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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.
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.
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.
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.
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).
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.
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 
The rate-corrected QT interval (QTc) prolongation is a risk factor for sudden cardiac death and may be induced by antipsychotic drugs.
To determine the clinical characteristics associated with QTc prolongation (440 msec or greater) in children and adolescents hospitalized for treatment of psychiatric disorders.
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.
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.
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.
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.
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)].
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.
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) 
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
QTC interval prolongation may have prognostic value in OPP.
PMCID: PMC3550412  PMID: 19876851
organophosphate; pesticide; poisoning; QT interval
8.  Analysis of Relationship between Levofloxacin and Corrected QT Prolongation Using a Clinical Data Warehouse 
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.
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.
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.
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.
PMCID: PMC3092995  PMID: 21818458
Long QT Syndrome; Ofloxacin; Data Mining; Product Surveillance; Post-marketing; Hospital Information Systems
9.  Changes in QTc Interval in the Citalopram for Agitation in Alzheimer's Disease (CitAD) Randomized Trial 
PLoS ONE  2014;9(6):e98426.
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.
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.
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.
Citalopram at 30 mg/day was associated with improvement in agitation in patients with AD but was also associated with QT prolongation.
Trial Registration NCT00898807
PMCID: PMC4051660  PMID: 24914549
10.  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.
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.
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.
PMCID: PMC4028611  PMID: 24603310
QTc interval; Gender; Marquette 12SL validation; Cardiovascular death; Risk prediction
11.  Multivariate analysis of risk factors for QT prolongation following subarachnoid hemorrhage 
Critical Care  2003;7(3):R7-R12.
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.
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.
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.
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
12.  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.
PMCID: PMC4190704  PMID: 25302185
Autonomic nervous system; Isometric exercise; Sudden cardiac death; QTc interval
13.  QTc and psychopharmacs: are there any differences between monotherapy and polytherapy 
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).
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.
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.
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.
PMCID: PMC1871590  PMID: 17477877
14.  Prevalence and clinical correlates of QT prolongation in patients with hypertrophic cardiomyopathy 
European Heart Journal  2011;32(9):1114-1120.
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).
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.
PMCID: PMC3086898  PMID: 21345853
Long QT syndrome; Hypertrophic cardiomyopathy; Sudden death; Ventricular arrhythmia; QT interval
15.  Effect of intravenous ondansetron on QT interval prolongation in patients with cardiovascular disease and additional risk factors for torsades: a prospective, observational study 
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.
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.
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.
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.
PMCID: PMC3202761  PMID: 22046106
ondansetron; QT prolongation; patient safety; antiemetics
16.  Differential Changes in QTc Duration during In-Hospital Haloperidol Use 
PLoS ONE  2011;6(9):e23728.
To evaluate changes in QT duration during low-dose haloperidol use, and determine associations between clinical variables and potentially dangerous QT prolongation.
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.
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).
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.
PMCID: PMC3178516  PMID: 21961030
17.  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.
PMCID: PMC3591877  PMID: 23229485
18.  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
19.  QTc prolongation is associated with impaired right ventricular function and predicts mortality in pulmonary hypertension 
International journal of cardiology  2012;167(3):669-676.
In rodent models of pulmonary hypertension (PH) and right ventricular hypertrophy (RVH), the QTc interval is prolonged, reflecting downregulation of repolarizing Kv channels in RV myocytes. The significance of QTc prolongation in human PH is unknown. We hypothesized that QTc prolongation occurs in human PH, is associated with RVH and decreased RV function, and predicts adverse prognosis.
Patients receiving a PAH-specific therapy (a prostanoid, endothelin-receptor antagonist and/or a phosphodiesterase-5 inhibitor), who had a 12-lead electrocardiogram (ECG) (n=202) were compared to age- and sex-matched controls (n=100). The duration of QTc on ECG was correlated with invasive hemodynamics (n=156) and with the status of the RV, as measured by Brain Natriuretic Peptide (NT-proBNP, n=145) and magnetic resonance imaging (n=24). Survival of the entire PH cohort and a subgroup with WHO Group 1 and 4 PAH was prospectively determined from the Social Security Death Index.
QTc intervals were longer in PH vs. controls (454.8±29 ms vs. 429.8±18 ms, p<0.001) and did not differ based on PAH-specific therapy. NT-proBNP increased proportionately with QTc and was higher for those in the upper quintile (QTc≥480ms) vs. those with QTc≤480ms (4004±6682 pg/mL vs. 1501±1822 pg/mL, p<0.001). The QTc interval also correlated directly with increasing RV end-diastolic volume (r=.67, p<0.001) and mass (r=.0.51, p<0.05), and inversely with RV ejection fraction (r=−.49, p<0.05). In the entire PH cohort and WHO Group 1 and 4 subgroup, QTc ≥480 ms and cardiac index were independent predictors of mortality.
QTc prolongation in PH patients reflects the status of the RV and is an independent predictor of mortality.
PMCID: PMC3389574  PMID: 22459397
Biomarkers; brain natriuretic peptide; cardiac repolarization; pulmonary hypertension; right ventricular failure; right ventricular hypertrophy
20.  Highly abnormal thermotests in familial dysautonomia suggest increased cardiac autonomic risk 
OBJECTIVE—Patients with familial dysautonomia have an increased risk of sudden death. In some patients with familial dysautonomia, sympathetic cardiac dysfunction is indicated by prolongation of corrected QT (QTc) interval, especially during stress tests. As many patients do not tolerate physical stress, additional indices are needed to predict autonomic risk. In familial dysautonomia there is a reduction of both sympathetic neurons and peripheral small nerve fibres which mediate temperature perception. Consequently, quantitative thermal perception test results might correlate with QTc values. If this assumption is correct, quantitative thermotesting could contribute to predicting increased autonomic risk.
METHODS—To test this hypothesis, QTc intervals were determined in 12 male and eight female patients with familial dysautonomia, aged 10 to 41 years (mean 21.7 (SD 10.1) years), in supine and erect positions and postexercise and correlated with warm and cold perception thresholds assessed at six body sites using a Thermotest.
RESULTS—Due to orthostatic presyncope, six patients were unable to undergo erect and postexercise QTc interval assessment. The QTc interval was prolonged (>440 ms) in two patients when supine and in two additional patients when erect and postexercise. Supine QTc intervals correlated significantly with thermal threshold values at the six body sites and with the number of sites with abnormal thermal perception (Spearman's rank correlation p<0.05). Abnormal Thermotest results were more frequent in the four patients with QTc prolongation and the six patients with intolerance to stress tests.
CONCLUSION—The results suggest that impaired thermal perception correlates with cardiac sympathetic dysfunction in patients with familial dysautonomia. Thus thermotesting may provide an alternative, albeit indirect, means of assessing sympathetic dysfunction in autonomic disorders.

PMCID: PMC2170226  PMID: 9728945
21.  Impact of Pheochromocytoma on Left Ventricular Hypertrophy and QTc Prolongation: Comparison with Takotsubo Cardiomyopathy 
Korean Circulation Journal  2014;44(2):89-96.
Background and Objectives
Excessive catecholamine causes the alteration of cardiac structure and function. This study evaluated if there is any difference in left ventricular hypertrophy (LVH) and QTc prolongation in conditions with pheochromocytoma and Takotsubo cardiomyopathy (TC).
Subjects and Methods
We reviewed the medical records of 20 pheochromocytoma patients for cardiovascular events prior to diagnosis. The patient's clinical history and electrocardiographic and echocardiographic findings were compared to those of 20 patients diagnosed with TC.
Left ventricular (LV) mass index (133.3±37.8 vs. 113.3±17.3, p=0.031), relative wall thickness (0.55±0.15 vs. 0.47±0.07, p=032) and elevated blood pressure (BP) were more prominent in pheochromocytoma compared to TC. The mean creatinine kinase-MB elevation, reduced LV systolic function and ST segment changes were more prominent in the TC group compared to the pheochromocytoma groups (all p<0.05). The prevalence of QTc prolongation was high in patients with pheochromocytoma (45%) and TC (55%), and TC male patients appeared to have a more prolonged QTc interval. Urine epinephrine (r=0.844, p=0.004) and norepinephrine level (r=0.782, p=0.013) were significantly correlated with LV mass index, and the predictors for the QTc prolongation were male gender and the presence of LVH.
A prolonged QTc was prominent in pheochromocytoma and TC regardless of BP and systolic LV function, and LVH was more prominent in pheochromocytoma than TC.
PMCID: PMC3958614  PMID: 24653738
Long QT syndrome; Hypertrophy, left ventricular; Catecholamines
22.  QTc Interval Prolongation Predicts Postoperative Mortality in Heart Failure Patients Undergoing Surgical Revascularization 
QTc interval prolongation is associated with increased mortality rates in patients with advanced heart failure. We investigated the predictive value of prolonged QTc interval in 567 patients with heart failure who were undergoing coronary artery bypass graft surgery. The patients were in New York Heart Association class III or IV, with left ventricular ejection fractions of 0.40 or less. Before surgery, the QT interval duration was measured in leads II and V4 of the standard electrocardiogram and corrected by use of the Bazett formula. The QTc interval was prolonged (>440 msec) in 243 patients (43%) and normal in 324 (57%). The 2 study groups—prolonged QTc versus normal QTc—did not differ in terms of age (62 ± 11 years vs 64 ± 10 years, P =0.65), sex (80% male vs 76% male, P =0.31), ejection fraction (0.29 ± 0.08 vs 0.29 ± 0.09, P =0.72), hypertension (82% vs 78%, P =0.34), or diabetes (11% vs 7%, P =0.10).
Within 1 month after coronary artery bypass grafting, 22 of 243 patients (9.1%) in the prolonged QTc group died, compared with 5 of 324 in the normal QTc group (1.5%) (P =0.0001). QTc interval prolongation was the only independent predictor of postoperative mortality on multivariate analysis (P =0.002). We conclude that patients with heart failure and preoperative QTc interval prolongation have increased mortality rates after coronary artery bypass grafting.
PMCID: PMC1413604  PMID: 16572860
Coronary disease/surgery; electrocardiography; heart failure; long QT syndrome; mortality; myocardial revascularization; prognosis; risk factors; treatment outcome
23.  Pathogenesis of Lethal Cardiac Arrhythmias in Mecp2 Mutant Mice: Implication for Therapy in Rett Syndrome 
Science translational medicine  2011;3(113):113ra125.
Rett Syndrome is a neurodevelopmental disorder typically caused by mutations in Methyl-CpG-Binding Protein 2 (MECP2) in which 26% of deaths are sudden and of unknown cause. To explore the hypothesis that these deaths may be due to cardiac dysfunction, we characterized the electrocardiograms (ECGs) in 379 people with Rett syndrome and found that 18.5% show prolongation of the corrected QT interval (QTc), indicating a repolarization abnormality that can predispose to the development of an unstable fatal cardiac rhythm. Male mice lacking MeCP2 function, Mecp2Null/Y, also have prolonged QTc and show increased susceptibility to induced ventricular tachycardia. Female heterozygous null mice, Mecp2Null/+, show an age-dependent prolongation of QTc associated with ventricular tachycardia and cardiac-related death. Genetic deletion of MeCP2 function in only the nervous system was sufficient to cause long QTc and ventricular tachycardia, implicating neuronally-mediated changes to cardiac electrical conduction as a potential cause of ventricular tachycardia in Rett syndrome. The standard therapy for prolonged QTc in Rett syndrome, β-adrenergic receptor blockers, did not prevent ventricular tachycardia in Mecp2Null/Y mice. To determine whether an alternative therapy would be more appropriate, we characterized cardiomyocytes from Mecp2Null/Y mice and found increased persistent sodium current, which was normalized when cells were treated with the sodium channel-blocking anti-seizure drug phenytoin. Treatment with phenytoin reduced both QTc and sustained ventricular tachycardia in Mecp2Null/Y mice. These results demonstrate that cardiac abnormalities in Rett syndrome are secondary to abnormal nervous system control, which leads to increased persistent sodium current. Our findings suggest that treatment in people with Rett syndrome would be more effective if it targeted the increased persistent sodium current in order to prevent lethal cardiac arrhythmias.
PMCID: PMC3633081  PMID: 22174313
Rett Syndrome; autonomic nervous system; arrhythmia; ventricular tachycardia; QT interval
24.  QT Interval Duration and Dispersion in Children and Adolescents Treated With Ziprasidone 
To assess the incidence of symptoms (palpitations, syncope) and electrocardiographic signs (increased QT duration and dispersion) of an increased risk of torsades de pointes in youth treated with ziprasidone.
Prospective, observational study of 29 youth (15.3±2.9 years) receiving ziprasidone (112.8±50.6 mg/day, range: 20–240mg/day) for 99.3±108.7 days. All patients had normal electrocardiograms (EKGs) and no serious medical illness at baseline. Patients had a mean of 2.7±1.3 (median=3, range: 1–7, total: 49) follow-up EKGs performed monthly for 3 months and every three months thereafter, with concurrent ziprasidone blood level measurements. Heart rate-corrected QT (QTc) duration and dispersion were measured manually in ≥6 EKG leads. QTc interval > 450msec or ≥60msec increase, and QTc dispersion >100msec were considered abnormal.
No patient reported syncope or symptomatic arrhythmias. Seven patients (24.1%) developed EKG abnormalities; 5 had peak QTc durations >450msec and 2 had peak QTc dispersion >100 msec. The baseline-to-peak QTc duration increased by 22.9±21msec (p<0.0001). The baseline-to-peak QTc dispersion increased by 6.1±31.4msec (p=0.30). The peak QTc duration and dispersion occurred after 47.6±45.2 and 60.4±72.1 treatment days, respectively. Baseline-to-peak QTc duration and dispersion changes were not correlated with ziprasidone dose (p=0.67) or plasma levels (p=0.37).
Ziprasidone was associated with a dose- and level-independent, significant prolongation of QTc duration in one quarter of youth. However, prolongation of QTc dispersion was non-significant, and no patient experienced concomitant abnormal prolongation of both QTc duration and QTc dispersion. The dissociation between prolonged QTc duration and dispersion suggests low arrhythmogenic potential in youth with normal baseline EKGs.
PMCID: PMC3319445  PMID: 21457682
Antipsychotic; Ziprasidone; cardiac; QTc; prolongation; dispersion; children; adolescents
25.  Incidence and Risk of QTc Interval Prolongation among Cancer Patients Treated with Vandetanib: A Systematic Review and Meta-analysis 
PLoS ONE  2012;7(2):e30353.
Vandetanib is a multikinase inhibitor that is under assessment for the treatment of various cancers. QTc interval prolongation is one of the major adverse effects of this drug, but the reported incidence varies substantially among clinical trials. We performed a systematic review and meta-analysis to obtain a better understanding in the risk of QTc interval prolongation among cancer patients administered vandetanib.
Methodology and Principal Findings
Eligible studies were phase II and III prospective clinical trials that involved cancer patients who were prescribed vandetanib 300 mg/d and that included data on QTc interval prolongation. The overall incidence and risk of QTc interval prolongation were calculated using random-effects or fixed-effects models, depending on the heterogeneity of the included studies. Nine trials with 2,188 patients were included for the meta-analysis. The overall incidence of all-grade and high-grade QTc interval prolongation was 16.4% (95% CI, 8.1–30.4%) and 3.7% (8.1–30.4%), respectively, among non-thyroid cancer patients, and 18.0% (10.7–28.6%) and 12.0% (4.5–28.0%), respectively, among thyroid cancer patients. Patients with thyroid cancer who had longer treatment duration also had a higher incidence of high-grade events, with a relative risk of 3.24 (1.57–6.71), than patients who had non-thyroid cancer. Vandetanib was associated with a significantly increased risk of all-grade QTc interval prolongation with overall Peto odds ratios of 7.26 (4.36–12.09) and 5.70 (3.09–10.53) among patients with non-thyroid cancer and thyroid cancer, respectively, compared to the controls.
Treatment with vandetanib is associated with a significant increase in the overall incidence and risk of QTc interval prolongation. Different cancer types and treatment durations may affect the risk of developing high-grade QTc interval prolongation.
PMCID: PMC3281826  PMID: 22363427

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