QT Interval In Women Research Articles

A shortened electrocardiographic diastolic interval is involved in diastolic dysfunction and HFpEF

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by left ventricular diastolic dysfunction (LVDD). We hypothesized that a short electrocardiographic diastolic time predisposes to LVDD and HFpEF by deteriorating diastolic function. This effect may be more pronounced in women than men, given longer QT interval in women. Methods To experimentally test if incremental shortening of the diastolic interval indeed worsens the diastolic function, we shortened electrical diastole using right atrial (RA) pacing and QT-prolonging medication (sotalol) in six pigs. We used 12-lead ECG and echocardiography to assess electrical diastole (TQ interval) and diastolic function. We next analyzed electrocardiograms and corresponding information on LVDD and HF in electronic health record data from 85,145 patients that visited one of 13 Cardiology Centers of the Netherlands. We sex-specifically assessed the association between TQ interval on the one hand and LVDD or HFpEF on the other. Results In pigs, baseline TQ interval was 257 (±SD 66) ms, which decreased to 232 (±SD 36) ms during RA pacing (100 bpm), and further to 193 (±SD 52) ms with concomitant sotalol administration (2 mg/kg iv, bolus). These changes in TQ interval resulted in reversal of E/A ratio, with a significant correlation between TQ interval and decreasing e’/a’ ratio (r=0.382, p=0.024) (Figure 1). In patients who underwent cardiac evaluation with ECG and echocardiography, diastolic abnormalities were documented as LVDD (n=26,009 (30%)) and HFpEF (n=2,551 (3%)). TQ intervals were significantly shorter in patients with LVDD and HFpEF (479 (±SD 128) and 485 ms (±SD 138), respectively) compared to the ones without LVDD or HFpEF (523 (±SD 137) ms). A shorter TQ interval increased the risk for having LVDD and HFpEF when adjusted for confounders (LVDD; ORadjusted= 1.37 (95% CI: 1.28, 1.45), HFpEF; ORadjusted= and 1.16 (95% CI: 1.01, 1.35) (Table 1). There was significant sex-interaction (p= 0.039) for TQ and LVDD risk, with stronger associations in women (ORadjusted= 1.43 (95% CI: 1.32, 1.56) compared to men (ORadjusted= 1.35 (95% CI: 1.10, 1.64) (Table 1). Conclusion Experimentally decreasing the electrical diastolic interval leads to diastolic function abnormalities in pigs. In humans, a shorter diastolic interval is associated with a higher risk of having either LVDD or HFpEF. Our findings imply that a shortened electrical diastolic interval may precede diastolic dysfunction and HFpEF. Therefore, prolonging or preserving electrical diastole may be effective in preventing or treating HFpEF, especially in women.Figure 1Table 1

Sex Differences in Drug-Induced Arrhythmogenesis.

The electrical activity in the heart varies significantly between men and women and results in a sex-specific response to drugs. Recent evidence suggests that women are more than twice as likely as men to develop drug-induced arrhythmia with potentially fatal consequences. Yet, the sex-specific differences in drug-induced arrhythmogenesis remain poorly understood. Here we integrate multiscale modeling and machine learning to gain mechanistic insight into the sex-specific origin of drug-induced cardiac arrhythmia at differing drug concentrations. To quantify critical drug concentrations in male and female hearts, we identify the most important ion channels that trigger male and female arrhythmogenesis, and create and train a sex-specific multi-fidelity arrhythmogenic risk classifier. Our study reveals that sex differences in ion channel activity, tissue conductivity, and heart dimensions trigger longer QT-intervals in women than in men. We quantify the critical drug concentration for dofetilide, a high risk drug, to be seven times lower for women than for men. Our results emphasize the importance of including sex as an independent biological variable in risk assessment during drug development. Acknowledging and understanding sex differences in drug safety evaluation is critical when developing novel therapeutic treatments on a personalized basis. The general trends of this study have significant implications on the development of safe and efficacious new drugs and the prescription of existing drugs in combination with other drugs.

The Association of Metabolic Syndrome and Its Components with Electrocardiogram Parameters and Abnormalities Among an Iranian Rural Population: The Fasa PERSIAN Cohort Study.

BackgroundMetabolic syndrome (MetS) as a set of cardiac risk factors and its growing prevalence is one of the major concerns in different societies. In this study, we aimed to investigate the relationship between Mets and electrocardiogram (ECG) parameters and abnormalities as indicators for subclinical cardiovascular diseases (CVD).MethodsIn this sub-analysis study, we used the data from Fasa PERSIAN Cohort Study which includes subjects age 35–70 years. Subjects with available ECG data included in the study (n=7002) and subjects with missing data on MetS components and non-sinus rhythm ECG were excluded (n=44). The MetS definition based on the Adult Treatment Panel (ATP) III guidelines and also a 12-lead ECG was obtained from all participants.ResultsOur study population (n=6958) showed a mean age of 48.60±9.34 years and also 1656 (24.2%) subjects had MetS. Except for P duration, PR interval and S amplitude in men and P amplitude, S amplitude, Sokolow-Lyon Index, and QT interval in women, other ECG parameters differ significantly between subjects with and without Mets (P<0.05). Also among ECG abnormalities, prolonged P duration (≥120ms), QRS duration (≥100ms), and QTc interval (>450ms in male, >470ms in female) had a significant association with MetS in the total population. Waist circumferences (WC) showed the most count of significant relationship with ECG parameters in both genders. In males, WC more than ATP cut-points had significant associations with prolonged P and QRS duration, and also blood pressure (BP) had significant associations with prolonged P and QRS durations and QTc interval. In females, the MetS component except triglyceride had at least a significant relationship with prolonged P and/or QRS duration.ConclusionMetS and its component especially WC and BP were associated with ECG parameters and abnormalities. These associations with ECG as a marker of subclinical CVD showed the importance of MetS and each component in our population to monitor in the further longitudinal studies.

Systematic Meta-Analysis of the Association Between a Common NOS1AP Genetic Polymorphism, the QTc Interval, and Sudden Death.

Contemporary studies have identified rs10494366 in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene as a new genetic marker in modulating the QT interval and sudden cardiac death (SCD) in general populations. However, the conclusions were not coincident. Therefore, we conducted for the first time a system evaluation of the relativity of rs10494366, the QT interval, and sudden death by meta-analysis. In our study, the meta-analysis displayed the GG genotype of rs10494366 correlated with the QT interval in women with no heterogeneity, and in diabetes mellitus (DM) patients with minor heterogeneity. In the Caucasian population, the correlation of rs10494366 and sudden death was significant. The heterogeneity referred to the relevance between rs10494366 and sudden death in the Asian population. In conclusion, the minor allele of rs10494366 may have an impact on the QT interval in women or DM patients and may have a potential role in sudden death in the Caucasian population.

Magnetocardiographic identification of prolonged fetal corrected QT interval in women receiving treatment for opioid use disorder.

Pregnant women undergoing treatment for opioid use disorder (OUD) may be exposed to multiple QT prolonging agents. We used magnetocardiography to measure fetal QT intervals in mothers with OUD on buprenorphine therapy. Fetal and maternal magnetocardiography was performed in pregnant women receiving buprenorphine-assisted treatment (Disorder group); these were matched by gestational age to pregnant women who were opiate naïve (Reference group). Corrected QT intervals were determined using Bazett's formula and compared between groups. A total of eight women in the Disorder group matched to eight in the Reference group. Seven of the mothers (88%) in the Disorder group were smokers; there were no smokers in the Reference group. The average fetal corrected QT was significantly longer (P = 0.022) in the Disorder group than that in the Reference group (505 milliseconds [ms] ± 68.6 [standard deviation] vs 383 ms ± 70.3 [standard deviation]). Novel data from this small sample demonstrate prolongation of fetal corrected QT in women with OUD participating in buprenorphine assisted therapy. Additional investigation from a larger sample is needed to clarify if fetal buprenorphine and/or tobacco exposure is associated with changes in fetal QT which would warrant further prenatal and postnatal testing.

Sex Differences in Cardiac Arrhythmias: Clinical and Research Implications.

Sex differences have the potential to impact diagnostic and therapeutic interventions in a wide variety of medical conditions, and cardiac arrhythmias are no exception.1 Studies evaluating pathophysiology, disease course, and therapeutic options for cardiac arrhythmias have been performed predominantly in male patients. However, catheter and device-based therapies coupled with landmark clinical trials have contributed to an improved understanding of this important aspect. The objective of this review is to present the current state of knowledge on sex differences in cardiac arrhythmias with a focus on clinical management, while highlighting gaps in knowledge that would benefit from future investigation. ### Atrial Fibrillation and Atrial Flutter #### Disease Burden Atrial fibrillation (AF) and atrial flutter (AFL) are the most commonly encountered tachyarrhythmias in clinical practice, with significant implications for public health and healthcare costs. Stroke, hospitalization, and loss of productivity are the major consequences of AF.2 The incidence of AF (per 1000 person-years) is reported to be between 1.6 and 2.7 in women and between 3.8 and 4.7 in men.2 The age-adjusted incidence and prevalence of AF is lower in women compared with that in men, and accordingly, the lifetime risk of AF from the Framingham Heart Study at 40 years of age was higher in men (26.0% for men versus 23.0% for women).3 Another analysis from the Framingham Heart Study demonstrated no significant sex differences in the risk of developing AFL.4 The prevalence of AF continues to rise among both men and women. In a study investigating the global burden of disease from 1980 to 2010, there was not only an increase in overall burden, incidence, and prevalence of AF, but most importantly an increase in AF-associated mortality in both men and women (Figure 1).5 The age-adjusted mortality for women was consistently higher compared with that for men from 1990 to 2010 (Figure …

Sudden Cardiac Death in Women With Suspected Ischemic Heart Disease, Preserved Ejection Fraction, and No Obstructive Coronary Artery Disease: A Report From the Women's Ischemia Syndrome Evaluation Study

BackgroundSudden cardiac death (SCD) is often the first presentation of ischemic heart disease; however, there is limited information on SCD among women with and without obstructive coronary artery disease (CAD). We evaluated SCD incidence in the WISE (Women's Ischemia Syndrome Evaluation) study.Methods and ResultsOverall, 904 women with suspected ischemic heart disease with preserved ejection fraction and core laboratory coronary angiography were followed for outcomes. In case of death, a death certificate and/or a physician or family narrative of the circumstances of death was obtained. A clinical events committee rated all deaths as cardiovascular or noncardiovascular and as SCD or non‐SCD. In total, 96 women (11%) died over a median of 6 years (maximum: 8 years). Among 65 cardiovascular deaths, 42% were SCD. Mortality per 1000 person‐hours increased linearly with CAD severity (no CAD: 5.8; minimal: 15.9; obstructive: 38.6; P<0.0001). However, the proportion of SCD was similar across CAD severity: 40%, 58%, and 38% for no, minimal, and obstructive CAD subgroups, respectively (P value not significant). In addition to traditional risk factors (age, diabetes mellitus, smoking), a history of depression (P=0.018) and longer corrected QT interval (P=0.023) were independent SCD predictors in the entire cohort. Corrected QT interval was an independent predictor of SCD in women without obstructive CAD (P=0.033).Conclusions SCD contributes substantially to mortality in women with and without obstructive CAD. Corrected QT interval is the single independent SCD risk factor in women without obstructive CAD. In addition to management of traditional risk factors, these data indicate that further investigation should address mechanistic understanding and interventions targeting depression and corrected QT interval in women.

Impact of Age and Sex on QT Prolongation in Patients Receiving Psychotropics.

To assess older age and female sex, 2 of the major risk factors for potentially fatal cardiac arrhythmias or sudden cardiac death in patients prescribed psychotropics, within the context of electrocardiographic evidence of time between start of Q wave and end of T wave (QT) interval prolongation, which is an indicator of an increased risk for potentially fatal cardiac arrhythmias. The literature on the relation between age, sex, and QT interval with respect to psychotropic drugs was reviewed. The QT interval must be corrected (QTc) for heart rate. Because slower heart rates prolong and faster heart rates shorten the QT interval, people with faster heart rates may have a prolonged QT interval that is not apparent until the correction is performed. QTc values for apparently healthy post-pubertal people are less than 450 ms for males and less than 470 ms for females. The longer QT intervals in women may account for their increased risk of potentially fatal cardiac arrhythmias on psychotropics. QTc increases with increasing age. Assessment of QTc in older people is especially important to identify people with a longer QTc who are more likely to attain a serious QT level with drugs that prolong QTc. The age-related increase in QTc is more evident in men than women, suggesting that male sex does not afford protection against potentially fatal arrhythmias at older age. The association of increasing age and female sex with greater QT intervals indicates the need to have an increased awareness of the QTc prior to use of these psychotropics and to evaluate the QTc after initiation of therapy.

Effect of follicle stimulating hormone and clomiphehne citrate on heart rate and QT intervals in women undergoing ovulation induction

OBJECTIVE: This study was designed to evaluate the effect of rising estradiol concentration on QT interval in women undergoing ovulation induction. DESIGN: 87 cycles received FSH alone, 59 cycles FSH plus clomiphene citrate (FSH/CC), and 49 cycles CC alone. MATERIALS AND METHODS: In patients receiving FSH, an EKG and E2 value were obtained at the onset of menses. FSH was begun on day 2. At follicular maturation a follow-up EKG and E2 were obtained. In the CC group an EKG was obtained at the onset of menses. Clomiphene was begun on day 3 for five days. At follicular maturity a follow-up EKG was obtained. Patients receiving FSH/CC had a baseline EKG and E2 level. CC was administered days 3-7 with FSH days 8, 9, 10. A follow-up EKG and E2 determined at follicular maturity. RR and QT intervals were measured and QTc was calculated using Bazett's formula QTc= QT/(R-R)1/2. RESULTS: In the FSH group the RR interval shortened after treatment (836+/−87 vs 791+/−87; p=.01). No change in heart rate was found in the other two groups. In the FSH group, a small but significant increase in the QTc was noted after treatment (pre-treatment 402+/−18 vs post-treatment 409+/−15; p=.002). No significant change was seen in the other two treatment groups. No significant change in the QT interval was seen in any of the three groups. There was no difference in age or maximum E2 concentration achieved between the FSH group and the FSH/CC group. However, the amount of FSH administered per patient was significantly greater in the FSH group compared to the FSH/CC group (1718 units vs. 741 units). In addition, the number of days exposed to FSH was greater in the FSH group compared to the FSH/CC group (9.2 days vs. 5.7 days). In the FSH group, no correlation was found between the change in QTc and the maximum E2 achieved. Similarly, no correlation was found between the change in QTc and the dose of FSH administered nor in days exposed to FSH. CONCLUSIONS: This study demonstrated a mild increase in heart rate, a minimal increase in QTc interval, and no change in QT interval in women treated with FSH. This effect was not seen in either group of patients treated with CC. Inhibition of estrogen receptors by CC prior to administration of FSH may explain the absence of the heart rate effect in the group who received both CC and FSH. These findings suggest that estrogen causes a mild increase in heart rate resulting in an increase in the QTc without affecting the QT interval.

Normal Standards for QT and QT Subintervals Derived from a Large Ethnically Diverse Population of Women Aged 50 to 79 Years (the Women’s Health Initiative [WHI

Available normal standards for rate-adjusted QT intervals in women are based on samples that include only whites, and no normal standards are available for QT subintervals. This study derived normal limits from percentile distributions for QT as well as QT and T-wave subintervals in 22,311 participants in the Women's Health Initiative (WHI), including 19,059 white, 1,771 African-American, 819 Hispanic, 82 American Indian, and 580 Asian women. Excluded were women with cardiovascular disease or who were using cardioactive drugs at baseline and cardiovascular morbidity or death during the subsequent mean 6.3-year follow-up. Normal limits for QT adjusted by Bazett's formula were strongly rate dependent, invalidating their use in practical applications. QT adjusted as a linear function of RR (QTrr) or by power functions of RR with exponent 0.5 (QTsqr) or 0.42 (QT0.42) using an appropriate regression function produced rate-invariant upper and lower normal limits for rate-adjusted QT. Adjusted QT is preferable to adjusted JT because the latter requires the incorporation of QRS duration as a covariate with RR. Normal limits were also derived for T-wave subintervals. Normal limits of QTrr in Asian women were 10 ms longer than in other ethnic groups. In conclusion, QT adjusted for rate as a linear function of RR is preferable to JT and other QT subintervals in the evaluation of QT prolongation. The adaptation of considerable revisions of the currently used limits for prolonged QT in women is suggested, with an additional race-specific adjustment in Asian women. Bazett's formula is inappropriate for testing new drugs or other applications.

Risk of proarrhythmia with class III antiarrhythmic agents: sex-based differences and other issues

Although men have a higher risk of atrial fibrillation compared with women, the absolute number of women with atrial fibrillation is greater. Congestive heart failure increases the risk of developing atrial fibrillation in women more than in men, and the prognosis for women with atrial fibrillation is worse than for men. The longer baseline corrected QT interval in women is well known. The mechanism is likely the result of increased circulating androgens, causing the QT interval to shorten in men after puberty. Female sex is associated with an increased risk of torsades de pointes in the setting of potassium antagonists. Class III antiarrhythmic drugs are frequently used for the treatment of atrial fibrillation in heart failure patients because of their neutral effect on mortality and their tolerance by patients with low ejection fractions. Although amiodarone and azimilide carry a low potential for producing torsades de pointes compared with sotalol and dofetilide, the prevalence of torsades de pointes in women is at least twice that in men for all these drugs. Careful monitoring of the QT interval and potassium level, as well as control of congestive heart failure, can help reduce the risk of proarrhythmia. Avoidance of polypharmacy with other potassium antagonists and unmonitored drug formulation changes are important in the management of all patients taking class III agents, but they are particularly crucial in women with additional risk factors for torsades de pointes.

Biologic and molecular mechanisms for sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics: Part I.

There are pharmacological differences between women and men that have important clinical consequences. For several drugs, there is a higher incidence in women of drug-induced QT prolongation and a potentially fatal arrhythmia, torsades de pointes. This may be a reflection of the longer baseline QT interval in women. A difference in cardiovascular disease between women and men is that women have a higher mortality rate after myocardial infarction (MI). Women also have a higher rate of hemorrhagic stroke after receiving thrombolytic therapy for an MI. Differences in effectiveness of analgesics have been demonstrated, with kappa opioids providing pain relief for women but not men. Drugs may have different pharmacokinetics in women and men because of differences in phase I and phase II enzymes that metabolize drugs. Conflicting results about biological sex differences have been reported for the major drug metabolizing enzyme, cytochrome P450 3A4 (3A4) and may be related to a role for P-glycoprotein, a cell membrane transporter, reported as two times higher in male livers than those of females. It has been reported that boys need a higher dose of 6-mercaptopurine, which is metabolized by thiopurine methyltransferase (TPMT). TPMT is reported to be 14% higher in male human liver biopsies than those from females. Verapamil, a drug for angina and hypertension, has different clearance and side effects in men and women. Ethnic/racial variations have also been demonstrated with the drug metabolizing enzymes, CYP2C9, 2C19, and 2D6.

Effects of gender on cardiac arrhythmias.

The purpose of this study is to review published data regarding gender differences in cardiac electrophysiology and in the occurrence of clinical arrhythmias. ECG differences between men and women include a faster resting heart rate in women, a longer corrected QT interval, and a lower QT dispersion than in men. The faster resting heart rate in women appears to be primarily related to differences in physical conditioning. The mechanism for the longer corrected QT interval in women is not completely known, but does not appear to be related to acute effects of estrogen or progesterone or differences in autonomic innervation. Women also appear to have a lower incidence of atrial fibrillation, a difference in the age distribution of supraventricular tachycardia, and a lower incidence of sudden death than men. Much of the lower incidence of sudden death in women may relate to a difference in the prevalence of coronary artery disease, but other factors such as inherent differences in repolarization, which may be reflected by a gender difference in the corrected QT interval, also may be operative. The paradox of a longer corrected QT interval and higher incidence of torsades de pointes, but lower population-based incidence of sudden death in women, has not been completely resolved. Further studies will be required to help better understand the basic mechanisms involved in gender differences in electrophysiology and arrhythmias and determine the extent to which these differences have implications for clinical management of cardiac arrhythmias.

Gender-Specific Differences in the QT Interval and the Effect of Autonomic Tone and Menstrual Cycle in Healthy Adults

Gender differences in the corrected QT interval have been noted since Bazett's initial description during the 1920s. The mechanism of this gender difference is unknown, and this study was undertaken to evaluate potential autonomic and menstrual cycle effects on the QT interval. The study population consisted of a healthy volunteer sample of 23 women and 20 men. Twelve-lead electrocardiographic determinations were made at rest and following double autonomic blockade (with atropine and propranolol) during the menstrual, follicular, and luteal phases of the menstrual cycle. Men were studied during 3 separate visits as controls. The corrected QT interval at baseline tended to be longer in women than men (421 ± 16 ms vs 414 ± 15 ms: p <0.07). Following double autonomic blockade, the corrected QT interval increased to 439 ± 11 ms: p <0.001). However, the gender difference in corrected QT interval was unchanged (443 ± 15 ms vs 437 ± 12 ms). At baseline, there was no significant difference in the corrected QT interval among the 3 phases of the menstrual cycle (421 ± 10, 423 ± 18, and 420 ± 18 in the menstrual, follicular, and luteal phases, respectively) and the corrected QT interval was longer in women than men at each visit. Following double autonomic blockade, the corrected QT interval in women was shorter in the luteal phase (438 ± 16 ms) versus the menstrual (446 ± 15 ms) or the follicular phase (444 ± 13 ms; p <0.05). However, this difference, which was not present at baseline, does not appear to be responsible for the gender difference in the QT interval at rest. In conclusion, our results confirm that the corrected QT interval tends to be longer in women than men. Differences in autonomic tone and menstrual cycle variability in the corrected QT in women at rest do not appear to be responsible for the gender differences in the QT interval. The mechanism responsible for the longer QT interval in women remains to be defined.

Effect of carbohydrate and vitamin B-6 on QTc intervals in women during exercise

Vitamin B-6 (B6), as pyridoxal 5′phosphate, is essential for glycogenolysis and gluconeogenesis. Changes in B6 status may alter fuels available for the heart and muscles during exercise (EX). We investigated whether dietary carbohydrate (CHO) and B6 could alter QT intervals in 5 young/trained, 5 young/untrained and 5 postmenopausal/untrained women fed a moderate CHO diet for 2 wk, a high CHO diet for 1 wk, a moderate CHO+B6 diet for 2 wk and a high CHO+B6 diet for 1 wk. EX testing included 20 min on a cycle ergometer at 80% V02max at the end of each dietary treatment. ECG tracings were monitored and QT corrected (QTc) was measured at rest and 80% maximal heart rate (MHR). There were significantly longer QTc intervals when the moderate CHO diet was fed as compared to when the other diets were fed. For all diets, QTc increased from rest to 80% MHR in all but the young/untrained group. The magnitude of change in QTc intervals from rest to 80% MHR was significantly different between the groups. QTc intervals measured occurred while subjects were in adequate B6 metabolism as indicated by plasma pyridoxal 5′-phosphate concentrations within normal range. This research supports the finding that diet (B6 and/or CHO) can alter QT intervals in women during exercise.