<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>Novel mechanisms and therapeutic targets in atherosclerosis: inflammation and beyond.</h4><i>Weber C, Habenicht AJR, von Hundelshausen P</i><br /><AbstractText>This review based on the ESC William Harvey Lecture in Basic Science 2022 highlights recent experimental and translational progress on the therapeutic targeting of the inflammatory components in atherosclerosis, introducing novel strategies to limit side effects and to increase efficacy. Since the validation of the inflammatory paradigm in CANTOS and COLCOT, efforts to control the residual risk conferred by inflammation have centred on the NLRP3 inflammasome-driven IL-1β-IL6 axis. Interference with the co-stimulatory dyad CD40L-CD40 and selective targeting of tumour necrosis factor-receptor associated factors (TRAFs), namely the TRAF6-CD40 interaction in macrophages by small molecule inhibitors, harbour intriguing options to reduce established atherosclerosis and plaque instability without immune side effects. The chemokine system crucial for shaping immune cell recruitment and homoeostasis can be fine-tuned and modulated by its heterodimer interactome. Structure-function analysis enabled the design of cyclic, helical, or linked peptides specifically targeting or mimicking these interactions to limit atherosclerosis or thrombosis by blunting myeloid recruitment, boosting regulatory T cells, inhibiting platelet activity, or specifically blocking the atypical chemokine MIF without notable side effects. Finally, adventitial neuroimmune cardiovascular interfaces in advanced atherosclerosis show robust restructuring of innervation from perivascular ganglia and employ sensory neurons of dorsal root ganglia to enter the central nervous system and to establish an atherosclerosis-brain circuit sensor, while sympathetic and vagal efferents project to the celiac ganglion to create an atherosclerosis-brain circuit effector. Disrupting this circuitry by surgical or chemical sympathectomy limited disease progression and enhanced plaque stability, opening exciting perspectives for selective and tailored intervention beyond anti-inflammatory strategies.</AbstractText><br /><br />© The Author(s) 2023. 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: 20 May 2023; epub ahead of print</small></div>

<div><h4>Hematopoietic Somatic Mosaicism Is Associated With an Increased Risk of Postoperative Atrial Fibrillation.</h4><i>Ninni S, Dombrowicz D, Kuznetsova T, Vicario R, ... Staels B, Montaigne D</i><br /><b>Background</b><br />On-pump cardiac surgery triggers sterile inflammation and postoperative complications such as postoperative atrial fibrillation (POAF). Hematopoietic somatic mosaicism (HSM) is a recently identified risk factor for cardiovascular diseases and results in a shift toward a chronic proinflammatory monocyte transcriptome and phenotype.<br /><b>Objectives</b><br />The aim of this study was to assess the prevalence, characteristics, and impact of HSM on preoperative blood and myocardial myeloid cells as well as on outcomes after cardiac surgery.<br /><b>Methods</b><br />Blood DNA from 104 patients referred for surgical aortic valve replacement (AVR) was genotyped using the HemePACT panel (576 genes). Four screening methods were applied to assess HSM, and postoperative outcomes were explored. In-depth blood and myocardial leukocyte phenotyping was performed in selected patients using mass cytometry and preoperative and postoperative RNA sequencing analysis of classical monocytes.<br /><b>Results</b><br />The prevalence of HSM in the patient cohort ranged from 29%, when considering the conventional HSM panel (97 genes) with variant allelic frequencies ≥2%, to 60% when considering the full HemePACT panel and variant allelic frequencies ≥1%. Three of 4 explored HSM definitions were significantly associated with higher risk for POAF. On the basis of the most inclusive definition, HSM carriers exhibited a 3.5-fold higher risk for POAF (age-adjusted OR: 3.5; 95% CI: 1.52-8.03; P = 0.003) and an exaggerated inflammatory response following AVR. HSM carriers presented higher levels of activated CD64<sup>+</sup>CD14<sup>+</sup>CD16<sup>-</sup> circulating monocytes and inflammatory monocyte-derived macrophages in presurgery myocardium.<br /><b>Conclusions</b><br />HSM is frequent in candidates for AVR, is associated with an enrichment of proinflammatory cardiac monocyte-derived macrophages, and predisposes to a higher incidence of POAF. HSM assessment may be useful in the personalized management of patients in the perioperative period. (Post-Operative Myocardial Incident & Atrial Fibrillation [POMI-AF]; NCT03376165).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 04 May 2023; 81:1263-1278</small></div>

<div><h4>Impact of Moderate Aortic Stenosis in Patients With Heart Failure With Reduced Ejection Fraction.</h4><i>Khan KR, Khan OA, Chen C, Liu Y, ... Langer NB, Elmariah S</i><br /><b>Background</b><br />Afterload from moderate aortic stenosis (AS) may contribute to adverse outcomes in patients with heart failure with reduced ejection fraction (HFrEF).<br /><b>Objectives</b><br />The authors evaluated clinical outcomes in patients with HFrEF and moderate AS relative to those without AS and with severe AS.<br /><b>Methods</b><br />Patients with HFrEF, defined by left ventricular ejection fraction (LVEF) <50% and no, moderate, or severe AS were retrospectively identified. The primary endpoint, defined as a composite of all-cause mortality and heart failure (HF) hospitalization, was compared across groups and within a propensity score-matched cohort.<br /><b>Results</b><br />We included 9,133 patients with HFrEF, of whom 374 and 362 had moderate and severe AS, respectively. Over a median follow-up time of 3.1 years, the primary outcome occurred in 62.7% of patients with moderate AS vs 45.9% with no AS (P < 0.0001); rates were similar with severe and moderate AS (62.0% vs 62.7%; P = 0.68). Patients with severe AS had a lower incidence of HF hospitalization (36.2% vs 43.6%; P < 0.05) and were more likely to undergo AVR within the follow-up period. Within a propensity score-matched cohort, moderate AS was associated with an increased risk of HF hospitalization and mortality (HR: 1.24; 95% CI: 1.04-1.49; P = 0.01) and fewer days alive outside of the hospital (P < 0.0001). Aortic valve replacement (AVR) was associated with improved survival (HR: 0.60; CI: 0.36-0.99; P < 0.05).<br /><b>Conclusions</b><br />In patients with HFrEF, moderate AS is associated with increased rates of HF hospitalization and mortality. Further investigation is warranted to determine whether AVR in this population improves clinical outcomes.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 04 May 2023; 81:1235-1244</small></div>

<div><h4>Evolution of genetic testing and gene therapy in hypertrophic cardiomyopathy.</h4><i>Chiswell K, Zaininger L, Semsarian C</i><br /><AbstractText>Studies over the last 30 years have identified hypertrophic cardiomyopathy (HCM) as predominantly an autosomal dominant disorder caused by disease-causing variants in genes encoding the sarcomere proteins critical for contractile function. The two most common disease genes implicated are the MYBPC3 and MYH7 genes, with disease-causing variants in these two genes accounting for 70-80% of all genotype-positive HCM patients. This increased knowledge of the genetic basis of HCM has heralded the era of precision medicine, with genetic testing leading to more improved and precise diagnosis, effective cascade genetic testing in at-risk family members, assistance with reproductive decisions, targeted therapeutics guided by both phenotype and genotype, and providing important insights into risk stratification and prognosis. Most recently, novel insights into genetic mechanisms have been elucidated, spanning non-Mendelian aetiologies, non-familial forms of HCM, and development of polygenic risk scores. These advances have laid the platform for exciting future endeavours such as newer gene therapy approaches in HCM, including gene replacement studies and genome editing approaches to ultimately cure disease. This brief review summarises the current role of genetic testing in HCM patients and families, and introduces some new mechanistic insights leading to the consideration of gene therapy approaches for HCM.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>Prog Cardiovasc Dis: 01 May 2023; epub ahead of print</small></div>

<div><h4>Distinct Hemodynamic Responses That Culminate With Postural Orthostatic Tachycardia Syndrome.</h4><i>de Oliveira MCS, Távora-Mehta MZP, Mehta N, Magajevski AS, ... Doubrawa E, Lofrano-Alves MS</i><br /><AbstractText>It is of paramount importance to characterize the individual hemodynamic response of patients with postural orthostatic tachycardia syndrome (POTS) to select the best therapeutic intervention. Our aim in this study was to describe the hemodynamic changes in 40 patients with POTS during the head-up tilt test and compare them with 48 healthy patients. Hemodynamic parameters were obtained by cardiac bioimpedance. Patients were compared in supine position and after 5, 10, 15, and 20 minutes of orthostatic position. Patients with POTS demonstrated higher heart rate (74 beats per minute [64 to 80] vs 67 [62 to 72], p <0.001) and lower stroke volume (SV) (83.0 ml [72 to 94] vs 90 [79 to 112], p <0.001) at supine position. The response to orthostatic challenge was characterized by a decrease in SV index (SVI) in both groups (ΔSVI in ml/m<sup>2</sup>: -16 [-25 to -7.] vs -11 [-17 to -6.1], p = NS). Peripheral vascular resistance (PVR) was reduced only in POTS (ΔPVR in dyne.seg/cm<sup>5</sup>:-52 [-279 to 163] vs 326 [58 to 535], p <0.001). According to the best cut-off points obtained using the receiver operating characteristic analysis for the variation of SVI (-15.5%) and PVR index (PVRI) (-5.5%), we observed 4 distinct groups of POTS: 10% presented an increase in both SVI and PVRI after the orthostatic challenge, 35% presented a PVRI decrease with SVI maintenance or increase, 37.5% presented an SVI decrease with PVRI maintenance or elevation, and 17.5% presented a reduction in both variables. Body mass index, ΔSVI, and ΔPVRI were strongly correlated with POTS (area under the curve = 0.86 [95% confidence interval 0.77 to 0.92], p <0.0001). In conclusion, the use of appropriate cut-off points for hemodynamic parameters using bioimpedance cardiography during the head-up tilt test could be a useful strategy to identify the main mechanism involved and to select the best individual therapeutic strategy in POTS.</AbstractText><br /><br />Copyright © 2023 Elsevier Inc. All rights reserved.<br /><br /><small>Am J Cardiol: 25 Apr 2023; 197:3-12</small></div>

<div><h4>Mechanisms of enhanced renal and hepatic erythropoietin synthesis by sodium-glucose cotransporter 2 inhibitors.</h4><i>Packer M</i><br /><AbstractText>Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major heart failure events, an action that is statistically linked to enhanced erythropoiesis, suggesting that stimulation of erythropoietin and cardioprotection are related to a shared mechanism. Four hypotheses have been proposed to explain how these drugs increase erythropoietin production: (i) renal cortical reoxygenation with rejuvenation of erythropoietin-producing cells; (ii) counterregulatory distal sodium reabsorption leading to increased tubular workload and oxygen consumption, and thus, to localized hypoxia; (iii) increased iron mobilization as a stimulus of hypoxia-inducible factor-2α (HIF-2α)-mediated erythropoietin synthesis; and (iv) direct HIF-2α activation and enhanced erythropoietin gene transcription due to increased sirtuin-1 (SIRT1) signaling. The first two hypotheses assume that the source of increased erythropoietin is the interstitial fibroblast-like cells in the deep renal cortex. However, SGLT2 inhibitors do not alter regional tissue oxygen tension in the non-diabetic kidney, and renal erythropoietin synthesis is markedly impaired in patients with anemia due to chronic kidney disease, and yet, SGLT2 inhibitors produce an unattenuated erythrocytic response in these patients. This observation raises the possibility that the liver contributes to the production of erythropoietin during SGLT2 inhibition. Hypoxia-inducible factor-2α and erythropoietin are coexpressed not only in the kidney but also in hepatocytes; the liver is a major site of production when erythropoietin stimulation is maintained for prolonged periods. The ability of SGLT2 inhibitors to improve iron mobilization by derepressing hepcidin and ferritin would be expected to increase cytosolic ferrous iron, which might stimulate HIF-2α expression in both the kidney and liver through the action of iron regulatory protein 1. Alternatively, the established ability of SGLT2 inhibitors to enhance SIRT1 might be the mechanism of enhanced erythropoietin production with these drugs. In hepatic cell lines, SIRT1 can directly activate HIF-2α by deacetylation, and additionally, through an effect of SIRT in the liver, peroxisome proliferator-activated receptor-γ coactivator-1α binds to hepatic nuclear factor 4 to promote transcription of the erythropoietin gene and synthesis of erythropoietin. Since SIRT1 up-regulation exerts direct cytoprotective effects on the heart and stimulates erythropoietin, it is well-positioned to represent the shared mechanism that links erythropoiesis to cardioprotection during SGLT2 inhibition.</AbstractText><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: 22 Apr 2023; epub ahead of print</small></div>

<div><h4>Design of A Multi-Institutional Neurocognitive Discovery Study in Adult Congenital Heart Disease (MINDS-ACHD).</h4><i>Cohen S, Gurvitz M, Burns KM, Wheaton O, ... Zaidi AN, Pediatric Heart Network Investigators and the Alliance for Adult Research in Congenital Cardiology</i><br /><b>Background</b><br />Neurocognitive dysfunction (NCD) is a common comorbidity among children with congenital heart disease (CHD). However, it is unclear how underlying CHD and its sequelae combine with genetics and acquired cardiovascular and neurological disease to impact NCD and outcomes across the lifespan in adults with CHD.<br /><b>Methods</b><br />The Multi-Institutional Neurocognitive Discovery Study in Adults with Congenital Heart Disease (MINDS-ACHD) is a partnership between the Pediatric Heart Network (PHN) and the Adult Alliance for Research in Congenital Cardiology (AARCC) that examines objective and subjective neurocognitive function and genetics in young ACHD. This multicenter cross-sectional pilot study is enrolling 500 young adults between 18 and 30 years with moderate or severe complexity CHD at 14 centers in North America. Enrollment includes 4 groups (125 participants each): 1) d-looped Transposition of the Great Arteries (d-TGA); 2) Tetralogy of Fallot (TOF); 3) single ventricle (SV) physiology; and 4) \"other moderately or severely complex CHD.\" Participants complete the standardized tests from the NIH Toolbox Cognitive Battery, the NeuroQoL, the Hospital Anxiety and Depression Scale, and the PROMIS Global QoL measure. Clinical and demographic variables are collected by interview and medical record review, and an optional biospecimen is collected for genetic analysis. Due to the COVID-19 pandemic, participation may be done remotely. Tests are reviewed by a Neurocognitive Core Laboratory.<br /><b>Conclusions</b><br />MINDS-ACHD is the largest study to date characterizing NCD in young adults with moderate or severely complex CHD in North America. Its results will provide valuable data to inform screening and management strategies for NCD in ACHD and improve lifelong care.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>Am Heart J: 19 Apr 2023; epub ahead of print</small></div>

<div><h4>Normal Values of 3D Right Ventricular Size and Function Measurements: Results of the World Alliance of Societies of Echocardiography Study.</h4><i>Addetia K, Miyoshi T, Amuthan V, Citro R, ... Lang RM, WASE Investigators</i><br /><b>Background</b><br />Normal values for 3D right ventricular (RV) size and function are not well established, as they originate from small studies that involved predominantly white North American and European populations, did not use RV-focused views and relied on older 3D RV analysis software . The World Alliance of Societies of Echocardiography (WASE) study was designed to generate reference ranges for normal subjects around the world. In this study, we sought to assess the world-wide capability of 3D imaging of the right ventricle and report size and function measurements, including their dependency on age, sex and ethnicity.<br /><b>Methods</b><br />Healthy subjects free of cardiac, pulmonary and renal disease were prospectively enrolled at 19 centers in 15 countries, including 6 continents. 3D wide-angle RV datasets were obtained and analyzed using dedicated RV software (Tomtec) to measure end-diastolic and end-systolic volumes (EDV, ESV), stroke volume (SV) and ejection fraction (EF). Results were categorized by sex, age (18-40, 41-65 and >65 years) and ethnicity.<br /><b>Results</b><br />Of the 2007 subjects with attempted 3D RV acquisitions, 1051 had adequate image quality for confident measurements. Upper and lower limits for BSA-indexed EDV (mL/m<sup>2</sup>) and ESV (mL/m<sup>2</sup>) and EF (%) were [48, 95], [19, 43] and [44, 58] for men and [42, 81], [16, 36] and [46, 61] for women. Men had significantly larger EDV, ESV and SV (even after BSA indexing) and lower EF than women (p<0.05). EDV and ESV did not show any meaningful differences between age groups. 3D RV volumes were smallest in Asians.<br /><b>Conclusions</b><br />Reliability of 3D RV acquisition is low worldwide underscoring the importance for future improvements in imaging techniques. Sex and race must be taken into consideration in the assessment of both RV volumes and EF.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>J Am Soc Echocardiogr: 19 Apr 2023; epub ahead of print</small></div>

<div><h4>Impact of Age and Sex on Left Ventricular Remodeling in Patients With Aortic Regurgitation.</h4><i>Akintoye E, Saijo Y, Braghieri L, Badwan O, ... Griffin BP, Popović ZB</i><br /><b>Background</b><br />Current guidelines for aortic regurgitation (AR) recommend the same linear left ventricular (LV) dimension for intervention regardless of age and sex.<br /><b>Objectives</b><br />The purpose of this study was to evaluate the impact of age and sex on the degree of LV remodeling and outcomes.<br /><b>Methods</b><br />We included consecutive patients with severe AR who were serially monitored by echocardiogram between 2010 and 2016. The 2 main endpoints were as follows: 1) LV end-systolic volume indexed to body surface area (LVESVi) and LV end-diastolic volume indexed to body surface area; and 2) adverse events (AE). We evaluated the longitudinal rate of LV remodeling and determined the association between LV volume and AE by age and sex.<br /><b>Results</b><br />A total of 525 adult patients (26% women) with a median echocardiogram follow-up of 2.0 years (IQR: 1.0-3.6 years) were included. At baseline, older patients (age ≥60 years) had smaller LV volumes compared with younger patients (age <60 years), eg, the mean LVESVi was 27.3 mL/m<sup>2</sup> vs 32.3 mL/m<sup>2</sup>, respectively. Similarly, women had smaller LV volumes compared with men (mean LVESVi was 23.3 mL/m<sup>2</sup> vs 32.4 mL/m<sup>2</sup>). On serial evaluation, older patients and women maintained smaller LV volumes compared with younger patients and men, respectively. There were 210 (40%) AE during follow-up. The optimal discriminatory threshold for AE varies by age and sex, eg, the LVESVi threshold was highest for young men (50 mL/m<sup>2</sup>), intermediate for older men (35 mL/m<sup>2</sup>), and lowest for women (27 mL/m<sup>2</sup>).<br /><b>Conclusions</b><br />On serial evaluation, older patients and women with chronic AR maintained smaller LV volumes than younger patients and men, respectively, and develop AE at lower LV volumes.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 18 Apr 2023; 81:1474-1487</small></div>

<div><h4>The Genetic Determinants of Aortic Distention.</h4><i>Pirruccello JP, Rämö JT, Choi SH, Chaffin MD, ... Lindsay ME, Ellinor PT</i><br /><b>Background</b><br />As the largest conduit vessel, the aorta is responsible for the conversion of phasic systolic inflow from ventricular ejection into more continuous peripheral blood delivery. Systolic distention and diastolic recoil conserve energy and are enabled by the specialized composition of the aortic extracellular matrix. Aortic distensibility decreases with age and vascular disease.<br /><b>Objectives</b><br />In this study, we sought to discover epidemiologic correlates and genetic determinants of aortic distensibility and strain.<br /><b>Methods</b><br />We trained a deep learning model to quantify thoracic aortic area throughout the cardiac cycle from cardiac magnetic resonance images and calculated aortic distensibility and strain in 42,342 UK Biobank participants.<br /><b>Results</b><br />Descending aortic distensibility was inversely associated with future incidence of cardiovascular diseases, such as stroke (HR: 0.59 per SD; P = 0.00031). The heritabilities of aortic distensibility and strain were 22% to 25% and 30% to 33%, respectively. Common variant analyses identified 12 and 26 loci for ascending and 11 and 21 loci for descending aortic distensibility and strain, respectively. Of the newly identified loci, 22 were not significantly associated with thoracic aortic diameter. Nearby genes were involved in elastogenesis and atherosclerosis. Aortic strain and distensibility polygenic scores had modest effect sizes for predicting cardiovascular outcomes (delaying or accelerating disease onset by 2%-18% per SD change in scores) and remained statistically significant predictors after accounting for aortic diameter polygenic scores.<br /><b>Conclusions</b><br />Genetic determinants of aortic function influence risk for stroke and coronary artery disease and may lead to novel targets for medical intervention.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 11 Apr 2023; 81:1320-1335</small></div>

<div><h4>GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma.</h4><i>Del Bufalo F, De Angelis B, Caruana I, Del Baldo G, ... Locatelli F, Precision Medicine Team–IRCCS Ospedale Pediatrico Bambino Gesù</i><br /><b>Background</b><br />Immunotherapy with chimeric antigen receptor (CAR)-expressing T cells that target the disialoganglioside GD2 expressed on tumor cells may be a therapeutic option for patients with high-risk neuroblastoma.<br /><b>Methods</b><br />In an academic, phase 1-2 clinical trial, we enrolled patients (1 to 25 years of age) with relapsed or refractory, high-risk neuroblastoma in order to test autologous, third-generation GD2-CAR T cells expressing the inducible caspase 9 suicide gene (GD2-CART01).<br /><b>Results</b><br />A total of 27 children with heavily pretreated neuroblastoma (12 with refractory disease, 14 with relapsed disease, and 1 with a complete response at the end of first-line therapy) were enrolled and received GD2-CART01. No failure to generate GD2-CART01 was observed. Three dose levels were tested (3-, 6-, and 10×10<sup>6</sup> CAR-positive T cells per kilogram of body weight) in the phase 1 portion of the trial, and no dose-limiting toxic effects were recorded; the recommended dose for the phase 2 portion of the trial was 10×10<sup>6</sup> CAR-positive T cells per kilogram. Cytokine release syndrome occurred in 20 of 27 patients (74%) and was mild in 19 of 20 (95%). In 1 patient, the suicide gene was activated, with rapid elimination of GD2-CART01. GD2-targeted CAR T cells expanded in vivo and were detectable in peripheral blood in 26 of 27 patients up to 30 months after infusion (median persistence, 3 months; range, 1 to 30). Seventeen children had a response to the treatment (overall response, 63%); 9 patients had a complete response, and 8 had a partial response. Among the patients who received the recommended dose, the 3-year overall survival and event-free survival were 60% and 36%, respectively.<br /><b>Conclusions</b><br />The use of GD2-CART01 was feasible and safe in treating high-risk neuroblastoma. Treatment-related toxic effects developed, and the activation of the suicide gene controlled side effects. GD2-CART01 may have a sustained antitumor effect. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT03373097.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 06 Apr 2023; 388:1284-1295</small></div>

<div><h4>Postexposure Doxycycline to Prevent Bacterial Sexually Transmitted Infections.</h4><i>Luetkemeyer AF, Donnell D, Dombrowski JC, Cohen S, ... Celum C, DoxyPEP Study Team</i><br /><b>Background</b><br />Interventions to reduce sexually transmitted infections (STIs) among men who have sex with men (MSM) are needed.<br /><b>Methods</b><br />We conducted an open-label, randomized study involving MSM and transgender women who were taking preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV) infection (PrEP cohort) or living with HIV infection (persons living with HIV infection [PLWH] cohort) and who had had <i>Neisseria gonorrhoeae</i> (gonorrhea), <i>Chlamydia trachomatis</i> (chlamydia), or syphilis in the past year. Participants were randomly assigned in a 2:1 ratio to take 200 mg of doxycycline within 72 hours after condomless sex (doxycycline postexposure prophylaxis) or receive standard care without doxycycline. STI testing was performed quarterly. The primary end point was the incidence of at least one STI per follow-up quarter.<br /><b>Results</b><br />Of 501 participants (327 in the PrEP cohort and 174 in the PLWH cohort), 67% were White, 7% Black, 11% Asian or Pacific Islander, and 30% Hispanic or Latino. In the PrEP cohort, an STI was diagnosed in 61 of 570 quarterly visits (10.7%) in the doxycycline group and 82 of 257 quarterly visits (31.9%) in the standard-care group, for an absolute difference of -21.2 percentage points and a relative risk of 0.34 (95% confidence interval [CI], 0.24 to 0.46; P<0.001). In the PLWH cohort, an STI was diagnosed in 36 of 305 quarterly visits (11.8%) in the doxycycline group and 39 of 128 quarterly visits (30.5%) in the standard-care group, for an absolute difference of -18.7 percentage points and a relative risk of 0.38 (95% CI, 0.24 to 0.60; P<0.001). The incidences of the three evaluated STIs were lower with doxycycline than with standard care; in the PrEP cohort, the relative risks were 0.45 (95% CI, 0.32 to 0.65) for gonorrhea, 0.12 (95% CI, 0.05 to 0.25) for chlamydia, and 0.13 (95% CI, 0.03 to 0.59) for syphilis, and in the PLWH cohort, the relative risks were 0.43 (95% CI, 0.26 to 0.71), 0.26 (95% CI, 0.12 to 0.57), and 0.23 (95% CI, 0.04 to 1.29), respectively. Five grade 3 adverse events and no serious adverse events were attributed to doxycycline. Of the participants with gonorrhea culture available, tetracycline-resistant gonorrhea occurred in 5 of 13 in the doxycycline groups and 2 of 16 in the standard-care groups.<br /><b>Conclusions</b><br />The combined incidence of gonorrhea, chlamydia, and syphilis was lower by two thirds with doxycycline postexposure prophylaxis than with standard care, a finding that supports its use among MSM with recent bacterial STIs. (Funded by the National Institutes of Health; DoxyPEP ClinicalTrials.gov number, NCT03980223.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 06 Apr 2023; 388:1296-1306</small></div>

<div><h4>Influence of Culprit Lesion Intervention on Outcomes in Infarct-Related Cardiogenic Shock With Cardiac Arrest.</h4><i>Zeymer U, Alushi B, Noc M, Mamas MA, ... Lauten A, Thiele H</i><br /><b>Background</b><br />Cardiac arrest (CA) is common in patients with infarct-related cardiogenic shock (CS).<br /><b>Objectives</b><br />The goal of this study was to identify the characteristics and outcomes of culprit lesion percutaneous coronary intervention (PCI) of patients with infarct-related CS stratified according to CA in the CULPRIT-SHOCK (Culprit Lesion Only PCI Versus Multivessel PCI in Cardiogenic Shock) randomized trial and registry.<br /><b>Methods</b><br />Patients with CS with and without CA from the CULPRIT-SHOCK study were analyzed. All-cause death or severe renal failure leading to renal replacement therapy within 30 days and 1-year death were assessed.<br /><b>Results</b><br />Among 1,015 patients, 550 (54.2%) had CA. Patients with CA were younger, more frequently male, had lower rates of peripheral artery disease, a glomerular filtration rate <30 mL/min, and left main disease, and they presented more often with clinical signs of impaired organ perfusion. The composite of all-cause death or severe renal failure within 30 days occurred in 51.2% of patients with CA vs 48.5% in non-CA patients (P = 0.39) and 1-year death in 53.8% vs 50.4% (P = 0.29), respectively. In a multivariate analysis, CA was an independent predictor of 1-year mortality (HR: 1.27; 95% CI: 1.01-1.59). In the randomized trial, culprit lesion-only PCI was superior to immediate multivessel PCI in patients both with and without CA (P for interaction = 0.6).<br /><b>Conclusions</b><br />More than 50% of patients with infarct-related CS had CA. These patients with CA were younger and had fewer comorbidities, but CA was an independent predictor of 1-year mortality. Culprit lesion-only PCI is the preferred strategy, both in patients with and without CA. (Culprit Lesion Only PCI Versus Multivessel PCI in Cardiogenic Shock [CULPRIT-SHOCK]; NCT01927549).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 28 Mar 2023; 81:1165-1176</small></div>

<div><h4>Acute Effects of Coffee Consumption on Health among Ambulatory Adults.</h4><i>Marcus GM, Rosenthal DG, Nah G, Vittinghoff E, ... Wall G, Olgin JE</i><br /><b>Background</b><br />Coffee is one of the most commonly consumed beverages in the world, but the acute health effects of coffee consumption remain uncertain.<br /><b>Methods</b><br />We conducted a prospective, randomized, case-crossover trial to examine the effects of caffeinated coffee on cardiac ectopy and arrhythmias, daily step counts, sleep minutes, and serum glucose levels. A total of 100 adults were fitted with a continuously recording electrocardiogram device, a wrist-worn accelerometer, and a continuous glucose monitor. Participants downloaded a smartphone application to collect geolocation data. We used daily text messages, sent over a period of 14 days, to randomly instruct participants to consume caffeinated coffee or avoid caffeine. The primary outcome was the mean number of daily premature atrial contractions. Adherence to the randomization assignment was assessed with the use of real-time indicators recorded by the participants, daily surveys, reimbursements for date-stamped receipts for coffee purchases, and virtual monitoring (geofencing) of coffee-shop visits.<br /><b>Results</b><br />The mean (±SD) age of the participants was 39±13 years; 51% were women, and 51% were non-Hispanic White. Adherence to the random assignments was assessed to be high. The consumption of caffeinated coffee was associated with 58 daily premature atrial contractions as compared with 53 daily events on days when caffeine was avoided (rate ratio, 1.09; 95% confidence interval [CI], 0.98 to 1.20; P = 0.10). The consumption of caffeinated coffee as compared with no caffeine consumption was associated with 154 and 102 daily premature ventricular contractions, respectively (rate ratio, 1.51; 95% CI, 1.18 to 1.94); 10,646 and 9665 daily steps (mean difference, 1058; 95% CI, 441 to 1675); 397 and 432 minutes of nightly sleep (mean difference, 36; 95% CI, 25 to 47); and serum glucose levels of 95 mg per deciliter and 96 mg per deciliter (mean difference, -0.41; 95% CI, -5.42 to 4.60).<br /><b>Conclusions</b><br />In this randomized trial, the consumption of caffeinated coffee did not result in significantly more daily premature atrial contractions than the avoidance of caffeine. (Funded by the University of California, San Francisco, and the National Institutes of Health; CRAVE ClinicalTrials.gov number, NCT03671759.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 23 Mar 2023; 388:1092-1100</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>Deep Learning for Improved Precision and Reproducibility of Left Ventricular Strain in Echocardiography: A Test-Retest Study.</h4><i>Salte IM, Østvik A, Olaisen SH, Karlsen S, ... Lovstakken L, Grenne B</i><br /><b>Aims</b><br />Assessment of left ventricular (LV) function by echocardiography is hampered by modest test-retest reproducibility. A novel artificial intelligence (AI) method based on deep learning provides fully automated measurements of LV global longitudinal strain (GLS) and may improve the clinical utility of echocardiography by reducing user related variability. The aim of this study was to assess within-patient test-retest reproducibility of LV GLS measured by the novel AI method in repeated echocardiograms recorded by different echocardiographers, and further, to compare the results to manual measurements.<br /><b>Methods and results</b><br />Two test-retest datasets (n=40 and n=32) were obtained at separate centers. Repeated recordings were acquired in immediate succession by two different echocardiographers at each center. For each dataset, four readers measured GLS in both recordings using a semi-automatic method to construct test-retest inter-reader and intra-reader scenarios. Agreement, mean absolute difference and minimal detectable change (MDC) were compared to analyses by AI. In a subset of 10 patients, beat-to-beat variability in three cardiac cycles was assessed by two readers and AI. Test-retest variability was lower with AI compared to inter-reader scenarios (dataset I: MDC 3.7 vs 5.5, mean absolute difference 1.4 vs 2.1; dataset II: MDC 3.9 vs 5.2, mean absolute difference 1.6 vs 1.9, all p<0.05). There was bias in GLS measurements in 13 of 24 test-retest inter-reader scenarios (largest bias 3.2 strain units). In contrast, there was no bias in measurements by AI. Beat-to-beat MDCs were 1,5, 2.1, and 2.3 for AI and the two readers, respectively. Processing time for analyses of GLS by the AI method was 7.9±2.8 seconds.<br /><b>Conclusion</b><br />A fast AI method for automated measurements of LV GLS reduced test-retest variability and removed bias between readers in both test-retest datasets. By improving the precision and reproducibility, AI may increase the clinical utility of echocardiography.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>J Am Soc Echocardiogr: 16 Mar 2023; epub ahead of print</small></div>

<div><h4>Effect of Prosthesis-Patient Mismatch on Long-Term Clinical Outcomes After Bioprosthetic Aortic Valve Replacement.</h4><i>Dismorr M, Glaser N, Franco-Cereceda A, Sartipy U</i><br /><b>Background</b><br />Prosthesis-patient mismatch (PPM) is common following surgical aortic valve replacement (SAVR).<br /><b>Objectives</b><br />The purpose of this study was to quantify the impact of PPM on all-cause mortality, heart failure hospitalization, and reintervention following bioprosthetic SAVR.<br /><b>Methods</b><br />This observational nationwide cohort study from SWEDEHEART (Swedish Web system for Enhancement and Development of Evidence based care in Heart disease Evaluated According to Recommended Therapies) and other national registers included all patients who underwent primary bioprosthetic SAVR in Sweden from 2003 to 2018. PPM was defined according to the Valve Academic Research Consortium 3 criteria. Outcomes were all-cause mortality, heart failure hospitalization, and aortic valve reintervention. Regression standardization was used to account for intergroup differences and to estimate cumulative incidence differences.<br /><b>Results</b><br />We included 16,423 patients (no PPM: 7,377 [45%]; moderate PPM: 8,502 [52%]; and severe PPM: 544 [3%]). After regression standardization, the cumulative incidence of all-cause mortality at 10 years was 43% (95% CI: 24%-44%) in the no PPM group compared with 45% (95% CI: 43%-46%) and 48% (95% CI: 44%-51%) in the moderate and severe PPM groups, respectively. The survival difference at 10 years was 4.6% (95% CI: 0.7%-8.5%) and 1.7% (95% CI: 0.1%-3.3%) in no vs severe PPM and no vs moderate PPM, respectively. The difference in heart failure hospitalization at 10 years was 6.0% (95% CI: 2.2%-9.7%) in severe vs no PPM. There was no difference in aortic valve reintervention in patients with or without PPM.<br /><b>Conclusions</b><br />Increasing grades of PPM were associated with long-term mortality, and severe PPM was associated with increased heart failure. Moderate PPM was common, but the clinical significance may be negligible because the absolute risk differences in clinical outcomes were small.<br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 14 Mar 2023; 81:964-975</small></div>

<div><h4>Sex Differences in Epidemiology, Care, and Outcomes in Patients With Acute Chest Pain.</h4><i>Dawson LP, Nehme E, Nehme Z, Davis E, ... Smith K, Stub D</i><br /><b>Background</b><br />Discrepancies in cardiovascular care for women are well described, but few data assess the entire patient journey for chest pain care.<br /><b>Objectives</b><br />This study aimed to assess sex differences in epidemiology and care pathways from emergency medical services (EMS) contact through to clinical outcomes following discharge.<br /><b>Methods</b><br />This is a state-wide population-based cohort study including consecutive adult patients attended by EMS for acute undifferentiated chest pain in Victoria, Australia (January 1, 2015, to June 30, 2019). EMS clinical data were individually linked to emergency and hospital administrative datasets, and mortality data and differences in care quality and outcomes were assessed using multivariable analyses.<br /><b>Results</b><br />In 256,901 EMS attendances for chest pain, 129,096 attendances (50.3%) were women, and mean age was 61.6 years. Age-standardized incidence rates were marginally higher for women compared with men (1,191 vs 1,135 per 100,000 person-years). In multivariable models, women were less likely to receive guideline-directed care across most care measures including transport to hospital, prehospital aspirin or analgesia administration, 12-lead electrocardiogram, intravenous cannula insertion, and off-load from EMS or review by emergency department clinicians within target times. Similarly, women with acute coronary syndrome were less likely to undergo angiography or be admitted to a cardiac or intensive care unit. Thirty-day and long-term mortality was higher for women diagnosed with ST-segment elevation myocardial infarction, but lower overall.<br /><b>Conclusions</b><br />Substantial differences in care are present across the spectrum of acute chest pain management from first contact through to hospital discharge. Women have higher mortality for STEMI, but better outcomes for other etiologies of chest pain compared with men.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 14 Mar 2023; 81:933-945</small></div>

<div><h4>Intrapericardial long non-coding RNA-Tcf21 antisense RNA inducing demethylation administration promotes cardiac repair.</h4><i>Zhu D, Liu S, Huang K, Li J, ... Li Z, Cheng K</i><br /><b>Aims</b><br />Epicardium and epicardium-derived cells are critical players in myocardial fibrosis. Mesenchymal stem cell-derived extracellular vesicles (EVs) have been studied for cardiac repair to improve cardiac remodelling, but the actual mechanisms remain elusive. The aim of this study is to investigate the mechanisms of EV therapy for improving cardiac remodelling and develop a promising treatment addressing myocardial fibrosis.<br /><b>Methods and results</b><br />Extracellular vesicles were intrapericardially injected for mice myocardial infarction treatment. RNA-seq, in vitro gain- and loss-of-function experiments, and in vivo studies were performed to identify targets that can be used for myocardial fibrosis treatment. Afterward, a lipid nanoparticle-based long non-coding RNA (lncRNA) therapy was prepared for mouse and porcine models of myocardial infarction treatment. Intrapericardial injection of EVs improved adverse myocardial remodelling in mouse models of myocardial infarction. Mechanistically, Tcf21 was identified as a potential target to improve cardiac remodelling. Loss of Tcf21 function in epicardium-derived cells caused increased myofibroblast differentiation, whereas forced Tcf21 overexpression suppressed transforming growth factor-β signalling and myofibroblast differentiation. LncRNA-Tcf21 antisense RNA inducing demethylation (TARID) that enriched in EVs was identified to up-regulate Tcf21 expression. Formulated lncRNA-TARID-laden lipid nanoparticles up-regulated Tcf21 expression in epicardium-derived cells and improved cardiac function and histology in mouse and porcine models of myocardial infarction.<br /><b>Conclusion</b><br />This study identified Tcf21 as a critical target for improving cardiac fibrosis. Up-regulating Tcf21 by using lncRNA-TARID-laden lipid nanoparticles could be a promising way to treat myocardial fibrosis. This study established novel mechanisms underlying EV therapy for improving adverse remodelling and proposed a lncRNA therapy for cardiac fibrosis.<br /><br />© The Author(s) 2023. 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: 14 Mar 2023; epub ahead of print</small></div>

<div><h4>Cardiac rehabilitation for heart failure: \'Cinderella\' or evidence-based pillar of care?</h4><i>Taylor RS, Dalal HM, Zwisler AD</i><br /><AbstractText>Cardiac rehabilitation remains the \'Cinderella\' of treatments for heart failure. This state-of-the-art review provides a contemporary update on the evidence base, clinical guidance, and status of cardiac rehabilitation delivery for patients with heart failure. Given that cardiac rehabilitation participation results in important improvements in patient outcomes, including health-related quality of life, this review argues that an exercise-based rehabilitation is a key pillar of heart failure management alongside drug and medical device provision. To drive future improvements in access and uptake, health services should offer heart failure patients a choice of evidence-based modes of rehabilitation delivery, including home, supported by digital technology, alongside traditional centre-based programmes (or combinations of modes, \'hybrid\') and according to stage of disease and patient preference.</AbstractText><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: 11 Mar 2023; epub ahead of print</small></div>

<div><h4>Randomized Trial of Targeted Transendocardial Mesenchymal Precursor Cell Therapy in Patients With Heart Failure.</h4><i>Perin EC, Borow KM, Henry TD, Mendelsohn FO, ... Itescu S, Greenberg B</i><br /><b>Background</b><br />Mesenchymal precursor cells (MPCs) are allogeneic, immunoselected cells with anti-inflammatory properties that could improve outcomes in heart failure with reduced ejection fraction (HFrEF).<br /><b>Objectives</b><br />This study assessed the efficacy and safety of MPCs in patients with high-risk HFrEF.<br /><b>Methods</b><br />This randomized, double-blind, multicenter study evaluated a single transendocardial administration procedure of MPCs or sham-control in 565 intention-to-treat patients with HFrEF on guideline-directed therapies. The primary endpoint was time-to-recurrent events caused by decompensated HFrEF or successfully resuscitated symptomatic ventricular arrhythmias. Hierarchical secondary endpoints included components of the primary endpoint, time-to-first terminal cardiac events, and all-cause death. Separate and composite major adverse cardiovascular events analyses were performed for myocardial infarction or stroke or cardiovascular death. Baseline and 12-month echocardiography was performed. Baseline plasma high-sensitivity C-reactive protein levels were evaluated for disease severity.<br /><b>Results</b><br />The primary endpoint was similar between treatment groups (HR: 1.17; 95% CI: 0.81-1.69; P = 0.41) as were terminal cardiac events and secondary endpoints. Compared with control subjects, MPCs increased left ventricular ejection fraction from baseline to 12 months, especially in patients with inflammation. MPCs decreased the risk of myocardial infarction or stroke by 58% (HR: 0.42; 95% CI: 0.23-0.76) and the risk of 3-point major adverse cardiovascular events by 28% (HR: 0.72; 95% CI: 0.51-1.03) in the analysis population (n = 537), and by 75% (HR: 0.25; 95% CI: 0.09-0.66) and 38% (HR: 0.62; 95% CI: 0.39-1.00), respectively, in patients with inflammation (baseline high-sensitivity C-reactive protein ≥2 mg/L).<br /><b>Conclusions</b><br />The primary and secondary endpoints of the trial were negative. Positive signals in prespecified, and post hoc exploratory analyses suggest MPCs may improve outcomes, especially in patients with inflammation.<br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 07 Mar 2023; 81:849-863</small></div>

<div><h4>Five-Year Follow-up after Transcatheter Repair of Secondary Mitral Regurgitation.</h4><i>Stone GW, Abraham WT, Lindenfeld J, Kar S, ... Mack MJ, COAPT Investigators</i><br /><b>Background</b><br />Data from a 5-year follow-up of outcomes after transcatheter edge-to-edge repair of severe mitral regurgitation, as compared with outcomes after maximal doses of guideline-directed medical therapy alone, in patients with heart failure are now available.<br /><b>Methods</b><br />We randomly assigned patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy to undergo transcatheter edge-to-edge repair plus receive medical therapy (device group) or to receive medical therapy alone (control group) at 78 sites in the United States and Canada. The primary effectiveness end point was all hospitalizations for heart failure through 2 years of follow-up. The annualized rate of all hospitalizations for heart failure, all-cause mortality, the risk of death or hospitalization for heart failure, and safety, among other outcomes, were assessed through 5 years.<br /><b>Results</b><br />Of the 614 patients enrolled in the trial, 302 were assigned to the device group and 312 to the control group. The annualized rate of hospitalization for heart failure through 5 years was 33.1% per year in the device group and 57.2% per year in the control group (hazard ratio, 0.53; 95% confidence interval [CI], 0.41 to 0.68). All-cause mortality through 5 years was 57.3% in the device group and 67.2% in the control group (hazard ratio, 0.72; 95% CI, 0.58 to 0.89). Death or hospitalization for heart failure within 5 years occurred in 73.6% of the patients in the device group and in 91.5% of those in the control group (hazard ratio, 0.53; 95% CI, 0.44 to 0.64). Device-specific safety events within 5 years occurred in 4 of 293 treated patients (1.4%), with all the events occurring within 30 days after the procedure.<br /><b>Conclusions</b><br />Among patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite guideline-directed medical therapy, transcatheter edge-to-edge repair of the mitral valve was safe and led to a lower rate of hospitalization for heart failure and lower all-cause mortality through 5 years of follow-up than medical therapy alone. (Funded by Abbott; COAPT ClinicalTrials.gov number, NCT01626079.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 05 Mar 2023; epub ahead of print</small></div>

<div><h4>Sex Differences in Extensive Mitral Annular Calcification With Associated Mitral Valve Dysfunction.</h4><i>Churchill TW, Yucel E, Bernard S, Namasivayam M, ... Hung J, Bertrand PB</i><br /><AbstractText>Mitral annular calcification (MAC)-related mitral valve (MV) dysfunction is an increasingly recognized entity, which confers a high burden of morbidity and mortality. Although more common among women, there is a paucity of data regarding how the phenotype of MAC and the associated adverse clinical implications may differ between women and men. A total of 3,524 patients with extensive MAC and significant MAC-related MV dysfunction (i.e., transmitral gradient ≥3 mm Hg) were retrospectively analyzed from a large institutional database, with the goal of defining gender differences in clinical and echocardiographic characteristics and the prognostic importance of MAC-related MV dysfunction. We stratified patients into low- (3 to 5 mm Hg), moderate- (5 to 10 mm Hg), and high- (≥10 mm Hg) gradient groups and analyzed the gender differences in phenotype and outcome. The primary outcome was all-cause mortality, assessed using adjusted Cox regression models. Women represented the majority (67%) of subjects, were older (79.3 ± 10.4 vs 75.5 ± 10.9 years, p <0.001) and had a lower burden of cardiovascular co-morbidities than men. Women had higher transmitral gradients (5.7 ± 2.7 vs 5.3 ± 2.6 mm Hg, p <0.001), more concentric hypertrophy (49% vs 33%), and more mitral regurgitation. The median survival was 3.4 years (95% confidence interval 3.0 to 3.6) among women and 3.0 years (95% confidence interval 2.6 to 4.5) among men. The adjusted survival was worse among men, and the prognostic impact of the transmitral gradient did not differ overall by gender. In conclusion, we describe important gender differences among patients with MAC-related MV dysfunction and show worse adjusted survival among men; although, the adverse prognostic impact of the transmitral gradient was similar between men and women.</AbstractText><br /><br />Copyright © 2023 Elsevier Inc. All rights reserved.<br /><br /><small>Am J Cardiol: 05 Mar 2023; 193:83-90</small></div>

<div><h4>Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients.</h4><i>Nissen SE, Lincoff AM, Brennan D, Ray KK, ... Nicholls SJ, CLEAR Outcomes Investigators</i><br /><b>Background</b><br />Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on cardiovascular outcomes remain uncertain.<br /><b>Methods</b><br />We conducted a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects (\"statin-intolerant\" patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.<br /><b>Results</b><br />A total of 13,970 patients underwent randomization; 6992 were assigned to the bempedoic acid group and 6978 to the placebo group. The median duration of follow-up was 40.6 months. The mean LDL cholesterol level at baseline was 139.0 mg per deciliter in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid. The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 [8.2%] vs. 663 [9.5%]; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P = 0.006); fatal or nonfatal myocardial infarction (261 [3.7%] vs. 334 [4.8%]; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P = 0.002); and coronary revascularization (435 [6.2%] vs. 529 [7.6%]; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = 0.001). Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels.<br /><b>Conclusions</b><br />Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization). (Funded by Esperion Therapeutics; CLEAR Outcomes ClinicalTrials.gov number, NCT02993406.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 04 Mar 2023; epub ahead of print</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>