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The association of QT interval components with atrial fibrillation.

ABSTRACT: BACKGROUND:Although abnormalities of the QT interval are associated with atrial fibrillation (AF), it is unclear whether ventricular depolarization (QRS duration) or repolarization (JT interval) is a more important marker of AF risk. METHODS:This analysis included 4,181 (95% white; 59% women) participants from the Cardiovascular Health Study (CHS) who were free of baseline AF and major intraventricular delay. A linear scale was used to compute heart rate adjusted QT (QTa), QRS (QRSa ), and JT (JTa ) intervals. Prolonged QTa , QRSa , and JTa were defined by values greater than the sex-specific 95th percentile for each measurement. AF events were ascertained during the annual study electrocardiograms and from hospitalization discharge data. Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the associations of prolonged QTa , QRSa , and JTa with AF, separately. RESULTS:Over a mean follow-up of 12.1 years, a total of 1,236 (30%) AF events were detected. An increased risk of AF (HR = 1.50. 95% CI = 1.20, 1.88) was observed with prolonged QTa . When we examined the association between individual components of the QTa interval and AF, the risk of AF was limited to prolonged JTa (HR = 1.31, 95% CI = 1.04, 1.65) and not prolonged QRSa (HR = 1.00, 95% CI = 0.77, 1.30). Similar results were obtained per 1-SD increase in QTa (HR = 1.07, 95% CI = 1.01, 1.13), QRSa (HR = 0.99, 95% CI = 0.94, 1.06), and JTa (HR = 1.07, 95% CI = 1.01, 1.13). CONCLUSIONS:The JT interval is a more important marker of AF risk in the QT interval among persons who do not have ventricular conduction delays.

SUBMITTER: Patel N

PROVIDER: S-EPMC5747556 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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The association of QT interval components with atrial fibrillation.

Patel Nikhil N O'Neal Wesley T WT Whalen S Patrick SP Soliman Elsayed Z EZ

Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc 20170629 2

<h4>Background</h4>Although abnormalities of the QT interval are associated with atrial fibrillation (AF), it is unclear whether ventricular depolarization (QRS duration) or repolarization (JT interval) is a more important marker of AF risk.<h4>Methods</h4>This analysis included 4,181 (95% white; 59% women) participants from the Cardiovascular Health Study (CHS) who were free of baseline AF and major intraventricular delay. A linear scale was used to compute heart rate adjusted QT (QTa), QRS (QR ...[more]

PMID: 28660734

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Project description:BackgroundThe QT interval measures cardiac repolarization, and prolongation is associated with adverse cardiovascular outcomes and death. The exponential Bazett correction formula overestimates the QT interval during tachycardia.ObjectiveWe evaluated 4 formulas of QT interval correction in individuals with sinus tachycardia for the identification of coronary artery disease, heart failure, and mortality.MethodsThe Penn Atrial Fibrillation Free study is a large cohort study of patients without atrial fibrillation. The present study examined 6723 Penn Atrial Fibrillation Free study patients without a history of heart failure and with baseline sinus rate ≥100 beats/min. Medical records were queried for index clinical parameters, incident cardiovascular events, and all-cause mortality. The QT interval was corrected by using Bazett (QT/RR(0.5)), Fridericia (QT/RR(0.33)), Framingham [QT + 0.154 * (1000 - RR)], and Hodges (QT + 105 * (1/RR - 1)) formulas.ResultsIn 6723 patients with a median follow-up of 4.5 years (interquartile range 1.9-6.4 years), the annualized cardiovascular event rate was 2.3% and the annualized mortality rate was 2.2%. QT prolongation was diagnosed in 39% of the cohort using the Bazett formula, 6.2% using the Fridericia formula, 3.7% using the Framingham formula, and 8.7% using the Hodges formula. Only the Hodges formula was an independent risk marker for death across the range of QT values (highest tertile: hazard ratio 1.26; 95% confidence interval 1.03-1.55).ConclusionAlthough all correction formulas demonstrated an association between QTc values and cardiovascular events, only the Hodges formula identified one-third of individuals with tachycardia that are at higher risk of all-cause mortality. Furthermore, the Bazett correction formula overestimates the number of patients with a prolonged QT interval and was not associated with mortality. Future work may validate these findings and result in changes to automated algorithms for QT interval assessment.

Project description:CONTEXT:Although the heritability of atrial fibrillation (AF) is established, the contribution of familial AF to predicting new-onset AF remains unknown. OBJECTIVE:To determine whether familial occurrence of AF is associated with new-onset AF beyond established risk factors. DESIGN, SETTING, AND PARTICIPANTS:The Framingham Heart Study, a prospective community-based cohort study started in 1948. Original and Offspring Cohort participants were aged at least 30 years, were free of AF at the baseline examination, and had at least 1 parent or sibling enrolled in the study. The 4421 participants in this analysis (mean age, 54 [SD, 13] years; 54% women) were followed up through December 31, 2007. MAIN OUTCOME MEASURES:Incremental predictive value of incorporating different features of familial AF (any familial AF, premature familial AF [onset ?65 years old], number of affected relatives, and youngest age of onset in a relative) into a risk model for new-onset AF. RESULTS:Across 11,971 examinations during the period 1968-2007, 440 participants developed AF. Familial AF occurred among 1185 participants (26.8%) and premature familial AF occurred among 351 participants (7.9%). Atrial fibrillation occurred more frequently among participants with familial AF than without familial AF (unadjusted absolute event rates of 5.8% and 3.1%, respectively). The association was not attenuated by adjustment for AF risk factors (multivariable-adjusted hazard ratio, 1.40; 95% confidence interval [CI], 1.13-1.74) or reported AF-related genetic variants. Among the different features of familial AF examined, premature familial AF was associated with improved discrimination beyond traditional risk factors to the greatest extent (traditional risk factors, C statistic, 0.842 [95% CI, 0.826-0.858]; premature familial AF, C statistic, 0.846 [95% CI, 0.831-0.862]; P = .004). Modest changes in integrated discrimination improvement were observed with premature familial AF (2.1%). Net reclassification improvement (assessed using 8-year risk thresholds of <5%, 5%-10%, and >10%) did not change significantly with premature familial AF (index statistic, 0.011; 95% CI, -0.021 to 0.042; P = .51), although categoryless net reclassification was improved (index statistic, 0.127; 95% CI, 0.064-0.189; P = .009). CONCLUSIONS:In this cohort, familial AF was associated with an increased risk of AF that was not attenuated by adjustment for AF risk factors including genetic variants. Assessment of premature familial AF was associated with a very slight increase in predictive accuracy compared with traditional risk factors.

Project description:Genome-wide association studies (GWAS) have suggested that sequence variation in cis-regulatory elements (CREs) modulate common disease risk and trait variation. However, identification of the majority of these causal variants and their mechanism of action have remained significant challenges. We used reporter assays for all common variants at the QT interval associated SCN5A GWAS locus with the goal of identifying causal variants for the association. A target region of ~500kb containing SCN5A was defined based on recombination hotspots (rate>10cM/Mb; estimated from HapMap) flanking the 5 independent QT interval GWAS hits. Within this region, all common variants (minor allele frequency >5%), from the 1000 Genomes European ancestry populations, in moderate linkage disequilibrium (LD; r2>0.3) with any of the 5 sentinel hits, were selected for analyses. Of a total 121 variants selected, 112 variants in 104 amplicons passed primer design (amplicon size 256-617bp; median 397bp), with both alleles of 106 variants successfully cloned along with flanking sequences into 98 amplicons upstream of a minimal promoter-driven firefly luciferase gene in pGL4.23. Cardiomyocyte cells, AC16 (human) and HL1 (mouse), were transfected with test constructs and Renilla luciferase vector (for transfection normalization) in triplicate; luciferase assays were performed 24h later. All cloning and reporter assays were performed in 96- and 24-well plates. In reporter assays across the two cell lines, compared to empty vector, 37 amplicons showed enhancer activity (z-score>99 %tile), with a concordance rate of ~70%. Of these 37 enhancer CREs, 9 overlapped open chromatin regions (DNase-seq peaks) observed in adult human heart tissue, largest among all human tissues evaluated by the RoadMap Epigenomics project. Of these 37 enhancer CREs, 12 showed allelic difference in reporter activity (P<0.05), thus identifying at least one enhancer CRE variant in high-to-moderate LD with each of the 5 sentinel hits. Using GTEx heart left ventricle (n=190) gene expression data, we showed correlation between SCN5A expression and the number of QT interval prolonging alleles across the 5 index SNPs. We are currently assessing the binding of cardiac nuclear factors at the 12 enhancer CRE variants by gel-shift assays and the effect of CRISPR-Cas9 mediated CRE deletion on SCN5A expression in AC16 and HL1 cells, an analyses helped by evaluation of AC16 and HL1 cells by RNA-seq, ATAC-seq and karyotyping. Thus, independent of the publicly available epigenomic data, which are of limited cell-type relevance, an unbiased in vitro reporter screen for CREs overlapping all common variants associated with QT interval at the SCN5A GWAS locus identified 12 common cis-regulatory variants that map to cardiac open chromatin regions and correlate with SCN5A cardiac expression.

Dataset Information

The association of QT interval components with atrial fibrillation.

Publications

The association of QT interval components with atrial fibrillation.

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