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The impact of varying autonomic states on the dynamic beat-to-beat QT-RR and QT-TQ interval relationships.

ABSTRACT: The beat-to-beat dynamicity of the QT-RR interval relationship is difficult to assess with the use of traditional correction factors (QTc) and changes in QTc do not accurately reflect or quantify arrhythmogenic risk. Further, the interpretation of arrhythmogenic risk is influenced by autonomic state. To visualize the QT-RR interval dynamics under varying conditions of autonomic state from impaired repolarization, we have developed a system to sequentially plot the beat-to-beat confluence of ECG data or 'clouds' obtained from conscious dogs and humans. To represent the non-uniformity of the clouds, a bootstrap sampling method that computes the mathematical centre of the uncorrected beat-to-beat QT value (QTbtb) and defines the upper and lower 95% confidence bounds is used. The same method can also be used to examine heterogeneity, hysteresis (both acceleration and deceleration) and restitution (beat-to-beat QT-TQ interval relationship). Impaired repolarization with the combination of E-4031 and L-768,673 (inhibitor of IKs current) increased heterogeneity of restitution at rest 55-91%; increased hysteresis during heart rate acceleration after isoproterenol challenge by approximately 40-60%; and dramatically diminished the minimum TQ boundary by 72% to only 28 ms. Impaired repolarization alters restitution during normal sinus rhythm and increases hysteresis/heterogeneity during heart rate acceleration following sympathetic stimulation. These findings are supported by similar clinical observations in LQT1 and LQT2 syndromes. Therefore, the assessment of the dynamic QT-RR and QT-TQ interval relationships through quantification of heterogeneity, hysteresis and restitution may allow a more accurate non-invasive evaluation of the conditions leading to cardiac arrhythmia.

SUBMITTER: Fossa AA

PROVIDER: S-EPMC2492089 | biostudies-other | 2008 Aug

REPOSITORIES: biostudies-other

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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.

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The impact of varying autonomic states on the dynamic beat-to-beat QT-RR and QT-TQ interval relationships.

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