Publications by authors named "Steven A Lubitz"

231 Publications

Temporal trends in cause-specific mortality among individuals with newly diagnosed atrial fibrillation in the Framingham Heart Study.

BMC Med 2021 Jul 29;19(1):170. Epub 2021 Jul 29.

Boston University's and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.

Background: All-cause mortality following atrial fibrillation (AF) has decreased over time. Data regarding temporal trends in causes of death among individuals with AF are scarce. The aim of our study was to analyze temporal trends in cause-specific mortality and predictors for cardiovascular (CVD) and non-CVD deaths among participants with incident AF in the Framingham Heart Study.

Methods: We categorized all newly diagnosed AF cases according to age at AF diagnosis (< 70, 70 to < 80, and ≥ 80 years) and epoch of AF diagnosis (< 1990, 1990-2002, and ≥ 2003). We followed participants until death or the last follow-up. We categorized death causes into CVD, non-CVD, and unknown causes. For each age group, we tested for trends in the cumulative incidence of cause-specific death across epochs. We fit multivariable Fine-Gray models to assess subdistribution hazard ratios (HR) between clinical risk factors at AF diagnosis and cause-specific mortality.

Results: We included 2125 newly diagnosed AF cases (mean age 75.5 years, 47.8% women). During a median follow-up of 4.8 years, 1657 individuals with AF died. There was evidence of decreasing CVD mortality among AF cases diagnosed < 70 years and 70 to < 80 years (p < 0.001) but not ≥ 80 years (p = 0.76). Among the cases diagnosed < 70 years, the cumulative incidence of CVD death at 75 years was 67.7% in epoch 1 and 13.9% in epoch 3; among those 70 to < 80 years, the incidence at 85 years was 58.9% in epoch 1 and 18.9% in epoch 3. Advancing age (HR per 1 SD increase 6.33, 95% CI 5.44 to 7.37), prior heart failure (HR 1.49, 95% CI 1.14-1.94), and prior myocardial infarction (HR 1.44, 95% CI 1.15-1.80) were associated with increased rate of CVD death.

Conclusions: In this community-based cohort, CVD mortality among AF cases decreased over time. Most deaths in individuals with AF are no longer CVD-related, regardless of age at AF diagnosis.
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http://dx.doi.org/10.1186/s12916-021-02037-xDOI Listing
July 2021

Rare Coding Variants Associated with Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-ancestry Analysis.

Circ Genom Precis Med 2021 Jul 28. Epub 2021 Jul 28.

University of Maryland School of Medicine & Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD.

- Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between ECG intervals and rare genetic variation at a population level are poorly understood. - Using a discovery sample of 29,000 individuals with whole-genome sequencing from TOPMed and replication in nearly 100,000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured ECG traits (RR, P-wave, PR, and QRS intervals and corrected QT interval [QTc]). - We found that rare variants associated with population-based ECG intervals identify established monogenic SCD genes (, , ), a controversial monogenic SCD gene (), and novel genes (, ) involved in cardiac conduction. Loss-of-function and pathogenic variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of first-degree atrioventricular block (=8.4x10). Similar variants in and (0.2% of individuals) were associated with a 23-fold increased odds of marked QTc prolongation (=4x10), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal ECG intervals. - Our findings indicate that large-scale high-depth sequence data and ECG analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked ECG interval prolongation.
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http://dx.doi.org/10.1161/CIRCGEN.120.003300DOI Listing
July 2021

Outpatient Prescription Practices in Patients with Atrial Fibrillation (From the NCDR PINNACLE Registry).

Am J Cardiol 2021 Jul 17. Epub 2021 Jul 17.

Healthcare Innovation Lab, BJC HealthCare/Washington University School of Medicine; Division of Cardiology, Washington University School of Medicine, St. Louis, Missouri.

This study sought to evaluate inappropriate prescribing practices in an atrial fibrillation (AF) population, as outlined by the 2016 ACC/AHA Clinical Performance and Quality Measures for Adults with Atrial Fibrillation or Atrial Flutter document. The 2016 AF quality measures document specified medications to avoid in certain AF populations, including aspirin and anticoagulant combination therapy in patients without cardiovascular disease, and non-dihydropyridine calcium channel blockers in patients with reduced ejection fraction. Using data from the NCDR PINNACLE registry, a national outpatient cardiology practice registry, we assessed rates of inappropriate prescription of two types of medications among AF outpatients from 5/1/2008-5/1/2016. Overall rates of inappropriate prescription and variation by practice were calculated. Patient and practice factors associated with inappropriate prescription were assessed in adjusted analyses. A total of 107,759 of 658,250 (16.4%) patients without cardiovascular disease were inappropriately prescribed an antiplatelet and anticoagulant together, and 5,731 of 150,079 (3.8%) patients with reduced ejection fraction were inappropriately prescribed a non-dihydropyridine calcium channel blocker. Overall, 14.8% of AF patients were prescribed medications that were not recommended. Both patient and practice factors were associated with inappropriate prescribing, and the adjusted practice-level median odds ratio for inappropriate prescription was 1.70 (95% CI: 1.61-1.82), indicating a 70% likelihood that 2 random practices would treat identical AF patients differently. In a large registry of AF patients treated in cardiology practices, overall rates of inappropriate prescription practices, as defined by the 2016 AF quality measures, were relatively low, but significant practice variation was present.
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http://dx.doi.org/10.1016/j.amjcard.2021.06.011DOI Listing
July 2021

Management of Congenital Long-QT Syndrome: Commentary From the Experts.

Circ Arrhythm Electrophysiol 2021 Jul 9;14(7):e009726. Epub 2021 Jul 9.

Clinical Cardiovascular Research Center, University of Rochester Medical Center, NY (W.Z.).

While published guidelines are useful in the care of patients with long-QT syndrome, it can be difficult to decide how to apply the guidelines to individual patients, particularly those with intermediate risk. We explored the diversity of opinion among 24 clinicians with expertise in long-QT syndrome. Experts from various regions and institutions were presented with 4 challenging clinical scenarios and asked to provide commentary emphasizing why they would make their treatment recommendations. All 24 authors were asked to vote on case-specific questions so as to demonstrate the degree of consensus or divergence of opinion. Of 24 authors, 23 voted and 1 abstained. Details of voting results with commentary are presented. There was consensus on several key points, particularly on the importance of the diagnostic evaluation and of β-blocker use. There was diversity of opinion about the appropriate use of other therapeutic measures in intermediate-risk individuals. Significant gaps in knowledge were identified.
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http://dx.doi.org/10.1161/CIRCEP.120.009726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301722PMC
July 2021

2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families.

J Arrhythm 2021 Jun 8;37(3):481-534. Epub 2021 Apr 8.

The First Affiliated Hospital of Nanjing Medical University Nanjing China.

This international multidisciplinary document intends to provide clinicians with evidence-based practical patient-centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families.
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http://dx.doi.org/10.1002/joa3.12449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207384PMC
June 2021

Deep Learning to Predict Cardiac Magnetic Resonance-Derived Left Ventricular Mass and Hypertrophy From 12-Lead ECGs.

Circ Cardiovasc Imaging 2021 Jun 15;14(6):e012281. Epub 2021 Jun 15.

Cardiovascular Disease Initiative (S.K., J.P.P., C.D.A., P.T.E., J.E.H., S.A.L.), Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge.

Background: Classical methods for detecting left ventricular (LV) hypertrophy (LVH) using 12-lead ECGs are insensitive. Deep learning models using ECG to infer cardiac magnetic resonance (CMR)-derived LV mass may improve LVH detection.

Methods: Within 32 239 individuals of the UK Biobank prospective cohort who underwent CMR and 12-lead ECG, we trained a convolutional neural network to predict CMR-derived LV mass using 12-lead ECGs (left ventricular mass-artificial intelligence [LVM-AI]). In independent test sets (UK Biobank [n=4903] and Mass General Brigham [MGB, n=1371]), we assessed correlation between LVM-AI predicted and CMR-derived LV mass and compared LVH discrimination using LVM-AI versus traditional ECG-based rules (ie, Sokolow-Lyon, Cornell, lead aVL rule, or any ECG rule). In the UK Biobank and an ambulatory MGB cohort (MGB outcomes, n=28 612), we assessed associations between LVM-AI predicted LVH and incident cardiovascular outcomes using age- and sex-adjusted Cox regression.

Results: LVM-AI predicted LV mass correlated with CMR-derived LV mass in both test sets, although correlation was greater in the UK Biobank (r=0.79) versus MGB (r=0.60, P<0.001 for both). When compared with any ECG rule, LVM-AI demonstrated similar LVH discrimination in the UK Biobank (LVM-AI c-statistic 0.653 [95% CI, 0.608 -0.698] versus any ECG rule c-statistic 0.618 [95% CI, 0.574 -0.663], P=0.11) and superior discrimination in MGB (0.621; 95% CI, 0.592 -0.649 versus 0.588; 95% CI, 0.564 -0.611, P=0.02). LVM-AI-predicted LVH was associated with incident atrial fibrillation, myocardial infarction, heart failure, and ventricular arrhythmias.

Conclusions: Deep learning-inferred LV mass estimates from 12-lead ECGs correlate with CMR-derived LV mass, associate with incident cardiovascular disease, and may improve LVH discrimination compared to traditional ECG rules.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.012281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217289PMC
June 2021

Accelerometer-derived physical activity and risk of atrial fibrillation.

Eur Heart J 2021 Jul;42(25):2472-2483

Cardiovascular Disease Initiative, Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, MA, USA.

Aims: Physical activity may be an important modifiable risk factor for atrial fibrillation (AF), but associations have been variable and generally based on self-reported activity.

Methods And Results: We analysed 93 669 participants of the UK Biobank prospective cohort study without prevalent AF who wore a wrist-based accelerometer for 1 week. We categorized whether measured activity met the standard recommendations of the European Society of Cardiology, American Heart Association, and World Health Organization [moderate-to-vigorous physical activity (MVPA) ≥150 min/week]. We tested associations between guideline-adherent activity and incident AF (primary) and stroke (secondary) using Cox proportional hazards models adjusted for age, sex, and each component of the Cohorts for Heart and Aging Research in Genomic Epidemiology AF (CHARGE-AF) risk score. We also assessed correlation between accelerometer-derived and self-reported activity. The mean age was 62 ± 8 years and 57% were women. Over a median of 5.2 years, 2338 incident AF events occurred. In multivariable adjusted models, guideline-adherent activity was associated with lower risks of AF [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.75-0.89; incidence 3.5/1000 person-years, 95% CI 3.3-3.8 vs. 6.5/1000 person-years, 95% CI 6.1-6.8] and stroke (HR 0.76, 95% CI 0.64-0.90; incidence 1.0/1000 person-years, 95% CI 0.9-1.1 vs. 1.8/1000 person-years, 95% CI 1.6-2.0). Correlation between accelerometer-derived and self-reported MVPA was weak (Spearman r = 0.16, 95% CI 0.16-0.17). Self-reported activity was not associated with incident AF or stroke.

Conclusions: Greater accelerometer-derived physical activity is associated with lower risks of AF and stroke. Future preventive efforts to reduce AF risk may be most effective when targeting adherence to objective activity thresholds.
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http://dx.doi.org/10.1093/eurheartj/ehab250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291334PMC
July 2021

Catheter Ablation for Brugada Syndrome.

J Innov Card Rhythm Manag 2021 May 15;12(5):4520-4524. Epub 2021 May 15.

Cardiac Arrhythmia Unit, Heart Center, Massachusetts General Hospital, Boston, MA, USA.

We report a case of catheter ablation of Brugada syndrome in a patient with refractory ventricular fibrillation despite quinidine therapy. We performed epicardial substrate mapping, which identified an area of abnormal fractionated, prolonged electrogram in the anterior right ventricular outflow tract. Warm saline infusion into the pericardial space induced further delay of the local electrogram, consistent with Brugada syndrome physiology. Coronary angiography confirmed that the area was distant from major coronary arteries. Ablation was performed in this area, which eliminated local abnormal electrograms and led to the disappearance of coved-type ST elevation in V1-V2. No ventricular fibrillation had recurred by five months of follow-up.
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http://dx.doi.org/10.19102/icrm.2021.120502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139310PMC
May 2021

Sex differences in inflammatory markers in patients hospitalized with COVID-19 infection: Insights from the MGH COVID-19 patient registry.

PLoS One 2021 28;16(4):e0250774. Epub 2021 Apr 28.

From the Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, United States of America.

Background: Men are at higher risk for serious complications related to COVID-19 infection than women. More robust immune activation in women has been proposed to contribute to decreased disease severity, although systemic inflammation has been associated with worse outcomes in COVID-19 infection. Whether systemic inflammation contributes to sex differences in COVID-19 infection is not known.

Study Design And Methods: We examined sex differences in inflammatory markers among 453 men (mean age 61) and 328 women (mean age 62) hospitalized with COVID-19 infection at the Massachusetts General Hospital from March 8 to April 27, 2020. Multivariable linear regression models were used to examine the association of sex with initial and peak inflammatory markers. Exploratory analyses examined the association of sex and inflammatory markers with 28-day clinical outcomes using multivariable logistic regression.

Results: Initial and peak CRP were higher in men compared with women after adjustment for baseline differences (initial CRP: ß 0.29, SE 0.07, p = 0.0001; peak CRP: ß 0.31, SE 0.07, p<0.0001) with similar findings for IL-6, PCT, and ferritin (p<0.05 for all). Men had greater than 1.5-greater odds of dying compared with women (OR 1.71, 95% CI 1.04-2.80, p = 0.03). Sex modified the association of peak CRP with both death and ICU admission, with stronger associations observed in men compared with women (death: OR 9.19, 95% CI 4.29-19.7, p <0.0001 in men vs OR 2.81, 95% CI 1.52-5.18, p = 0.009 in women, Pinteraction = 0.02).

Conclusions: In a sample of 781 men and women hospitalized with COVID-19 infection, men exhibited more robust inflammatory activation as evidenced by higher initial and peak inflammatory markers, as well as worse clinical outcomes. Better understanding of sex differences in immune responses to COVID-19 infection may shed light on the pathophysiology of COVID-19 infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250774PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081177PMC
May 2021

Rationale and design of a large population study to validate software for the assessment of atrial fibrillation from data acquired by a consumer tracker or smartwatch: The Fitbit heart study.

Am Heart J 2021 Aug 15;238:16-26. Epub 2021 Apr 15.

Harvard Medical School, Boston, MA; Biostatistics Center, Massachusetts General Hospital, Boston, MA.

Background: Early detection of atrial fibrillation or flutter (AF) may enable prevention of downstream morbidity. Consumer wrist-worn wearable technology is capable of detecting AF by identifying irregular pulse waveforms using photoplethysmography (PPG). The validity of PPG-based software algorithms for AF detection requires prospective assessment.

Methods: The Fitbit Heart Study (NCT04380415) is a single-arm remote clinical trial examining the validity of a novel PPG-based software algorithm for detecting AF. The proprietary Fitbit algorithm examines pulse waveform intervals during analyzable periods in which participants are sufficiently stationary. Fitbit consumers with compatible wrist-worn trackers or smartwatches were invited to participate. Enrollment began May 6, 2020 and as of October 1, 2020, 455,699 participants enrolled. Participants in whom an irregular heart rhythm was detected were invited to attend a telehealth visit and eligible participants were then mailed a one-week single lead electrocardiographic (ECG) patch monitor. The primary study objective is to assess the positive predictive value of an irregular heart rhythm detection for AF during the ECG patch monitor period. Additional objectives will examine the validity of irregular pulse tachograms during subsequent heart rhythm detections, self-reported AF diagnoses and treatments, and relations between irregular heart rhythm detections and AF episode duration and time spent in AF.

Conclusions: The Fitbit Heart Study is a large-scale remote clinical trial comprising a unique software algorithm for detection of AF. The study results will provide critical insights into the use of consumer wearable technology for AF detection, and for characterizing the nature of AF episodes detected using consumer-based PPG technology.
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http://dx.doi.org/10.1016/j.ahj.2021.04.003DOI Listing
August 2021

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.

Nat Commun 2021 04 12;12(1):2182. Epub 2021 Apr 12.

Division of Cardiology, George Washington University School of Medicine and Healthcare Sciences, Washington, DC, USA.

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
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http://dx.doi.org/10.1038/s41467-021-22339-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042019PMC
April 2021

Robust, flexible, and scalable tests for Hardy-Weinberg equilibrium across diverse ancestries.

Genetics 2021 May;218(1)

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.
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http://dx.doi.org/10.1093/genetics/iyab044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128395PMC
May 2021

Usefulness of Rhythm Monitoring Following Acute Ischemic Stroke.

Am J Cardiol 2021 05 20;147:44-51. Epub 2021 Feb 20.

Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

We characterized monitor utilization in stroke survivors and assessed associations with underlying clinical atrial fibrillation (AF) risk. We retrospectively analyzed consecutive patients with acute ischemic stroke 10/2018-6/2019 without prevalent AF and assessed the 6-month incidence of monitor utilization (Holter/ECG, event/patch, implantable loop recorder [ILR]) using Fine-Gray models accounting for the competing risk of death. We assessed for predictors of monitor utilization using cause-specific hazards regression adjusted for the Cohorts for Heart and Aging Research in Genomic Epidemiology AF (CHARGE-AF) score, stroke subtype, and discharge disposition. Of 493 patients with acute ischemic stroke (age 65±16; 47% women), the 6-month incidence of monitor utilization was 36.5% (95% CI 31.7, 41.3), and 6-month mortality was 13.6% (10.4, 16.8). Monitoring was performed with Holter/event (n = 107; 72.3%), ILR (n = 34; 23.0%) or both (n = 7; 4.7%). Monitoring was more likely after cryptogenic (hazard ratio [HR] 4.53 [3.22, 6.39]; 6-month monitor incidence 70.6%) and cardioembolic (HR 2.43 [1.28, 4.62]; incidence 47.7%) stroke, versus other/undocumented (incidence 22.7%). Among patients with cryptogenic stroke, the 6-month incidence of ILR was 27.5% [18.5, 36.5]. Monitoring was more likely after discharge home (HR 1.80 [1.29, 2.52]; incidence 46.1%) versus facility (incidence 24.9%). Monitoring was not associated with CHARGE-AF score (HR 1.08 per 1-SD increase [0.91, 1.27]), even though CHARGE-AF was associated with incident AF (HR 1.56 [1.03, 2.35]). In conclusion, rhythm monitors are utilized after one-third of ischemic strokes. Monitoring is more frequent after cryptogenic strokes, though ILR use is low. Monitor utilization is not associated with AF risk.
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http://dx.doi.org/10.1016/j.amjcard.2021.01.038DOI Listing
May 2021

The Implementation and Acceptability of a Mobile Application for Screening for Atrial Fibrillation at Home.

Telemed J E Health 2021 Feb 22. Epub 2021 Feb 22.

Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Although patients are able to easily record electrocardiograms using consumer devices, these are typically not shared with their clinicians. This article discusses the development and acceptability of a mobile application (app) that integrates with the electronic health record to facilitate screening for atrial fibrillation (AF). After app development and implementation, we compared workflows with and without the mobile app. Seven older adults used it during a prospective twice-daily 2-week home-based AF screening protocol and completed an acceptability survey with Likert scale responses. Compliance with the screening protocol was 82%. Acceptability and usability was favorable. Patients reported confidence in the connection between the app and their medical record. The availability of apps to capture data and facilitate a connection with health systems is critical. The app developed is a feasible solution for older patients with AF to self-monitor and report results to their health provider.
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http://dx.doi.org/10.1089/tmj.2020.0427DOI Listing
February 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Approximate conditional phenotype analysis based on genome wide association summary statistics.

Sci Rep 2021 Jan 28;11(1):2518. Epub 2021 Jan 28.

Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.

Because single genetic variants may have pleiotropic effects, one trait can be a confounder in a genome-wide association study (GWAS) that aims to identify loci associated with another trait. A typical approach to address this issue is to perform an additional analysis adjusting for the confounder. However, obtaining conditional results can be time-consuming. We propose an approximate conditional phenotype analysis based on GWAS summary statistics, the covariance between outcome and confounder, and the variant minor allele frequency (MAF). GWAS summary statistics and MAF are taken from GWAS meta-analysis results while the traits covariance may be estimated by two strategies: (i) estimates from a subset of the phenotypic data; or (ii) estimates from published studies. We compare our two strategies with estimates using individual level data from the full GWAS sample (gold standard). A simulation study for both binary and continuous traits demonstrates that our approximate approach is accurate. We apply our method to the Framingham Heart Study (FHS) GWAS and to large-scale cardiometabolic GWAS results. We observed a high consistency of genetic effect size estimates between our method and individual level data analysis. Our approach leads to an efficient way to perform approximate conditional analysis using large-scale GWAS summary statistics.
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http://dx.doi.org/10.1038/s41598-021-82000-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843738PMC
January 2021

Research Priorities in Atrial Fibrillation Screening: A Report From a National Heart, Lung, and Blood Institute Virtual Workshop.

Circulation 2021 Jan 25;143(4):372-388. Epub 2021 Jan 25.

Division of Cardiology and Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (R.D.L., J.P.P., S.M.A.-K.).

Clinically recognized atrial fibrillation (AF) is associated with higher risk of complications, including ischemic stroke, cognitive decline, heart failure, myocardial infarction, and death. It is increasingly recognized that AF frequently is undetected until complications such as stroke or heart failure occur. Hence, the public and clinicians have an intense interest in detecting AF earlier. However, the most appropriate strategies to detect undiagnosed AF (sometimes referred to as subclinical AF) and the prognostic and therapeutic implications of AF detected by screening are uncertain. Our report summarizes the National Heart, Lung, and Blood Institute's virtual workshop focused on identifying key research priorities related to AF screening. Global experts reviewed major knowledge gaps and identified critical research priorities in the following areas: (1) role of opportunistic screening; (2) AF as a risk factor, risk marker, or both; (3) relationship between AF burden detected with long-term monitoring and outcomes/treatments; (4) designs of potential randomized trials of systematic AF screening with clinically relevant outcomes; and (5) role of AF screening after ischemic stroke. Our report aims to inform and catalyze AF screening research that will advance innovative, resource-efficient, and clinically relevant studies in diverse populations to improve the diagnosis, management, and prognosis of patients with undiagnosed AF.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047633DOI Listing
January 2021

Non-Vitamin K Antagonist Oral Anticoagulant vs Warfarin for Post Cardiac Surgery Atrial Fibrillation.

Ann Thorac Surg 2021 Jan 10. Epub 2021 Jan 10.

Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts, USA. Electronic address:

Background: Treatment guidelines for non-valvular atrial fibrillation (AF) recommend use of non-vitamin K antagonist oral anticoagulants (NOAC) 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 including 30-day mortality, major bleeding complications and stroke/transient ischemic attack (TIA). Secondary outcomes included post-operative length of stay (LOS) and 30-day myocardial infarction, venous thromboembolism and pericardial effusion/tamponade.

Results: 9,769 (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 (OR=0.76,95% CI 0.49-1.18), stroke/TIA (OR=0.94,95% CI 0.53-1.67) or mortality (OR=1.08,95% CI 0.80-1.45). Following 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=1.17,95% CI 0.62-2.22), venous thromboembolism (OR=0.91,95% CI 0.47-1.78) or pericardial effusion/tamponade (OR=1.09,95% CI 0.80-1.47) between the two groups. NOAC therapy was associated with a half-day reduction in post-operative LOS (β=-0.47,95% CI -0.62 to -0.33).

Conclusions: NOACs are associated with a reduction in post-operative LOS, without excess bleeding or other short-term complications, compared to 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.
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http://dx.doi.org/10.1016/j.athoracsur.2020.12.031DOI Listing
January 2021

Genetic Risk Score to Identify Risk of Venous Thromboembolism in Patients With Cardiometabolic Disease.

Circ Genom Precis Med 2021 02 12;14(1):e003006. Epub 2021 Jan 12.

TIMI Study Group, Division of Cardiovascular Medicine, Department of Medicine (N.A.M., G.E.M.M., Y.G., F.K.K., R.P.G., B.M.S., E.B., M.S.S., C.T.R.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Background: Venous thromboembolism (VTE) is a major cause of cardiovascular morbidity and mortality and has a known genetic contribution. We tested the performance of a genetic risk score for its ability to predict VTE in 3 cohorts of patients with cardiometabolic disease.

Methods: We included patients from the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) trials (history of a major atherosclerotic cardiovascular event, myocardial infarction, and diabetes, respectively) who consented for genetic testing and were not on baseline anticoagulation. We calculated a VTE genetic risk score based on 297 single nucleotide polymorphisms with established genome-wide significance. Patients were divided into tertiles of genetic risk. Cox proportional hazards models were used to calculate hazard ratios for VTE across genetic risk groups. The polygenic risk score was compared with available clinical risk factors (age, obesity, smoking, history of heart failure, and diabetes) and common monogenic mutations.

Results: A total of 29 663 patients were included in the analysis with a median follow-up of 2.4 years, of whom 174 had a VTE event. There was a significantly increased gradient of risk across VTE genetic risk tertiles (-trend <0.0001). After adjustment for clinical risk factors, patients in the intermediate and high genetic risk groups had a 1.88-fold (95% CI, 1.23-2.89; =0.004) and 2.70-fold (95% CI, 1.81-4.06; <0.0001) higher risk of VTE compared with patients with low genetic risk. In a continuous model adjusted for clinical risk factors, each standard deviation increase in the genetic risk score was associated with a 47% (95% CI, 29-68) increased risk of VTE (<0.0001).

Conclusions: In a broad spectrum of patients with cardiometabolic disease, a polygenic risk score is a strong, independent predictor of VTE after accounting for available clinical risk factors, identifying 1/3 of patients who have a risk of VTE comparable to that seen with established monogenic thrombophilia.
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http://dx.doi.org/10.1161/CIRCGEN.120.003006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887088PMC
February 2021

The role of obesity in inflammatory markers in COVID-19 patients.

Obes Res Clin Pract 2021 Jan-Feb;15(1):96-99. Epub 2020 Dec 23.

The Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, United States; Division of Cardiology, Massachusetts General Hospital, Boston, MA, United States. Electronic address:

Obesity has emerged as a significant risk factor for severe COVID-19 worldwide. Given both COVID-19 infection and obesity have been associated with increased systemic inflammation, we evaluated inflammatory markers in obese and non-obese individuals hospitalized for COVID-19 at Massachusetts General Hospital. We hypothesized that obese patients would have a more exuberant inflammatory response as evidenced by higher initial and peak inflammatory markers along with worse clinical outcomes. Of the 781 patients, 349 were obese (45%). Obese individuals had higher initial and peak levels of CRP and ESR as well as higher peak d-dimer (P < 0.01 for all) in comparison to non-obese individuals, while. IL-6 and ferritin were similar. In addition, obese individuals had a higher odds of requiring vasopressor use (OR 1.54, 95% CI 1.00-2.38, P = 0.05), developing hypoxemic respiratory failure (OR 1.58, 95% CI 1.04-2.40, P = 0.03) and death (OR 2.20, 95% CI 1.31-3.70, P = 0.003) within 28 days of presentation to care. Finally, higher baseline levels of CRP and D-dimer were associated with worse clinical outcomes even after adjustment for BMI. Our findings suggest greater disease severity in obese individuals is characterized by more exuberant inflammation.
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http://dx.doi.org/10.1016/j.orcp.2020.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833898PMC
February 2021

Association Between Frailty and Atrial Fibrillation in Older Adults: The Framingham Heart Study Offspring Cohort.

J Am Heart Assoc 2021 01 29;10(1):e018557. Epub 2020 Dec 29.

Department of Biostatistics Boston University School of Public Health Boston MA.

Background Frailty is associated bidirectionally with cardiovascular disease. However, the relations between frailty and atrial fibrillation (AF) have not been fully elucidated. Methods and Results Using the FHS (Framingham Heart Study) Offspring cohort, we sought to examine both the association between frailty (2005-2008) and incident AF through 2016 and the association between prevalent AF and frailty status (2011-2014). Frailty was defined using the Fried phenotype. Models adjusted for age, sex, and smoking. Cox proportional hazards models, adjusted for competing risk of death, assessed the association between prevalent frailty and incident AF. Logistic regression models assessed the association between prevalent AF and new-onset frailty. For the incident AF analysis, we included 2053 participants (56% women; mean age, 69.7±6.9 years). By Fried criteria, 1018 (50%) were robust, 903 (44%) were prefrail, and 132 (6%) were frail. In total, 306 incident cases of AF occurred during an average 9.2 (SD, 3.1) follow-up years. After adjustment, there was no statistically significant association between prevalent frailty status and incident AF (prefrail versus robust: hazard ratio [HR], 1.22 [95% CI, 0.95-1.55]; frail versus robust: HR, 0.92 [95% CI, 0.57-1.47]). At follow-up, there were 111 new cases of frailty. After adjustment, there was no statistically significant association between prevalent AF and new-onset frailty (odds ratio, 0.48 [95% CI, 0.17-1.36]). Conclusions Although a bidirectional association between frailty and cardiovascular disease has been suggested, we did not find evidence of an association between frailty and AF. Our findings may be limited by sample size and should be further explored in other populations.
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http://dx.doi.org/10.1161/JAHA.120.018557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955470PMC
January 2021

Massachusetts general hospital Covid-19 registry reveals two distinct populations of hospitalized patients by race and ethnicity.

PLoS One 2020 22;15(12):e0244270. Epub 2020 Dec 22.

Harvard Medical School, Boston, Massachusetts, United States of America.

Objective: To evaluate differences by race/ethnicity in clinical characteristics and outcomes among hospitalized patients with Covid-19 at Massachusetts General Hospital (MGH).

Methods: The MGH Covid-19 Registry includes confirmed SARS-CoV-2-infected patients hospitalized at MGH and is based on manual chart reviews and data extraction from electronic health records (EHRs). We evaluated differences between White/Non-Hispanic and Hispanic patients in demographics, complications and 14-day outcomes among the N = 866 patients hospitalized with Covid-19 from March 11, 2020-May 4, 2020.

Results: Overall, 43% of patients hospitalized with Covid-19 were women, median age was 60.4 [IQR = (48.2, 75)], 11.3% were Black/non-Hispanic and 35.2% were Hispanic. Hispanic patients, representing 35.2% of patients, were younger than White/non-Hispanic patients [median age 51y; IQR = (40.6, 61.6) versus 72y; (58.0, 81.7) (p<0.001)]. Hispanic patients were symptomatic longer before presenting to care (median 5 vs 3d, p = 0.039) but were more likely to be sent home with self-quarantine than be admitted to hospital (29% vs 16%, p<0.001). Hispanic patients had fewer comorbidities yet comparable rates of ICU or death (34% vs 36%). Nonetheless, a greater proportion of Hispanic patients recovered by 14 days after presentation (62% vs 45%, p<0.001; OR = 1.99, p = 0.011 in multivariable adjusted model) and fewer died (2% versus 18%, p<0.001).

Conclusions: Hospitalized Hispanic patients were younger and had fewer comorbidities compared to White/non-Hispanic patients; despite comparable rates of ICU care or death, a greater proportion recovered. These results have implications for public health policy and the design and conduct of clinical trials.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244270PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755195PMC
January 2021

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.

Nat Commun 2020 12 18;11(1):6417. Epub 2020 Dec 18.

The Institute for Translational Genomics and Population Sciences, Department of Pediatrics and Los Angeles Biomedical Research Institute, Harbor-UCLA, Torrance, CA, USA.

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.
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http://dx.doi.org/10.1038/s41467-020-20086-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749177PMC
December 2020

Automated Electronic Phenotyping of Cardioembolic Stroke.

Stroke 2021 01 10;52(1):181-189. Epub 2020 Dec 10.

Cardiovascular Research Center and Cardiac Arrhythmia Service (W.G., S.K., A.T.T.L., L.X.H., S.A.L.), Massachusetts General Hospital, Boston.

Background And Purpose: Oral anticoagulation is generally indicated for cardioembolic strokes, but not for other stroke causes. Consequently, subtype classification of ischemic stroke is important for risk stratification and secondary prevention. Because manual classification of ischemic stroke is time-intensive, we assessed the accuracy of automated algorithms for performing cardioembolic stroke subtyping using an electronic health record (EHR) database.

Methods: We adapted TOAST (Trial of ORG 10172 in Acute Stroke Treatment) features associated with cardioembolic stroke for derivation in the EHR. Using administrative codes and echocardiographic reports within Mass General Brigham Biobank (N=13 079), we iteratively developed EHR-based algorithms to define the TOAST cardioembolic stroke features, revising regular expression algorithms until achieving positive predictive value ≥80%. We compared several machine learning-based statistical algorithms for discriminating cardioembolic stroke using the feature algorithms applied to EHR data from 1598 patients with acute ischemic strokes from the Massachusetts General Hospital Ischemic Stroke Registry (2002-2010) with previously adjudicated TOAST and Causative Classification of Stroke subtypes.

Results: Regular expression-based feature extraction algorithms achieved a mean positive predictive value of 95% (range, 88%-100%) across 11 echocardiographic features. Among 1598 patients from the Massachusetts General Hospital Ischemic Stroke Registry, 1068 had any cardioembolic stroke feature within predefined time windows in proximity to the stroke event. Cardioembolic stroke tended to occur at an older age, with more TOAST-based comorbidities, and with atrial fibrillation (82.3%). The best model was a random forest with 92.2% accuracy and area under the receiver operating characteristic curve of 91.1% (95% CI, 87.5%-93.9%). Atrial fibrillation, age, dilated cardiomyopathy, congestive heart failure, patent foramen ovale, mitral annulus calcification, and recent myocardial infarction were the most discriminatory features.

Conclusions: Machine learning-based identification of cardioembolic stroke using EHR data is feasible. Future work is needed to improve the accuracy of automated cardioembolic stroke identification and assess generalizability of electronic phenotyping algorithms across clinical settings.
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http://dx.doi.org/10.1161/STROKEAHA.120.030663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769922PMC
January 2021

Performance of Atrial Fibrillation Risk Prediction Models in Over 4 Million Individuals.

Circ Arrhythm Electrophysiol 2021 01 9;14(1):e008997. Epub 2020 Dec 9.

Cardiovascular Disease Initiative, Broad Institute of the Massachusetts Institute of Technology & Harvard University, Cambridge (S.K., J.M.A., A.P., A.V.K., P.T.E., S.A.L.).

Background: Atrial fibrillation (AF) is associated with increased risks of stroke and heart failure. Electronic health record (EHR)-based AF risk prediction may facilitate efficient deployment of interventions to diagnose or prevent AF altogether.

Methods: We externally validated an electronic health record AF (EHR-AF) score in IBM Explorys Life Sciences, a multi-institutional dataset containing statistically deidentified EHR data for over 21 million individuals (Explorys Dataset). We included individuals with complete AF risk data, ≥2 office visits within 2 years, and no prevalent AF. We compared EHR-AF to existing scores including CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology Atrial Fibrillation), CHEST (coronary artery disease or chronic obstructive pulmonary disease, hypertension, elderly, systolic heart failure, thyroid disease), and CHADS-VASc. We assessed association between AF risk scores and 5-year incident AF, stroke, and heart failure using Cox proportional hazards modeling, 5-year AF discrimination using C indices, and calibration of predicted AF risk to observed AF incidence.

Results: Of 21 825 853 individuals in the Explorys Dataset, 4 508 180 comprised the analysis (age 62.5, 56.3% female). AF risk scores were strongly associated with 5-year incident AF (hazard ratio per SD increase 1.85 using CHADS-VASc to 2.88 using EHR-AF), stroke (1.61 using CHEST to 1.92 using CHARGE-AF), and heart failure (1.91 using CHADS-VASc to 2.58 using EHR-AF). EHR-AF (C index, 0.808 [95% CI, 0.807-0.809]) demonstrated favorable AF discrimination compared to CHARGE-AF (0.806 [95% CI, 0.805-0.807]), CHEST (0.683 [95% CI, 0.682-0.684]), and CHADS-VASc (0.720 [95% CI, 0.719-0.722]). Of the scores, EHR-AF demonstrated the best calibration to incident AF (calibration slope, 1.002 [95% CI, 0.997-1.007]). In subgroup analyses, AF discrimination using EHR-AF was lower in individuals with stroke (C index, 0.696 [95% CI, 0.692-0.700]) and heart failure (0.621 [95% CI, 0.617-0.625]).

Conclusions: EHR-AF demonstrates predictive accuracy for incident AF using readily ascertained EHR data. AF risk is associated with incident stroke and heart failure. Use of such risk scores may facilitate decision support and population health management efforts focused on minimizing AF-related morbidity.
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http://dx.doi.org/10.1161/CIRCEP.120.008997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856013PMC
January 2021

Clinical Application of a Novel Genetic Risk Score for Ischemic Stroke in Patients With Cardiometabolic Disease.

Circulation 2021 Feb 13;143(5):470-478. Epub 2020 Nov 13.

TIMI Study Group, Boston, MA (N.A.M., F.K.K., F.N., G.M.M., R.P.G., B.M.S., M.L.O'D., E.M.A., E.B., M.S.S., C.T.R.).

Background: Genome-wide association studies have identified single-nucleotide polymorphisms that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in 5 trials across the spectrum of cardiometabolic disease.

Methods: Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), SOLID-TIMI 52 (Stabilization of Plaques Using Darapladib), SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trials were included in this analysis. A set of 32 single-nucleotide polymorphisms associated with ischemic stroke was used to calculate a GRS in each patient and identify tertiles of genetic risk. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk factors.

Results: In 51 288 subjects across the 5 trials, a total of 960 subjects had an ischemic stroke over a median follow-up period of 2.5 years. After adjusting for clinical risk factors, a higher GRS was strongly and independently associated with increased risk for ischemic stroke ( trend=0.009). In comparison with individuals in the lowest third of the GRS, individuals in the middle and top tertiles of the GRS had adjusted hazard ratios of 1.15 (95% CI, 0.98-1.36) and 1.24 (95% CI 1.05-1.45) for ischemic stroke, respectively. Stratification into subgroups revealed that the performance of the GRS appeared stronger in the primary prevention cohort with an adjusted hazard ratio for the top versus lowest tertile of 1.27 (95% CI, 1.04-1.53), in comparison with an adjusted hazard ratio of 1.06 (95% CI, 0.81-1.41) in subjects with previous stroke. In an exploratory analysis of patients with atrial fibrillation and CHADS-VASc score of 2, high genetic risk conferred a 4-fold higher risk of stroke and an absolute risk equivalent to those with CHADS-VASc score of 3.

Conclusions: Across a broad spectrum of subjects with cardiometabolic disease, a 32-single-nucleotide polymorphism GRS was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation but lower CHADS-VASc scores, the GRS identified patients with risk comparable to those with higher CHADS-VASc scores.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856243PMC
February 2021

Associations Between Alcohol Intake and Genetic Predisposition With Atrial Fibrillation Risk in a National Biobank.

Circ Genom Precis Med 2020 12 6;13(6):e003111. Epub 2020 Nov 6.

Cardiovascular Disease Initiative, The Broad Institute of MIT & Harvard, Cambridge (J.L.H., L.-C.W., S.H.C., S.J.J., V.N.M., S.K., P.T.E., S.A.L.).

Background: Excess alcohol intake and inherited predisposition may increase risk of atrial fibrillation (AF). We assessed the association between alcohol intake, polygenic predisposition to AF, and incident AF in the UK Biobank, a prospective cohort study.

Methods: In 376 776 UK Biobank participants enrolled between 2006 and 2010, we tested alcohol consumption (stratified by the Centers of Disease Control and Prevention acceptable range of ≤98 g/wk for women or ≤196 g/wk for men; and as a continuous variable) and an AF polygenic risk score for association with incident AF.

Results: Among participants (47.5% male, mean age 56.9 years), 6293 developed AF during a median of 6.9 years of follow-up. Alcohol consumption was associated with AF (hazard ratio, 1.10 [95% CI, 1.05-1.16] for intake above an acceptable range; hazard ratio, 1.04 per 100 g/wk [95% CI, 1.02-1.06]). An AF polygenic risk score was associated with AF (hazard ratio, 1.38 per SD [95% CI, 1.35-1.41]). In models including both alcohol and the AF polygenic risk score, each remained associated with AF. The 5-year cumulative risk of AF for individuals with alcohol intake above an acceptable range and in the highest decile of polygenic risk was 2.33% (95% CI, 2.07-2.59), compared with 0.69% (95% CI, 0.58-0.80) for those with alcohol intake within an acceptable range and in the lowest decile of polygenic risk.

Conclusions: Alcohol consumption is associated with increased risk of AF across a range of polygenic predisposition to AF and adds to inherited and clinical predisposition to increase AF susceptibility. Preventive efforts focused on minimizing alcohol intake may be broadly applicable.
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http://dx.doi.org/10.1161/CIRCGEN.120.003111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738370PMC
December 2020

Epigenetic Analyses of Human Left Atrial Tissue Identifies Gene Networks Underlying Atrial Fibrillation.

Circ Genom Precis Med 2020 12 6;13(6):e003085. Epub 2020 Nov 6.

Cardiovascular Research Center, Massachusetts General Hospital, Boston (A.W.H., S.A.L., N.R.T., P.T.E.).

Background: Atrial fibrillation (AF) often arises from structural abnormalities in the left atria (LA). Annotation of the noncoding genome in human LA is limited, as are effects on gene expression and chromatin architecture. Many AF-associated genetic variants reside in noncoding regions; this knowledge gap impairs efforts to understand the molecular mechanisms of AF and cardiac conduction phenotypes.

Methods: We generated a model of the LA noncoding genome by profiling 7 histone post-translational modifications (active: H3K4me3, H3K4me2, H3K4me1, H3K27ac, H3K36me3; repressive: H3K27me3, H3K9me3), binding, and gene expression in samples from 5 individuals without structural heart disease or AF. We used MACS2 to identify peak regions (<0.01), applied a Markov model to classify regulatory elements, and annotated this model with matched gene expression data. We intersected chromatin states with expression quantitative trait locus, DNA methylation, and HiC chromatin interaction data from LA and left ventricle. Finally, we integrated genome-wide association data for AF and electrocardiographic traits to link disease-related variants to genes.

Results: Our model identified 21 epigenetic states, encompassing regulatory motifs, such as promoters, enhancers, and repressed regions. Genes were regulated by proximal chromatin states; repressive states were associated with a significant reduction in gene expression (<2×10). Chromatin states were differentially methylated, promoters were less methylated than repressed regions (<2×10). We identified over 15 000 LA-specific enhancers, defined by homeobox family motifs, and annotated several cardiovascular disease susceptibility loci. Intersecting AF and PR genome-wide association studies loci with long-range chromatin conformation data identified a gene interaction network dominated by , , , and .

Conclusions: Profiling the noncoding genome provides new insights into the gene expression and chromatin regulation in human LA tissue. These findings enabled identification of a gene network underlying AF; our experimental and analytic approach can be extended to identify molecular mechanisms for other cardiac diseases and traits.
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http://dx.doi.org/10.1161/CIRCGEN.120.003085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240092PMC
December 2020

2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families.

Heart Rhythm 2021 01 19;18(1):e1-e50. Epub 2020 Oct 19.

The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

This international multidisciplinary document intends to provide clinicians with evidence-based practical patient-centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families.
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http://dx.doi.org/10.1016/j.hrthm.2020.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194370PMC
January 2021
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