Circadian rhythmicity of heart rate and QTc interval in diabetic autonomic neuropathy: Implications for the mechanism of sudden death

Ong, James J.C.; Sarma, J. S. M.; Venkataraman, Kalyanasundaram; Levin, Seymour R.; Singh, Bramah N.

doi:10.1016/0002-8703(93)90166-7

Cited by 82 publications

(38 citation statements)

References 43 publications

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“…12 In a general population prospective study, 13 persons with high resting heart rate and low heart rate variability had increased risk for future development of diabetes mellitus. Ong et al 14 found the QTc to be shorter if patients had signs of neuropathy, although these patients' heart rate was higher and their circadian patterns seemed to be preserved. Valensi et al 15 found an unchanged QTc in mild neuropathy, although the circadian day/ night QTc pattern was reversed.…”

Section: Ecg Measures Of Cardiac Autonomic Neuropathymentioning

confidence: 97%

The ECG in Diabetes Mellitus

Stern

2009

Circulation

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Section: Ecg Measures Of Cardiac Autonomic Neuropathymentioning

confidence: 97%

The ECG in Diabetes Mellitus

Stern

2009

Circulation

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“…[55][56][57][58][59] Circadian rhythm is characteristic for QTc as well. [60][61][62][63][64][65][66] Figure 4 shows pooled, individually corrected (as described earlier) QT intervals before treatment vs the clock time in 26 unrelated healthy individuals from the previously presented data. The smoothing line indicates a circadian variation in QTc I with the peak near 10 am.…”

Section: Circadian Rhythm In Qt and Qtcmentioning

confidence: 99%

Pharmacokinetic-pharmacodynamic modeling in the data analysis and interpretation of drug-induced QT/QTc prolongation

Piotrovsky¹

2005

AAPS J

109

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A BSTRACTIn this review, factors affecting the QT interval and the methods that are currently in use in the analysis of drug effects on the QT interval duration are overviewed with the emphasis on (population) pharmacokinetic-pharmacodynamic (PK-PD) modeling. Among which the heart rate (HR) and the circadian rhythm are most important since they may interfere with the drug effect and need to be taken into account in the data analysis. The HR effect or the RR interval (the distance between 2 consecutive R peaks) effect is commonly eliminated before any further analysis, and many formulae have been suggested to correct QT intervals for changes in RR intervals. The most often used are Bazett and Fridericia formulae introduced in 1920. They are both based on the power function and differ in the exponent parameter. However, both assume the same exponent for different individuals. More recent fi ndings do not confi rm this assumption, and individualized correction is necessary to avoid under-or overcorrection that may lead to artifi cial observations of drug-induced QT interval prolongation. Despite the fact that circadian rhythm in QT and QTc intervals is a welldocumented phenomenon, it is usually overlooked when drug effects are evaluated. This may result in a false-positive outcome of the analysis as the QTc peak due to the circadian rhythm may coincide with the peak of the drug plasma concentration. In view of these effects interfering with a potential drug effect on the QTc interval and having in mind low precision of QT interval measurements, a preferable way to evaluate the drug effect is to apply a population PK-PD modeling. In the literature, however, there are only a few publications in which population PK-PD modeling is applied to QT interval prolongation data, and they all refer to antiarrhythmic agents. In this review, after the most important sources of variability are outlined, a comprehensive population PK-PD model is presented that incorporates an individualized QT interval correction, a circadian rhythm in the individually corrected QT intervals, and a drug effect. The model application is illustrated using real data obtained with 2 compounds differing in their QT interval prolongation potential. The usefulness of combining data of several studies is stressed. Finally, the standard approach based on the raw observations and formal statistics, as described in the Preliminary Concept paper of the International Conference on Harmonization, is briefl y compared with the method based on population PK-PD modeling, and the advantages of the latter are outlined.

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“…Blood samples were taken and ECG's recorded hourly, with the QTc interval defined as the maximum of that recorded at glucose nadir, or glucose nadir +1 h. Of the seven subjects who became hypoglycaemic, the time of hypoglycaemia was 4 a.m. in three cases, 5 a.m. in two cases and midnight and 3 a.m. in the other two. QT interval exhibits circadian rhythmicity with highest values between 1 a.m. and 5 a.m. [12]. We therefore selected 4 a.m. as the start time for control data during non-hypoglycaemia nights in which we recorded the ECG for similar periods to those recorded during hypoglycaemic nights.…”

Section: Statistics and Analysismentioning

confidence: 99%

Changes in cardiac repolarization during clinical episodes of nocturnal hypoglycaemia in adults with Type 1 diabetes

et al. 2004

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Aims/hypothesis. Experimental hypoglycaemia leads to abnormal cardiac repolarization manifest by a lengthened QT interval and caused by adrenergic stimulation. However it is less clear whether spontaneous clinical episodes lead to similar changes. We have therefore measured cardiac ventricular repolarization and counterregulatory responses in patients with Type 1 diabetes during hypoglycaemic and euglycaemic nights. Methods. We studied 22 patients with Type 1 diabetes (mean age 40.4±17.2 years, duration of diabetes 17.2±9.3 years, HbA1c 8.2±1.2% overnight). Measurements were taken hourly of blood glucose, plasma potassium, catecholamines and high resolution electrocardiograms. Results. Hypoglycaemia (blood glucose level <2.5 mmol/l) occurred on 7 of the 22 nights. During overnight hypoglycaemia, QTc interval increased by 27 ms (±15) above baseline, compared with 9 ms (±19) during nights with no nocturnal hypoglycaemia (p=0.034, 95%CI 2, 35). Adrenaline increased by 0.33 nmol/l (±0.21) above baseline during hypoglycaemia, compared with −0.05 nmol/l (±0.08) during euglycaemia (p=0.001, 95%CI 0.19, 0.56 nmol/l). There was no significant difference between potassium, and noradrenaline concentrations between the two groups. Conclusion/interpretation. QTc interval lengthens significantly during spontaneous nocturnal hypoglycaemia. Increases are generally less than those observed during experimental hypoglycaemia and could reflect attenuated sympathoadrenal responses during clinical episodes. The clinical relevance of these changes is uncertain but is consistent with the hypothesis that clinical hypoglycaemia can cause abnormal cardiac repolarization and an attendant risk of cardiac arrhythmia. [Diabetologia (2004) 47:312-315]

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Circadian rhythmicity of heart rate and QTc interval in diabetic autonomic neuropathy: Implications for the mechanism of sudden death

Cited by 82 publications

References 43 publications

The ECG in Diabetes Mellitus

The ECG in Diabetes Mellitus

Pharmacokinetic-pharmacodynamic modeling in the data analysis and interpretation of drug-induced QT/QTc prolongation

Changes in cardiac repolarization during clinical episodes of nocturnal hypoglycaemia in adults with Type 1 diabetes

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