Circadian rhythmicity of rate-normalized QT interval in hypothyroidism and its significance for development of class III antiarrhythmic agents

Sarma, J. S. M.; Venkataraman, Kalyanasundaram; Nicod, Pascal; Polikar, Ralf; Smith, Johana; Schoenbaum, Mary P.; Singh, Bramah N.

doi:10.1016/0002-9149(90)90933-r

Cited by 56 publications

(37 citation statements)

References 23 publications

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“…Hypothyroidism has been associated with prolongation of the QTc interval (Sarma et al 1990, Fazio et al 1992. The mechanism behind this association might be an enhanced sympathetic activity (Colzani et al 2001).…”

Section: Discussionmentioning

confidence: 99%

“…3 mU/l and free T 4 !11 pmol/l) or subclinical hypothyroidism (TSHO4 . 3 mU/l and free T 4 R11 pmol/l; nZ72), since hypothyroidism is associated with QTc prolongation (Sarma et al 1990, Fazio et al 1992. Furthermore, we excluded participants with ECG evidence of left ventricular hypertrophy (nZ44), left and right bundle branch block (nZ17 and 30 respectively) and/or participants using digoxin (nZ21), antithyroid drugs (nZ6), and thyroid hormones (nZ11), since these conditions can alter the QTc interval (Kulan et al 1998, Piotrowicz et al 2007).…”

Section: Study Populationmentioning

confidence: 99%

“…Relatively little, however, is known about the effect of thyroid hormone on ventricular repolarization. It has been reported that hypothyroidism is associated with prolongation of the heart rate-corrected QT (QTc) interval (Sarma et al 1990, Fazio et al 1992, a measure of duration of ventricular repolarization. In hyperthyroidism, the situation is more controversial, since prolonged and shortened QTc intervals both have been reported (Linder 1955, Johnson et al 1973, Fisher 1982, Sharp et al 1985, Binah et al 1987, Gomberg-Maitland & Frishman 1998, Colzani et al 2001, Dorr et al 2006, Owecki et al 2006.…”

Section: Introductionmentioning

confidence: 99%

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High free thyroxine levels are associated with QTc prolongation in males

Noord¹,

Deure²,

Sturkenboom³

et al. 2008

Journal of Endocrinology

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The literature on the effect of excess thyroid hormone on ventricular repolarization is controversial. To study whether free thyroxine (T 4 ) and TSH are associated with QTc prolongation we conducted population-based cohort study. This study was conducted as part of the Rotterdam Study and included 365 men and 574 women aged 55 years and older with an electrocardiogram, who were randomly sampled for the assessment of thyroid status (free T 4 /TSH) at baseline, after exclusion of participants with hypothyroidism, use of antithyroid drugs, thyroid hormones or digoxin, left ventricular hypertrophy, and left and right bundle branch block. Endpoints were the length of the QTc interval and risk of borderline QTc prolongation. The associations were examined by means of linear and logistic regression analysis, adjusted for age and gender, diabetes mellitus, myocardial infarction, hypertension, and heart failure. Overall, there was no significant association between TSH and QTc interval (0 . 8 ms (95% confidence interval (CI) K3 . 5, 5 . 2) in the first quintile compared with the fifth quintile). Subjects in the fifth quintile of free T 4 did not have an increased QTc interval (3 . 2 ms (95% CI K1 . 1, 7 . 6)); stratification on gender showed an increment of 10 . 9 ms (95% CI 3 . 4, 18 . 3) in the fifth quintile in men and 1 . 1 ms (95% CI K4 . 2, 6 . 3) in the fifth quintile of free T 4 in women. When compared with subjects in the first quintile, male subjects in the fifth quintile of free T 4 had a significantly increased risk of a borderline QTc interval and QTc prolongation (odds ratio 2 . 40 (95% CI 1 . 20, 4 . 80)). High levels of free T 4 are associated with substantial QTc prolongation in men of up to 10 ms. The fact that free T 4 is also associated with a significantly increased risk of borderline and prolonged QTc values with its risk of sudden cardiac death, endorses the clinical importance of our findings.

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Section: Discussionmentioning

confidence: 99%

Section: Study Populationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

High free thyroxine levels are associated with QTc prolongation in males

Noord¹,

Deure²,

Sturkenboom³

et al. 2008

Journal of Endocrinology

View full text Add to dashboard Cite

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“…observed in other species such as dogs, pigs and humans (Harada et al, 2005;Kano et al, 2005;Malik et al, 2002) and might also be caused by circadian rhythm (Sarma et al, 1990) or by changes in autonomic nervous activity (Harada et al -es of circadian rhythm, drug effects were compared with a time-matched vehicle control in this study. The maximum difference of QTci interval at almost the same RR interval was about 30 msec (Fig.…”

Section: Discussionmentioning

confidence: 99%

Prediction of drug-induced QT interval prolongation in telemetered common marmosets

et al. 2008

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-Drug-induced QT interval prolongation is a critical issue in development of new chemical entities, so the pharmaceutical industry needs to evaluate risk as early as possible. Common marmosets have been in the limelight in early-stage development due to their small size, which requires only a small amount of test drug. The purpose of this study was to determine the utility of telemetered common marmosets for predicting drug-induced QT interval prolongation. Telemetry transmitters were implanted in common marmosets (male and female), and QT and RR intervals were measured. The QT interval was corrected for the RR interval by applying Bazett's and Fridericia's correction formulas and individual rate correction. Individual correction showed the least slope for the linear regression of corrected QT (QTc) intervals against RR intervals, indicating that it dissociated changes in heart rate most effectively. With the individual correction method, the QT-prolonging drugs (astemizole, dl-sotalol) showed QTc interval prolongations and the non-QT-prolonging drugs (dl-propranolol, nifedipine) did not show QTc interval prolongations. The plasma concentrations of astemizole and dl-sotalol associated with QTc interval prolongations in common marmosets were similar to those in humans, suggesting that the sensitivity of common marmosets would be appropriate for evaluating risk of drug-induced QT interval prolongation. In conclusion, telemetry studies in common marmosets are useful for predicting clinical QT prolonging potential of drugs in early stage development and require only a small amount of test drug.

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“…It varies with heart rate [15,16, 17, 18,19, 20, 21,22, 23, 24,25, 26] with electrolyte changes, and also exhibits a diurnal variation [17, 18, 19,20, 21, 22] that is only partly explained by changes in the heart rate [18, 22, 25, 26], but not solely of function of rate [17, 18, 19,20, 21, 22,23, 24, 25,26]. Both rate-dependent and rate- independent factors, mediated by autonomic tone and by circulating catecholamines, play a role in the normal circadian variation of the QT interval [17, 18, 19, 20, 21, 22, 23, 24, 25, 26]. A hysteresis in QT-RR relationship when the heart rate rapidly changes has previously been reported to occur during postural changes [27] and exercise [28].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of a 12-Lead Digital Holter System for 24-Hour QT Interval Assessment

et al. 2006

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Background: Drug induced QT prolongation may precipitate life threatening cardiac arrhythmias. Evaluation of the QT prolonging effect of new pharmaceutical agents in a ‘thorough QT/QTc study’ is being mandated by FDA. The purpose of this study was to evaluate an automated 12-lead digital Holter system for a thorough QT/QTc study. Methods: Five healthy volunteers underwent 24-hour digital Holter monitoring. Each recording underwent a fully automated QT analysis (AQA) followed by an onscreen complete manual over read (MOR). Each recording was analyzed twice at least 2 weeks apart. The effect of data sampling (5-min segment/hour), the system sensitivity to detect 5-ms increase in QT, and the ability to assess circadian variation were evaluated. Results: The AQA resulted in identical QT for the first and second analyses, but with obvious errors in QT measurements. Compared to the complete onscreen MOR, the mean QT was longer with AQA (416 ± 41 vs. 387 ± 30 ms, p < 0.001), correlation; r = 0.3. The reproducibility of AQA with complete MOR was very good (QT: 387 ± 30 vs. 387 ± 30 ms, coefficient of variation: 0.2%, r = 0.986. The 5-min mean QT intervals correlated well with the hourly mean QT intervals (r = 0.994, p < 0.001, coefficient of variation = 1 ms) and both showed a similar circadian variation. The system was sensitive to detect a 5-ms change in QT intervals (5 ± 2 ms, coefficient of variation = 0.6%, r = 0.998, p < 0.001). Conclusions: The AQA is not an acceptable method, while the automatic analysis with complete MOR is a highly sensitive and reproducible method. Data sampling by analyzing 5-min segments per hour is sensitive and reproducible.

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Circadian rhythmicity of rate-normalized QT interval in hypothyroidism and its significance for development of class III antiarrhythmic agents

Cited by 56 publications

References 23 publications

High free thyroxine levels are associated with QTc prolongation in males

High free thyroxine levels are associated with QTc prolongation in males

Prediction of drug-induced QT interval prolongation in telemetered common marmosets

Evaluation of a 12-Lead Digital Holter System for 24-Hour QT Interval Assessment

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