Dataset Information

Circadian pattern of short-term variability of the QT-interval in primary prevention ICD patients - EU-CERT-ICD methodological pilot study.

ABSTRACT:

Objective

Short-term variability of the QT-interval (STV-QT) was shown to be associated with an increased risk of ventricular arrhythmias. We aimed at investigating (a) whether STV-QT exhibits circadian pattern, and (b) whether such pattern differs between patients with high and low arrhythmia risk.

Methods

As part of the ongoing EU-CERT-ICD study, 24h high resolution digital ambulatory 12-lead Holter recordings are collected prior to ICD implantation for primary prophylactic indication. Presently available patients were categorized based on their arrhythmia score (AS), a custom-made weighted score of the number of arrhythmic events on the recording. STV-QT was calculated every hour in 30 patients of which 15 and 15 patients had a high and a low AS, respectively.

Results

The overall dynamicity of STV-QT showed high intra- and inter-individual variability with different circadian patterns associated with low and high AS. High AS patients showed a prominent peak both at 08:00 and 18:00. At these times, STV-QT was significantly higher in the high AS patients compared to the low AS patients (1.22ms±0.55ms vs 0.60ms±0.24ms at 08:00 and 1.12ms±0.39ms vs 0.64ms±0.29ms at 18:00, both p < 0.01).

Conclusion

In patients with high AS, STV-QT peaks in the early morning and late afternoon. This potentially reflects increased arrhythmia risk at these times. Prospective STV-QT determination at these times might thus be more sensitive to identify patients at high risk of ventricular arrhythmias.

SUBMITTER: Sprenkeler DJ

PROVIDER: S-EPMC5565185 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Circadian pattern of short-term variability of the QT-interval in primary prevention ICD patients - EU-CERT-ICD methodological pilot study.

Sprenkeler David J DJ Tuinenburg Anton E AE Ritsema van Eck Henk J HJ Malik Marek M Zabel Markus M Vos Marc A MA

PloS one 20170821 8

<h4>Objective</h4>Short-term variability of the QT-interval (STV-QT) was shown to be associated with an increased risk of ventricular arrhythmias. We aimed at investigating (a) whether STV-QT exhibits circadian pattern, and (b) whether such pattern differs between patients with high and low arrhythmia risk.<h4>Methods</h4>As part of the ongoing EU-CERT-ICD study, 24h high resolution digital ambulatory 12-lead Holter recordings are collected prior to ICD implantation for primary prophylactic indi ...[more]

PMID: 28827816

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Project description:AimsThe EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter-Defibrillators (EU-CERT-ICD), a prospective investigator-initiated, controlled cohort study, was conducted in 44 centres and 15 European countries. It aimed to assess current clinical effectiveness of primary prevention ICD therapy.Methods and resultsWe recruited 2327 patients with ischaemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM) and guideline indications for prophylactic ICD implantation. Primary endpoint was all-cause mortality. Clinical characteristics, medications, resting, and 12-lead Holter electrocardiograms (ECGs) were documented at enrolment baseline. Baseline and follow-up (FU) data from 2247 patients were analysable, 1516 patients before first ICD implantation (ICD group) and 731 patients without ICD serving as controls. Multivariable models and propensity scoring for adjustment were used to compare the two groups for mortality. During mean FU of 2.4 ± 1.1 years, 342 deaths occurred (6.3%/years annualized mortality, 5.6%/years in the ICD group vs. 9.2%/years in controls), favouring ICD treatment [unadjusted hazard ratio (HR) 0.682, 95% confidence interval (CI) 0.537-0.865, P = 0.0016]. Multivariable mortality predictors included age, left ventricular ejection fraction (LVEF), New York Heart Association class <III, and chronic obstructive pulmonary disease. Adjusted mortality associated with ICD vs. control was 27% lower (HR 0.731, 95% CI 0.569-0.938, P = 0.0140). Subgroup analyses indicated no ICD benefit in diabetics (adjusted HR = 0.945, P = 0.7797, P for interaction = 0.0887) or those aged ≥75 years (adjusted HR 1.063, P = 0.8206, P for interaction = 0.0902).ConclusionIn contemporary ICM/DCM patients (LVEF ≤35%, narrow QRS), primary prophylactic ICD treatment was associated with a 27% lower mortality after adjustment. There appear to be patients with less survival advantage, such as older patients or diabetics.

Project description:Cardiovascular diseases, including ventricular arrhythmias are responsible for increased mortality in patients with acromegaly. Acromegaly may cause repolarization abnormalities such as QT prolongation and impairment of repolarization reserve enhancing liability to arrhythmia. The aim of this study was to determine the short-term beat-to-beat QT variability in patients with acromegaly. Thirty acromegalic patients (23 women and 7 men, mean age±SD: 55.7±10.4 years) were compared with age- and sex-matched volunteers (mean age 51.3±7.6 years). Cardiac repolarization parameters including frequency corrected QT interval, PQ and QRS intervals, duration of terminal part of T waves (Tpeak-Tend) and short-term variability of QT interval were evaluated. All acromegalic patients and controls underwent transthoracic echocardiographic examination. Autonomic function was assessed by means of five standard cardiovascular reflex tests. Comparison of the two groups revealed no significant differences in the conventional ECG parameters of repolarization (QT: 401.1±30.6 ms vs 389.3±16.5 ms, corrected QT interval: 430.1±18.6 ms vs 425.6±17.3 ms, QT dispersion: 38.2±13.2 ms vs 36.6±10.2 ms; acromegaly vs control, respectively). However, short-term beat-to-beat QT variability was significantly increased in acromegalic patients (4.23±1.03 ms vs 3.02±0.80, P<0.0001). There were significant differences between the two groups in the echocardiographic dimensions (left ventricular end diastolic diameter: 52.6±5.4 mm vs 48.0±3.9 mm, left ventricular end systolic diameter: 32.3±5.2 mm vs 29.1±4.4 mm, interventricular septum: 11.1±2.2 mm vs 8.8±0.7 mm, posterior wall of left ventricle: 10.8±1.4 mm vs 8.9±0.7 mm, P<0.05, respectively). Short-term beat-to-beat QT variability was elevated in patients with acromegaly in spite of unchanged conventional parameters of ventricular repolarization. This enhanced temporal QT variability may be an early indicator of increased liability to arrhythmia.

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

Circadian pattern of short-term variability of the QT-interval in primary prevention ICD patients - EU-CERT-ICD methodological pilot study.

Objective

Methods

Results

Conclusion

Publications

Circadian pattern of short-term variability of the QT-interval in primary prevention ICD patients - EU-CERT-ICD methodological pilot study.

Similar Datasets

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