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Women and Drug-induced QT Prolongation and Torsades

Women are at higher risk than men for developing drug-induced QT prolongation and torsade de pointes (TdP). (1-7)
A systematic review of the literature found the proportion of women receiving antiarrhythmic drugs was approximately 40%, indicating a lower exposure to these drugs in females. However, close to 70% of 332 cases of TdP induced by antiarrhythmics occurred in women.(8) Another publication reported that 15 of 16 cases of TdP associated with probucol were women.(9) A large international trial (Survival With Oral d-Sotalol) found female gender as the major risk factor associated with increased risk of arrhythmic death in a post-myocardial infarction population.(10) Similarly, there was an increased propensity in women for TdP during complete heart block with drugs that prolong the QT.(11) A review of the literature and FDA adverse event database revealed that a much higher percentage of women than men develop TdP after taking a variety of drugs such as antihistamines (terfenadine) (12), antibiotics (erythromycin)(13), antimalarials (halofantrine)(14), antiarrhythmics (quinidine (15,16), d-sotalol (17, 18)), antipsychotics (19) and miscellaneous other drugs. A study of 38 men and 20 women found that women were more susceptible to the QT-prolonging effects of an ibutilide infusion, with a more pronounced effect-magnitude during menses, as compared to the ovulatory and luteal phases.(20) See www.qtdrugs.org.
The mechanisms responsible for the predisposition of women to drug induced QT prolongation and TdP are unknown but there are several sex differences.

  1. The baseline electrocardiographic rate corrected QT (QTc) interval is naturally longer in women than in men. This is because the QTc interval in males begins to shorten at puberty and returns to equal that of women at about age 50. (21,22) This period of QTc shortening occurs at the time when androgen levels are highest in males, which suggests that one or more male hormones may be responsible for the QTc shortening and relatively lower risk of drug-induced TdP in men. (23, 24)
  2. In isolated perfused rabbit hearts (Langendorf technique), female rabbit hearts display greater baseline and drug-induced (quinidine and d-sotalol) changes in QT intervals than male hearts.(25)
  3. There are sex-related differences in QT dispersion.(26)
  4. The density of the repolarizing potassium current ions (Ikr-rapid component of the delayed rectifier potassium current) is found to be significantly lower in ventricular cardiomyocytes from female rabbits compared with those from males.(23)
  5. There are sex differences in the rate of cardiac repolarization.(27)
  6. There may be sex specific differences in drug transport and/or metabolism that result in different plasma and intracellular levels acting along a dose response effect on Ikr block. (28, 29)
  7. Other sex differences may be relevant. (27,30,31)

Reference List

1. Drici MD, Burklow TR, Haridasse V, Glazer RI, Woosley RL. Sex hormones prolong the QT interval and downregulate potassium channel expression in the rabbit heart. Circulation 1996; 94(6):1471-1474.
2. Drici MD, Baker L, Plan P, Barhanin J, Romey G, Salama G. Mice display sex differences in halothane-induced polymorphic ventricular tachycardia. Circulation 2002; 106(4):497-503.
3. Ebert SN, Liu XK, Woosley RL. Female gender as a risk factor for drug-induced cardiac arrhythmias: evaluation of clinical and experimental evidence. J Womens Health 1998; 7(5):547-557.
4. Lehmann MH, Timothy KW, Frankovich D et al. Age-gender influence on the rate-corrected QT interval and the QT-heart rate relation in families with genotypically characterized long QT syndrome. J Am Coll Cardiol 1997; 29(1):93-99.
5. Liu T, Choi BR, Drici MD, Salama G. Sex modulates the arrhythmogenic substrate in prepubertal rabbit hearts with Long QT 2. J Cardiovasc Electrophysiol 2005; 16(5):516-524.
6. Liu XK, Wang W, Ebert SN, Franz MR, Katchman A, Woosley RL. Female gender is a risk factor for torsades de pointes in an in vitro animal model. J Cardiovasc Pharmacol 1999; 34(2):287-294.
7. Locati EH, Zareba W, Moss AJ et al. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Circulation 1998; 97(22):2237-2244.
8. Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993; 270(21):2590-2597.
9. Reinoehl J, Frankovich D, Machado C et al. Probucol-associated tachyarrhythmic events and QT prolongation: importance of gender. Am Heart J 1996; 131(6):1184-1191.
10. Waldo AL, Camm AJ, deRuyter H et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet 1996; 348(9019):7-12.
11. Kawasaki R, Machado C, Reinoehl J et al. Increased propensity of women to develop torsades de pointes during complete heart block. J Cardiovasc Electrophysiol 1995; 6(11):1032-1038.
12. Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA 1993; 269(12):1532-1536.
13. Drici MD, Knollmann BC, Wang WX, Woosley RL. Cardiac actions of erythromycin: influence of female sex. JAMA 1998; 280(20):1774-1776.
14. Wesche DL, Schuster BG, Wang WX, Woosley RL. Mechanism of cardiotoxicity of halofantrine. Clin Pharmacol Ther 2000; 67(5):521-529.
15. Roden DM, Woosley RL, Primm RK. Incidence and clinical features of the quinidine-associated long QT syndrome: implications for patient care. Am Heart J 1986; 111(6):1088-1093.
16. Benton RE, Sale M, Flockhart DA, Woosley RL. Greater quinidine-induced QTc interval prolongation in women. Clin Pharmacol Ther 2000; 67(4):413-418.
17. Lehmann MH, Hardy S, Archibald D, quart B, MacNeil DJ. Sex difference in risk of torsade de pointes with d,l-sotalol. Circulation 1996; 94(10):2535-2541.
18. Lehmann MH, Hardy S, Archibald D, MacNeil DJ. JTc prolongation with d,l-sotalol in women versus men. Am J Cardiol 1999; 83(3):354-359.
19. Drici MD, Wang WX, Liu XK, Woosley RL, Flockhart DA. Prolongation of QT interval in isolated feline hearts by antipsychotic drugs. J Clin Psychopharmacol 1998; 18(6):477-481.
20. Rautaharju PM, Karvonen MJ, LEUTHOLD E. Sex differences in the orientation and magnitude of the mean spatial QRS and T vectors. Acta Med Scand 1961; 169:405-410.
20. Rodriguez I, Kilborn MJ, Liu XK, Pezzullo JC, Woosley RL. Drug-induced QT prolongation in women during the menstrual cycle. JAMA. 2001 Mar 14;285(10):1322-6.
21. Rautaharju PM, Zhou SH, Wong S et al. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol 1992; 8(7):690-695.
22. Rautaharju PM, Prineas RJ, Kadish A, Larson JC, Hsia J, Lund B. Normal standards for QT and QT subintervals derived from a large ethnically diverse population of women aged 50 to 79 years (the Women's Health Initiative [WHI]). Am J Cardiol 2006; 97(5):730-737.
23. Liu XK, Katchman A, Whitfield BH et al. In vivo androgen treatment shortens the QT interval and increases the densities of inward and delayed rectifier potassium currents in orchiectomized male rabbits. Cardiovasc Res 2003; 57(1):28-36.
24. Shuba YM, Degtiar VE, Osipenko VN, Naidenov VG, Woosley RL. Testosterone-mediated modulation of HERG blockade by proarrhythmic agents. Biochem Pharmacol 2001; 62(1):41-49.
25. Liu XK, Katchman A, Drici MD et al. Gender difference in the cycle length-dependent QT and potassium currents in rabbits. J Pharmacol Exp Ther 1998; 285(2):672-679.
26. Kassotis J, Costeas C, Bedi AK, Tolat A, Reiffel J. Effects of aging and gender on QT dispersion in an overtly healthy population. Pacing Clin Electrophysiol 2000; 23(7):1121-1126.
27. Yang H, Elko P, LeCarpentier GL et al. Sex differences in the rate of cardiac repolarization. J Electrocardiol 1994; 27 Suppl:72-73.
28. Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs 1995; 50(2):222-239.
29. Cummins CL, Wu CY, Benet LZ. Sex-related differences in the clearance of cytochrome P450 3A4 substrates may be caused by P-glycoprotein. Clin Pharmacol Ther 2002; 72(5):474-489.
30. Lehmann MH. QT prolongation in end-stage liver disease: a result of altered sex hormone metabolism? Hepatology 1997; 26(1):244.
31. Lehmann MH, Frankovich D, Baga JJ et al. Does subclinical hypothyroidism explain the increased susceptibility of women to torsades de pointes? Am J Cardiol 1997; 79(7):963-965.

 


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