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1.  Corrected QT Interval in Children With Brain Death 
Pediatric Cardiology  2010;31(7):1064-1069.
Prolongation of the QT interval is a well-documented finding in adults with severe brain injury. However, QT prolongation has not been well documented in the pediatric population with brain injury. Our objective was to determine the range of QT intervals in children with the diagnosis of brain death, hypothesizing that the QT interval corrected for heart rate (QTc) is longer in this population than in a normal population. All previously healthy children (<18 years) dying in our hospital from 1995 to 2007 with a diagnosis of brain death and at least one electrocardiogram (ECG) with normal anatomy by echocardiogram were included. Admission details, past medical and family history, demographic data, and laboratory data were collected. The QT and preceding RR intervals from three sinus beats on a standard 12-lead ECG were measured. The QTc was calculated with the Bazett method, and the values were averaged. Thirty-seven patients met inclusion criteria. Five had event histories concerning for possible underlying rhythm disturbances; data analysis was performed with and without these patients. The QTc data were normally distributed. The mean (SD) QTc for the entire cohort was 452 (61) ms. Excluding the five patients, it was 449 (62) ms. On multivariate analysis, sex (QTc female < male) and hypokalemia were associated with QTc prolongation. QTc in children with brain death is normally distributed but significantly longer than QTc in normal children. Until rapid genetic testing for channelopathies is universally available, our findings suggest that potential pediatric cardiac donors with isolated prolongation of the QTc in this setting may be acceptable in the absence of other exclusionary criteria.
doi:10.1007/s00246-010-9766-x
PMCID: PMC2948159  PMID: 20725721
Brain death; Brain injury; Electrocardiographic changes; Long QT
2.  Retrospective analysis of low-dose methadone and QTc prolongation in chronic pain patients 
Korean Journal of Anesthesiology  2010;58(4):338-343.
Background
Methadone is a synthetic opioid that is widely used for the treatment of chronic pain. The association between methadone treatment and QT interval prolongation or which can lead to torsades de pointes has been confirmed with larger studies on high dose methadone. The aim of this study was to determine the effect of methadone on the QTc interval in patients, whether the daily dose of methadone should be lower than what has been previously investigated.
Methods
A total of 130 patients were included, with 90 patients in the methadone group and 40 patients in the control group. For each ECG, heart rate, QT interval and corrected QT (QTc) interval were recorded. The patient demographics, methadone dose and serum level, duration of methadone use and past medical history were collected.
Results
The QTc interval was significantly longer in the treatment group than in the control group (443 ± 30.0 ms versus 408 ± 28.0 ms, respectively, P < 0.0001) and more patients in the treatment group had a QTc interval greater than 450 ms (36.7% versus 7.5%, respectively, P = 0.0005). The QTc interval was not associated with methadone dose P = 0.9278), serum level (P = 0.2256) or duration of treatment (P = 0.1822).
Conclusions
This study has shown that methadone use is associated with longer QTc intervals, even among patients with daily doses of less than 80 mg. In this study, no correlation was found between QTc duration and methadone dose, serum levels or duration of use. However, the magnitude of the QTc interval was associated with female gender and the use of antidepressants.
doi:10.4097/kjae.2010.58.4.338
PMCID: PMC2876853  PMID: 20508789
Methadone; Opioid; QT interval
3.  Antipsychotic Drug Administration Does Not Correlate with Prolonged Rate-Corrected QT Interval in Children and Adolescents: Results from a Nested Case–Control Study 
Abstract
Background
The rate-corrected QT interval (QTc) prolongation is a risk factor for sudden cardiac death and may be induced by antipsychotic drugs.
Objective
To determine the clinical characteristics associated with QTc prolongation (440 msec or greater) in children and adolescents hospitalized for treatment of psychiatric disorders.
Method
We determined the frequency of baseline prolongation of QTc in 811 psychiatric pediatric inpatients (15.5 ± 2.4 years of age). QTc duration was 440 msec or greater (range 441–481 msec) in 16 patients (1.97%). In a 1:5 nested case–control design, the 16 patients with prolonged QTc were age- and gender-matched with 80 patients with QTc of <421 msec.
Results
Patients with normal and prolonged QTc had similar utilization of antipsychotics (43.8% vs. 40.8%) and daily chlorpromazine equivalents (165 ± 110 vs. 168 ± 218 mg). Hypokalemia (p = 0.009) and obesity (p = 0.032) were more common among patients with prolonged QTc. The correlation between obesity and QTc prolongation was confirmed in logistic regression analysis.
Conclusions
In a large cohort of youth hospitalized for treatment of psychiatric disorders, a prolonged QTc on admission was rare and correlated with the presence of obesity, but not with current use of antipsychotic drugs.
doi:10.1089/cap.2011.0024
PMCID: PMC3157748  PMID: 21823910
4.  Determinants of Prolonged QT Interval and Their Contribution to Sudden Death Risk in Coronary Artery Disease: The Oregon Sudden Unexpected Death Study 
Circulation  2009;119(5):663-670.
Background
In a recent cohort study, prolongation of the corrected QT interval (QTc) was associated with independent, increased risk of sudden cardiac death (SCD). We evaluated determinants of prolonged QTc as well as the relationship of prolonged QTc to SCD risk among patients with coronary artery disease (CAD) in the general population.
Methods and Results
A case-control design was utilized. Cases were SCDs with coronary artery disease (CAD) among a metropolitan area of 1,000,000 residents (2002-06) and controls were area residents with CAD, but no history of SCD. All cases were required to have an ECG suitable for QTc analysis prior and unrelated to the occurrence of SCD. A total of 373 cases and 309 control subjects met criteria for analysis. Mean QTc was significantly longer in cases vs. controls (450±45 vs. 433±37 ms, p<0.0001). In a multivariate model, gender, diabetes mellitus and QTc prolonging drugs were significant determinants of QTc prolongation in control subjects. In a logistic regression model predicting SCD, diabetes [OR 1.97 (1.32 – 2.96)] and use of QTc prolonging drugs [OR 2.90 (1.92 – 4.37)] were significant predictors of SCD among subjects with normal or borderline QTc. However, abnormally prolonged QTc in the absence of diabetes and QT-prolonging medications was the strongest predictor of SCD [OR 5.53, (3.20-9.57)].
Conclusions
Diabetes and QTc-affecting drugs determined QTc prolongation and were predictors of SCD in CAD. However, idiopathic abnormal QTc prolongation was associated with five-fold increased odds of SCD. A continued search for novel determinants of QTc prolongation, such as genomic factors, is likely to enhance risk stratification for SCD in CAD.
doi:10.1161/CIRCULATIONAHA.108.797035
PMCID: PMC2734945  PMID: 19171855
Death; sudden; epidemiology; population; ventricular; repolarization; risk stratification
5.  Analysis of Orders for QTc-Prolonging Medication for Intensive and Cardiac Care Unit Patients with Pre-existing QTc Prolongation (QTIPPP Study) 
Background:
A prolonged QTc interval on electrocardiography is often used as a surrogate marker for ventricular arrhythmia. Medications that can prolong the QTc interval may increase the risk of cardiac complications, although the exact incidence is unknown. It is reasonable to assume that administration of QTc-prolonging medications to patients with pre-existing QTc prolongation will further increase the risk of cardiac consequences. This study was designed to examine the frequency of prescription of QTc-prolonging medications in such patients and to explore the potential for clinical pharmacists to minimize the associated risks.
Objectives:
The primary objective was to identify the number of patients with pre-existing prolonged QTc interval for whom QTc-prolonging medications were prescribed, from among all patients with orders for QTc-prolonging medications. The secondary objectives were to determine patterns of intervention by clinical pharmacists in these cases and to document any further QTc prolongation and occurrence of cardiac events.
Methods:
A prospective, observational, quality assessment study was conducted over 4.5 months. Adult patients admitted to beds with cardiac monitoring by telemetry for whom one or more QTc-prolonging medications were ordered were eligible for inclusion. Patients were included if the QTc interval was longer than 450 ms on the most recent 12-lead electrocardiogram before the QTc-prolonging medication was ordered. These patients were followed to identify outcomes of interest after administration of QTc-prolonging medication.
Results:
Overall, a QTc-prolonging medication was prescribed for 207 patients. Of these, 53 patients (26%) had pre-existing prolongation of the QTc interval. Clinical pharmacists made recommendations related to 28 medication orders; of these, 16 (57%) were accepted by the physician. Fifty-one (96%) of the 53 patients received at least one dose of QTc-prolonging medication and were monitored daily for complications. Nine (18%) of the 51 patients who underwent daily monitoring experienced at least one cardiac event.
Conclusions:
A substantial proportion (26%) of patients for whom QTc-prolonging medications were prescribed had pre-existing prolongation of the QTc interval. Clinical pharmacists may have a role in reducing the risk of subsequent complications.
PMCID: PMC3242574  PMID: 22479096
QTc interval; torsade de pointes; pre-existing prolongation; pharmacist practice; intervalle QTc; torsade de pointes; allongement préexistant de l’intervalle QTc; pratique du pharmacien
6.  The Effect of Oral Methadone on the QTc Interval in Advanced Cancer Patients: A Prospective Pilot Study 
Journal of Palliative Medicine  2010;13(1):33-38.
Abstract
Background
Recent reports suggest that high doses of methadone may prolong QTc interval and occasionally cause torsades de pointes; however, few of these studies involved the palliative care population.
Objective
The purpose of this study was to determine the effect of initiation of methadone on QTc interval in patients with cancer pain seen at the palliative care setting.
Methods
We enrolled 100 patients with cancer in this prospective study. Patients were followed clinically and electrocardiographically for QTc changes at baseline, 2, 4, and 8 weeks. Contributing factors for QTc prolongation such as medications, cardiovascular diseases, and electrolytes disturbances were documented. QTc prolongation was defined as greater than 430 ms in males and greater than 450 ms in females, and significant QTc prolongation was defined as QTc interval greater than 25% increase from baseline or 500 ms or more.
Results
Electrocardiographic (ECG) assessments were available for 100, 64, 41, and 27 patients at baseline, 2-, 4-, and 8-week follow-up, respectively. At baseline prior to initiation of methadone, 28 (28%) patients had QTc prolongation. Clinically significant increase in QTc occurred in only 1 of 64 (1.6%) patients at week 2, and none at weeks 4 and 8. There was no clinical evidence of torsades de pointes, ventricular fibrillation, or sudden death. QTc prolongation was more frequent among patients with increased baseline QTc interval.
Conclusions
Baseline QTc prolongation was common, whereas significant QTc interval 500 ms or more after methadone initiation rarely occurred, with no evidence of clinically significant arrhythmias. This study supports the safety of methadone use for pain control in patients with advanced cancer in the palliative care setting.
doi:10.1089/jpm.2009.0184
PMCID: PMC2939847  PMID: 19824814
7.  Prognostic value of long QT interval in acute and severe organophosphate poisoning 
Journal of Medical Toxicology  2009;5(4):196-199.
Introduction
Suicidal poisoning with organophosphorus (OP) pesticides is common, particularly from rural areas. This high-lights the importance of determining an OP poisoning prognosis to decide how aggressive treatment should be. There are reports suggesting a relationship between prolonged corrected QT (QTC) interval and the severity of poisoning. We aimed to evaluate the prognostic utility of this clinical tool in OP poisoning (OPP) patients.
Methods
Patients with the primary diagnosis of OPP who were admitted to the intensive care unit (ICU) of Loghman-Hakim Hospital Poison Centre (LHHPC) were the subjects of this prospective study. Cholinesterase (CE) activity and the QTC interval was determined for each patient using the Bazett formula and considering <440 msec as normal. Comparative outcomes of the study were duration of both hospitalization and mechanical ventilation, serum CE activity on admission and its daily level, total amount of atropine administered, analysis of the QT and QTC intervals in the primary ECG on admission and at the end of hospitalization, and rate of mortality.
Results
The study included 42 patients with a diagnosis of OPP. The mean age of the patients was 32, ranged from 12 to 81 years old. The mortality rate was 37.5%. There was no significant difference between two groups (prolonged and normal QTC intervals) according to gender and age (p=.491 andp=.133, respectively). The CE level for long and normal QTC interval groups was 3.90±0.33 kU/L vs. 4.41±0.23 kU/L, respectively. The mortality rate in the long QTC group was significantly higher than that of the normal QTC group (p=.044). Moreover, the average period of hospitalization in patients with prolonged QTC interval was higher than the other group (p=.02). The average atropine required to control the muscarinic signs and symptoms such as salivation, bronchorrehea, and miosis in patients with prolonged QTC interval was 38.60 mg; in patients with normal QTC interval it was 20.02 mg (p=.013).
Conclusion
QTC interval prolongation may have prognostic value in OPP.
doi:10.1007/BF03178266
PMCID: PMC3550412  PMID: 19876851
organophosphate; pesticide; poisoning; QT interval
8.  Analysis of Relationship between Levofloxacin and Corrected QT Prolongation Using a Clinical Data Warehouse 
Objective
The aim of this study was to examine whether or not levofloxacin has any relationship with QT prolongation in a real clinical setting by analyzing a clinical data warehouse of data collected from different hospital information systems.
Methods
Electronic prescription data and medical charts from 3 different hospitals spanning the past 9 years were reviewed, and a clinical data warehouse was constructed. Patients who were both administrated levofloxacin and given electrocardiograms (ECG) were selected. The correlations between various patient characteristics, concomitant drugs, corrected QT (QTc) prolongation, and the interval difference in QTc before and after levofloxacin administration were analyzed.
Results
A total of 2,176 patients from 3 different hospitals were included in the study. QTc prolongation was found in 364 patients (16.7%). The study revealed that age (OR 1.026, p < 0.001), gender (OR 0.676, p = 0.007), body temperature (OR 1.267, p = 0.024), and cigarette smoking (OR 1.641, p = 0.022) were related with QTc prolongation. After adjusting for related factors, 12 drugs concomitant with levofloxacin were associated with QTc prolongation. For patients who took ECGs before and after administration of levofloxacin during their hospitalization (n = 112), there was no significant difference in QTc prolongation.
Conclusions
The age, gender, body temperature, cigarette smoking and various concomitant drugs might be related with QTc prolongation. However, there was no definite causal relationship or interaction between levofloxacin and QTc prolongation. Alternative surveillance methods utilizing the massive accumulation of electronic medical data seem to be essential to adverse drug reaction surveillance in future.
doi:10.4258/hir.2011.17.1.58
PMCID: PMC3092995  PMID: 21818458
Long QT Syndrome; Ofloxacin; Data Mining; Product Surveillance; Post-marketing; Hospital Information Systems
9.  Association between a prolonged corrected QT interval and outcomes in patients in a medical Intensive Care Unit 
Introduction:
Patients admitted into a medical Intensive Care Unit (ICU) have varying illnesses and risk factors. An electrocardiogram (ECG) is a useful tool to assess the cardiac status. The aim of the study was to determine the prevalence of QT prolongation of the ECG in patients admitted to a medical ICU in a tertiary hospital, to assess outcomes in terms of mortality, cardiovascular events, and duration of ICU stay.
Materials and Methods:
Prospective observational study, 6 months duration, assessing the prevalence of prolonged corrected QT interval (QTc) at admission into a medical ICU. A QTc calculated by Bazett's formula, of >440 ms for males and >460 ms for females was considered prolonged. Details of illness, clinical and lab parameters were monitored.
Results:
The total number of patients screened was 182. There was a high prevalence of prolonged QTc (30%) on admission to the ICU. This reduced to 19% on day 3 (P = 0.011). In patients with a prolonged QTc the odds ratio of adverse outcome from ICU was 3.17 (confidence interval [CI]: 1.52–6.63) (P = 0.001) and of adverse outcome for hospital stay was 2.27 (CI: 1.11–4.66) (P = 0.014). In the study, 35% of all patients received drugs with QT prolonging action. Of patients with a prolonged QTc at admission 18 (35%) received a QT prolonging drug.
Conclusions:
We found that prolonged QTc is common (30%) in our medical ICU at admission and a large proportion (35%) received drugs capable of prolonging QT interval. These patients with QTc prolongation have a higher odds ratio for adverse outcomes.
doi:10.4103/0972-5229.158271
PMCID: PMC4478673  PMID: 26195858
Critical care; electrocardiography; intensive care unit; India; predictors; QT prolongation
10.  Changes in QTc Interval in the Citalopram for Agitation in Alzheimer's Disease (CitAD) Randomized Trial 
PLoS ONE  2014;9(6):e98426.
Background
A Food and Drug Administration (FDA) safety communication in August 2011 warned that citalopram was associated with a dose dependent risk of QT prolongation and recommended dose restriction in patients over the age of 60 but did not provide data for this age group.
Methods
CitAD was a randomized, double-masked, placebo-controlled, multicenter clinical trial for agitation in Alzheimer's disease (AD). Participants were assigned to citalopram (target dose of 30 mg/day) or placebo in a 1∶1 ratio. 186 people, 181 of whom were over the age of 60, having probable AD with clinically significant agitation were recruited from September 2009 to January 2013. After the FDA safety communication about citalopram, ECG was added to the required study procedures before enrollment and repeated at week 3 to monitor change in QTc interval. Forty-eight participants were enrolled after enhanced monitoring began.
Results
Citalopram treatment was associated with a larger increase in QTc interval than placebo (difference in week 3 QTc adjusting for baseline QTc: 18.1 ms [95% CI: 6.1, 30.1]; p = 0.004). More participants in the citalopram group had an increase ≥30 ms from baseline to week 3 (7 in citalopram versus 1 in placebo; Fisher's exact p = 0.046), but only slightly more in the citalopram group met a gender-specific threshold for prolonged QTc (450 ms for males; 470 ms for females) at any point during follow-up (3 in citalopram versus 1 in placebo, Fisher's exact p = 0.611). One of the citalopram participants who developed prolonged QTc also displayed ventricular bigeminy. No participants in either group had a cardiovascular-related death.
Conclusion
Citalopram at 30 mg/day was associated with improvement in agitation in patients with AD but was also associated with QT prolongation.
Trial Registration
ClinicalTrials.gov NCT00898807
doi:10.1371/journal.pone.0098426
PMCID: PMC4051660  PMID: 24914549
11.  Risk prediction of cardiovascular death based on the QTc interval: evaluating age and gender differences in a large primary care population 
European Heart Journal  2014;35(20):1335-1344.
Aims
Using a large, contemporary primary care population we aimed to provide absolute long-term risks of cardiovascular death (CVD) based on the QTc interval and to test whether the QTc interval is of value in risk prediction of CVD on an individual level.
Methods and results
Digital electrocardiograms from 173 529 primary care patients aged 50–90 years were collected during 2001–11. The Framingham formula was used for heart rate-correction of the QT interval. Data on medication, comorbidity, and outcomes were retrieved from administrative registries. During a median follow-up period of 6.1 years, 6647 persons died from cardiovascular causes. Long-term risks of CVD were estimated for subgroups defined by age, gender, cardiovascular disease, and QTc interval categories. In general, we observed an increased risk of CVD for both very short and long QTc intervals. Prolongation of the QTc interval resulted in the worst prognosis for men whereas in women, a very short QTc interval was equivalent in risk to a borderline prolonged QTc interval. The effect of the QTc interval on the absolute risk of CVD was most pronounced in the elderly and in those with cardiovascular disease whereas the effect was negligible for middle-aged women without cardiovascular disease. The most important improvement in prediction accuracy was noted for women aged 70–90 years. In this subgroup, a total of 9.5% were reclassified (7.2% more accurately vs. 2.3% more inaccurately) within clinically relevant 5-year risk groups when the QTc interval was added to a conventional risk model for CVD.
Conclusion
Important differences were observed across subgroups when the absolute long-term risk of CVD was estimated based on QTc interval duration. The accuracy of the personalized CVD prognosis can be improved when the QTc interval is introduced to a conventional risk model for CVD.
doi:10.1093/eurheartj/ehu081
PMCID: PMC4028611  PMID: 24603310
QTc interval; Gender; Marquette 12SL validation; Cardiovascular death; Risk prediction
12.  Multivariate analysis of risk factors for QT prolongation following subarachnoid hemorrhage 
Critical Care  2003;7(3):R7-R12.
Background
Subarachnoid hemorrhage (SAH) often causes a prolongation of the corrected QT (QTc) interval during the acute phase. The aim of the present study was to examine independent risk factors for QTc prolongation in patients with SAH by means of multivariate analysis.
Method
We studied 100 patients who were admitted within 24 hours after onset of SAH. Standard 12-lead electrocardiography (ECG) was performed immediately after admission. QT intervals were measured from the ECG and were corrected for heart rate using the Bazett formula. We measured serum levels of sodium, potassium, calcium, adrenaline (epinephrine), noradrenaline (norepinephrine), dopamine, antidiuretic hormone, and glucose.
Results
The average QTc interval was 466 ± 46 ms. Patients were categorized into two groups based on the QTc interval, with a cutoff line of 470 ms. Univariate analyses showed significant relations between categories of QTc interval, and sex and serum concentrations of potassium, calcium, or glucose. Multivariate analyses showed that female sex and hypokalemia were independent risk factors for severe QTc prolongation. Hypokalemia (<3.5 mmol/l) was associated with a relative risk of 4.53 for severe QTc prolongation as compared with normokalemia, while the relative risk associated with female sex was 4.45 as compared with male sex. There was a significant inverse correlation between serum potassium levels and QTc intervals among female patients.
Conclusion
These findings suggest that female sex and hypokalemia are independent risk factors for severe QTc prolongation in patients with SAH.
PMCID: PMC270671  PMID: 12793884
female; hypokalemia; multivariate analysis; QT prolongation; subarachnoid hemorrhage
13.  Relationship between HIV protease inhibitors and QTc interval duration in HIV-infected patients: a cross-sectional study 
AIMS
QTc interval prolongation and torsades de pointes have been reported in HIV-infected patients. Protease inhibitors (PIs) are suspected to contribute to this adverse reaction. However, many factors can prolong QTc interval. We examined factors influencing QTc duration in HIV-infected patients.
METHODS
Unselected HIV-infected patients (n = 978) were enrolled in this prospective, single-centre cross-sectional study. Variables related to infection and treatments were collected. A digital electrocardiographic record was recorded in each patient and QT interval duration was measured and corrected using both Bazett's (QTcB) and Fridericia's (QTcF) formula. Results were analysed with a multivariable linear model.
RESULTS
After excluding arrhythmias and complete bundle branch blocks, QT interval was measured in 956 patients. The mean (SD) QTcB was 418 ms (23) and QTcF was 405 ms (20). QTc was found prolonged (>450 ms in women and >440 ms in men) in 129 [13.5%; 95% confidence interval (CI) 11.5, 15.8] and 38 (4%; 95% CI 2.9, 5.4) patients using Bazett and Fridericia corrections, respectively. On multivariable analysis, incomplete bundle branch block, ventricular hypertrophy, signs of ischaemic cardiopathy, female gender, White ethnic origin and age were significantly associated with QTc prolongation. The only HIV variable independently associated with QTc prolongation was the duration of infection (P = 0.023). After adjustment, anti-HIV treatment, in particular PI (P = 0.99), was not associated with QTc prolongation.
CONCLUSIONS
Although PIs block in vitro hERG current, they are not independently associated with QTc interval prolongation. Prolonged QTc interval in HIV-infected patients is primarily associated with factors commonly known to prolong QT and with the duration of HIV infection.
doi:10.1111/j.1365-2125.2008.03332.x
PMCID: PMC2668087  PMID: 19076152
electrocardiography; HIV infection; HIV protease inhibitors; long QT syndrome
14.  Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol 
Aim
To study the differences in QTc interval on ECG in response to a single oral dose of rac-sotalol in men and women.
Methods
Continuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration–QTc analyses were performed using a linear mixed effects model.
Results
Rac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QTcI) most effectively removed the heart rate dependency of the QTc interval. Mean QTcI was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QTcI in both genders. The largest mean change in QTcI (ΔQTcI) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean Cmax 1.8 μg ml−1 (range 1.1–2.8) vs. 1.4 μg ml−1 (range 0.9–1.9), P = 0.0009). The slope of the concentration–ΔQTcI relationship was steeper in women (30 ms per μg ml−1 vs. 23 ms per μg ml−1 in men; P = 0.0135).
Conclusions
The study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization.
doi:10.1111/bcp.12201
PMCID: PMC4371537  PMID: 23819796
gender; gender difference; PK/PD; QT prolongation; QT/QTc; rac-sotalol
15.  Effect of Isometric Exercise on QTc Interval 
Introduction: The QTc interval is affected by heart rate, autonomic nervous system and diseases like diabetes. However, the affect of exercise which alters autonomic nervous system activity, on QTc is not clear. On the other hand, the incidence of sudden cardiac death increases many fold post exercise. These events may be better explained by studying the effect of exercise on QTc.
Aim: This study was designed with an aim to record the QTc interval changes in response to isometric exercise in a group of normal individuals with or without parental history of diabetes mellitus. Also the QTc duration was correlated with the LF-HF ratio.
Materials and Methods: Twenty nine, healthy medical students were subjected to isometric hand grip test for 5min. ECG was recorded pre-exercise and at various time intervals post-exercise.
Statistical Analysis: All data are expressed in mean ± SD. Intra group comparison was done using paired t-test and unpaired t-test was used for comparison among group I and group II subjects, and among males and females.
Result: The difference in the pre and post exercise QTc values both within and between groups was statistically significant with group I subjects recording lower values. The post exercise LF: HF values were significantly increased when compared to pre exercise values in both the groups. There was no correlation between LF: HF and QTc.
Conclusion: A longer than normal QTc interval predisposes to arrhythmia. Exercise brings about detectable changes in the QTc interval after a period of isometric exercise in normal individuals which in high risk individuals may predispose to sudden cardiac death. In addition women may be more susceptible to post-exercise arrhythmia owing to a longer QTc even at rest.
doi:10.7860/JCDR/2014/9533.4673
PMCID: PMC4190704  PMID: 25302185
Autonomic nervous system; Isometric exercise; Sudden cardiac death; QTc interval
16.  QTc and psychopharmacs: are there any differences between monotherapy and polytherapy 
Background
Some psychotropic drugs are connected with prolongation of QT interval, increased risk of cardiac arrhythmias and greater incidence of sudden death, especially when used in combination. Concomitant use of antipsychotics and antidepressants is not rare in our clinical practice. The study compares the length of QT interval in patients on monotherapy with an antipsychotic or an antidepressant and patients taking polytherapy (an antipsychotic agent combined with an antidepressant).
Methods
Sixty-one hospitalized women who met the ICD-10 criteria for schizophrenia, schizoaffective psychosis, delusional disorder and mood disorder were included in the study. The monotherapy group was consisted of thirty-two women treated with an antipsychotic or an antidepressant while the polytherapy group was composed of twenty-nine women treated with an antipsychotic agent plus an antidepressant. Two electrocardiograms (ECGs) were obtained for each patient: the first was carried out before the treatment and the second after two weeks of treatment.
Statistical analysis was carried out by SPSS program and included unpaired and paired t test and Fisher's exact test.
Results
Mean baseline QTc values did not differ between the groups (439 ± 22 ms was the same value found in the both groups; unpaired t test, p > 0.5). Mean QTc intervals after two weeks of treatment were also similar (439 ± 24 ms in the monotherapy group and 440 ± 20 ms in the polytherapy group; unpaired t test, p > 0.5). Fisher's exact test did not reveal significant difference in the number of patients with borderline (451–470 ms) or prolonged (> 470 ms) QTc between groups, neither before treatment nor after two weeks of treatment. Twenty two women of the total of sixty one patients (36%) had QTc > 450 ms before applying therapy.
Conclusion
We did not find significant QT prolongation in our patients after two weeks of treatment with antipsychotics and/or antidepressants. The QTc interval length did not differ significantly in the monotherapy and the polytherapy group. More than one third of included women exceeded the threshold value of borderline QTc interval (450 ms) before starting treatment. This finding calls for caution when prescribing drugs to female psychiatric patients, especially if they have other health problems.
doi:10.1186/1744-859X-6-13
PMCID: PMC1871590  PMID: 17477877
17.  Increased prevalence of ECG markers for sudden cardiac arrest in refractory epilepsy 
Background and aim
People with epilepsy are at increased risk of sudden cardiac arrest (SCA) due to ECG-confirmed ventricular tachycardia/fibrillation, as seen in a community-based study. We aimed to determine whether ECG-risk markers of SCA are more prevalent in people with epilepsy.
Methods
In a cross-sectional, retrospective study, we analysed the ECG recordings of 185 people with refractory epilepsy and 178 controls without epilepsy. Data on epilepsy characteristics, cardiac comorbidity, and drug use were collected, and general ECG variables (heart rate (HR), PQ and QRS intervals) assessed. We analysed ECGs for three markers of SCA risk: severe QTc prolongation (male >450 ms, female >470 ms), Brugada ECG pattern, and early repolarisation pattern (ERP). Multivariate regression models were used to analyse differences between groups, and to identify associated clinical and epilepsy-related characteristics.
Results
People with epilepsy had higher HR (71 vs 62 bpm, p<0.001) and a longer PQ interval (162.8 vs 152.6 ms, p=0.001). Severe QTc prolongation and ERP were more prevalent in people with epilepsy (QTc prolongation: 5% vs 0%; p=0.002; ERP: 34% vs 13%, p<0.001), while the Brugada ECG pattern was equally frequent in both groups (2% vs 1%, p>0.999). After adjustment for covariates, epilepsy remained associated with ERP (ORadj 2.4, 95% CI 1.1 to 5.5) and severe QTc prolongation (ORadj 9.9, 95% CI 1.1 to 1317.7).
Conclusions
ERP and severe QTc prolongation appear to be more prevalent in people with refractory epilepsy. Future studies must determine whether this contributes to increased SCA risk in people with epilepsy.
doi:10.1136/jnnp-2014-307772
PMCID: PMC4345521  PMID: 24946773
Anticonvulsants; Channels; Epilepsy; Sudden Death
18.  Prevalence and clinical correlates of QT prolongation in patients with hypertrophic cardiomyopathy 
European Heart Journal  2011;32(9):1114-1120.
Aims
Congenital or acquired QT prolongation is a risk factor for life-threatening arrhythmias. In patients with hypertrophic cardiomyopathy (HCM), the QT interval may be intrinsically prolonged. However, the prevalence, cause, and significance of QT prolongation among patients with HCM are unknown.
Methods and results
After exclusion of patients on QT-prolonging drugs, a blinded, retrospective analysis of electrocardiograms, echocardiograms, and genotype status in 479 unrelated patients with HCM [201 females, age at diagnosis 41 ± 18 years, maximal left ventricular wall thickness (MLVWT) 22 ± 6 mm] from two independent centres was performed. The mean QTc was 440 ± 28 ms. The QTc exceeded 480 ms in 13% of patients. Age, gender, family history of HCM or sudden cardiac arrest, and genotype status had no association with QTc. Patients with a QTc over 480 ms were more symptomatic at diagnosis (P < 0.001), had a higher MLVWT (P = 0.03), were more obstructive (P < 0.001), and were more likely to have undergone septal reduction therapy (P = 0.02). There was a weak but significant direct linear relationship between QTc and peak outflow gradient (r2 = 0.05, P < 0.0001).
Conclusions
Compared with <1 in 200 otherwise healthy adults, QT prolongation (QTc > 480 ms) was present in 1 out of 8 patients with HCM. The QTc was partly reflective of the degree of cardiac hypertrophy and left ventricular outflow tract obstruction. Because of its pro-arrhythmic potential and its potential relevance to management and risk stratification, routine QTc assessment should be performed in patients with HCM, particularly when concomitant use of QT-prolonging medications is considered.
doi:10.1093/eurheartj/ehr021
PMCID: PMC3086898  PMID: 21345853
Long QT syndrome; Hypertrophic cardiomyopathy; Sudden death; Ventricular arrhythmia; QT interval
19.  Effect of intravenous ondansetron on QT interval prolongation in patients with cardiovascular disease and additional risk factors for torsades: a prospective, observational study 
Background:
The 5-hydroxytryptamine type 3 antagonists, or setrons (eg, ondansetron), are commonly used for nausea and vomiting in the hospital setting. In 2001, droperidol was given a black box warning because it was found to prolong the QT interval and induce arrhythmias. The setrons share with droperidol the same potential proarrhythmic mechanisms, but limited data exist concerning their effects on the QT interval in individuals at high risk for torsades de pointes.
Methods:
Forty hospitalized patients admitted for heart failure or acute coronary syndromes with one or more risk factors for torsades de pointes and an order for intravenous ondansetron 4 mg were enrolled in this prospective, observational study. The QT interval corrected for heart rate (QTc) was obtained via a 12-lead electrocardiogram on admission and again 120 minutes after the first dose of ondansetron in order to determine the mean change in QTc following ondansetron exposure.
Results:
The mean time interval between obtaining the baseline electrocardiogram and the second electrocardiogram following ondansetron administration was 3.5 ± 2.14 hours. In the total population, the QTc interval was prolonged by 19.3 ± 18 msec (P < 0.0001) 120 minutes after ondansetron administration. For patients with an acute coronary syndrome and those with heart failure, QTc was prolonged by 18.3 ± 20 msec (P < 0.0001) and 20.6 ± 20 msec (P < 0.0012), respectively. Following ondansetron exposure, 31% and 46% in the heart failure and acute coronary syndromes groups, respectively, met gender-related thresholds for a prolonged QTc.
Conclusion:
Our study found QTc prolongation due to ondansetron administration similar to that found in previous studies. When used in patients with cardiovascular disease (eg, heart failure or acute coronary syndromes) with one or more risk factors for torsades de pointes, ondansetron may significantly increase the QTc interval for up to 120 minutes after administration. From a patient safety perspective, patients who are at high risk for torsades de pointes and receiving ondansetron should be followed via telemetry when admitted to hospital.
doi:10.2147/DHPS.S25623
PMCID: PMC3202761  PMID: 22046106
ondansetron; QT prolongation; patient safety; antiemetics
20.  Nomenclature, categorization and usage of formulae to adjust QT interval for heart rate 
World Journal of Cardiology  2015;7(6):315-325.
Assessment of the QT interval on a standard 12 lead electrocardiogram is of value in the recognition of a number of conditions. A critical part of its use is the adjustment for the effect of heart rate on QT interval. A systematic search was conducted to identify studies that proposed formulae to standardize the QT interval by heart rate. A nomenclature was developed for current and subsequent equations based on whether they are corrective (QTc) or predictive (QTp). QTc formulae attempt to separate the dependence of the length of the QT interval from the length of the RR interval. QTp formulae utilize heart rate and the output QTp is compared to the uncorrected QT interval. The nomenclature consists of the first letter of the first author’s name followed by the next two consonance (whenever possible) in capital letters; with subscripts in lower case alphabetical letter if the first author develops more than one equation. The single exception was the Framingham equation, because this cohort has developed its own “name” amongst cardiovascular studies. Equations were further categorized according to whether they were linear, rational, exponential, logarithmic, or power based. Data show that a person’s QT interval adjusted for heart rate can vary dramatically with the different QTc and QTp formulae depending on the person’s heart rate and QT interval. The differences in the QT interval adjustment equations encompasses values that are considered normal or significant prolonged. To further compare the equations, we considered that the slope of QTc versus heart rate should be zero if there was no correlation between QT and heart rate. Reviewing a sample of 107 patient ECGs from a hospital setting, the rank order of the slope - from best (closest to zero) to worst was QTcDMT, QTcRTHa, QTcHDG, QTcGOT, QTcFRM, QTcFRD, QTcBZT and QTcMYD. For two recent formulae based on large data sets specifically QTcDMT and QTcRTHa, there was no significant deviation of the slope from zero. In summary a nomenclature permits easy reference to QT formulae that adjust for heart rate. Twenty different formulae can produce discordant calculations of an adjusted QT interval. While the formulae developed by Bazett and Fridericia (QTcBZT and QTcFRD respectively) may continue to be used clinically, recent formulae from large population studies specifically QTcDMT and QTcRTHa appear to be better to adjust QT for heart rate in clinical practice.
doi:10.4330/wjc.v7.i6.315
PMCID: PMC4478566  PMID: 26131336
QT interval; Heart rate adjustment
21.  Differential Changes in QTc Duration during In-Hospital Haloperidol Use 
PLoS ONE  2011;6(9):e23728.
Aims
To evaluate changes in QT duration during low-dose haloperidol use, and determine associations between clinical variables and potentially dangerous QT prolongation.
Methods
In a retrospective cohort study in a tertiary university teaching hospital in The Netherlands, all 1788 patients receiving haloperidol between 2005 and 2007 were studied; ninety-seven were suitable for final analysis. Rate-corrected QT duration (QTc) was measured before, during and after haloperidol use. Clinical variables before haloperidol use and at the time of each ECG recording were retrieved from hospital charts. Mixed model analysis was used to estimate changes in QT duration. Risk factors for potentially dangerous QT prolongation were estimated by logistic regression analysis.
Results
Patients with normal before-haloperidol QTc duration (male ≤430 ms, female ≤450 ms) had a significant increase in QTc duration of 23 ms during haloperidol use; twenty-three percent of patients rose to abnormal levels (male ≥450 ms, female ≥470 ms). In contrast, a significant decrease occurred in patients with borderline (male 430–450 ms, female 450–470 ms) or abnormal before-haloperidol QTc duration (15 ms and 46 ms, respectively); twenty-three percent of patients in the borderline group, and only 9% of patients in the abnormal group obtained abnormal levels. Potentially dangerous QTc prolongation was independently associated with surgery before haloperidol use (ORadj 34.9, p = 0.009) and before-haloperidol QTc duration (ORadj 0.94, p = 0.004).
Conclusion
QTc duration during haloperidol use changes differentially, increasing in patients with normal before-haloperidol QTc duration, but decreasing in patients with prolonged before-haloperidol QTc duration. Shorter before-haloperidol QTc duration and surgery before haloperidol use predict potentially dangerous QTc prolongation.
doi:10.1371/journal.pone.0023728
PMCID: PMC3178516  PMID: 21961030
22.  Effect of Combined Fluoroquinolone and Azole Use on QT Prolongation in Hematology Patients 
QTc prolongation is a risk factor for development of torsades de pointes (TdP). Combination therapy with fluoroquinolones and azoles is used in patients with hematologic malignancies for prophylaxis and treatment of infection. Both drug classes are implicated as risk factors for QTc prolongation. The cumulative effect on and incidence of QTc prolongation for this combination have not been previously described. A retrospective chart review was performed with hospitalized inpatients from 1 September 2008 to 31 January 2010 comparing QTc interval data from electrocardiogram (ECG) assessment at baseline and after the initiation of combination therapy. Ninety-four patients were eligible for inclusion. The majority, 88 patients (93.6%), received quinolone therapy with levofloxacin. Fifty-three patients (56.4%) received voriconazole; 40 (42.6%) received fluconazole. The overall mean QTc change from baseline was 6.1 (95% confidence interval [CI], 0.2 to 11.9) ms. Twenty-one (22.3%) of the studied patients had clinically significant changes in the QTc while receiving combination fluoroquinolone-azole therapy. Statistically significant risk factors for clinically significant changes in QTc were hypokalemia (P = 0.03) and a left-ventricular ejection fraction of <55% (P = 0.02). Low magnesium (P = 0.11), exposure to 2 or more drugs with the potential to prolong the QTc interval (P = 0.17), and female sex (P = 0.21) trended toward significance. Combination therapy with fluoroquinolone and azole antifungals is associated with increased QTc from baseline in hospitalized patients with hematologic malignancies. One in five patients had a clinically significant change in the QTc, warranting close monitoring and risk factor modification to prevent the possibility of further QTc prolongation and risk of TdP.
doi:10.1128/AAC.00958-12
PMCID: PMC3591877  PMID: 23229485
23.  Dispersion of QT and QTc interval in healthy children, and effects of sinus arrhythmia on QT dispersion 
Heart  1998;80(1):77-79.
Objective—To determine the normal values of QT and QTc dispersion and the effects of sinus arrhythmia on QT dispersion in healthy children.
Patients and setting—The study was carried out in a university hospital on 372 local schoolchildren (200 male, 172 female), aged seven to 18 years.
Methods—The QT and preceding RR intervals of at least one sinus beat were measured manually in a range of nine to 12 leads on standard 12 lead surface ECGs. The corrected QT interval was computed by the method of Bazett. Dispersion of QT and QTc were defined as (1) the difference between the maximum and minimum QT and QTc intervals occurring in any of the 12 leads (QTD and QTcD), (2) the standard deviation of the QT and QTc interval in the measurable leads (QT-SD and QTc-SD).
Results—There was no significant difference in QT, QTc, and RR dispersion between girls and boys. Overall 53% of children had sinus arrhythmia. Although QTD and QT-SD were not affected by sinus arrhythmia, both QTcD and QTc-SD were significantly greater in children with sinus arrhythmia than in those without (QTcD: 52.9 (17.4) v 40.9 (13.1); QTc-SD: 17.5 (5.9) v 13.2 (4.0); p < 0.001).
Conclusions—As calculation of QTc dispersion is affected by sinus arrhythmia, which is common in childhood, we suggest that QT dispersion should not be corrected for heart rate in children.

 Keywords: QT dispersion;  heart rate;  children;  sinus arrhythmia
PMCID: PMC1728755  PMID: 9764065
24.  Cardiac and non-cardiac causes of T-wave inversion in the precordial leads in adult subjects: A Dutch case series and review of the literature 
World Journal of Cardiology  2015;7(2):86-100.
AIM: To describe the electrocardiographic (ECG) phenomena characterized by T-wave inversion in the precordial leads in adults and to highlight its differential diagnosis.
METHODS: A retrospective chart review of 8 adult patients who were admitted with ECG T-wave inversion in the anterior chest leads with or without prolongation of corrected QT (QTc) interval. They had different clinical conditions. Each patient underwent appropriate clinical assessment including investigation for myocardial involvement. Single and multimodality non-invasive, semi-invasive and invasive diagnostic approach were used to ascertain the diagnosis. The diagnostic assessment included biochemical investigation, cardiac and abdominal ultrasound, cerebral and chest computed tomography, nuclear medicine and coronary angiography.
RESULTS: Eight adult subjects (5 females) with a mean age of 66 years (range 51 to 82) are analyzed. The etiology of T-wave inversion in the precordial leads were diverse. On admission, all patients had normal blood pressure and the ECG showed sinus rhythm. Five patients showed marked prolongation of the QTc interval. The longest QTc interval (639 ms) was found in the patient with pheochromocytoma. Giant T-wave inversion (≥ 10 mm) was found in pheochromocytoma followed by electroconvulsive therapy and finally ischemic heart disease. The deepest T-wave was measured in lead V3 (5 ×). In 3 patients presented with mild T-wave inversion (patients 1, 5 and 4 mm), the QTc interval was not prolonged (432, 409 and 424 msec), respectively.
CONCLUSION: T-wave inversion associated with or without QTc prolongation requires meticulous history taking, physical examination and tailored diagnostic modalities to reach rapid and correct diagnosis to establish appropriate therapeutic intervention.
doi:10.4330/wjc.v7.i2.86
PMCID: PMC4325305  PMID: 25717356
T-wave inversion; Coronary angiography; Pulmonary computed tomography angiography; Magnetic resonance imaging; Differential diagnosis
25.  Effect of single doses of maraviroc on the QT/QTc interval in healthy subjects 
Aims
To assess the effect of a single dose of maraviroc on the QTc interval in healthy subjects and to evaluate the QTc interval–concentration relationship.
Methods
A single-dose, placebo- and active-controlled, five-way crossover study was conducted to investigate the effects of maraviroc (100, 300, 900 mg) on QTc in healthy subjects. Moxifloxacin (400 mg) was used as the active comparator. The study was double-blind with respect to maraviroc/placebo and open label for moxifloxacin. There was a 7-day wash-out period between each dose. QT interval measurements obtained directly from the electrocardiogram (ECG) recorder were corrected for heart rate using Fridericia's correction (QTcF). A placebo run-in day was conducted before period 3, when ECGs were collected at intervals while subjects were resting or during exercise. These ECGs plus other predose ECGs were used to evaluate the QT/RR relationship for each subject to enable calculation of an individual's heart rate correction for their QT measurements (QTcI). ECGs were taken at various intervals pre- and postdose in each study period. Pharmacokinetic parameters were determined for each maraviroc dose. The end-points that were evaluated were QTcF at median time to maximum concentration (Tmax) based on the machine readings and QTcI at median Tmax based on manual over-reads of the QT/RR data. A separate analysis of variance was used for each of the pair-wise comparisons for each end-point. The relationship between QTc interval and plasma concentration was also investigated using a mixed-effects modelling approach, as implemented by the NONMEM software system. A one-stage model was employed in which the relationship between QT and RR and the effects of maraviroc plasma concentration on QT were estimated simultaneously.
Results
The mean difference from placebo in machine-read QTcF at median Tmax for maraviroc 900 mg was 3.6 ms [90% confidence interval (CI) 1.5, 5.8]. For the active comparator, moxifloxacin, the mean difference from placebo in machine-read QTcF was 13.7 ms. The changes from placebo for each of the end-points were similar for men and women. No subjects receiving maraviroc or placebo had a QTcF ≥ 450 ms (men) or QTcF ≥ 470 ms (women), nor did any subject experience a QTcF increase ≥ 60 ms from baseline at any time point. Analysis based on the QTcI data obtained from the manual over-readings of the ECGs gave numerically very similar results. The QT:RR relationship was similar pre- and postdose and was not related to maraviroc concentration. The population estimate of the QT:RR correction factor was 0.324 (95% CI 0.309, 0.338). The population estimate of the slope describing the QT–concentration relationship was 0.97 μs ml ng−1 (95% CI −0.571, 2.48), equivalent to an increase of 0.97 ms in QT per 1000 ng maraviroc plasma concentration. Most adverse events were mild to moderate in severity.
Conclusions
Single doses of maraviroc, up to and including 900 mg, had no clinically relevant effect on QTcF or QTcI. At all maraviroc doses and for both end-points, the mean difference from placebo for QTc was <4 ms. There was no apparent relationship between QT interval and maraviroc plasma concentration up to 2363 ng ml−1. This conclusion held in both male and female subjects, and there was no evidence of a change in the QT/RR relationship with concentration.
doi:10.1111/j.1365-2125.2008.03138.x
PMCID: PMC2311415  PMID: 18333868
CCR5 inhibitor; maraviroc; moxifloxacin; pharmacokinetics; QTcF; QTcI; safety

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