<div><h4>Normative Echocardiographic Left Ventricular Parameters and Reference Intervals in Infants.</h4><i>Vøgg ROB, Sillesen AS, Wohlfahrt J, Pihl C, ... Boyd HA, Bundgaard H</i><br /><b>Background</b><br />In pediatric echocardiography, reference intervals are required to distinguish normal variation from pathology. Left ventricular (LV) parameters are particularly important predictors of clinical outcome. However, data from healthy newborns are limited, and current reference intervals provide an inadequate approximation of normal reference ranges.<br /><b>Objectives</b><br />Normative reference intervals and z-scores for 2-dimensional echocardiographic measurements of LV structure and function based on a large group of healthy newborns were developed.<br /><b>Methods</b><br />The study population included 13,454 healthy newborns from the Copenhagen Baby Heart Study who were born at term to healthy mothers, had an echocardiogram performed within 30 days of birth, and did not have congenital heart disease. To develop normative reference intervals, this study modeled 10 LV parameters as a function of body surface area through joint modeling of 4 statistical components.<br /><b>Results</b><br />Infants in the study population (48.5% were female) had a median body surface area of 0.23 m<sup>2</sup> (IQR: 0.22-0.25 m<sup>2</sup>) and median age of 12.0 days (IQR: 8.0-15.0 days) at examination. All normative reference intervals performed well in both sexes without stratification on infant sex. In contrast, creation of separate reference models for infants examined at <7 days of age and those examined at 7-30 days of age was necessary to optimize the performance of the reference intervals.<br /><b>Conclusions</b><br />This study provides normative reference intervals and z-scores for 10 clinical, widely used echocardiographic measures of LV structure and function based on a large cohort of newborns. These results provide highly needed reference material for clinical application by pediatric cardiologists.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 06 Jun 2023; 81:2175-2185</small></div>

<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>Lipoprotein(a), Oxidized Phospholipids, and Coronary Artery Disease Severity and Outcomes.</h4><i>Gilliland TC, Liu Y, Mohebi R, Miksenas H, ... Januzzi JL, Natarajan P</i><br /><b>Background</b><br />Lipoprotein(a) (Lp[a]) and oxidized phospholipids (OxPLs) are each independent risk factors for atherosclerotic cardiovascular disease. The extent to which Lp(a) and OxPLs predict coronary artery disease (CAD) severity and outcomes in a contemporary, statin-treated cohort is not well established.<br /><b>Objectives</b><br />This study sought to evaluate the relationships between Lp(a) particle concentration and OxPLs associated with apolipoprotein B (OxPL-apoB) or apolipoprotein(a) (OxPL-apo[a]) with angiographic CAD and cardiovascular outcomes.<br /><b>Methods</b><br />Among 1,098 participants referred for coronary angiography in the CASABLANCA (Catheter Sampled Blood Archive in Cardiovascular Diseases) study, Lp(a), OxPL-apoB, and OxPL-apo(a) were measured. Logistic regression estimated the risk of multivessel coronary stenoses by Lp(a)-related biomarker level. Cox proportional hazards regression estimated the risk of major adverse cardiovascular events (MACEs) (coronary revascularization, nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) in follow-up.<br /><b>Results</b><br />Median Lp(a) was 26.45 nmol/L (IQR: 11.39-89.49 nmol/L). Lp(a), OxPL-apoB, and OxPL-apo(a) were highly correlated (Spearman R ≥0.91 for all pairwise combinations). Lp(a) and OxPL-apoB were associated with multivessel CAD. Odds of multivessel CAD per doubling of Lp(a), OxPL-apoB, and OxPL-apo(a) were 1.10 (95% CI: 1.03-1.18; P = 0.006), 1.18 (95% CI: 1.03-1.34; P = 0.01), and 1.07 (95% CI: 0.99-1.16; P = 0.07), respectively. All biomarkers were associated with cardiovascular events. HRs for MACE per doubling of Lp(a), OxPL-apoB, and OxPL-apo(a) were 1.08 (95% CI: 1.03-1.14; P = 0.001), 1.15 (95% CI: 1.05-1.26; P = 0.004), and 1.07 (95% CI: 1.01-1.14; P = 0.02), respectively.<br /><b>Conclusions</b><br />In patients undergoing coronary angiography, Lp(a) and OxPL-apoB are associated with multivessel CAD. Lp(a), OxPL-apoB, and OxPL-apo(a) are associated with incident cardiovascular events. (Catheter Sampled Blood Archive in Cardiovascular Diseases [CASABLANCA]; NCT00842868).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 09 May 2023; 81:1780-1792</small></div>

<div><h4>Heart Failure With Preserved Ejection Fraction: JACC Scientific Statement.</h4><i>Borlaug BA, Sharma K, Shah SJ, Ho JE</i><br /><AbstractText>The incidence and prevalence of heart failure with preserved ejection fraction (HFpEF) continue to rise in tandem with the increasing age and burdens of obesity, sedentariness, and cardiometabolic disorders. Despite recent advances in the understanding of its pathophysiological effects on the heart, lungs, and extracardiac tissues, and introduction of new, easily implemented approaches to diagnosis, HFpEF remains under-recognized in everyday practice. This under-recognition presents an even greater concern given the recent identification of highly effective pharmacologic-based and lifestyle-based treatments that can improve clinical status and reduce morbidity and mortality. HFpEF is a heterogenous syndrome and recent studies have suggested an important role for careful, pathophysiological-based phenotyping to improve patient characterization and to better individualize treatment. In this JACC Scientific Statement, we provide an in-depth and updated examination of the epidemiology, pathophysiology, diagnosis, and treatment of HFpEF.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 09 May 2023; 81:1810-1834</small></div>

<div><h4>Impact of cardiac surgery on left-sided infective endocarditis with intermediate-length vegetations.</h4><i>Scheggi V, Bohbot Y, Tribouilloy C, Trojette F, ... Habib G, Marchionni N</i><br /><b>Objective</b><br />The best strategy to manage patients with left-sided infective endocarditis (IE) and intermediate-length vegetations (10-15 mm) remains uncertain. We aimed to evaluate the role of surgery in patients with intermediate-length vegetations and no other European Society of Cardiology guidelines-approved surgical indication.<br /><b>Methods</b><br />We retrospectively enrolled 638 consecutive patients admitted to three academic centres (Amiens, Marseille and Florence University Hospitals) between 2012 and 2022 for left-sided definite IE (native or prosthetic) with intermediate-length vegetations (10-15 mm). We compared four clinical groups: medically (n=50) or surgically (n=345) treated complicated IE, medically (n=194) or surgically (n=49) treated uncomplicated IE.<br /><b>Results</b><br />Mean age was 67±14 years. Women were 182 (28.6%). The rate of embolic events on admission was 40% in medically treated and 61% in surgically treated complicated IE, 31% in medically treated and 26% in surgically treated uncomplicated IE. The analysis of all-cause mortality showed the lowest 5-year survival rate for medically treated complicated IE (53.7%). We found a similar 5-year survival rate for surgically treated complicated IE (71.4%) and medically treated uncomplicated IE (68.4%). The highest 5-year survival rate was observed in surgically treated uncomplicated IE group (82.4%, log-rank p<0.001). The analysis of the propensity score-matched cohort estimated an HR of 0.23 for uncomplicated IE treated surgically compared with medical therapy (p=0.005, 95% CI: 0.079 to 0.656).<br /><b>Conclusions</b><br />Our results suggest that surgery is associated with lower all-cause mortality than medical therapy in patients with uncomplicated left-sided IE with intermediate-length vegetations even in the absence of other guideline-based indications.<br /><br />© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>Heart: 05 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>Health Status and Clinical Outcomes in Older Adults With Chronic Coronary Disease: The ISCHEMIA Trial.</h4><i>Nguyen DD, Spertus JA, Alexander KP, Newman JD, ... Hochman JS, ISCHEMIA Research Group</i><br /><b>Background</b><br />Whether initial invasive management in older vs younger adults with chronic coronary disease and moderate or severe ischemia improves health status or clinical outcomes is unknown.<br /><b>Objectives</b><br />The goal of this study was to examine the impact of age on health status and clinical outcomes with invasive vs conservative management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial.<br /><b>Methods</b><br />One-year angina-specific health status was assessed with the 7-item Seattle Angina Questionnaire (SAQ) (score range 0-100; higher scores indicate better health status). Cox proportional hazards models estimated the treatment effect of invasive vs conservative management as a function of age on the composite clinical outcome of cardiovascular death, myocardial infarction, or hospitalization for resuscitated cardiac arrest, unstable angina, or heart failure.<br /><b>Results</b><br />Among 4,617 participants, 2,239 (48.5%) were aged <65 years, 1,713 (37.1%) were aged 65 to 74 years, and 665 (14.4%) were aged ≥75 years. Baseline SAQ summary scores were lower in participants aged <65 years. Fully adjusted differences in 1-year SAQ summary scores (invasive minus conservative) were 4.90 (95% CI: 3.56-6.24) at age 55 years, 3.48 (95% CI: 2.40-4.57) at age 65 years, and 2.13 (95% CI: 0.75-3.51) at age 75 years (P<sub>interaction</sub> = 0.008). Improvement in SAQ Angina Frequency was less dependent on age (P<sub>interaction</sub> = 0.08). There were no age differences between invasive vs conservative management on the composite clinical outcome (P<sub>interaction</sub> = 0.29).<br /><b>Conclusions</b><br />Older patients with chronic coronary disease and moderate or severe ischemia had consistent improvement in angina frequency but less improvement in angina-related health status with invasive management compared with younger patients. Invasive management was not associated with improved clinical outcomes in older or younger patients. (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 02 May 2023; 81:1697-1709</small></div>

<div><h4>Gut Microbiome-Based Management of Patients With Heart Failure: JACC Review Topic of the Week.</h4><i>Mamic P, Snyder M, Tang WHW</i><br /><AbstractText>Despite therapeutic advances, chronic heart failure (HF) is still associated with significant risk of morbidity and mortality. The course of disease and responses to therapies vary widely among individuals with HF, highlighting the need for precision medicine approaches. Gut microbiome stands to be an important aspect of precision medicine in HF. Exploratory clinical studies have revealed shared patterns of gut microbiome dysregulation in this disease, with mechanistic animal studies providing evidence for active involvement of the gut microbiome in development and pathophysiology of HF. Deeper insights into gut microbiome-host interactions in patients with HF promise to deliver novel disease biomarkers, preventative and therapeutic targets, and improve disease risk stratification. This knowledge may enable a paradigm shift in how we care for patients with HF, and pave the path toward improved clinical outcomes through personalized HF care.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 02 May 2023; 81:1729-1739</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>Statin loading before coronary artery bypass grafting: a randomized trial.</h4><i>Liakopoulos OJ, Kuhn EW, Hellmich M, Schlömicher M, ... Wahlers T, StaRT-CABG Investigators</i><br /><b>Aims</b><br />Evidence suggests that a high-dose statin loading before a percutaneous coronary revascularization improves outcomes in patients receiving long-term statins. This study aimed to analyse the effects of such an additional statin therapy before surgical revascularization.<br /><b>Methods and results</b><br />This investigator-initiated, randomized, double-blind, and placebo-controlled trial was conducted from November 2012 to April 2019 at 14 centres in Germany. Adult patients (n = 2635) with a long-term statin treatment (≥30 days) who were scheduled for isolated coronary artery bypass grafting (CABG) were randomly assigned to receive a statin-loading therapy or placebo at 12 and 2 h prior to surgery using a web-based system. The primary outcome of major adverse cardiac and cerebrovascular events (MACCE) was a composite consisting of all-cause mortality, myocardial infarction (MI), and a cerebrovascular event occuring within 30 days after surgery. Key secondary endpoints included a composite of cardiac death and MI, myocardial injury, and death within 12 months. Non-statistically relevant differences were found in the modified intention-to-treat analysis (2406 patients; 1203 per group) between the statin (13.9%) and placebo groups (14.9%) for the primary outcome [odds ratio (OR) 0.93, 95% confidence interval (CI) 0.74-1.18; P = 0.562] or any of its individual components. Secondary endpoints including cardiac death and MI (12.1% vs. 13.5%; OR 0.88, 95% CI 0.69-1.12; P = 0.300), the area under the troponin T-release curve (median 0.398 vs. 0.394 ng/ml, P = 0.333), and death at 12 months (3.1% vs. 2.9%; P = 0.825) were comparable between treatment arms.<br /><b>Conclusion</b><br />Additional statin loading before CABG failed to reduce the rate of MACCE occuring within 30 days of surgery.<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: 22 Apr 2023; epub ahead of print</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>Use of the Inspiris Valve in the Native Right Ventricular Outflow Tract is Associated with Early Prosthetic Regurgitation.</h4><i>Nguyen SN, Vinogradsky AV, Sevensky R, Crystal MA, Bacha EA, Goldstone AB</i><br /><b>Objective</b><br />The Inspiris Resilia prosthesis (Edwards Lifesciences, Irvine, CA) has been increasingly used in the pulmonic position with limited performance data. We sought to investigate its durability as a surgical pulmonary valve replacement (PVR).<br /><b>Methods</b><br />We retrospectively reviewed patients who underwent PVR or conduit replacement with an Inspiris or non-Inspiris valve/conduit from 2018-2022. The primary endpoint was freedom from a composite of at least moderate pulmonary regurgitation (PR), pulmonary stenosis (PS), or valve/conduit reintervention. Secondary endpoints were individual components of the composite outcome. To account for baseline differences, propensity matching identified 70 patient pairs.<br /><b>Results</b><br />A total of 227 patients (median age: 19.3 years [IQR, 11.8-34.4]) underwent PVR or conduit replacement (Inspiris: n=120 [52.9%], non-Inspiris: n=107 [47.1%]). Median follow-up was 26.6 months [IQR, 12.4-41.1]. Among matched patients, 2-year freedom from valve failure was lower in the Inspiris group (53.5%±9.3% vs. 78.5%±5.9%, p=0.03), as was freedom from at least moderate PR (54.2%±9.6% vs. 86.4%±4.9%, p<0.01). There was no difference in 2-year freedom from at least moderate PS (p=0.61) or reintervention (p=0.92). Inspiris durability was poorer when implanted in the native right ventricular outflow tract compared to as a conduit, with 18-month freedom from valve failure of 59.0%±9.5% vs. 85.9%±9.5% (p=0.03).<br /><b>Conclusions</b><br />Early durability of the Inspiris valve is poor when implanted in the native right ventricular outflow tract; its unique design may be incompatible with the compliant pulmonary root. Modified implantation techniques or alternative prostheses should be considered.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>J Thorac Cardiovasc Surg: 21 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>Heart Failure Following Anti-Inflammatory Medications in Patients With Type 2 Diabetes Mellitus.</h4><i>Holt A, Strange JE, Nouhravesh N, Nielsen SK, ... Schou M, Lamberts M</i><br /><b>Background</b><br />Fluid retention and endothelial dysfunction have been related to use of nonsteroidal anti-inflammatory drugs (NSAIDs), and type 2 diabetes mellitus (T2DM) has been linked to both a decline in kidney function and subclinical cardiomyopathy.<br /><b>Objectives</b><br />The authors hypothesized that short-term use of NSAIDs could lead to subsequent development of incident heart failure (HF) in patients with T2DM.<br /><b>Methods</b><br />Using nationwide Danish registers, we identified patients diagnosed with T2DM during 1998 to 2021 and included patients without previous HF, rheumatic disease, or use of NSAIDs 120 days before diagnosis. Associations between NSAIDs and first-time HF hospitalization were investigated using a case-crossover design with 28-day exposure windows, and ORs with 95% CIs were reported.<br /><b>Results</b><br />Included were 331,189 patients with T2DM: 44.2% female, median age of 62 years (IQR: 52-71 years); 23,308 patients were hospitalized with HF during follow-up, and 16% of patients claimed at least 1 NSAID prescription within 1 year. Short-term use of NSAIDs was associated with increased risk of HF hospitalization (OR: 1.43; 95% CI: 1.27-1.63), most notably in subgroups with age ≥80 years (OR: 1.78; 95% CI: 1.39-2.28), elevated hemoglobin (Hb) A1c levels treated with 0 to 1 antidiabetic drug (OR: 1.68; 95% CI: 1.00-2.88), and without previous use of NSAIDs (OR: 2.71; 95% CI: 1.78-4.23).<br /><b>Conclusions</b><br />NSAIDs were widely used and were associated with an increased risk of first-time HF hospitalization in patients with T2DM. Patients with advanced age, elevated HbA1c levels, and new users of NSAID seemed more susceptible. These findings could guide physicians prescribing NSAIDs.<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; 81:1459-1470</small></div>

<div><h4>Effect of Donor Sex on Recipient Mortality in Transfusion.</h4><i>Chassé M, Fergusson DA, Tinmouth A, Acker JP, ... Maddison H, Tokessy M</i><br /><b>Background</b><br />Conflicting observational evidence exists regarding the association between the sex of red-cell donors and mortality among transfusion recipients. Evidence to inform transfusion practice and policy is limited.<br /><b>Methods</b><br />In this multicenter, double-blind trial, we randomly assigned patients undergoing red-cell transfusion to receive units of red cells from either male donors or female donors. Patients maintained their trial-group assignment throughout the trial period, including during subsequent inpatient and outpatient encounters. Randomization was conducted in a 60:40 ratio (male donor group to female donor group) to match the historical allocation of red-cell units from the blood supplier. The primary outcome was survival, with the male donor group as the reference group.<br /><b>Results</b><br />A total of 8719 patients underwent randomization before undergoing transfusion; 5190 patients were assigned to the male donor group, and 3529 to the female donor group. At baseline, the mean (±SD) age of the enrolled patients was 66.8±16.4 years. The setting of the first transfusion was as an inpatient in 6969 patients (79.9%), of whom 2942 (42.2%) had been admitted under a surgical service. The baseline hemoglobin level before transfusion was 79.5±19.7 g per liter, and patients received a mean of 5.4±10.5 units of red cells in the female donor group and 5.1±8.9 units in the male donor group (difference, 0.3 units; 95% confidence interval [CI], -0.1 to 0.7). Over the duration of the trial, 1141 patients in the female donor group and 1712 patients in the male donor group died. In the primary analysis of overall survival, the adjusted hazard ratio for death was 0.98 (95% CI, 0.91 to 1.06).<br /><b>Conclusions</b><br />This trial showed no significant difference in survival between a transfusion strategy involving red-cell units from female donors and a strategy involving red-cell units from male donors. (Funded by the Canadian Institutes of Health Research; iTADS ClinicalTrials.gov number, NCT03344887.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 13 Apr 2023; 388:1386-1395</small></div>

<div><h4>Tranexamic Acid to Prevent Obstetrical Hemorrhage after Cesarean Delivery.</h4><i>Pacheco LD, Clifton RG, Saade GR, Weiner SJ, ... Macones GA, Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network</i><br /><b>Background</b><br />Prophylactic use of tranexamic acid at the time of cesarean delivery has been shown to decrease the calculated blood loss, but the effect on the need for blood transfusions is unclear.<br /><b>Methods</b><br />We randomly assigned patients undergoing cesarean delivery at 31 U.S. hospitals to receive either tranexamic acid or placebo after umbilical-cord clamping. The primary outcome was a composite of maternal death or blood transfusion by hospital discharge or 7 days post partum, whichever came first. Key secondary outcomes were estimated intraoperative blood loss of more than 1 liter (prespecified as a major secondary outcome), interventions for bleeding and related complications, the preoperative-to-postoperative change in the hemoglobin level, and postpartum infectious complications. Adverse events were assessed.<br /><b>Results</b><br />A total of 11,000 participants underwent randomization (5529 to the tranexamic acid group and 5471 to the placebo group); scheduled cesarean delivery accounted for 50.1% and 49.2% of the deliveries in the respective groups. A primary-outcome event occurred in 201 of 5525 participants (3.6%) in the tranexamic acid group and in 233 of 5470 (4.3%) in the placebo group (adjusted relative risk, 0.89; 95.26% confidence interval [CI], 0.74 to 1.07; P = 0.19). Estimated intraoperative blood loss of more than 1 liter occurred in 7.3% of the participants in the tranexamic acid group and in 8.0% of those in the placebo group (relative risk, 0.91; 95% CI, 0.79 to 1.05). Interventions for bleeding complications occurred in 16.1% of the participants in the tranexamic acid group and in 18.0% of those in the placebo group (relative risk, 0.90; 95% CI, 0.82 to 0.97); the change in the hemoglobin level was -1.8 g per deciliter and -1.9 g per deciliter, respectively (mean difference, -0.1 g per deciliter; 95% CI, -0.2 to -0.1); and postpartum infectious complications occurred in 3.2% and 2.5% of the participants, respectively (relative risk, 1.28; 95% CI, 1.02 to 1.61). The frequencies of thromboembolic events and other adverse events were similar in the two groups.<br /><b>Conclusions</b><br />Prophylactic use of tranexamic acid during cesarean delivery did not lead to a significantly lower risk of a composite outcome of maternal death or blood transfusion than placebo. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT03364491.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 13 Apr 2023; 388:1365-1375</small></div>

<div><h4>Septal Annular Dilation in Chronic Ovine Functional Tricuspid Regurgitation.</h4><i>Iwasieczko A, Jazwiec T, Gaddam M, Gaweda B, ... Rausch MK, Timek TA</i><br /><b>Introduction</b><br />Annular reduction with prosthetic rings represents current surgical treatment of functional tricuspid regurgitation (FTR). However, alterations of annular geometry and dynamics associated with FTR are not well characterized.<br /><b>Methods</b><br />FTR was induced in 29 adult sheep with either eight weeks of pulmonary artery banding (PAB, n=15) or 3 weeks of tachycardia induced cardiomyopathy (TIC, n=14). Eight healthy sheep served as controls (CTL). At terminal procedure, all animals underwent sternotomy, epicardial echocardiography, and implantation of sonomicrometry crystals on the tricuspid annulus (TA) and RV free wall while on cardiopulmonary bypass. Simultaneous hemodynamic, sonomicrometry, and echocardiographic data were acquired after weaning from CPB and stabilization. Annular geometry and dynamics were calculated from 3D crystal coordinates.<br /><b>Results</b><br />Mean FTR grade (0-4) was 3.2±1.2 and 3.2±0.5 for PAB and TIC, respectively with both models of FTR associated with similar degree of RV dysfunction (RVFAC 38±7% and 37±9% for PAB and TIC, respectively). LV ejection fraction was significantly reduced in TIC versus baseline (33±9%, vs 58±4%, p=0.0001). TA area was 651±109, 881±242, and 995±232 mm<sup>2</sup> for CTL, FTR, and TIC, respectively (p=0.006) with TA area contraction of 16.6±4.2, 11.5±8.0, and 6.0±4.0%, respectively (p=0.003). Septal annulus increased from 33.8±3.1 to 39.7±6.4 and 43.1±3.2 mm for CTL, PAB, and TIC, respectively (p<0.0001).<br /><b>Conclusion</b><br />Ovine FTR was associated with annular dilation and reduced annular area contraction. Significant dilation of septal annulus was observed in both models of FTR. As tricuspid rings do not completely stabilize the septal annulus, continued remodeling may contribute to recurrent FTR after repair.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>J Thorac Cardiovasc Surg: 13 Apr 2023; epub ahead of print</small></div>

<div><h4>Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland.</h4><i>Wright CF, Campbell P, Eberhardt RY, Aitken S, ... Firth HV, DDD Study</i><br /><b>Background</b><br />Pediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genomewide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits.<br /><b>Methods</b><br />We conducted a large-scale sequencing study involving more than 13,500 families with probands with severe, probably monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services in the United Kingdom and Ireland. Standardized phenotypic data were collected, and exome sequencing and microarray analyses were performed to investigate novel genetic causes. We developed an iterative variant analysis pipeline and reported candidate variants to clinical teams for validation and diagnostic interpretation to inform communication with families. Multiple regression analyses were performed to evaluate factors affecting the probability of diagnosis.<br /><b>Results</b><br />A total of 13,449 probands were included in the analyses. On average, we reported 1.0 candidate variant per parent-offspring trio and 2.5 variants per singleton proband. With the use of clinical and computational approaches to variant classification, a diagnosis was made in approximately 41% of probands (5502 of 13,449), of whom 76% had a pathogenic de novo variant. Another 22% of probands (2997 of 13,449) had variants of uncertain significance in genes that were strongly linked to monogenic developmental disorders. Recruitment in a parent-offspring trio had the largest effect on the probability of diagnosis (odds ratio, 4.70; 95% confidence interval [CI], 4.16 to 5.31). Probands were less likely to receive a diagnosis if they were born extremely prematurely (i.e., 22 to 27 weeks\' gestation; odds ratio, 0.39; 95% CI, 0.22 to 0.68), had in utero exposure to antiepileptic medications (odds ratio, 0.44; 95% CI, 0.29 to 0.67), had mothers with diabetes (odds ratio, 0.52; 95% CI, 0.41 to 0.67), or were of African ancestry (odds ratio, 0.51; 95% CI, 0.31 to 0.78).<br /><b>Conclusions</b><br />Among probands with severe, probably monogenic, difficult-to-diagnose developmental disorders, multimodal analysis of genomewide data had good diagnostic power, even after previous attempts at diagnosis. (Funded by the Health Innovation Challenge Fund and Wellcome Sanger Institute.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 12 Apr 2023; epub ahead of print</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>