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Competing Interests: Disclosures The authors have no conflicts of interest to disclose.

Fibrotic diseases affect multiple organs and are associated with morbidity and mortality. To examine organ-specific and shared biologic mechanisms that underlie fibrosis in different organs, we developed machine learning models to quantify T1 time, a marker of interstitial fibrosis, in the liver, pancreas, heart and kidney among 43,881 UK Biobank participants who underwent magnetic resonance imaging. In phenome-wide association analyses, we demonstrate the association of increased organ-specific T1 time, reflecting increased interstitial fibrosis, with prevalent diseases across multiple organ systems. In genome-wide association analyses, we identified 27, 18, 11 and 10 independent genetic loci associated with liver, pancreas, myocardial and renal cortex T1 time, respectively. There was a modest genetic correlation between the examined organs. Several loci overlapped across the examined organs implicating genes involved in a myriad of biologic pathways including metal ion transport (SLC39A8, HFE and TMPRSS6), glucose metabolism (PCK2), blood group antigens (ABO and FUT2), immune function (BANK1 and PPP3CA), inflammation (NFKB1) and mitosis (CENPE). Finally, we found that an increasing number of organs with T1 time falling in the top quintile was associated with increased mortality in the population. Individuals with a high burden of fibrosis in ≥3 organs had a 3-fold increase in mortality compared to those with a low burden of fibrosis across all examined organs in multivariable-adjusted analysis (hazard ratio = 3.31, 95% confidence interval 1.77-6.19; P = 1.78 × 10 -4 ). By leveraging machine learning to quantify T1 time across multiple organs at scale, we uncovered new organ-specific and shared biologic pathways underlying fibrosis that may provide therapeutic targets., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT)., Methods: We performed multiancestry meta-analyses of genome-wide association studies to identify genetic loci for AVNRT (4 studies) and AVAP/AVRT (7 studies). We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and examining prior genome-wide association studies., Results: Analyses comprised 2384 AVNRT cases and 106 489 referents, and 2811 AVAP/AVRT cases and 1,483 093 referents. We identified 2 significant loci for AVNRT, which implicate NKX2-5 and TTN as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of NKX2-5 and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate SCN5A , SCN10A , and TTN/CCDC141 . Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals., Conclusions: Our findings highlight gene regions associated with ion channel function (AVAP/AVRT), as well as cardiac development and the sarcomere (AVAP/AVRT and AVNRT) as important potential effectors of supraventricular tachycardia susceptibility., Competing Interests: Disclosures Dr Lubitz is a full-time employee of Novartis as of July 2022. Previously, Dr Lubitz received research support from Bristol Myers Squibb/Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, IBM, Medtronic, and Premier, Inc, and consulted for Bristol Myers Squibb/Pfizer, Bayer AG, Blackstone Life Sciences, and Invitae. Dr Ellinor receives research support from Bayer AG, IBM, and Bristol Myers Squibb/Pfizer and has consulted for Novartis, MyoKardia, and Bayer AG. Dr Damrauer receives research support for RenalytixAI and has consulted for Calico Labs. Dr Svendsen is a member of Medtronic advisory boards and has received speaker honoraria and research grants from Medtronic outside this work. Dr Cutler has consulted for Janssen Scientific. Dr Roselli is supported by a grant from Bayer AG to the Broad Institute focused on the development of therapeutics for cardiovascular disease. The other authors report no conflicts.

Background: Disorders affecting cardiac conduction are associated with substantial morbidity. Understanding the epidemiology and risk factors for conduction disorders may enable earlier diagnosis and preventive efforts., Objectives: The purpose of this study was to quantify contemporary frequency and risk factors for electrocardiogram (ECG)-defined cardiac conduction disorders in a large multi-institutional primary care sample., Methods: We quantified prevalence and incidence of conduction disorders among adults receiving longitudinal primary care between 2001 and 2019, each with at least one 12-lead ECG performed prior to the start of follow-up and at least one ECG during follow-up. We defined conduction disorders using curated terms extracted from ECG diagnostic statements by cardiologists. We grouped conduction disorders by inferred anatomic location of abnormal conduction. We tested associations between clinical factors and incident conduction disease using multivariable proportional hazards regression., Results: We analyzed 189,163 individuals (median age 55 years; 58% female). The overall prevalence of conduction disorders was 27% among men and 15% among women. Among 119,926 individuals (median age 55 years; 51% female), 6,802 developed an incident conduction system abnormality over a median of 10 years (Q1, Q3: 6, 15 years) of follow-up. Incident conduction disorders were more common in men (8.78 events/1,000 person-years) vs women (4.34 events/1,000 person-years, P  < 0.05). In multivariable models, clinical factors including older age (HR: 1.25 per 5-year increase [95% CI: 1.24-1.26]) and myocardial infarction (HR: 1.39 [95% CI: 1.26-1.54]) were associated with incident conduction disorders., Conclusions: Cardiac conduction disorders are common in a primary care population, especially among older individuals with cardiovascular risk factors., Competing Interests: Dr Lubitz is a full-time employee of Novartis as of July 2022. He received sponsored research support from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Fitbit, Medtronic, Premier, and IBM, and has consulted for Bristol Myers Squibb, Pfizer, Blackstone Life Sciences, and Invitae. Dr Ellinor receives sponsored research support from Bayer AG and IBM and has consulted for Novartis, MyoKardia, and Bayer AG. Dr Ho has received sponsored research support from Bayer AG. Dr Batra receives sponsored research support from Bayer AG and IBM and has consulted for Novartis and Prometheus Biosciences. Dr Philippakis is a Venture Partners and employee at GV, has consulted for Novartis and Rakuten, and receives sponsored research support from Verily, Microsoft, IBM, Intel, Pfizer, Abbvie, Biogen, Ionnis and Bayer. Investigators were supported by 10.13039/100000002National Institutes of Health grants K23HL169839-01 (Dr Khurshid), R38HL150212 (Dr Haimovich); R01HL139731 (Dr Lubitz), R01HL157635 (Dr Lubitz), R01HL134893 (Dr Ho), R01HL140224 (Dr Ho), K24HL153669 (Dr Ho), 2R01HL092577 (Dr Ellinor), and 1R01AG066010, R01HL092577 (Dr Benjamin); 10.13039/100000968American Heart Association grants 18SFRN34250007 (Dr Lubitz), AF 18SFRN34110082 (Dr Benjamin), 2023CDA1050571 (Dr Khurshid) and 18SFRN34110082 (Dr Ellinor); and by a grant from the European Union, MAESTRIA 965286 (Dr Ellinor). Dr Kornej has received funding from the 10.13039/100018694Marie Sklodowska-Curie Actions under the European Union’s 10.13039/100010661Horizon 2020 research and innovation programme (Agreement No 838259). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Increased left atrial volume and decreased left atrial function have long been associated with atrial fibrillation. The availability of large-scale cardiac magnetic resonance imaging data paired with genetic data provides a unique opportunity to assess the genetic contributions to left atrial structure and function, and understand their relationship with risk for atrial fibrillation. Here, we use deep learning and surface reconstruction models to measure left atrial minimum volume, maximum volume, stroke volume, and emptying fraction in 40,558 UK Biobank participants. In a genome-wide association study of 35,049 participants without pre-existing cardiovascular disease, we identify 20 common genetic loci associated with left atrial structure and function. We find that polygenic contributions to increased left atrial volume are associated with atrial fibrillation and its downstream consequences, including stroke. Through Mendelian randomization, we find evidence supporting a causal role for left atrial enlargement and dysfunction on atrial fibrillation risk., (© 2024. The Author(s).)

Competing Interests: Conflict of interest: P.N. reports research grants from Allelica, Apple, Amgen, Boston Scientific, Genentech/Roche, and Novartis; personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, and Novartis; scientific advisory board membership of Esperion Therapeutics, Preciseli, and TenSixteen Bio; scientific co-founder of TenSixteen Bio; equity in Preciseli and TenSixteen Bio; and spousal employment at Vertex Pharmaceuticals (all unrelated to the present work). M.C.H. reports consulting fees from CRISPR Therapeutics, advisory board service for Miga Health, and grant support from Genentech (all unrelated to this work).

Introduction: Pregnancy may contribute to an excess risk of thrombotic or cardiovascular events. COVID-19 increases the risk of these events, although the risk is relatively limited among outpatients. We sought to determine whether outpatient pregnant women with COVID-19 are at a high risk for cardiovascular or thrombotic events., Materials & Methods: We analyzed pregnant outpatients with COVID-19 from the multicenter CORONA-VTE-Network registry. The main study outcomes were a composite of adjudicated venous or arterial thrombotic events, and a composite of adjudicated cardiovascular events. Events were assessed 90 days after the COVID-19 diagnosis and reported for non-pregnant women ≤45 years, and for men ≤45 years, as points of reference., Results: Among 6585 outpatients, 169 were pregnant at diagnosis. By 90-day follow-up, two pregnant women during the third trimester had lower extremity venous thrombosis, one deep and one superficial vein thrombosis. The cumulative incidence of thrombotic events was 1.20 % (95 % confidence interval [CI]: 0.0 to 2.84 %). Respective rates were 0.47 % (95 % CI: 0.14 % to 0.79 %) among non-pregnant women, and 0.49 % (95 % CI: 0.06 % to 0.91 %) among men ≤45 years. No non-thrombotic cardiovascular events occurred in pregnant women. The rates of cardiovascular events were 0.53 % (95 % CI: 0.18 to 0.87) among non-pregnant women, and 0.68 % (95 % CI: 0.18 to 1.18) in men aged ≤45 years., Conclusions: Thrombotic and cardiovascular events are rare among outpatients with COVID-19. Although a higher event rate among outpatient pregnant women cannot be excluded, the absolute event rates are low and do not warrant population-wide cardiovascular interventions to optimize outcomes., Competing Interests: Declaration of competing interest Dr. Bikdeli is supported by a Career Development Award from the American Heart Association and VIVA Physicians (#938814). Dr. Bikdeli was supported by the Scott Schoen and Nancy Adams IGNITE Award and is supported by the Mary Ann Tynan Research Scientist award from the Mary Horrigan Connors Center for Women's Health and Gender Biology at Brigham and Women's Hospital to conduct sex-informed analyses of cardiovascular diseases, and the Heart and Vascular Center Junior Faculty Award from Brigham and Women's Hospital to understand the epidemiology and therapeutics for COVID-19-assocaited thrombosis. Dr. Bikdeli reports that he is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters (no involvement or financial compensation in 2022 or 2023), is a member of the Medical Advisory Board for North American Thrombosis Forum, and serves in the Data Safety and Monitory Board of the NAIL-IT trial funded by the National Heart, Lung, and Blood Institute, and Translational Sciences. Dr. Grandone has received consulting fees from Kedrion, Novo-Nordisk, Werfen, Techdow Pharma, Rovi and CSL-Behring. Drs. Bonaca, Hsia and Nehler receive salary support from CPC, a non-profit academic research organization affiliated with the University of Colorado, that receives or has received research grant/consulting funding between February 2021 and February 2023 from the following organizations: Abbott Laboratories, Adamis Pharmaceuticals Corporation, Agios Pharmaceuticals, Inc., Alexion Pharma, Alnylam Pharmaceuticals, Inc., Amgen Inc., Angionetics, Inc., ARCA Biopharma, Inc., Array BioPharma, Inc., AstraZeneca and Affiliates, Atentiv LLC, Audentes Therapeutics, Inc., Bayer and Affiliates, Beth Israel Deaconess Medical Center, Better Therapeutics, Inc., BIDMC, Boston Clinical Research Institute, Bristol-Meyers Squibb Company, Cambrian Biopharma, Inc., Cardiol Therapeutics Inc., CellResearch Corp., Cleerly Health, Cook Medical Incorporated, Covance, CSL Behring LLC, Eidos Therapeutics, Inc., EP Trading Co. Ltd., EPG Communication Holdings Ltd., Epizon Pharma, Inc., Esperion Therapeutics, Inc., Everly Well, Inc., Exicon Consulting Pvt. Ltd., Faraday Pharmaceuticals, Inc., Foresee Pharmaceuticals Co. Ltd., Fortress Biotech, Inc., HDL Therapeutics Inc., HeartFlow Inc., Hummingbird Bioscience, Insmed Inc., Ionis Pharmaceuticals, IQVIA Inc., JanOne Biotech Holdings Inc., Janssen and Affiliates, Kaneka, Kowa Research Institute, Inc., Kyushu University, Lexicon Pharmaceuticals, Inc., LSG Kyushu University, Medimmune Ltd., Medpace, Merck & Affiliates, Novartis Pharmaceuticals Corp., Novate Medical, Ltd., Novo Nordisk, Inc., Pan Industry Group, Pfizer Inc., PhaseBio Pharmaceuticals, Inc., PPD Development, LP, Prairie Education and Research Cooperative, Prothena Biosciences Limited, Regeneron Pharmaceuticals, Inc., Regio Biosciences, Inc., Rexgenero, Sanifit Therapeutics S.A., Sanofi-Aventis Groupe, Silence Therapeutics PLC, Smith & Nephew plc, Stealth BioTherapeutics Inc., State of Colorado CCPD Grant, The Brigham & Women's Hospital, Inc., The Feinstein Institutes for Medical Research, Thrombosis Research Institute, University of Colorado, University of Pittsburgh, VarmX, Virta Health Corporation, WCT Atlas, Worldwide Clinical Trials Inc., WraSer, LLC, and Yale Cardiovascular Research Group. Dr. Hsia also reports owning AstraZeneca stock. Dr. Bonaca receives support from the AHA SFRN under award numbers 18SFRN3390085 (BWH-DH SFRN Center) and 18SFRN33960262 (BWH-DH Clinical Project). Dr. Bonaca also reports stock in Medtronic and Pfizer. Dr. Sharma reports that he receives institutional grant funding from Boston Scientific Corporation and Vascular Medcure, is a board member for the Society for Vascular Medicine, and receives Speaking honoraria from Boston Scientific Corporation. Dr. Goldhaber reports research support from Bayer, BMS, Boston Scientific BTG EKOS, Janssen, NHLBI, and Pfizer, and consulting fees from Pfizer. Dr. Piazza has received research support from Bristol-Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen and Boston Scientific Corporation, and consulting fees from Bristol-Myers Squibb/Pfizer Alliance, Boston Scientific Corporation, Janssen, NAMSA, Penumbra, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen. The remaining authors have no Disclosures to report., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: Epicardial and pericardial adipose tissue (EPAT) has been associated with cardiovascular diseases such as atrial fibrillation or flutter (AF) and coronary artery disease (CAD), but studies have been limited in sample size or drawn from selected populations. It has been suggested that the association between EPAT and cardiovascular disease could be mediated by local or paracrine effects., Objective: To evaluate the association of EPAT with prevalent and incident cardiovascular disease and to elucidate the genetic basis of EPAT in a large population cohort., Design, Setting, and Participants: A deep learning model was trained to quantify EPAT area from 4-chamber magnetic resonance images using semantic segmentation. Cross-sectional and prospective cardiovascular disease associations were evaluated, controlling for sex and age. Prospective associations were additionally controlled for abdominal visceral adipose tissue (VAT) volumes. A genome-wide association study was performed, and a polygenic score (PGS) for EPAT was examined in independent FinnGen cohort study participants. Data analyses were conducted from March 2022 to December 2023., Exposures: The primary exposures were magnetic resonance imaging-derived continuous measurements of epicardial and pericardial adipose tissue area and visceral adipose tissue volume., Main Outcomes and Measures: Prevalent and incident CAD, AF, heart failure (HF), stroke, and type 2 diabetes (T2D)., Results: After exclusions, this study included 44 475 participants (mean [SD] age, 64.1 [7.7] years; 22 972 female [51.7%]) from the UK Biobank. Cross-sectional and prospective cardiovascular disease associations were evaluated for a mean (SD) of 3.2 (1.5) years of follow-up. Prospective associations were additionally controlled for abdominal VAT volumes for 38 527 participants. A PGS for EPAT was examined in 453 733 independent FinnGen cohort study participants. EPAT was positively associated with male sex (β = +0.78 SD in EPAT; P < 3 × 10-324), age (Pearson r = 0.15; P = 9.3 × 10-229), body mass index (Pearson r = 0.47; P < 3 × 10-324), and VAT (Pearson r = 0.72; P < 3 × 10-324). EPAT was more elevated in prevalent HF (β = +0.46 SD units) and T2D (β = +0.56) than in CAD (β = +0.23) or AF (β = +0.18). EPAT was associated with incident HF (hazard ratio [HR], 1.29 per +1 SD in EPAT; 95% CI, 1.17-1.43), T2D (HR, 1.63; 95% CI, 1.51-1.76), and CAD (HR, 1.19; 95% CI, 1.11-1.28). However, the associations were no longer significant when controlling for VAT. Seven genetic loci were identified for EPAT, implicating transcriptional regulators of adipocyte morphology and brown adipogenesis (EBF1, EBF2, and CEBPA) and regulators of visceral adiposity (WARS2 and TRIB2). The EPAT PGS was associated with T2D (odds ratio [OR], 1.06; 95% CI, 1.05-1.07; P =3.6 × 10-44), HF (OR, 1.05; 95% CI, 1.04-1.06; P =4.8 × 10-15), CAD (OR, 1.04; 95% CI, 1.03-1.05; P =1.4 × 10-17), AF (OR, 1.04; 95% CI, 1.03-1.06; P =7.6 × 10-12), and stroke in FinnGen (OR, 1.02; 95% CI, 1.01-1.03; P =3.5 × 10-3) per 1 SD in PGS., Conclusions and Relevance: Results of this cohort study suggest that epicardial and pericardial adiposity was associated with incident cardiovascular diseases, but this may largely reflect a metabolically unhealthy adiposity phenotype similar to abdominal visceral adiposity.

Background and Aims: Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion of blood cells with preleukemic mutations, is associated with atherosclerotic cardiovascular disease and heart failure. This study aimed to test the association of CHIP with new-onset arrhythmias., Methods: UK Biobank participants without prevalent arrhythmias were included. Co-primary study outcomes were supraventricular arrhythmias, bradyarrhythmias, and ventricular arrhythmias. Secondary outcomes were cardiac arrest, atrial fibrillation, and any arrhythmia. Associations of any CHIP [variant allele fraction (VAF) ≥ 2%], large CHIP (VAF ≥10%), and gene-specific CHIP subtypes with incident arrhythmias were evaluated using multivariable-adjusted Cox regression. Associations of CHIP with myocardial interstitial fibrosis [T1 measured using cardiac magnetic resonance (CMR)] were also tested., Results: This study included 410 702 participants [CHIP: n = 13 892 (3.4%); large CHIP: n = 9191 (2.2%)]. Any and large CHIP were associated with multi-variable-adjusted hazard ratios of 1.11 [95% confidence interval (CI) 1.04-1.18; P = .001] and 1.13 (95% CI 1.05-1.22; P = .001) for supraventricular arrhythmias, 1.09 (95% CI 1.01-1.19; P = .031) and 1.13 (95% CI 1.03-1.25; P = .011) for bradyarrhythmias, and 1.16 (95% CI, 1.00-1.34; P = .049) and 1.22 (95% CI 1.03-1.45; P = .021) for ventricular arrhythmias, respectively. Associations were independent of coronary artery disease and heart failure. Associations were also heterogeneous across arrhythmia subtypes and strongest for cardiac arrest. Gene-specific analyses revealed an increased risk of arrhythmias across driver genes other than DNMT3A. Large CHIP was associated with 1.31-fold odds (95% CI 1.07-1.59; P = .009) of being in the top quintile of myocardial fibrosis by CMR., Conclusions: CHIP may represent a novel risk factor for incident arrhythmias, indicating a potential target for modulation towards arrhythmia prevention and treatment., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Coronavirus disease 2019 (COVID-19) is associated with excess risk of cardiovascular and thrombotic events in the early post-infection period and during convalescence. Despite the progress in our understanding of cardiovascular complications, uncertainty persists with respect to more recent event rates, temporal trends, association between vaccination status and outcomes, and findings within vulnerable subgroups such as older adults (aged 65 years or older), or those undergoing hemodialysis. Sex-informed findings, including results among pregnant and breastfeeding women, as well as adjusted comparisons between male and female adults are similarly understudied., Methods: Adult patients, aged ≥18 years, with polymerase chain reaction-confirmed COVID-19 who received inpatient or outpatient care at the participating centers of the registry are eligible for inclusion. A total of 10,000 patients have been included in this multicenter study, with Brigham and Women's Hospital (Boston, MA) serving as the coordinating center. Other sites include Beth Israel Deaconess Medical Center, Anne Arundel Medical Center, University of Virginia Medical Center, University of Colorado Health System, and Thomas Jefferson University Health System. Data elements will be ascertained manually for accuracy. The two main outcomes are 1) a composite of venous or arterial thrombotic events, and 2) a composite of major cardiovascular events, defined as venous or arterial thrombosis, myocarditis or heart failure with inpatient treatment, new atrial fibrillation/flutter, or cardiovascular death. Clinical outcomes are adjudicated by independent physicians. Vaccination status and time of inclusion in the study will be ascertained for subgroup-specific analyses. Outcomes are pre-specified to be reported separately for hospitalized patients versus those who were initially receiving outpatient care. Outcomes will be reported at 30-day and 90-day follow-up. Data cleaning at the sites and the data coordinating center and outcomes adjudication process are in-progress., Conclusions: The CORONA-VTE-Network study will share contemporary information related to rates of cardiovascular and thrombotic events in patients with COVID-19 overall, as well as within key subgroups, including by time of inclusion, vaccination status, patients undergoing hemodialysis, the elderly, and sex-informed analyses such as comparison of women and men, or among pregnant and breastfeeding women., Competing Interests: Declaration of competing interest Dr. Bikdeli is supported by a Career Development Award from the American Heart Association and VIVA Physicians (#938814) for the PE-EHR+ study. Dr. Bikdeli was supported by the Scott Schoen and Nancy Adams IGNITE Award, and is supported by the Mary Ann Tynan Research Scientist award from the Mary Horrigan Connors Center for Women's Health and Gender Biology at Brigham and Women's Hospital, and the Heart and Vascular Center Junior Faculty Award from Brigham and Women's Hospital. Dr. Bikdeli reports that he is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters. Mr. Fanikos has served as a consultant to Pfizer, AstraZeneca, and Mallinckrodt. Drs. Bonaca, Hsia and Nehler receive salary support from CPC, a non-profit academic research organization affiliated with the University of Colorado, that receives or has received research grant/consulting funding between February 2021 and February 2023 from the following organizations: Abbott Laboratories, Adamis Pharmaceuticals Corporation, Agios Pharmaceuticals, Inc., Alexion Pharma, Alnylam Pharmaceuticals, Inc., Amgen Inc., Angionetics, Inc., ARCA Biopharma, Inc., Array BioPharma, Inc., AstraZeneca and Affiliates, Atentiv LLC, Audentes Therapeutics, Inc., Bayer and Affiliates, Beth Israel Deaconess Medical Center, Better Therapeutics, Inc., Boston Clinical Research Institute, Bristol-Meyers Squibb Company, Cambrian Biopharma, Inc., Cardiol Therapeutics Inc., CellResearch Corp., Cook Medical Incorporated, Covance, CSL Behring LLC, Eidos Therapeutics, Inc., EP Trading Co. Ltd., EPG Communication Holdings Ltd., Epizon Pharma, Inc., Esperion Therapeutics, Inc., Everly Well, Inc., Exicon Consulting Pvt. Ltd., Faraday Pharmaceuticals, Inc., Foresee Pharmaceuticals Co. Ltd., Fortress Biotech, Inc., HDL Therapeutics Inc., HeartFlow Inc., Hummingbird Bioscience, Insmed Inc., Ionis Pharmaceuticals, IQVIA Inc., JanOne Biotech Holdings Inc., Janssen and Affiliates, Kaneka, Kowa Research Institute, Inc., Kyushu University, Lexicon Pharmaceuticals, Inc., LSG Kyushu University, Medimmune Ltd., Medpace, Merck & Affiliates, Novartis Pharmaceuticals Corp., Novate Medical, Ltd., Novo Nordisk, Inc., Pan Industry Group, Pfizer Inc., PhaseBio Pharmaceuticals, Inc., PPD Development, LP, Prairie Education and Research Cooperative, Prothena Biosciences Limited, Regeneron Pharmaceuticals, Inc., Regio Biosciences, Inc., Rexgenero, Sanifit Therapeutics S.A., Sanofi-Aventis Groupe, Silence Therapeutics PLC, Smith & Nephew plc, Stealth BioTherapeutics Inc., State of Colorado CCPD Grant, The Brigham & Women's Hospital, Inc., The Feinstein Institutes for Medical Research, Thrombosis Research Institute, University of Colorado, University of Pittsburgh, VarmX, Virta Health Corporation, WCT Atlas, Worldwide Clinical Trials Inc., WraSer, LLC, and Yale Cardiovascular Research Group. Dr. Hsia also reports owning AstraZeneca stock. Dr. Bonaca receives support from the AHA SFRN under award numbers 18SFRN3390085 (BWH-DH SFRN Center) and 18SFRN33960262 (BWH-DH Clinical Project). Dr. Bonaca also reports stock in Medtronic and Pfizer. Dr. Sharma reports that he receives institutional grant funding from Boston Scientific Corporation and Vascular Medcure, is a board member for the Society for Vascular Medicine, and receives Speaking honoraria from Boston Scientific Corporation. Dr. Goldhaber reports research support from Bayer, BMS, Boston Scientific BTG EKOS, Janssen, NHLBI, and Pfizer, and consulting fees from Pfizer. Dr. Piazza has received research support from Bristol-Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, Esperion, Boston Scientific Corporation and the NHLBI (1R01HL164717–01), and consulting/advisory fees from BMS, Boston Scientific Corporation, Janssen, PERC, NAMSA, Regeneron, Penumbra, and Amgen., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Myocardial interstitial fibrosis is associated with cardiovascular disease and adverse prognosis. Here, to investigate the biological pathways that underlie fibrosis in the human heart, we developed a machine learning model to measure native myocardial T1 time, a marker of myocardial fibrosis, in 41,505 UK Biobank participants who underwent cardiac magnetic resonance imaging. Greater T1 time was associated with diabetes mellitus, renal disease, aortic stenosis, cardiomyopathy, heart failure, atrial fibrillation, conduction disease and rheumatoid arthritis. Genome-wide association analysis identified 11 independent loci associated with T1 time. The identified loci implicated genes involved in glucose transport (SLC2A12), iron homeostasis (HFE, TMPRSS6), tissue repair (ADAMTSL1, VEGFC), oxidative stress (SOD2), cardiac hypertrophy (MYH7B) and calcium signaling (CAMK2D). Using a transforming growth factor β1-mediated cardiac fibroblast activation assay, we found that 9 of the 11 loci consisted of genes that exhibited temporal changes in expression or open chromatin conformation supporting their biological relevance to myofibroblast cell state acquisition. By harnessing machine learning to perform large-scale quantification of myocardial interstitial fibrosis using cardiac imaging, we validate associations between cardiac fibrosis and disease, and identify new biologically relevant pathways underlying fibrosis., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Left ventricular mass is a risk marker for cardiovascular events, and may indicate an underlying cardiomyopathy. Cardiac magnetic resonance is the gold-standard for left ventricular mass estimation, but is challenging to obtain at scale. Here, we use deep learning to enable genome-wide association study of cardiac magnetic resonance-derived left ventricular mass indexed to body surface area within 43,230 UK Biobank participants. We identify 12 genome-wide associations (1 known at TTN and 11 novel for left ventricular mass), implicating genes previously associated with cardiac contractility and cardiomyopathy. Cardiac magnetic resonance-derived indexed left ventricular mass is associated with incident dilated and hypertrophic cardiomyopathies, and implantable cardioverter-defibrillator implant. An indexed left ventricular mass polygenic risk score ≥90 th percentile is also associated with incident implantable cardioverter-defibrillator implant in separate UK Biobank (hazard ratio 1.22, 95% CI 1.05-1.44) and Mass General Brigham (hazard ratio 1.75, 95% CI 1.12-2.74) samples. Here, we perform a genome-wide association study of cardiac magnetic resonance-derived indexed left ventricular mass to identify 11 novel variants and demonstrate that cardiac magnetic resonance-derived and genetically predicted indexed left ventricular mass are associated with incident cardiomyopathy., (© 2023. The Author(s).)

Background: Absence of a dicrotic notch on finger photoplethysmography is an easily ascertainable and inexpensive trait that has been associated with age and prevalent cardiovascular disease. However, the trait exists along a continuum, and little is known about its genetic underpinnings or prognostic value for incident cardiovascular disease., Methods: In 169 787 participants in the UK Biobank, we identified absent dicrotic notch on photoplethysmography and created a novel continuous trait reflecting notch smoothness using machine learning. Next, we determined the heritability, genetic basis, polygenic risk, and clinical relations for the binary absent notch trait and the newly derived continuous notch smoothness trait., Results: Heritability of the continuous notch smoothness trait was 7.5%, compared with 5.6% for the binary absent notch trait. A genome-wide association study of notch smoothness identified 15 significant loci, implicating genes including NT5C2 ( P =1.2×10 -26 ), IGFBP3 ( P =4.8×10 -18 ), and PHACTR1 ( P =1.4×10 -13 ), compared with 6 loci for the binary absent notch trait. Notch smoothness stratified risk of incident myocardial infarction or coronary artery disease, stroke, heart failure, and aortic stenosis. A polygenic risk score for notch smoothness was associated with incident cardiovascular disease and all-cause death in UK Biobank participants without available photoplethysmography data., Conclusions: We found that a machine learning derived continuous trait reflecting dicrotic notch smoothness on photoplethysmography was heritable and associated with genes involved in vascular stiffness. Greater notch smoothness was associated with greater risk of incident cardiovascular disease. Raw digital phenotyping may identify individuals at risk for disease via specific genetic pathways.

Physical activity is regarded as favorable to health but effects across the spectrum of human disease are poorly quantified. In contrast to self-reported measures, wearable accelerometers can provide more precise and reproducible activity quantification. Using wrist-worn accelerometry data from the UK Biobank prospective cohort study, we test associations between moderate-to-vigorous physical activity (MVPA) - both total MVPA minutes and whether MVPA is above a guideline-based threshold of ≥150 min/week-and incidence of 697 diseases using Cox proportional hazards models adjusted for age, sex, body mass index, smoking, Townsend Deprivation Index, educational attainment, diet quality, alcohol use, blood pressure, anti-hypertensive use. We correct for multiplicity at a false discovery rate of 1%. We perform analogous testing using self-reported MVPA. Among 96,244 adults wearing accelerometers for one week (age 62 ± 8 years), MVPA is associated with 373 (54%) tested diseases over a median 6.3 years of follow-up. Greater MVPA is overwhelmingly associated with lower disease risk (98% of associations) with hazard ratios (HRs) ranging 0.70-0.98 per 150 min increase in weekly MVPA, and associations spanning all 16 disease categories tested. Overall, associations with lower disease risk are enriched for cardiac (16%), digestive (14%), endocrine/metabolic (10%), and respiratory conditions (8%) (chi-square p < 0.01). Similar patterns are observed using the guideline-based threshold of ≥150 MVPA min/week. Some of the strongest associations with guideline-adherent activity include lower risks of incident heart failure (HR 0.65, 95% CI 0.55-0.77), type 2 diabetes (HR 0.64, 95% CI 0.58-0.71), cholelithiasis (HR 0.61, 95% CI 0.54-0.70), and chronic bronchitis (HR 0.42, 95% CI 0.33-0.54). When assessed within 456,374 individuals providing self-reported MVPA, effect sizes for guideline-adherent activity are substantially smaller (e.g., heart failure HR 0.84, 95% CI 0.80-0.88). Greater wearable device-based physical activity is robustly associated with lower disease incidence. Future studies are warranted to identify potential mechanisms linking physical activity and disease, and assess whether optimization of measured activity can reduce disease risk., (© 2022. The Author(s).)

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization., (© 2022. The Author(s).)

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity., (© 2022. The Author(s).)

Background: The left ventricular outflow tract (LVOT) and ascending aorta are spatially complex, with distinct pathologies and embryologic origins. Prior work examined the genetics of thoracic aortic diameter in a single plane., Objectives: We sought to elucidate the genetic basis for the diameter of the LVOT, aortic root, and ascending aorta., Methods: Using deep learning, we analyzed 2.3 million cardiac magnetic resonance images from 43,317 UK Biobank participants. We computed the diameters of the LVOT, the aortic root, and at 6 locations of ascending aorta. For each diameter, we conducted a genome-wide association study and generated a polygenic score. Finally, we investigated associations between these scores and disease incidence., Results: A total of 79 loci were significantly associated with at least 1 diameter. Of these, 35 were novel, and most were associated with 1 or 2 diameters. A polygenic score of aortic diameter approximately 13 mm from the sinotubular junction most strongly predicted thoracic aortic aneurysm (n = 427,016; mean HR: 1.42 per SD; 95% CI: 1.34-1.50; P = 6.67 × 10 -21 ). A polygenic score predicting a smaller aortic root was predictive of aortic stenosis (n = 426,502; mean HR: 1.08 per SD; 95% CI: 1.03-1.12; P = 5 × 10 -6 )., Conclusions: We detected distinct genetic loci underpinning the diameters of the LVOT, aortic root, and at several segments of ascending aorta. We spatially defined a region of aorta whose genetics may be most relevant to predicting thoracic aortic aneurysm. We further described a genetic signature that may predispose to aortic stenosis. Understanding genetic contributions to proximal aortic diameter may enable identification of individuals at risk for aortic disease and facilitate prioritization of therapeutic targets., Competing Interests: Funding Support and Author Disclosures This work was supported by the Fondation Leducq (14CVD01), and by grants from the National Institutes of Health (NIH) to Dr Pirruccello (K08HL159346), Dr Ellinor (1RO1HL092577, K24HL105780), and Dr Ho (R01HL134893, R01HL140224, K24HL153669). This work was also supported by a Sarnoff Cardiovascular Research Foundation Scholar Award to Dr Pirruccello. Dr Nauffal is supported by NIH grant 5T32HL007604-35. Dr Lubitz is supported by NIH grant R01HL139731 and American Heart Association 18SFRN34250007. This work was supported by a grant from the American Heart Association Strategically Focused Research Networks to Dr Ellinor. Dr Lindsay is supported by the Fredman Fellowship for Aortic Disease and the Toomey Fund for Aortic Dissection Research. This work was funded by a collaboration between the Broad Institute and IBM Research. Dr Pirruccello has served as a consultant for Maze Therapeutics. Dr Lubitz receives sponsored research support from Bristol Myers Squibb/Pfizer, Bayer AG, Boehringer Ingelheim, and Fitbit; has consulted for Bristol Myers Squibb/Pfizer and Bayer AG; and participates in a research collaboration with IBM. Dr Ng is employed by IBM Research. Dr Batra receives sponsored research support from Bayer AG and IBM; and has consulted for Novartis and Prometheus Biosciences. Dr Ho has received research grant support from Bayer AG focused on machine learning and cardiovascular disease; and has received research supplies from EcoNugenics. Dr Philippakis is supported by a grant from Bayer AG to the Broad Institute focused on machine learning for clinical trial design. Dr Ellinor has received sponsored research support from Bayer AG and from IBM Research; and has served on advisory boards or consulted for Bayer AG, MyoKardia, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Genetic variants in LMNA may cause cardiac disease, but population-level contributions of variants to cardiac disease burden are not well-characterized., Objectives: We sought to determine the frequency and contribution of rare LMNA variants to cardiomyopathy and arrhythmia risk among ambulatory adults., Methods: We included 185,990 UK Biobank participants with whole-exome sequencing. We annotated rare loss-of-function and missense LMNA variants for functional effect using 30 in silico prediction tools. We assigned a predicted functional effect weight to each variant and calculated a score for each carrier. We tested associations between the LMNA score and arrhythmia (atrial fibrillation, bradyarrhythmia, ventricular arrhythmia) or cardiomyopathy outcomes (dilated cardiomyopathy and heart failure). We also examined associations for variants located upstream vs downstream of the nuclear localization signal., Results: Overall, 1,167 (0.63%) participants carried an LMNA variant and 15,079 (8.11%) had an arrhythmia or cardiomyopathy event during a median follow-up of 10.9 years. The LMNA score was associated with arrhythmia or cardiomyopathy (OR: 2.21; P < 0.001) and the association was more significant when restricted to variants upstream of the nuclear localization signal (OR: 5.05; P < 0.001). The incidence rate of arrhythmia or cardiomyopathy was 8.43 per 1,000 person-years (95% CI: 6.73-10.12 per 1,000 person-years) among LMNA variant carriers and 6.38 per 1,000 person-years (95% CI: 6.27-6.50 per 1,000 person-years) among noncarriers. Only 3 (1.2%) of the variants were reported as pathogenic in ClinVar., Conclusions: Middle-aged adult carriers of rare missense or loss-of-function LMNA variants are at increased risk for arrhythmia and cardiomyopathy., Competing Interests: Fundings Support and Author Disclosures Dr Lazarte is supported by the Canadian Institutes of Health Research (Doctoral Research Award) and the Canada Graduate Scholarships-Michael Smith Foreign Study Supplements. Dr Jurgens is supported by student scholarships from the Dutch Heart Foundation (Hartstichting Nederland) and the Amsterdams Universiteitsfonds. Dr Weng has received sponsored research support from IBM to the Broad Institute. Dr Nauffal is funded by a training grant from the National Institutes of Health (T32HL007604). Dr Ellinor is supported by the National Institutes of Health (1R01HL092577, K24HL105780), American Heart Association (18SFRN34110082), Foundation Leducq (14CVD01), and MAESTRIA (965286); has received sponsored research support from Bayer AG and IBM Health; and has consulted for Bayer AG, Novartis, and MyoKardia. Dr Lubitz is supported by National Institutes of Health grants 1R01HL139731 and R01HL157635 and American Heart Association 18SFRN34250007; receives sponsored research support from Bristol Myers Squibb/Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, and IBM; and has consulted for Bristol Myers Squibb/Pfizer, Blackstone Life Sciences, and Invitae. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Congenital heart diseases often involve maldevelopment of the evolutionarily recent right heart chamber. To gain insight into right heart structure and function, we fine-tuned deep learning models to recognize the right atrium, right ventricle and pulmonary artery, measuring right heart structures in 40,000 individuals from the UK Biobank with magnetic resonance imaging. Genome-wide association studies identified 130 distinct loci associated with at least one right heart measurement, of which 72 were not associated with left heart structures. Loci were found near genes previously linked with congenital heart disease, including NKX2-5, TBX5/TBX3, WNT9B and GATA4. A genome-wide polygenic predictor of right ventricular ejection fraction was associated with incident dilated cardiomyopathy (hazard ratio, 1.33 per standard deviation; P = 7.1 × 10 -13 ) and remained significant after accounting for a left ventricular polygenic score. Harnessing deep learning to perform large-scale cardiac phenotyping, our results yield insights into the genetic determinants of right heart structure and function., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: 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 variations to the QT interval in the population., Methods: We performed a genome-wide association study of the QTc in 84 630 UK Biobank participants and created a polygenic risk score (PRS). Among 26 976 participants with whole-genome sequencing and ECG data in the TOPMed (Trans-Omics for Precision Medicine) 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., Results: Fifty-four independent loci were identified by genome-wide association study in the UK Biobank. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS composed of 1 110 494 common variants was significantly associated with the QTc in TOPMed (ΔQTc /decile of PRS =1.4 ms [95% CI, 1.3 to 1.5]; P =1.1×10 -196 ). Carriers of putative pathogenic rare variants had longer QTc than noncarriers (ΔQTc=10.9 ms [95% CI, 7.4 to 14.4]). Of individuals with QTc>480 ms, 23.7% carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS)., Conclusions: 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.

Aims: Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder., Methods and Results: We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors., Conclusion: We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-β signalling molecules and spectrin β. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cardiometabolic diseases are the leading cause of death worldwide. Despite a known genetic component, our understanding of these diseases remains incomplete. Here, we analyzed the contribution of rare variants to 57 diseases and 26 cardiometabolic traits, using data from 200,337 UK Biobank participants with whole-exome sequencing. We identified 57 gene-based associations, with broad replication of novel signals in Geisinger MyCode. There was a striking risk associated with mutations in known Mendelian disease genes, including MYBPC3, LDLR, GCK, PKD1 and TTN. Many genes showed independent convergence of rare and common variant evidence, including an association between GIGYF1 and type 2 diabetes. We identified several large effect associations for height and 18 unique genes associated with blood lipid or glucose levels. Finally, we found that between 1.0% and 2.4% of participants carried rare potentially pathogenic variants for cardiometabolic disorders. These findings may facilitate studies aimed at therapeutics and screening of these common disorders., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background Myocardial injury in patients with COVID-19 is associated with increased mortality during index hospitalization; however, the relationship to long-term sequelae of SARS-CoV-2 is unknown. This study assessed the relationship between myocardial injury (high-sensitivity cardiac troponin T level) during index hospitalization for COVID-19 and longer-term outcomes. Methods and Results This is a prospective cohort of patients who were hospitalized at a single center between March and May 2020 with SARS-CoV-2. Cardiac biomarkers were systematically collected. Outcomes were adjudicated and stratified on the basis of myocardial injury. The study cohort includes 483 patients who had high-sensitivity cardiac troponin T data during their index hospitalization. During index hospitalization, 91 (18.8%) died, 70 (14.4%) had thrombotic complications, and 126 (25.6%) had cardiovascular complications. By 12 months, 107 (22.2%) died. During index hospitalization, 301 (62.3%) had cardiac injury (high-sensitivity cardiac troponin T≧14 ng/L); these patients had 28.6%, 32.2%, and 33.2% mortality during index hospitalization, at 6 months, and at 12 months, respectively, compared with 4.1%, 4.9%, and 4.9% mortality for those with low-level positive troponin and 0%, 0%, and 0% for those with undetectable troponin. Of 392 (81.2%) patients who survived the index hospitalization, 94 (24%) had at least 1 readmission within 12 months, of whom 61 (65%) had myocardial injury during the index hospitalization. Of 377 (96%) patients who were alive and had follow-up after the index hospitalization, 211 (56%) patients had a documented, detailed clinical assessment at 6 months. A total of 78 of 211 (37.0%) had ongoing COVID-19-related symptoms; 34 of 211 (16.1%) had neurocognitive decline, 8 of 211 (3.8%) had increased supplemental oxygen requirements, and 42 of 211 (19.9%) had worsening functional status. Conclusions Myocardial injury during index hospitalization for COVID-19 was associated with increased mortality and may predict who are more likely to have postacute sequelae of COVID-19. Among patients who survived their index hospitalization, the incremental mortality through 12 months was low, even among troponin-positive patients.

Background: Treatment guidelines for nonvalvular atrial fibrillation (AF) recommend use of non-vitamin K antagonist oral anticoagulants (NOACs) over warfarin, yet clinical trials excluded individuals with post cardiac surgery AF. We sought to compare outcomes with NOACs vs warfarin for new onset post cardiac surgery AF., Methods: We examined 26,522 patients from The Society of Thoracic Surgeons' database with post cardiac surgery AF who were discharged on oral anticoagulation from July 2017-December 2018. Three primary outcomes were evaluated: 30-day mortality, major bleeding complications, and stroke/transient ischemic attack. Secondary outcomes included postoperative length of stay, 30-day myocardial infarction, venous thromboembolism, and pericardial effusion/tamponade., Results: A total of 9769 (36.8%) participants were prescribed NOACs and 16,753 (63.2%) warfarin. In multivariable analysis, there was no association between type of anticoagulant and 30-day major bleeding complications (odds ratio [OR] NOAC/warfarin 0.76, 95% confidence interval [CI] 0.49-1.18), stroke/transient ischemic attack (OR NOAC/warfarin 0.94, 95% CI 0.53-1.67) or mortality (OR NOAC/warfarin 1.08, 95% CI 0.80-1.45). After stratification by renal function or isolated coronary bypass vs valve surgery, there remained no difference in the primary outcomes. Additionally, there was no difference in 30-day myocardial infarction (OR NOAC/warfarin 1.17, 95% CI 0.62-2.22), venous thromboembolism (OR NOAC/warfarin 0.91, 95% CI 0.47-1.78), or pericardial effusion/tamponade (OR NOAC/warfarin 1.09, 95% CI 0.80-1.47) between the 2 groups. NOAC therapy was associated with a half-day reduction in postoperative length of stay (β NOAC/warfarin -0.47, 95% CI -0.62 to -0.33)., Conclusions: NOACs are associated with a reduction in postoperative length of stay, without excess bleeding or other short-term complications, compared with warfarin. These findings support the broader use of NOACs as a safe alternative to warfarin in patients with post cardiac surgery AF at elevated stroke risk and acceptable bleeding risk., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Aims: Risk stratification algorithms for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) and regional differences in clinical practice have evolved over time. We sought to compare primary prevention implantable cardioverter defibrillator (ICD) implantation rates and associated clinical outcomes in US vs. non-US tertiary HCM centres within the international Sarcomeric Human Cardiomyopathy Registry., Methods and Results: We included patients with HCM enrolled from eight US sites (n = 2650) and five non-US (n = 2660) sites and used multivariable Cox-proportional hazards models to compare outcomes between sites. Primary prevention ICD implantation rates in US sites were two-fold higher than non-US sites (hazard ratio (HR) 2.27 [1.89-2.74]), including in individuals deemed at high 5-year SCD risk (≥6%) based on the HCM risk-SCD score (HR 3.27 [1.76-6.05]). US ICD recipients also had fewer traditional SCD risk factors. Among ICD recipients, rates of appropriate ICD therapy were significantly lower in US vs. non-US sites (HR 0.52 [0.28-0.97]). No significant difference was identified in the incidence of SCD/resuscitated cardiac arrest among non-recipients of ICDs in US vs. non-US sites (HR 1.21 [0.74-1.97])., Conclusion: Primary prevention ICDs are implanted more frequently in patients with HCM in US vs. non-US sites across the spectrum of SCD risk. There was a lower rate of appropriate ICD therapy in US sites, consistent with a lower-risk population, and no significant difference in SCD in US vs. non-US patients who did not receive an ICD. Further studies are needed to understand what drives malignant arrhythmias, optimize ICD allocation, and examine the impact of different ICD utilization strategies on long-term outcomes in HCM., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Cardiovascular complications have been reported in patients with COVID-19. We sought to examine the association of ABO blood group type with cardiovascular complications in COVID-19. We examined 409 individuals enrolled in the COVID-19 Registry to Assess Frequency, Management, and Outcomes of Arterial and Venous Thromboembolic Complications (CORONA-VTE) who had ABO blood group data available. Multiple logistic regression was used to assess the association of ABO blood group types with three primary outcomes: major adverse cardiovascular events (MACE), major arterial and venous thrombosis and all-cause mortality. 201, 121, 61 and 26 individuals had blood group O, A, B and AB, respectively. In multivariable analysis, blood group A was associated with a 2.5-fold higher odds of MACE than blood group O (OR 2.47[1.18-5.18]). There was an effect suggesting a 2-fold higher odds of major thrombotic events in blood group A vs. O that did not reach statistical significance (OR 2.15 [0.89-5.20]). No association between blood group type and all-cause mortality was found. Compared with the other blood group types, blood group A was associated with an increased odds of MACE(OR A/non-A 2.18[1.11-4.29]), while blood group O was associated with lower odds of MACE(OR O/non-O 0.50[0.26-0.97]). In conclusion, blood group A was associated with an increased odds of MACE, whereas blood group O was associated with a reduction in the odds of MACE in patients with COVID-19. These findings may inform risk stratification of COVID-19 patients for cardiovascular complications. Additional studies are needed to validate our findings.

Background: Surgical aortic valve replacement (SAVR) is associated with adverse outcomes in patients with radiation-associated aortic stenosis. Transcatheter aortic valve replacement (TAVR) may improve outcomes in this population., Methods: We evaluated 1668 TAVR and 2611 patients with SAVR enrolled in the Society of Thoracic Surgeons' database between 2011 and 2018. Multiple logistic regression was used to compare 30- day outcomes between TAVR and SAVR. Propensity-matched analysis was performed to confirm results of the overall cohort. Additionally, the cohort was stratified into early (2011-2014) versus contemporary (2015-2018) TAVR eras, and 30-day outcomes for TAVR and SAVR were compared. Finally, outcomes with transfemoral TAVR versus SAVR were compared., Results: In the overall cohort, TAVR was associated with significantly reduced 30-day mortality (odds ratio [OR] TAVR/SAVR =0.60 [0.40-0.91]). Postoperative atrial fibrillation, pneumonia, pleural effusion, renal failure, and bleeding also occurred less frequently with TAVR. Stroke/transient ischemic attack (TIA; OR TAVR/SAVR , 2.03 [1.09-3.77]) and pacemaker implantation (OR TAVR/SAVR , 1.62 [1.21-2.17]) were higher with TAVR. Propensity-matched analysis yielded similar results as the overall cohort. Following stratification by era, TAVR versus SAVR was associated with reduced 30-day mortality in the contemporary but not early era (OR Early , 0.78 [0.48-1.28]; OR Contemporary , 0.31 [0.14-0.65]). Pacemaker implantation was higher with TAVR versus SAVR in both eras (OR Early , 1.60 [1.03-2.46]; OR Contemporary , 1.64 [1.10-2.45]). There was also a nonsignificant trend towards increased stroke/TIA with TAVR during both eras (OR Early , 1.39 [0.58-3.36]; OR Contemporary , 2.46 [0.99-6.10]). Finally, transfemoral TAVR (N=1369) versus SAVR revealed similar findings as the overall cohort; however, the association of TAVR with stroke/TIA was not statistically significant (OR Stroke/TIA , 1.57 [0.79-3.09])., Conclusions: TAVR provides an effective and evolving alternative to SAVR for radiation-associated severe aortic stenosis and was associated with lower 30-day mortality and postoperative complications. TAVR was associated with increased pacemaker implantation and a trend towards increased stroke/TIA. In this unique population with extensive valvular and vascular calcifications, the risk of stroke/TIA with TAVR requires careful consideration and further investigation.

Background: Cardiovascular complications, including myocardial infarction, ischemic stroke, and pulmonary embolism, represent an important source of adverse outcomes in coronavirus disease-2019 (COVID-19)., Objectives: To assess the frequency of arterial and venous thromboembolic disease, risk factors, prevention and management patterns, and outcomes in patients with COVID-19, the authors designed a multicenter, observational cohort study., Methods: We analyzed a retrospective cohort of 1,114 patients with COVID-19 diagnosed through our Mass General Brigham integrated health network. The total cohort was analyzed by site of care: intensive care (n = 170); hospitalized nonintensive care (n = 229); and outpatient (n = 715). The primary study outcome was a composite of adjudicated major arterial or venous thromboembolism., Results: Patients with COVID-19 were 22.3% Hispanic/Latinx and 44.2% non-White. Cardiovascular risk factors of hypertension (35.8%), hyperlipidemia (28.6%), and diabetes (18.0%) were common. Prophylactic anticoagulation was prescribed in 89.4% of patients with COVID-19 in the intensive care cohort and 84.7% of those in the hospitalized nonintensive care setting. Frequencies of major arterial or venous thromboembolism, major cardiovascular adverse events, and symptomatic venous thromboembolism were highest in the intensive care cohort (35.3%, 45.9%, and 27.0 %, respectively) followed by the hospitalized nonintensive care cohort (2.6%, 6.1%, and 2.2%, respectively) and the outpatient cohort (0% for all)., Conclusions: Major arterial or venous thromboembolism, major adverse cardiovascular events, and symptomatic venous thromboembolism occurred with high frequency in patients with COVID-19, especially in the intensive care setting, despite a high utilization rate of thromboprophylaxis., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Coronavirus disease-2019 (COVID-19), a contagious disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has reached pandemic status. As it spreads across the world, it has overwhelmed health care systems, strangled the global economy, and led to a devastating loss of life. Widespread efforts from regulators, clinicians, and scientists are driving a rapid expansion of knowledge of the SARS-CoV-2 virus and COVID-19. The authors review the most current data, with a focus on the basic understanding of the mechanism(s) of disease and translation to the clinical syndrome and potential therapeutics. The authors discuss the basic virology, epidemiology, clinical manifestation, multiorgan consequences, and outcomes. With a focus on cardiovascular complications, they propose several mechanisms of injury. The virology and potential mechanism of injury form the basis for a discussion of potential disease-modifying therapies., (© 2020 Published by Elsevier on behalf of the American College of Cardiology Foundation.)

Inflammation promotes adverse ventricular remodeling. T1 mapping has been used to noninvasively assess interstitial myocardial fibrosis. We examined the association of baseline markers of systemic inflammation with interstitial myocardial fibrosis measured by extracellular volume fraction (ECV) and native T1 mapping at 10-year follow-up in the MESA (Multi-Ethnic Study of Atherosclerosis). Seven hundred seventy-two participants had complete baseline data and underwent cardiac magnetic resonance imaging. All analyses were stratified by sex. Multivariable linear regression models were constructed to assess the associations of baseline CRP (C-reactive protein), IL (interleukin)-6, and fibrinogen with native T1 time and ECV. Longer native T1 times and higher percentages of ECV represent increasing myocardial fibrosis. A 1-SD increment of log-transformed IL-6 levels was associated with 0.4% higher ECV in men (β=0.4; P=0.05). CRP and fibrinogen were not associated to ECV. A 1-SD increment in the log-transformed CRP levels was associated with 4.9 ms higher native T1 (β=4.9; P=0.03). In women, the inflammatory markers did not demonstrate association with native T1 nor ECV. Higher IL-6 and CRP levels are associated with increased interstitial myocardial fibrosis assessed by cardiac magnetic resonance in men. However, no inflammatory markers were associated to myocardial fibrosis in women.

Background: Cardiac resynchronization therapy (CRT) devices reduce mortality through pacing-induced cardiac resynchronization and implantable cardioverter defibrillator (ICD) therapy for ventricular arrhythmias (VAs). Whether certain factors can predict if patients will benefit more from implantation of CRT pacemakers (CRT-P) or CRT defibrillators (CRT-D) remains unclear., Methods and Results: We followed 305 primary prevention CRT-D recipients for the two primary outcomes of HF hospitalization and ICD therapy for VAs. Serum biomarkers, electrocardiographic and clinical variables were collected prior to implant. Multivariable analysis using Cox-proportional hazards model was used to fit the final models. Among 282 patients with follow-up outcome data, 75 (26.6%) were hospitalized for HF and 31 (11%) received appropriate ICD therapy. Independent predictors of HF hospitalization were atrial fibrillation (HR = 1.8 (1.1,2.9)), NYHA class III/IV (HR = 2.2 (1.3,3.6)), ejection fraction <20% (HR = 1.7 (1.1,2.7)), HS-IL6 >4.03pg/ml (HR = 1.7 (1.1,2.9)) and hemoglobin (<12g/dl) (HR = 2.2 (1.3,3.6)). Independent predictors of appropriate therapy included BUN >20mg/dL (HR = 3.0 (1.3,7.1)), HS-CRP >9.42mg/L (HR = 2.3 (1.1,4.7)), no beta blocker therapy (HR = 3.2 (1.4,7.1)) and hematocrit ≥38% (HR = 2.7 (1.03,7.0)). Patients with 0-1 risk factors for appropriate therapy (IR 1 per 100 person-years) and ≥3 risk factors for HF hospitalization (IR 23 per 100-person-years) were more likely to die prior to receiving an appropriate ICD therapy., Conclusions: Clinical and biomarker data can risk stratify CRT patients for HF progression and VAs. These findings may help characterize subgroups of patients that may benefit more from the use of CRT-P vs. CRT-D systems., Trial Registration: ClinicalTrials.gov NCT00733590.

Background: Peripheral artery disease (PAD) is important to public health as a major contributor to cardiovascular morbidity and mortality. Recent developments in magnetic resonance imaging (MRI) techniques permit improved assessment of PAD anatomy and physiology, and may serve as surrogate end points after proangiogenic therapies., Methods: The PACE study is a randomized, double-blind, placebo-controlled clinical trial designed to assess the physiologic impact and potential clinical efficacy of autologous bone marrow-derived ALDH br stem cells. The primary MRI end points of the study are as follows: (1) total collateral count, (2) calf muscle plasma volume (a measure of capillary perfusion) by dynamic contrast-enhanced MRI, and (3) peak hyperemic popliteal flow by phase-contrast MRI (PC-MRI)., Results: The interreader and intrareader and test-retest results demonstrated good-to-excellent reproducibility (interclass correlation coefficient range 0.61-0.98) for all magnetic resonance measures. The PAD participants (n=82) had lower capillary perfusion measured by calf muscle plasma volume (3.8% vs 5.6%) and peak hyperemic popliteal flow (4.1 vs 13.5mL/s) as compared with the healthy participants (n=16), with a significant level of collateralization., Conclusions: Reproducibility of the MRI primary end points in PACE was very good to excellent. The PAD participants exhibited decreased calf muscle capillary perfusion as well as arterial flow reserve when compared with healthy participants. The MRI tools used in PACE may advance PAD science by enabling accurate measurement of PAD microvascular anatomy and perfusion before and after stem cell or other PAD therapies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Red blood cell transfusion after coronary artery bypass graft surgery has been associated with increased late all-cause death. Yet, whether this association is, first, independent of the packed red blood cells and perioperative morbidity association, and second, of a cardiac versus noncardiac etiology remains unknown., Methods: We analyzed patients undergoing coronary artery bypass graft surgery at two Ohio hospitals (n = 6,947) from 1994 to 2007. Salvage operations and patients with preoperative renal failure were excluded. Long-term outcomes and leading cause of death (cardiac, noncardiac, all cause) were derived from the US Social Security Death Index and later from Ohio Department of Health Death Index. Fifteen-year mortality cumulative incidence functions were compared for transfusion groups (yes, n = 2,540; no, n = 4,806) overall, and then stratified based on perioperative complications status (yes, n = 2,638; no, n = 4,708). Comprehensive, 32 covariates, risk-adjusted transfusion effects were estimated by competing risk regression. Results were confirmed by propensity score adjusted analysis., Results: Perioperative transfusions and complications occurred in 33.9% and 35.2% of patients, respectively. In all, 3,108 deaths (48.1%) have been documented (median time to death, 7.43 years). Both transfusion rates (25.6% versus 49.1%, p < 0.001) and deaths (58.2% versus 38.5%, p < 0.001) were more frequent among complications patients. Red blood cells transfusion increased intermediate to late mortality risk overall (15-year adjusted hazard ratio [AHR] 1.21, 95% confidence interval [CI]: 1.11 to 1.31), and for complications (AHR 1.24, 95% CI: 1.11 to 1.39) and no complications (AHR 1.16, 95% CI: 1.03 to 1.31). The increased mortality was true for cardiac and noncardiac etiologies (AHR 1.19, 95% CI: 1.03 to 1.36, and AHR 1.14, 95% CI: 1.01 to 1.29, respectively). Red blood cell transfusion increased mostly cardiac deaths (AHR 1.38, 95% CI: 1.14 to 1.66) among the complications group, and noncardiac mortality (AHR 1.24, 95% CI: 1.05 to 1.47) for the no complications group. A parallel propensity matched sensitivity analysis confirmed these findings., Conclusions: Perioperative red blood cells transfusion is associated with significant adverse late death effects among both complicated patients and noncomplicated patients, principally seen between 0 and 5 years postoperatively, and is driven by both increased cardiovascular and noncardiovascular mortality. Further studies are needed to elucidate the mechanisms behind these findings, including their potential dose dependence., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality among individuals with dyssynchronous systolic heart failure (HF). However, patient outcomes vary, with some at higher risk than others for HF progression and death., Objective: To develop a risk prediction score incorporating variables associated with mortality, left ventricular assist device (LVAD) implant, or heart transplant in recipients of a primary prevention cardiac resynchronization therapy-defibrillator (CRT-D)., Methods: We followed 305 CRT-D patients from the Prospective Observational Study of Implantable Cardioverter-Defibrillators for the composite outcome of all-cause mortality, LVAD implant, or heart transplant soon after device implantation. Serum biomarkers and electrocardiographic and clinical variables were collected at implant. Multivariable analysis using the Cox proportional hazards model with stepwise selection method was used to fit the final model., Results: Among 305 patients, 53 experienced the composite endpoint. In multivariable analysis, 5 independent predictors ("HF-CRT") were identified: high-sensitivity C-reactive protein >9.42 ng/L (HR = 2.5 [1.4, 4.5]), New York Heart Association functional class III/IV (HR = 2.3 [1.2, 4.5]), creatinine >1.2 mg/dL (HR = 2.7 [1.4, 5.1]), red blood cell count <4.3 × 10(6)/μL (HR = 2.4 [1.3, 4.7]), and cardiac troponin T >28 ng/L (HR = 2.7 [1.4, 5.2]). One point was attributed to each predictor and 3 score categories were identified. Patients with scores 0-1, 2-3, and 4-5 had a 3-year cumulative event-free survival of 96.8%, 79.7%, and 35.2%, respectively (log-rank, P < .001)., Conclusion: A simple score combining clinical and readily available biomarker data can risk-stratify CRT patients for HF progression and death. These findings may help identify patients who are in need of closer monitoring or early application of more aggressive circulatory support., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure patients with primary prevention implantable cardioverter-defibrillators (ICD) may experience an improvement in left ventricular ejection fraction (LVEF) over time. However, it is unclear how LVEF improvement affects subsequent risk for mortality and sudden cardiac death., Objectives: This study sought to assess changes in LVEF after ICD implantation and the implication of these changes on subsequent mortality and ICD shocks., Methods: We conducted a prospective cohort study of 538 patients with repeated LVEF assessments after ICD implantation for primary prevention of sudden cardiac death. The primary endpoint was appropriate ICD shock defined as a shock for ventricular tachyarrhythmias. The secondary endpoint was all-cause mortality., Results: Over a mean follow-up of 4.9 years, LVEF decreased in 13.0%, improved in 40.0%, and was unchanged in 47.0% of the patients. In the multivariate Cox models comparing patients with an improved LVEF with those with an unchanged LVEF, the hazard ratios were 0.33 (95% confidence interval: 0.18 to 0.59) for mortality and 0.29 (95% confidence interval: 0.11 to 0.78) for appropriate shock. During follow-up, 25% of patients showed an improvement in LVEF to >35% and their risk of appropriate shock decreased but was not eliminated., Conclusions: Among primary prevention ICD patients, 40.0% had an improved LVEF during follow-up and 25% had LVEF improved to >35%. Changes in LVEF were inversely associated with all-cause mortality and appropriate shocks for ventricular tachyarrhythmias. In patients whose follow-up LVEF improved to >35%, the risk of an appropriate shock remained but was markedly decreased., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: Recent studies have indicated that coronary artery bypass grafting (CABG) outcomes in patients with prior stents are suboptimal. We aimed to study the impact of prior percutaneous coronary intervention (PCI) with stenting (PCI-S) on late CABG mortality in diabetic patients with triple-vessel disease., Methods: We reviewed the primary nonemergency CABG experience from a single U.S. institution (n = 7005; 1996-2007, Toledo, Ohio). Diabetics with triple-vessel disease (n = 1583) were identified and divided into 2 groups: (1) prior PCI-S (n = 202); and (2) no prior PCI (No-PCI [n = 1381]). Hierarchic Cox proportional hazards models were used to assess the effect of prior PCI-S on 5-year mortality after CABG. A propensity score for PCI-S and No-PCI patients was derived using a nonparsimonious logistic regression and used to generate a 1:1 (PCI-S to No-PCI) matched cohort., Results: In model 1, after adjusting for preoperative clinical characteristics, medications, off-pump surgery, and isolated CABG surgery status, prior PCI-S was associated with a 39% increased risk of mortality (hazard ratio [HR] = 1.39, with 95% confidence interval [CI; 1.02, 1.90]; P = .04). Further adjustment for date of surgery (model 2) (HR = 1.39, with 95% CI [1.02, 1.91]; P = .04) or operative parameters (model 3) (HR = 1.38, with 95% CI [1.01, 1.88]; P = .046) did not alter the association. The 1:1 matched-cohort analysis confirmed the increased risk associated with PCI-S (HR = 1.61, with 95% CI [1.03, 2.51]; P = .037)., Conclusions: Patients who have both diabetes and triple-vessel disease, and have undergone prior PCI-S, have poorer long-term outcomes after CABG compared with those who have had no prior PCI-S., (Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)