QT-prolonging Drugs Research Articles

Distribution of Eight QT-Prolonging Drugs and Their Main Metabolites Between Postmortem Cardiac Tissue and Blood Reveals Potential Pitfalls in Toxicological Interpretation.

Femoral blood concentrations are usually used in postmortem toxicology to assess possible toxic effects of drugs. This includes QT-prolongation and other cardiac dysrhythmia, which could have been the cause of death. However, blood concentration is only a surrogate for the active site concentration, and therefore cardiac tissue concentration may provide a more accurate toxicological interpretation. Thus, cardiac tissue and femoral and cardiac blood concentrations were examined for eight frequently used QT-prolonging drugs (QTD) and their metabolites in a mentally ill population. In total, 180 cases were included from the Danish autopsy-based forensic study SURVIVE. The concentrations were analyzed using ultra-performance liquid chromatography coupled with tandem mass spectrometry utilizing stable isotopically labeled internal standards. The results showed that the cardiac tissue concentrations were significantly higher compared to femoral and cardiac blood concentrations, with two exceptions. The median cardiac tissue-to-femoral blood concentration ratio (Kb) ranged from 2.2 (venlafaxine) to 15 (nortriptyline). The inter-individual fold difference between the minimum and maximum Kb ranged from 2.6-fold (Z-hydroxynortriptyline) to 61 (venlafaxine). For 12 compounds, postmortem redistribution appeared to be minimal, whereas four compounds displayed some degree of postmortem redistribution. Citalopram and quetiapine were selected for in-depth analysis of the relation between the toxicological interpretation and femoral blood/cardiac tissue concentrations. Within this dataset, citalopram displayed a wide overlap in cardiac tissue concentrations (~50%) between non-toxic and toxic citalopram cases, as estimated from femoral blood concentrations. In contrast, quetiapine displayed no overlap in cardiac tissue concentrations between non-toxic and toxic quetiapine cases based on femoral blood concentrations. The implication of the citalopram finding is that possible intoxications can be overlooked when only considering femoral blood concentrations. Based on the present findings, non-toxic cardiac tissue 10th-90th percentile concentration ranges were estimated for citalopram (0.93-4.4 mg/kg) and quetiapine (0.0073-0.60 mg/kg).

Towards Bridging Translational Gap in Cardiotoxicity Prediction: an Application of Progressive Cardiac Risk Assessment Strategy in TdP Risk Assessment of Moxifloxacin

Drug-induced cardiac arrhythmia, especially occurrence of torsade de pointes (TdP), has been a leading cause of attrition and post-approval re-labeling and withdrawal of many drugs. TdP is a multifactorial event, reflecting more than just drug-induced cardiac ion channel inhibition and QT interval prolongation. This presents a translational gap in extrapolating pre-clinical and clinical cardiac safety assessment to estimate TdP risk reliably, especially when the drug of interest is used in combination with other QT-prolonging drugs for treatment of diseases such as tuberculosis. A multi-scale mechanistic modeling framework consisting of physiologically based pharmacokinetics (PBPK) simulations of clinically relevant drug exposures combined with Quantitative Systems Toxicology (QST) models of cardiac electro-physiology could bridge this gap. We illustrate this PBPK-QST approach in cardiac risk assessment as exemplified by moxifloxacin, an anti-tuberculosis drug with abundant clinical cardiac safety data. PBPK simulations of moxifloxacin concentrations (systemic circulation and estimated in heart tissue) were linked with in vitro measurements of cardiac ion channel inhibition to predict the magnitude of QT prolongation in healthy individuals. Predictions closely reproduced the clinically observed QT interval prolongation, but no arrhythmia was observed, even at ×10 exposure. However, the same exposure levels in presence of physiological risk factors, e.g., hypokalemia and tachycardia, led to arrhythmic event in simulations, consistent with reported moxifloxacin-related TdP events. Application of a progressive PBPK-QST cardiac risk assessment paradigm starting in early development could guide drug development decisions and later define a clinical “safe space” for post-approval risk management to identify high-risk clinical scenarios.

Sex Differences in Cardiac Arrhythmias: Clinical and Research Implications.

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

MHRA: quinine QT-prolonging effects and drug interactions

MHRA: quinine QT-prolonging effects and drug interactions

Approach to initiating QT-prolonging oncology drugs in the ambulatory setting.

Since the introduction of regulatory drug approval guidance on the evaluation of QT interval prolongation, an increasing number of drug monographs has included cautions on the risk of QT prolongation. For example, QT prolongation is mentioned in the Canadian product monographs of 29 drugs commonly seen in oncology practice. This presents two major challenges. First, most guidelines and risk predictive tools for QT prolongation have been developed for hospitalized patients in acute care settings. In contrast, most QT-prolonging oncology drugs are used in medically stable patients in the ambulatory setting. Second, many oncology drugs are unique for their indications and non-QT prolonging alternative agents are often not available. In this review, we will outline an empiric initial approach to ambulatory cancer patients who are treated with oncology drugs which may prolong QT interval. This includes the predictive value of QT prolongation on torsades de pointes, the risk factors of the patients and the drugs, and the limitations of existing guidance in this area.

Risk factors for QTc interval prolongation.

Prolongation of the QTc interval may result in Torsade de Pointes, a ventricular arrhythmia. Numerous risk factors for QTc interval prolongation have been described, including the use of certain drugs. In clinical practice, there is much debate about the management of the risks involved. In this study, we quantified the effect of these risk factors on the length of the QTc interval. We analyzed all ECGs that were taken during routine practice between January 2013 and October 2016 in the Spaarne Gasthuis, a general teaching hospital in the Netherlands. We collected laboratory values in the week before the ECG recording and the drugs prescribed. For the identification of risk factors, we used multilevel linear regression analysis to correct for multiple ECG recordings per patient. We included 133,359 ECGs in our study, taken in 40,037 patients. Patients using one QT-prolonging drug had a 11.08ms (95% CI 10.63-11.52; p< 0.001) longer QTc interval. Patients using two QT-prolonging drugs had a 3.04ms (95% CI 2.06-4.02; p < 0.001) increase in the QTc interval compared to patients using one QT-prolonging drug. Women had a longer QTc interval compared to men (16.30ms 95% CI 14.59-18.01; p < 0.001). The QTc interval increased with increasing age, but the difference between men and women diminished. Other independent risk factors that significantly prolonged the QTc interval with at least 10ms were hypokalemia, hypocalcemia, and the use of loop diuretics. We identified and quantified various risk factors for QTc interval prolongation.

Prevalence and Outcome of High-Risk QT Prolongation Recorded in the Emergency Department from an Institution-Wide QT Alert System

BackgroundQT prolongation is an independent risk factor for sudden death, stroke, and all-cause mortality. However, additional studies have shown that in certain settings, QT prolongation may be transient and a result of external factors. ObjectiveIn this study, we evaluated the clinical characteristics and outcomes of patients seen in the emergency department (ED) with QT prolongation. MethodsBetween November 2010 and June 2011, 7522 patients had an electrocardiogram (ECG) obtained during their evaluation in the ED. Clinical, laboratory, and therapeutic information was collected for all patients with QT prolongation (i.e., ≥ 500 ms and QRS < 120 ms). Potential QT-inciting factors (drugs, electrolyte disturbances, and comorbidities) were synthesized into a pro-QT score. ResultsAmong the 7522 patients with an ECG obtained in the ED, a QT alert was activated in 93 (1.2%; mean QTc 521 ± 34 ms). The majority of ED patients (64%) had more than one underlying condition associated with QT prolongation, with electrolyte disturbances in 51%, a QT prolonging condition in 56%, and QT-prolonging drugs in 77%. Thirty-day mortality was 13% for patients with QT prolongation noted in the ED. ConclusionsOne percent of patients evaluated with an ECG in the ED activated our prolonged QTc warning system, with most demonstrating > 1 QT-prolonging condition. Thirty-day mortality was significant, but it requires further investigation to determine whether the QTc simply provided a non-invasive indicator of increased risk or heralded the presence of a vulnerable host at risk of a QT-mediated sudden dysrhythmic death.

Outpatient Co-prescription of Ondansetron With Other QT-Prolonging Drugs in a Large Community-Based Health System: A Warning Ignored

Introduction: Ondansetron is a 5HT-3 serotonin receptor antagonist that is commonly used to treat nausea and vomiting. The FDA has warned of QT-prolonging effects of ondansetron, especially when combined with other QT-prolonging drugs, or in patients with known cardiac disease. Electronic medical records with warning systems for drug-drug interactions have been promoted for patient safety. We present a review of de-identified data from a large community-based health system to determine how providers responded to electronic warnings when prescribing ondansetron combined with other QT-prolonging drugs. Methods: All prescriptions for ondansetron in combination with QT-prolonging drugs at NorthShore University HealthSystem between January and March 2016 were included in the initial database as part of a quality improvement project. Inpatient orders and IV ondansetron orders were removed. The name and class of co-prescribed QT-prolonging drugs, warning severity, response to the warning by prescribing practitioner (over-ride warning and prescribe, or cancel order), reason for the warning over-ride, patient age and gender were evaluated. Results: There were a total of 9203 episodes of co-prescription of ondansetron and another QT-prolonging drug in 2739 adult patients during the study time period. After filtering, there were 770 outpatient co-prescriptions in 500 patients. Mean patient age was 46.2 years (range 18 to 90 years). Orders were for 592 females (76.8%) and 178 males (33.2%). All warnings were considered “major interactions”. Most orders, 651 (84.5%) prescriptions were administered, while only 119 (15.5%) orders were canceled. The most common classes of co-prescribed QT-prolonging drugs were macrolide antibiotics (40.0%), flouroquinolone antibiotics (17.0%), SARI antidepressants (13.4%), and SSRI antidepressants (9.9%), (Table 1). There were nine (1.4%) cases of co-prescriptions with antiarrhythmic drugs (amioderone and flecainide). The most commonly co-prescribed QT-prolonging medications were azithromycin, levofloxacin, and trazadone (Table 2). Reasons for warning overrides were “benefit outweighs risk” in 266 (40.8%) and “not clinically significant” in 116 cases (17.7%).Table: Table. Classes of Drugs Co-Prescribed with OndansentronTable: Table. List of Drugs Co-Prescribed with OndansetronConclusion: After viewing warnings, practitioners still prescribed ondansetron with other QT-prolonging drugs 85% of the time. This form of co-prescription with ondansetron neglects FDA recommendations and could put patients at risk for cardiac arrhythmias.

Clinical significance of QT-prolonging drug use in patients with MDR-TB or NTM disease.

Many drugs with potential QT prolongation effects (QT drugs) have already been used for decades in patients with multidrug-resistant TB (MDR-TB) or non-tuberculous mycobacterial (NTM) disease, but without a common consensus. To investigate the effects of QT drugs on cardiac events in patients with MDR-TB or NTM disease. We retrospectively reviewed 373 patients (mean age: 56.4 years) with MDR-TB or NTM disease treated for >1 month with clofazimine (CFZ), moxifloxacin (MFX), bedaquiline (BDQ), delamanid (DLM) or macrolides (clarithromycin or azithromycin). Adverse cardiac events, death and QTcF changes were evaluated. Forty-four per cent had MDR-TB; 165 (44%), 315 (85%), 10 (3%), 229 (61%) and 1 patient received CFZ, MFX, BDQ, macrolides and DLM, respectively. Except for three patients (0.8%) lost to follow-up with unknown cause of death, 3 (0.8%, 95%CI 0.2-2.4) adverse cardiac events were documented: atrial fibrillation, cardiac tamponade due to TB pericarditis and cardiac arrest, which was determined to not have been caused by QT drugs. Clinically significant QTcF changes (QTcF > 500 msec or an increase > 60 msec) were observed in 10/60 patients (17%, 95%CI 8.0-30.7) without clinical events. The use of QT drugs, alone or in combination, in the treatment of MDR-TB or NTM disease is relatively safe.

Combinations of QTc-prolonging drugs: towards disentangling pharmacokinetic and pharmacodynamic effects in their potentially additive nature.

Background:Whether arrhythmia risks will increase if drugs with electrocardiographic (ECG) QT-prolonging properties are combined is generally supposed but not well studied. Based on available evidence, the Arizona Center for Education and Research on Therapeutics (AZCERT) classification defines the risk of QT prolongation for exposure to single drugs. We aimed to investigate how combining AZCERT drug categories impacts QT duration and how relative drug exposure affects the extent of pharmacodynamic drug–drug interactions.Methods:In a cohort of 2558 psychiatric inpatients and outpatients, we modeled whether AZCERT class and number of coprescribed QT-prolonging drugs correlates with observed rate-corrected QT duration (QTc) while also considering age, sex, inpatient status, and other QTc-prolonging risk factors. We concurrently considered administered drug doses and pharmacokinetic interactions modulating drug clearance to calculate individual weights of relative exposure with AZCERT drugs. Because QTc duration is concentration-dependent, we estimated individual drug exposure with these drugs and included this information as weights in weighted regression analyses.Results:Drugs attributing a ‘known’ risk for clinical consequences were associated with the largest QTc prolongations. However, the presence of at least two versus one QTc-prolonging drug yielded nonsignificant prolongations [exposure-weighted parameter estimates with 95% confidence intervals for ‘known’ risk drugs + 0.93 ms (–8.88;10.75)]. Estimates for the ‘conditional’ risk class increased upon refinement with relative drug exposure and co-administration of a ‘known’ risk drug as a further risk factor.Conclusions:These observations indicate that indiscriminate combinations of QTc-prolonging drugs do not necessarily result in additive QTc prolongation and suggest that QT prolongation caused by drug combinations strongly depends on the nature of the combination partners and individual drug exposure. Concurrently, it stresses the value of the AZCERT classification also for the risk prediction of combination therapies with QT-prolonging drugs.

A review of ECG and QT interval measurement use in a public psychiatric inpatient setting.

There is an increased rate of sudden cardiac death (SCD) in mental health patients. Some antipsychotic medications are known to prolong the QT interval, thus increasing a patient's risk of SCD via the arrhythmia, torsades de pointes (TdP). Our aim was to evaluate assessment for QT prolongation within a public inpatient mental health facility by auditing electrocardiograph (ECG) use. We reviewed records of all mental health inpatient admissions to a public emergency mental health inpatient unit between 1 January 2016 and 11 February 2016. ECG availability was noted and QT interval was manually measured and assessed for risk of TdP using the QT nomogram when present. Demographic information and medication use was collected. Of 263 mental health inpatient admissions, 50 (19%) presentations had an ECG. A total of four (8%) had a prolonged QT interval. Of the 50 patients with an ECG, 12 (24%) were taking medication known to prolong the QT interval. There was very limited risk assessment for QT prolongation in a public hospital psychiatric inpatient unit, with less than 20% of patients having an ECG performed. Our study supports an association between QT-prolonging drugs and a clinically significant prolonged QT interval; however, a larger study with routine ECG screening is required.

QT interval prolongation in hospitalized patients on cardiology wards: a prospective observational study.

Prolonged QT interval may lead to a lethal form of arrhythmia, torsades de pointes (TdP), which is associated with cardiovascular mortality. Therefore, we aimed to identify prevalence of QT interval prolongation, compare clinical characteristics of patients with normal and prolonged QT interval, and identify predictors of QT interval prolongation. A prospective observational study was conducted in cardiology wards of two teaching hospitals in Pakistan. Bazett's correction formula was used for the calculation of QTc interval. Prevalence of QT prolongation and pro-QTc scores were calculated. Comparative analysis was performed with respect to various clinical characteristics by applying t test and chi-square test. Odds ratios were calculated using regression analysis. Among 417 patients, 44.6% were found having prolonged QT interval, of which, 17.3% presented with an abnormally high QTc interval (> 500ms). Significant difference was recorded between the groups (normal vs. prolonged) with respect to age, all prescribed medications, QT drugs, number of risk factors, QT-DDIs (QT-prolonging drug-drug interactions), gender, and diuretics use. Multivariate logistic regression analysis showed significant results for various predictors such as male gender (p=0.03), various age categories 41-50years (p=0.04), 51-60years (p=0.01), and > 60years (p<0.001), and diuretics (p=0.008). A substantial number of patients in cardiology wards presented with QT prolongation. Proper considerations are needed in order to minimize the associated risk particularly in patients with abnormally high QT prolongation, old age, polypharmacy, one or more QT-prolonging drugs, and high pro-QTc scores.

Abstract 56: Individual Susceptibility to Drug-induced QTc Prolongation Did Not Correlate With Subject-specific Induced Pluripotent Stem Cells in a Small Sample of Healthy Subjects

Background: Induced pluripotent stem cells (iPSCs) carry patient-specific genetic information and have the potential to become an important tool for predicting individual clinical response to therapies in an in vitro assay. Here, we investigate if subject-specific iPSC cardiomyocytes (iPSC-CMs) derived from healthy volunteers could be used to predict individual response to 2 QT-prolonging drugs which they received in a clinical trial. Methods and Results: Independent stem cell manufacturer (Stem Cell Theranostics) used commercially available Sendai virus encoding for Oct4 , Sox2 , Klf4 , and c-Myc to reprogram subject’s peripheral blood mononuclear cells (PBMCs) into iPSCs. They then applied chemically defined growth factors, and serum-free protocols to successfully differentiate iPSCs into iPSC-CMs for 17 out of 20 subjects (one batch per subject) enrolled in a randomized, double-blind, placebo-controlled, cross-over trial of dofetilide and moxifloxacin. Effects of the same 2 drugs on cellular action potential duration (APD) were recorded for 16 iPSC-CMs lines using a high-throughput optical imaging system (CellOPTIQ, Clyde Biosciences) using consistent in vitro protocols, including reproducible drug doses and exposure, cell culture and recording conditions. Both dofetilide (0.5-8 nM) and moxifloxacin (10-200 μM) induced dose-dependent prolongation of rate-corrected action potential duration (APD) in each iPSC-CM line. iPSC-CM drug responses were compared with individual clinical response represented by the slope of the linear regression fit through baseline and placebo-controlled drug-induced changes in QTc interval vs. plasma drug concentration. We found no statistical significant correlation between subject-specific iPSC-CMs drug-induced APD prolongation and individual QTc prolongation to either moxifloxacin [Spearman’s ρ = 0.191] or dofetilide [Spearman’s ρ = 0.068]. Conclusion: This study failed to find correlation between clinical and stem cell drug responses in a small sample of healthy subjects. More experiments with a larger sample size and iPSC-CMs batch-to-batch variability controls are required to further investigate the potential of patient-derived stem cells to predict individual clinical response.

Prevalence and Risk Factors of Drug-Associated Corrected QT Prolongation in Elderly Hospitalized Patients: Results of a Retrospective Analysis of Data Obtained Over 6Months.

Little information exists on the frequency and determinants of drug-associated long QT syndrome in older adults. The objectives of this study were to assess the prevalence and identify risk factors of drug-associated long QT syndrome in a population of elderly hospitalized patients. This was a retrospective study performed over 6months in hospital geriatric medicine. Various QT-correction equations were fitted to the individual QT-RR data to evaluate the most appropriate equation. Long QT syndrome was defined as corrected QT ≥450ms. Available data were compared in patients with and without long QT syndrome. Logistic regression and classification and regression tree analysis were performed to identify determinants of long QT syndrome. Thirty-three of 152 patients (22%) exhibited corrected QT ≥450ms. The different QT correction equations provided similar results, except the Bazett equation. In patients with long QT syndrome, there was a higher proportion of male subjects (58 vs. 33%, p=0.009) and a higher number of QT-prolonging drugs than in patients without long QT syndrome. Male sex (odds ratio, 3.25) and the number of prescribed QT-prolonging agents (odds ratio, 1.77) were significantly associated with the probability of long QT syndrome. The number of QT-prolonging drugs had a stronger influence on the risk of long QT syndrome in men than in women. Male sex was found to be a significant risk factor of corrected QT prolongation in elderly hospitalized patients. The risk also increased with the number of QT-prolonging agents, especially in men. Those findings may help to mitigate the risk of long QT syndrome in elderly patients in clinical practice.

Overexpression of KCNJ2 in induced pluripotent stem cell-derived cardiomyocytes for the assessment of QT-prolonging drugs

Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes hold great potentials to predict pro-arrhythmic risks in preclinical cardiac safety screening, although the hiPSC cardiomyocytes exhibit rather immature functional and structural characteristics, including spontaneous activity. Our physiological characterization and mathematical simulation showed that low expression of the inward-rectifier potassium (IK1) channel is a determinant of spontaneous activity. To understand impact of the low IK1 expression on the pharmacological properties, we tested if transduction of hiPSC-derived cardiomyocytes with KCNJ2, which encodes the IK1 channel, alters pharmacological response to cardiac repolarization processes. The transduction of KCNJ2 resulted in quiescent hiPSC-derived cardiomyocytes, which need pacing to elicit action potentials. Significant prolongation of paced action potential duration in KCNJ2-transduced hiPSC-derived cardiomyocytes was stably measured at 0.1 μM E-4031, although the same concentration of E-4031 ablated firing of non-treated hiPSC-derived cardiomyocytes. These results in single cells were confirmed by mathematical simulations. Using the hiPSC-derived cardiac sheets with KCNJ2-transduction, we also investigated effects of a range of drugs on field potential duration recorded at 1 Hz. The KCNJ2 overexpression in hiPSC-derived cardiomyocytes may contribute to evaluate a part of QT-prolonging drugs at toxicological concentrations with high accuracy.

Application of optical action potentials in human induced pluripotent stem cells-derived cardiomyocytes to predict drug-induced cardiac arrhythmias

IntroductionHuman induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are emerging as new and human-relevant source in vitro model for cardiac safety assessment that allow us to investigate a set of 20 reference drugs for predicting cardiac arrhythmogenic liability using optical action potential (oAP) assay. MethodsHere, we describe our examination of the oAP measurement using a voltage sensitive dye (Di-4-ANEPPS) to predict adverse compound effects using hiPS-CMs and 20 cardioactive reference compounds. Fluorescence signals were digitized at 10kHz and the records subsequently analyzed off-line. Cells were exposed to 30min incubation to vehicle or compound (n=5/dose, 4 doses/compound) that were blinded to the investigating laboratory. Action potential parameters were measured, including rise time (Trise) of the optical action potential duration (oAPD). ResultsSignificant effects on oAPD were sensitively detected with 11 QT-prolonging drugs, while oAPD shortening was observed with ICa-antagonists, IKr-activator or ATP-sensitive K+ channel (KATP)-opener. Additionally, the assay detected varied effects induced by 6 different sodium channel blockers. The detection threshold for these drug effects was at or below the published values of free effective therapeutic plasma levels or effective concentrations by other studies. DiscussionThe results of this blinded study indicate that OAP is a sensitive method to accurately detect drug-induced effects (i.e., duration/QT-prolongation, shortening, beat rate, and incidence of early after depolarizations) in hiPS-CMs; therefore, this technique will potentially be useful in predicting drug-induced arrhythmogenic liabilities in early de-risking within the drug discovery phase.

Common Genetic Variant Risk Score Is Associated With Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study.

Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known. We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, crossover trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine, and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject's drug-induced increase in heart rate-corrected QT (QTc) versus drug concentration. The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide (r=0.55; 95% confidence interval, 0.09-0.81; P=0.02), 23% in response to quinidine (r=0.48; 95% confidence interval, -0.03 to 0.79; P=0.06), and 27% in response to ranolazine (r=0.52; 95% confidence interval, 0.05-0.80; P=0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared with 771 controls (r2=12%, P=1×10-7). We demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to improve individualized risk-benefit assessment for pharmacological therapies. Replication of these findings in larger samples is needed to more precisely estimate variance explained and to establish the individual variants that drive these effects. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01873950.

Sudden Cardiac Death: Pharmacotherapy and Proarrhythmic Drugs: A Nationwide Cohort Study in Denmark.

This study sought to describe the use of pharmacotherapy in a nationwide cohort of young patients withsudden cardiac death (SCD). Several drugs have been associated with an increased risk of SCD and sudden arrhythmic death syndrome (SADS). It remains unclear how pharmacotherapy may contribute to the overall burden of SCD in the generalpopulation. This was a nationwide study that included all deaths that occurred between 2000 and 2009 and between 2007 and 2009 in people age 1 to 35 years and 36 to 49 years, respectively. Two physicians identified all SCDs throughreview of death certificates. Autopsy reports were collected. Pharmacotherapy prescribed within 90 days before SCD was identified in the Danish Registry of Medicinal Product Statistics. We identified 1,363 SCDs; median age was 38 years (interquartile range: 29 to 45 years), and 72% (n= 975) were men. Autopsy was performed in 55%. Overall, 58% of SCD cases (n= 786) received at least 1 drug within 90 days before death. The most common drugs were analgesic drugs (n= 239; 18%), antihypertensive drugs (n= 234; 17%), andantibiotic drugs (n= 218; 16%). After multivariable adjustment, prescription of "brugadogenic" drugs or >1 QT-prolonging drug was associated with an increased risk of SADS compared with explained SCD (odds ratio: 2.16 [95%confidence interval: 1.12 to 4.17] and 2.91 [95% confidence interval: 1.46 to 5.81], respectively). Pharmacotherapy was identified in 58% of the SCD cases. After multivariable adjustment, there wasa2- and 3-fold increased risk of SADS compared with explained SCD in patients receiving brugadogenic drugs or>1QT-prolonging drug, respectively. Identification of high-risk patients is warranted to lower the burden of SCD.

Arsenic trioxide-induced QT interval prolongation: A case report

QT prolongation refers to the prolonged QT interval in electrocardiography (ECG) which can even lead to life-threatening events such as ventricular arrhythmias, torsades de pointes, etc., several drugs can cause QT prolongation which includes sotalol, quinidine, arsenic, disopyramide, procainamide, amiodarone, haloperidol, etc., Arsenic trioxide (ATO) is used as an effective treatment option in promyelocytic leukemia (PML). Acute myeloid leukemia (AML) is a cancer that affects the blood and bone marrow. Acute promyelocytic leukemia (APL) is the M3 subtype of AML that affects mainly the white blood cells. In APL, immature granulocytes accumulate abnormally to form promyelocytes. ATO helps in the apoptosis of these cancerous promyelocytic cells. In patients on arsenic therapy, ECGs must be monitored to ensure QT prolongation as it a major side effect of the drug. Here is the case of a 58-year-old female patient and was newly diagnosed with APL. She developed QT prolongation with arsenic therapy. Other confounding factors such as electrolytes and presence of other QT-prolonging drugs were also corrected.

Characteristics of electromechanical window in anesthetized rabbit models of short QT and long QT syndromes.

The current regulatory guidelines recommend the use of QT interval to assess the risk of arrhythmogenic potential of new chemical entities. Recently, the electromechanical window (EMW), the difference in duration between electrical and mechanical systole, has been proposed as markers for drug-induced torsades de pointes (TdP); however, data of EMW in short QT model are not available. This study aimed to characterize the EMW as a marker for drug-induced ventricular arrhythmias in anesthetized rabbit model of long QT syndrome type 2 (LQT2) and short QT syndrome (SQTS) infused with reference compounds known to lengthen or shorten QT intervals. After rabbits were anesthetized with isoflurane, body surface electrocardiograms and left ventricular pressure were recorded. The LQT2 was produced by intravenous infusion with dofetilide (n = 6), quinidine (n = 6) and sotalol (n = 6) whereas the SQTS was induced by intravenous escalating concentrations of nicorandil (n = 7), pinacidil (n = 5) and cromakalim (n = 5). The EMW in anesthetized rabbits ranged from 1.3 to 53.3 msec. All three drugs known to lengthen QT intervals prolonged QT and QTcF interval while the EMW was markedly decreased to negative values. Pinacidil significantly produced QT and QTcF shortening and significantly abbreviated the EMW (p < 0.05). This study demonstrated that the EMW is associated with QT intervals (p < 0.001). It is negative in the presence of QT-prolonging drugs while it is more positive in the presence of QT-shortening drugs. The results suggest that the EMW in anesthetized rabbits can be used in drug safety evaluation in addition to the QT interval.