Publications by authors named "Dawood Darbar"

153 Publications

Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes.

JAMA Cardiol 2021 Sep 8. Epub 2021 Sep 8.

Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Importance: Early-onset atrial fibrillation (AF) can be the initial manifestation of a more serious underlying inherited cardiomyopathy or arrhythmia syndrome.

Objective: To examine the results of genetic testing for early-onset AF.

Design, Setting, And Participants: This prospective, observational cohort study enrolled participants from an academic medical center who had AF diagnosed before 66 years of age and underwent whole genome sequencing through the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine program. Participants were enrolled from November 23, 1999, to June 2, 2015. Data analysis was performed from October 24, 2020, to March 11, 2021.

Exposures: Rare variants identified in a panel of 145 genes that are included on cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories.

Main Outcomes And Measures: Sequencing data were analyzed using an automated process followed by manual review by a panel of independent, blinded reviewers. The primary outcome was classification of rare variants using American College of Medical Genetics and Genomics criteria: benign, likely benign, variant of undetermined significance, likely pathogenic, or pathogenic. Disease-associated variants were defined as pathogenic/likely pathogenic variants in genes associated with autosomal dominant or X-linked dominant disorders.

Results: Among 1293 participants (934 [72.2%] male; median [interquartile range] age at enrollment, 56 [48-61] years; median [interquartile range] age at AF diagnosis, 50 [41-56] years), genetic testing identified 131 participants (10.1%) with a disease-associated variant, 812 (62.8%) with a variant of undetermined significance, 92 (7.1%) as heterozygous carriers for an autosomal recessive disorder, and 258 (20.0%) with no suspicious variant. The likelihood of a disease-associated variant was highest in participants with AF diagnosed before the age of 30 years (20 of 119 [16.8%; 95% CI, 10.0%-23.6%]) and lowest after the age of 60 years (8 of 112 [7.1%; 95% CI, 2.4%-11.9%]). Disease-associated variants were more often associated with inherited cardiomyopathy syndromes compared with inherited arrhythmias. The most common genes were TTN (n = 38), MYH7 (n = 18), MYH6 (n = 10), LMNA (n = 9), and KCNQ1 (n = 8).

Conclusions And Relevance: In this cohort study, genetic testing identified a disease-associated variant in 10% of patients with early-onset AF (the percentage was higher if diagnosed before the age of 30 years and lower if diagnosed after the age of 60 years). Most pathogenic/likely pathogenic variants are in genes associated with cardiomyopathy. These results support the use of genetic testing in early-onset AF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamacardio.2021.3370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427496PMC
September 2021

Deciphering the Electrophysiological Mechanisms for Ibrutinib-Induced Ventricular Arrhythmias.

JACC CardioOncol 2020 Nov 17;2(4):630-631. Epub 2020 Nov 17.

Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaccao.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352279PMC
November 2020

Common genetic variation in circadian clock genes are associated with cardiovascular risk factors in an African American and Hispanic/Latino cohort.

Int J Cardiol Heart Vasc 2021 Jun 3;34:100808. Epub 2021 Jun 3.

Department of Medicine, Division of Cardiology, University of Illinois at Chicago, Chicago, IL, USA.

Misalignment of the internal circadian time with external physical time due to environmental factors or due to genetic variantion in circadian clock genes has been associated with increased incidence of cardiovascular risk factors. Common genetic variation in circadian genes in the United States have been identified predominantly in European ancestry individuals. We therefore examined the association between circadian clock single nucleotide polymorphisms (SNPs) in genes and cardiovascular risk factors in African Americans and Hispanic/Latinos. We analyzed 17 candidate circadian SNPs in 1,166 subjects who self-identified as African-American or Hispanic/Latino and were enrolled in the UIC Cohort of Patients, Family and Friends. We found significant differences in the minor allele frequencies between African American and Hispanic/Latino subjects. Our analyses also established ethnic-specific SNPs that are associated with cardiovascular risk factors. In Hispanic/Latinos, the rs6850524 in was associated with increased risk for hypertension, meanwhile rs12649507, rs4864546, and rs4864548 reduced the risk, also rs8192440 () reduced the risk for type 2 diabetes. In African Americans, the rs1801260 and rs6850524 were negatively associated with the presence of obesity; rs11022775 reduced the risk for dyslipidemia; and the rs2292912 increased the risk for dyslipidemia and diabetes. Genetic variations in candidate circadian-clock genes are associated with risk factors for cardiovascular disease in African-Americans and Hispanic/Latinos. Our findings may help to improve cardiovascular risk assessment as well as better understand how circadian misalignment impacts cardiovascular risk in diverse populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcha.2021.100808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188044PMC
June 2021

Human induced pluripotent stem cell-derived atrial cardiomyocytes carrying an SCN5A mutation identify nitric oxide signaling as a mediator of atrial fibrillation.

Stem Cell Reports 2021 Jun 20;16(6):1542-1554. Epub 2021 May 20.

Division of Cardiology, Department of Medicine, Chicago, IL, USA; Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA; Jesse Brown Veterans Administration Medical Center, Chicago, IL, USA. Electronic address:

Mutations in SCN5A, encoding the cardiac sodium channel, are linked with familial atrial fibrillation (AF) but the underlying pathophysiologic mechanisms and implications for therapy remain unclear. To characterize the pathogenesis of AF-linked SCN5A mutations, we generated patient-specific induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) from two kindreds carrying SCN5A mutations (E428K and N470K) and isogenic controls using CRISPR-Cas9 gene editing. We showed that mutant AF iPSC-aCMs exhibited spontaneous arrhythmogenic activity with beat-to-beat irregularity, prolonged action potential duration, and triggered-like beats. Single-cell recording revealed enhanced late sodium currents (I) in AF iPSC-aCMs that were absent in a heterologous expression model. Gene expression profiling of AF iPSC-aCMs showed differential expression of the nitric oxide (NO)-mediated signaling pathway underlying enhanced I. We showed that patient-specific AF iPSC-aCMs exhibited striking in vitro electrophysiological phenotype of AF-linked SCN5A mutations, and transcriptomic analyses supported that the NO signaling pathway modulated the I and triggered AF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.stemcr.2021.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190590PMC
June 2021

Common genetic variants associated with obesity in an African-American and Hispanic/Latino population.

PLoS One 2021 13;16(5):e0250697. Epub 2021 May 13.

Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America.

Introduction: Over 35% of all adults in the world are currently obese and risk of obesity in racial or ethnic minority groups exist in the US, but the causes of these differences are not all known. As obesity is a leading cause of cardiovascular disease, an improved understanding of risk factors across racial and ethnic groups may improve outcomes.

Objective: The objective of this study was to determine if susceptibility to obesity is associated with genetic variation in candidate single nucleotide polymorphisms (SNPs) in African Americans and Hispanic/Latinos.

Materials And Methods: We examined data from 534 African Americans and 557 Hispanic/Latinos participants from the UIC Cohort of Patients, Family and Friends. Participants were genotyped for the top 26 obesity-associated SNPs within FTO, MC4R, TUB, APOA2, APOA5, ADIPOQ, ARL15, CDH13, KNG1, LEPR, leptin, and SCG3 genes.

Results: The mean (SD) age of participants was 49±13 years, 55% were female, and mean body mass index (BMI) was 31±7.5 kg/m2. After adjusting for age and sex, we found that rs8050136 in FTO (odds ratio [OR] 1.40, 95% confidence interval [CI] 1.1-1.8; P = 0.01) among African Americans and rs2272383 in TUB (OR 1.34, 95% CI 1.04-1.71; P = 0.02) among Hispanic/Latinos were associated with obesity. However, none of the SNPs in multivariable analysis of either AA or H/L cohorts were significant when adjusted for multiple correction.

Conclusions: We show that candidate SNPs in the FTO and TUB genes are associated with obesity in African Americans and Hispanic/Latinos individuals respectively. While the underlying pathophysiological mechanisms by which common genetic variants cause obesity remain unclear, we have identified novel therapeutic targets across racial and ethnic groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250697PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118531PMC
October 2021

Genetics of atrial fibrillation-practical applications for clinical management: if not now, when and how?

Cardiovasc Res 2021 Jun;117(7):1718-1731

Department of Cardiology, University Heart and Vascular Center, University Medical Center Hamburg Eppendorf, Martinistraße 52, 20251 Hamburg, Hamburg, Germany.

The prevalence and economic burden of atrial fibrillation (AF) are predicted to more than double over the next few decades. In addition to anticoagulation and treatment of concomitant cardiovascular conditions, early and standardized rhythm control therapy reduces cardiovascular outcomes as compared with a rate control approach, favouring the restoration, and maintenance of sinus rhythm safely. Current therapies for rhythm control of AF include antiarrhythmic drugs (AADs) and catheter ablation (CA). However, response in an individual patient is highly variable with some remaining free of AF for long periods on antiarrhythmic therapy, while others require repeat AF ablation within weeks. The limited success of rhythm control therapy for AF is in part related to incomplete understanding of the pathophysiological mechanisms and our inability to predict responses in individual patients. Thus, a major knowledge gap is predicting which patients with AF are likely to respond to rhythm control approach. Over the last decade, tremendous progress has been made in defining the genetic architecture of AF with the identification of rare mutations in cardiac ion channels, signalling molecules, and myocardial structural proteins associated with familial (early-onset) AF. Conversely, genome-wide association studies have identified common variants at over 100 genetic loci and the development of polygenic risk scores has identified high-risk individuals. Although retrospective studies suggest that response to AADs and CA is modulated in part by common genetic variation, the development of a comprehensive clinical and genetic risk score may enable the translation of genetic data to the bedside care of AF patients. Given the economic impact of the AF epidemic, even small changes in therapeutic efficacy may lead to substantial improvements for patients and health care systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cvr/cvab153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208749PMC
June 2021

Association of Rare Genetic Variants and Early-Onset Atrial Fibrillation in Ethnic Minority Individuals.

JAMA Cardiol 2021 Jul;6(7):811-819

Department of Medicine, University of Illinois at Chicago.

Importance: Although rare variants in cardiac ion channels, transcription factors, and myocardial structural proteins are associated with early-onset atrial fibrillation (AF) in White individuals of European descent, it remains unclear whether genetic variation also contributes to the cause of AF in those of minority ethnicity.

Objectives: To assess the prevalence of rare and novel pathogenic variants in candidate genes in ethnic minority probands with early-onset AF and determine genotype-phenotype associations.

Design, Setting, And Participants: In this cohort, family-based study, probands of African and Hispanic descent with early-onset AF (defined as AF occurring in individuals aged ≤66 years) prospectively enrolled in a clinical and genetic biorepository underwent sequencing of 60 candidate genes. Recruitment took place from July 1, 2015, to June 30, 2019. Data were analyzed from February 1 to February 28, 2020.

Exposures: Rare and novel variants categorized as pathogenic or likely pathogenic.

Main Outcomes And Measures: The prevalence of rare and novel pathogenic variants in African American and Hispanic/Latinx probands with early-onset AF and genotype-phenotype associations.

Results: Among 227 probands with early-onset AF, mean (SD) age at onset of AF was 51.0 (9.9) years, 132 probands (58.1%) were men, 148 (65.2%) were African American, and 79 (34.8%) were Hispanic/Latinx. A family history of AF was verified in 24 probands with early-onset AF (10.6%). Sequencing 60 candidate genes identified 53 (23 rare and 30 novel) variants with 16 of the 227 (7.0%) probands harboring likely pathogenic (43.8%) or pathogenic (56.2%) variants, with most loss-of-function variants in TTN, the gene encoding the sarcomeric protein titin (46.7%). In 6 families with more than 2 affected members, variants of unknown significance in sodium channel (SCN10A), potassium channel (KCNE5), sarcomeric proteins (MYH6 and TTN), and atrial natriuretic peptide (NPPA) cosegregated with AF.

Conclusions And Relevance: In this study, likely pathogenic and pathogenic variants were identified, with most loss-of-function variants in TTN, that increase susceptibility to early-onset AF in African American and Hispanic/Latinx individuals. These findings provide further understanding toward molecular phenotyping of AF and suggest novel mechanism-based therapeutic approaches for this common arrhythmia in ethnic minority groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamacardio.2021.0994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100900PMC
July 2021

Bioengineering approaches to mature induced pluripotent stem cell-derived atrial cardiomyocytes to model atrial fibrillation.

Exp Biol Med (Maywood) 2021 Aug 25;246(16):1816-1828. Epub 2021 Apr 25.

Department of Bioengineering, University of Illinois at Chicago, Chicago, IL 60607, USA.

Induced pluripotent stem cells (iPSCs) serve as a robust platform to model several human arrhythmia syndromes including atrial fibrillation (AF). However, the structural, molecular, functional, and electrophysiological parameters of patient-specific iPSC-derived atrial cardiomyocytes (iPSC-aCMs) do not fully recapitulate the mature phenotype of their human adult counterparts. The use of physiologically inspired microenvironmental cues, such as postnatal factors, metabolic conditioning, extracellular matrix (ECM) modulation, electrical and mechanical stimulation, co-culture with non-parenchymal cells, and 3D culture techniques can help mimic natural atrial development and induce a more mature adult phenotype in iPSC-aCMs. Such advances will not only elucidate the underlying pathophysiological mechanisms of AF, but also identify and assess novel mechanism-based therapies towards supporting a more 'personalized' (i.e. patient-specific) approach to pharmacologic therapy of AF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/15353702211009146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381703PMC
August 2021

Atrial Fibrillation and Longitudinal Change in Cognitive Function in CKD.

Kidney Int Rep 2021 Mar 5;6(3):669-674. Epub 2021 Jan 5.

Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

Background: Studies in the general population suggest that atrial fibrillation (AF) is an independent risk factor for decline in cognitive function, but this relationship has not been examined in adults with chronic kidney disease (CKD). We investigated the association between incident AF and changes in cognitive function over time in this population.

Methods And Results: We studied a subgroup of 3254 adults participating in the Chronic Renal Insufficiency Cohort Study. Incident AF was ascertained by 12-lead electrocardiogram (ECG) obtained at a study visit and/or identification of a hospitalization with AF during follow-up. Cognitive function was assessed biennially using the Modified Mini-Mental State Exam. Linear mixed effects regression was used to evaluate the association between incident AF and longitudinal change in cognitive function. Compared with individuals without incident AF ( = 3158), those with incident AF ( = 96) were older, had a higher prevalence of cardiovascular disease and hypertension, and lower estimated glomerular filtration rate. After median follow-up of 6.8 years, we observed no significant multivariable association between incident AF and change in cognitive function test score.

Conclusion: In this cohort of adults with CKD, incident AF was not associated with a decline in cognitive function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ekir.2020.12.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938064PMC
March 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%.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Atrial Fibrillation in Inherited Channelopathies.

Card Electrophysiol Clin 2021 03 8;13(1):155-163. Epub 2021 Jan 8.

Division of Cardiology, Department of Medicine, University of Illinois at Chicago, 820 S Wood Street, Suite 920S, Chicago, IL 60612, USA; Division of Cardiology, Department of Pharmacology, University of Illinois at Chicago, 820 S Wood Street, Suite 920S, Chicago, IL 60612, USA; Department of Medicine, Jesse Brown Veterans Administration, 820 S Wood Street, Suite 920S, Chicago, IL 60612, USA. Electronic address:

Atrial fibrillation (AF), the common sustained arrhythmia in clinical practice, has major public health implications due to its associated morbidity and increased mortality. The AF epidemic is due to the burgeoning elderly population and the identification of novel risk factors, for example, genetics. Since the diagnosis of AF has a major impact on the clinical assessment and management of patients with inherited arrhythmia syndromes, improved understanding of the cause and pathogenesis of AF has provided important insights into the underlying pathophysiological mechanisms of this common arrhythmia and identified potential mechanism-based therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccep.2020.10.004DOI Listing
March 2021

Unraveling the genomic basis of congenital heart disease.

Authors:
Dawood Darbar

J Clin Invest 2021 01;131(2)

Division of Cardiology, Departments of Medicine and Pharmacology, University of Illinois at Chicago, Chicago, Illinois, USA.

The genetic, epigenetic, and environmental etiologic basis of congenital heart disease (CHD) for most heart anomalies remains unexplained. In this issue of the JCI, Lahm et al. performed the largest genome-wide association study (GWAS) to date of European individuals with CHD and clinical subtypes. The comprehensive meta-analysis included over 4000 patients and 8000 controls and uncovered common genetic variants that associated with cardiac anomalies. Lahm and colleagues performed single-cell analysis of induced pluripotent stem cells and heart cells, revealing a role for MACROD2, GOSR2, WNT3, and MSX1 in the developing heart. This study advances our understanding of the genetic basis of common forms of CHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI145377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810466PMC
January 2021

Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Nature 2020 10 14;586(7831):763-768. Epub 2020 Oct 14.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944936PMC
October 2020

Pathogenic mutations perturb calmodulin regulation of Na1.8 channel.

Biochem Biophys Res Commun 2020 11 15;533(1):168-174. Epub 2020 Sep 15.

Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA; Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA; Jesse Brown Veterans Administration, Chicago, IL, USA. Electronic address:

The voltage-gated sodium channels play a key role in the generation and propagation of the cardiac action potential. Emerging data indicate that the Na1.8 channel, encoded by the SCN10A gene, is a modulator of cardiac conduction and variation in the gene has been associated with arrhythmias such as atrial fibrillation (AF) and Brugada syndrome (BrS). The voltage gated sodium channels contain a calmodulin (CaM)-binding IQ domain involved in channel slow inactivation, we here investigated the role of CaM regulation of Na1.8 channel function, and showed that CaM enhanced slow inactivation of the Na1.8 channel and hyperpolarized steady-state inactivation curve of sodium currents. The effects of CaM on the channel gating were disrupted in the Na1.8 channel truncated IQ domain. We studied Na1.8 IQ domain mutations associated with AF and BrS, and found that a BrS-linked mutation (R1863Q) reduced the CaM-induced hyperpolarization shift, AF-linked mutations (R1869C and R1869G) disrupted CaM-induced enhanced inactivation, and effects of CaM on both development and recovery from slow inactivation were attenuated in all pathogenic mutations. Our findings indicate a role of CaM in the regulation of Na1.8 channel function in cardiac arrhythmias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2020.08.010DOI Listing
November 2020

Ion Channel and Structural Remodeling in Obesity-Mediated Atrial Fibrillation.

Circ Arrhythm Electrophysiol 2020 08 12;13(8):e008296. Epub 2020 Jul 12.

Department of Medicine (M.D.M., L.H., A.S., A.M., S.P., M.Z., I.B.d.S., M.G.B., J.R., D.D.), Rush University Medical Center.

Background: Epidemiological studies have established obesity as an independent risk factor for atrial fibrillation (AF), but the underlying pathophysiological mechanisms remain unclear. Reduced cardiac sodium channel expression is a known causal mechanism in AF. We hypothesized that obesity decreases Nav1.5 expression via enhanced oxidative stress, thus reducing , and enhancing susceptibility to AF.

Methods: To elucidate the underlying electrophysiological mechanisms a diet-induced obese mouse model was used. Weight, blood pressure, glucose, F-isoprostanes, NOX2 (NADPH oxidase 2), and PKC (protein kinase C) were measured in obese mice and compared with lean controls. Invasive electrophysiological, immunohistochemistry, Western blotting, and patch clamping of membrane potentials was performed to evaluate the molecular and electrophysiological phenotype of atrial myocytes.

Results: Pacing-induced AF in 100% of diet-induced obese mice versus 25% in controls (<0.01) with increased AF burden. Cardiac sodium channel expression, and atrial action potential duration were reduced and potassium channel expression (Kv1.5) and current () and F-isoprostanes, NOX2, and PKC-α/δ expression and atrial fibrosis were significantly increased in diet-induced obese mice as compared with controls. A mitochondrial antioxidant reduced AF burden, restored , , , action potential duration, and reversed atrial fibrosis in diet-induced obese mice as compared with controls.

Conclusions: Inducible AF in obese mice is mediated, in part, by a combined effect of sodium, potassium, and calcium channel remodeling and atrial fibrosis. Mitochondrial antioxidant therapy abrogated the ion channel and structural remodeling and reversed the obesity-induced AF burden. Our findings have important implications for the management of obesity-mediated AF in patients. Graphic Abstract: A graphic abstract is available for this article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCEP.120.008296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935016PMC
August 2020

Multi-Ethnic Genome-Wide Association Study of Decomposed Cardioelectric Phenotypes Illustrates Strategies to Identify and Characterize Evidence of Shared Genetic Effects for Complex Traits.

Circ Genom Precis Med 2020 08 30;13(4):e002680. Epub 2020 Jun 30.

Gillings School of Global Public Health (A.R.B., H.M.H., R.G., M.G., C.J.H., A.A.S., E.A.W., K.E.N., C.L.A.), University of North Carolina at Chapel Hill.

Background: We examined how expanding electrocardiographic trait genome-wide association studies to include ancestrally diverse populations, prioritize more precise phenotypic measures, and evaluate evidence for shared genetic effects enabled the detection and characterization of loci.

Methods: We decomposed 10 seconds, 12-lead electrocardiograms from 34 668 multi-ethnic participants (15% Black; 30% Hispanic/Latino) into 6 contiguous, physiologically distinct (P wave, PR segment, QRS interval, ST segment, T wave, and TP segment) and 2 composite, conventional (PR interval and QT interval) interval scale traits and conducted multivariable-adjusted, trait-specific univariate genome-wide association studies using 1000-G imputed single-nucleotide polymorphisms. Evidence of shared genetic effects was evaluated by aggregating meta-analyzed univariate results across the 6 continuous electrocardiographic traits using the combined phenotype adaptive sum of powered scores test.

Results: We identified 6 novels (, and ) and 87 known loci (adaptive sum of powered score test <5×10). Lead single-nucleotide polymorphism rs3211938 at was common in Blacks (minor allele frequency=10%), near monomorphic in European Americans, and had effects on the QT interval and TP segment that ranked among the largest reported to date for common variants. The other 5 novel loci were observed when evaluating the contiguous but not the composite electrocardiographic traits. Combined phenotype testing did not identify novel electrocardiographic loci unapparent using traditional univariate approaches, although this approach did assist with the characterization of known loci.

Conclusions: Despite including one-third as many participants as published electrocardiographic trait genome-wide association studies, our study identified 6 novel loci, emphasizing the importance of ancestral diversity and phenotype resolution in this era of ever-growing genome-wide association studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.119.002680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520945PMC
August 2020

Impact of traditional risk factors for the outcomes of atrial fibrillation across race and ethnicity and sex groups.

Int J Cardiol Heart Vasc 2020 Jun 29;28:100538. Epub 2020 May 29.

Departments of Medicine, University of Illinois at Chicago, USA.

Background: Although traditional risk factors for atrial fibrillation (AF) and its outcomes are established in whites, their role in the pathogenesis of AF across race-ethnicity and both sexes remain unclear. Cohort studies have consistently shown worse AF-related outcomes in these groups. The objective of this study was to determine the role played by race- and sex-specific risk factors in AF outcomes in non-Hispanic blacks (NHBs), Hispanics/Latinos (H/Ls), and non-Hispanic whites (NHWs).

Methods: Using electronic health records (EHR), 3607 patients with an ICD-9 code for AF were identified over a 7-year period. Risk factors were identified from ICD to 9 CM claims data: hypertension (HTN), type 2 diabetes mellitus (T2DM), stroke/transient ischemic attack (TIA), smoking, chronic obstructive pulmonary disease (COPD), coronary artery disease (CAD), peripheral arterial disease (PAD) and obstructive sleep apnea (OSA). Multivariate analysis of variance was used to compare the incidence of AF risk factors.

Results: NHBs and H/Ls with AF experienced more stroke than NHWs (27% and 24% vs. 19% P < 0.01). Females had less HTN (48.4% vs 51.6% [males], P = 0.0002), CAD (47.4% vs 55.7% [males], P = 0.02), and smoking rates (38.2% vs 61.8% [males], P < 0.0001) but higher stroke rates (25.9% [female] vs 21.8% [males], P < 0.0001). Age-adjusted risk factors for stroke varied markedly across race-ethnicity and sex.

Conclusions: We identified differences in risk factors for AF and stroke across race-ethnicity and sex. The findings of our study are hypothesis generating and should be used to direct future studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcha.2020.100538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262442PMC
June 2020

Genetic Susceptibility for Atrial Fibrillation in Patients Undergoing Atrial Fibrillation Ablation.

Circ Arrhythm Electrophysiol 2020 03 14;13(3):e007676. Epub 2020 Feb 14.

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.B.S., C.S., L.L.R., D.M.C., J.M., Z.Y., Q.W., T.I., P.W., G.M.).

Background: Ablation is a widely used therapy for atrial fibrillation (AF); however, arrhythmia recurrence and repeat procedures are common. Studies examining surrogate markers of genetic susceptibility to AF, such as family history and individual AF susceptibility alleles, suggest these may be associated with recurrence outcomes. Accordingly, the aim of this study was to test the association between AF genetic susceptibility and recurrence after ablation using a comprehensive polygenic risk score for AF.

Methods: Ten centers from the AF Genetics Consortium identified patients who had undergone de novo AF ablation. AF genetic susceptibility was measured using a previously described polygenic risk score (N=929 single-nucleotide polymorphisms) and tested for an association with clinical characteristics and time-to-recurrence with a 3 month blanking period. Recurrence was defined as >30 seconds of AF, atrial flutter, or atrial tachycardia. Multivariable analysis adjusted for age, sex, height, body mass index, persistent AF, hypertension, coronary disease, left atrial size, left ventricular ejection fraction, and year of ablation.

Results: Four thousand two hundred seventy-six patients were eligible for analysis of baseline characteristics and 3259 for recurrence outcomes. The overall arrhythmia recurrence rate between 3 and 12 months was 44% (1443/3259). Patients with higher AF genetic susceptibility were younger (<0.001) and had fewer clinical risk factors for AF (=0.001). Persistent AF (hazard ratio [HR], 1.39 [95% CI, 1.22-1.58]; <0.001), left atrial size (per cm: HR, 1.32 [95% CI, 1.19-1.46]; <0.001), and left ventricular ejection fraction (per 10%: HR, 0.88 [95% CI, 0.80-0.97]; =0.008) were associated with increased risk of recurrence. In univariate analysis, higher AF genetic susceptibility trended towards a higher risk of recurrence (HR, 1.08 [95% CI, 0.99-1.18]; =0.07), which became less significant in multivariable analysis (HR, 1.06 [95% CI, 0.98-1.15]; =0.13).

Conclusions: Higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors but not recurrence. Arrhythmia recurrence after AF ablation may represent a genetically different phenotype compared to AF susceptibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCEP.119.007676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080569PMC
March 2020

Association Between Obesity-Mediated Atrial Fibrillation and Therapy With Sodium Channel Blocker Antiarrhythmic Drugs.

JAMA Cardiol 2020 01;5(1):57-64

Division of Cardiology, Department of Medicine, University of Illinois at Chicago.

Importance: The association between obesity, an established risk factor for atrial fibrillation (AF), and response to antiarrhythmic drugs (AADs) remains unclear.

Objective: To test the hypothesis that obesity differentially mediates response to AADs in patients with symptomatic AF and in mice with diet-induced obesity (DIO) and pacing induced AF.

Design, Setting, And Participants: An observational cohort study was conducted including 311 patients enrolled in a clinical-genetic registry. Mice fed a high-fat diet for 10 weeks were also evaluated. The study was conducted from January 1, 2018, to June 2, 2019.

Main Outcomes And Measures: Symptomatic response was defined as continuation of the same AAD for at least 3 months. Nonresponse was defined as discontinuation of the AAD within 3 months of initiation because of poor symptomatic control of AF necessitating alternative rhythm control therapy. Outcome measures in DIO mice were pacing-induced AF and suppression of AF after 2 weeks of treatment with flecainide acetate or sotalol hydrochloride.

Results: A total of 311 patients (mean [SD] age, 65 [12] years; 120 women [38.6%]) met the entry criteria and were treated with a class I or III AAD for symptomatic AF. Nonresponse to class I AADs in patients with obesity was less than in those without obesity (30% [obese] vs 6% [nonobese]; difference, 0.24; 95% CI, 0.11-0.37; P = .001). Both groups had similar symptomatic response to a potassium channel blocker AAD. On multivariate analysis, obesity, AAD class (class I vs III AAD [obese] odds ratio [OR], 4.54; 95% Wald CI, 1.84-11.20; P = .001), female vs male sex (OR, 2.31; 95% Wald CI, 1.07-4.99; P = .03), and hyperthyroidism (OR, 4.95; 95% Wald CI, 1.23-20.00; P = .02) were significant indicators of the probability of failure to respond to AADs. Pacing induced AF in 100% of DIO mice vs 30% (P < .001) in controls. Furthermore, DIO mice showed a greater reduction in AF burden when treated with sotalol compared with flecainide (85% vs 25%; P < .01).

Conclusions And Relevance: Results suggest that obesity differentially mediates response to AADs in patients and in mice with AF, possibly reducing the therapeutic effectiveness of sodium channel blockers. These findings may have implications for the management of AF in patients with obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamacardio.2019.4513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902234PMC
January 2020

Clinical and Genetic Contributors to New-Onset Atrial Fibrillation in Critically Ill Adults.

Crit Care Med 2020 01;48(1):22-30

Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.

Objectives: New-onset atrial fibrillation during critical illness is an independent risk factor for mortality. The ability to identify patients at high risk for new-onset atrial fibrillation is limited. We hypothesized that genetic susceptibility contributes to risk of new-onset atrial fibrillation in the ICU.

Design: Retrospective sub-study of a prospective observational cohort study.

Setting: Medical and general surgical ICUs in a tertiary academic medical center.

Patients: One-thousand three-hundred sixty-nine critically ill patients admitted to the ICU for at least 2 days with no known history of atrial fibrillation who had DNA available for genotyping.

Interventions: None.

Measurements And Main Results: We genotyped 21 single-nucleotide polymorphisms associated with atrial fibrillation in ambulatory studies using a Sequenom platform (San Diego, CA). We collected demographics, medical history, and development of new-onset atrial fibrillation during the first four days of ICU admission. New-onset atrial fibrillation occurred in 98 patients (7.2%) and was associated with age, male sex, coronary artery disease, and vasopressor use. Single-nucleotide polymorphisms associated with new-onset atrial fibrillation were rs3853445 (near PITX2, p = 0.0002), rs6838973 (near PITX2, p = 0.01), and rs12415501 (in NEURL, p = 0.03) on univariate testing. When controlling for clinical factors, rs3853445 (odds ratio, 0.47; 95% CI, 0.30-0.73; p = 0.001) and rs12415501 (odds ratio, 1.72; 95% CI, 1.27-2.59; p = 0.01) remained significantly associated with new-onset atrial fibrillation. The addition of genetic variables to clinical factors improved new-onset atrial fibrillation discrimination in a multivariable logistic regression model (C-statistic 0.82 vs 0.78; p = 0.0009).

Conclusions: We identified several single-nucleotide polymorphisms associated with new-onset atrial fibrillation in a large cohort of critically ill ICU patients, suggesting there is genetic susceptibility underlying this common clinical condition. This finding may provide new targets for future mechanistic studies and additional insight into the application of genomic information to identify patients at elevated risk for a common and important condition in the ICU.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCM.0000000000004034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910934PMC
January 2020

GWAS of QRS duration identifies new loci specific to Hispanic/Latino populations.

PLoS One 2019 28;14(6):e0217796. Epub 2019 Jun 28.

Cardiovascular Health Research Unit, University of Washington, Seattle, WA, United States of America.

Background: The electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored.

Methods: We performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n = 15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis.

Results: We identified six loci associated with QRS (P<5x10-8), including two novel loci: MYOCD, a nuclear protein expressed in the heart, and SYT1, an integral membrane protein. The top SNP in the MYOCD locus, intronic SNP rs16946539, was found in Hispanics/Latinos with a minor allele frequency (MAF) of 0.04, but is monomorphic in European and African descent populations. The most significant QRS duration association was with intronic SNP rs3922344 (P = 1.19x10-24) in SCN5A/SCN10A. Three other previously identified loci, CDKN1A, VTI1A, and HAND1, also exceeded the GWAS significance threshold among Hispanics/Latinos. A total of 27 of 32 previously identified QRS duration SNPs were shown to generalize in Hispanics/Latinos.

Conclusions: Our QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217796PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599128PMC
February 2020

Electrophysiologic and molecular mechanisms of a frameshift NPPA mutation linked with familial atrial fibrillation.

J Mol Cell Cardiol 2019 07 8;132:24-35. Epub 2019 May 8.

Departments of Medicine, University of Illinois at Chicago, Chicago, IL, United States of America; Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, United States of America; Pharmacology, University of Illinois at Chicago, Chicago, IL, United States of America. Electronic address:

A frameshift (fs) mutation in the natriuretic peptide precursor A (NPPA) gene, encoding a mutant atrial natriuretic peptide (Mut-ANP), has been linked with familial atrial fibrillation (AF) but the underlying mechanisms by which the mutation causes AF remain unclear. We engineered 2 transgenic (TG) mouse lines expressing the wild-type (WT)-NPPA gene (H-WT-NPPA) and the human fs-Mut-NPPA gene (H-fsMut-NPPA) to test the hypothesis that mice overexpressing the human NPPA mutation are more susceptible to AF and elucidate the underlying electrophysiologic and molecular mechanisms. Transthoracic echocardiography and surface electrocardiography (ECG) were performed in H-fsMut-NPPA, H-WT-NPPA, and Non-TG mice. Invasive electrophysiology, immunohistochemistry, Western blotting and patch clamping of membrane potentials were performed. To examine the role of the Mut-ANP in ion channel remodeling, we measured plasma cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity in the 3 groups of mice. In H-fsMut-NPPA mice mean arterial pressure (MAP) was reduced when compared to H-WT-NPPA and Non-TG mice. Furthermore, injection of synthetic fs-Mut-ANP lowered the MAP in H-WT-NPPA and Non-TG mice while synthetic WT-ANP had no effect on MAP in the 3 groups of mice. ECG characterization revealed significantly prolonged QRS duration in H-fsMut-NPPA mice when compared to the other two groups. Trans-Esophageal (TE) atrial pacing of H-fsMut-NPPA mice showed increased AF burden and AF episodes when compared with H-WT-NPPA or Non-TG mice. The cardiac Na (NaV1.5) and Ca (CaV1.2/CaV1.3) channel expression and currents (I, I) and action potential durations (APD/APD/APD) were significantly reduced in H-fsMut-NPPA mice while the rectifier K channel current (I) was markedly increased when compared to the other 2 groups of mice. In addition, plasma cGMP levels were only increased in H-fsMut-NPPA mice with a corresponding reduction in plasma cAMP levels and PKA activity. In summary, we showed that mice overexpressing an AF-linked NPPA mutation are more prone to develop AF and this risk is mediated in part by remodeling of the cardiac Na, Ca and K channels creating an electrophysiologic substrate for reentrant AF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yjmcc.2019.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599642PMC
July 2019

Association Between Family History and Early-Onset Atrial Fibrillation Across Racial and Ethnic Groups.

JAMA Netw Open 2018 09 7;1(5):e182497. Epub 2018 Sep 7.

Department of Medicine, University of Illinois at Chicago.

Importance: There is a genetic predisposition to early-onset atrial fibrillation (EOAF) in European American individuals. However, the role of family history in the pathogenesis of EOAF in racial and ethnic minorities remains unclear.

Objective: To determine whether probands with EOAF across racial and ethnic groups have a higher rate of AF in first-degree family members than racially and ethnically matched control patients with non-early-onset AF (non-EOAF).

Design, Setting, And Participants: In this cohort study, patients prospectively enrolled in a clinical and genetic biorepository were administered baseline questionnaires that included questions about family history of AF. Early-onset AF was defined as AF occurring in probands aged 60 years or younger in the absence of structural heart disease. All other forms were categorized as non-EOAF. Recruitment took place from July 2015 to December 2017. Analysis was performed in January 2018.

Main Outcomes And Measures: Primary analysis of reported family history of AF in first-degree relatives with sensitivity analysis restricted to those in whom a family history was confirmed by medical record review and electrocardiogram.

Results: Of 664 patients enrolled (mean [SD] age, 62 [12] years; 407 [61%] male), 267 (40%) were European American; 258 (39%), African American; and 139 (21%), Hispanic/Latino. There was a family history of AF in 36 probands with EOAF (49%) compared with 128 patients with non-EOAF (22%) (difference, 27%; 95% CI, 14%-40%; P < .001). On multivariable analysis, the adjusted odds of a proband with EOAF who was of African descent (odds ratio [OR], 2.69; 95% CI, 1.06-6.91; P < .001) or Hispanic descent (OR, 9.25; 95% CI, 2.37-36.23; P = .002) having a first-degree relative with AF were greater than those of European descent (OR, 2.51; 95% CI, 1.29-4.87; P = .006). Overall, probands with EOAF were more likely to have a first-degree relative with AF compared with patients with non-EOAF (adjusted OR, 3.02; 95% CI, 1.82-4.95; P < .001) across the 3 racial and ethnic groups. Atrial fibrillation in a first-degree family member was confirmed in 32% of probands with EOAF vs 11% of those with non-EOAF (difference, 21%; 95% CI, 11%-33%; P < .001). Furthermore, African American (28% vs 5%; difference, 23%; 95% CI, 4%-43%; P = .001), European American (35% vs 20%; difference, 15%; 95% CI, 1%-30%; P = .03), and Hispanic/Latino (30% vs 5%; difference, 25%; 95% CI, 4%-54%; P = .02) probands with EOAF were more likely to have a first-degree relative with confirmed AF vs racially and ethnically matched control patients with non-EOAF. The positive and negative predictive values for a family history of confirmed AF were both 89%.

Conclusions And Relevance: Probands of African or Hispanic/Latino descent with EOAF were more likely to have a first-degree relative with AF when compared with European American individuals. These findings support genetic predisposition to EOAF across all 3 races.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2018.2497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324458PMC
September 2018

Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation.

JAMA 2018 12;320(22):2354-2364

Department of Molecular and Functional Genomics, Geisinger, Danville, Pennsylvania.

Importance: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood.

Objective: To perform large-scale whole-genome sequencing to identify genetic variants related to AF.

Design, Setting, And Participants: The National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18 526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa. This case-control study included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank (346 546 participants) and the MyCode Study (42 782 participants).

Exposures: Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome.

Main Outcomes And Measures: Early-onset AF (defined as AF onset in persons <66 years of age). Due to multiple testing, the significance threshold for the rare variant analysis was P = 4.55 × 10-3.

Results: Among 2781 participants with early-onset AF (the case group), 72.1% were men, and the mean (SD) age of AF onset was 48.7 (10.2) years. Participants underwent whole-genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least 1 LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of case participants compared with 1.1% in control participants (odds ratio [OR], 1.76 [95% CI, 1.04-2.97]). The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend, 4.92 × 10-4), and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (OR, 5.94 [95% CI, 2.64-13.35]; P = 1.65 × 10-5). The association between TTN LOF variants and AF was replicated in an independent study of 1582 patients with early-onset AF (cases) and 41 200 control participants (OR, 2.16 [95% CI, 1.19-3.92]; P = .01).

Conclusions And Relevance: In a case-control study, there was a statistically significant association between an LOF variant in the TTN gene and early-onset AF, with the variant present in a small percentage of participants with early-onset AF (the case group). Further research is necessary to understand whether this is a causal relationship.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2018.18179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436530PMC
December 2018

Coding variants in and increase risk of atrial fibrillation.

Commun Biol 2018 12;1:68. Epub 2018 Jun 12.

HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway.

Most sequence variants identified hitherto in genome-wide association studies (GWAS) of atrial fibrillation are common, non-coding variants associated with risk through unknown mechanisms. We performed a meta-analysis of GWAS of atrial fibrillation among 29,502 cases and 767,760 controls from Iceland and the UK Biobank with follow-up in samples from Norway and the US, focusing on low-frequency coding and splice variants aiming to identify causal genes. We observe associations with one missense (OR = 1.20) and one splice-donor variant (OR = 1.50) in , the first ribosomal gene implicated in atrial fibrillation to our knowledge. Analysis of 167 RNA samples from the right atrium reveals that the splice-donor variant in results in exon skipping. We also observe an association with a missense variant in (OR = 1.38), encoding a component of the intercalated discs of cardiomyocytes. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-018-0068-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123807PMC
June 2018

Race and Socioeconomic Status Regulate Lifetime Risk of Atrial Fibrillation.

Circ Arrhythm Electrophysiol 2018 07;11(7):e006584

Division of Cardiology, University of Illinois at Chicago. Jesse Brown Veterans Administration, Chicago, IL.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCEP.118.006584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061964PMC
July 2018

Relation of Body Mass Index to Symptom Burden in Patients withAtrial Fibrillation.

Am J Cardiol 2018 07 1;122(2):235-241. Epub 2018 May 1.

Department of Medicine, University of Illinois at Chicago, Jesse Brown VA Medical Center, Chicago, Illinois; Departments of Medicine and Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee. Electronic address:

Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with significant morbidity and increased mortality. As body mass index (BMI) is increasingly recognized as an important risk factor for the development of AF, we tested the hypothesis that BMI modulates symptomatic AF burden. Cross-sectional data collected from 1,382 patients in the Vanderbilt AF Registry were analyzed. AF severity was assessed using the Toronto atrial fibrillation severity scale (AFSS). BMI was categorized according to World Health Organization guidelines and patients were grouped according to their present AF treatment regimen: no treatment (n = 185), rate control therapy with atrioventricular nodal blocking agents (n = 351), rhythm control with antiarrhythmic drugs (n = 636), and previous AF ablation (n = 210). Patients with BMI >35 kg/m had higher AFSS scores than those with BMI <30 kg/m in the rate control (43.57 vs 38.21: p = 0.0057), rhythm control (46.61 vs 41.08: p = 1.6 × 10), and ablation (44.01 vs 39.02: p = 0.047) groups. Inunivariate linear models, BMI was associated with an increase in the AFSS score in the rate control (0.27, 95% confidence interval [CI] 0.05 to 0.5, p = 0.02), rhythm control (0.38, 95% CI 0.21 to 0.56, p = 2.49 × 10), and ablation (0.38, 95% CI 0.03 to 0.73, p = 0.03) groups. The association remained significant in the rhythm control groups after adjusting for age, gender, race, and comorbidities (0.29, 95% CI 0.11 to 0.49, p = 0.002). In conclusion, increasing BMI was directly associated with patient reported measures of AF symptom severity, burden, and quality of life. This was most significant in patients treated with rhythm-control strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.amjcard.2018.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028292PMC
July 2018

Multi-ethnic genome-wide association study for atrial fibrillation.

Nat Genet 2018 06 11;50(9):1225-1233. Epub 2018 Jun 11.

Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-018-0133-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136836PMC
June 2018

Electrophysiologic Characterization of Calcium Handling in Human Induced Pluripotent Stem Cell-Derived Atrial Cardiomyocytes.

Stem Cell Reports 2018 06 3;10(6):1867-1878. Epub 2018 May 3.

Division of Cardiology, Department of Medicine, University of Illinois at Chicago, 840 S. Wood Street, 920S (MC 715), Chicago, IL 60612, USA; Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA. Electronic address:

Human induced pluripotent stem cell (hiPSC)-derived atrial cardiomyocytes (CMs) hold great promise for elucidating underlying cellular mechanisms that cause atrial fibrillation (AF). In order to use atrial-like hiPSC-CMs for arrhythmia modeling, it is essential to better understand the molecular and electrophysiological phenotype of these cells. We performed comprehensive molecular, transcriptomic, and electrophysiologic analyses of retinoic acid (RA)-guided hiPSC atrial-like CMs and demonstrate that RA results in differential expression of genes involved in calcium ion homeostasis that directly interact with an RA receptor, chicken ovalbumin upstream promoter-transcription factor 2 (COUP-TFII). We report a mechanism by which RA generates an atrial-like electrophysiologic signature through the downstream regulation of calcium channel gene expression by COUP-TFII and modulation of calcium handling. Collectively, our results provide important insights into the underlying molecular mechanisms that regulate atrial-like hiPSC-CM electrophysiology and support the use of atrial-like CMs derived from hiPSCs to model AF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.stemcr.2018.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989733PMC
June 2018
-->