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

<div><h4>The response to the COVID-19 pandemic: With hindsight what lessons can we learn?</h4><i>Faghy M, Arena R, Hills AP, Yates J, ... Lavie CJ, Smith A</i><br /><AbstractText>The purpose of this paper is to put forward some evidence-based lessons that can be learned from how to respond to a Pandemic that relate to healthy living behaviours (HLB). A 4-step methodology was followed to conduct a narrative review of the literature and to present a professional practice vignette. The narrative review identified 8 lessons: 1) peer review; 2) historical perspectives; 3) investing in resilience and protection; 4) unintended consequences; 5) protecting physical activity; 6) school closures; 7) mental health; and 8) obesity. As in all probability there will be another Pandemic, it is important that the lessons learned over the last three years in relation to HLB are acted upon. Whilst there will not always be a consensus on what to emphasise, it is important that many evidence-based positions are presented. The authors of this paper recognise that this work is a starting point and that the lessons presented here will need to be revisited as new evidence becomes available.</AbstractText><br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>Prog Cardiovasc Dis: 05 Dec 2022; epub ahead of print</small></div>

<div><h4>The association of disparities in neighborhood median household income and mortality in patients admitted to the hospital with atrial fibrillation.</h4><i>Dhore-Patil A, Crawford M, Nedunchezhian S, El Hajjar AH, ... Sidhu G, Marrouche N</i><br /><b>Background</b><br />Lower neighborhood median household income (nMHI) is associated with increased adverse outcomes in patients with atrial fibrillation (AF). However, its effect on mortality is yet unknown.<br /><b>Methods</b><br />Data from the regional United States (U.S.) electronic medical records database, Research Action for Health Network (REACHnet), was extracted for adult patients with AF at Tulane Medical Center over 10 years. Annual nMHI & neighborhood high school graduation (HSG) data was collected from the US Census bureau. Only African Americans (AA) and Caucasians (CC) who had socioeconomic data were included. Low nMHI and low HSG were defined as ≤$25,000 & <90% respectively. High nMHI and HSG were defined as >$50,000 & ≥90% respectively. Primary endpoints were all cause and cardiovascular (CV) mortality. Cox-proportional hazard ratios were used to evaluate the endpoints.<br /><b>Results</b><br />We included 4616 patients diagnosed with AF. During a median follow up of 4.6 years, 434 patients died of which 32.7% patients had CV mortality. There was a stepwise decrease in incidence of both all-cause and CV mortality as nMHI increased. Patients with low nMHI had the greatest risk of all-cause mortality (HR 1.9, C.I. 1.2-3.2, P 0.004). The association between low nMHI and all-cause mortality persisted after adjusting for age, sex, race, HSG and stroke risk factors using CHA<sub>2</sub>DS<sub>2</sub>VASC, delta CHA<sub>2</sub>DS<sub>2</sub>VASC scores and oral anticoagulant use. CV mortality followed a similar trend as all-cause mortality, however, this association was not significant after adjusting for the above variables. Apart from low nMHI, CHA<sub>2</sub>DS<sub>2</sub>VASC delta CHA<sub>2</sub>DS<sub>2</sub>VASC were statistically significant independent predictors of both all-cause and CV mortality.<br /><b>Conclusion</b><br />Low nMHI is an independent risk factor for all cause and CV mortality in AF. Higher burden of co-morbidities is the driving force behind this disparity. Future studies should evaluate the role of educational and therapeutic intervention in these populations to reduce mortality.<br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>Prog Cardiovasc Dis: 30 Nov 2022; epub ahead of print</small></div>

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

<div><h4>Premature ventricular contractions (PVCs) in young athletes.</h4><i>Gomez SE, Hwang CE, Kim DS, Froelicher VF, Wheeler MT, Perez MV</i><br /><AbstractText>There is a growing body of literature focusing on the morphology, management, and outcomes of PVCs in athletes. This review summarizes this literature and establishes recommendations on management, treatment, and indications for specialist referral in this patient population. The sports medicine physician\'s responses and recommendation should be made in conjunction with the athletes wishes. Medications or ablations are not always necessary in all athletes if they are followed with regular evaluations.</AbstractText><br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>Prog Cardiovasc Dis: 26 Oct 2022; epub ahead of print</small></div>

<div><h4>Progressive Reduction in Right Ventricular Contractile Function Due to Altered Actin Expression in an Aging Mouse Model of Arrhythmogenic Cardiomyopathy.</h4><i>Camors EM, Roth AH, Alef JR, Sullivan RD, ... Purevjav E, Towbin JA</i><br /><b>Background</b><br />Arrhythmogenic cardiomyopathy (ACM) is an inherited genetic disorder of desmosomal dysfunction, and plakophilin-2 (PKP2) has been reported to be the most common disease-causing gene when mutation-positive. In the early \"concealed\" phase, the ACM heart is at high risk of sudden cardiac death before cardiac remodeling occurs due to mistargeted ion channels and altered Ca<sup>2+</sup> handling. However, the results of pathogenic PKP2 variants on myocyte contraction in ACM pathogenesis remain unknown.<br /><b>Methods</b><br />We studied the outcomes of a human truncating variant of PKP2 on myocyte contraction using a novel knock-in mouse model with insertion of thymidine in exon 5 of <i>Pkp2</i>, which mimics a familial case of ACM (PKP2-L404fsX5). We used serial echocardiography, electrocardiography, blood pressure measurements, histology, cardiomyocyte contraction, intracellular calcium measurements, and gene and protein expression studies.<br /><b>Results</b><br />Serial echocardiography of Pkp2 heterozygous (Pkp2-Het) mice revealed progressive failure of the right ventricle (RV) in animals older than three months of age. By contrast, left ventricular (LV) function remained normal. Electrocardiograms of six-month-old anesthetized Pkp2-Het mice showed normal baseline heart rates and QRS complexes. Cardiac responses to β-adrenergic agonist isoproterenol (2 mg.kg<sup>-1</sup>) plus caffeine (120 mg.kg<sup>-1</sup>) were also normal. However, adrenergic stimulation enhanced the susceptibility of Pkp2-Het hearts to tachyarrhythmia and sudden cardiac death. Histologic staining showed no significant fibrosis or adipocyte infiltration in the RVs and LVs of six- and twelve-month-old Pkp2-Het hearts. Contractility assessment of isolated myocytes demonstrated progressively reduced Pkp2-Het RV cardiomyocyte function consistent with RV failure measured by echocardiography. However, aging Pkp2-Het and control RV myocytes loaded with intracellular Ca<sup>2+</sup> indicator Fura-2 showed comparable Ca<sup>2+</sup> transients. Western blotting of Pkp2-RV homogenates revealed a 40% decrease in actin, while actin immunoprecipitation followed by a 2, 4-dinitrophenylhydrazine staining showed doubled oxidation level. This correlated with a 39% increase in troponin-I phosphorylation. In contrast, Pkp2-Het LV myocytes had normal contraction, actin expression and oxidation, and troponin-I phosphorylation. Finally, Western blotting of cardiac biopsies revealed actin expression was 40% decreased in RVs of end-stage ACM patients.<br /><b>Conclusions</b><br />During the early \"concealed\" phase of ACM, reduced actin expression drives loss of RV myocyte contraction, contributing to progressive RV dysfunction.<br /><br /><br /><br /><small>Circulation: 19 Apr 2022; epub ahead of print</small></div>

<div><h4>Monogenic and Polygenic Contributions to QTc Prolongation in the Population.</h4><i>Nauffal V, Morrill VN, Jurgens SJ, Choi SH, ... Ellinor PT, Lubitz SA</i><br /><AbstractText><b>Background:</b> Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variation to the QT interval in the population. <br /><b>Methods:</b><br/>We performed a genome wide association study (GWAS) of the QTc in 84,630 United Kingdom Biobank (UKB) participants and created a polygenic risk score (PRS). Among 26,976 participants with whole genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine (TOPMed) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed. <br /><b>Results:</b><br/>Fifty-four independent loci were identified by GWAS in the UKB. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS comprising 1,110,494 common variants was significantly associated with the QTc in TOPMed (ΔQTc/<sub>decile of PRS</sub> = 1.4 ms, 95% CI 1.3 -1.5; p-value=1.1×10<sup>-196</sup>). Carriers of putative pathogenic rare variants had longer QTc than non-carriers (ΔQTc=10.9 ms [7.4-14.4]). 23.7% of individuals with QTc>480 ms carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS). <b>Conclusions:</b> QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.</AbstractText><br /><br /><br /><br /><small>Circulation: 07 Apr 2022; epub ahead of print</small></div>

<div><h4>Defining the importance of stress reduction in managing cardiovascular disease - the role of exercise.</h4><i>Popovic D, Bjelobrk M, Tesic M, Seman S, ... Arena R, PIVOT Network</i><br /><AbstractText>Traditional risk factors for cardiovascular disease (CVD) have long been the focus of preventive strategies. The impact of family stress, depression, anxiety, hostility, pessimism, job strain, social isolation, lack of purpose in life and social support, are well recognized risks for CVD development, however they are under-appreciated in clinical practice guidelines. The purpose of this article is to review the impact of acute and chronic stress on CVD risk, elaborate repositioning in guidelines, with emphasis to approaches for stress reduction. Regular exercise, both aerobic and resistance, leads to better adaptiveness to other types of stress, however, it remains unknown whether the total amount of stress one can receive before negative health effects is unlimited. Evidently, marked reductions in stress related disorders are shown following formal cardiac rehabilitation programs. Attendance of cardiac rehabilitation is highly recommended for the stress-related mortality risk reduction. Innovative approaches to offset the broad challenges that CVD pose, augmented by sustained exposure to stress, are desperately needed, but hindered by a lack of successful population-level interventions that promote lasting change.</AbstractText><br /><br />Copyright © 2021. Published by Elsevier Inc.<br /><br /><small>Prog Cardiovasc Dis: 03 Feb 2022; epub ahead of print</small></div>

<div><h4>Novel plasma biomarkers predicting biventricular involvement in arrhythmogenic right ventricular cardiomyopathy.</h4><i>Akdis D, Chen L, Saguner AM, Zhang N, ... Song J, Duru F</i><br /><b>Background</b><br />Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease characterized by fibrofatty replacement of the myocardium and ventricular arrhythmias. Biventricular involvement in ARVC may lead to heart failure. This study aimed to investigate the role of plasma biomarkers soluble (s)ST2, Galectin-3 (Gal-3) and GDF-15 in predicting biventricular involvement and adverse outcomes in ARVC.<br /><b>Methods and results</b><br />ARVC patients from 2 independent cohorts, were studied. The Bejing (Chinese) cohort (n = 108) was the discovery cohort, whereas the Zurich (Swiss) cohort (n = 47) served as validation. All patients had a definite ARVC diagnosis at time of blood withdrawal. Biomarkers were independently correlated with NT-proBNP and left ventricular (LV)-function. ARVC patients with LV involvement had higher levels of sST2 and GDF-15 as compared to controls and patients with isolated right ventricle (RV) involvement. sST2 and GDF-15 were significantly correlated with late gadolinium enhancement in CMR and with adverse heart failure outcomes. Gal-3 was elevated in ARVC patients with and without LV involvement. The combined use of the three biomarkers (sST2, GDF-15 and NT-proBNP) showed the best performance in predicting LV involvement in both cohorts. Plasma drawn from the coronary arteries and coronary sinus indicated a transmyocardial elevation of sST2, but no transmyocardial gradient of GDF-15. After heart transplantation, both sST2 and GDF-15 returned to near-normal levels.<br /><b>Conclusion</b><br />Our study showed that sST2 and GDF-15 may predict biventricular involvement in ARVC. The combined use of sST2, GDF-15 and NT-proBNP showed the best prediction of biventricular involvement in ARVC.<br /><br />Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>Am Heart J: 30 Jan 2022; 244:66-76</small></div>

<div><h4>Arrhythmia Variant Associations and Reclassifications in the eMERGE-III Sequencing Study.</h4><i>Glazer AM, Davogustto GE, Shaffer CM, Vanoye CG, ... Roden DM, eMERGE Network</i><br /><AbstractText><b>Background:</b> Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results (RoR) is unclear. In addition, the majority of discovered variants are currently classified as Variants of Uncertain Significance (VUS), limiting clinical actionability. <br /><b>Methods:</b><br/>The eMERGE-III study is a multi-center prospective cohort which included 21,846 participants without prior indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with Electronic Health Record (EHR)-derived phenotypes and follow-up clinical examination. Selected VUS (n=50) were characterized <i>in vitro</i> with automated electrophysiology experiments in HEK293 cells. <br /><b>Results:</b><br/>As previously reported, 3.0% of participants had pathogenic or likely pathogenic (P/LP) variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared to non-carriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their EHRs. Fifty four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long QT syndrome), and 12/19 of these diagnoses were made only after variant results were returned (0.05%). After <i>in vitro</i> functional evaluation of 50 variants of uncertain significance (VUS), we reclassified 11 variants: 3 to likely benign and 8 to P/LP. <b>Conclusions:</b> Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, EHR phenotypes, and <i>in vitro</i> functional studies.</AbstractText><br /><br /><br /><br /><small>Circulation: 20 Dec 2021; epub ahead of print</small></div>

<div><h4>Single Nuclei Sequencing Reveals Novel Insights Into the Regulation of Cellular Signatures in Children With Dilated Cardiomyopathy.</h4><i>Nicin L, Abplanalp WT, Schänzer A, Sprengel A, ... Rupp S, Dimmeler S</i><br /><b>Background</b><br />Dilated cardiomyopathy (DCM) is a leading cause of death in children with heart failure. The outcome of pediatric heart failure treatment is inconsistent, and large cohort studies are lacking. Progress may be achieved through personalized therapy that takes age- and disease-related pathophysiology, pathology, and molecular fingerprints into account. We present single nuclei RNA sequencing from pediatric patients with DCM as the next step in identifying cellular signatures.<br /><b>Methods</b><br />We performed single nuclei RNA sequencing with heart tissues from 6 children with DCM with an age of 0.5, 0.75, 5, 6, 12, and 13 years. Unsupervised clustering of 18 211 nuclei led to the identification of 14 distinct clusters with 6 major cell types.<br /><b>Results</b><br />The number of nuclei in fibroblast clusters increased with age in patients with DCM, a finding that was confirmed by histological analysis and was consistent with an age-related increase in cardiac fibrosis quantified by cardiac magnetic resonance imaging. Fibroblasts of patients with DCM >6 years of age showed a profoundly altered gene expression pattern with enrichment of genes encoding fibrillary collagens, modulation of proteoglycans, switch in thrombospondin isoforms, and signatures of fibroblast activation. In addition, a population of cardiomyocytes with a high proregenerative profile was identified in infant patients with DCM but was absent in children >6 years of age. This cluster showed high expression of cell cycle activators such as <i>cyclin D</i> family members, increased glycolytic metabolism and antioxidative genes, and alterations in ß-adrenergic signaling genes.<br /><b>Conclusions</b><br />Novel insights into the cellular transcriptomes of hearts from pediatric patients with DCM provide remarkable age-dependent changes in the expression patterns of fibroblast and cardiomyocyte genes with less fibrotic but enriched proregenerative signatures in infants.<br /><br /><br /><br /><small>Circulation: 26 Apr 2021; 143:1704-1719</small></div>

<div><h4>Prognostic Value of Nonischemic Ringlike Left Ventricular Scar in Patients With Apparently Idiopathic Nonsustained Ventricular Arrhythmias.</h4><i>Muser D, Nucifora G, Muser D, Nucifora G, ... Marchlinski FE, Santangeli P</i><br /><b>Background</b><br />Left ventricular (LV) scar on late gadolinium enhancement (LGE) cardiac magnetic resonance has been correlated with life-threatening arrhythmic events in patients with apparently idiopathic ventricular arrhythmias (VAs). We investigated the prognostic significance of a specific LV-LGE phenotype characterized by a ringlike pattern of fibrosis.<br /><b>Methods</b><br />A total of 686 patients with apparently idiopathic nonsustained VA underwent contrast-enhanced cardiac magnetic resonance. A ringlike pattern of LV scar was defined as LV subepicardial/midmyocardial LGE involving at least 3 contiguous segments in the same short-axis slice. The end point of the study was time to the composite outcome of all-cause death, resuscitated cardiac arrest because of ventricular fibrillation or hemodynamically unstable ventricular tachycardia and appropriate implantable cardioverter defibrillator therapy.<br /><b>Results</b><br />A total of 28 patients (4%) had a ringlike pattern of scar (group A), 78 (11%) had a non-ringlike pattern (group B), and 580 (85%) had normal cardiac magnetic resonance with no LGE (group C). Group A patients were younger compared with groups B and C (median age, 40 vs 52 vs 45 years; <i>P</i><0.01), more frequently men (96% vs 82% vs 55%; <i>P</i><0.01), with a higher prevalence of family history of sudden cardiac death or cardiomyopathy (39% vs 14% vs 6%; <i>P</i><0.01) and more frequent history of unexplained syncope (18% vs 9% vs 3%; <i>P</i><0.01). All patients in group A showed VA with a right bundle-branch block morphology versus 69% in group B and 21% in group C (<i>P</i><0.01). Multifocal VAs were observed in 46% of group A patients compared with 26% of group B and 4% of group C (<i>P</i><0.01). After a median follow-up of 61 months (range, 34-84 months), the composite outcome occurred in 14 patients (50.0%) in group A versus 15 (19.0%) in group B and 2 (0.3%) in group C (<i>P</i><0.01). After multivariable adjustment, the presence of LGE with ringlike pattern remained independently associated with increased risk of the composite end point (hazard ratio, 68.98 [95% CI, 14.67-324.39], <i>P</i><0.01).<br /><b>Conclusions</b><br />In patients with apparently idiopathic nonsustained VA, nonischemic LV scar with a ringlike pattern is associated with malignant arrhythmic events.<br /><br /><br /><br /><small>Circulation: 05 Apr 2021; 143:1359-1373</small></div>

<div><h4>Replacement Myocardial Fibrosis in Patients With Mitral Valve Prolapse: Relation to Mitral Regurgitation, Ventricular Remodeling, and Arrhythmia.</h4><i>Constant Dit Beaufils AL, Huttin O, Jobbe-Duval A, Senage T, ... Selton-Suty C, Le Tourneau T</i><br /><b>Background</b><br />Mitral valve prolapse (MVP) is a frequent disease that can be complicated by mitral regurgitation (MR), heart failure, arterial embolism, rhythm disorders, and death. Left ventricular (LV) replacement myocardial fibrosis, a marker of maladaptive remodeling, has been described in patients with MVP, but the implications of this finding remain scarcely explored. We aimed at assessing the prevalence, pathophysiological and prognostic significance of LV replacement myocardial fibrosis through late gadolinium enhancement (LGE) by cardiac magnetic resonance in patients with MVP.<br /><b>Methods</b><br />Four hundred patients (53±15 years of age, 55% male) with MVP (trace to severe MR by echocardiography) from 2 centers, who underwent a comprehensive echocardiography and LGE cardiac magnetic resonance, were included. Correlates of replacement myocardial fibrosis (LGE+), influence of MR degree, and ventricular arrhythmia were assessed. The primary outcome was a composite of cardiovascular events (cardiac death, heart failure, new-onset atrial fibrillation, arterial embolism, and life-threatening ventricular arrhythmia).<br /><b>Results</b><br />Replacement myocardial fibrosis (LGE+) was observed in 110 patients (28%; 91 with myocardial wall including 71 with basal inferolateral wall, 29 with papillary muscle). LGE+ prevalence was 13% in trace-mild MR, 28% in moderate MR, and 37% in severe MR, and was associated with specific features of mitral valve apparatus, more dilated LV and more frequent ventricular arrhythmias (45% versus 26%, <i>P</i><0.0001). In trace-mild MR, despite the absence of significant volume overload, abnormal LV dilatation was observed in 16% of patients and ventricular arrhythmia in 25%. Correlates of LGE+ in multivariable analysis were LV mass (odds ratio, 1.01 [95% CI, 1.002-1.017], <i>P</i>=0.009) and moderate-severe MR (odds ratio, 2.28 [95% CI, 1.21-4.31], <i>P</i>=0.011). LGE+ was associated with worse 4-year cardiovascular event-free survival (49.6±11.7 in LGE+ versus 73.3±6.5% in LGE-, <i>P</i><0.0001). In a stepwise multivariable Cox model, MR volume and LGE+ (hazard ratio, 2.6 [1.4-4.9], <i>P</i>=0.002) were associated with poor outcome.<br /><b>Conclusions</b><br />LV replacement myocardial fibrosis is frequent in patients with MVP; is associated with mitral valve apparatus alteration, more dilated LV, MR grade, and ventricular arrhythmia; and is independently associated with cardiovascular events. These findings suggest an MVP-related myocardial disease. Last, cardiac magnetic resonance provides additional information to echocardiography in MVP.<br /><br /><br /><br /><small>Circulation: 03 Jan 2021; 143:1763-1774</small></div>

<div><h4>Long-Term Follow-Up of Patients With Tetralogy of Fallot and Implantable Cardioverter Defibrillator: The DAI-T4F Nationwide Registry.</h4><i>Waldmann V, Bouzeman A, Duthoit G, Koutbi L, ... Marijon E, DAI-T4F Investigators*</i><br /><b>Background</b><br />Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, and sudden cardiac death represents an important mode of death in these patients. Data evaluating the implantable cardioverter defibrillator (ICD) in this patient population remain scarce.<br /><b>Methods</b><br />A Nationwide French Registry including all patients with tetralogy of Fallot with an ICD was initiated in 2010 by the French Institute of Health and Medical Research. The primary time to event end point was the time from ICD implantation to first appropriate ICD therapy. Secondary outcomes included ICD-related complications, heart transplantation, and death. Clinical events were centrally adjudicated by a blinded committee.<br /><b>Results</b><br />A total of 165 patients (mean age, 42.2±13.3 years, 70.1% males) were included from 40 centers, including 104 (63.0%) in secondary prevention. During a median (interquartile range) follow-up of 6.8 (2.5-11.4) years, 78 (47.3%) patients received at least 1 appropriate ICD therapy. The annual incidence of the primary outcome was 10.5% (7.1% and 12.5% in primary and secondary prevention, respectively; <i>P</i>=0.03). Overall, 71 (43.0%) patients presented with at least 1 ICD complication, including inappropriate shocks in 42 (25.5%) patients and lead dysfunction in 36 (21.8%) patients. Among 61 (37.0%) patients in primary prevention, the annual rate of appropriate ICD therapies was 4.1%, 5.3%, 9.5%, and 13.3% in patients with, respectively, 0, 1, 2, or ≥3 guidelines-recommended risk factors. QRS fragmentation was the only independent predictor of appropriate ICD therapies (hazard ratio, 3.47 [95% CI, 1.19-10.11]), and its integration in a model with current criteria increased the 5-year time-dependent area under the curve from 0.68 to 0.81 (<i>P</i>=0.006). Patients with congestive heart failure or reduced left ventricular ejection fraction had a higher risk of nonarrhythmic death or heart transplantation (hazard ratio, 11.01 [95% CI, 2.96-40.95]).<br /><b>Conclusions</b><br />Patients with tetralogy of Fallot and an ICD experience high rates of appropriate therapies, including those implanted in primary prevention. The considerable long-term burden of ICD-related complications, however, underlines the need for careful candidate selection. A combination of easy-to-use criteria including QRS fragmentation might improve risk stratification. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03837574.<br /><br /><br /><br /><small>Circulation: 26 Oct 2020; 142:1612-1622</small></div>

<div><h4>Reduction in Filamin C transcript is associated with arrhythmogenic cardiomyopathy in Ashkenazi Jews.</h4><i>Oz S, Yonath H, Visochyk L, Ofek E, ... Arad M, Nof E</i><br /><b>Background</b><br />Filamin C is a cytoskeletal protein expressed in cardiac cells. Nonsense variations in the filamin C gene (FLNC) were associated with dilated and arrhythmogenic cardiomyopathies.<br /><b>Methods and results</b><br />We identified an intronic variation in FLNC gene (c.3791-1G > C) in three unrelated Ashkenazi Jewish families with variable expression of arrhythmia and cardiomyopathy. cDNA was prepared from a mutation carrier\'s cultured skin fibroblasts. Quantitative PCR demonstrated a reduction in total FLNC transcript, and no other FLNC splice variants were found. Single-nucleotide polymorphism (SNP) analysis revealed heterozygous variations in the genomic DNA that were not expressed in the messenger RNA. Immunohistochemical analysis of cardiac sections detected a normal distribution of filamin C protein in the heart ventricles.<br /><b>Conclusion</b><br />The transcript that included the FLNC variant was degraded. Haploinsufficiency in filamin C underlies arrhythmogenic cardiomyopathy with variable symptoms.<br /><br />Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.<br /><br /><small>Int J Cardiol: 14 Oct 2020; 317:133-138</small></div>

<div><h4>An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of -Catecholaminergic Polymorphic Ventricular Tachycardia.</h4><i>Ng K, Titus EW, Lieve KV, Roston TM, ... Deo RC, Roberts JD</i><br /><b>Background</b><br />Genetic variants in calsequestrin-2 () cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of -CPVT was sought through an international multicenter collaboration.<br /><b>Methods</b><br />Genotype-phenotype segregation in -CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominantmissense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure.<br /><b>Results</b><br />A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenicvariant, were identified. Amonghomozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6-11). Fifty-one of 66heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative toheterozygotes,homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3-8.0; =0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6-269.1; <0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominantmissense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers.<br /><b>Conclusions</b><br />This international multicenter study of -CPVT redefines its heritability and confirms that pathogenic heterozygousvariants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.<br /><br /><br /><br /><small>Circulation: 07 Oct 2020; 142:932-947</small></div>

<div><h4>The ACTN3 577XX Null Genotype Is Associated with Low Left Ventricular Dilation-Free Survival Rate in Patients with Duchenne Muscular Dystrophy.</h4><i>Nagai M, Awano H, Yamamoto T, Bo R, Matsuo M, Iijima K</i><br /><b>Background</b><br />Duchenne muscular dystrophy (DMD) is a fatal progressive muscle-wasting disease caused by mutations in the DMD gene. Dilated cardiomyopathy is the leading cause of death in DMD; therefore, further understanding of this complication is essential to reduce morbidity and mortality.<br /><b>Methods</b><br />A common null variant (R577X) in the ACTN3 gene, which encodes α-actinin-3, has been studied in association with muscle function in healthy individuals; however it has not yet been examined in relationship to the cardiac phenotype in DMD. In this study, we determined the ACTN3 genotype in 163 patients with DMD and examined the correlation between ACTN3 genotypes and echocardiographic findings in 77 of the 163 patients.<br /><b>Results</b><br />The genotypes 577RR(RR), 577RX(RX) and 577XX(XX) were identified in 13 (17%), 44 (57%) and 20 (26%) of 77 patients, respectively. We estimated cardiac involvement-free survival rate analyses using Kaplan-Meier curves. Remarkably, the left ventricular dilation (> 55 mm)-free survival rate was significantly lower in patients with the XX null genotype (P < 0.01). The XX null genotype showed a higher risk for LV dilation (hazard ratio 9.04).<br /><b>Conclusions</b><br />This study revealed that the ACTN3 XX null genotype was associated with a lower left ventricular dilation-free survival rate in patients with DMD. These results suggest that the ACTN3 genotype should be determined at the time of diagnosis of DMD to improve patients\' cardiac outcomes.<br /><br />Copyright © 2020 Elsevier Inc. All rights reserved.<br /><br /><small>J Card Fail: 29 Sep 2020; 26:841-848</small></div>

<div><h4>Usefulness of Neuromuscular Co-morbidity, Left Bundle Branch Block, and Atrial Fibrillation to Predict the Long-Term Prognosis of Left Ventricular Hypertrabeculation/Noncompaction.</h4><i>Stöllberger C, Hasun M, Winkler-Dworak M, Finsterer J</i><br /><b></b><br />The prognosis of patients with left ventricular hypertrabeculation/noncompaction (LVHT) is assessed controversially. LVHT is associated with other cardiac abnormalities and with neuromuscular disorders (NMD). Aim of the study was to assess cardiac and neurological findings as predictors of mortality rate in adult LVHT-patients. Included were patients with LVHT diagnosed between 1995 and 2019 in 1 echocardiographic laboratory. Patients underwent a baseline cardiologic examination and were invited for a neurological investigation. In January 2020, their survival status was assessed. End points were death or heart transplantation. LVHT was diagnosed by echocardiography in 310 patients (93 female, aged 53 ± 18 years) with a prevalence of 0.4%/year. A neurologic investigation was performed in 205 patients (67%). A specific NMD was found in 33 (16%), NMD of unknown etiology in 123 (60%) and the neurological investigation was normal in 49 (24%) patients. During follow-up of 84 ± 71 months, 59 patients received electronic devices, 105 patients died, and 6 underwent heart transplantation. The mortality was 4.7%/year, the rate of heart transplantation/death 5%/year. By multivariate analysis, the following parameters were identified to elevate the risk of mortality/heart transplantation: increased age (p = 0.005), inpatient (p = 0.001), presence of a specific NMD (p = 0.0312) or NMD of unknown etiology (p = 0.0365), atrial fibrillation (p = 0.0000), ventricular premature complexes (p = 0.0053), exertional dyspnea (p = 0.0023), left bundle branch block (p = 0.0201), and LVHT of the posterior wall (p = 0.0158). In conclusion, LVHT patients should be systematically investigated neurologically since neurological co-morbidity has a prognostic impact.<br /><br />Copyright © 2020 Elsevier Inc. All rights reserved.<br /><br /><small>Am J Cardiol: 31 Jul 2020; 128:168-173</small></div>

<div><h4>Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.</h4><i>Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, ... Tanck MWT, Bezzina CR</i><br /><b>Background</b><br />Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility.<br /><b>Methods</b><br />We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score.<br /><b>Results</b><br />Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (<5×10) near , , and , and 1 missense variant in (p.Asp85Asn) at the suggestive threshold (<10). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r=0.40; =3.2×10). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (<0.005).<br /><b>Conclusions</b><br />This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.<br /><br /><br /><br /><small>Circulation: 27 Jul 2020; 142:324-338</small></div>

<div><h4>Prognostic Value of Magnetic Resonance Phenotype in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy.</h4><i>Aquaro GD, De Luca A, Cappelletto C, Raimondi F, ... Di Bella G, Sinagra G</i><br /><b>Background</b><br />Cardiac magnetic resonance (CMR) is widely used to assess tissue and functional abnormalities in arrhythmogenic right ventricular cardiomyopathy (ARVC). Recently, a ARVC risk score was proposed to predict the 5-year risk of malignant ventricular arrhythmias in patients with ARVC. However, CMR features such as fibrosis, fat infiltration, and left ventricular (LV) involvement were not considered.<br /><b>Objectives</b><br />The authors sought to evaluate the prognostic role of CMR phenotype in patients with definite ARVC and to evaluate the effectiveness of the novel 5-year ARVC risk score to predict cardiac events in different CMR presentations.<br /><b>Methods</b><br />A total of 140 patients with definite ARVC were enrolled (mean age 42 ± 17 years, 97 males) in this multicenter prospective registry. As per study design, CMR was performed in all the patients at enrollment. The novel 5-year ARVC risk score was retrospectively calculated using the patient\'s characteristics at the time of enrollment. During a median follow-up of 5 years (2 to 8 years), the combined endpoint of sudden cardiac death, appropriate implantable cardioverter-defibrillator intervention, and aborted cardiac arrest was considered.<br /><b>Results</b><br />CMR was completely negative in 14 patients (10%), isolated right ventricular (RV) involvement was found in 58 (41%), biventricular in 52 (37%), and LV dominant in 16 (12%). During the follow-up, 48 patients (34%) had major events, but none occurred in patients with negative CMR. At Kaplan-Meier analysis, patients with LV involvement (LV dominant and biventricular) had a worse prognosis than those with lone RV (p < 0.0001). At multivariate analysis, the LV involvement, a LV-dominant phenotype, and the 5-year ARVC risk score were independent predictors of major events. The estimated 5-year risk was able to predict the observed risk in patients with lone RV but underestimated the risk in those with LV involvement.<br /><b>Conclusions</b><br />Different CMR presentations of ARVC are associated with different prognoses. The 5-year ARVC risk score is valid for the estimation of risk in patients with lone-RV presentation but underestimated the risk when LV is involved.<br /><br />Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 08 Jun 2020; 75:2753-2765</small></div>

<div><h4>Inherited Thoracic Aortic Disease: New Insights and Translational Targets.</h4><i>Fletcher AJ, Syed MBJ, Aitman TJ, Newby DE, Walker NL</i><br /><b></b><br />Inherited thoracic aortopathies denote a group of congenital conditions that predispose to disease of the thoracic aorta. Aortic wall weakness and abnormal aortic hemodynamic profiles predispose these patients to dilatation of the thoracic aorta, which is generally silent but can precipitate aortic dissection or rupture with devastating and often fatal consequences. Current strategies to assess the future risk of aortic dissection or rupture are based primarily on monitoring aortic diameter. However, diameter alone is a poor predictor of risk, with many patients experiencing dissection or rupture below current intervention thresholds. Developing tools that improve the risk assessment of those with aortopathy is internationally regarded as a research priority. A robust understanding of the molecular pathways that lead to aortic wall weakness is required to identify biomarkers and therapeutic targets that could improve patient management. Here, we summarize the current understanding of the genetically determined mechanisms underlying inherited aortopathies and critically appraise the available blood biomarkers, imaging techniques, and therapeutic targets that have shown promise for improving the management of patients with these important and potentially fatal conditions.<br /><br /><br /><br /><small>Circulation: 11 May 2020; 141:1570-1587</small></div>

<div><h4>Desmoplakin Cardiomyopathy, a Fibrotic and Inflammatory Form of Cardiomyopathy Distinct from Typical Dilated or Arrhythmogenic Right Ventricular Cardiomyopathy.</h4><i>Smith ED, Lakdawala NK, Papoutsidakis N, Aubert G, ... McNally EM, Helms AS</i><br /><b></b><br />Mutations in desmoplakin (), the primary force transducer between cardiac desmosomes and intermediate filaments, cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy (ARVC). Clinical correlates ofcardiomyopathy have been limited to small case series.Clinical and genetic data were collected on 107 patients with pathogenicmutations and 81 patients with pathogenicmutations as a comparison cohort. A composite outcome of severe ventricular arrhythmia was assessed.andcohorts included similar proportions of probands (41% vs. 42%) and patients with truncating mutations (98% vs. 100%). Left ventricular (LV) predominant cardiomyopathy was exclusively present amongpatients (55% vs. 0% for , p<0.001), whereas right ventricular (RV) cardiomyopathy was present in only 14% ofpatients vs. 40% for(p<0.001). ARVC diagnostic criteria had poor sensitivity forcardiomyopathy. LV late gadolinium enhancement (LGE) was present in a primarily subepicardial distribution in 40% ofpatients (23/57 with MRIs). LV LGE occurred with normal LV systolic function in 35% (8/23) ofpatients. Episodes of acute myocardial injury (chest pain with troponin elevation and normal coronary angiography) occurred in 15% ofpatients and were strongly associated with LV LGE (90%), even in cases of acute myocardial injury with normal ventricular function (4/5, 80% with LGE). In 4cases with F-fluorodeoxyglucose positron emission tomography scans, acute LV myocardial injury was associated with myocardial inflammation misdiagnosed initially as cardiac sarcoidosis or myocarditis. LVEF <55% was strongly associated with severe ventricular arrhythmias forcases (p<0.001, sensitivity 85%, specificity 53%). RVEF <45% was associated with severe arrhythmias forcases (p<0.001) but was poorly associated forcases (p=0.8). Frequent PVCs were common among patients with severe arrhythmias for both(80%) and(91%) groups (p=NS).cardiomyopathy is a distinct form of arrhythmogenic cardiomyopathy characterized by episodic myocardial injury, left ventricular fibrosis that precedes systolic dysfunction, and a high incidence of ventricular arrhythmias. A genotype specific approach for diagnosis and risk stratification should be used.<br /><br /><br /><br /><small>Circulation: 05 May 2020; epub ahead of print</small></div>

<div><h4>Cardiomyopathy associated with the Ala143Thr variant of the gene.</h4><i>Valtola K, Nino-Quintero J, Hedman M, Lottonen-Raikaslehto L, ... Laakso M, Kuusisto J</i><br /><b>Objective</b><br />To investigate whether the Ala143Thr variant of thegene (A143T/), with conflicting interpretations of pathogenicity, is associated with Fabry cardiomyopathy.<br /><b>Methods</b><br />The index patient, a woman in her 60s with cardiomyopathy, was screened for variants in 59 cardiomyopathy-related genes. A143T/, the only rare variant found, was screened in 10 relatives. GLA activity and lyso-Gb3 levels were measured and echocardiography was performed in 8 of 9 subjects carrying A143T/. Cardiac magnetic resonance (CMR) imaging and F-fluorodeoxyglucose (FDG) positron emission tomography/CT (PET/CT) were performed in four adult A143T/ carriers. Endomyocardial biopsy was obtained from two adult A143T/ carrying sons of the index patient.<br /><b>Results</b><br />The index patient and her elder son had a pacemaker implantation because of sick sinus syndrome and atrioventricular block. GLA activities were decreased to 25%-40% of normal in both sons and one granddaughter. Lyso-Gb3 levels were elevated in both sons. In CMR, the index patient and her two sons had left ventricular (LV) hypertrophy and/or dilatation. The elder son had late gadolinium enhancement, high CMR-derived T1 time and positive FDG signal in PET/CT in the basal inferolateral LV wall. The younger son had low T1 time and the mother had positive FDG signal in PET/CT in the basal inferolateral LV wall. Endomyocardial biopsy of both sons showed myocardial accumulation compatible with glycolipids in light and electron microscopy, staining with anti-Gb3 antibody available for the younger son. Five female relatives with A143T/ had no cardiomyopathy in cardiac imaging.<br /><b>Conclusions</b><br />A143T/ is likely a late-onset Fabry cardiomyopathy causing variant with incomplete penetrance.<br /><br />© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>Heart: 30 Mar 2020; 106:609-615</small></div>

<div><h4>Stem Cell-Derived Cardiomyocytes and Beta-Adrenergic Receptor Blockade in Duchenne Muscular Dystrophy Cardiomyopathy.</h4><i>Kamdar F, Das S, Gong W, Klaassen Kamdar A, ... Zhang J, Garry DJ</i><br /><b>Background</b><br />Although cardiomyopathy has emerged as a leading cause of death in Duchenne muscular dystrophy (DMD), limited studies and therapies have emerged for dystrophic heart failure.<br /><b>Objectives</b><br />The purpose of this study was to model DMD cardiomyopathy using DMD patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and to identify physiological changes and future drug therapies.<br /><b>Methods</b><br />To explore and define therapies for DMD cardiomyopathy, the authors used DMD patient-specific hiPSC-derived cardiomyocytes to examine the physiological response to adrenergic agonists and β-blocker treatment. The authors further examined these agents in vivo using wild-type and mdx mouse models.<br /><b>Results</b><br />At baseline and following adrenergic stimulation, DMD hiPSC-derived cardiomyocytes had a significant increase in arrhythmic calcium traces compared to isogenic controls. Furthermore, these arrhythmias were significantly decreased with propranolol treatment. Using telemetry monitoring, the authors observed that mdx mice, which lack dystrophin, had an arrhythmic death when stimulated with isoproterenol; the lethal arrhythmias were rescued, in part, by propranolol pre-treatment. Using single-cell and bulk RNA sequencing (RNA-seq), the authors compared DMD and control hiPSC-derived cardiomyocytes, mdx mice, and control mice (in the presence or absence of propranolol and isoproterenol) and defined pathways that were perturbed under baseline conditions and pathways that were normalized after propranolol treatment in the mdx model. The authors also undertook transcriptome analysis of human DMD left ventricle samples and found that DMD hiPSC-derived cardiomyocytes have dysregulated pathways similar to the human DMD heart. The authors further determined that relatively few patients with DMD see a cardiovascular specialist or receive β-blocker therapy.<br /><b>Conclusions</b><br />The results highlight mechanisms and therapeutic interventions from human to animal and back to human in the dystrophic heart. These results may serve as a prelude for an adequately powered clinical study that examines the impact of β-blocker therapy in patients with dystrophinopathies.<br /><br />Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 16 Mar 2020; 75:1159-1174</small></div>

<div><h4>Integrin β1D Deficiency-Mediated RyR2 Dysfunction Contributes to Catecholamine-Sensitive Ventricular Tachycardia in ARVC.</h4><i>Wang Y, Li C, Shi L, Chen X, ... Song LS, Zhao S</i><br /><b></b><br />Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary heart disease characterized by fatty infiltration, life-threatening arrhythmias and increased risk of sudden cardiac death (SCD). The guideline for management of ARVC patients is to improve quality of life by reducing arrhythmic symptoms and to prevent SCD. However, the mechanism underlying ARVC-associated cardiac arrhythmias remains poorly understood.Using protein mass spectrometry analyses, we identified integrin β1 is down-regulated in ARVC hearts without changes to Ca-handling proteins. As adult cardiomyocytes express only the β1D isoform, we generated a cardiac specific β1D knockout (β1D) mouse model, and performed functional imaging and biochemical analyses to determine the consequences from integrin β1D loss of function in the heart in vivo and in vitro.Integrin β1D deficiency and RyR2 Ser-2030 hyper-phosphorylation were detected by western blotting in left ventricular tissues from patients with ARVC but not in patients with ischemic or hypertrophic cardiomyopathy. Using lipid bilayer patch clamp single channel recordings, we found purified integrin β1D protein could stabilize RyR2 function by decreasing RyR2 open probability (Po), mean open time (To), and increasing mean close time (Tc). β1D mice exhibited normal cardiac function and morphology, but presented with catecholaminesensitive polymorphic ventricular tachycardia, consistent with increased RyR2 Ser-2030 phosphorylation and aberrant Ca handling in β1D cardiomyocytes. Mechanistically, we revealed that loss of desmoplakin induces integrin β1D deficiency in ARVC mediated through an ERK1/2 - fibronectin - ubiquitin/lysosome pathway.Our data suggest that integrin β1D deficiency represents a novel mechanism underlying the increased risk of ventricular arrhythmias in patients with ARVC.<br /><br /><br /><br /><small>Circulation: 02 Mar 2020; epub ahead of print</small></div>

<div><h4>The evolution of gene-guided management of inherited arrhythmia syndromes: Peering beyond monogenic paradigms towards comprehensive genomic risk scores.</h4><i>Rowe MK, Roberts JD</i><br /><b></b><br />Inherited arrhythmia syndromes have traditionally been viewed as monogenic forms of disease whose pathophysiology is driven by a single highly penetrant rare genetic variant. Although an accurate depiction of a proportion of genetic variants, the variable penetrance frequently noted in genotype positive families and the presence of sporadic genotype negative cases have long highlighted a more nuanced truth being operative. Coupled with our more recent recognition that many rare variants implicated in inherited arrhythmia syndromes possess unexpectedly high allele frequencies within the general population, these observations have contributed to the realization that a spectrum of pathogenicity exists among clinically relevant genetic variants. Notably, variable mutation pathogenicity and corresponding variable degrees of penetrance emphasize a limitation of contemporary guidelines, which attempt to dichotomize genetic variants as pathogenic or benign. Recognition of the existence of low and intermediate penetrant variants insufficient to be causative for disease in isolation has served to emphasize the importance of additional genetic, clinical, and environmental factors in the pathogenesis of rare inherited arrhythmia syndromes. Despite being rare, it has also become increasingly evident that common genetic variants play critical roles in both heritable channelopathies and cardiomyopathies and in aggregate may even be the primary drivers in certain instances, such as genotype negative Brugada syndrome. Our growing realization that the genetic substrates of inherited arrhythmia syndromes have intricacies that extend beyond traditionally perceived monogenic paradigms has highlighted a potential value of leveraging more comprehensive genomic risk scores for predicting disease development and arrhythmic risk.<br /><br />© 2020 Wiley Periodicals, Inc.<br /><br /><small>J Cardiovasc Electrophysiol: 26 Feb 2020; epub ahead of print</small></div>

<div><h4>Pediatric Liddle Syndrome Caused by a Novel SCNN1G Variant in a Chinese Family and Characterized by Early-Onset Hypertension.</h4><i>Fan P, Pan XC, Zhang D, Yang KQ, ... Cai J, Zhou XL</i><br /><b>Background</b><br />Liddle syndrome (LS), an autosomal dominant disorder, is a common monogenic hypertension in pediatrics. In this study, we reported a novel SCNN1G variant in a Chinese family with pediatric LS, and conduct a systematic review of epithelial sodium channel (ENaC)-gene-positive LS cases to conclude the clinical genetic features of LS in childhood.<br /><b>Methods</b><br />Next-generation sequencing and in silico analysis were performed in the proband to discover candidate variants. Sanger sequencing was used to identify the predicted likely pathogenic variant. LS patients in this family were treated with amiloride. The Medline database was searched to summarize clinical features of pediatric LS cases whose age at genetic diagnosis was not more than 18 years.<br /><b>Results</b><br />Genetic analysis identified a novel SCNN1G missense variant (c.1874C>T, p.Pro625Leu) in the proband with LS in childhood. In silico analysis revealed this heterozygous variant was highly conserved and deleterious. A total of 38 publications described pediatric LS associated with 25 pathogenic variants in SCNN1B and SCNN1G in 54 children. Despite the phenotypic heterogeneity, early-onset hypertension is the most common feature. All LS patients in this family or the reviewed cases showed significantly improvements in hypertension and hypokalemia after treatment with ENaC inhibitors.<br /><b>Conclusions</b><br />This study identified a novel SCNN1G missense variant in a patient with pediatric LS, expanding the genetic spectrum of SCNN1G and demonstrating the PY motif of γ-ENaC as a potential mutant region. Early identification and specific management of LS in children and adolescents are important to prevent the development of hypertensive end-organ disease.<br /><br />© The Author(s) 2020. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.<br /><br /><small>Am J Hypertens: 17 Jan 2020; 33:670-675</small></div>

<div><h4>Routine CYP2C19 Genotyping to Adjust Thienopyridine Treatment After Primary PCI for STEMI: Results of the GIANT Study.</h4><i>Hulot JS, Chevalier B, Belle L, Cayla G, ... Montalescot G, </i><br /><b>Objectives</b><br />The aim of this study was to evaluate prospectively the clinical impact of routine transmission of CYP2C19 genotype in the management of acute ST-segment elevation myocardial infarction with primary percutaneous coronary intervention.<br /><b>Background</b><br />Response to clopidogrel differs widely among patients, notably because of CYP2C19 genetic polymorphisms.<br /><b>Methods</b><br />CYP2C19 genotype (6 alleles) was determined centrally and communicated within 4.1 ± 1.9 days of primary percutaneous coronary intervention in 1,445 patients with ST-segment elevation myocardial infarction recruited at 57 centers in France. CYP2C19 metabolic status was predicted from genotype and served to adjust thienopyridine treatment. The primary endpoint was differences in 12-month outcomes (death, myocardial infarction, and stent thrombosis) between patients with the wild-type genotype or gain-of-function allele (class 1, n = 1,118) and those with loss-of-function (LOF) alleles (class 2, n = 272) who received optimized thienopyridine treatment.<br /><b>Results</b><br />Detection of LOF alleles resulted in adjustment of P2Y inhibition in 85% of patients, with significantly higher use of prasugrel or double-dose clopidogrel. The primary endpoint did not differ between class 1 and class 2 patients (3.31% vs. 3.04%, respectively; p = 0.82). In contrast, carriers of LOF alleles without treatment adjustment had significantly worse outcomes (15.6%; p < 0.05). Bleeding rates were not different between groups.<br /><b>Conclusions</b><br />In a real-world setting, a complete CYPC2C19 genotype can be mostly determined in <7 days using analysis of saliva deoxyribonucleic acid collected during the in-hospital phase among patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. Genotype information led to stronger platelet inhibition treatment in the vast majority of LOF allele carriers and to similar clinical outcomes as in patients carrying the wild-type genotype or gain-of-function allele. (Genotyping Infarct Patients to Adjust and Normalize Thienopyridine Treatment [GIANT]; NCT01134380).<br /><br />Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Cardiovasc Interv: 08 Jan 2020; 13:621-630</small></div>

<div><h4>Indication and prognostic significance of programmed ventricular stimulation in asymptomatic patients with Brugada syndrome.</h4><i>Asada S, Morita H, Watanabe A, Nakagawa K, ... Nishii N, Ito H</i><br /><b>Aims</b><br />To establish the indication for programmed ventricular stimulation (PVS) for asymptomatic patients with Brugada syndrome (BrS), we evaluated the prognostic significance of PVS based on abnormal electrocardiogram (ECG) markers.<br /><b>Methods and results</b><br />One hundred and twenty-five asymptomatic patients with BrS were included. We performed PVS at two sites of the right ventricle with up to three extrastimuli [two pacing cycle lengths and minimum coupling interval (MCI) of 180 ms]. We followed the patients for 133 months and evaluated ventricular fibrillation (VF) events. Fragmented QRS (fQRS) and Tpeak-Tend (Tpe) interval were evaluated as ECG markers for identifying high-risk patients. Fragmented QRS and long Tpe interval (≥100 ms) were observed in 66 and 37 patients, respectively. Ventricular fibrillation was induced by PVS in 60 patients. During follow-up, 10 patients experienced VF events. Fragmented QRS, long Tpe interval, and PVS-induced VF with an MCI of 180 ms or up to two extrastimuli were associated with future VF events (fQRS: P = 0.015, Tpe ≥ 100 ms: P = 0.038, VF induction: P < 0.001). However, PVS-induced VF with an MCI of 200 ms was less specific (P = 0.049). The frequencies of ventricular tachyarrhythmia events during follow-up were 0%/year with no ECG markers and 0.1%/year with no VF induction. The existence of two ECG factors with induced VF was strongly associated with future VF events (event rate: 4.4%/year, P < 0.001), and the existence of one ECG factor with induced VF was also associated (event rate: 1.3%/year, P = 0.011).<br /><b>Conclusion</b><br />We propose PVS with a strict protocol for asymptomatic patients with fQRS and/or long Tpe interval to identify high-risk patients.<br /><br />Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.<br /><br /><small>Europace: 31 Dec 2019; 22:972-979</small></div>

<div><h4>Right ventricular strain rate during exercise accurately identifies male athletes with right ventricular arrhythmias.</h4><i>Claeys M, Claessen G, Claus P, De Bosscher R, ... Heidbuchel H, La Gerche A</i><br /><b>Aims</b><br />Athletes with right ventricular (RV) arrhythmias, even in the absence of desmosomal mutations, may have subtle RV abnormalities which can be unmasked by deformation imaging. As exercise places a disproportionate stress on the right ventricle, evaluation of cardiac function and deformation during exercise might improve diagnostic performance.<br /><b>Methods and results</b><br />We performed bicycle stress echocardiography in 17 apparently healthy endurance athletes (EAs), 12 non-athletic controls (NAs), and 17 athletes with RV arrhythmias without desmosomal mutations (EI-ARVCs) and compared biventricular function at rest and during low (25% of upright peak power) and moderate intensity (60%). At rest, we observed no differences in left ventricular (LV) or RV function between groups. During exercise, however, the increase in RV fractional area change (RVFAC), RV free wall strain (RVFWSL), and strain rate (RVFWSRL) were significantly attenuated in EI-ARVCs as compared to EAs and NAs. At moderate exercise intensity, EI-ARVCs had a lower RVFAC, RVFWSL, and RVFWSRL (all P < 0.01) compared to the control groups. Exercise-related increases in LV ejection fraction, strain, and strain rate were also attenuated in EI-ARVCs (P < 0.05 for interaction). Exercise but not resting parameters identified EI-ARVCs and RVFWSRL with a cut-off value of >-2.35 at moderate exercise intensity had the greatest accuracy to detect EI-ARVCs (area under the curve 0.95).<br /><b>Conclusion</b><br />Exercise deformation imaging holds promise as a non-invasive diagnostic tool to identify intrinsic RV dysfunction concealed at rest. Strain rate appears to be the most accurate parameter and should be incorporated in future, prospective studies to identify subclinical disease in an early stage.<br /><br />Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.<br /><br /><small>Eur Heart J Cardiovasc Imaging: 31 Dec 2019; 21:282-290</small></div>

<div><h4>Atrial fibrillation ablation in patients with transthyretin cardiac amyloidosis.</h4><i>Donnellan E, Wazni O, Kanj M, Elshazly MB, ... Saliba W, Jaber WA</i><br /><b>Aims</b><br />Atrial fibrillation (AF) occurs in as many as 70% of patients with transthyretin cardiac amyloidosis (ATTR CA). The aim of our study was to investigate the impact of AF ablation on freedom from recurrent arrhythmia, hospitalization for AF or heart failure (HF), and mortality.<br /><b>Methods and results</b><br />This was a retrospective observational cohort study of 72 patients with ATTR CA and AF, of whom 24 underwent AF ablation and were matched in a 2:1 manner based on age, gender, ATTR CA stage, New York Heart Association functional class, ejection fraction, and date of AF diagnosis with 48 patients with ATTR CA and AF undergoing medical management. During a mean follow-up of 39 ± 26 months, 10 (42%) patients remained free of recurrent arrhythmia following ablation. Ablation was significantly more effective in those with Stage I or II ATTR CA, with 9/14 (64%) patients with Stage I or II ATTR CA remaining free of recurrent arrhythmia compared to only 1/10 (10%) patients with Stage III disease (P = 0.005). Death occurred in 7 (29%) patients in the ablation group compared to 36 (75%) in the non-ablation arm (P = 0.01). Rates of ischaemic stroke were similar in both groups. Ablation was associated with a significant reduction in the frequency of hospitalization for HF/arrhythmia (1.7 ± 2.4 hospitalizations vs. 4 ± 3.5, P = 0.005). On Cox proportional hazards analyses, ablation was associated with improved survival (hazard ratio 0.38, 95% confidence intervals 0.17-0.86; P = 0.02).<br /><b>Conclusion</b><br />Atrial fibrillation ablation is associated with reduced mortality in ATTR CA and is most effective when performed earlier during the disease process.<br /><br />Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.<br /><br /><small>Europace: 31 Dec 2019; 22:259-264</small></div>

<div><h4>Association of Rare PTGIS Variants With Susceptibility and Pulmonary Vascular Response in Patients With Idiopathic Pulmonary Arterial Hypertension.</h4><i>Wang XJ, Xu XQ, Sun K, Liu KQ, ... Zhang X, Jing ZC</i><br /><b>Importance</b><br />Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease with high heritability; however, the bone morphogenetic protein receptor 2 (BMPR2) gene only accounts for 17% of IPAH. The genetic basis of IPAH needs further investigation.<br /><b>Objective</b><br />To identify novel IPAH susceptibility genes other than BMPR2.<br /><b>Design, setting, and participants</b><br />This 2-stage, case-control genetic association study enrolled 230 patients with IPAH from 2 referral pulmonary hypertension centers in China. Eligible patients had no BMPR2 variants and were compared with 968 healthy control participants. Data were collected from January 1, 2000, to July 31, 2015, and analyzed from August 1, 2015, to May 30, 2018.<br /><b>Exposures</b><br />PTGIS rare variants.<br /><b>Main outcomes and measures</b><br />Whole-genome sequencing was performed to identify putative IPAH genes in a discovery cohort, with validation in an independent referral cohort. Correlation of genotype and hemodynamic characteristics was then evaluated at baseline and after pulmonary vasodilator testing. Functional assessments were conducted to analyze the effects of identified genetic variants on transcript splicing, enzymatic activity, and endothelial cell phenotypes.<br /><b>Results</b><br />Among 230 patients with IPAH (164 female [71.3%]; mean [SD] age, 34 [18] years), an enrichment of rare variants in a gene encoding prostacyclin synthase (PTGIS) was identified in the discovery cohort. The association of PTGIS rare variants with IPAH was confirmed in the replication cohort. In the combined data set, PTGIS rare variants were found in 14 of 230 cases (6.1%) and 8 of 968 controls (0.8%) (odds ratio, 7.8; 95% CI, 3.2-18.8; P = 5 × 10-6, logistic regression). Compared with patients without PTGIS variants, inhaled iloprost induced a more significant decrease of pulmonary vascular resistance (difference in the least square mean, -21.7%; 95% CI, -31.4% to -12.0%; P < .001, linear regression model) and an increase of cardiac index (difference in the least square mean, 18.3%; 95% CI, 8.8%-27.8%; P < .001, linear regression model) in patients with PTGIS variants. The minigene assay indicated that the c.521 + 1G>A variant resulted in aberrant messenger RNA transcripts. The functional studies showed that the 2 missense rare variants (R252Q and A447T) resulted in a decrease in prostacyclin production and increased cell death of pulmonary microvascular endothelial cells.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />This study identified 3 rare loss-of-function variants in the PTGIS gene from 2 independent cohorts with IPAH. The genetic variants of PTGIS predispose pulmonary vascular responses to the iloprost stimulation. These findings suggest that PTGIS variants may be involved in the pathogenesis of IPAH.<br /><br /><br /><br /><small>JAMA Cardiol: 31 Dec 2019; 5:677-684</small></div>

<div><h4>Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants.</h4><i>Herkert JC, Verhagen JMA, Yotti R, Haghighi A, ... Seidman CE, van de Laar IMBH</i><br /><b>Introduction</b><br />Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined.<br /><b>Methods and results</b><br />We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10<sup>-5</sup>; U.S. cohort, P = 2.2×10<sup>-13</sup>).<br /><b>Conclusion</b><br />Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy.<br /><br />Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.<br /><br /><small>Am Heart J: 30 Dec 2019; 225:108-119</small></div>

<div><h4>Microsomal triglyceride transfer protein inhibitor (lomitapide) efficacy in the treatment of patients with homozygous familial hypercholesterolaemia.</h4><i>Kolovou G, Diakoumakou O, Kolovou V, Fountas E, ... Mavrogeni S, Hatzigeorgiou G</i><br /><b>Aims</b><br />The aim of this study was to evaluate the effect of microsomal triglyceride transfer protein inhibitor (lomitapide) in patients with homozygous familial hypercholesterolaemia.<br /><b>Methods and results</b><br />In 12 homozygous familial hypercholesterolaemia patients treated with lipid-lowering drugs ± biweekly lipoprotein apheresis sessions (nine patients), daily lomitapide was added. The lipid profile (total cholesterol, low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol) before and after lomitapide treatment was evaluated. The follow-up period with lomitapide treatment was 3-24 months (13.8 ± 7.9). The median baseline low-density lipoprotein cholesterol level was 900 mg/dl (348-1070), after lipid-lowering drugs therapy was 383.5 mg/dl (214-866) and after lipid-lowering drugs + time-averaged level was 288 mg/dl (183.7-716.6). The addition of lomitapide lowered low-density lipoprotein cholesterol levels further by 56.8% compared to lipid-lowering drugs alone (mean reduction 262, 95% confidence interval (105.5-418.7),  = 0.005) and by 54% (mean reduction 182.9, 95% confidence interval (-342 - -23),  = 0.031) comparing to lipid-lowering drugs + lipoprotein apheresis (time-averaged level). The time-averaged level of low-density lipoprotein cholesterol in lipid-lowering drugs + lipoprotein apheresis patients compared with lipid-lowering drugs + lomitapide was 54% in favour of lomitapide ( = 0.031).<br /><b>Conclusions</b><br />Treatment with lomitapide in homozygous familial hypercholesterolaemia patients has a beneficial effect with a constant decrease of low-density lipoprotein cholesterol by 57% compared with classical lipid-lowering therapy and by 54% compared with classical lipid-lowering therapy and time-averaged level of low-density lipoprotein cholesterol.<br /><br /><br /><br /><small>Eur J Prev Cardiol: 30 Dec 2019; 27:157-165</small></div>

<div><h4>Role of ADAM9 and miR-126 in the development of abdominal aortic aneurysm.</h4><i>Shen G, Sun Q, Yao Y, Li S, ... Xu Y, Wang H</i><br /><b>Background:</b><br/>and aims</b><br />Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease when aortic rupture occurs, especially for elders. There is an urgent need to understand the mechanisms of AAA formation and development at molecular level. Our previous study showed that disintegrin and metalloprotease 10 (ADAM10) played an important role in abdominal aortic aneurysm formation. In this study, we investigated the effects of another ADAM protein (ADMA9) in AAA formation.<br /><b>Method and results</b><br />Using AngII treated human aortic smooth muscle cells (HASMCs) and human aortic endothelial cells (hAoECs) as in vitro AAA model and murine AAA model, ADAM9 was overexpressed suggesting that ADAM9 may play important roles in AAA formation. Further investigation showed that ADAM9 induced inflammation leading to increased macrophage infiltration. ADAM9 was also found to induce cell apoptosis. AKT/NF-κB pathway was activated in murine AAA. Bioinformatic analysis showed that the 3\' UTR of ADMA9 was a potential target of miR-126. We investigated the potential of using miR-126 to modulate ADAM9 expression. The expression level of miR-126 was decreased and inversely correlated with the expression of ADAM9 in the in vitro AAA model. Further investigation showed that miR-126 negatively regulated gene expression of ADAM9 and suppressed the production of inflammatory cytokines. miR-126 was also found to improve cell survival and significantly reduce AAA formation in murine AAA.<br /><b>Conclusions</b><br />Our data revealed a link between ADAM9 and AAA formation, providing an approach to control AAA development using miR-126, possibly through modulation of the expression level of ADAM9.<br /><br />Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.<br /><br /><small>Atherosclerosis: 30 Dec 2019; 297:47-54</small></div>

<div><h4>Progress of Gene Therapy in Cardiovascular Disease.</h4><i>Shimamura M, Nakagami H, Sanada F, Morishita R</i><br /><AbstractText>Gene therapy has been extensively studied in peripheral and cardiac ischemia, heart and vein graft failure, and dyslipidemia, but most clinical trials failed to show their efficacies despite good outcomes in preclinical studies. So far, 2 gene therapies for dyslipidemia and one for critical limb ischemia in peripheral artery disease have been approved. In critical limb ischemia, gene therapy using proangiogenic factors has emerged as a novel therapeutic modality for promoting angiogenesis. Initial researches mainly focused on vascular endothelial growth factor, fibroblast growth factor, or hepatocyte growth factor. After the favorable results of basic research, several phase I and II clinical trials of these proangiogenic factors have shown promising results. However, only a phase III clinical trial of the intramuscular injection of hepatocyte growth factor plasmid DNA has shown successful outcomes, and it was recently approved in Japan for treating patients with critical limb ischemia who have ulcers and for whom no alternative therapeutic options are available. DNA vaccine is another promising modality of gene therapy. An antitumor vaccine suppressing angiogenesis through the inhibition of proangiogenic factors and an antihypertensive vaccine inhibiting the renin-angiotensin system are representative DNA vaccines. The advantage of DNA vaccine is its long-term effectiveness with a few vaccinations; however, the benefits and risks, such as adverse T-cell reaction against self-antigen or long-term side effects, of DNA vaccines should be carefully evaluated. In this review, we discuss the recent advances in proangiogenic gene therapy for critical limb ischemia and DNA vaccine for hypertension.</AbstractText><br /><br /><br /><br /><small>Hypertension: 30 Dec 2019; 76:1038-1044</small></div>

<div><h4>Predictors of Fabry disease in patients with hypertrophic cardiomyopathy: How to guide the diagnostic strategy?</h4><i>Azevedo O, Marques N, Reis L, Cruz I, ... Cunha D, group of investigators</i><br /><b>Background</b><br />Fabry disease (FD) is a treatable cause of hypertrophic cardiomyopathy (HCM). We aimed to determine the independent predictors of FD and to define a clinically useful strategy to discriminate FD among HCM.<br /><b>Methods</b><br />Multicenter study including 780 patients with the ESC definition of HCM. FD screening was performed by enzymatic assay in males and genetic testing in females. Multivariate regression analysis identified independent predictors of FD in HCM. A discriminant function analysis defined a score based on the weighted combination of these predictors.<br /><b>Results</b><br />FD was found in 37 of 780 patients with HCM (4.7%): 31 with p.F113L mutation due to a founder effect; and 6 with other variants (p.C94S; p.M96V; p.G183V; p.E203X; p.M290I; p.R356Q/p.G360R). FD prevalence in HCM adjusted for the founder effect was 0.9%. Symmetric HCM (OR 3.464, CI95% 1.151-10.430), basal inferolateral late gadolinium enhancement (LGE) (OR 10.677, CI95% 3.633-31.380), bifascicular block (OR 10.909, CI95% 2.377-50.059) and ST-segment depression (OR 4.401, CI95% 1.431-13.533) were independent predictors of FD in HCM. The score ID FABRY-HCM [-0.729 + (2.781xBifascicular block) + (0.590xST depression) + (0.831xSymmetric HCM) + (2.130xbasal inferolateral LGE)] had a negative predictive value of 95.8% for FD, with a cut-off of 1.0, meaning that, in the absence of both bifascicular block and basal inferolateral LGE, FD is a less probable cause of HCM, being more appropriate to perform HCM gene panel than targeted FD screening.<br /><b>Conclusion</b><br />FD prevalence in HCM was 0.9%. Bifascicular block and basal inferolateral LGE were the most powerful predictors of FD in HCM. In their absence, HCM gene panel is the most appropriate step in etiological study of HCM.<br /><br />Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.<br /><br /><small>Am Heart J: 30 Dec 2019; 226:114-126</small></div>

<div><h4>Cardiac resynchronization therapy improves the ventricular function of patients with Fontan physiology.</h4><i>Joyce J, O\'Leary ET, Mah DY, Harrild DM, Rhodes J</i><br /><AbstractText>Past studies have not detected consistent improvement in ventricular function (VFxn) following initiation of cardiac resynchronization therapy (CRT) in Fontan patients. However, these studies used qualitative assessments of VFxn and/or quantitative assessments of VFxn that rely upon anatomic and/or geometric assumptions that may not be valid in patients with single ventricles. To address this, we used quantitative indices of global VFxn (dP/dt<sub>ic</sub> and the Tei index) that are not encumbered by the limitations associated with the indices used in previous studies of CRT in Fontan patients.</AbstractText><br /><b>Methods</b><br />Patients with Fontan physiology who had received CRT therapy from 2004 to 2019 were included in the study. They were compared to a concurrent group of Fontan patients who had received standard dual-chamber pacemakers (DCPMs).<br /><b>Results</b><br />VFxn was assessed at 3 time points: prior to, shortly after, and late after initiation of pacemaker therapy. Prior to initiation of pacemaker therapy, VFxn of the CRT patients tended to be worse than that of the DCPM patients. For both groups, VFxn appeared to be stable or slightly improved shortly after initiation of pacemaker therapy. In the CRT group, VFxn improved significantly between early and late follow-up. In contrast, VFxn in DCPM patients tended to decline during this period. Changes in VFxn correlated with concurrent changes in New York Heart Association classification.<br /><b>Conclusions</b><br />Quantitative assessments of VFxn using indices not confounded by complex cardiac anatomy, segmental wall motions abnormalities, or inappropriate geometric assumptions revealed that CRT in Fontan patients is associated with preservation or improvement VFxn compared to standard DCPM. Changes in VFxn correlate with concurrent changes in New York Heart Association classification.<br /><br />Copyright © 2020 Elsevier Inc. All rights reserved.<br /><br /><small>Am Heart J: 30 Dec 2019; 230:82-92</small></div>

<div><h4>Distinct Subgroups in Hypertrophic Cardiomyopathy in the NHLBI HCM Registry.</h4><i>Neubauer S, Kolm P, Ho CY, Kwong RY, ... Kramer CM, </i><br /><b>Background</b><br />The HCMR (Hypertrophic Cardiomyopathy Registry) is a National Heart, Lung, and Blood Institute-funded, prospective registry of 2,755 patients with hypertrophic cardiomyopathy (HCM) recruited from 44 sites in 6 countries.<br /><b>Objectives</b><br />The authors sought to improve risk prediction in HCM by incorporating cardiac magnetic resonance (CMR), genetic, and biomarker data.<br /><b>Methods</b><br />Demographic and echocardiographic data were collected. Patients underwent CMR including cine imaging, late gadolinium enhancement imaging (LGE) (replacement fibrosis), and T1 mapping for measurement of extracellular volume as a measure of interstitial fibrosis. Blood was drawn for the biomarkers N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (cTnT), and genetic analysis.<br /><b>Results</b><br />A total of 2,755 patients were studied. Mean age was 49 ± 11 years, 71% were male, and 17% non-white. Mean ESC (European Society of Cardiology) risk score was 2.48 ± 0.56. Eighteen percent had a resting left ventricular outflow tract (LVOT) gradient ≥30 mm Hg. Thirty-six percent had a sarcomere mutation identified, and 50% had any LGE. Sarcomere mutation-positive patients were more likely to have reverse septal curvature morphology, LGE, and no significant resting LVOT obstruction. Those that were sarcomere mutation negative were more likely to have isolated basal septal hypertrophy, less LGE, and more LVOT obstruction. Interstitial fibrosis was present in segments both with and without LGE. Serum NT-proBNP and cTnT levels correlated with increasing LGE and extracellular volume in a graded fashion.<br /><b>Conclusions</b><br />The HCMR population has characteristics of low-risk HCM. Ninety-three percent had no or only mild functional limitation. Baseline data separated patients broadly into 2 categories. One group was sarcomere mutation positive and more likely had reverse septal curvature morphology, more fibrosis, but less resting obstruction, whereas the other was sarcomere mutation negative and more likely had isolated basal septal hypertrophy with obstruction, but less fibrosis. Further follow-up will allow better understanding of these subgroups and development of an improved risk prediction model incorporating all these markers.<br /><br />Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 11 Nov 2019; 74:2333-2345</small></div>

<div><h4>The prognostic value of biventricular long axis strain using standard cardiovascular magnetic resonance imaging in patients with hypertrophic cardiomyopathy.</h4><i>Yang F, Wang J, Li Y, Li W, ... Han Y, Chen Y</i><br /><b>Background</b><br />Long axis strain (LAS) is a parameter derived from standard cardiovascular magnetic resonance imaging. However, the prognostic value of biventricular LAS in hypertrophic cardiomyopathy (HCM) is unknown.<br /><b>Methods</b><br />Patients with HCM (n = 384) and healthy volunteers (n = 150) were included in the study. Left ventricular (LV)-LAS was defined as the percentage change in the length measured from the epicardial border of the LV apex to the midpoint of a line connecting the mitral annulus at end-systole and end-diastole. Right ventricular (RV)-LAS represented the percentage change of length between epicardial border of the LV apex to the midpoint of a line connecting the tricuspid annulus at end-systole and end-diastole. The primary endpoint was a combination of all-cause death and sudden cardiac death aborted by appropriate implantable cardioverter-defibrillator discharge and cardiopulmonary resuscitation after syncope. The secondary endpoint was a combination of the primary endpoint and hospitalization for congestive heart failure.<br /><b>Results</b><br />Twenty-nine patients (7.6%) achieved the primary endpoint, and the secondary endpoint occurred in 66 (17.2%) patients. In multivariate Cox regression analysis, RV-LAS was an independent prognostic factor for the primary (hazard ratio (HR), 1.13) and secondary (HR, 1.11) endpoints. In the subgroup of patients with a normal RV ejection fraction (EF) (>45.0%, n = 345), impaired RV-LAS was associated with adverse outcomes and might add incremental prognostic value to RVEF and tricuspid annular plane systolic excursion (TAPSE) (p < 0.01).<br /><b>Conclusions</b><br />RV-LAS is an independent predictor of adverse prognosis in HCM in addition to RVEF and TAPSE.<br /><br />Copyright © 2019 Elsevier B.V. All rights reserved.<br /><br /><small>Int J Cardiol: 31 Oct 2019; 294:43-49</small></div>

<div><h4>Enhanced NOX-2 derived oxidative stress in offspring of patients with early myocardial infarction.</h4><i>Loffredo L, Martino F, Zicari AM, Carnevale R, ... Barillà F, Violi F</i><br /><b>Background</b><br />Offspring of patients with early myocardial infarction have a higher risk to develop cardiovascular events; the underlying physiopathology is still unclear. Several lines of evidence support a role for oxidative stress in atherogenesis and NADPH oxidase-2 (NOX-2) is considered a major source of O2 in human. Furthermore, oxidative stress regulates arachidonic acid metabolism via activation of platelet phospholipase-A2. The aim of this study was to address NOX-2 activity as well as serum thromboxane B2 (TXB2) and 8-isoPGF2-alpha in offspring of patients with premature myocardial infarction.<br /><b>Methods</b><br />Ninety-two consecutive subjects, including 46 offspring of patients with premature myocardial infarction and 46 healthy subjects (HS) matched for age and gender, were recruited. A cross sectional study was performed to compare serum activity of soluble NOX-2-dp (sNOX-2-dp), blood levels of isoprostanes and serum TXB2 in these two groups.<br /><b>Results</b><br />Compared with HS, offspring of patients with early myocardial infarction had higher values of serum TxB2, isoprostanes and sNOX-2-dp. Bivariate analysis in the overall population showed that serum sNOX-2-dp levels were significantly associated with serum isoprostanes and TXB2. A multiple linear regression analysis was performed to define the independent predictors of sNOX-2-dp. Serum isoprostanes (SE: 0.07; standardized coefficient β: 0.579; P < 0.001) and TXB2 levels (SE: 0.06; standardized coefficient β: 0.211; P < 0.001) were significantly associated to sNOX-2-dp (R2: 0.42).<br /><b>Conclusion</b><br />This study shows that Nox-2 activation is a key determinant of oxidative stress and platelet activation in offspring of patients with premature myocardial infarction.<br /><br />Copyright © 2019 Elsevier B.V. All rights reserved.<br /><br /><small>Int J Cardiol: 14 Oct 2019; 293:56-59</small></div>

<div><h4>Effect of Systolic Blood Pressure on Left Ventricular Structure and Function: A Mendelian Randomization Study.</h4><i>Hendriks T, Said MA, Janssen LMA, van der Ende MY, ... Verweij N, van der Harst P</i><br /><b></b><br />We aimed to estimate the effects of a lifelong exposure to high systolic blood pressure (SBP) on left ventricular (LV) structure and function using Mendelian randomization. A total of 5596 participants of the UK Biobank were included for whom cardiovascular magnetic resonance imaging and genetic data were available. Major exclusion criteria included nonwhite ethnicity, major cardiovascular disease, and body mass index >30 or <18.5 kg/m. A genetic risk score to estimate genetically predicted SBP (gSBP) was constructed based on 107 previously established genetic variants. Manual cardiovascular magnetic resonance imaging postprocessing analyses were performed in 300 individuals at the extremes of gSBP (150 highest and lowest). Multivariable linear regression analyses of imaging biomarkers were performed using gSBP as continuous independent variable. All analyses except myocardial strain were validated using previously derived imaging parameters in 2530 subjects. The mean (SD) age of the study population was 62 (7) years, and 52% of subjects were female. Corrected for age, sex, and body surface area, each 10 mm Hg increase in gSBP was significantly (<0.0056) associated with 4.01 g (SE, 1.28; =0.002) increase in LV mass and with 2.80% (SE, 0.97; =0.004) increase in LV global radial strain. In the validation cohort, after correction for age, sex, and body surface area, each 10 mm Hg increase in gSBP was associated with 5.27 g (SE, 1.50; <0.001) increase in LV mass. Our study provides a novel line of evidence for a causal relationship between SBP and increased LV mass and with increased LV global radial strain.<br /><br /><br /><br /><small>Hypertension: 29 Sep 2019; 74:826-832</small></div>

<div><h4>Cardiac and Neuromuscular Features of Patients with LMNA-Related Cardiomyopathy.</h4><i>Peretto G, Di Resta C, Perversi J, Forleo C, ... Sala S, </i><br /><b>Background</b><br />Mutations in the LMNA (lamin A/C) gene have been associated with neuromuscular and cardiac manifestations, but the clinical implications of these signs are not well understood.<br /><b>Objective</b><br />To learn more about the natural history of LMNA-related disease.<br /><b>Design</b><br />Observational study.<br /><b>Setting</b><br />13 clinical centers in Italy from 2000 through 2018.<br /><b>Patients</b><br />164 carriers of an LMNA mutation.<br /><b>Measurements</b><br />Detailed cardiologic and neurologic evaluation at study enrollment and for a median of 10 years of follow-up.<br /><b>Results</b><br />The median age at enrollment was 38 years, and 51% of participants were female. Neuromuscular manifestations preceded cardiac signs by a median of 11 years, but by the end of follow-up, 90% of the patients had electrical heart disease followed by structural heart disease. Overall, 10 patients (6%) died, 14 (9%) received a heart transplant, and 32 (20%) had malignant ventricular arrhythmias. Fifteen patients had gait loss, and 6 had respiratory failure. Atrial fibrillation and second- and third-degree atrioventricular block were observed, respectively, in 56% and 51% of patients with combined cardiac and neuromuscular manifestations and 37% and 33% of those with heart disease only.<br /><b>Limitations</b><br />Some of the data were collected retrospectively. Neuromuscular manifestations were more frequent in this analysis than in previous studies.<br /><b>Conclusion</b><br />Many patients with an LMNA mutation have neurologic symptoms by their 30s and develop progressive cardiac manifestations during the next decade. A substantial proportion of these patients will have life-threatening neurologic or cardiologic conditions.<br /><b>Primary funding source</b><br />None.<br /><br /><br /><br /><small>Ann Intern Med: 02 Sep 2019; epub ahead of print</small></div>

<div><h4>Loss of SRSF3 in Cardiomyocytes Leads to Decapping of Contraction-Related mRNAs and Severe Systolic Dysfunction.</h4><i>Ortiz-Sánchez P, Villalba-Orero M, López-Olañeta MM, Larrasa-Alonso J, ... García-Pavía P, Lara-Pezzi E</i><br /><b>Rationale</b><br />RBPs (RNA binding proteins) play critical roles in the cell by regulating mRNA transport, splicing, editing, and stability. The RBP SRSF3 (serine/arginine-rich splicing factor 3) is essential for blastocyst formation and for proper liver development and function. However, its role in the heart has not been explored.<br /><b>Objective</b><br />To investigate the role of SRSF3 in cardiac function.<br /><b>Methods and results</b><br />Cardiac SRSF3 expression was high at mid gestation and decreased during late embryonic development. Mice lacking SRSF3 in the embryonic heart showed impaired cardiomyocyte proliferation and died in utero. In the adult heart, SRSF3 expression was reduced after myocardial infarction, suggesting a possible role in cardiac homeostasis. To determine the role of this RBP in the adult heart, we used an inducible, cardiomyocyte-specific SRSF3 knockout mouse model. After SRSF3 depletion in cardiomyocytes, mice developed severe systolic dysfunction that resulted in death within 8 days. RNA-Seq analysis revealed downregulation of mRNAs encoding sarcomeric and calcium handling proteins. Cardiomyocyte-specific SRSF3 knockout mice also showed evidence of alternative splicing of mTOR (mammalian target of rapamycin) mRNA, generating a shorter protein isoform lacking catalytic activity. This was associated with decreased phosphorylation of 4E-BP1 (eIF4E-binding protein 1), a protein that binds to eIF4E (eukaryotic translation initiation factor 4E) and prevents mRNA decapping. Consequently, we found increased decapping of mRNAs encoding proteins involved in cardiac contraction. Decapping was partially reversed by mTOR activation.<br /><b>Conclusions</b><br />We show that cardiomyocyte-specific loss of SRSF3 expression results in decapping of critical mRNAs involved in cardiac contraction. The molecular mechanism underlying this effect likely involves the generation of a short mTOR isoform by alternative splicing, resulting in reduced 4E-BP1 phosphorylation. The identification of mRNA decapping as a mechanism of systolic heart failure may open the way to the development of urgently needed therapeutic tools.<br /><br /><br /><br /><small>Circ Res: 04 Jul 2019; 125:170-183</small></div>

<div><h4>Cardiac Troponin T and Troponin I in the General Population.</h4><i>Welsh P, Preiss D, Hayward C, Shah ASV, ... Mills NL, Sattar N</i><br /><b>Background</b><br />There is great interest in widening the use of high-sensitivity cardiac troponins for population cardiovascular disease (CVD) and heart failure screening. However, it is not clear whether cardiac troponin T (cTnT) and troponin I (cTnI) are equivalent measures of risk in this setting. We aimed to compare and contrast (1) the association of cTnT and cTnI with CVD and non-CVD outcomes, and (2) their determinants in a genome-wide association study.<br /><b>Methods</b><br />High-sensitivity cTnT and cTnI were measured in serum from 19 501 individuals in Generation Scotland Scottish Family Health Study. Median follow-up was 7.8 years (quartile 1 to quartile 3, 7.1-9.2). Associations of each troponin with a composite CVD outcome (1177 events), CVD death (n=266), non-CVD death (n=374), and heart failure (n=216) were determined by using Cox models. A genome-wide association study was conducted using a standard approach developed for the cohort.<br /><b>Results</b><br />Both cTnI and cTnT were strongly associated with CVD risk in unadjusted models. After adjusting for classical risk factors, the hazard ratio for a 1 SD increase in log transformed troponin was 1.24 (95% CI, 1.17-1.32) and 1.11 (1.04-1.19) for cTnI and cTnT, respectively; ratio of hazard ratios 1.12 (1.04-1.21). cTnI, but not cTnT, was associated with myocardial infarction and coronary heart disease. Both cTnI and cTnT had strong associations with CVD death and heart failure. By contrast, cTnT, but not cTnI, was associated with non-CVD death; ratio of hazard ratios 0.77 (0.67-0.88). We identified 5 loci (53 individual single-nucleotide polymorphisms) that had genome-wide significant associations with cTnI, and a different set of 4 loci (4 single-nucleotide polymorphisms) for cTnT.<br /><b>Conclusions</b><br />The upstream genetic causes of low-grade elevations in cTnI and cTnT appear distinct, and their associations with outcomes also differ. Elevations in cTnI are more strongly associated with some CVD outcomes, whereas cTnT is more strongly associated with the risk of non-CVD death. These findings help inform the selection of an optimal troponin assay for future clinical care and research in this setting.<br /><br /><br /><br /><small>Circulation: 10 Jun 2019; 139:2754-2764</small></div>

<div><h4>Beyond the One Gene-One Disease Paradigm: Complex Genetics and Pleiotropy in Inheritable Cardiac Disorders</h4><i>Cerrone M, Remme CA, Tadros R, Bezzina CR, Delmar M</i><br /><b></b><br />Inheritable cardiac disorders, which may be associated with cardiomyopathic changes, are often associated with increased risk of sudden death in the young. Early linkage analysis studies in Mendelian forms of these diseases, such as hypertrophic cardiomyopathy and long-QT syndrome, uncovered large-effect genetic variants that contribute to the phenotype. In more recent years, through genotype-phenotype studies and methodological advances in genetics, it has become evident that most inheritable cardiac disorders are not monogenic but, rather, have a complex genetic basis wherein multiple genetic variants contribute (oligogenic or polygenic inheritance). Conversely, studies on genes underlying these disorders uncovered pleiotropic effects, with a single gene affecting multiple and apparently unrelated phenotypes. In this review, we explore these 2 phenomena: on the one hand, the evidence that variants in multiple genes converge to generate one clinical phenotype, and, on the other, the evidence that variants in one gene can lead to apparently unrelated phenotypes. Although multiple conditions are addressed to illustrate these concepts, the experience obtained in the study of long-QT syndrome, Brugada syndrome, and arrhythmogenic cardiomyopathy, and in the study of functions related to SCN5A (the gene coding for the α-subunit of the most abundant sodium channel in the heart) and PKP2 (the gene coding for the desmosomal protein plakophilin-2), as well, is discussed in more detail.<br /><br /><br /><br /><small>Circulation: 12 Jan 2019; 140:595-610</small></div>

<div><h4>Paradigm of Sudden Death Prevention in Hypertrophic Cardiomyopathy.</h4><i>Maron BJ, Rowin EJ, Maron MS</i><br /><b></b><br />Hypertrophic cardiomyopathy (HCM) is a worldwide genetic heart disease and a common cause of sudden death in the young. Penetration of the implantable cardioverter-defibrillator (ICD) into this patient population over the past 20 years has made accurate selection of patients for primary prevention ICDs a priority. Consequently, a new paradigm has emerged in the management of this complex disease with ICD therapy responsible for a substantial decrease in overall HCM-related mortality (to 0.5%/y) and independent of patient age. Selection of candidates for ICDs has matured substantially with the formulation of an enhanced risk stratification algorithm. One or more contemporary risk markers judged major within a given patient\'s clinical profile, in association with physician judgment and shared decision-making, is sufficient to consider a primary prevention ICD implant. An enhanced American College of Cardiology/American Heart Association risk factor model (including new contrast-magnetic resonance-based markers, such as left ventricular apical aneurysm) used prospectively to make ICD decisions proved to be 95% sensitive for identifying patients who would experience ≥1 appropriate device therapies terminating ventricular tachycardia/fibrillation. The number of HCM patients required to treat with ICDs to save 1 patient with abolition of lethal ventricular tachyarrhythmias was 6:1, similar to randomized defibrillator trials in other cardiomyopathies. In contrast to patients with ischemic heart disease, after ICD shock HCM patients rarely experience transformation to heart failure deterioration or sudden arrhythmic death. The mathematically derived risk score model proposed by the European Society of Cardiology was inferior for identifying high-risk patients susceptible to arrhythmic sudden death with a sensitivity of only 33%, leaving many patients exposed to the possibility of sudden death without ICDs. In conclusion, introduction of the ICD associated with a matured risk stratification algorithm has altered management strategy and clinical course of many HCM patients, making the likelihood of sudden death prevention a reality and fulfilling the aspiration of preservation of life and reduced mortality for this vulnerable patient population.<br /><br /><br /><br /><small>Circ Res: 01 Jan 2019; 125:370-378</small></div>

<div><h4>Assessment of the Relationship Between Genetic Determinants of Thyroid Function and Atrial Fibrillation: A Mendelian Randomization Study.</h4><i>Ellervik C, Roselli C, Christophersen IE, Alonso A, ... Albert CM, Chasman DI</i><br /><b>Importance</b><br />Increased free thyroxine (FT4) and decreased thyrotropin are associated with increased risk of atrial fibrillation (AF) in observational studies, but direct involvement is unclear.<br /><b>Objective</b><br />To evaluate the potential direct involvement of thyroid traits on AF.<br /><b>Design, setting, and participants</b><br />Study-level mendelian randomization (MR) included 11 studies, and summary-level MR included 55 114 AF cases and 482 295 referents, all of European ancestry.<br /><b>Exposures</b><br />Genomewide significant variants were used as instruments for standardized FT4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT3):FT4 ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism. Mendelian randomization used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data.<br /><b>Main outcomes and measures</b><br />Prevalent and incident AF.<br /><b>Results</b><br />The study-level analysis included 7679 individuals with AF and 49 233 referents (mean age [standard error], 62 [3] years; 15 859 men [29.7%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT4 levels (nanograms per deciliter) for incident AF was 1.55 (95% CI, 1.09-2.20; P = .02; I2 = 76%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95% CI, 1.41-5.54; P = .003; I2 = 64%) in multivariable-adjusted analyses. The FT4 genetic risk score was associated with an increase in FT4 by 0.082 SD (standard error, 0.007; P < .001) but not with incident AF (risk ratio, 0.84; 95% CI, 0.62-1.14; P = .27) or prevalent AF (OR, 1.32; 95% CI, 0.64-2.73; P = .46). Similarly, in summary-level inverse-variance weighted random-effects MR, gene-based FT4 within the reference range was not associated with AF (OR, 1.01; 95% CI, 0.89-1.14; P = .88). However, gene-based increased FT3:FT4 ratio, increased thyrotropin within the reference range, and hypothyroidism were associated with AF with inverse-variance weighted random-effects OR of 1.33 (95% CI, 1.08-1.63; P = .006), 0.88 (95% CI, 0.84-0.92; P < .001), and 0.94 (95% CI, 0.90-0.99; P = .009), respectively, and robust to tests of horizontal pleiotropy. However, the subset of hypothyroidism single-nucleotide polymorphisms involved in autoimmunity and thyroid peroxidase antibodies levels were not associated with AF. Gene-based hyperthyroidism was associated with AF with MR-Egger OR of 1.31 (95% CI, 1.05-1.63; P = .02) with evidence of horizontal pleiotropy (P = .045).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Genetically increased FT3:FT4 ratio and hyperthyroidism, but not FT4 within the reference range, were associated with increased AF, and increased thyrotropin within the reference range and hypothyroidism were associated with decreased AF, supporting a pathway involving the pituitary-thyroid-cardiac axis.<br /><br /><br /><br /><small>JAMA Cardiol: 31 Dec 2018; 4:144-152</small></div>