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J Electrocardiol. 2015 Jul-Aug;48(4):533-8. doi: 10.1016/j.jelectrocard.2015.03.011. Epub 2015 Mar 12.

Investigation of potential mechanisms of sex differences in quinidine-induced torsade de pointes risk.

Author information

1
Division of Biomedical Physics, Office of Science and Engineering Laboratories, Center for Device and Radiological Health, US Food and Drug Administration, Silver Spring, MD, USA; Division of Cardiovascular and Renal Products, Office of New Drugs, Center of Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA; BSICoS Group, Aragón Institute for Engineering Research (I3A), IIS Aragón, University of Zaragoza, Zaragoza, Spain.
2
Duke Clinical Research Institute, Durham, NC, USA; Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
3
Division of Biomedical Physics, Office of Science and Engineering Laboratories, Center for Device and Radiological Health, US Food and Drug Administration, Silver Spring, MD, USA; Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center of Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
4
Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center of Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
5
Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
6
Duke Clinical Research Institute, Durham, NC, USA.
7
AZCERT, Inc., Oro Valley, AZ, USA.
8
Division of Biomedical Physics, Office of Science and Engineering Laboratories, Center for Device and Radiological Health, US Food and Drug Administration, Silver Spring, MD, USA; Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. Electronic address: david.strauss@fda.hhs.gov.

Abstract

INTRODUCTION:

The electrocardiographic index Tpeak-Tend has been proposed as a marker of dispersion of repolarization and may be a stronger predictor of torsade de pointes risk than QTc prolongation.

METHODS AND RESULTS:

We assessed whether quinidine-induced Tpeak-Tend prolongation is greater in women than men. The relationship between QTc prolongation and quinidine concentration was greater in women than men (38 ± 10 vs. 28 ± 9 ms/μg/ml, p=0.02), but there was no difference for Tpeak-Tend prolongation (39 ± 13 vs. 32 ± 13 ms/μg/ml, p=0.21). There was a delay (hysteresis) between peak concentration and both maximum QTc and Tpeak-Tend prolongation and a trend toward higher serum quinidine concentration in men than women. Analysis controlling for hysteresis showed no sex difference for QTc (55 ± 18 vs. 43 ± 19 ms/μg/ml, p=0.14), without changing the lack of sex difference with Tpeak-Tend (61 ± 22 vs. 55 ± 21 ms/μg/ml, p=0.49).

CONCLUSIONS:

Women do not have a greater quinidine-induced Tpeak-Tend prolongation than men. Sex differences in hysteresis and serum quinidine concentration in this study may have contributed to sex differences in quinidine-induced QTc prolongation.

KEYWORDS:

QTc prolongation; Quinidine; Sex differences; T wave notching; Torsade de pointes

[Indexed for MEDLINE]

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