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Competing Interests: None.

Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia. Comprehensive modification of established AF risk factors combined with dietary interventions and breaking deleterious habits has been shown to reduce AF burden and recurrence. Numerous AF risk factors, such as diabetes, obesity or hypertension can be partially related to dietary and lifestyle choices. Therefore, dietary interventions may have potential as a therapeutic approach in AF. Based on available data, current guidelines recommend alcohol abstinence or reduction to decrease AF symptoms, burden, and progression, and do not indicate the need for caffeine abstention to prevent AF episodes (unless it is a trigger for AF symptoms). Uncertainty persists regarding harms or benefits of other dietary factors including chocolate, fish, salt, polyunsaturated and monounsaturated fatty acids, vitamins, and micronutrients. This article provides a systematic review of the association between AF and both dietary patterns and components. Additionally, it discusses potentially related mechanisms and introduces different strategies to assess patients' nutrition patterns, including mobile health solutions and diet indices. Finally, it highlights the gaps in knowledge requiring future investigation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Here, we present a complete genome of Deinococcus sonorensis KR-87 T , a biofilm-producing mesophile from the Arizonan Sonoran Desert. The sequence, assembled using Oxford Nanopore Technologies' long-read sequencing platform, predicts a genome size of 4.78 Mbp, with 6 replicons, 4,361 protein-coding genes, and a G+C content of 69.0%., Competing Interests: The authors declare no conflict of interest.

The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare ( < 0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal-regulatory, intergenic-regulatory and deep-intronic annotation. We observed 29 independent variants associated with height at P <  6 × 10 - 10 after conditioning on previously reported variants, with effect sizes ranging from -7cm to +4.7 cm. We also identified and replicated non-coding aggregate-based associations proximal to HMGA1 containing variants associated with a 5 cm taller height and of highly-conserved variants in MIR497HG on chromosome 17. We have developed an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits., (© 2024. The Author(s).)

Purpose: B7-H3 is an immunoregulatory protein overexpressed by many pediatric solid tumors with limited expression on critical organs, making it an attractive immunotherapy target. We present a first-in-human phase I clinical trial systemically administered B7-H3 chimeric antigen receptor (CAR) T cells for young patients with relapsed or refractory solid tumors., Patients and Methods: Patients were enrolled onto a phase I trial to examine the safety of B7-H3-specific CARs at various dose levels (DLs) using a standard 3 + 3 dose escalation design., Results: Sixteen patients (range, 11-24 years; median, 18.5 years) were enrolled, and nine were treated at DL1 (0.5 × 10 6 CAR T cells/kg; n = 3) or DL2 (1 × 10 6 CAR T cells/kg; n = 6). There were no first infusion dose-limiting toxicities. Maximum first-infusion circulating CAR T cells detected in the peripheral blood were 4.98 cells/μL (range, 0-4.98 cells/μL) with detection of CAR T cells colocalizing with tumor cells at the site of metastatic disease in one patient. Patients were eligible for subsequent infusions. An objective partial response by PERCIST criteria was observed 28 days after a second CAR T cell infusion in a patient who did not have an objective response after the first infusion. The second infusion demonstrated marked enhancement of CAR T cell expansion to 1,590 cells/μL and was accompanied by cytokine release syndrome and dose-limiting transaminitis. Detailed peripheral blood cytokine profiling revealed elevated IL-21 levels preinfusion 2 compared with infusion 1., Conclusion: B7-H3 CAR T cells are tolerable and demonstrate limited antitumor activity without acute on-target, off-tumor toxicity. High levels of CAR T cell expansion may be necessary to achieve objective responses, but undefined host and tumor microenvironment factors appear to be critical (ClinicalTrials.gov identifier: NCT04483778).

Background: Autosomal dominant polycystic kidney disease (ADPKD) is primarily of adult-onset and caused by pathogenic variants in PKD1 or PKD2 . Yet, disease expression is highly variable and includes very early-onset PKD presentations in utero or infancy. In animal models, the RNA-binding molecule Bicc1 has been shown to play a crucial role in the pathogenesis of PKD., Methods: To study the interaction between BICC1, PKD1 and PKD2 we combined biochemical approaches, knockout studies in mice and Xenopus, genetic engineered human kidney cells as well as genetic association studies in a large ADPKD cohort., Results: We first demonstrated that BICC1 physically binds to the proteins Polycystin-1 and -2 encoded by PKD1 and PKD2 via distinct protein domains. Furthermore, PKD was aggravated in loss-of-function studies in Xenopus and mouse models resulting in more severe disease when Bicc1 was depleted in conjunction with Pkd1 or Pkd2 . Finally, in a large human patient cohort, we identified a sibling pair with a homozygous BICC1 variant and patients with very early onset PKD (VEO-PKD) that exhibited compound heterozygosity of BICC1 in conjunction with PKD1 and PKD2 variants. Genome editing demonstrated that these BICC1 variants were hypomorphic in nature and impacted disease-relevant signaling pathways., Conclusions: These findings support the hypothesis that BICC1 cooperates functionally with PKD1 and PKD2 , and that BICC1 variants may aggravate disease severity highlighting RNA metabolism as an important new concept for disease modification in ADPKD.

Competing Interests: Dr Fishman is a co-founder and has an equity interest in Script Biosciences. Dr Wang is a co-founder of HrtEx Inc; is a co-founder and consultant to EpiEndoAF; is a consultant to Soneira Inc; reports stock options for this relationship; and reports a research contract with TDK Inc. Dr Narayan reports grant support from National Institutes of Health (R01 HL83359, R01 HL149134, R01 HL162260, and T32 HL166155), consulting from UpToDate Inc, and TDK Inc, and intellectual property owned by the University of California Regents and Stanford University. Dr Eckhardt reports consulting fees from UpToDate Inc. Dr Albert reports research grant support from St. Jude Medical Foundation, serves as a consultant to Medtronic Inc and Novartis, and serves as an Advisory Board Member to Element Science Inc, Boston Scientific Inc, and Illumina Inc. The other authors report no conflicts.

Background: Sudden cardiac death (SCD) is a major source of mortality and is the first manifestation of heart disease for most cases. Thus, there is a definite need to identify risk factors for SCD that can be modified on the population level. Short-term exposures to temperature have been implicated as a potential risk factor. Our objective was to determine if short-term temperature exposures were associated with increased risk of SCD in a US-based time-stratified case-crossover study., Methods: A total of 465 cases of SCD were identified among participants of the prospective Nurses' Health Study (NHS). Control days were selected from all other matching days of the week within the same month as the case day. Average ambient temperature on the current day (Lag 0 ) and preceding 27 days (Lags 1-27 ) was determined at the residence level using 800-m resolution estimates. Conditional logistic distributed lag nonlinear models (DLNMs) were used to assess the relative risk (RR) of the full range of temperature exposures over the lag period., Results: Warmer exposures in the days before event and colder temperatures 21-28 days prior were associated with increased risks of SCD. These results were driven by associations in regions other than the Northeast and among married women., Conclusions: Both warm and cold ambient temperatures are suggestively associated with risks of SCD among middle-aged and older women living across the United States., Competing Interests: The authors declare that they have no conflicts of interest with regard to the content of this report., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

Background: The causes of symptoms in patients with paroxysmal atrial fibrillation (AF) remains unclear., Objective: The purpose of this study was to correlate the magnitudes of skin sympathetic nerve activity (SKNA) with symptoms in patients with AF., Methods: We prospectively enrolled patients with symptomatic paroxysmal AF for ambulatory electrocardiography and SKNA recording. Heart rhythms at the time of symptoms were categorized as AF or normal sinus rhythm (NSR). Maximal and average skin sympathetic nerve activity (aSKNA) and heart rate (HR) were compared between symptomatic and asymptomatic AF and NSR episodes using mixed effects models to account for within-patient correlations., Results: Among the 31 enrolled patients, 16 (52%) had at least 1 episode of AF, and 24 (77%) endorsed symptoms during the monitoring period. Compared with asymptomatic AF episodes, symptomatic AF episodes had higher maximal aSKNA (1.260 [interquartile range (IQR) 1.114-1.723] μV vs 1.108 [IQR 0.974-1.312] μV; P <0.001) and higher maximal HR (152 ± 24 bpm vs 132 ± 19 bpm; P <.001). Symptomatic NSR episodes were associated with higher maximal aSKNA (1.612 [IQR 1.287-2.027] μV vs 1.332 [IQR 1.033-1.668] μV; P = .001) and higher maximal HR (152 ± 24 bpm vs 105 ± 16 bpm; P <.001) than asymptomatic NSR episodes. Of the symptomatic episodes, 66 (73%) occurred during NSR and 24 (27%) during AF. All P values were obtained from mixed effects models., Conclusion: Symptomatic episodes in patients with paroxysmal AF were more frequently associated with NSR than AF. Symptomatic AF and NSR episodes were associated with higher aSKNA than asymptomatic episodes. In patients with paroxysmal AF, symptoms correlate better with SKNA than heart rhythm., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Sudden cardiac death (SCD) is an important public health problem worldwide, accounting for an estimated 6-20% of total mortality. A significant proportion of SCD is caused by inherited heart disease, especially among the young. An autopsy is crucial to establish a diagnosis of inherited heart disease, allowing for subsequent identification of family members who require cardiac evaluation. Autopsy of cases of unexplained sudden death in the young is recommended by both the European Society of Cardiology and the American Heart Association. Overall autopsy rates, however, have been declining in many countries across the globe, and there is a lack of skilled trained pathologists able to carry out full autopsies. Recent studies show that not all cases of sudden death in the young are autopsied, likely due to financial, administrative, and organizational limitations as well as awareness among police, legal authorities, and physicians. Consequently, diagnoses of inherited heart disease are likely missed, along with the opportunity for treatment and prevention among surviving relatives. This article reviews the evidence for the role of autopsy in sudden death, how the cardiologist should interpret the autopsy-record, and how this can be integrated and implemented in clinical practice. Finally, we identify areas for future research along with potential for healthcare reform aimed at increasing autopsy awareness and ultimately reducing mortality from SCD., Competing Interests: Conflict of interest: I have read the journal’s policy and the authors of this manuscript have the following competing interests. Co-author C.M.A.: Investigator Initiated Grant Support from NHLBI, St. Jude Medical, Roche Diagnostics, and Abbott to Study Biologic Markers of SCD; Advisory Board Member for Element Science, Inc, Medtronic, Illumina Inc, and consultant, Novartis. The remaining authors have declared that no competing interests exist., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Atrial fibrillation (AF) often escapes detection, given its frequent paroxysmal and asymptomatic presentation. Deep learning of transthoracic echocardiograms (TTEs), which have structural information, could help identify occult AF. We created a two-stage deep learning algorithm using a video-based convolutional neural network model that (1) distinguished whether TTEs were in sinus rhythm or AF and then (2) predicted which of the TTEs in sinus rhythm were in patients who had experienced AF within 90 days. Our model, trained on 111,319 TTE videos, distinguished TTEs in AF from those in sinus rhythm with high accuracy in a held-out test cohort (AUC 0.96 (0.95-0.96), AUPRC 0.91 (0.90-0.92)). Among TTEs in sinus rhythm, the model predicted the presence of concurrent paroxysmal AF (AUC 0.74 (0.71-0.77), AUPRC 0.19 (0.16-0.23)). Model discrimination remained similar in an external cohort of 10,203 TTEs (AUC of 0.69 (0.67-0.70), AUPRC 0.34 (0.31-0.36)). Performance held across patients who were women (AUC 0.76 (0.72-0.81)), older than 65 years (0.73 (0.69-0.76)), or had a CHA 2 DS 2 VASc ≥2 (0.73 (0.79-0.77)). The model performed better than using clinical risk factors (AUC 0.64 (0.62-0.67)), TTE measurements (0.64 (0.62-0.67)), left atrial size (0.63 (0.62-0.64)), or CHA 2 DS 2 VASc (0.61 (0.60-0.62)). An ensemble model in a cohort subset combining the TTE model with an electrocardiogram (ECGs) deep learning model performed better than using the ECG model alone (AUC 0.81 vs. 0.79, p = 0.01). Deep learning using TTEs can predict patients with active or occult AF and could be used for opportunistic AF screening that could lead to earlier treatment., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: Sequencing-based genetic testing often identifies variants of uncertain significance (VUS) or fails to detect pathogenic variants altogether. We evaluated the utility of RNA sequencing (RNA-seq) to clarify VUS or identify missing variants in a clinical setting., Methods: Over a 2-year period, genetics providers at a single institution referred 26 cases for clinical RNA-seq. Cases had either no candidate variant identified by prior testing or a VUS suspected to impact splicing or expression. A committee reviewed each submission to ensure it met study criteria., Results: Among 26 cases, 8 could not be sequenced because of poor expression in an accessible tissue, 2 did not meet inclusion criteria, 3 were solved prior to collection, and 4 families declined participation or did not complete sample collection. For the 9 cases sequenced, the clinical laboratory reported two positive, four negative, and three "indeterminate." For all three indeterminate cases, original RNA-seq data was manually evaluated and deemed explanatory., Conclusion: Clinical RNA-seq can clarify VUS, especially splice variants, but laboratory-specific interpretation guidelines may lead to indeterminate results. Identifying individuals likely to benefit from RNA-seq and providing appropriate counseling poses unique challenges., Competing Interests: DEM holds stock options in MyOme, is on a scientific advisory board at Oxford Nanopore Technologies (ONT), is engaged in a research agreement with ONT, and has received travel support from ONT.

Background: Preoperative risk assessments used in clinical practice are insufficient in their ability to identify risk for postoperative mortality. Deep-learning analysis of electrocardiography can identify hidden risk markers that can help to prognosticate postoperative mortality. We aimed to develop a prognostic model that accurately predicts postoperative mortality in patients undergoing medical procedures and who had received preoperative electrocardiographic diagnostic testing., Methods: In a derivation cohort of preoperative patients with available electrocardiograms (ECGs) from Cedars-Sinai Medical Center (Los Angeles, CA, USA) between Jan 1, 2015 and Dec 31, 2019, a deep-learning algorithm was developed to leverage waveform signals to discriminate postoperative mortality. We randomly split patients (8:1:1) into subsets for training, internal validation, and final algorithm test analyses. Model performance was assessed using area under the receiver operating characteristic curve (AUC) values in the hold-out test dataset and in two external hospital cohorts and compared with the established Revised Cardiac Risk Index (RCRI) score. The primary outcome was post-procedural mortality across three health-care systems., Findings: 45 969 patients had a complete ECG waveform image available for at least one 12-lead ECG performed within the 30 days before the procedure date (59 975 inpatient procedures and 112 794 ECGs): 36 839 patients in the training dataset, 4549 in the internal validation dataset, and 4581 in the internal test dataset. In the held-out internal test cohort, the algorithm discriminates mortality with an AUC value of 0·83 (95% CI 0·79-0·87), surpassing the discrimination of the RCRI score with an AUC of 0·67 (0·61-0·72). The algorithm similarly discriminated risk for mortality in two independent US health-care systems, with AUCs of 0·79 (0·75-0·83) and 0·75 (0·74-0·76), respectively. Patients determined to be high risk by the deep-learning model had an unadjusted odds ratio (OR) of 8·83 (5·57-13·20) for postoperative mortality compared with an unadjusted OR of 2·08 (0·77-3·50) for postoperative mortality for RCRI scores of more than 2. The deep-learning algorithm performed similarly for patients undergoing cardiac surgery (AUC 0·85 [0·77-0·92]), non-cardiac surgery (AUC 0·83 [0·79-0·88]), and catheterisation or endoscopy suite procedures (AUC 0·76 [0·72-0·81])., Interpretation: A deep-learning algorithm interpreting preoperative ECGs can improve discrimination of postoperative mortality. The deep-learning algorithm worked equally well for risk stratification of cardiac surgeries, non-cardiac surgeries, and catheterisation laboratory procedures, and was validated in three independent health-care systems. This algorithm can provide additional information to clinicians making the decision to perform medical procedures and stratify the risk of future complications., Funding: National Heart, Lung, and Blood Institute., Competing Interests: Declaration of interests DO reports support from the National Institute of Health (NIH; NHLBI R00HL157421) and Alexion, and consulting or honoraria for lectures from EchoIQ, Ultromics, Pfizer, InVision, the Korean Society of Echo, and the Japanese Society of Echo. JWH reports funding from the National Science Foundation (DGE-1656518). PE reports research support from the NIH (T32HL007854-21) and serves on the American College of Cardiology Innovation Council. BC reports consulting from Alnylam, Cardurion, Corvia, CVRX, Cytokinetics, Intellia, and Rocket. TP reports stock in Abbot and Baxter, and research support from the American Heart Association, Eido, Pfizer, Edwards, and the New York Academy of Medicine. JHC reports research funding from NIH/National Institute of Aging (AI17812101), NIH/National Institute on Drug Abuse (UG1DA015815-CTN-0136), AIMI-HAI Partnership, Doris Duke Charitable Foundation (20211260), Google (SPO136094), American Heart Association, and Clinical and Translational Sciences Awards Program by the National Center for Advancing Translational Sciences (R56LM013365); is a co-founder of Reaction Explorer; and receives consulting fees from Sutton Pierce and Younker Hyde MacFarlane. MP reports research support from the NIH (HL136390), patents for ECG-based cardiac arrhythmia detection (WO2014205310A3), and consulting fees from Apple, Biotronik, Boston Scientific, QALY, Johnson and Johnson, and Bristol Myers Squibb. CMA reports support from NIH (HL165840), consulting fees from Medtronic, Novartis, Illumina, and Medtronic, and participation in advisory boards for Boston Scientific, Medtronic, and Element Science; and is a trustee on the board for the Heart Rhythm Society. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND license. Published by Elsevier Ltd.. All rights reserved.)

Purpose of Review: Environmental exposures have been associated with increased risk of cardiovascular mortality and acute coronary events, but their relationship with out-of-hospital cardiac arrest (OHCA) and sudden cardiac death (SCD) remains unclear. SCD is an important contributor to the global burden of cardiovascular disease worldwide., Recent Findings: Current literature suggests a relationship between environmental exposures and cardiovascular disease, but their relationship with OHCA/SCD remains unclear. A literature search was conducted in PubMed, Embase, Web of Science, and Global Health. Of 5138 studies identified by our literature search, this review included 30 studies on air pollution, 42 studies on temperature, 6 studies on both air pollution and temperature, and 1 study on altitude exposure and OHCA/SCD. Particulate matter air pollution, ozone, and both hot and cold temperatures are associated with increased risk of OHCA/SCD. Pollution and other exposures related to climate change play an important role in OHCA/SCD incidence., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Sustained forms of atrial fibrillation (AF) are associated with lower treatment success rates and poorer prognosis compared with paroxysmal AF. Yet, little is known about risk factors that predispose to persistent AF on initial presentation. Our objective was to define risk factors associated with new-onset persistent AF., Methods: We prospectively examined the differential associations between lifestyle, clinical, and socioeconomic risk factors and AF pattern (persistent versus paroxysmal) at the time of diagnosis among 25 119 participants without a history of cardiovascular disease, AF, or cancer in the VITAL rhythm study (Vitamin D and Omega-3)., Results: During a median follow-up of 5.3 years, 900 participants developed AF and 346 (38.4%) were classified as persistent at the time of diagnosis. In multivariable competing risk models, increasing age, male sex, White race, height, weight, body mass index ≥30 kg/m 2 , hypertension, current or past smoking, alcohol intake ≥2 drinks/day, postcollege education, and randomized treatment with vitamin D were significantly associated with incident persistent AF. Compared with paroxysmal AF, increasing age, male sex, weight, body mass index ≥30 kg/m 2 , and postcollege education were more strongly associated with persistent AF in multivariable models regardless of whether interim cardiovascular disease and heart failure events were censored., Conclusions: In a prospective cohort without baseline AF or cardiovascular disease, over one-third of AF at the time of diagnosis is persistent. Older age, male sex, postcollege education, and obesity were preferentially associated with persistent AF and represent a high-risk AF subset for population-based intervention., Competing Interests: Disclosures Dr Albert reported receipt of research grants from St. Jude Medical, Abbott, and Roche Diagnostics and has served as a consultant for Medtronic, Boston Scientific, Element Science, and Novartis. The other authors report no conflicts.

Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue that most often occurs in adolescents and young adults. Despite an international coordinated approach, several nuances, discrepancies, and debates remain in defining the standard of care for treating ES. In this review, the authors leverage the expertise assembled by formation of the National Ewing Sarcoma Tumor Board, a multi-institution, multidisciplinary virtual tumor board that meets monthly to discuss complicated and challenging cases of ES. This report is focused on select topics that apply to the management of patients with newly diagnosed ES. The specific topics covered include indications for bone marrow aspirate and biopsy for initial evaluation compared with fluorodeoxyglucose-positron emission tomography, the role of interval compressed chemotherapy in patients aged 18 years and older, the role of adding ifosfamide/etoposide to vincristine/doxorubicin/cyclophosphamide for patients with metastatic disease, the data on and role of high-dose chemotherapy with autologous stem cell transplantation, maintenance therapy, and whole-lung irradiation. The data referenced are often limited to subgroup analyses and/or compiled from multiple sources. Although not intended to replace the clinical judgement of treating physicians, the guidelines are intended to provide clarity and recommendations for the upfront management of patients with ES. PLAIN LANGUAGE SUMMARY: Ewing sarcoma is a malignant tumor of bone and soft tissue that most often occurs in adolescents and young adults. For this review, the authors used the experience of the National Ewing Sarcoma Tumor Board, a multi-institution, multidisciplinary virtual tumor board that meets monthly to discuss complicated and challenging cases of Ewing sarcoma. Although not intended to replace the clinical judgement of treating physicians, the guidelines will focus on the development of consensus statements for the upfront management of patients with Ewing sarcoma., (© 2023 American Cancer Society.)

Malignant bone tumors are commonly classified as pediatric or adolescent malignancies, and clinical trials for these diseases have generally focused on these populations. Of primary bone cancers, osteosarcoma is among the most common. Osteosarcoma has a bimodal age distribution, with the first peak occurring in patients from 10 to 14 years old, and the second peak occurring in patients older than 65, with about 25% of cases occurring in adults between 20 and 59 years old. Notably, adult osteosarcoma patients have worse outcomes than their pediatric counterparts. It remains unclear whether age itself is a poor prognostic factor, or if inherent differences in tumor biology exist between age groups. Despite these unknowns, current treatment strategies for adults are largely extrapolated from pediatric studies since the majority of clinical trials for osteosarcoma treatments are based on younger patient populations. In light of the different prognoses observed in pediatric and adult osteosarcoma, we summarize the current understanding of the molecular etiology of osteosarcoma and how it may differ between age groups, hypothesizing why adult patients have worse outcomes compared to children.

This study aimed to investigate whether n-3 fatty acid supplementation reduced cardiovascular disease (CVD) events in a novel analysis using hierarchical composite CVD outcomes based on win ratio in the VITamin D and OmegA-3 TriaL (VITAL). This was a secondary analysis of our VITAL randomized trial, which assessed the effects of marine n-3 fatty acids (1 g/day) and vitamin D3 on incident CVD and cancer among healthy older adults ( n = 25,871). The primary analysis estimated win ratios of a composite of major CVD outcomes prioritized as fatal coronary heart disease, other fatal CVD including stroke, non-fatal myocardial infarction (MI), and non-fatal stroke, comparing n-3 fatty acids to placebo. The primary result was a nonsignificant benefit of this supplementation for the prioritized primary CVD outcome (reciprocal win ratio [95% confidence interval]: 0.90 [0.78-1.04]), similar to the 0.92 (0.80-1.06) hazard ratio in our original time-to-first event analysis without outcome prioritization. Its benefits came from reducing MI (0.71 [0.57-0.88]) but not stroke (1.01 [0.80 to 1.28]) components. For the primary CVD outcome, participants with low fish consumption at baseline benefited (0.79 [0.65-0.96]) more than those with high consumption (1.05 [0.85-1.30]). These results are consistent with, but slightly stronger than, those without outcome prioritization.

Despite major advancements in cardiovascular medicine, sudden cardiac death (SCD) continues to be an enormous medical and societal challenge, claiming millions of lives every year. Efforts to prevent SCD are hampered by imperfect risk prediction and inadequate solutions to specifically address arrhythmogenesis. Although resuscitation strategies have witnessed substantial evolution, there is a need to strengthen the organisation of community interventions and emergency medical systems across varied locations and health-care structures. With all the technological and medical advances of the 21st century, the fact that survival from sudden cardiac arrest (SCA) remains lower than 10% in most parts of the world is unacceptable. Recognising this urgent need, the Lancet Commission on SCD was constituted, bringing together 30 international experts in varied disciplines. Consistent progress in tackling SCD will require a completely revamped approach to SCD prevention, with wide-sweeping policy changes that will empower the development of both governmental and community-based programmes to maximise survival from SCA, and to comprehensively attend to survivors and decedents' families after the event. International collaborative efforts that maximally leverage and connect the expertise of various research organisations will need to be prioritised to properly address identified gaps. The Commission places substantial emphasis on the need to develop a multidisciplinary strategy that encompasses all aspects of SCD prevention and treatment. The Commission provides a critical assessment of the current scientific efforts in the field, and puts forth key recommendations to challenge, activate, and intensify efforts by both the scientific and global community with new directions, research, and innovation to reduce the burden of SCD worldwide., Competing Interests: Declaration of interests CMA declares grants from St Jude Medical Foundation and NIH–NHLBI; consulting fees from Medtronic, Illumina, and Novartis; payment or honoraria for lectures from Medtronic; and participation on a data safety monitoring board or advisory board for Medtronic, Element Science, and Boston Scientific. J-BLPDW declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Medtronic, Biotronik, Boston Scientific, and Abbott. MTB declares grants from the EU ESCAPE-NET project, funded by the EU's Horizon 2020 research and innovation programme under grant agreement 733381; and grants from European Foundation for the Study of Diabetes (for project Improvement of CVD risk stratification: an innovative method for optimal timing of ECG monitoring). LC declares grants from Grant Horizon 2020 (2016–22) ESCAPE-NET; ERA-CVD Empathy (2020–23) for the electromechanical presages of sudden cardiac death in the young: integrating imaging, modelling, and genetics for patient stratification; grants from AIFA (2020–23) for novel therapy for the long QT syndrome type 2 based on the mechanism of action of the disease-causing mutations; grants from EJP RD (European Joint Program on Rare Disesase) LQTS-NEXT (2020–23) to the next level of risk prediction in patients with long QT syndrome; grants from EJP RD Silence-LQTS (2021–24) for SGK1 inhibition as a novel therapeutic approach in long QT syndrome; and participation on a data safety monitoring board or advisory board for Bristol Myers Squibb. FF declares grants and support for attending meetings or travel from Novo Nordisk Foundation NNF19OC0055142. GH declares grants from European Commission (PROFID project public grant for the development of a risk stratification tool to predict SCD and to evaluate the risk predictor in a clinical trial; NCT04540289) and German Federal Joint Committee (G-BA; RESET CRT public grant for a clinical trial comparing CRT-D versus CRT-P). JI declares research support from National Health and Medical Research Council Australia, Heart Foundation Australia, and New South Wales Health. JJ declares grants from Academy of Finland, Finnish Foundation for Cardiovascular Research, and Sigrid Juselius Foundation; support for attending meetings and travel from AstraZeneca, Bayer, Boehringer Ingelheim, Pfizer, and Orion Pharma; and participation on a data safety monitoring board or advisory board for Novo Nordisk, Bayer, and Boehringer Ingelheim. EM declares research grants from Abbott, Biotronik, Boston Scientific, Medtronic, MicroPort, and Zoll; consulting fees from Medtronic, Boston Scientific, Zoll, and Abbott; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Medtronic, Boston Scientific, Zoll, and Abbott. MEHO declares other financial or non-financial interests from TIIM Healthcare and Global Healthcare SG. TMO declares participation on a data safety monitoring board for the COCA trial (a randomised controlled trial evaluating calcium during cardiac arrest). MP declares grants from St George's, University of London for research on cardiac risk in the young and consulting fees from Bristol Myers Squibb. CS declares being an employee at American Heart Association. H-FT declares research grants from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Daiichi Sankyo, Medtronic, Novartis, Pfizer, and Sanofi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Boehringer Ingelheim, Boston Scientific, Daiichi Sankyo, Medtronic, Pfizer, and Sanofi; and support for attending meetings and travel from Boehringer Ingelheim. ZT declares grants or contracts from National Institutes of Health (NIH) and National Heart, Lung, and Blood Institute (NHLBI; NIH/NHLBI R01 HL 102090, NIH/NHLBI R01 HL 126555, NIH/NHLBI R01 HL 147035, and NIH/NHLBI R01 HL 157247), NIH and National Institute of Allergy and Infectious Diseases (NIAID; NIH/NIAID P01 AI 169606), and Centers for Disease Control and Prevention (6 NU38DP000019-01-01 and 1 NU38DP000019-01-00). All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Nonischemic cardiomyopathy (NICM) is common and patients are at significant risk for early mortality secondary to ventricular arrhythmias. Current guidelines recommend implantable cardioverter-defibrillator (ICD) therapy to decrease sudden cardiac death (SCD) in patients with heart failure and reduced left ventricular ejection fraction. However, in randomized clinical trials comprised solely of patients with NICM, primary prevention ICDs did not confer significant mortality benefit. Moreover, left ventricular ejection fraction has limited sensitivity and specificity for predicting SCD. Therefore, precise risk stratification algorithms are needed to define those at the highest risk of SCD. This review examines mechanisms of sudden arrhythmic death in patients with NICM, discusses the role of ICD therapy and treatment of heart failure for prevention of SCD in patients with NICM, examines the role of cardiac magnetic resonance imaging and computational modeling for SCD risk stratification, and proposes new strategies to guide future clinical trials on SCD risk assessment in patients with NICM., Competing Interests: Funding Support and Author Disclosures Dr Chrispin has received consulting fees from Biosense Webster; and has received honorarium from Abbott. Dr Navara has equity ownership in SafeBeat Rx. Dr Torbe has ownership of Boston Scientific stocks. Dr Cheung has received consulting fees from Abbott, Biotronik, and Boston Scientific; has received research grant support from Boston Scientific; and has received fellowship grant support from Abbott, Biosense, Biotronik, Boston Scientific, and Medtronic. Dr Lakdawala has received research support from Pfizer Inc; and has received consulting fees from Pfizer Inc, Bristol Myers Squibb, Cytokinetics, and Tenaya Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The relationship between omega-3 fatty acids and atrial fibrillation (AF) remains controversial., Objectives: This study aimed to determine the prospective associations of blood or adipose tissue levels of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with incident AF., Methods: We used participant-level data from a global consortium of 17 prospective cohort studies, each with baseline data on blood or adipose tissue omega-3 fatty acid levels and AF outcomes. Each participating study conducted a de novo analyses using a prespecified analytical plan with harmonized definitions for exposures, outcome, covariates, and subgroups. Associations were pooled using inverse-variance weighted meta-analysis., Results: Among 54,799 participants from 17 cohorts, 7,720 incident cases of AF were ascertained after a median 13.3 years of follow-up. In multivariable analysis, EPA levels were not associated with incident AF, HR per interquintile range (ie, the difference between the 90th and 10th percentiles) was 1.00 (95% CI: 0.95-1.05). HRs for higher levels of DPA, DHA, and EPA+DHA, were 0.89 (95% CI: 0.83-0.95), 0.90 (95% CI: 0.85-0.96), and 0.93 (95% CI: 0.87-0.99), respectively., Conclusions: In vivo levels of omega-3 fatty acids including EPA, DPA, DHA, and EPA+DHA were not associated with increased risk of incident AF. Our data suggest the safety of habitual dietary intakes of omega-3 fatty acids with respect to AF risk. Coupled with the known benefits of these fatty acids in the prevention of adverse coronary events, our study suggests that current dietary guidelines recommending fish/omega-3 fatty acid consumption can be maintained., Competing Interests: Funding Support and Author Disclosures The Fatty Acid Research Institute retrospectively provided a small honorarium to a subset of the analysts who participated in this study, but it had no role in the design, analysis, manuscript writing, nor decision to submit for publication. Detailed funding information for the individual cohorts can be found in the Supplemental Appendix, specifically Supplemental Table 4. None of the funders/sponsors played any role in the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Dr O'Donoghue is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Amgen, Novartis, Janssen, and AstraZeneca; and has received consulting fees from Amgen, Novartis, Janssen, and AstraZeneca. Dr Albert has received consulting fees from Boston Scientific, Medtronic, Novartis, and Element Science. Dr Morrow is a member of the TIMI Study group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott Laboratories, Amgen, Anthos Therapeutics, Arca Biopharma, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc, Daiichi-Sankyo, Eisai, Intarcia, Janssen, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron, Roche, Siemens, The Medicines Company, and Zora Biosciences; and has received consulting fees from ARCA, InCarda, Inflammatix, Merck, Novartis, and Roche Diagnostics. Dr O’Keefe has a major ownership interest in Cardiotabs (a company that markets supplements including omega-3). Dr Mozaffarian, outside of the submitted work, has received research funding from the Gates Foundation, The Rockefeller Foundation, and the Vail Institute for Global Research; has received personal fees from Acasti Pharma, Barilla, Danone, and Motif FoodWorks; has served on the scientific advisory board of Beren Therapeutics, Brightseed, Calibrate, DayTwo (ended June 20, 2023), Elysium Health, Filtricine, Foodome, HumanCo, January Inc, Perfect Day, Season, and Tiny Organics; has stock ownership in Calibrate and HumanCo; and has chapter royalties from UpToDate. Dr Harris holds stock in OmegaQuant Analytics, LLC (a laboratory that offers blood fatty acid testing); and is on the Scientific Advisory Boards for the Schiff Institute Science and Innovation, Synspira, and the Seafood Nutrition Partnership. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Beneficial and adverse associations with arrhythmias have been reported for omega-3 fatty acids (omega-3 FA) and Vitamin D. The 12 lead electrocardiogram (ECG) contains quantitative measures reflecting diverse aspects of electrophysiology that might provide insights into mechanisms underlying these associations. In a pre-specified ancillary study of the VITaminD and omegA-3 (VITAL) trial, we examined the effect of 1 g of marine omega-3 FA per day, comprised of 460 mg eicosapentanoic acid and 380 mg of docosahexaenoic acid, and 2000 IU VitaminD 3 per day on ECG characteristics associated with atrial and ventricular arrhythmias among individuals age 50 years or greater. A total of 911 study participants underwent ECGs at baseline and again at 2 years after the randomization. Individuals randomized to active omega-3 FA demonstrated significant net increase in PR-interval duration (p = 0.005) and P-wave duration (p = 0.03) as well significant net decrease in P-wave amplitude (p = 0.037) as compared to placebo. RMSSD increased to a greater extent in the omega-3 FA arm compared to placebo (p = 0.040). For Vitamin D 3 , the Cornell voltage increased to a lesser extent in the participants assigned to active treatment as compared to placebo (p = 0.044). There were no other significant differences in QRS, QTc, Cornell voltage or heart rate. Thus, randomized treatment with omega-3 FA supplements resulted in changes on the ECG that are potentially reflective of heightened vagal tone and/or slowing of intraatrial and AV conduction. Vitamin D 3 supplementation resulted in modest reductions in progressive LV voltage suggestive of a potential antihypertrophic effect.Trial registration ClinicalTrials.gov Identifiers: NCT01169259, NCT02178410 (06/26/2010 and 06/30/2014)., (© 2023. The Author(s).)