Dataset Information

Longitudinal Community-Based Study of QT Interval and Mortality in Southeast Asians.

ABSTRACT:

Introduction

The prognostic impact of QT interval prolongation has not been well studied in healthy Asians. We investigated the association between the QT interval with mortality and cardiovascular events in a healthy Southeast Asian population.

Methods

The QT interval corrected for heart rate using the Bazett's formula (QTc) was measured in 2536 (825 men, mean age 65.7±7.5 years) Singaporean adults free of cardiovascular disease in the population-based Singapore Longitudinal Ageing Study. Outcomes were all-cause mortality and incident cardiovascular events (cardiovascular mortality, myocardial infarction (MI) and/or stroke).

Results

Over a mean 7.78 years (19695 person-years) of follow-up, there were 202 deaths (45 from cardiovascular causes), 62 cases of myocardial infarction and 64 cases of stroke. Adjusting for age, sex, and cardiovascular risk factors, QTcB prolongation remained independently associated with increased all-cause mortality (HR(per standard deviation) 1.27 (1.10-1.48), p = 0.0015), as well as increased risk of cardiovascular events (HR 1.20 (1.01-1.43), p = 0.0415) and MI/stroke (HR 1.22 (1.01-1.47), p = 0.0455), but not cardiovascular mortality alone (HR 1.05 (0.77-1.44), p = 0.7562).

Conclusions

We provide the first community-based estimates of the independent association of QT prolongation with all-cause mortality and cardiovascular events in Southeast Asians.

SUBMITTER: Yap J

PROVIDER: S-EPMC4858262 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

Longitudinal Community-Based Study of QT Interval and Mortality in Southeast Asians.

Yap Jonathan J Jin Ai Zhen AZ Nyunt Shwe Zin SZ Ng Tze Pin TP Richards A Mark AM Lam Carolyn S P CS

PloS one 20160505 5

<h4>Introduction</h4>The prognostic impact of QT interval prolongation has not been well studied in healthy Asians. We investigated the association between the QT interval with mortality and cardiovascular events in a healthy Southeast Asian population.<h4>Methods</h4>The QT interval corrected for heart rate using the Bazett's formula (QTc) was measured in 2536 (825 men, mean age 65.7±7.5 years) Singaporean adults free of cardiovascular disease in the population-based Singapore Longitudinal Agei ...[more]

PMID: 27148971

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Project description:IntroductionIn this study, we investigated the outcomes for patients with intentional organophosphate poisoning. Previous reports indicate that in contrast to normal heart rate-corrected QT intervals (QTc), QTc prolongation might be indicative of a poor prognosis for patients exposed to organophosphates.MethodsWe analyzed the records of 118 patients who were referred to Chang Gung Memorial Hospital for management of organophosphate poisoning between 2000 and 2011. Patients were grouped according to their initial QTc interval, i.e., normal (<0.44 s) or prolonged (>0.44 s). Demographic, clinical, laboratory, and mortality data were obtained for analysis.ResultsThe incidence of hypotension in patients with prolonged QTc intervals was higher than that in the patients with normal QTc intervals (P = 0.019). By the end of the study, 18 of 118 (15.2%) patients had died, including 3 of 75 (4.0%) patients with normal QTc intervals and 15 of 43 (34.9%) patients with prolonged QTc intervals. Using multivariate-Cox-regression analysis, we found that hypotension (OR = 10.930, 95% CI = 2.961-40.345, P = 0.000), respiratory failure (OR = 4.867, 95% CI = 1.062-22.301, P = 0.042), coma (OR = 3.482, 95% CI = 1.184-10.238, P = 0.023), and QTc prolongation (OR = 7.459, 95% CI = 2.053-27.099, P = 0.002) were significant risk factors for mortality. Furthermore, it was revealed that non-survivors not only had longer QTc interval (503.00±41.56 versus 432.71±51.21 ms, P = 0.002), but also suffered higher incidences of hypotension (83.3 versus 12.0%, P = 0.000), shortness of breath (64 versus 94.4%, P = 0.010), bronchorrhea (55 versus 94.4%, P = 0.002), bronchospasm (50.0 versus 94.4%, P = 0.000), respiratory failure (94.4 versus 43.0%, P = 0.000) and coma (66.7 versus 11.0%, P = 0.000) than survivors. Finally, Kaplan-Meier analysis demonstrated that cumulative mortality was higher among patients with prolonged QTc intervals than among those with normal QTc intervals (Log-rank test, Chi-square test = 20.36, P<0.001).ConclusionsQTc interval helps predict mortality after intentional organophosphate poisoning.

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

Longitudinal Community-Based Study of QT Interval and Mortality in Southeast Asians.

Introduction

Methods

Results

Conclusions

Publications

Longitudinal Community-Based Study of QT Interval and Mortality in Southeast Asians.

Similar Datasets

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