<div><h4>Early versus Later Anticoagulation for Stroke with Atrial Fibrillation.</h4><i>Fischer U, Koga M, Strbian D, Branca M, ... Dawson J, ELAN Investigators</i><br /><b>Background</b><br />The effect of early as compared with later initiation of direct oral anticoagulants (DOACs) in persons with atrial fibrillation who have had an acute ischemic stroke is unclear.<br /><b>Methods</b><br />We performed an investigator-initiated, open-label trial at 103 sites in 15 countries. Participants were randomly assigned in a 1:1 ratio to early anticoagulation (within 48 hours after a minor or moderate stroke or on day 6 or 7 after a major stroke) or later anticoagulation (day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke). Assessors were unaware of the trial-group assignments. The primary outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization. Secondary outcomes included the components of the composite primary outcome at 30 and 90 days.<br /><b>Results</b><br />Of 2013 participants (37% with minor stroke, 40% with moderate stroke, and 23% with major stroke), 1006 were assigned to early anticoagulation and 1007 to later anticoagulation. A primary-outcome event occurred in 29 participants (2.9%) in the early-treatment group and 41 participants (4.1%) in the later-treatment group (risk difference, -1.18 percentage points; 95% confidence interval [CI], -2.84 to 0.47) by 30 days. Recurrent ischemic stroke occurred in 14 participants (1.4%) in the early-treatment group and 25 participants (2.5%) in the later-treatment group (odds ratio, 0.57; 95% CI, 0.29 to 1.07) by 30 days and in 18 participants (1.9%) and 30 participants (3.1%), respectively, by 90 days (odds ratio, 0.60; 95% CI, 0.33 to 1.06). Symptomatic intracranial hemorrhage occurred in 2 participants (0.2%) in both groups by 30 days.<br /><b>Conclusions</b><br />In this trial, the incidence of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death at 30 days was estimated to range from 2.8 percentage points lower to 0.5 percentage points higher (based on the 95% confidence interval) with early than with later use of DOACs. (Funded by the Swiss National Science Foundation and others; ELAN ClinicalTrials.gov number, NCT03148457.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 24 May 2023; epub ahead of print</small></div>

<div><h4>Subepicardial Cardiomyopathy: A Disease Underlying J-Wave Syndromes and Idiopathic Ventricular Fibrillation.</h4><i>Miles C, Boukens BJ, Scrocco C, Wilde AAM, ... Coronel R, Behr ER</i><br /><AbstractText>Brugada syndrome (BrS), early repolarization syndrome (ERS), and idiopathic ventricular fibrillation (iVF) have long been considered primary electrical disorders associated with malignant ventricular arrhythmia and sudden cardiac death. However, recent studies have revealed the presence of subtle microstructural abnormalities of the extracellular matrix in some cases of BrS, ERS, and iVF, particularly within right ventricular subepicardial myocardium. Substrate-based ablation within this region has been shown to ameliorate the electrocardiographic phenotype and to reduce arrhythmia frequency in BrS. Patients with ERS and iVF may also exhibit low-voltage and fractionated electrograms in the ventricular subepicardial myocardium, which can be treated with ablation. A significant proportion of patients with BrS and ERS, as well as some iVF survivors, harbor pathogenic variants in the voltage-gated sodium channel gene, <i>SCN5A</i>, but the majority of genetic susceptibility of these disorders is likely to be polygenic. Here, we postulate that BrS, ERS, and iVF may form part of a spectrum of subtle subepicardial cardiomyopathy. We propose that impaired sodium current, along with genetic and environmental susceptibility, precipitates a reduction in epicardial conduction reserve, facilitating current-to-load mismatch at sites of structural discontinuity, giving rise to electrocardiographic changes and the arrhythmogenic substrate.</AbstractText><br /><br /><br /><br /><small>Circulation: 23 May 2023; 147:1622-1633</small></div>

<div><h4>Nonthrombogenic Roles of the Left Atrial Appendage: JACC Review Topic of the Week.</h4><i>Alkhouli M, Di Biase L, Natale A, Rihal CS, ... Lakkireddy D, Friedman PA</i><br /><AbstractText>The atrial appendage (LAA) is a well-established source of cardioembolism in patients with atrial fibrillation. Therefore, research involving the LAA has largely focused on its thrombogenic attribute and the utility of its exclusion in stroke prevention. However, recent studies have highlighted several novel functions of the LAA that may have important therapeutic implications. In this paper, we provide a concise overview of the LAA anatomy and summarize the emerging data on its nonthrombogenic roles.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 21 Mar 2023; 81:1063-1075</small></div>

<div><h4>Association of Cardiac Remodeling with Aortic Regurgitation Outcomes: The AR Consortium of the SCMR Registry.</h4><i>Malahfji M, Crudo V, Kaolawanich Y, Nguyen DT, ... Kim R, Shah DJ</i><br /><b>Background</b><br />Quantitative cardiac magnetic resonance (CMR) outcome studies in aortic regurgitation (AR) are few. It is unclear if volume measurements are beneficial over diameters.<br /><b>Objectives</b><br />To evaluate the association of CMR quantitative thresholds and outcomes in AR patients.<br /><b>Methods</b><br />in a multicenter study, asymptomatic patients with moderate or severe AR on CMR with preserved LV ejection fraction (LVEF) were evaluated. Primary outcome was development of symptoms or decrease in LVEF to <50%, guideline indications for surgery based on LV dimensions, or death under medical management. Secondary outcome was the same excluding surgery for remodeling indications. We excluded patients who underwent surgery within 30 days of CMR. ROC analyses for the association with outcome were performed.<br /><b>Results</b><br />We studied 458 patients, median age 60 (IQR 46-70) years. During a median follow-up of 2.4 years (IQR 0.9, 5.3), 133 events occurred. Optimal thresholds were regurgitant volume of 47 ml and regurgitant fraction of 43%, indexed LV end-systolic (iLVES) volume of 43 ml/m<sup>2,</sup> iLVED volume of 109 ml/m<sup>2</sup>, and iLVES diameter of 2 cm/m<sup>2</sup>. In multivariable regression analysis, iLVES volume ≥43 ml/m<sup>2</sup> (HR 2.53 (1.75, 3.66), P<0.001) and and iLVED volume ≥ 109 ml/m<sup>2</sup> were independently associated with the outcomes and provided additional discrimination improvement over iLVES diameter, whereas iLVES diameter was independently associated with the primary outcome but not the secondary outcome.<br /><b>Conclusion</b><br />In asymptomatic AR patients with preserved LVEF, CMR findings can be used to guide management. CMR based LV end-systolic volume assessment performed favorably compared to LV diameters.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>J Am Coll Cardiol: 03 Mar 2023; epub ahead of print</small></div>

<div><h4>Left Ventricular Filling Pressure in Chronic Thromboembolic Pulmonary Hypertension.</h4><i>Gerges C, Pistritto AM, Gerges M, Friewald R, ... Klepetko W, Lang IM</i><br /><b>Background</b><br />Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by obstruction of major pulmonary arteries with organized thrombi. Clinical risk factors for pulmonary hypertension due to left heart disease including metabolic syndrome, left-sided valvular heart disease, and ischemic heart disease are common in CTEPH patients.<br /><b>Objectives</b><br />The authors sought to investigate prevalence and prognostic implications of elevated left ventricular filling pressures (LVFP) in CTEPH.<br /><b>Methods</b><br />A total of 593 consecutive CTEPH patients undergoing a first diagnostic right and left heart catheterization were included in this study. Mean pulmonary arterial wedge pressure (mPAWP) and left ventricular end-diastolic pressure (LVEDP) were utilized for assessment of LVFP. Two cutoffs were applied to identify patients with elevated LVFP: 1) for the primary analysis mPAWP and/or LVEDP >15 mm Hg, as recommended by the current pulmonary hypertension guidelines; and 2) for the secondary analysis mPAWP and/or LVEDP >11 mm Hg, representing the upper limit of normal. Clinical and echocardiographic features, and long-term mortality were assessed.<br /><b>Results</b><br />LVFP was >15 mm Hg in 63 (10.6%) and >11 mm Hg in 222 patients (37.4%). Univariable logistic regression analysis identified age, systemic hypertension, diabetes, atrial fibrillation, calcific aortic valve stenosis, mitral regurgitation, and left atrial volume as significant predictors of elevated LVFP. Atrial fibrillation, calcific aortic valve stenosis, mitral regurgitation, and left atrial volume remained independent determinants of LVFP in adjusted analysis. At follow-up, higher LVFPs were measured in patients who had meanwhile undergone pulmonary endarterectomy (P = 0.002). LVFP >15 mm Hg (P = 0.021) and >11 mm Hg (P = 0.006) were both associated with worse long-term survival.<br /><b>Conclusions</b><br />Elevated LVFP is common, appears to be due to comorbid left heart disease, and predicts prognosis in CTEPH.<br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 21 Feb 2023; 81:653-664</small></div>

<div><h4>Trial of Endovascular Therapy for Acute Ischemic Stroke with Large Infarct.</h4><i>Huo X, Ma G, Tong X, Zhang X, ... Miao Z, ANGEL-ASPECT Investigators</i><br /><b>Background</b><br />The role of endovascular therapy for acute stroke with a large infarction has not been extensively studied in differing populations.<br /><b>Methods</b><br />We conducted a multicenter, prospective, open-label, randomized trial in China involving patients with acute large-vessel occlusion in the anterior circulation and an Alberta Stroke Program Early Computed Tomography Score of 3 to 5 (range, 0 to 10, with lower values indicating larger infarction) or an infarct-core volume of 70 to 100 ml. Patients were randomly assigned in a 1:1 ratio within 24 hours from the time they were last known to be well to undergo endovascular therapy and receive medical management or to receive medical management alone. The primary outcome was the score on the modified Rankin scale at 90 days (scores range from 0 to 6, with higher scores indicating greater disability), and the primary objective was to determine whether a shift in the distribution of the scores on the modified Rankin scale at 90 days had occurred between the two groups. Secondary outcomes included scores of 0 to 2 and 0 to 3 on the modified Rankin scale. The primary safety outcome was symptomatic intracranial hemorrhage within 48 hours after randomization.<br /><b>Results</b><br />A total of 456 patients were enrolled; 231 were assigned to the endovascular-therapy group and 225 to the medical-management group. Approximately 28% of the patients in both groups received intravenous thrombolysis. The trial was stopped early owing to the efficacy of endovascular therapy after the second interim analysis. At 90 days, a shift in the distribution of scores on the modified Rankin scale toward better outcomes was observed in favor of endovascular therapy over medical management alone (generalized odds ratio, 1.37; 95% confidence interval, 1.11 to 1.69; P = 0.004). Symptomatic intracranial hemorrhage occurred in 14 of 230 patients (6.1%) in the endovascular-therapy group and in 6 of 225 patients (2.7%) in the medical-management group; any intracranial hemorrhage occurred in 113 (49.1%) and 39 (17.3%), respectively. Results for the secondary outcomes generally supported those of the primary analysis.<br /><b>Conclusions</b><br />In a trial conducted in China, patients with large cerebral infarctions had better outcomes with endovascular therapy administered within 24 hours than with medical management alone but had more intracranial hemorrhages. (Funded by Covidien Healthcare International Trading [Shanghai] and others; ANGEL-ASPECT ClinicalTrials.gov number, NCT04551664.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 10 Feb 2023; epub ahead of print</small></div>

<div><h4>In Vivo Dissection of Chamber-Selective Enhancers Reveals Estrogen-Related Receptor as a Regulator of Ventricular Cardiomyocyte Identity.</h4><i>Cao Y, Zhang X, Akerberg BN, Yuan H, ... Kelly DP, Pu WT</i><br /><b>Background</b><br />Cardiac chamber-selective transcriptional programs underpin the structural and functional differences between atrial and ventricular cardiomyocytes (aCMs and vCMs). The mechanisms responsible for these chamber-selective transcriptional programs remain largely undefined.<br /><b>Methods</b><br />We nominated candidate chamber-selective enhancers (CSEs) by determining the genome-wide occupancy of 7 key cardiac transcription factors (GATA4, MEF2A, MEF2C, NKX2-5, SRF, TBX5, TEAD1) and transcriptional coactivator P300 in atria and ventricles. Candidate enhancers were tested using an adeno-associated virus-mediated massively parallel reporter assay. Chromatin features of CSEs were evaluated by performing assay of transposase accessible chromatin sequencing and acetylation of histone H3 at lysine 27-highly integrative chromatin immunoprecipitation on aCMs and vCMs. CSE sequence requirements were determined by systematic tiling mutagenesis of 29 CSEs at 5 bp resolution. Estrogen-related receptor (ERR) function in cardiomyocytes was evaluated by Cre-loxP-mediated inactivation of ERRα and ERRγ in cardiomyocytes.<br /><b>Results</b><br />We identified 152 832 and 54 824 regions reproducibly occupied by at least 1 transcription factor or P300, in atria or ventricles, respectively. Enhancer activities of 2639 regions bound by transcription factors or P300 were tested in aCMs and vCMs by adeno-associated virus-mediated massively parallel reporter assay. This identified 1092 active enhancers in aCMs or vCMs. Several overlapped loci associated with cardiovascular disease through genome-wide association studies, and 229 exhibited chamber-selective activity in aCMs or vCMs. Many CSEs exhibited differential chromatin accessibility between aCMs and vCMs, and CSEs were enriched for aCM- or vCM-selective acetylation of histone H3 at lysine 27-anchored loops. Tiling mutagenesis of 29 CSEs identified the binding motif of ERRα/γ as important for ventricular enhancer activity. The requirement of ERRα/γ to activate ventricular CSEs and promote vCM identity was confirmed by loss of the vCM gene profile in ERRα/γ knockout vCMs.<br /><b>Conclusions</b><br />We identified 229 CSEs that could be useful research tools or direct therapeutic gene expression. We showed that chamber-selective multi-transcription factor, P300 occupancy, open chromatin, and chromatin looping are predictive features of CSEs. We found that ERRα/γ are essential for maintenance of ventricular identity. Finally, our gene expression, epigenetic, 3-dimensional genome, and enhancer activity atlas provide key resources for future studies of chamber-selective gene regulation.<br /><br /><br /><br /><small>Circulation: 27 Jan 2023; epub ahead of print</small></div>

<div><h4>Sortilin enhances fibrosis and calcification in aortic valve disease by inducing interstitial cell heterogeneity.</h4><i>Iqbal F, Schlotter F, Becker-Greene D, Lupieri A, ... Sonawane AR, Aikawa E</i><br /><b>Aims</b><br />Calcific aortic valve disease (CAVD) is the most common valve disease, which consists of a chronic interplay of inflammation, fibrosis, and calcification. In this study, sortilin (SORT1) was identified as a novel key player in the pathophysiology of CAVD, and its role in the transformation of valvular interstitial cells (VICs) into pathological phenotypes is explored.<br /><b>Methods and results</b><br />An aortic valve (AV) wire injury (AVWI) mouse model with sortilin deficiency was used to determine the effects of sortilin on AV stenosis, fibrosis, and calcification. In vitro experiments employed human primary VICs cultured in osteogenic conditions for 7, 14, and 21 days; and processed for imaging, proteomics, and transcriptomics including single-cell RNA-sequencing (scRNA-seq). The AVWI mouse model showed reduced AV fibrosis, calcification, and stenosis in sortilin-deficient mice vs. littermate controls. Protein studies identified the transition of human VICs into a myofibroblast-like phenotype mediated by sortilin. Sortilin loss-of-function decreased in vitro VIC calcification. ScRNA-seq identified 12 differentially expressed cell clusters in human VIC samples, where a novel combined inflammatory myofibroblastic-osteogenic VIC (IMO-VIC) phenotype was detected with increased expression of SORT1, COL1A1, WNT5A, IL-6, and serum amyloid A1. VICs sequenced with sortilin deficiency showed decreased IMO-VIC phenotype.<br /><b>Conclusion</b><br />Sortilin promotes CAVD by mediating valvular fibrosis and calcification, and a newly identified phenotype (IMO-VIC). This is the first study to examine the role of sortilin in valvular calcification and it may render it a therapeutic target to inhibit IMO-VIC emergence by simultaneously reducing inflammation, fibrosis, and calcification, the three key pathological processes underlying CAVD.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 20 Jan 2023; epub ahead of print</small></div>

<div><h4>Psychosocial Functioning in Transgender Youth after 2 Years of Hormones.</h4><i>Chen D, Berona J, Chan YM, Ehrensaft D, ... Tishelman AC, Olson-Kennedy J</i><br /><b>Background</b><br />Limited prospective outcome data exist regarding transgender and nonbinary youth receiving gender-affirming hormones (GAH; testosterone or estradiol).<br /><b>Methods</b><br />We characterized the longitudinal course of psychosocial functioning during the 2 years after GAH initiation in a prospective cohort of transgender and nonbinary youth in the United States. Participants were enrolled in a four-site prospective, observational study of physical and psychosocial outcomes. Participants completed the Transgender Congruence Scale, the Beck Depression Inventory-II, the Revised Children\'s Manifest Anxiety Scale (Second Edition), and the Positive Affect and Life Satisfaction measures from the NIH (National Institutes of Health) Toolbox Emotion Battery at baseline and at 6, 12, 18, and 24 months after GAH initiation. We used latent growth curve modeling to examine individual trajectories of appearance congruence, depression, anxiety, positive affect, and life satisfaction over a period of 2 years. We also examined how initial levels of and rates of change in appearance congruence correlated with those of each psychosocial outcome.<br /><b>Results</b><br />A total of 315 transgender and nonbinary participants 12 to 20 years of age (mean [±SD], 16±1.9) were enrolled in the study. A total of 190 participants (60.3%) were transmasculine (i.e., persons designated female at birth who identify along the masculine spectrum), 185 (58.7%) were non-Latinx or non-Latine White, and 25 (7.9%) had received previous pubertal suppression treatment. During the study period, appearance congruence, positive affect, and life satisfaction increased, and depression and anxiety symptoms decreased. Increases in appearance congruence were associated with concurrent increases in positive affect and life satisfaction and decreases in depression and anxiety symptoms. The most common adverse event was suicidal ideation (in 11 participants [3.5%]); death by suicide occurred in 2 participants.<br /><b>Conclusions</b><br />In this 2-year study involving transgender and nonbinary youth, GAH improved appearance congruence and psychosocial functioning. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 19 Jan 2023; 388:240-250</small></div>

<div><h4>The Safety of Inpatient Health Care.</h4><i>Bates DW, Levine DM, Salmasian H, Syrowatka A, ... Reynolds ME, Mort E</i><br /><b>Background</b><br />Adverse events during hospitalization are a major cause of patient harm, as documented in the 1991 Harvard Medical Practice Study. Patient safety has changed substantially in the decades since that study was conducted, and a more current assessment of harm during hospitalization is warranted.<br /><b>Methods</b><br />We conducted a retrospective cohort study to assess the frequency, preventability, and severity of patient harm in a random sample of admissions from 11 Massachusetts hospitals during the 2018 calendar year. The occurrence of adverse events was assessed with the use of a trigger method (identification of information in a medical record that was previously shown to be associated with adverse events) and from review of medical records. Trained nurses reviewed records and identified admissions with possible adverse events that were then adjudicated by physicians, who confirmed the presence and characteristics of the adverse events.<br /><b>Results</b><br />In a random sample of 2809 admissions, we identified at least one adverse event in 23.6%. Among 978 adverse events, 222 (22.7%) were judged to be preventable and 316 (32.3%) had a severity level of serious (i.e., caused harm that resulted in substantial intervention or prolonged recovery) or higher. A preventable adverse event occurred in 191 (6.8%) of all admissions, and a preventable adverse event with a severity level of serious or higher occurred in 29 (1.0%). There were seven deaths, one of which was deemed to be preventable. Adverse drug events were the most common adverse events (accounting for 39.0% of all events), followed by surgical or other procedural events (30.4%), patient-care events (which were defined as events associated with nursing care, including falls and pressure ulcers) (15.0%), and health care-associated infections (11.9%).<br /><b>Conclusions</b><br />Adverse events were identified in nearly one in four admissions, and approximately one fourth of the events were preventable. These findings underscore the importance of patient safety and the need for continuing improvement. (Funded by the Controlled Risk Insurance Company and the Risk Management Foundation of the Harvard Medical Institutions.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 12 Jan 2023; 388:142-153</small></div>

<div><h4>Biventricular Noncompaction Cardiomyopathy in a Patient Presenting With a New Cerebrovascular Event.</h4><i>Madnawat H, Atallah I, Ahmad A, Harjai K</i><br /><AbstractText>Noncompaction (NC) cardiomyopathy (NCCM) is a rare, genetically heterogeneous cardiomyopathy (CM) caused by failure to compact the intertrabecular recesses of the myocardium. This condition usually affects the apical segment of the left ventricle, yet there are noted basal segment, biventricular, and right ventricular predominant cases. NCCM is largely diagnosed in the pediatric population; however, there is increasing recognition in older patients with heart failure and stroke and patients with arrhythmias. Treatment focuses on symptomatic management of heart failure, anticoagulation, and implantable cardiac defibrillators.</AbstractText><br /><br />Copyright © 2022 Elsevier Inc. All rights reserved.<br /><br /><small>Am J Cardiol: 06 Jan 2023; 190:110-112</small></div>

<div><h4>Adults With Congenital Heart Disease: Trends in Event-Free Survival Past Middle Age.</h4><i>Dellborg M, Giang KW, Eriksson P, Liden H, ... Rosengren A, Mandalenakis Z</i><br /><b>Background</b><br />The survival of children with congenital heart disease has increased substantially over the past decades, with 97% currently reaching adulthood. The total effect of advanced treatment on future mortality and morbidity in adult survivors with congenital heart disease (CHD) is less well described.<br /><b>Methods</b><br />We used data from the Swedish National Inpatient, Outpatient, and Cause of Death Register to identify patients with CHD who were born between 1950 and 1999 and were alive at 18 years of age. Ten controls identified from the Total Population Register were matched for year of birth and sex and with each patient with CHD. Follow-up was from 1968 and 18 years of age until death or at the end of the study (2017). Survival percentage with 95% CI for all-cause mortality were performed with Kaplan-Meier survival function. Cox proportional hazard regression models with hazard ratios (HRs) and 95% CI were used to estimate the risk of all-cause mortality.<br /><b>Results</b><br />We included 37 278 patients with adult CHD (ACHD) and 412 799 controls. Mean follow-up was 19.2 years (±13.6). Altogether, 1937 patients with ACHD (5.2%) and 6690 controls (1.6%) died, a death rate of 2.73 per 1000 person-years and 0.84 per 1000 person years, respectively. Mortality was 3.2 times higher (95% CI, 3.0-3.4; <i>P</i><0.001) among patients with ACHD compared with matched controls. Up to the maximum of 50 years of follow-up, >75% of patients with ACHD were still alive. Mortality was highest among patients with conotruncal defects (HR, 10.13 [95% CI, 8.78-11.69]), but also significantly higher for the more benign lesions, with the lowest risk in patients with atrial septal defects (HR, 1.36 [95% CI, 1.19-1.55]). At least 75% of patients with ACHD alive at 18 years of age lived past middle age and became sexagenerians.<br /><b>Conclusions</b><br />In this large, nationwide, register-based cohort study of patients with ACHD surviving to 18 years of age, the risk of mortality up to 68 years of age was >3 times higher compared with matched controls without ACHD. Despite this, at least 75% of patients with CHD alive at 18 years of age lived past middle age and became sexagenerians. A notable risk decline in the mortality for patients with ACHD was noted for those born after 1975.<br /><br /><br /><br /><small>Circulation: 26 Dec 2022; epub ahead of print</small></div>

<div><h4>Massively Hypertrophied Right-Sided Heart with Hypoplastic Left-Sided Heart in a Neonate (A Rare Type of Hypertrophic Cardiomyopathy).</h4><i>Roberts WC, Chinta S, Guileyardo JM</i><br /><AbstractText>Described herein is a newborn boy with likely right-sided hypertrophic cardiomyopathy (HC), who survived for 18 hours after birth. At necropsy, he had a severely thickened right ventricular free wall, ventricular septum, right atrial wall and a hypoplastic left-sided heart. There was a large fossa ovale type atrial septal defect and also a patent ductus arteriosus. During peak systole, the right ventricular outflow tract was obstructed, and its contents were pushed into the thick-walled right atrium, then rapidly into the thin-walled left atrium via a large fossa ovale atrial septal defect. The contents were then pushed into the thin-walled left ventricle and finally into the small ascending aorta and into the lungs via a large patent ductus arteriosus. We were unable to find a similar published case.</AbstractText><br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>Am J Cardiol: 15 Dec 2022; epub ahead of print</small></div>

<div><h4>Pathophysiology, Echocardiographic Diagnosis, and Treatment of Atrial Functional Mitral Regurgitation: JACC State-of-the-Art Review.</h4><i>Farhan S, Silbiger JJ, Halperin JL, Zhang L, ... Sharma S, Lerakis S</i><br /><AbstractText>The conventional view holds that functional mitral regurgitation (MR) is caused by restriction of leaflet motion resulting from displacement of the papillary muscle-bearing segments of the left ventricle. In the past decade, evidence has accrued suggesting functional MR can also be caused by left atrial enlargement. This underrecognized cause of secondary MR-atrial functional MR (AF-MR)-is mechanistically linked to annular enlargement, perturbations of annular contraction, and atriogenic leaflet tethering. AF-MR has been described in patients with atrial fibrillation and heart failure with preserved ejection fraction. Preliminary data suggest rhythm control may decrease MR severity in patients with atrial fibrillation. Additionally, several studies have reported reductions in MR and symptomatic improvement with restrictive annuloplasty and transcatheter edge-to-edge repair. This review discusses the pathophysiology, echocardiographic diagnosis, and treatment of AF-MR. AF-tricuspid regurgitation is also discussed.</AbstractText><br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 13 Dec 2022; 80:2314-2330</small></div>

<div><h4>Cardiopulmonary Exercise Testing in Athletes With Hypertrophic Cardiomyopathy.</h4><i>Newman DB, Garmany R, Contreras AM, Bos JM, ... Ommen SR, Ackerman MJ</i><br /><AbstractText>Patients with hypertrophic cardiomyopathy (HCM) have historically been restricted from athletic participation because of the perceived risk of sudden cardiac death. More contemporary research has highlighted the relative safety of competitive athletics with HCM. However, lack of published data on reference values for cardiopulmonary exercise testing (CPET) complicates clinical management and counseling on sports participation in the individual athlete. We conducted a single-center, retrospective cohort study to investigate CPET in athletes with HCM and clinical characteristics associated with objective measures of aerobic capacity. We identified 58 athletes with HCM (74% male, mean age 18 ± 3 years, mean left ventricular (LV) wall thickness 20 ± 7 mm). LV outflow tract obstruction was present in 22 (38%). A total of 15 (26%) athletes were taking a β blocker (BB), but only 4 (7%) reported exertional symptoms. Overall, exercise capacity was mildly reduced, with a peak myocardial oxygen consumption (peak VO<sub>2</sub>) of 37.9 ml/min/kg (83% of predicted peak VO<sub>2</sub>). Both LV outflow tract obstruction and BB use were associated with reduced exercise capacity. Limited peak heart rate was more common in athletes taking BB (47% vs 9%, p = 0.002). At a mean 5.6 years follow-up, 5 patients underwent myectomy (9%), and 8 (14%) received an implantable cardioverter defibrillator (ICD) for primary prevention. One individual with massive LV hypertrophy experienced recurrent ICD shocks for ventricular fibrillation and underwent myectomy 7 years after initial evaluation and was no longer participating in sports. There were no deaths over the follow-up period. In conclusion, the prognostic role of CPET remains unclear in athletes with HCM. Mildly reduced exercise capacity was common; however, reduced peak VO<sub>2</sub> did not correlate with symptom status or clinical outcomes. A significant proportion went on to require myectomy and/or ICD, thus highlighting the need for close follow-up. These data provide some initial insight into the clinical evaluation of \"real world\" athletes with HCM; however, further study is warranted to help guide shared decision-making, return-to-play discussions, and the potential long-term safety of competitive athletic participation.</AbstractText><br /><br />Copyright © 2022 Elsevier Inc. All rights reserved.<br /><br /><small>Am J Cardiol: 09 Dec 2022; 189:49-55</small></div>

<div><h4>Translational opportunities of single-cell biology in atherosclerosis.</h4><i>de Winther MPJ, Bäck M, Evans P, Gomez D, ... Bochaton-Piallat ML, Monaco C</i><br /><AbstractText>The advent of single-cell biology opens a new chapter for understanding human biological processes and for diagnosing, monitoring, and treating disease. This revolution now reaches the field of cardiovascular disease (CVD). New technologies to interrogate CVD samples at single-cell resolution are allowing the identification of novel cell communities that are important in shaping disease development and direct towards new therapeutic strategies. These approaches have begun to revolutionize atherosclerosis pathology and redraw our understanding of disease development. This review discusses the state-of-the-art of single-cell analysis of atherosclerotic plaques, with a particular focus on human lesions, and presents the current resolution of cellular subpopulations and their heterogeneity and plasticity in relation to clinically relevant features. Opportunities and pitfalls of current technologies as well as the clinical impact of single-cell technologies in CVD patient care are highlighted, advocating for multidisciplinary and international collaborative efforts to join the cellular dots of CVD.</AbstractText><br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 07 Dec 2022; epub ahead of print</small></div>

<div><h4>Vinculin phosphorylation impairs vascular endothelial junctions promoting atherosclerosis.</h4><i>Shih YT, Wei SY, Chen JH, Wang WL, ... Chien S, Chiu JJ</i><br /><b>Background:</b><br/>and aims</b><br />Atherosclerosis preferentially develops in arterial branches and curvatures where vascular endothelium is exposed to disturbed flow. In this study, the effects of disturbed flow on the regulation of vascular endothelial phosphoproteins and their contribution to therapeutic application in atherogenesis were elucidated.<br /><b>Methods</b><br />Porcine models, large-scale phosphoproteomics, transgenic mice, and clinical specimens were used to discover novel site-specific phosphorylation alterations induced by disturbed flow in endothelial cells (ECs).<br /><b>Results</b><br />A large-scale phosphoproteomics analysis of native endothelium from disturbed (athero-susceptible) vs. pulsatile flow (athero-resistant) regions of porcine aortas led to the identification of a novel atherosclerosis-related phosphoprotein vinculin (VCL) with disturbed flow-induced phosphorylation at serine 721 (VCLS721p). The induction of VCLS721p was mediated by G-protein-coupled receptor kinase 2 (GRK2)S29p and resulted in an inactive form of VCL with a closed conformation, leading to the VE-cadherin/catenin complex disruption to enhance endothelial permeability and atherogenesis. The generation of novel apolipoprotein E-deficient (ApoE-/-) mice overexpressing S721-non-phosphorylatable VCL mutant in ECs confirmed the critical role of VCLS721p in promoting atherosclerosis. The administration of a GRK2 inhibitor to ApoE-/- mice suppressed plaque formation by inhibiting endothelial VCLS721p. Studies on clinical specimens from patients with coronary artery disease (CAD) revealed that endothelial VCLS721p is a critical clinicopathological biomarker for atherosclerosis progression and that serum VCLS721p level is a promising biomarker for CAD diagnosis.<br /><b>Conclusions</b><br />The findings of this study indicate that endothelial VCLS721p is a valuable hemodynamic-based target for clinical assessment and treatment of vascular disorders resulting from atherosclerosis.<br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 16 Nov 2022; epub ahead of print</small></div>

<div><h4>Progression of Atrial Fibrillation after Cryoablation or Drug Therapy.</h4><i>Andrade JG, Deyell MW, Macle L, Wells GA, ... Verma A, EARLY-AF Investigators</i><br /><b>Background</b><br />Atrial fibrillation is a chronic, progressive disorder, and persistent forms of atrial fibrillation are associated with increased risks of thromboembolism and heart failure. Catheter ablation as initial therapy may modify the pathogenic mechanism of atrial fibrillation and alter progression to persistent atrial fibrillation.<br /><b>Methods</b><br />We report the 3-year follow-up of patients with paroxysmal, untreated atrial fibrillation who were enrolled in a trial in which they had been randomly assigned to undergo initial rhythm-control therapy with cryoballoon ablation or to receive antiarrhythmic drug therapy. All the patients had implantable loop recorders placed at the time of trial entry, and evaluation was conducted by means of downloaded daily recordings and in-person visits every 6 months. Data regarding the first episode of persistent atrial fibrillation (lasting ≥7 days or lasting 48 hours to 7 days but requiring cardioversion for termination), recurrent atrial tachyarrhythmia (defined as atrial fibrillation, flutter, or tachycardia lasting ≥30 seconds), the burden of atrial fibrillation (percentage of time in atrial fibrillation), quality-of-life metrics, health care utilization, and safety were collected.<br /><b>Results</b><br />A total of 303 patients were enrolled, with 154 patients assigned to undergo initial rhythm-control therapy with cryoballoon ablation and 149 assigned to receive antiarrhythmic drug therapy. Over 36 months of follow-up, 3 patients (1.9%) in the ablation group had an episode of persistent atrial fibrillation, as compared with 11 patients (7.4%) in the antiarrhythmic drug group (hazard ratio, 0.25; 95% confidence interval [CI], 0.09 to 0.70). Recurrent atrial tachyarrhythmia occurred in 87 patients in the ablation group (56.5%) and in 115 in the antiarrhythmic drug group (77.2%) (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). The median percentage of time in atrial fibrillation was 0.00% (interquartile range, 0.00 to 0.12) in the ablation group and 0.24% (interquartile range, 0.01 to 0.94) in the antiarrhythmic drug group. At 3 years, 8 patients (5.2%) in the ablation group and 25 (16.8%) in the antiarrhythmic drug group had been hospitalized (relative risk, 0.31; 95% CI, 0.14 to 0.66). Serious adverse events occurred in 7 patients (4.5%) in the ablation group and in 15 (10.1%) in the antiarrhythmic drug group.<br /><b>Conclusions</b><br />Initial treatment of paroxysmal atrial fibrillation with catheter cryoballoon ablation was associated with a lower incidence of persistent atrial fibrillation or recurrent atrial tachyarrhythmia over 3 years of follow-up than initial use of antiarrhythmic drugs. (Funded by the Cardiac Arrhythmia Network of Canada and others; EARLY-AF ClinicalTrials.gov number, NCT02825979.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 07 Nov 2022; epub ahead of print</small></div>

<div><h4>Defibrillation Strategies for Refractory Ventricular Fibrillation.</h4><i>Cheskes S, Verbeek PR, Drennan IR, McLeod SL, ... Dorian P, Scales DC</i><br /><b>Background</b><br />Despite advances in defibrillation technology, shock-refractory ventricular fibrillation remains common during out-of-hospital cardiac arrest. Double sequential external defibrillation (DSED; rapid sequential shocks from two defibrillators) and vector-change (VC) defibrillation (switching defibrillation pads to an anterior-posterior position) have been proposed as defibrillation strategies to improve outcomes in patients with refractory ventricular fibrillation.<br /><b>Methods</b><br />We conducted a cluster-randomized trial with crossover among six Canadian paramedic services to evaluate DSED and VC defibrillation as compared with standard defibrillation in adult patients with refractory ventricular fibrillation during out-of-hospital cardiac arrest. Patients were treated with one of these three techniques according to the strategy that was randomly assigned to the paramedic service. The primary outcome was survival to hospital discharge. Secondary outcomes included termination of ventricular fibrillation, return of spontaneous circulation, and a good neurologic outcome, defined as a modified Rankin scale score of 2 or lower (indicating no symptoms to slight disability) at hospital discharge.<br /><b>Results</b><br />A total of 405 patients were enrolled before the data and safety monitoring board stopped the trial because of the coronavirus disease 2019 pandemic. A total of 136 patients (33.6%) were assigned to receive standard defibrillation, 144 (35.6%) to receive VC defibrillation, and 125 (30.9%) to receive DSED. Survival to hospital discharge was more common in the DSED group than in the standard group (30.4% vs. 13.3%; relative risk, 2.21; 95% confidence interval [CI], 1.33 to 3.67) and more common in the VC group than in the standard group (21.7% vs. 13.3%; relative risk, 1.71; 95% CI, 1.01 to 2.88). DSED but not VC defibrillation was associated with a higher percentage of patients having a good neurologic outcome than standard defibrillation (relative risk, 2.21 [95% CI, 1.26 to 3.88] and 1.48 [95% CI, 0.81 to 2.71], respectively).<br /><b>Conclusions</b><br />Among patients with refractory ventricular fibrillation, survival to hospital discharge occurred more frequently among those who received DSED or VC defibrillation than among those who received standard defibrillation. (Funded by the Heart and Stroke Foundation of Canada; DOSE VF ClinicalTrials.gov number, NCT04080986.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 06 Nov 2022; epub ahead of print</small></div>

<div><h4>Pathogenesis of Cardiomyopathy Caused by Variants in , an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere.</h4><i>Agarwal R, Wakimoto H, Paulo JA, Zhang Q, ... Seidman JG, Seidman CE</i><br /><b>Background</b><br /><i>ALPK3</i> encodes α-kinase 3, a muscle-specific protein of unknown function. <i>ALPK3</i> loss-of-function variants cause cardiomyopathy with distinctive clinical manifestations in both children and adults, but the molecular functions of ALPK3 remain poorly understood.<br /><b>Methods</b><br />We explored the putative kinase activity of ALPK3 and the consequences of damaging variants using isogenic human induced pluripotent stem cell-derived cardiomyocytes, mice, and human patient tissues.<br /><b>Results</b><br />Multiple sequence alignment of all human α-kinase domains and their orthologs revealed 4 conserved residues that were variant only in ALPK3, demonstrating evolutionary divergence of the ALPK3 α-kinase domain sequence. Phosphoproteomic evaluation of both ALPK3 kinase domain inhibition and overexpression failed to detect significant changes in catalytic activity, establishing ALPK3 as a pseudokinase. Investigations into alternative functions revealed that ALPK3 colocalized with myomesin proteins (MYOM1, MYOM2) at both the nuclear envelope and the sarcomere M-band. <i>ALPK3</i> loss-of-function variants caused myomesin proteins to mislocalize and also dysregulated several additional M-band proteins involved in sarcomere protein turnover, which ultimately impaired cardiomyocyte structure and function.<br /><b>Conclusions</b><br />ALPK3 is an essential cardiac pseudokinase that inserts in the nuclear envelope and the sarcomere M-band. Loss of ALPK3 causes mislocalization of myomesins, critical force-buffering proteins in cardiomyocytes, and also dysregulates M-band proteins necessary for sarcomere protein turnover. We conclude that <i>ALPK3</i> cardiomyopathy induces ventricular dilatation caused by insufficient myomesin-mediated force buffering and hypertrophy by impairment of sarcomere proteostasis.<br /><br /><br /><br /><small>Circulation: 02 Nov 2022; epub ahead of print</small></div>

<div><h4>Early Active Mobilization during Mechanical Ventilation in the ICU.</h4><i>TEAM Study Investigators and the ANZICS Clinical Trials Group, Hodgson CL, Bailey M, Bellomo R, ... Webb S, Young PJ</i><br /><b>Background</b><br />Intensive care unit (ICU)-acquired weakness often develops in patients who are undergoing invasive mechanical ventilation. Early active mobilization may mitigate ICU-acquired weakness, increase survival, and reduce disability.<br /><b>Methods</b><br />We randomly assigned 750 adult patients in the ICU who were undergoing invasive mechanical ventilation to receive increased early mobilization (sedation minimization and daily physiotherapy) or usual care (the level of mobilization that was normally provided in each ICU). The primary outcome was the number of days that the patients were alive and out of the hospital at 180 days after randomization.<br /><b>Results</b><br />The median number of days that patients were alive and out of the hospital was 143 (interquartile range, 21 to 161) in the early-mobilization group and 145 days (interquartile range, 51 to 164) in the usual-care group (absolute difference, -2.0 days; 95% confidence interval [CI], -10 to 6; P = 0.62). The mean (±SD) daily duration of active mobilization was 20.8±14.6 minutes and 8.8±9.0 minutes in the two groups, respectively (difference, 12.0 minutes per day; 95% CI, 10.4 to 13.6). A total of 77% of the patients in both groups were able to stand by a median interval of 3 days and 5 days, respectively (difference, -2 days; 95% CI, -3.4 to -0.6). By day 180, death had occurred in 22.5% of the patients in the early-mobilization group and in 19.5% of those in the usual-care group (odds ratio, 1.15; 95% CI, 0.81 to 1.65). Among survivors, quality of life, activities of daily living, disability, cognitive function, and psychological function were similar in the two groups. Serious adverse events were reported in 7 patients in the early-mobilization group and in 1 patient in the usual-care group. Adverse events that were potentially due to mobilization (arrhythmias, altered blood pressure, and desaturation) were reported in 34 of 371 patients (9.2%) in the early-mobilization group and in 15 of 370 patients (4.1%) in the usual-care group (P = 0.005).<br /><b>Conclusions</b><br />Among adults undergoing mechanical ventilation in the ICU, an increase in early active mobilization did not result in a significantly greater number of days that patients were alive and out of the hospital than did the usual level of mobilization in the ICU. The intervention was associated with increased adverse events. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; TEAM ClinicalTrials.gov number, NCT03133377.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 26 Oct 2022; epub ahead of print</small></div>

<div><h4>Cerebral Embolic Protection during Transcatheter Aortic-Valve Replacement.</h4><i>Kapadia SR, Makkar R, Leon M, Abdel-Wahab M, ... Linke A, PROTECTED TAVR Investigators</i><br /><b>Background</b><br />Transcatheter aortic-valve replacement (TAVR) for the treatment of aortic stenosis can lead to embolization of debris. Capture of debris by devices that provide cerebral embolic protection (CEP) may reduce the risk of stroke.<br /><b>Methods</b><br />We randomly assigned patients with aortic stenosis in a 1:1 ratio to undergo transfemoral TAVR with CEP (CEP group) or without CEP (control group). The primary end point was stroke within 72 hours after TAVR or before discharge (whichever came first) in the intention-to-treat population. Disabling stroke, death, transient ischemic attack, delirium, major or minor vascular complications at the CEP access site, and acute kidney injury were also assessed. A neurology professional examined all the patients at baseline and after TAVR.<br /><b>Results</b><br />A total of 3000 patients across North America, Europe, and Australia underwent randomization; 1501 were assigned to the CEP group and 1499 to the control group. A CEP device was successfully deployed in 1406 of the 1489 patients (94.4%) in whom an attempt was made. The incidence of stroke within 72 hours after TAVR or before discharge did not differ significantly between the CEP group and the control group (2.3% vs. 2.9%; difference, -0.6 percentage points; 95% confidence interval, -1.7 to 0.5; P = 0.30). Disabling stroke occurred in 0.5% of the patients in the CEP group and in 1.3% of those in the control group. There were no substantial differences between the CEP group and the control group in the percentage of patients who died (0.5% vs. 0.3%); had a stroke, a transient ischemic attack, or delirium (3.1% vs. 3.7%); or had acute kidney injury (0.5% vs. 0.5%). One patient (0.1%) had a vascular complication at the CEP access site.<br /><b>Conclusions</b><br />Among patients with aortic stenosis undergoing transfemoral TAVR, the use of CEP did not have a significant effect on the incidence of periprocedural stroke, but on the basis of the 95% confidence interval around this outcome, the results may not rule out a benefit of CEP during TAVR. (Funded by Boston Scientific; PROTECTED TAVR ClinicalTrials.gov number, NCT04149535.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 17 Sep 2022; epub ahead of print</small></div>

<div><h4>Rivaroxaban in Rheumatic Heart Disease-Associated Atrial Fibrillation.</h4><i>Connolly SJ, Karthikeyan G, Ntsekhe M, Haileamlak A, ... Yusuf S, INVICTUS Investigators</i><br /><b>Background</b><br />Testing of factor Xa inhibitors for the prevention of cardiovascular events in patients with rheumatic heart disease-associated atrial fibrillation has been limited.<br /><b>Methods</b><br />We enrolled patients with atrial fibrillation and echocardiographically documented rheumatic heart disease who had any of the following: a CHA<sub>2</sub>DS<sub>2</sub>VASc score of at least 2 (on a scale from 0 to 9, with higher scores indicating a higher risk of stroke), a mitral-valve area of no more than 2 cm<sup>2</sup>, left atrial spontaneous echo contrast, or left atrial thrombus. Patients were randomly assigned to receive standard doses of rivaroxaban or dose-adjusted vitamin K antagonist. The primary efficacy outcome was a composite of stroke, systemic embolism, myocardial infarction, or death from vascular (cardiac or noncardiac) or unknown causes. We hypothesized that rivaroxaban therapy would be noninferior to vitamin K antagonist therapy. The primary safety outcome was major bleeding according to the International Society of Thrombosis and Hemostasis.<br /><b>Results</b><br />Of 4565 enrolled patients, 4531 were included in the final analysis. The mean age of the patients was 50.5 years, and 72.3% were women. Permanent discontinuation of trial medication was more common with rivaroxaban than with vitamin K antagonist therapy at all visits. In the intention-to-treat analysis, 560 patients in the rivaroxaban group and 446 in the vitamin K antagonist group had a primary-outcome event. Survival curves were nonproportional. The restricted mean survival time was 1599 days in the rivaroxaban group and 1675 days in the vitamin K antagonist group (difference, -76 days; 95% confidence interval [CI], -121 to -31; P<0.001). A higher incidence of death occurred in the rivaroxaban group than in the vitamin K antagonist group (restricted mean survival time, 1608 days vs. 1680 days; difference, -72 days; 95% CI, -117 to -28). No significant between-group difference in the rate of major bleeding was noted.<br /><b>Conclusions</b><br />Among patients with rheumatic heart disease-associated atrial fibrillation, vitamin K antagonist therapy led to a lower rate of a composite of cardiovascular events or death than rivaroxaban therapy, without a higher rate of bleeding. (Funded by Bayer; INVICTUS ClinicalTrials.gov number, NCT02832544.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 28 Aug 2022; epub ahead of print</small></div>

<div><h4>Acetazolamide in Acute Decompensated Heart Failure with Volume Overload.</h4><i>Mullens W, Dauw J, Martens P, Verbrugge FH, ... Dupont M, ADVOR Study Group</i><br /><b>Background</b><br />Whether acetazolamide, a carbonic anhydrase inhibitor that reduces proximal tubular sodium reabsorption, can improve the efficiency of loop diuretics, potentially leading to more and faster decongestion in patients with acute decompensated heart failure with volume overload, is unclear.<br /><b>Methods</b><br />In this multicenter, parallel-group, double-blind, randomized, placebo-controlled trial, we assigned patients with acute decompensated heart failure, clinical signs of volume overload (i.e., edema, pleural effusion, or ascites), and an N-terminal pro-B-type natriuretic peptide level of more than 1000 pg per milliliter or a B-type natriuretic peptide level of more than 250 pg per milliliter to receive either intravenous acetazolamide (500 mg once daily) or placebo added to standardized intravenous loop diuretics (at a dose equivalent to twice the oral maintenance dose). Randomization was stratified according to the left ventricular ejection fraction (≤40% or >40%). The primary end point was successful decongestion, defined as the absence of signs of volume overload, within 3 days after randomization and without an indication for escalation of decongestive therapy. Secondary end points included a composite of death from any cause or rehospitalization for heart failure during 3 months of follow-up. Safety was also assessed.<br /><b>Results</b><br />A total of 519 patients underwent randomization. Successful decongestion occurred in 108 of 256 patients (42.2%) in the acetazolamide group and in 79 of 259 (30.5%) in the placebo group (risk ratio, 1.46; 95% confidence interval [CI], 1.17 to 1.82; P<0.001). Death from any cause or rehospitalization for heart failure occurred in 76 of 256 patients (29.7%) in the acetazolamide group and in 72 of 259 patients (27.8%) in the placebo group (hazard ratio, 1.07; 95% CI, 0.78 to 1.48). Acetazolamide treatment was associated with higher cumulative urine output and natriuresis, findings consistent with better diuretic efficiency. The incidence of worsening kidney function, hypokalemia, hypotension, and adverse events was similar in the two groups.<br /><b>Conclusions</b><br />The addition of acetazolamide to loop diuretic therapy in patients with acute decompensated heart failure resulted in a greater incidence of successful decongestion. (Funded by the Belgian Health Care Knowledge Center; ADVOR ClinicalTrials.gov number, NCT03505788.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 27 Aug 2022; epub ahead of print</small></div>

<div><h4>Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction.</h4><i>Solomon SD, McMurray JJV, Claggett B, de Boer RA, ... Langkilde AM, DELIVER Trial Committees and Investigators</i><br /><b>Background</b><br />Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain.<br /><b>Methods</b><br />We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis.<br /><b>Results</b><br />Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups.<br /><b>Conclusions</b><br />Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 27 Aug 2022; epub ahead of print</small></div>

<div><h4>Benefit of Early Revascularization Based on Inducible Ischemia and Left Ventricular Ejection Fraction.</h4><i>Rozanski A, Miller RJH, Gransar H, Han D, ... Thomson L, Berman DS</i><br /><b>Background</b><br />The utility of performing early myocardial revascularization among patients presenting with inducible myocardial ischemia and low left ventricular ejection fraction (LVEF) is currently unknown.<br /><b>Objectives</b><br />In this study, we sought to assess the relationship between stress-induced myocardial ischemia, revascularization, and all-cause mortality (ACM) among patients with normal vs low LVEF.<br /><b>Methods</b><br />We evaluated 43,443 patients undergoing stress-rest single-photon emission computed tomography myocardial perfusion imaging from 1998 to 2017. Median follow-up was 11.4 years. Myocardial ischemia was assessed for its interaction between early revascularization and mortality. A propensity score was used to adjust for nonrandomization to revascularization, followed by multivariable Cox modeling adjusted for the propensity score and clinical variables to predict ACM.<br /><b>Results</b><br />The frequency of myocardial ischemia varied markedly according to LVEF and angina, ranging from 6.7% among patients with LVEF ≥55% and no typical angina to 64.0% among patients with LVEF <45% and typical angina (P < 0.001). Among 39,883 patients with LVEF ≥45%, early revascularization was associated with increased mortality risk among patients without ischemia and lower mortality risk among patients with severe (≥15%) ischemia (HR: 0.70; 95% CI: 0.52-0.95). Among 3,560 patients with LVEF <45%, revascularization was not associated with mortality benefit among patients with no or mild ischemia, and was associated with decreased mortality among patients with moderate (10%-14%) (HR: 0.67; 95% CI: 0.49-0.91) and severe (≥15%) (HR: 0.55; 95% CI: 0.38-0.80) ischemia.<br /><b>Conclusions</b><br />Within this cohort, early myocardial revascularization was associated with a significant reduction in mortality among both patients with normal LVEF and severe inducible myocardial ischemia and patients with low LVEF and moderate or severe inducible myocardial ischemia.<br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>J Am Coll Cardiol: 19 Jul 2022; 80:202-215</small></div>

<div><h4>Clinical Spectrum of Children with Acute Hepatitis of Unknown Cause.</h4><i>Kelgeri C, Couper M, Gupte GL, Brant A, ... Sharif K, Hartley J</i><br /><b>Background</b><br />Since January 2022, there has been an increase in reports of cases of acute hepatitis of unknown cause in children. Although cases have been reported across multiple continents, most have been reported in the United Kingdom. Investigations are ongoing to identify the causative agent or agents.<br /><b>Methods</b><br />We conducted a retrospective study involving children referred to a single pediatric liver-transplantation center in the United Kingdom between January 1 and April 11, 2022. These children were 10 years of age or younger and had hepatitis that met the case definition of the U.K. Health Security Agency for confirmed acute hepatitis that was not hepatitis A through E and did not have a metabolic, inherited or genetic, congenital, or mechanical cause, in the context of a serum aminotransferase level greater than 500 IU per liter. We reviewed medical records and documented demographic characteristics, clinical features, and results of liver biochemical, serologic, and molecular tests for hepatotropic and other viruses, as well as radiologic and clinical outcomes. The outcomes were classified as an improving condition, liver transplantation, or death.<br /><b>Results</b><br />A total of 44 children had hepatitis that met the confirmed case definition, and most were previously healthy. The median age was 4 years (range, 1 to 7). Common presenting features were jaundice (in 93% of the children), vomiting (in 54%), and diarrhea (in 32%). Among the 30 patients who underwent molecular testing for human adenovirus, 27 (90%) were positive. Fulminant liver failure developed in 6 patients (14%), all of whom received a liver transplant. None of the patients died. All the children, including the 6 who received liver transplants, were discharged home.<br /><b>Conclusions</b><br />In this series involving 44 young children with acute hepatitis of uncertain cause, human adenovirus was isolated in most of the children, but its role in the pathogenesis of this illness has not been established.<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 13 Jul 2022; epub ahead of print</small></div>