF who underwent invasive cardiopulmonary exercise testing. Pulsatile BP was evaluated as proportionate pulse pressure (PrPP), the ratio of pulse pressure to systolic pressure. We measured pulmonary arterial catheter pressures, Fick cardiac output, respiratory gas exchange, and arterial stiffness. We correlated BP changes to central hemodynamics and cardiovascular outcome (nonelective cardiovascular hospitalization) and compared findings with 57 patients with HFrEF from the same referral population.<br /><b>Results</b><br />In HFpEF, only age (standardized beta = 0.593; P < 0.001), exercise stroke volume (standardized beta = 0.349; P < 0.001), and baseline arterial stiffness (standardized beta = 0.182; P = 0.02) were significant predictors of peak exercise PrPP in multivariable analysis (R = 0.661). In HFpEF, lower PrPP was associated with lower risk of cardiovascular events, despite adjustment for confounders (HR:0.53 for PrPP below median; 95% CI: 0.28-0.98; P = 0.043). In HFrEF, lower exercise PrPP was not associated with arterial stiffness but was associated with lower peak exercise stroke volume (P = 0.013) and higher risk of adverse cardiovascular outcomes (P = 0.004).<br /><b>Conclusions</b><br />In HFpEF, greater inducible BP pulsatility measured using exercise PrPP reflects greater arterial stiffness and higher risk of adverse cardiovascular outcomes, in contrast to HFrEF where inducible exercise BP pulsatility relates to stroke volume reserve and favorable outcome.<br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 31 Mar 2022; 10:278-286</small></div>
Namasivayam M, Lau ES, Zern EK, Schoenike MW, ... Malhotra R, Lewis GD
JACC Heart Fail: 31 Mar 2022; 10:278-286 | PMID: 35361448
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<div><h4>Challenges Facing Heart Failure Patients With Limited English Proficiency: A Qualitative Analysis Leveraging Interpreters\' Perspectives.</h4><i>Latif Z, Makuvire T, Feder SL, Wadhera RK, ... Pinzon PQ, Warraich HJ</i><br /><b>Objectives</b><br />The authors sought to understand the challenges facing heart failure (HF) patients with limited English proficiency (LEP) using medical interpreters\' perspectives.<br /><b>Background</b><br />LEP HF patients experience worse HF outcomes, including higher readmission rates and emergency department visits. To elucidate the challenges this population faces, we interviewed interpreters to identify gaps in care quality and ways to improve care for LEP HF patients.<br /><b>Methods</b><br />We conducted a qualitative study using semistructured interviews with interpreters working at an academic medical center. All interpreters employed by the medical center were eligible to participate. Interviews were analyzed using thematic analysis.<br /><b>Results</b><br />We interviewed 20 interpreters from 9 languages (mean age: 48 ± 14.3 years; mean experience: 16.3 ± 10.6 years). Two themes regarding the challenges of care delivery to LEP HF patients emerged: 1) LEP patients often had a limited understanding of HF etiology, prognosis, and treatment options, and interpreters cited difficulty explaining HF given the complexity of the subject; and 2) practical steps to improve the discharge process for LEP HF patients. Integrating interpreters into both the inpatient and outpatient HF teams was a strongly supported intervention. Additionally, conducting pre-encounter huddles, providing the interpreter service phone number at the time of discharge, involving family members when appropriate, and considering nutrition referrals were all important steps highlighted by interpreters.<br /><b>Conclusions</b><br />This study illuminates challenges that LEP HF patients face and provides potential solutions to improve care for this vulnerable group. Integrating interpreters as part of the HF team and designing practical discharge plans for LEP HF patients could reduce current disparities.<br /><br />Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 21 Mar 2022; epub ahead of print</small></div>
Latif Z, Makuvire T, Feder SL, Wadhera RK, ... Pinzon PQ, Warraich HJ
JACC Heart Fail: 21 Mar 2022; epub ahead of print | PMID: 35370123
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<div><h4>Complications and Mortality Following CRT-D Versus ICD Implants in Older Medicare Beneficiaries With Heart Failure.</h4><i>Zeitler EP, Austin AM, Leggett CG, Gilstrap LG, ... Skinner JS, Al-Khatib SM</i><br /><b>Objectives</b><br />This study sought to assess the comparative effectiveness of cardiac resynchronization therapy with defibrillator (CRT-D) over implantable cardioverter-defibrillator (ICD) alone in older Medicare patients with heart failure with reduced ejection fraction (HFrEF).<br /><b>Background</b><br />Despite growing numbers of older patients with HFrEF, the benefits of cardiac resynchronization therapy (CRT) in this group are largely unknown.<br /><b>Methods</b><br />A cohort of fee-for-service Medicare beneficiaries ≥65 years of age with HFrEF and enrolled in Medicare Part D who underwent CRT-D or ICD implantation from January 2008 to August 2015 was identified. Beneficiaries were divided by age (65-74, 75-84, and 85+ years), and outcomes were compared between the CRT-D and ICD groups after inverse probability weighting.<br /><b>Results</b><br />Compared with the ICD group, the CRT-D group was older and more likely to be White, be female, and have left bundle branch block. After weighting, overall complications were high across age and device groups (14%-20%). The 1-year mortality was high across all groups. In the 2 oldest age strata, the hazard of death was lower in the CRT-D group (HR: 0.90; 95% CI: 0.86-0.95 and HR: 0.81; 95% CI: 0.72-0.90, respectively; P < 0.001); the hazard of heart failure hospitalization was lower for CRT-D vs ICD in the 85+ years age group (HR: 0.82; 95% CI: 0.74-0.92; P < 0.001).<br /><b>Conclusions</b><br />In older Medicare beneficiaries undergoing ICD with or without CRT, complications and 1-year mortality were high. Compared with ICD alone, CRT-D was associated with a lower hazard of mortality in patients ≥74 years of age and lower hazard of HF hospitalization in those ≥85 years of age. These findings support the use of CRT in eligible older patients undergoing ICD implantation.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 27 Feb 2022; 10:147-157</small></div>
Zeitler EP, Austin AM, Leggett CG, Gilstrap LG, ... Skinner JS, Al-Khatib SM
JACC Heart Fail: 27 Feb 2022; 10:147-157 | PMID: 35241242
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<div><h4>NT-proBNP and ICD in Nonischemic Systolic Heart Failure: Extended Follow-Up of the DANISH Trial.</h4><i>Butt JH, Yafasova A, Elming MB, Dixen U, ... Thune JJ, Køber L</i><br /><b>Objectives</b><br />In this extended follow-up study of the DANISH (Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators in Patients with Non-ischemic Systolic Heart Failure on Mortality) trial, adding 4 years of additional follow-up, we examined the effect of implantable cardioverter-defibrillator (ICD) implantation according to baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) level.<br /><b>Background</b><br />In the DANISH trial, NT-proBNP level at baseline appeared to modify the response to ICD implantation.<br /><b>Methods</b><br />In the DANISH trial, 1,116 patients with nonischemic systolic HF were randomized to receive an ICD (N = 556) or usual clinical care (N = 550). Outcomes were analyzed according to NT-proBNP levels (below/above median) at baseline. The primary outcome was death from any cause.<br /><b>Results</b><br />All 1,116 patients in the DANISH trial had an available NT-proBNP measurement at baseline (median: 1,177 pg/mL; range: 200-22,918 pg/mL). There was a trend toward a reduction in all-cause death with ICD implantation, compared with usual clinical care, in patients with NT-proBNP levels lower than the median (HR: 0.75 [95% CI: 0.55-1.03]), but not in those with higher NT-proBNP levels (HR: 0.95 [95% CI: 0.74-1.21]) (P<sub>interaction</sub> = 0.28). Similarly, ICD implantation significantly reduced the rate of cardiovascular (CV) and sudden cardiovascular death (SCD) in patients with NT-proBNP levels lower than the median (CV death, HR: 0.69 [95% CI: 0.47-1.00]; SCD, HR: 0.37 [95% CI: 0.19-0.75]), but not in those with higher levels (CV death, HR: 0.94 [95% CI: 0.70-1.25]; SCD, HR: 0.86 [95% CI: 0.49-1.51]) (P<sub>interaction</sub> = 0.20 and 0.08 for CV death and SCD, respectively).<br /><b>Conclusions</b><br />Lower baseline NT-proBNP levels could identify patients with nonischemic systolic HF who may derive benefit from ICD implantation. (Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators in Patients with Non-ischemic Systolic Heart Failure on Mortality [DANISH]; NCT00542945).<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 27 Feb 2022; 10:161-171</small></div>
Butt JH, Yafasova A, Elming MB, Dixen U, ... Thune JJ, Køber L
JACC Heart Fail: 27 Feb 2022; 10:161-171 | PMID: 35241243
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<div><h4>Renal Compression in Heart Failure: The Renal Tamponade Hypothesis.</h4><i>Boorsma EM, Ter Maaten JM, Voors AA, van Veldhuisen DJ</i><br /><AbstractText>Renal dysfunction is one of the strongest predictors of outcome in heart failure. Several studies have revealed that both reduced perfusion and increased congestion (and central venous pressure) contribute to worsening renal function in heart failure. This paper proposes a novel factor in the link between cardiac and renal dysfunction: \"renal tamponade\" or compression of renal structures caused by the limited space for expansion. This space can be limited either by the rigid renal capsule that encloses the renal interstitial tissue or by the layer of fat around the kidneys or by the peritoneal space exerting pressure on the retroperitoneal kidneys. Renal decapsulation in animal models of heart failure and acute renal ischemia has been shown effective in alleviating pressure-related injury within the kidney itself, thus supporting this concept and making it a potentially interesting novel treatment in heart failure.</AbstractText><br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 27 Feb 2022; 10:175-183</small></div>
Boorsma EM, Ter Maaten JM, Voors AA, van Veldhuisen DJ
JACC Heart Fail: 27 Feb 2022; 10:175-183 | PMID: 35241245
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<div><h4>Baseline Characteristics of Patients With HF With Mildly Reduced and Preserved Ejection Fraction: DELIVER Trial.</h4><i>Solomon SD, Vaduganathan M, Claggett BL, de Boer RA, ... Petersson M, McMurray JJV</i><br /><b>Objectives</b><br />This report describes the baseline clinical profiles and management of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial participants and how these compare with those in other contemporary heart failure with preserved ejection fraction trials.<br /><b>Background</b><br />The DELIVER trial was designed to evaluate the effects of the sodium-glucose cotransporter-2 inhibitor dapagliflozin on cardiovascular death, heart failure (HF) hospitalization, or urgent HF visits in patients with HF with mildly reduced and preserved left ventricular ejection fraction (LVEF).<br /><b>Methods</b><br />Adults with symptomatic HF and LVEF >40%, with or without type 2 diabetes mellitus, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and evidence of structural heart disease were randomized to dapagliflozin 10 mg once daily or matching placebo.<br /><b>Results</b><br />A total of 6,263 patients were randomized (mean age: 72 ± 10 years; 44% women; 45% type 2 diabetes mellitus; 45% with body mass index ≥30 kg/m<sup>2</sup>; and 57% with history of atrial fibrillation or flutter). Most participants had New York Heart Association functional class II symptoms (75%). Baseline mean LVEF was 54.2 ± 8.8% and median NT-proBNP of 1,399 pg/mL (IQR: 962 to 2,210 pg/mL) for patients in atrial fibrillation/flutter compared with 716 pg/mL (IQR: 469 to 1,281 pg/mL) in those who were not. Patients in both hospitalized and ambulatory settings were enrolled, including 10% enrolled in-hospital or within 30 days of a hospitalization for HF. Eighteen percent of participants had HF with improved LVEF.<br /><b>Conclusions</b><br />DELIVER is the largest and broadest clinical trial of this population to date and enrolled high-risk, well-treated patients with HF with mildly reduced and preserved LVEF. (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [NCT03619213]).<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 27 Feb 2022; 10:184-197</small></div>
Solomon SD, Vaduganathan M, Claggett BL, de Boer RA, ... Petersson M, McMurray JJV
JACC Heart Fail: 27 Feb 2022; 10:184-197 | PMID: 35241246
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<div><h4>Clinical Outcomes With Metformin and Sulfonylurea Therapies Among Patients With Heart Failure and Diabetes.</h4><i>Khan MS, Solomon N, DeVore AD, Sharma A, ... Fonarow GC, Greene SJ</i><br /><b>Objectives</b><br />The authors sought to characterize associations between initiation of metformin and sulfonylurea therapy and clinical outcomes among patients with comorbid heart failure (HF) and diabetes (overall and by ejection fraction [EF] phenotype).<br /><b>Background</b><br />Metformin and sulfonylureas are frequently prescribed to patients with diabetes for glycemic control. The impact of these therapies on clinical outcomes among patients with comorbid HF and diabetes is unclear.<br /><b>Methods</b><br />The authors evaluated Medicare beneficiaries hospitalized for HF in the Get With The Guidelines-Heart Failure Registry between 2006 and 2014 with diabetes and not prescribed metformin or sulfonylurea before admission. In parallel separate analyses for metformin and sulfonylurea, patients with newly prescribed therapy within 90 days of discharge were compared with patients not prescribed therapy. Multivariable models landmarked at 90 days evaluated associations between prescription of therapy, and mortality and hospitalization for HF (HHF) at 12 months. Negative control (falsification) endpoints included hospitalization for urinary tract infection, hospitalization for gastrointestinal bleed, and influenza vaccination. Prespecified subgroup analyses were stratified by EF ≤40% versus >40%.<br /><b>Results</b><br />Of 5,852 patients, 454 (7.8%) were newly prescribed metformin and 504 (8.6%) were newly prescribed sulfonylurea. After adjustment, metformin prescription was independently associated with reduced risk of composite mortality/HHF (HR: 0.81; 95% CI: 0.67-0.98; P = 0.03), but individual components were not statistically significant. Findings among patients with EF >40% accounted for associations with mortality/HHF (HR: 0.68; 95% CI: 0.52-0.90) and HHF (HR: 0.58; 95% CI: 0.40-0.85) endpoints (all P for interaction ≤0.04). After adjustment, sulfonylurea initiation was associated with increased risk of mortality (HR: 1.24; 95% CI: 1.00-1.52; P = 0.045) and HHF (HR: 1.22; 95% CI: 1.00-1.48; P = 0.050) with nominal statistical significance. Associations between sulfonylurea initiation and endpoints were consistent regardless of EF (all P for interaction >0.11). Neither metformin initiation nor sulfonylurea initiation were associated with negative control endpoints.<br /><b>Conclusions</b><br />In this population of older U.S. adults hospitalized for HF with comorbid diabetes, metformin initiation was independently associated with substantial improvements in 12-month clinical outcomes, driven by findings among patients with EF >40%. By contrast, sulfonylurea initiation was associated with excess risk of death and HF hospitalization, regardless of EF.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 27 Feb 2022; 10:198-210</small></div>
Khan MS, Solomon N, DeVore AD, Sharma A, ... Fonarow GC, Greene SJ
JACC Heart Fail: 27 Feb 2022; 10:198-210 | PMID: 34895861
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<div><h4>Effect of Dapagliflozin, Compared With Placebo, According to Baseline Risk in DAPA-HF.</h4><i>Docherty KF, Simpson J, Jhund PS, Inzucchi SE, ... McMurray JJV, DAPA-HF Investigators and Committees</i><br /><b>Objectives</b><br />The authors sought to examine the effect of dapagliflozin across the spectrum of risk in patients enrolled in DAPA-HF.<br /><b>Background</b><br />In the DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) trial, the sodium-glucose cotransporter 2 inhibitor dapagliflozin decreased the risk of worsening HF events and cardiovascular death in patients with HF and reduced ejection fraction.<br /><b>Methods</b><br />The MAGGIC (Meta-analysis Global Group in Chronic Heart Failure) and the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) PREDICT-HF (Risk of Events and Death in the Contemporary Treatment of Heart Failure) risk models were used to categorize patients according to risk score quintiles. The authors analyzed rates of the primary composite outcome of a worsening HF event or cardiovascular death, its components, and all-cause mortality according to risk quintile and whether risk modified the effect of dapagliflozin.<br /><b>Results</b><br />The MAGGIC score was available for 4,740 of 4,744 patients in DAPA-HF (median score 22 [IQR: 18-25]). A1-point increase was associated with an 8.2% (95% CI: 6.9%-9.4%) higher relative risk of the primary endpoint (P < 0.001). The benefit of dapagliflozin over placebo for the primary endpoint was similar across the spectrum of MAGGIC risk score (interaction P = 0.71). Applying the overall relative risk reduction (26%) with dapagliflozin added to standard therapy resulted in 7 fewer patients in the highest MAGGIC risk quintile experiencing a primary outcome, compared with 2 in the lowest quintile, per 100 person-years of treatment. The findings with PREDICT-HF were similar, although this model led to better risk discrimination.<br /><b>Conclusions</b><br />The benefits of dapagliflozin were consistent across the broad spectrum of baseline risk in DAPA-HF.<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 30 Jan 2022; 10:104-118</small></div>
Docherty KF, Simpson J, Jhund PS, Inzucchi SE, ... McMurray JJV, DAPA-HF Investigators and Committees
JACC Heart Fail: 30 Jan 2022; 10:104-118 | PMID: 35115084
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<div><h4>Early B-Type Natriuretic Peptide Change in HFrEF Patients Treated With Sacubitril/Valsartan: A Pooled Analysis of EVALUATE-HF and PROVE-HF.</h4><i>Myhre PL, Prescott MF, Murphy SP, Fang JC, ... Solomon SD, Januzzi JL</i><br /><b>Objectives</b><br />This study assessed changes in B-type natriuretic peptide (BNP) among patients with heart failure with reduced ejection fraction (HFrEF) treated with sacubitril/valsartan (Sac/Val) according to standard prescribing information.<br /><b>Background</b><br />Through inhibition of neprilysin, Sac/Val may increase BNP concentrations.<br /><b>Methods</b><br />In an individual patient analysis from the EVALUATE-HF (Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction) (n = 221) and the PROVE-HF (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes) (n = 146) studies, we examined changes in BNP, N-terminal pro-BNP (NT-proBNP), and urinary cyclic guanosine monophosphate (ucGMP) from baseline to week 4 and week 12.<br /><b>Results</b><br />Median (IQRs) concentration of BNP at baseline, week 4, and week 12 were 145 [IQR: 55-329], 136 [IQR: 50-338], and 135 [IQR: 51-299] ng/L, respectively. There was no significant change from baseline to week 4 (0% [-30% to +41%]; P = 0.36) or week 12 (+1% [-36% to +50%]; P = 0.97). By week 12, one-half of the study participants had a BNP decline. There was no association between Sac/Val dose and BNP changes. Change in BNP was directly associated with change in NT-proBNP (rho: = 0.81; P < 0.001), which decreased by -30% (-50% to -8%) and -32% (-54% to -1%) to weeks 4 and 12 (P < 0.001 for both). In contrast, change in BNP was only weakly associated with change in ucGMP (rho: = 0.19; P < 0.001). Increases in ucGMP were observed regardless of whether BNP was decreased (+11% [-34% to +115%]), unchanged (+34% [-15% to +205%]), or increased (+57% [-12% to +14%]).<br /><b>Conclusions</b><br />In this pooled analysis of patients with HFrEF with standard indications for Sac/Val treatment, there was no significant overall increase in BNP concentrations, and patients demonstrated increase in ucGMP regardless of the trajectory of BNP change. (Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction [EVALUATE-HF]; NCT02874794) (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183).<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 30 Jan 2022; 10:119-128</small></div>
Myhre PL, Prescott MF, Murphy SP, Fang JC, ... Solomon SD, Januzzi JL
JACC Heart Fail: 30 Jan 2022; 10:119-128 | PMID: 35115085
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<div><h4>Transthyretin V142I Genetic Variant and Cardiac Remodeling, Injury, and Heart Failure Risk in Black Adults.</h4><i>Coniglio AC, Segar MW, Loungani RS, Savla JJ, ... Mentz RJ, Pandey A</i><br /><b>Objectives</b><br />This study evaluated the association of transthyretin (TTR) gene variant, in which isoleucine substitutes for valine at position 122 (V142I), with cardiac structure, function, and heart failure (HF) risk among middle-aged Black adults.<br /><b>Background</b><br />The valine-to-isoleucine substitution in the TTR protein is prevalent in Black individuals and causes cardiac amyloidosis.<br /><b>Methods</b><br />Jackson Heart Study participants without HF at baseline who had available data on the TTR V142I variant were included. The association of the TTR V142I variant with baseline echocardiographic parameters and repeated measures of high-sensitivity cardiac troponin-I (hs-cTnI) was assessed using adjusted linear regression models and linear mixed models, respectively. Adjusted Cox models, restricted mean survival time analysis, and Anderson-Gill models were constructed to determine the association of TTR V142I variant with the risk of incident HF, survival free of HF, and total HF hospitalizations.<br /><b>Results</b><br />A total of 119 of 2,960 participants (4%) were heterozygous carriers of the TTR V142I variant. The TTR V142I variant was not associated with measures of cardiac parameters at baseline but was associated with a greater increase in high-sensitivity troponin I (hs-TnI) levels over time. In adjusted Cox models, TTR V142I variant carriers had significantly higher risk of incident HF (HR: 1.80; 95% CI: 1.07-3.05; P = 0.03), lower survival free of HF (mean difference: 4.0 year; 95% CI: 0.6-6.2 years); P = 0.02), and higher risk of overall HF hospitalizations (HR: 2.12; 95% CI: 1.23-3.63; P = 0.007).<br /><b>Conclusions</b><br />The TTR V142I variant in middle-aged Black adults is not associated with adverse cardiac remodeling but was associated with a significantly higher burden of chronic myocardial injury, and greater risk of incident HF and overall HF hospitalizations.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 30 Jan 2022; 10:129-138</small></div>
Coniglio AC, Segar MW, Loungani RS, Savla JJ, ... Mentz RJ, Pandey A
JACC Heart Fail: 30 Jan 2022; 10:129-138 | PMID: 35115086
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<div><h4>Postimplant Phosphodiesterase-5 Inhibitor Use in Centrifugal Flow Left Ventricular Assist Devices.</h4><i>Xanthopoulos A, Wolski K, Wang Q, Blackstone EH, ... Triposkiadis F, Starling RC</i><br /><b>Objectives</b><br />This study examined the association between phosphodiesterase-5 inhibitor (PDE-5i) use and outcomes in patients with contemporary centrifugal flow left ventricular assist devices (LVADs).<br /><b>Background</b><br />PDE-5i use may affect outcomes in patients with continuous flow LVADs.<br /><b>Methods</b><br />Patients enrolled in INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support), with HeartMate 3 (n = 4,628) or HeartWare Ventricular Assist Device (HVAD) (n = 2,601) implant were included in the analysis. The mean duration of follow-up was 11.94 ± 8.65 months. PDE-5is were used in 2,173 patients. The primary endpoint was the composite of all-cause mortality, ischemic stroke, and pump thrombosis. Propensity matching and stabilized inverse probability of treatment weights were used to adjust for baseline differences between patients receiving and not receiving PDE-5i. Adjusted Cox proportional hazards analysis was performed for each outcome.<br /><b>Results</b><br />The primary endpoint was lower in the PDE-5i group (adjusted HR: 0.77; 95% CI: 0.69-0.86; P < 0.0001; HeartMate 3: adjusted HR: 0.77; 95% CI: 0.64-0.92; P = 0.0044; HVAD: adjusted HR: 0.76; 95% CI: 0.66-0.88; P = 0.0002). All-cause mortality was lower with PDE-5is (adjusted HR: 0.75; 95% CI: 0.65-0.86; P < 0.0001; HeartMate 3: adjusted HR: 0.70; 95% CI: 0.57-0.86; P = 0.0007; HVAD: adjusted HR: 0.78; 95% CI: 0.65-0.94; P = 0.0098) and fewer ischemic strokes with PDE-5is were observed (adjusted HR: 0.71; 95% CI: 0.56-0.89; P = 0.003; HeartMate 3: adjusted HR: 0.67; 95% CI: 0.45-0.99; P = 0.045; HVAD: adjusted HR: 0.73; 95% CI: 0.56-0.97; P = 0.03). LVAD thrombosis was unchanged with PDE-5is, with overall low event rates observed.<br /><b>Conclusions</b><br />Postimplant PDE-5i use was associated with lower mortality and ischemic strokes in patients with centrifugal flow LVADs.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 30 Jan 2022; 10:89-100</small></div>
Xanthopoulos A, Wolski K, Wang Q, Blackstone EH, ... Triposkiadis F, Starling RC
JACC Heart Fail: 30 Jan 2022; 10:89-100 | PMID: 35115092
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<div><h4>A Systematic Review and Network Meta-Analysis of Pharmacological Treatment of Heart Failure With Reduced Ejection Fraction.</h4><i>Tromp J, Ouwerkerk W, van Veldhuisen DJ, Hillege HL, ... Lam CSP, Voors AA</i><br /><b>Objectives</b><br />This study sought to estimate and compare the aggregate treatment benefit of pharmacological therapy for heart failure (HF) with reduced ejection fraction.<br /><b>Background</b><br />The estimated treatment effects of various combinations of contemporary HF medical therapies are not well characterized.<br /><b>Methods</b><br />We performed a systematic network meta-analysis, using MEDLINE/EMBASE and the Cochrane Central Register of Controlled Trials for randomized controlled trials published between January 1987 and January 2020. We included angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers (BB), mineralocorticoid receptor antagonists (MRAs), digoxin, hydralazine-isosorbide dinitrate, ivabradine, angiotensin receptor-neprilysin inhibitors (ARNi), sodium glucose cotransporter-2 inhibitors (SGLT2i), vericiguat, and omecamtiv-mecarbil. The primary outcome was all-cause death. We estimated the life-years gained in 2 HF populations (BIOSTAT-CHF [BIOlogy Study to TAilored Treatment in Chronic Heart Failure] and ASIAN-HF [Asian Sudden Cardiac Death in Heart Failure Registry]).<br /><b>Results</b><br />We identified 75 relevant trials representing 95,444 participants. A combination of ARNi, BB, MRA, and SGLT2i was most effective in reducing all-cause death (HR: 0.39; 95% CI: 0.31-0.49); followed by ARNi, BB, MRA, and vericiguat (HR: 0.41; 95% CI: 0.32-0.53); and ARNi, BB, and MRA (HR: 0.44; 95% CI: 0.36-0.54). Results were similar for the composite outcome of cardiovascular death or first hospitalization for HF (HR: 0.36; 95% CI: 0.29-0.46 for ARNi, BB, MRA, and SGLT2i; HR: 0.44; 95% CI: 0.35-0.56 for ARNi, BB, MRA, and omecamtiv-mecarbil; and HR: 0.43; 95% CI: 0.34-0.55 for ARNi, BB, MRA, and vericiguat). The estimated additional number of life-years gained for a 70-year-old patient on ARNi, BB, MRA, and SGLT2i was 5.0 years (2.5-7.5 years) compared with no treatment in secondary analyses.<br /><b>Conclusions</b><br />In patients with HF with reduced ejection fraction, the estimated aggregate benefit is greatest for a combination of ARNi, BB, MRA, and SGLT2i.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 30 Jan 2022; 10:73-84</small></div>
Tromp J, Ouwerkerk W, van Veldhuisen DJ, Hillege HL, ... Lam CSP, Voors AA
JACC Heart Fail: 30 Jan 2022; 10:73-84 | PMID: 34895860
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This program is still in alpha version.