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Female gender as a risk for Torsades de Pointes associated with cardiovascular drugs
Abstract
To test the hypothesis that female prevalence is greater than expected among reported cases of torsades de pointes associated with cardiovascular drugs that prolong cardiac repolarization.
A MEDLINE search of the English-language literature for the period of 1980 through 1992, using the terms torsade de pointes, polymorphic ventricular tachycardia, atypical ventricular tachycardia, proarrhythmia, and drug-induced ventricular tachycardia, supplemented by pertinent references (dating back to 1964) from the reviewed articles and by personal communications with researchers involved in this field.
Ninety-three articles were identified describing at least one case of polymorphic ventricular tachycardia (with gender specified) associated with quinidine, procainamide hydrochloride, disopyramide, amiodarone, sotalol hydrochloride, bepridil hydrochloride, or prenylamine. A total of 332 patients were included in the analysis following application of prospectively defined criteria (eg, corrected QT [QTc] interval of 0.45 second or greater while receiving drug).
Clinical and electrocardiographic descriptors were extracted for analysis. Expected female prevalence for torsades de pointes associated with quinidine, procainamide, disopyramide, and aminodarone was conservatively estimated from gender-specific data reported for antiarrhythmic drug prescriptions in 1986, as derived from the National Disease and Therapeutic Index, a large pharmaceutical database; expected female prevalence for torsades de pointes associated with sotalol, bepridil, and prenylamine was assumed to be 50% or less since these agents are prescribed for male-predominant cardiovascular conditions.
Women made up 70% (95% confidence interval, 64% to 75%) of the 332 reported cases of cardiovascular-drug-related torsades de pointes, and a female prevalence exceeding 50% was observed in 20 (83%) of 24 studies having at least four included cases. When analyzed according to various descriptors, women still constituted the majority (range, 51% to 94% of torsades de pointes cases), irrespective of the presence or absence of underlying coronary artery or rheumatic heart disease, left ventricular dysfunction, type of underlying arrhythmia, hypokalemia, hypomagnesemia, bradycardia, concomitant digoxin treatment, or level of QTc at baseline or while receiving drug. When cases of torsades de pointes were analyzed by individual drug, observed female prevalence was always greater than expected, representing a statistically significant difference (P < .05) for all agents except procainamide.
These findings strongly suggest that women are more prone than men to develop torsades de pointes during administration of cardiovascular drugs that prolong cardiac repolarization. The pathophysiological basis for, and therapeutic implications of, this gender disparity should be further investigated.
... We hypothesised that possible reasons for OST clients' increasing DRD-rate with age included the methadone prescribed to older clients (Dimitropoulou et al., 2016), as directly implicated or indirectly through co-morbidities. Electrocardiograms are recommended for older or persistent methadone clients on higher doses (Medicines and Healthcare products Regulatory Agency (MHRA), 2006) to detect QTc prolongation (see Discussion section, below), for which being female (Makkar et al., 1993; Kest et al., 2000; Lee and Ho, 2013; Graziani and Nistico, 2015; Bawor et al., 2014 ), comorbidities and co-prescribing are also risk factors. As access to OST has expanded, the opioid-specificity of DRDs in Scotland, as elsewhere, has changed (Strang et al., 2010; Zador and Sunjic, 2002; Seymour et al., 2003; McCowan et al., 2009; Bird and Robertson, 2011; Pilgrim et al., 2013; Bernard et al., 2013; Cousins et al., 2016; Winker et al., 2014; Kimber et al., 2015). ...
... Whether undiagnosed QTc prolongation contributes to the tally of methadone-specific DRDs is unknowable because prolongation leaves no detectable trace at autopsy (Chugh et al., 2008). Other risk factors for QTc prolongation include co-morbidities such as renal impairment, heart or liver disease; and being female (Makkar et al., 1993; Kest et al., 2000; Lee and Ho, 2013; Graziani and Nistico, 2015; Bawor et al., 2014). In 2006, MHRA recommended that any patient requiring more than 100 mg of methadone per day should be closely monitored. ...
... Seventh, association is not causation (Hill, 1965): age over 45 years and higher quantity of methadone prescribed may be respectively demographic and pharmacological markers for harder-to-support clients whose opioid dependency is chronic and likewise their HCV progression (Eap et al., 2002). Research into gender differences in opioid analgesia and addiction has given conflicting results (Lee and Ho, 2013; Graziani and Nistico, 2015; Bawor et al., 2014) but being female is a risk-factor for QTc prolongation (Makkar et al., 1993), which may partly explain why, for females, the risk of methadone-specific DRDs is not lower than for their male counterparts. ...
Aim:
To quantify gender, age-group and quantity of methadone prescribed as risk factors for drugs-related deaths (DRDs), and for methadone-specific DRDs, in Scotland's methadone-prescription clients.
Design:
Linkage to death-records for Scotland's methadone-clients with one or more Community Health Index (CHI)-identified methadone prescriptions during July 2009 to June 2013.
Setting:
Scotland's Prescribing Information System and National Records of Scotland.
Measurements:
Covariates defined at first CHI-identified methadone prescription, and person-years at-risk (pys) thereafter until the earlier of death-date or 31 December 2013. Methadone-specific DRDs were defined as: methadone implicated but neither heroin nor buprenorphine. Hazard ratios (HRs) were assessed using proportional hazards regression.
Findings:
Scotland's CHI-identified methadone-prescription cohort comprised 33,128 clients, 121,254 pys, 1,171 non-DRDs and 760 DRDs (6.3 per 1,000 pys), of which 362 were methadone-specific. Irrespective of gender, methadone-specific DRD-rate, per 1,000 pys, was higher in the 35+ age-group (4.2; 95% CI: 3.6-4.7) than for younger clients (1.9; 95% CI: 1.5-2.2). For methadone-specific DRDs, age-related HRs (e.g., 2.9 at 45+ years; 95% CI: 2.1-3.9) were steeper than for all DRDs (1.9; 95% CI: 1.5-2.4); there was no hazard-reduction for females; no gender by age-group interaction; and, unlike for all DRDs, the highest quintile for quantity of prescribed methadone at cohort-entry (>1960mg) was associated with increased HR (1.8; 95% CI: 1.3-2.5).
Conclusion:
Higher methadone-specific DRD rates in older clients, irrespective of gender, call for better understanding of methadone's pharmaco-dynamics in older, opioid-dependent clients, many with progressive physical or mental ill-health.
... The occurrence of ventricular tachycardia, Torsade de Pointes (TdP) increase in the reproductively active women. 5 Throughout the menstrual cycle in reproductive women there is cyclic variation of sex hormones occurs and this variation results in to physiological alteration of cardiovascular activities which ultimately affects Electrocardiogram (ECG) parameters. 6 Progesterone shortens the duration of action potential and QT interval duration in the woman due to effect on ventricular repolarization. ...
... In prior studies it has been shown that there is decrease in QTc interval during secretory phase of menstrual cycle. 1,5,7,9 ...
Alteration in the release of female steroid hormones like progesterone and estrogen in a systematic manner is due to periodic ovarian variation. The alteration in female steroid hormones causes physiological alteration of cardiovascular activities and ultimately affects Electrocardiogram (ECG) parameters.
: To analyze the heart rate and the changes in PR interval and duration of ST segment in ECG during menstrual phases.
: To investigate any change in heart rate, PR interval and duration of ST segment in ECG during different phases of menstrual cycle.
30 apparently healthy female aged between 18-25 years were selected for the study and ECG was recorded using Electrocardiograph during the different phase of menstrual cycle:- a): Menstrual phase(MP) (2nd day), b): Proliferative phase(PP) (11th day) c): Secretory phase(SP) (22nd day).
Statistical analysis paired t-test was done by using online statistical calculator. There was statistical significant change in Heart rate, PR interval and ST segment duration. HR is increased more as compared to menstrual phase, it showing p-value of 0.000133 in paired t-test between Menstrual phase with secretory phase. There was no statistical significant change in PR interval during proliferative change on comparison with menstrual Phase.
Cyclical fluctuation of hormones during menstrual cycle changes electrophysiological parameters, affecting cardiovascular system.
... Ряд предыдущих исследований подтверждает, что пациентки женского пола склонны не только к большей продолжительности корригированного интервала QT в покое, но и к более выраженному удлинению интервала QT в ответ на прием лекарственных препаратов, а также к развитию лекарственно-индуцированной полиморфной ЖТ типа «пируэт» [8,11,[21][22][23][24]. ...
... Впервые эта связь была отмечена в 1993 г. в мета-анализе проаритмогенных побочных эффектов антиаритмических препаратов, главным образом хинидина [21]. Из 332 случаев ЖТ типа «пируэт», описанных в 93 наблюдениях, доля женщин составила 70 %. ...
Female gender is traditionally considered to be a risk factor for the QT interval prolongation and polymorphic ventricular tachycardia «torsades de pointes». However, despite a large number of studies on electrocardiographic features in patients with congenital long QT interval syndrome, there is relatively little information on gender ECG differences in the drug-induced QT interval prolongation.
The aim of this study is to evaluate the gender characteristics of electrocardiographic parameters characterizing myocardial depolarization and repolarization in patients with drug-induced QT interval prolongation induced by class III antiarrhythmic drugs.
67 patients with drug-induced QT interval prolongation induced class III antiarrhythmic drugs (amiodarone or sotalol) were examined, of which 38 (56.8 %) women and 29 (43.2 %) men, mean age – 57.1 ± 9.5 years. All patients underwent clinical laboratory and non-invasive electrophysiological studies, which included 12-lead ECG recording and 24-hour Holter monitoring. The patients of both genders were comparable in age and clinical characteristics, with the exception of a higher prevalence of AF in men (82.7 % vs 52.6 %, p = 0.03). The total duration of taking class III antiarrhythmic drugs in male patients was 3.79 ± 1.49 days, which significantly differed from female patients (3.11 ± 1.15 days, p = 0.044). When analyzing the initial standard ECG of patients recorded before starting antiarrhythmic drugs, there were no statistically significant differences between the groups, with the exception of large values of the corrected cardioelectrophysiological balance index (QTc/QRS) in female patients ( p = 0.037). While taking class III antiarrhythmic drugs, women had a higher duration of QTc ( p = 0.03) and JTc ( p = 0.023) intervals, as well as a dispersion of QT ( p = 0.012) and JT ( p = 0.006) intervals. According to Holter monitoring data, female patients were more likely to have an increased risk of developing non-sustained polymorphic VT ( p = 0.105).
These results suggest a complex interplay between gender and repolarization that needs further investigation. Considering the gender characteristics of the process of myocardial repolarization, it should be taken into account not only when prescribing class III antiarrhythmic drugs to women, but also during preclinical and clinical development of drugs that have the QT interval prolonging effect.
... To our knowledge, however, no simulationbased approach has considered any risk factor for Torsade in their predictive pipelines. An emblematic example is represented by the female sex: it is well established that women are more susceptible to Torsade than men when treated with QT-prolonging drugs, [20][21][22] suggesting that TdP risk classifiers could benefit from inclusion of this variable. However, female sex is highly underrepresented in both basic research 23 and clinical studies 24 involved in the drug development process, with important consequences on the identification of accurate TdP predictors. ...
... It is also important to understand sex-differences in TdP outcome in high-risk drugs, which also demonstrate female sex-prevalence, as demonstrated for quinidine, amiodarone, sotalol, disopyramide, bepridil, prenylamine (but not procainamide) 20 . ...
Torsade de Pointes (TdP), a rare but lethal ventricular arrhythmia, is a potential cardiac side effect of drugs.
To assess TdP risk, safety regulatory guidelines require to quantify the effects of new therapeutic compounds on hERG channel block in vitro and QT interval prolongation in vivo. Unfortunately, these have
proven to be poor predictors of torsadogenic risk, and are likely to have prevented safe compounds from
reaching the clinical phase. While this has stimulated numerous efforts to define new paradigms for cardiac
safety, none of the recently developed strategies accounts for patient conditions. In particular, despite being
a well-established independent risk factor for TdP, female sex is vastly underrepresented in both basic research and clinical studies, and thus current TdP metrics are likely biased toward the male sex. Here, we
apply statistical learning to synthetic data, generated by simulating drug effects on cardiac myocyte models
capturing male and female electrophysiology, to develop new sex-specific classification frameworks for
TdP risk. We show that 1) TdP classifiers require different features in females vs. males; 2) male-based
classifiers perform more poorly when applied to female data; 3) female-based classifier performances are
largely unaffected by acute effects of hormones (i.e., during various phases of the menstrual cycle). Notably,
when predicting TdP risk of intermediate drugs on female simulated data, male-biased predictive models
consistently underestimate TdP risk in women. Therefore, we conclude that pipelines for preclinical cardiotoxicity risk assessment should consider sex as a key variable to avoid potentially life-threatening consequences for the female population.
... The time of occurrence of an AV block differed between males and females, however no difference was observed with respect to the duration of pauses, indicating that the severity of seconddegree AV block did not differ between males and females. Gender-specific cardiac differences have been observed before, which might be explained by hormone-driven regulation of ion channels (34). However, the pathophysiological basis has not been fully elucidated (34,35). ...
... Gender-specific cardiac differences have been observed before, which might be explained by hormone-driven regulation of ion channels (34). However, the pathophysiological basis has not been fully elucidated (34,35). The absence of relevant pauses may contribute to the fact that the vast majority of events were not associated with any symptoms. ...
Background: First dose observation for cardiac effects is required for fingolimod. Previous results in patients with relapsing remitting multiple sclerosis (RRMS) suggest that transient bradycardia and conduction abnormalities during the observation phase are rare, benign and reversible. Prior analyses corroborate these findings. The present large scale dataset allows subgroup analyses for differences in the incidence of cardiac findings depending on patient characteristics.
Methods: START was an open-label, multi-center study that enrolled 6,998 RRMS patients. Primary endpoints were incidence of bradycardia (heart rate < 45 bpm) and second-/third-degree atrioventricular (AV) block during treatment initiation. Subgroup analyses were performed according to age, gender, body mass index (BMI), baseline expanded disability status scale (EDSS), and concomitant medication to determine the impact of these variables on cardiac outcomes parameters.
Results: 63 patients (0.9%) developed bradycardia (<45 bpm), 120 patients (1.7%) had a second-degree Mobitz I (Wenkebach) block and/or 2:1 AV block. One case of an asymptomatic third-degree AV block occurred. No Mobitz II AV block was observed. After 1 week, no second-/third-degree AV block was observed. The incidence of second- or third-degree AV blocks was significantly higher in older patients (≥50 years; p = 0.014 vs. patients 35–49 years). Second- or third-degree AV blocks were more frequent in females (87.5% of all patients with a second- or third-degree AV block; p < 0.001), while bradycardia occurred more often in males (58.7% of all bradycardia events; p < 0.001). Furthermore, patients with a BMI below 25 had a higher incidence of second- or third-degree AV block.
Conclusions: In summary, transient bradycardia and AV conduction abnormalities after the first dose of fingolimod were rare and asymptomatic. When compared to females, male patients might have a higher risk for bradycardia during treatment initiation, presumably due to a lower resting heart rate. Furthermore, a low heart rate before treatment initiation, low body weight, or low BMI possibly increases the risk for bradycardia. Second- or third-degree AV blocks were more frequent in females, older patients and patients with a low BMI. Nevertheless, these cardiac events remained rare and benign, confirming the favorable cardiac safety profile of fingolimod upon treatment initiation in MS patients without cardiovascular comorbidities.
... This study concluded that there is insufficient evidence to state whether LTG treatment increases the risk of these outcomes in these individuals, compared with other ASM or placebo (53). Furthermore, a Danish registry-based study (54) found no evidence that LTG elevates the risk of cardiac conduction disorders in individuals without known cardiac morbidity or increases the mortality from all causes in individuals with pre-existing cardiac disorders. The study included individuals with a prescription for LTG, but a diagnosis of epilepsy was not a prerequisite for inclusion. ...
The risk of sudden unexpected death in epilepsy (SUDEP) increases with the frequency of generalized tonic–clonic seizures. Carbamazepine (CBZ) and lamotrigine (LTG) have been suggested to increase the risk. However, the prevailing viewpoint is that the choice of antiseizure medication (ASM) does not influence the occurrence. We have explored the approach to addressing this question in relevant studies to evaluate the validity of the conclusions reached. A systematic search was performed in PubMed to identify all controlled studies on SUDEP risk in individuals on CBZ or LTG. Studies were categorized according to whether idiopathic generalized epilepsy (IGE) or females were considered separately, and whether data were adjusted for seizure frequency. Eight studies on CBZ and six studies on LTG were identified. For CBZ, one study showed a significantly increased risk of SUDEP without adjustment for seizure frequency. Another study found significantly increased risk after statistical adjustment for seizure frequency and one study found increased risk with high blood levels. Five other studies found no increase in risk. For LTG, one study showed a significantly increased risk in patients with IGE as opposed to focal epilepsy, and another study showed a significantly increased risk in females. None of the subsequent studies on LTG and none of the studies on CBZ considered females with IGE separately. Taken together the available studies suggest that LTG, and possibly CBZ, may increase occurrence of SUDEP when used in females with IGE. Additional studies with sub-group analysis of females with IGE are needed.
... Estrogen potentiates the prolongation of the QT interval induced by bradycardia and the development of arrhythmia. Conversely, androgens reduce the QT interval and make it less sensitive to drugs [26][27][28] . ...
Benzodiazepine (BDZ) addiction is a widespread and multifaceted phenomenon. For many patients, especially females, the concomitant use of other drugs also increases their risk of QTc prolongation, possibly leading to complications such as seizures and even sudden death. However, the relationship between BDZ use and QTc prolongation is currently unclear. The present study aims to examine patterns of polysubstance use among a sample of Italian adults with BDZ dependence in relation with their QTc prolongation risk. We used Latent Class Analysis (LCA) on data collected from 251 inpatients of the Addiction Medicine Unit in Verona to group patients into three classes according to their substance use and their QTc prolongation risk. Results showed no significant relationship between QTc prolongation and BDZ use in any of the classes considered. We conclude that BDZs, even if used long-term and at high dosages, can be considered safe in terms of cardiovascular complications for patients.
... Still, our study investigated only acute administration of AAD without its chronic use and proved no difference in terms of adverse actions between both genders. One should note, however, that former report suggested higher risk of QTc interval prolongation in women, translating into greater risk of torsade de pointes in females [21]. Still, no such case was reported in our population, presumably given lack of sotalol administration. ...
Background/aims:
Data on gender differences in terms of action of antiarrhythmic agents (AAD) is limited. The aim of the study was to evaluate clinical profile of AF patients, and efficacy and safety of AAD used for pharmacological cardioversion (PCV) of atrial fibrillation (AF).
Methods:
This research was a sub-analysis of retrospective multicenter Cardioversion with ANTazoline II (CANT) registry, which comprised 1365 patients with short-duration AF referred for urgent PCV with the use of AAD. Patients were categorized in terms of gender and compared in terms of clinical parameters and outcome of PCV. The primary endpoint was return of sinus rhythm within 12 hours after drug infusion and the composite safety endpoint involved bradycardia <45 bpm, hypotension, syncope or death.
Results:
The sex distribution of patients qualified for PCV was even (men, n=725, 53.1%). Females were older and more symptomatic, had higher CHA2DS2-VASc score, greater prevalence of tachyarrhythmia and higher utilization of chronic anticoagulation. The overall efficacy (71.4% vs.70.1%, P = 0.59) and safety (5.2% vs. 4.6%, P = 0.60) of PCV was comparable in men and women. Amiodarone (68.3% vs.65.9%, P = 0.66) and antazoline (77.1% vs.80.0%, P = 0.19) had similar efficacy in men and women, but propafenone had lower rate of rhythm conversion in men (64.7% vs.79.3%, P = 0.046). None of the assessed AAD differed in terms of safety profile in both genders.
Conclusion:
Female patients with AF share different clinical profile and similar efficacy and safety of AAD as compared to male participants. Propafenone has significantly lower efficacy in men, which requires further investigation.
... Conversely, androgens reduce the QT interval and make it less sensitive to drugs. (Drici & Clément, 2001;Makkar et al., 1993;Zeltser et al., 2003a). ...
BDZ addiction is a widespread and multifaceted phenomenon. For many patients, especially females, the concomitant use of other drugs also increases their risk of QTc prolongation, possibly leading to complications such as seizures and even sudden death. However, the relationship between BDZ use and QTc prolongation is currently unclear. The present study aims to examine patterns of polysubstance use among a sample of Italian adults with BDZ dependence in relation with their QTc prolongation risk. We used Latent Class Analysis (LCA) on data collected from 251 inpatients of the Addiction Medicine Unit in Verona to group patients into three classes according to their substance use and QTc prolongation risk. Results showed no significant relationship between QTc prolongation and BDZ use in any of the classes considered. We conclude that BDZs, even if used long-term and at high dosages, can be considered safe in terms of cardiovascular complications for patients.
... Particularly notable become such differences when comparing the prevalence of cardiac arrhythmias between sexes. Women are significantly more prone to symptomatic Long-QT Syndrome (LQTS) and Torsade de Pointes (TdP) tachycardia than men (Ebert et al., 1998;Makkar, 1993). It is widely assumed that differences in ion channel expression and function account for the sex-specific differences in phenotype. ...
Ventricular repolarization shows notable sex-specificity, with female sex being associated with longer QT-intervals in electrocardiography irrespective of the species studied. From a clinical point of view, women are at a greater risk for drug-induced torsade de pointes and symptomatic long-QT syndrome. Here, we present an optical mapping (OM) approach to reveal sex-specific action potential (AP) heterogeneity in a slice preparation of mouse hearts. Left ventricular epicardial repolarization in female versus male mice shows longer and, interindividually, more variable AP duration (APD), yielding a less prominent transmural APD gradient. By combining OM with mathematical modeling, we suggest a significant role of IKto,f and IKur in AP broadening in females. Other transmembrane currents, including INaL , only marginally affect basal APD. As in many cardiac pathophysiologies, increasing [Ca2+ ]i poses a risk for arrhythmia, the response of AP morphology to enhanced activation of L-type calcium channels (LTCC) was assessed in a sex-selective manner. Both APD and its variation increased significantly more in female versus male mice after pharmacological LTCC activation, which we hypothesize to be due to sex-specific INaL expression based on mathematical modeling. Altogether, we demonstrate a more delayed repolarization of LV epicardium, a leveled LV transmural APD gradient, and a more pronounced epicardial APD response to Ca2+ influx in females versus males. Mathematical modeling quantifies the relative contributions of selected ionic currents to sex-specific AP morphology under normal and pathophysiological conditions.
... For example, women have higher heart rates compared with age-matched males [122]. Still, they also have longer QT interval [122], shorter sinus node recovery times [123], and increased parasympathetic activity [124], all of which impact electrical conduction in the heart and could contribute to the higher risk of LQT and torsades de pointes [125] in females. Not surprisingly, the expression and activity of ion channels contribute to cardiac repolarization differences between sexes. ...
For years, females were thought of as smaller men with complex hormonal cycles; as a result, females have been largely excluded from preclinical and clinical research. However, in the last ten years, with the increased focus on sex as a biological variable, it has become clear that this is not the case, and in fact, male and female cardiovascular biology and cardiac stress responses differ substantially. Premenopausal women are protected from cardiovascular diseases, such as myocardial infarction and resultant heart failure, having preserved cardiac function, reduced adverse remodeling, and increased survival. Many underlying biological processes that contribute to ventricular remodeling differ between the sexes, such as cellular metabolism; immune cell responses; cardiac fibrosis and extracellular matrix remodeling; cardiomyocyte dysfunction; and endothelial biology; however, it is unclear how these changes afford protection to the female heart. Although many of these changes are dependent on protection provided by female sex hormones, several of these changes occur independent of sex hormones, suggesting that the nature of these changes is more complex than initially thought. This may be why studies focused on the cardiovascular benefits of hormone replacement therapy in post-menopausal women have provided mixed results. Some of the complexity likely stems from the fact that the cellular composition of the heart is sexually dimorphic and that in the setting of MI, different subpopulations of these cell types are apparent. Despite the documented sex-differences in cardiovascular (patho)physiology, the underlying mechanisms that contribute are largely unknown due to inconsistent findings amongst investigators and, in some cases, lack of rigor in reporting and consideration of sex-dependent variables. Therefore, this review aims to describe current understanding of the sex-dependent differences in the myocardium in response to physiological and pathological stressors, with a focus on the sex-dependent differences that contribute to post-infarction remodeling and resultant functional decline.
... For example, young adult male patients are at increased risk of myocarditis associated with coronavirus disease 2019 (COVID-19) vaccination [4][5][6]. Conversely, female sex has been identified as a risk factor for drug-induced QT prolongation and Torsades de pointes [7][8][9], as well as congenital long-QT syndrome [10]. Additionally, lower doses of the hypnotic agent zolpidem are recommended for women, who eliminate zolpidem more slowly and are more prone to impairment of daytime activities than men [11]. ...
IntroductionIdentifying individual characteristics or underlying conditions linked to adverse drug reactions (ADRs) can help optimise the benefit–risk ratio for individuals. A systematic evaluation of statistical methods to identify subgroups potentially at risk using spontaneous ADR report datasets is lacking.Objectives
In this study, we aimed to assess concordance between subgroup disproportionality scores and European Medicines Agency Pharmacovigilance Risk Assessment Committee (PRAC) discussions of potential subgroup risk.Methods
The subgroup disproportionality method described by Sandberg et al., and variants, were applied to statistically screen for subgroups at potential increased risk of ADRs, using data from the US FDA Adverse Event Reporting System (FAERS) cumulative from 2004 to quarter 2 2021. The reference set used to assess concordance was manually extracted from PRAC minutes from 2015 to 2019. Mentions of subgroups presenting potential differentiated risk and overlapping with the Sandberg method were included.ResultsTwenty-seven PRAC subgroup examples representing 1719 subgroup drug–event combinations (DECs) in FAERS were included. Using the Sandberg methodology, 2 of the 27 could be detected (one for age and one for sex). No subgroup examples for pregnancy and underlying condition were detected. With a methodological variant, 14 of 27 examples could be detected.Conclusions
We observed low concordance between subgroup disproportionality scores and PRAC discussions of potential subgroup risk. Subgroup analyses performed better for age and sex, while for covariates not well-captured in FAERS, such as underlying condition and pregnancy, additional data sources should be considered.
... While on average, QTc increases with age, age was additionally associated with increased QTc prolongation of dofetilide and decreased QTc prolongation from metolazone, lactulose, or rifaximin [22]. Women, on average, have longer QTcs and a higher risk of experiencing TdP while on QTc-prolonging medications [23,24]. Tisdale et al [8] found that female sex had an odds ratio of 1.5 for QTc prolongation (defined as a QTc of >500 milliseconds or an increase of >60 milliseconds). ...
Background
Drug-induced prolongation of the corrected QT interval (QTc) increases the risk for Torsades de Pointes (TdP) and sudden cardiac death. Medication effects on the QTc have been studied in controlled settings but may not be well evaluated in real-world settings where medication effects may be modulated by patient demographics and comorbidities as well as the usage of other concomitant medications.
Objective
We demonstrate a new, high-throughput method leveraging electronic health records (EHRs) and the Surescripts pharmacy database to monitor real-world QTc-prolonging medication and potential interacting effects from demographics and comorbidities.
Methods
We included all outpatient electrocardiograms (ECGs) from September 2008 to December 2019 at a large academic medical system, which were in sinus rhythm with a heart rate of 40-100 beats per minute, QRS duration of
... Conversely, androgens reduce the QT interval and make it less sensitive to drugs. (26)(27)(28). ...
Zolpidem is indicated in cases of severe insomnia in adults and, as for BDZs, its assumption should be limited to short periods under close medical supervision. Since several drugs cause corrected QT interval (QTc) elongation, the authors investigated whether high daily doses of Zolpidem could cause QTc elongation. The study was conducted in the Addiction Medicine Unit of the G.B. Rossi University Hospital in Verona. The data were collected from hospitalizations carried out between January 2015 and February 2020 and refer to a total of 74 patients, 38 males and 36 females, who were treated for detoxification from high doses of Zolpidem with the “Verona Detox Approach With Flumazenil.” One patient out of 74 had QTc elongation (479 ms). The patient was male and took a daily dose of 50 mg of Zolpidem; he did not take concomitant therapies that could cause QTc lengthening. He had no electrolyte alterations, no contemporary or previous intake of barbiturates, heroin, cocaine, THC, alcohol, NMDA or nicotine which could cause an elongation of the QTc interval. The present study highlights the low risk of QTc elongation due to high dosages of Zolpidem; however, if, on one hand, we can affirm that Zolpidem is a safe drug, on the other, the widespread use of high dosages of this drug for prolonged periods of time is problematic and worrying.
... Also, female rabbit ventricular myocytes have lower outward potassium currents, which determine the repolarization phase of the cardiac action potential, and current densities in the heart compared to males [13]. In a systemic review and meta-analysis that included 332 cases of torsades de pointe (TdP) associated with cardiovascular drugs that prolonged QTc, 70% (95% CI: 64-75%) were women even after adjusting for other TdP risk factors [14], suggesting that women are inherently more sensitive to drug-induced arrhythmias. ...
COVID-19 raised concern regarding cardiotoxicity and QTc prolongation of hydroxychloroquine (HCQ) and chloroquine (CQ). We examined the frequency and patient factors associated with ECG testing and the detection of prolonged QTc among new HCQ/CQ users in a large academic medical system. 10,248 subjects with a first HCQ/CQ prescription (1/2015–3/2020) were included. We assessed baseline (1 year prior to and including day of initiation of HCQ/CQ through 2 months after initial HCQ/CQ prescription) and follow-up (10 months after the baseline period) patient characteristics and ECGs obtained from electronic health records. Among 8384 female HCQ/CQ new users, ECGs were obtained for 22.3%, 14.3%, and 7.6%, at baseline, follow, and both periods, respectively. Among 1864 male HCQ/CQ new users, ECGs were obtained more frequently at baseline (29.7%), follow-up (18.0%), and both periods (11.3%). Female HCQ/CQ users with a normal QTc at baseline but prolonged QTc (> 470 ms) at follow-up (13.1%) were older at HCQ/CQ initiation [mean 64.7 (SD 16.5) vs. 58.7 (SD 16.9) years, p = 0.004] and more likely to have history of myocardial infarction (41.0% vs. 21.6%, p = 0.0003) compared to those who had normal baseline and follow-up QTc. The frequency of prolonged QTc development was similar (12.4%) among male HCQ/CQ new users (> 450 ms). Prior to COVID-19, ECG testing before and after HCQ/CQ prescription was infrequent, particularly for females who are disproportionately affected by rheumatic diseases and were just as likely to develop prolonged QTc (> 1/10 new users). Prospective studies are needed to guide future management of HCQ/CQ therapy in rheumatic populations.
... Conditions leading to greater potency are depicted in red, and would shift leftward and, on an ECG, would lead to more prolongation, as seen in the insert and as depicted in red. Assets for the ECG traces obtained from Servier Medical Art (Servier 2021) individual's genetic background (Echt et al. 1991;Makkar et al. 1993;Roden and Viswanathan 2005). Aside from these patient-specific factors, a drug's proarrhythmic propensity can also be modified by other systemic/acquired factors in patients such as electrolyte disturbances, acidosis, febrile temperatures and coadministration with other drugs. ...
Drug-induced long QT syndrome (diLQTS) is the phenomenon by which the administration of drugs causes prolongation of cardiac repolarisation and leads to an increased risk of the ventricular tachycardia known as torsades de pointes (TdP). In most cases of diLQTS, the primary molecular target is the human ether-à-go-go-related gene protein (hERG) potassium channel, which carries the rapid delayed rectifier current (I Kr ) in the heart. However, the proarrhythmic risk associated with drugs that block hERG can be modified in patients by a range of environmental- and disease-related factors, such as febrile temperatures, alterations in pH, dyselectrolytaemias such as hypokalaemia and hypomagnesemia and coadministration with other drugs. In this review, we will discuss the clinical occurrence of drug-induced LQTS in the context of these modifying factors as well as the mechanisms by which they contribute to altered hERG potency and proarrhythmic risk.
... Our ndings concur with those of the RACE trial, which indicated that rhythm control in females with AF leads to three times higher cardiovascular morbidity and mortality [24]. It has been suggested that a higher rate of antiarrhythmic drug adverse effects in female patients could constitute the underlying cause [24][25][26], as well as their increased risk for torsades de pointes when treated with sotalol and bradyarrhythmias under antiarrhythmic medication [27]. However, Roy et al. demonstrated that rhythm-control did not result in a reduction in all-cause mortality [28]. ...
Purpose
To assess the gender-related differences in the treatment patterns of patients with atrial fibrillation (AF), and their prognostic value.
Methods
In this post-hoc analysis of a randomized controlled trial, 1140 hospitalized patients with comorbid AF were followed-up for a median of 2.6 years. Kaplan-Meier and multivariable Cox-regression analyses assessed the adjusted hazard ratios (aHRs) for outcomes in males and females, according to oral anticoagulation (OAC) type (vitamin K antagonist or non-vitamin K antagonist oral anticoagulants), rhythm or rate control treatment. The primary outcome was all-cause mortality and the secondary outcomes were stroke and the composite of any hospitalization or cardiovascular death.
Results
Among 622 males and 518 females, use of OAC (61% vs 62%), rate control (56% vs 57%), and rhythm control (31% vs 28%) treatments was similar (all p>0.05). In males, use of rate control, as compared with rhythm control, was independently associated with higher rates of all-cause mortality (aHR=2.06; 95% confidence interval [CI] 1.24-3.41) and the composite of hospitalization or cardiovascular death (aHR=1.34, 95% CI 1.01-1.85). In females, use of rhythm control was significantly associated with higher rates of hospitalization-or cardiovascular mortality (aHR=1.74, 95% CI 1.03-2.94). Among genders, stroke rates were similar regardless of OAC type, rate or rhythm control treatment.
Conclusions
In patients discharged from the hospital with comorbid AF, the use of OAC, rhythm or rate control treatment was similar among genders. However, males seemed to benefit more from rhythm, whereas females from rate control treatment.
... A significant pharmacodynamic sex difference is the increased prevalence of QT interval prolongation in women which is reported for many drugs (Table 4), leading to an increased incidence of ventricular tachyarrythmias, syncope and increased risk of the cardiac arrythmia Torsades de Pointes. An early study investigated 32 cases of arrhythmia induced Torsades de Pointes and found 70% of all cases occurred in women [243]. The antiarrhythmic agent quinidine shows greater QT prolongation in females than men for Table 2 Sex-specific differences in the drug pharmacokinetics in humans following oral administration. ...
Professor Henry Higgins in My Fair Lady said, ‘Why can’t a woman be more like a man?’. Perhaps unintended, such narration extends to the reality of current drug development. A clear sex-gap exists in pharmaceutical research spanning from preclinical studies, clinical trials to post-marketing surveillance with a bias towards males. Consequently, women experience adverse drug reactions from approved drug products more often than men. Distinct differences in pharmaceutical response across drug classes and the lack of understanding of disease pathophysiology also exists between the sexes, often leading to suboptimal drug therapy in women. This review explores the influence of sex as a biological variable in drug delivery, pharmacokinetic response and overall efficacy in the context of pharmaceutical research and practice in the clinic. Prospective recommendations are provided to guide researchers towards the consideration of sex differences in methodologies and analyses. The promotion of disaggregating data according to sex to strengthen scientific rigour, encouraging innovation through the personalisation of medicines and adopting machine learning algorithms is vital for optimised drug development in the sexes and population health equity.
... However, the first cardiac event tends to be more often fatal in males than in females [77]. Additionally, in response to QT prolonging drugs, women are also more at risk of developing arrhythmias than men [79][80][81]. ...
Sudden cardiac death poses a unique challenge to clinicians because it may be the only symptom of an inherited heart condition. Indeed, inherited heart diseases can cause sudden cardiac death in older and younger individuals. Two groups of familial diseases are responsible for sudden cardiac death: cardiomyopathies (mainly hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy) and channelopathies (mainly long QT syndrome, Brugada syndrome, short QT syndrome, and catecholaminergic polymorphic ventricular tachycardia). This review focuses on cardiac channelopathies, which are characterized by lethal arrhythmias in the structurally normal heart, incomplete penetrance, and variable expressivity. Arrhythmias in these diseases result from pathogenic variants in genes encoding cardiac ion channels or associated proteins. Due to a lack of gross structural changes in the heart, channelopathies are often considered as potential causes of death in otherwise unexplained forensic autopsies. The asymptomatic nature of channelopathies is cause for concern in family members who may be carrying genetic risk factors, making the identification of these genetic factors of significant clinical importance.
... In the general adult population, female gender is associated with a higher risk of torsades de pointes. This arrhythmia occurs twice as often in women as it does in men (Makkar et al., 1993; Yap & Camm, 2003; Roden, 2004; Coker, 2008). Women of childbearing age are at greater risk of QT prolongation during the follicular phase (Burke et al., 1997; Endres et al., 2004; Nakagawa et al., 2006). ...
QT interval prolongation, corrected for heart rate (QTc), either spontaneous or drug-induced, is associated with an increased risk of torsades de pointes and sudden death. Women have longer QTc than men and are at higher risk of torsades de pointes, particularly during post-partum and the follicular phase. Men with peripheral hypogonadism have longer QTc than healthy controls. The role of the main sex steroid hormones has been extensively studied with inconsistent findings. Overall, estradiol is considered to promote QTc lengthening while progesterone and testosterone shorten QTc. New findings suggest more complex regulation of QTc by sex steroid hormones involving gonadotropins (i.e. follicle-stimulating hormone), the relative concentrations of sex steroid hormones (which depends on gender, i.e., progesterone/estradiol ratio in women). Aldosterone, another structurally related steroid hormone, can also prolong ventricular repolarization in both sex. Better understanding of pathophysiological hormonal processes which may lead to increased susceptibility of women (and possibly hypogonadic men) to drug-induced arrhythmia may foster preventive treatments (e.g. progesterone in women). Exogenous hormonal intake might offer new therapeutic opportunities or, alternatively, increase the risk of torsades de pointes. Some exogenous sex steroids may also have paradoxical effects on ventricular repolarization. Lastly, variations of QTc in women linked to the menstrual cycle and sex hormone fluctuations are generally ignored in regulatory thorough QT studies. Investigators and regulatory agencies promoting inclusion of women in thorough QT studies should be aware of this source of variability especially when studying drugs over several days of administration.
... In the healthy population, from puberty to menopause, women have longer QTc interval duration (QTc) than men [1,2] . This is associated with a higher risk of torsades de pointes or drug-induced arrhythmia [3][4][5]. The role of sex steroid hormones on cardiac repolarization, mainly oestradiol, progesterone and testosterone, has been suggested for many years but is still a matter of debate. ...
Context:
QT interval duration is longer in women than in men. Sex steroid hormones have inconsistently been suggested to explain this difference. The implication of gonadotropins has never been studied.
Objective:
We report here the combined influence of sex steroid hormones and gonadotropins on QT interval duration in healthy subjects and patients with congenital adrenal hyperplasia (CAH) as a model of T and progesterone overexpression.
Design and patients:
Eighty-four CAH patients (58 women) and 84 healthy subjects matched and paired for sex and age were prospectively included. Circulating concentrations of 17-OH-progesterone, progesterone, T, estradiol, FSH, and LH were measured concomitantly to the recording of a digitized electrocardiogram.
Results:
QTcFridericia (QTcF) was shorter in women with CAH than in control women (404 ± 2 vs 413 ± 2.1 milliseconds; P ≤ .001). 17-OH-progesterone, progesterone, the progesterone/estradiol ratio, and total T were higher in women with CAH than in female controls (P < .05), whereas FSH was lower (P ≤ .05). According to multivariable analysis in all women, the progesterone/estradiol ratio (β = -0.33) and FSH levels (β = 0.34) were related to QTcF (r = 0.5; P < .0001), with no influence of CAH or healthy status. QTcF was not different between CAH (404.7 ± 3.7 milliseconds) or healthy men (396 ± 2.8 milliseconds). For men, QTcF (r = 0.48; P < .01) was negatively related to free T (β = -0.29) and positively to FSH levels (β = 0.34).
Conclusion:
Cardiac repolarization is influenced by complex interactions between sex steroid hormones and gonadotropins, depending on gender. Our results indicate that the progesterone/estradiol ratio in women, T in men, and FSH in both genders are major determinants of ventricular repolarization with opposite effects on QTc interval.
Pulsatile gonadotropin‐releasing hormone (GnRH) release is critical for reproduction. Disruptions to GnRH secretion patterns may contribute to polycystic ovary syndrome (PCOS). Prenatally androgenized (PNA) female mice recapitulate many neuroendocrine abnormalities observed in PCOS patients. PNA and development induce changes in spontaneous GnRH neuron firing rate, response to synaptic input, and the afterhyperpolarization potential of the action potential. We hypothesized potassium currents are altered by PNA treatment and/or development. Whole‐cell patch‐clamp recordings were made of transient and residual potassium currents of GnRH neurons in brain slices from 3‐week‐old and adult control and PNA females. At 3 weeks of age, PNA treatment increased transient current density versus controls. Development and PNA altered voltage‐dependent activation and inactivation of the transient current. In controls, transient current activation and inactivation were depolarized at 3 weeks of age versus in adulthood. In GnRH neurons from 3‐week‐old mice, transient current activation and inactivation were more depolarized in control than PNA mice. Development and PNA treatment interacted to shift the time‐dependence of inactivation and recovery from inactivation. Notably, in cells from adult PNA females, recovery was prolonged compared to all other groups. Activation of the residual current occurred at more depolarized membrane potentials in 3‐week‐old than adult controls. PNA depolarized activation of the residual current in adults. These findings demonstrate the properties of GnRH neuron potassium currents change during typical development, potentially contributing to puberty, and further suggest PNA treatment may both alter some typical developmental changes and induce additional modifications, which together may underlie aspects of the PNA phenotype. There was not any clinical trial involved in this work.
Women have been under-represented in trials of antipsychotic medications.
Our primary objective was to evaluate five adverse events (AE) associated with first-generation antipsychotics (FGAs) among women relative to men through an analysis of the FDA Adverse Event Reporting System (FAERS).
We queried 24.6 million AE reports from 2000 to 2023 involving FGAs. The study cohort consisted of chlorpromazine (n = 3317), fluphenazine (n = 1124), haloperidol (n = 16,709), loxapine (n = 3151), perphenazine (n = 816), thioridazine (n = 665), thiothixene (n = 244), and trifluoperazine (n = 360). Cases of neuroleptic malignant syndrome (NMS), tardive dyskinesia (TD), Torsades de Pointes (TdP), agranulocytosis (AG), and cerebrovascular adverse events (CVAE) were identified. Reporting odds ratios (ROR) and associated 95% confidence intervals (CI) were calculated with logistic regression for each AE among women relative to men.
A total of 2,857 serious AEs were evaluated in the study cohort (NMS = 1810, TD = 434, TdP = 260, AG = 149, CVAE = 204). The ROR for women compared to men was 0.79 (95% CI, 0.71–0.87) for NMS, 0.83 (0.68–1.01) for TD, 1.21 (0.94–1.53) for TdP, 0.71 (0.51–0.98) for AG, and 0.91 (0.68–1.19) for CVAE. A secondary analysis revealed a higher odds in women compared to men of hospitalization associated with reports of TD (ROR = 1.95, 1.29–2.94) and death associated with reports of AG (ROR = 2.46, 1.15–5.24). A subgroup analysis of haloperidol revealed an ROR = 1.67 (1.26–2.21) for women relative to men for TdP.
The subgroup analysis of haloperidol AEs revealed a significantly higher reporting odds ratio for TdP. Additionally, the secondary study findings suggest that women were more vulnerable to worse outcomes associated with certain AEs of FGAs.
Background:
Sotalol and dronedarone are both used for maintenance of sinus rhythm for patients with atrial fibrillation. However, while sotalol requires initial monitoring for QT prolongation and proarrhythmia, dronedarone does not. These treatments can be used in comparable patients, but their safety and effectiveness have not been compared head to head. Therefore, we retrospectively evaluated the effectiveness and safety using data from a large health care system.
Methods:
Using Veterans Health Administration data, we identified 11 296 antiarrhythmic drug-naive patients with atrial fibrillation prescribed dronedarone or sotalol in 2012 or later. We excluded patients with prior conduction disease, pacemakers or implantable cardioverter-defibrillators, ventricular arrhythmia, cancer, renal failure, liver disease, or heart failure. We used natural language processing to identify and compare baseline left ventricular ejection fraction between treatment arms. We used 1:1 propensity score matching, based on patient demographics, comorbidities, and medications, and Cox regression to compare strategies. To evaluate residual confounding, we performed falsification analysis with nonplausible outcomes.
Results:
The matched cohort comprised 6212 patients (3106 dronedarone and 3106 sotalol; mean [±SD] age, 71±10 years; 2.5% female; mean [±SD] CHA2DS2-VASC, 2±1.3). The mean (±SD) left ventricular ejection fraction was 55±11 and 58±10 for dronedarone and sotalol users, correspondingly. Dronedarone, compared with sotalol, did not demonstrate a significant association with risk of cardiovascular hospitalization (hazard ratio, 1.03 [95% CI, 0.88-1.21]) or all-cause mortality (hazard ratio, 0.89 [95% CI, 0.68-1.16]). However, dronedarone was associated with significantly lower risk of ventricular proarrhythmic events (hazard ratio, 0.53 [95% CI, 0.38-0.74]) and symptomatic bradycardia (hazard ratio, 0.56 [95% CI, 0.37-0.87]). The primary findings were stable across sensitivity analyses. Falsification analyses were not significant.
Conclusions:
Dronedarone, compared with sotalol, was associated with a lower risk of ventricular proarrhythmic events and conduction disorders while having no difference in risk of incident cardiovascular hospitalization and mortality. These observational data provide the basis for prospective efficacy and safety trials.
In the struggle against COVID-19 pandemic, chloroquine (CQ) (a 4-aminoquinoline) and its derivative hydroxychloroquine (HCQ) have both been used as a potential form of treatment among infected patients. Originally known as an antimalarial quinolone, many countries have adopted their use as an option to treat COVID-19 patients. In humans, dose-dependent chloroquine induces QT interval prolongation. It also blocks the human ether-a-go-go-related gene (hERG), which encodes the rapidly activating delayed rectifier K+ channel. The action potential duration is then prolonged, as the eventual QTc interval of the electrocardiogram (ECG), resulting in torsade de pointes and cardiac arrhythmias that could lead to sudden death. It is yet unknown whether COVID-19 itself has any effect on the QTc interval. The current review established what is new and different from other studies involving the use of chloroquine and hydroxychloroquine among COVID-19 patients plus the corresponding QT interval prolongation in affected individuals.
Atrial fibrillation (AF) is the most common rhythm disorder seen in doctors' offices and emergency departments (EDs). In both settings, an AF holistic pathway including anticoagulation or stroke avoidance, better symptom management, and cardiovascular and comorbidity optimization should be followed. However, other considerations need to be assessed in the ED, such as haemodynamic instability, the onset of AF, the presence of acute heart failure and pre-excitation. Although the Advanced Cardiovascular Life Support guidelines (European Society of Cardiology guidelines, Acute Cardiac Care Association/European Heart Rhythm Association position statements) and several recent AF publications have greatly assisted physicians in treating AF with rapid ventricular response in the ED, further practical clinical guidance is required to improve physicians' skill and knowledge in providing the best treatment for patients. Herein, we combine multiple strategies with supporting evidence-based treatment and experiences encountered in clinical practice into practical stepwise approaches. We hope that the stepwise algorithm may assist residents and physicians in managing AF in the ED.
There is a growing appreciation for differences in epidemiology, treatment, and outcomes of cardiovascular conditions by sex. Historically, cardiovascular clinical trials have under-represented females, but findings have nonetheless been applied to clinical care in a sex-agnostic manner. Thus, much of the collective knowledge about sex-specific cardiovascular outcomes result from post hoc and secondary analyses. In some cases, these investigations have revealed important sex-based differences with implications for optimizing care for female patients with arrhythmias. This review explores the available evidence related to cardiac arrhythmia care among females, with emphasis on areas in which important sex differences are known or suggested. Considerations related to improving female enrollment in clinical trials as a way to establish more robust clinical evidence for the treatment of females are discussed. Areas of remaining evidence gaps are provided, and recommendations for areas of future research and specific action items are suggested. The overarching goal is to improve appreciation for sex-based differences in cardiac arrhythmia care as 1 component of a comprehensive plan to optimize arrhythmia care for all patients.
Heart failure (HF) and atrial fibrillation (AF) demonstrate a constantly increasing prevalence during the 21st century worldwide, as a result of the aging population and the successful interventions of the clinical practice in the deterioration of adverse cardiovascular outcomes. HF and AF share common risk factors and pathophysiological mechanisms, creating the base of a constant interrelation. AF impairs systolic and diastolic function, resulting in the increasing incidence of HF, whereas the structural and neurohormonal changes in HF with preserved or reduced ejection fraction increase the possibility of the AF development. The temporal relationship of the development of either condition affects the diagnostic algorithms, the prognosis and the ideal therapeutic strategy that leads to euvolaemia, management of non-cardiovascular comorbidities, control of heart rate or restoration of sinus rate, ventricular synchronization, prevention of sudden death, stroke, embolism, or major bleeding and maintenance of a sustainable quality of life. The indicated treatment for the concomitant HF and AF includes rate or/and rhythm control as well as thromboembolism prophylaxis, while the progress in the understanding of their pathophysiological interdependence and the introduction of the genetic profiling, create new paths in the diagnosis, the prognosis and the prevention of these diseases.
Torsade de Pointes (TdP), a rare but lethal ventricular arrhythmia, is a toxic side effect of many drugs. To assess TdP risk, safety regulatory guidelines require quantification of hERG channel block in vitro and QT interval prolongation in vivo for all new therapeutic compounds. Unfortunately, these have proven to be poor predictors of torsadogenic risk, and are likely to have prevented safe compounds from reaching clinical phases. While this has stimulated numerous efforts to define new paradigms for cardiac safety, none of the recently developed strategies accounts for patient conditions. In particular, despite being a well‐established independent risk factor for TdP, female sex is vastly underrepresented in both basic research and clinical studies, and thus current TdP metrics are likely biased toward the male sex. Here, we apply statistical learning to synthetic data, generated by simulating drug effects on cardiac myocyte models capturing male and female electrophysiology, to develop new sex‐specific classification frameworks for TdP risk. We show that (1) TdP classifiers require different features in females vs. males; (2) male‐based classifiers perform more poorly when applied to female data; (3) female‐based classifier performance is largely unaffected by acute effects of hormones (i.e., during various phases of the menstrual cycle). Notably, when predicting TdP risk of intermediate drugs on female simulated data, male‐biased predictive models consistently underestimate TdP risk in women. Therefore, we conclude that pipelines for preclinical cardiotoxicity risk assessment should consider sex as a key variable to avoid potentially life‐threatening consequences for the female population.
Sex-related differences in prevalence, clinical presentation, and outcome of cardiac channelopathies are increasingly recognized, despite their autosomal transmission and hence equal genetic predisposition among sexes. In congenital long-QT syndrome, adult women carry a greater risk for Torsades de pointes and sudden cardiac death than do men. In contrast, Brugada syndrome is observed predominantly in adult men, with a considerably higher risk of arrhythmic sudden cardiac death in adult men than in women. In both conditions, the risk for arrhythmias varies with age. Sex-associated differences appear less evident in other cardiac channelopathies, likely a reflection of their rare(r) occurrence and our limited knowledge. In several cardiac channelopathies, sex-specific predictors of outcome have been identified. Together with genetic and environmental factors, sex hormones contribute to the sex-related disparities in cardiac channelopathies through modulation of the expression and function of cardiac ion channels. Despite these insights, essential knowledge gaps exist in the mechanistic understanding of these differences, warranting further investigation. Precise application of the available knowledge may improve the individualized care of patients with cardiac channelopathies. Promoting the reporting of sex-related phenotype and outcome parameters in clinical and experimental studies and advancing research on cardiac channelopathy animal models should translate into improved patient outcomes. This review provides a critical digest of the current evidence for sex-related differences in cardiac channelopathies and emphasizes their clinical implications and remaining gaps requiring further research.
Adverse drug reactions are the fourth leading cause of death in the US. Although women take longer to metabolize medications and experience twice the risk of developing adverse reactions compared with men, these sex differences are not comprehensively understood. Real-world clinical data provide an opportunity to estimate safety effects in otherwise understudied populations, i.e., women. These data, however, are subject to confounding biases and correlated covariates. We present AwareDX, a pharmacovigilance algorithm that leverages advances in machine learning to predict sex risks. Our algorithm mitigates these biases and quantifies the differential risk of a drug causing an adverse event in either men or women. AwareDX demonstrates high precision during validation against clinical literature and pharmacogenetic mechanisms. We present a resource of 20,817 adverse drug effects posing sex-specific risks. AwareDX, and this resource, present an opportunity to minimize adverse events by tailoring drug prescription and dosage to sex.
Aims
Prolonged QT interval on electrocardiogram (ECG) increases the risk of ventricular arrhythmia. Patients admitted to acute medical units (AMU) may be at risk of QT prolongation from multiple, recognised risk factors. Few data exist regarding incidence or outcomes of QT prolongation in acute general medical admissions.
The aims were to determine the incidence of Bazett's‐corrected QT (QTc) prolongation upon admission to AMU; the relationship between QTc and inpatient mortality, length of stay and readmission; proportion with prolonged QTc subsequently administered QT interval‐prolonging drugs.
Methods
Retrospective, observational study of 1000 consecutive patients admitted to an AMU in a large urban hospital. Exclusion criteria: age <18 years, ventricular pacing, poor quality/absent ECG. QTc determined manually from ECG obtained within 4‐hours of admission. QTc prolongation considered ≥470 milliseconds (males) and ≥480 milliseconds (females). In both genders, >500 milliseconds was considered severe. Study end‐points, (a) incidence of QTc prolongation at admission; (b) inpatient mortality, length of stay and readmission rates; (c) proportion with QTc prolongation subsequently administered QT interval‐prolonging drugs.
Results
Of 1000 patients, 288 patients were excluded, therefore final sample was n = 712. Patient age (mean ± SD) was 63.1 ± 19.4 years; females 49%. QTc prolongation was present in n = 50 (7%) at admission; 1.7% had QTc interval >500 ms. Of the 50 patients admitted with prolonged QTc, 6 (12%) were subsequently administered QT interval‐prolonging drugs. QTc prolongation was not associated with worse inpatient mortality or readmission rate. Length of stay was greater in those with prolonged QTc, 7.2 (IQR 2.4‐13.2) days vs 3.3 (IQR 1.3‐10.0; P = 0.004), however, in a regression model, presence of QTc did not independently affect length of stay.
Conclusions
QTc interval prolongation is frequent among patients admitted to AMU. QT interval‐prolonging drugs are commonly prescribed to patients presenting with prolonged QTc but whether this affects clinical outcomes is uncertain.
Background:
While the prevalence of short QT syndrome (SQTS) in children and adolescents is low, early detection is important because SQTS can cause life-threatening arrhythmia. The aim of this study was to determine the tentative screening criteria for short QT interval in children and adolescents.Methods and Results:A total of 75,040 digitally stored electrocardiograms (ECG) of participants in a school-based ECG screening program were obtained between 2009 and 2013 in Kagoshima, Japan. ECG with a corrected QT interval (QTc) below the 10th percentile for each grade and sex were selected: 2,581 first graders (M/F, 1,296/1,285); 2,792 7th graders (M/F, 1,400/1,392); and 2018 10th graders (M/F, 979/1,039). Three consecutive QT/RR intervals were manually measured and corrected using Bazett's formula. The prevalence of SQTS was estimated at 1/30,000-1/10,000, which was set compared with the prevalence of long QT syndrome, then the screening points of the prevalence of short QT interval were assumed to be between 1/5,000 and 1/2,000 to exclude the possibility of false negative. We obtained the following tentative criteria based on frequency distribution charts: 325, 315 and 305 ms for male 1st, 7th and 10th graders, respectively; and 320 ms for female 1st, 7th, and 10th graders.
Conclusions:
For primary SQTS screening of children and adolescents, the QTc values for short QT interval should be adapted according to grade and sex.
Purpose of Review
The prevalence of heart diseases is growing in recent years and will further rise because of the increased longevity of elderly population, mainly reported for the female gender.
Recent Findings
Several studies have demonstrated the presence of a large sex-specific variability on physiopathology, presentation, and overall prognosis of cardiovascular diseases (CVD). Women, in particular, tend to present heart diseases generally later than men, have a higher number of comorbidities, and report worse outcomes. Moreover, atypical symptomatology of heart diseases in older women constitutes a potential source of delay in the identification of such pathologies, influencing the management of CVDs that is still characterized by a lesser access to invasive procedures for the female gender compared with the male one. The lack of knowledge in the field of sex-specific disparities in CVDs is probably due to the underrepresentation of women in the first large cardiovascular trials, with the processing of guidelines for the prevention, identification, and treatment of CVDs that do not consider gender variability.
Summary
Although growing attention has been recently dedicated to this topic, further investigations are needed to fully analyze heart diseases in elderly women with the aim of developing new and targeted recommendations for clinical practice.
Dr. Zareba has reported that he has received research grants from Gilead Sciences.
Objective To evaluate the frequency, validity, and relevance of statistically significant (P<0.05) sex-treatment interactions in randomized controlled trials in Cochrane meta-analyses.
Design Meta-epidemiological study.
Data sources Cochrane Database of Systematic Reviews (CDSR) and PubMed.
Eligibility criteria for study selection Reviews published in the CDSR with sex-treatment subgroup analyses in the forest plots, using data from randomized controlled trials.
Data extraction Information on the study design and sex subgroup data were extracted from reviews and forest plots that met inclusion criteria. For each statistically significant sex-treatment interaction, the potential for biological plausibility and clinical significance was considered.
Results Among the 41 reviews with relevant data, there were 109 separate treatment-outcome analyses (“topics”). Among the 109 topics, eight (7%) had a statistically significant sex-treatment interaction. The 109 topics included 311 randomized controlled trials (162 with both sexes, 46 with males only, 103 with females only). Of the 162 individual randomized controlled trials that included both sexes, 15 (9%) had a statistically significant sex-treatment interaction. Of four topics where the first published randomized controlled trial had a statistically significant sex-treatment interaction, no meta-analyses that included other randomized controlled trials retained the statistical significance and no meta-analyses showed statistical significance when data from the first published randomized controlled trial were excluded. Of the eight statistically significant sex-treatment interactions from the overall analyses, only three were discussed by the CDSR reviewers for a potential impact on different clinical management for males compared with females. None of these topics had a sex-treatment interaction that influenced treatment recommendations in recent guidelines. UpToDate, an online physician-authored clinical decision support resource, suggested differential management of men and women for one of these sex-treatment interactions.
Conclusion Statistically significant sex-treatment interactions are only slightly more frequent than what would be expected by chance and there is little evidence of subsequent corroboration or clinical relevance of sex-treatment interactions.
Sex-specific differences in the epidemiology, pathophysiology, presentation, prognosis, and treatment of atrial fibrillation (AF) are increasingly recognized. Women with AF generally experience worse symptoms, poorer quality of life, and have higher risk of stroke and death than men with AF. Effective treatment of the arrhythmia in women is critical to reduce the rate of adverse events. We review the current evidence on sex-specific differences in the utilization and outcomes of treatments for AF, including rate-control and rhythm-control strategies, and stroke-prevention therapy. In addition, we provide a critical evaluation of potential disparities and biases in health-care use that might be associated with differences in the outcomes between women and men. We underscore current knowledge gaps that need to be addressed in future studies to improve the management of AF in women. In particular, we suggest several strategies to produce high-quality evidence from randomized clinical trials for women with AF.
QTc prolongation has a high prevalence of and is associated with increased all-cause mortality. Nonetheless, QTc prolonging medications are often used during patient hospitalizations despite baseline prolongation and QTc changes. Data regarding the real world relative risk of QTc prolongation in the hospital setting is lacking. In this study, we sought to quantify the degree and relative risk of QTc prolongation in patients receiving Arizona Center for Education and Research on Therapeutics (AzCERT) “known risk” medications. Electronic medical records of patients receiving an electrocardiogram (ECG) at the University of Chicago, admitted in 2011 were analyzed. The longest QTc interval and medications administered within the preceding 24 hours were evaluated. Medications were classified into 4 categories according to the AzCERT classification. Of a total of 14,804 patients, mean QTc intervals were 485ms vs 454ms for men and 469ms vs 453ms for women receiving known risk medications compared to those receiving no risk medications (p<0.001). The rate of QTc prolongation was 71% vs 48% for men and 50% vs 34% for women respectively. There was no significant increase in QTc prolongation for patients administered multiple QT-relevant medications or for those administered only conditional or possible risk medications. In conclusion, the prevalence of significant QTc prolongation in patients receiving AzCERT known risk medications is high. This may be a reflection of inadequate awareness or overall quality inadequacies.
Background:
Female gender increases the risk of torsades de pointes (TdP) in the long QT syndrome, and this increased risk is assumed to be due to their longer QT interval.
Objective:
The purpose of this study was to study the interplay between gender, duration of the QT interval, and risk of TdP during AV block.
Methods:
We studied 250 patients (48% women) with AV block. QT interval was measured at the time of most severe bradycardia. We then constructed different receiver operating characteristic curves for the QTc of males and females for predicting TdP.
Results:
As expected, patients with TdP had longer QTc intervals than did patients with uncomplicated AV block (564 ± 81 ms vs 422 ± 62 ms, P < .001). This correlation between longer QTc and higher risk of TdP was true for both genders. However, the QT of females with TdP was shorter than the respective value for males with TdP. Despite similar severity of bradycardia, the QT was shorter for females (QT 672 ± 88 ms vs 727 ± 57 ms for females with TdP vs males with TdP, P = .022). The QTc/TdP risk curve for females was shifted to the left in comparison to the pertinent graph for males. Female gender was an independent predictor of TdP.
Conclusion:
Women are at increased risk for developing TdP during AV block, but this increased risk is independent of their longer QT interval. Females develop TdP with QT intervals that are not necessarily arrhythmogenic for males.
Female sex is an independent risk factor for development of torsade de pointes (TdP) arrhythmias not only in congenital long QT syndromes but also in acquired long QT syndromes. Clinical and experimental evidences suggest that the gender differences may be due to, at least in part, gender differences in regulation of rate-corrected QT (QTC) interval between men and women. In adult women, both QTC interval and arrhythmic risks in TdP alter cyclically during menstrual cycle, suggesting a critical role of female sex hormones in cardiac repolarization process. These gender differences in fundamental cardiac electrophysiology result from variable ion channel expression and diverse sex hormonal regulation via long term genomic and acute non-genomic actions, and sex differences in drug responses and metabolisms. In particular, non-genomic actions of testosterone and progesterone on cardiac ion channels are likely to contribute to the gender differences in cardiac repolarization processes. This review summarizes current knowledge on sex hormonal regulation of cardiac ion channels which contribute to cardiac repolarization processes and its implication for gender differences in drug-induced long QT syndromes.
Objectives:
There is no evidence regarding the effect of ondansetron on the QT interval in pediatric patients in the ICU. This study aimed to describe the effect of ondansetron on the corrected QT interval in patients cared for in the PICU.
Design:
Retrospective cohort, consecutive enrollment study.
Setting:
Single-center, tertiary-level, medical/surgical PICU.
Patients:
All patients less than 8 years old who received ondansetron over an 11-month period were included. Exclusion criteria were atrial arrhythmia, bundle-branch block, known congenital long QT syndrome, and concomitant administration of proarrhythmic antiarrhythmic agents.
Interventions:
None.
Measurements and main results:
Overall, 210 doses of ondansetron were administered to 107 patients, with a mean age 10.5 ± 4.8 years; 49% were men. Corrected QT interval increased to 460-500 ms in 29% and to more than 500 ms in 11% of events of ondansetron administration. The mean baseline corrected QT interval even before ondansetron administration was higher for these groups (460-500 and > 500 ms; 457 ± 33 and 469 ± 45, respectively; p ≤ 0.05). In multivariate analysis, both groups were associated significantly with underlying electrolyte abnormalities (odds ratio, 2.2; 95% CI, 1.1-4.4 and odds ratio, 5.1; 95% CI, 1.8-15.7, respectively); the group with corrected QT interval more than 500 ms was also significantly associated with organ dysfunction (odds ratio, 3.2; 95% CI, 1.1-9.4). As the numbers of risk factors increased from only ondansetron to three additional QT aggravating factors (electrolyte abnormalities, administration of other QT-prolonging drugs, and organ dysfunction), the likelihood of being associated with corrected QT interval more than 500 ms increased.
Conclusions:
Prolonged QT interval is observed commonly in PICUs following the administration of ondansetron. Underlying risk factors, such as electrolyte abnormalities and organ dysfunction, seem to pose the highest risk of prolongation of QT interval in these patients. The awareness of prevalent risk factors for increased corrected QT interval may help identify patients at high risk for arrhythmias.
Electrocardiography (ECG) in rats is a widely applied experimental method in basic cardiovascular
research. The technique of ECG recordings is simple; however, the interpretation of electrocardiographic parameters is challenging. This is because the analysis may be biased by experimental settings, such as the type of anaesthesia, the strain or age of animals. Here, we aimed to review electrocardiographic parameters in rats, their normal range, as well as the effect of experimental settings on the parameters variation.
Furthermore, differences and similarities between rat and human ECG are discussed in the context of translational cardiovascular research.
Background:
Stratification of atrial fibrillation (AF) patients according to mechanistic and prognostic criteria may optimize effectiveness and safety of catheter ablation. In women, AF is associated with more severe symptoms and worse prognosis.
Objective:
We sought to assess sex-related differences in catheter ablation procedures and outcome in a large AF-patient-cohort.
Methods:
A total of 3652 patients (1198 females (f), 33%; 2454 males (m), 67%) included in the German Ablation Registry were analyzed. Periprocedural parameters and outcome at 12 months follow-up were compared between male and female patients.
Results:
Women were older at the time of ablation (f:63.6 years; m:59.1 years; P<.0001) and exhibited a higher prevalence of paroxysmal AF (f:72%; m:61%; P<.0001). They were less often affected by cardiovascular disease and reduced left ventricular function. Duration of energy-application and overall procedure times were shorter in women. Conversely, the rate of major in-hospital complications was increased in female patients (1.9% versus 0.8%, P=.023) and mainly driven by major bleedings. At follow-up, women experienced higher AF-recurrence rates (f:50%; m:45%; P=.017) and more often received oral medication for rhythm and rate control. Additionally, the rate of pacemaker implantation was higher in the female cohort. Women more frequently reported femoral access site complications (f:6%, m:3%; P<.001). Overall, male patients were more often free from AF-related symptoms and satisfied with the treatment.
Conclusion:
Catheter ablation of AF was associated with a distinct sex-related outcome and complication profile that requires consideration in clinical practice.
One hundred and twelve patients with heart block and chronic tendency to syncope were ECG-monitored during syncope. Ventricular tachycardia and/or fibrillation (VT-VF) was observed as the cause of syncope in 11 patients: in 6 of 20 patients with chronic third degree A-V block, in 3 of 65 with paroxysmal A-V block and in 2 of 27 with S-A block. The R-R interval preceding the escape beat which initiated VT-VF varied between 1.2 and 2.2 seconds. The cerebral attacks were amenable to long-term pacemaker treatment. However, relapses of VT-VF were observed during pacing with a low rate of 55 per minute and during short interruptions in pacing, as produced by intermittent pacemaker failure or threshold determination. In one patient, supplementary treatment with a beta-blocking agent had to be given to suppress exercise-induced attacks of VT-VF after pacemaker implantation.
A 69 year old woman was treated with sotalol (320 mg daily) for intermittent atrial fibrillation. Sotalol was initially well tolerated and reversion to sinus rhythm with sinus bradycardia occurred 4 weeks after initiation of therapy. Shortly thereafter, the patient developed recurrent syncope due to torsade de pointes. This was treated successfully with intravenous magnesium infusion and withdrawal of sotalol. Subsequently, the atrial fibrillation was adequately managed using amiodarone, with no recurrence of torsade de pointes. Development of bradycardia associated with reversion to sinus rhythm represents a potential cause of 'late' pro-arrhythmic effects of sotalol.
A case of fatal torsade de pointes in a 53 year old patient treated with disopyramide is described. The arrhythmia followed the development of acute hepatocellular dysfunction and may have been due to failure of the liver to efficiently degrade the drug to its metabolites.
AVT is a potentially lethal arrhythmia that is being more frequently recognized. Since it is mostly associated with the use of drugs prescribed in everyday medical practice, it is important that the physician be able to recognize the arrhythmia and be familiar with the various causes and treatment of AVT.
A case of torsade de pointes attributed to prenylamine is described. In addition, the authors show QRS axis variation of a similar nature in sinus rhythm. It is postulated that these changes of QRS axis direction, seen in ventricular tachycardia and sinus rhythm, are both manifestations of partial refractoriness, within the ventricle, producing gross changes in the mean QRS vector.
The short- and long-term outcomes of patients treated with class I antiarrhythmic drugs were studied. A total of 968 patients who began class I antiarrhythmic therapy in our hospital were followed up for a mean of 13 ± 8 months. Discontinuation rates were similar for the entire group of patients during short-term therapy (52%) and long-term therapy (50%). During short-term therapy, 28% of patients stopped treatment because of side effects, and 21% of patients discontinued treatment because of ineffectiveness. Discontinuation rates during short-term therapy were significantly lower with encainide, flecainide, and procainamide than with the other agents (disopyramide, mexiletine, qunidine gluconate, quinidine sulfate, and tocainide) (P < 0.05). However, encainide, flecainide, and procainamide were associated with a higher incidence of side effects necessitating discontinuation in the long-term study. Side effects during long-term therapy accounted for 27% of discontinuations, while loss of efficacy accounted for only 6%. Discontinuation rates were significantly lower with mexiletine, quinidine sulfate, and tocainide than with the other agents during long-term therapy (P < 0.05). The discontinuation rate with quinidine gluconate was significantly less than that with quinidine sulfate. All antiarrhythmic agents possess a substantial potential for toxicity. Short-term response and tolerance to class I antiarrhythmics do not predict the ultimate response to therapy. Thus patients receiving class I antiarrhythmic therapy must be monitored for the duration of treatment.
Episodes of ventricular tachycardia of the ‘torsade de pointes’ (VTTP) types provoked by prenylamine were observed in 7 patients: 5 females ad 2 males. They all received prenylamine in a dose of 120–180 mg daily for anginal pains. Syncope or syncopal equivalents occurred in all 7 patients. Q-T intervals ranged from 0.52 to 0.64 s. Review of the literature revealed 11 patients with prenylamine-induced VTTP, of whom 8 were females. The female preponderance (72.2%), hitherto not commented upon in the literature, is highlighted. Prenylamine-induced VTTP may appear late after initiation of therapy, consequently clinical and ECG long-term folow-up is mandatory. The drug should promptly be discontinued in symptomatic patients, and particularly in females showing prolonged Q-T.Copyright © 1983 S. Karger AG, Basel
An unusual ventricular tachyarrhythmia developed in a 57 year old woman with recurrent ventricular tachycardia and toxic disopyramide plasma concentrations. The rhythm was similar to the patient's previous ventricular tachycardia, but the rate was slower and the QRS complex was markedly widened, mimicking the electrocardiographic changes associated with electrolyte abnormalities. Disopyramide, which has electrophysiologic properties similar to those of quinidine, probably caused the arrhythmia and should be added to the list of drugs associated with atypical ventricular tachycardia.
Poorly controlled supraventricular arrhythmias in a hypokalaemic 74 year old woman were treated with oral amiodarone. This caused torsades de pointes, and was preceded by marked prolongation of the QT interval. The induction of torsades de pointes by amiodarone is thought to be an idiosyncratic reaction to amiodarone itself which is facilitated by electrolytic abnormalities. The present case, however, indicates the possibility of a pro-arrhythmic effect secondary to an interaction between amiodarone and digoxin.
The study group consisted of 26 patients with a history of documented Torsade de Pointes (TdP) who were divides into 3 groups according to the causes of TdP. Group I consisted of 5 patients with congenital long QT syndrome. Group II consisted of 15 patients with TdP caused by antiarrhythmic drugs. Group III consisted of 6 patients with TdP caused by bradycardia resulting from third degree atrioventricular block. The QT interval was determined from a 12-lead electrocardiogram. Monophasic Action Potential (MAP) was recorded by a 6 F USCI electrode catheter. Isoproterenol infusion resulted in TU abnormality in all patients in Group I and induced a hump at phase 3 slope of MAP in all 3 patients tested. The QT interval change before and after IA administration was significantly larger in Group II patients compared to those without TdP (0.132 +/- 0.062 vs 0.029 +/- 0.31 sec, less than 0.005). Injection of 100 mg. of disopyramide in 2 patients in Group II resulted a hump at phase 3 slope of the MAP in both of them. The QT prolongation associated with decreasing the pacing rate from 70 to 50/min was significantly larger in patients with Group III compared to patients with bradycardia but without TdP (0.02 +/- 0.04 vs 0.07 +/- 0.05 sec, p less than 0.005). The results suggests: 1) different approaches are necessary for evaluation of TU abnormalities in patients with TdP according to the causes of TdP, 2) MAP might be a useful method for evaluating TU abnormality in patients with TdP.
Worsening of ventricular arrhythmias has been reported during therapy with class I antiarrhythmic agents.1 N-acetyl procainamide (NAPA), the first metabolite of procainamide, has been implicated as a cause of polymorphic nonsustained ventricular tachycardia (VT) in 1 patient.2 Sudden death has occurred during NAPA therapy, but recurrent ventricular fibrillation (VF) resulting from NAPA treatment alone has not been documented previously.3,4 The following case demonstrates this phenomenon.
Idiosyncratic and proarrhythmic reactions to antiarrhythmic drugs are a well-recognized phenomenon and appear to correlate poorly with Q-T prolongation or with the serum concentration of the drug. It therefore becomes difficult to identify patients clinically with an underlying electrophysiologic substrate for ventricular tachycardia which was made manifest by an antiarrhythmic drug, or to determine whether the drug is causing an idiosyncratic reaction (the classic "long Q-T syndrome"). We recently studied a patient with ischemic heart disease and a prolonged corrected Q-T interval (Q-Tc) due to chronic left bundle-branch block. She developed "quinidine syncope," and the Q-Tc was unchanged despite stopping administration of the drug; however, electrophysiologic studies demonstrated reproducibly inducible "torsade de pointes" while the patient was being rechallenged with quinidine, while no inducible arrhythmia was seen during control studies. We conclude that electrophysiologic studies are of clinical value in the clarification of possible drug-induced arrhythmias.
Torsade de pointes represents a potential complication of chronic amiodarone therapy. Several reports have emphasized the need for a loading dose in order to achieve therapeutic blood levels rapidly. We report a case of torsade de pointes following a single oral dose of amiodarone (1400 mg or 30 mg kg-1) administered after short intravenous loading for prevention of paroxysmal atrial flutter. Torsades de pointes were preceded and associated with marked QT prolongation and bradycardia. This report suggests that careful monitoring of patients undergoing oral amiodarone loading is necessary.
This report describes a patient with a functioning permanent pacemaker who developed torsades de pointes. Although overdrive cardiac pacing has been used to suppress this arrhythmia, cardiac pacing was not protective in this patient. This case also illustrates the difficulty in interpreting Q-T intervals in the presence of paced beats.
A 65-year-old woman presented with new onset atrial fibrillation. Medical therapy with digoxin and quinidine was not effective in controlling the arrhythmia. Subsequently, complications developed including a stroke and torsades de pointes. The arrhythmia was successfully controlled by overdrive suppression by esophageal pacing. This case illustrates the usefulness of esophageal pacing and how it may be applied in emergencies when transvenous pacing cannot be readily performed outside the intensive care unit setting.
We describe the appearance of long QT interval and polymorphous ventricular tachycardia in a patient treated with amiodarone who presented with hypokalemia secondary to chronic diuretic therapy. Ventricular pacing was initiated upon admission. The hypokalemia was corrected and amiodarone was discontinued. After three days the patient showed a normal QT interval and was free of ventricular tachyarrhythmias. Although hypokalemia could itself have been the arrhythmogenic factor in this particular patient, the additional toxic effect of amiodarone cannot be ruled out. It seems reasonable to consider the combination of both as dangerous when we take into account that the majority of patients cited as having amiodarone-induced torsade de pointes had also potassium depletion.
Bepridil has been shown to block both slow- and fast-channel activity in the heart. Electrophysiologic studies in man demonstrate that oral and intravenous bepridil prolongs sinus cycle length, PR interval and QT interval, without apparently changing the QRS interval. In addition, the drug depresses atrioventricular (AV) nodal conduction, resulting in an increased AH interval. Refractoriness in the AV node, atrium and ventricle is increased. There is usually little or no change in the HV interval. The antiarrhythmic properties of bepridil have been noted in patients with supraventricular tachycardia, ventricular premature complexes (VPCs) and sustained ventricular tachycardia (VT). In 17 patients, intravenous bepridil was compared with either verapamil or ajmaline. AV nodal reentrant tachycardia was terminated in all patients with bepridil and verapamil. However, ajmaline was somewhat more effective than bepridil in patients with AV reentry (8 of 8 versus 5 of 8). In 12 of these 17 patients, oral bepridil (500 mg/day for 3 days) suppressed the induction of tachycardia or slowed its rate. In 3 studies of oral bepridil for VPCs, the drug was effective in 68%, 69% and 70% of patients. Another group of studies evaluated bepridil in a total of 30 patients with sustained VT. Intravenous bepridil terminated VT in 17 of 26 patients. The induction of VT by programmed ventricular stimulation was also prevented in 7 of 17 patients. Although torsade de pointes has been reported, its incidence appears to be low.
Two patients treated with a combination of amiodarone and quinidine for minor arrhythmia developed atypical ventricular tachycardia (torsades de pointes). Both patients had QT-interval prolongation. A combination of amiodarone and quinidine given to a healthy volunteer raised the plasma quinidine concentration and prolonged the QT interval, confirming the observation of a clinically important interaction between the two drugs.
Although the terminal cardiac rhythm is often well documented in many cases of sudden cardiac death, the antecedent or premonitory arrhythmias are usually not retrievable. The ambulatory electrocardiographic recordings of 12 patients who sustained ventricular fibrillation or torsade de pointes while wearing a long-term electrocardiographic monitor were analyzed in detail. A printout of the entire electrocardiographic recording was made and hand counts of ventricular arrhythmias were correlated with heart rate, QTc interval, RR interval preceding ventricular fibrillation or torsade de pointes and (RR')/QT initiating ventricular fibrillation or torsade de pointes. Common ambulatory electrocardiographic features in these 12 patients experiencing ventricular fibrillation or torsade de pointes included: 1) a period of high density of increasingly frequent or complex ventricular arrhythmias, or both, preceding ventricular fibrillation or torsade de pointes (11 patients); 2) R on T beats frequently initiating ventricular fibrillation or torsade de pointes (9 patients); and 3) repolarization abnormalities present for several hours before ventricular fibrillation or torsade de pointes (7 patients). No consistent relation between the RR and RR' interval initiating ventricular fibrillation or torsade de pointes was found; no consistent alteration in heart rate occurred before ventricular fibrillation or torsade de pointes. Thus, ventricular arrhythmias leading to sudden death in an ambulatory population do not occur in isolation but are preceded by a period of increased ventricular ectopic activity. Future guidelines for assessment of antiarrhythmic drug efficacy should include an evaluation of a drug's impact not only on ectopic beat frequency but also on arrhythmia density.
A case of sotalol-induced polymorphous ventricular tachycardia (torsade de pointes) is presented. The patient had moderately prolonged Q-T interval before medication with sotalol with further prolongation after application of this drug. Electrophysiological study during rechallenge with sotalol demonstrated a uniform ventricular tachycardia with a somewhat polymorphous onset; whether or not this tachycardia represented replication of the patient's spontaneous arrhythmia is questionable. Without antiarrhythmic drugs and during medication with pindolol ventricular tachycardia was not inducible.
