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Establishment of a new formula for QT interval correction using a large colony of cynomolgus monkeys.

ABSTRACT: The demand for monkeys for medical research is increasing, because their ionic mechanism of repolarization is similar to that of humans. The QT interval is the distance between the Q wave and T wave, but this interval is affected by heart rate. Therefore, QT correction methods are commonly used in clinical settings. However, an accurate correction formula for the QT interval in cynomolgus monkeys has not been reported. We assessed snapshot electrocardiograms (ECGs) of 353 ketamine-immobilized monkeys, including aged animals, and contrived a new formula for the corrected QT interval (QTc) as a marker of QT interval prolongation in cynomolgus monkeys. Values for QTc were calculated using the formula [QTc] = [QT] / [RR]n, along with several other formulas commonly used to calculate QTc. We found that the optimal exponent of the QT interval corrected for heart rate, n, was 0.576. The mean value of QTc in healthy monkeys determined using the new formula was 373 ± 31 mm, and there were no significant differences between the sexes. Other ECG parameters were not significantly different between the sexes and there were no age-related effects on QTc. Prolongation of QTc to over 405 ms, as calculated by the new formula, was observed in 50 monkeys with underlying diseases. Additionally, all monkeys with QTc above 440 ms by the new formula had some underlying disease. The results resemble those in humans, suggesting that the new QTc formula could be useful for diagnosis of QT interval prolongation in cynomolgus monkeys.

SUBMITTER: Nakayama S

PROVIDER: S-EPMC7004807 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Establishment of a new formula for QT interval correction using a large colony of cynomolgus monkeys.

Nakayama Shunya S Koie Hiroshi H Kato-Tateishi Miyoko M Pai Chungyu C Ito-Fujishiro Yasuyo Y Kanayama Kiichi K Sankai Tadashi T Yasutomi Yasuhiro Y Ageyama Naohide N

Experimental animals 20190712 1

The demand for monkeys for medical research is increasing, because their ionic mechanism of repolarization is similar to that of humans. The QT interval is the distance between the Q wave and T wave, but this interval is affected by heart rate. Therefore, QT correction methods are commonly used in clinical settings. However, an accurate correction formula for the QT interval in cynomolgus monkeys has not been reported. We assessed snapshot electrocardiograms (ECGs) of 353 ketamine-immobilized mo ...[more]

PMID: 31308302

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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:BackgroundQT interval as an indicator of ventricular repolarization is a clinically important parameter on an electrocardiogram (ECG). QT prolongation predisposes individuals to different ventricular arrhythmias and sudden cardiac death. The current study aimed to identify the best heart rate corrected QT interval for a non-hospitalized Iranian population based on cardiovascular mortality.MethodsUsing Fasa PERSIAN cohort study data, this study enrolled 7071 subjects aged 35-70 years. Corrected QT intervals (QTc) were calculated by the QT interval measured by Cardiax® software from ECGs and 6 different correction formulas (Bazett, Fridericia, Dmitrienko, Framingham, Hodges, and Rautaharju). Mortality status was checked using an annual telephone-based follow-up and a minimum 3-year follow-up for each participant. Bland-Altman, QTc/RR regression, sensitivity analysis, and Cox regression were performed in IBM SPSS Statistics v23 to find the best QT. Also, for calculating the upper and lower limits of normal of different QT correction formulas, 3952 healthy subjects were selected.ResultsIn this study, 56.4% of participants were female, and the mean age was 48.60 ± 9.35 years. Age, heart rate in females, and QT interval in males were significantly higher. The smallest slopes of QTc/RR analysis were related to Fridericia in males and Rautaharju followed by Fridericia in females. Thus, Fridericia's formula was identified as the best mathematical formula and Bazett's as the worst in males. In the sensitivity analysis, however, Bazett's formula had the highest sensitivity (23.07%) among all others in cardiac mortality. Also, in the Cox regression analysis, Bazett's formula was better than Fridericia's and was identified as the best significant cardiac mortality predictor (Hazard ratio: 4.31, 95% CI 1.73-10.74, p value = 0.002).ConclusionFridericia was the best correction formula based on mathematical methods. Bazett's formula despite its poorest performance in mathematical methods, was the best one for cardiac mortality prediction. Practically, it is suggested that physicians use QTcB for a better evaluation of cardiac mortality risk. However, in population-based studies, QTcFri might be the one to be used by researchers.

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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Establishment of a new formula for QT interval correction using a large colony of cynomolgus monkeys.

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Establishment of a new formula for QT interval correction using a large colony of cynomolgus monkeys.

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