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QT Prolongation (qt + prolongation)
Selected AbstractsQT Prolongation With Migraine MedicationsHEADACHE, Issue 7 2003Randolph W. Evans MD No abstract is available for this article. [source] New-Onset QT Prolongation and Torsades De Pointes Accompanied by Left Ventricular Dysfunction Secondary to Acute PancreatitisPACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 8 2003PIROOZ S. MOFRAD A 70-year-old woman presented with acute pancreatitis and new-onset QT prolongation with subsequent torsades de pointes. Coronary catheterization was performed and was unremarkable. After persistent QT prolongation, despite temporary atrial pacing, a permanent dual chamber cardioverter defibrillator was implanted. In addition to the QT prolongation, significant depression in the left ventricular function was noted. Both resolved once the pancreatitis abated. (PACE 2003; 26:1765,1768) [source] Drug-Induced QT Prolongation: An UpdateANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 1 2006Arthur J. Moss M.D. No abstract is available for this article. [source] Inhibition of hERG Channel Trafficking: An Under-Explored Mechanism for Drug-Induced QT ProlongationCHEMMEDCHEM, Issue 2 2009Kap-Sun Yeung Dr. No abstract is available for this article. [source] Myocardial perfusion defects in Bartter and Gitelman syndromesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 12 2008R. Scognamiglio ABSTRACT Background, Normotensive hypokalaemic tubulopathies (Bartter and Gitelman syndromes (BS/GS)) are genetic diseases that are considered benign. However, QT prolongation, left ventricular dysfunction and reduction of cardiac index upon exercise leading to arrhythmias and sudden cardiac death have been reported in these patients. Hence, we aimed to verifying whether an isometric exercise could represent a useful tool for the identification of patients at risk for future cardiac events. Patients and methods, Myocardial function (MF) and perfusion, evaluated as myocardial blood flow (MBF) of 10 BS/GS patients and 10 healthy controls, were investigated at rest and during isometric exercise. MF and MBF were evaluated using quantitative two-dimensional and myocardial contrast echocardiography. Results, BS/GS patients had normal baseline MF and MBF. During exercise in BS/GS patients, corrected QT (QTc) was prolonged to peak value of 494 ± 9·1 ms (P < 0·001). In controls, MF increased from resting to peak exercise (left ventricular ejection fraction: 65 ± 4% to 78 ± 5%, P < 0·003) while in seven BS/GS patients (Group 1) it declined (64 ± 5% to 43 ± 9%, P < 0·001). Myocardial perfusion increased upon exercise in controls as shown by changes of its markers: , (a measure of myocardial flow velocity; 0·89 ± 0·12 vs. 0·99 ± 0·12, P < 0·001) and myocardial blood volume (14·4 ± 2 vs. 20·2 ± 0·25, P < 0·001), while in Group 1 BS/GS it decreased (0·87 ± 0·15 vs. 0·67 ± 0·15, P < 0·001; and 14·5 ± 1·9 vs. 8·3 ± 0·22, P < 0·001, respectively). Conclusions, Our results document for the first time that exercise induce coronary microvascular and myocardial defects in BS/GS patients. Therefore, this may challenge the idea that BS/GS are benign diseases. In addition, the diagnostic approach to these syndromes should include an in-depth cardiac assessment in order to identify patients at higher risk. [source] Cardiotoxicity with 5-fluorouracil and capecitabine: more than just vasospastic anginaINTERNAL MEDICINE JOURNAL, Issue 4 2010T. Stewart Abstract In this case series we present a variety of different cardiac toxicities with 5-fluorouracil and its pro-drug capecitabine, including myocardial infarction, cardiomyopathy, sinoatrial and atrioventricular node dysfunction, tako-tsubo cardiomyopathy and QT prolongation with torsade-de pointes ventricular tachycardia. We stress the fact that while vasospasm is a well-recognized side-effect of this class of chemotherapeutic agent, broader cardiotoxicity is commonly seen and an increased awareness of the range of toxicity is necessary if repeat toxicity is to be avoided. [source] Cardiac Calsequestrin: The New Kid on the Block in ArrhythmiasJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 10 2009NAGESH CHOPRA M.D. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited disease characterized by physical or emotional stress-induced ventricular arrhythmias in the absence of any structural heart disease or QT prolongation. Thus far, mutations in genes encoding the sarcoplasmic reticulum Ca2+ release channel (RYR2) and the sarcoplasmic reticulum Ca2+ binding protein cardiac calsequestrin (CASQ2) have been identified in CPVT patients. Here, we review the role of cardiac calsequestrin in health and disease, with a particular focus on how calsequestrin deficiency can cause arrhythmia susceptibility. Clinical implications and a promising new drug therapy for CPVT are discussed. [source] Comparative Pharmacology of Guinea Pig Cardiac Myocyte and Cloned hERG (IKr) ChannelJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 11 2004CHRISTINA DAVIE Ph.D. Introduction: This study used whole-cell, patch clamp techniques on isolated guinea pig ventricular myocytes and HEK293 cells expressing cloned human ether-a-go-go-related gene (hERG) to examine the action of drugs causing QT interval prolongation and torsades de pointes (TdP) in man. Similarities and important differences in drug actions on cardiac myocytes and cloned hERG IKr channels were established. Qualitative actions of the drugs on cardiac myocytes corresponded with results obtained from Purkinje fibers and measurement of QT interval prolongation in animal and human telemetry studies. Methods and Results: Adult guinea pig ventricular myocytes were isolated by enzymatic digestion. Cells were continuously perfused with Tyrode's solution at 33,35°C. Recordings were made using the whole-cell, patch clamp technique. Action potentials (APs) were elicited under current clamp. Voltage clamp was used to study the effect of drugs on IKr (rapidly activating delayed rectifier potassium current), INa (sodium current), and ICa (L-type calcium current). Dofetilide increased the myocyte action potential duration (APD) in a concentration-dependent manner, with a pIC50 of 7.3. Dofetilide 1 ,M elicited early afterdepolarizations (EADs) but had little affect on ICa or INa. E-4031 increased APD in a concentration-dependent manner, with a pIC50 of 7.2. In contrast, 10 ,M loratadine, desloratadine, and cetirizine had little effect on APD or IKr. Interestingly, cisapride displayed a biphasic effect on myocyte APD and inhibited ICa at 1 ,M. Even at this high concentration, cisapride did not elicit EADs. A number of AstraZeneca compounds were tested on cardiac myocytes, revealing a mixture of drug actions that were not observed in hERG currents in HEK293 cells. One compound, particularly AR-C0X, was a potent blocker of myocyte AP (pIC50 of 8.4). AR-C0X also elicited EADs in cardiac myocytes. The potencies of the same set of drugs on the cloned hERG channel also were assessed. The pIC50 values for dofetilide, E-4031, terfenadine, loratadine, desloratadine, and cetirizine were 6.8, 7.1, 7.3, 5.1, 5.2, and <4, respectively. Elevation of temperature from 22 to 35°C significantly enhanced the current kinetics and amplitudes of hERG currents and resulted in approximately fivefold increase in E-4031 potency. Conclusion: Our study demonstrates the advantages of cardiac myocytes over heterologously expressed hERG channels in predicting QT interval prolongation and TdP in man. The potencies of some drugs in cardiac myocytes were similar to hERG, but only myocytes were able to detect important changes in APD characteristics and display EADs predictive of arrhythmia development. We observed similar qualitative drug profiles in cardiac myocytes, dog Purkinje fibers, and animal and human telemetry studies. Therefore, isolated native cardiac myocytes are a better predictor of drug-induced QT prolongation and TdP than heterologously expressed hERG channels. Isolated cardiac myocytes, when used with high-throughput patch clamp instruments, may have an important role in screening potential cardiotoxic compounds in the early phase of drug discovery. This would significantly reduce the attrition rate of drugs entering preclinical and/or clinical development. The current kinetics and amplitudes of the cloned hERG channel were profoundly affected by temperature, significantly altering the potency of one drug (E-4031). This finding cautions against routine drug testing at room temperature compared to physiologic temperature when using the cloned hERG channel. [source] Heterogeneous Regional Endocardial Repolarization is Associated with Increased Risk for Ischemia-Dependent Ventricular Fibrillation after Myocardial InfarctionJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 8 2003Michael H. Swann M.SC. Introduction: The aim of this study was to investigate whether the characteristics of endocardial ventricular repolarization are associated with differential risk for sudden death. Prolonged surface QT interval is associated with increased arrhythmic risk after myocardial infarction (MI), but the underlying mechanism of QT prolongation and its relation to lethal arrhythmias are unclear. Methods and Results: Ventricular fibrillation (VF) risk was assessed in 12 dogs 1 month after anterior MI during an exercise test coupled with brief circumflex coronary occlusion. Susceptible dogs (n = 5) developed VF during the brief ischemic episode, whereas resistant dogs did not (n = 7). Surface QT interval was measured at rest. Endocardial electroanatomic catheter maps of left ventricular repolarization were obtained in four unique regions identified by echocardiography and compared between groups. Compared to resistant dogs, susceptible dogs were characterized by prolonged surface QT intervals (240 ± 10 msec vs 222 ± 7 msec, P = 0.04). In addition, they had lower baroreflex sensitivity (9.7 ± 1.5 msec/mmHg vs 28 ± 9.8 msec/mmHg, P < 0.01) and a tachycardic response to acute ischemia suggesting higher propensity for stronger sympathetic reflexes. Surface QT interval prolongation in susceptible dogs was due to a marked heterogeneity of endocardial left ventricular repolarization (239 ± 42 msec, basal anterior wall vs 197 ± 35, lateral wall; P < 0.001). Resistant animals had no regional differences in endocardial repolarization. Conclusion: Sympathetic activation following MI not only produces adverse structural remodeling but also contributes to adverse electrophysiologic remodeling resulting in heterogeneous ventricular repolarization and in a myocardial substrate conducive to lethal reentrant arrhythmias. (J Cardiovasc Electrophysiol, Vol. 14, pp. 873-879, August 2003) [source] Microvolt T Wave Alternans Inducibility in Normal Newborn Puppies: Effects of DevelopmentJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 6 2002Ph.D., SALIM F. IDRISS M.D. T Wave Alternans in Normal Newborn Puppies.Introduction: The cause of sudden infant death syndrome is unknown, but increased cardiac vulnerability due to repolarization instability may be a contributing factor. The QT interval normally is long at birth and increases further during the first few postnatal months. Although excessive QT intervals indicate increased cardiac vulnerability in the long QT syndrome, the impact of less pronounced QT prolongation during this developmental period is unclear. In adults and older children, the ease of inducing microvolt-level T wave alternans (TWA) is used as a measure of repolarization instability and arrhythmia vulnerability. The aim of this study was to determine if TWA is inducible in normal newborn puppies. Methods and Results: Atrial pacing was performed in 15 anesthetized beagle puppies 7 to 35 days old. The pacing drive cycle length was systematically decreased in 20-msec steps from baseline until AV conduction blocked. Pacing was performed for 8 minutes at each cycle length. Three-lead ECGs were recorded continuously during the last 5 minutes of pacing at each cycle length. The recordings were analyzed off-line for the presence of microvolt-level TWA using a sensitive spectral analysis technique. Microvolt-level TWA was present in all puppies. TWA was not present at baseline but developed and increased in amplitude as heart rate increased. The threshold heart rate for TWA did not correlate with age. However, due to age-dependent changes in baseline heart rate, the 7- to 14-day-old animals needed a 50% to 78% increase in heart rate to reach threshold heart rate, whereas the oldest animals needed only a 5% to 25% increase. Conclusion: These data suggest that developmentally dependent dynamic repolarization instability exists in puppies as manifest by the inducibility of TWA. [source] Inhibitory effect of erythromycin on potassium currents in rat ventricular myocytes in comparison with disopyramideJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2003Erika Hanada ABSTRACT Disopyramide, a class la antiarrhythmic agent, has been reported to induce torsades de pointes (TdP) associated with excessive QT prolongation in electrocardiogram (ECG), especially when concomitantly administered with erythromycin, a macrolide antibiotic agent. In this study, we have evaluated the effects of erythromycin on action potential duration (APD) and potassium currents in rat ventricular myocytes in comparison with disopyramide. We have evaluated the relationship between in-vitro potassium current inhibition and in-vivo QT prolongation observed in a previous study. Action potentials and membrane potassium currents, including delayed rectifier current (IK) and transient outward current (Ito), were recorded using a whole-cell patch clamp method in enzymatically-dissociated ventricular cells. Erythromycin and disopyramide prolonged APD in a concentration-dependent manner. Disopyramide (10,100 ,m) and erythromycin (100 ,m) led to increases in the APD at 90% repolarization level. Disopyramide reduced IK (IC50 = 37.2 + 0.17 ,m) and Ito (IC50 = 20.9 + 0.13 ,m) while erythromycin reduced IK (IC50 = 60.1 + 0.29 ,m) but not Ito. The observed prolongation of APD might be ascribed to the inhibition of potassium currents. Erythromycin produced the prolongation of APD and the inhibition of potassium currents with a lag time after addition of the drugs, which suggested that erythromycin might not reach potassium channels from outside the ventricular cells. The potency of disopyramide was almost equivalent under in-vitro and in-vivo conditions. However, potency of erythromycin in-vitro was far weaker than that in-vivo reported in a previous study, presumably due to a difference in the uptake of erythromycin into ventricular myocytes between in-vivo and in-vitro conditions. Therefore, when drug-induced risks of QT prolongation are to be evaluated, the difference of potencies between in-vitro and in-vivo should be taken into consideration. [source] The efficacy and safety of external biphasic defibrillation in toy breed dogsJOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE, Issue 4 2008Seung-Gon Lee DVM Abstract Objective: To evaluate the efficacy and safety of biphasic (BP) defibrillation in toy breed dogs (<5 kg of body weight). Design: Prospective, clinical experimental study. Setting: Veterinary teaching hospital. Animals: Five dogs (pilot study) and 10 dogs (comparison study of biphasic versus monophasic defibrillation). Measurements and main results: The efficacy of defibrillation was compared by estimating E80 (80% probability of successful defibrillation) after biphasic (BP) and monophasic (MP) defibrillations. The E80 for BP defibrillation was 7.24±1.33 J (2.24±0.41 J/kg) and 10.24±1.34 J (3.18±0.12 J/kg) for MP defibrillation. BP waveform required 30% less shock energy for a successful defibrillation. In order to compare the safety of defibrillation, we evaluated changes in cardiac biomarkers, electrocardiogram, echocardiographical left ventricular index, and aortic pressure during and after BP and MP defibrillation. All dogs treated by either BP or MP defibrillation survived. Pulseless electrical activity occurred in 2 of 5 dogs during MP defibrillation. The levels of cardiac biomarkers were elevated and sustained for longer periods in the MP defibrillation group. Electrocardiographic changes (e.g., QT prolongation, the time to return to an isoelectric ST segment after shocks) were more severe and longer in the MP defibrillation group. In addition, overall left ventricular cardiac performance was severely depressed in the MP group compared with the BP group. Conclusion: Our findings suggest that BP defibrillation is more effective and safer than MP defibrillation. We determined the acceptable shock energy to be 2,4 J/kg for toy breed dogs. [source] How Revealing Are Insertable Loop Recorders in Pediatrics?PACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 3 2008PATRICIA A. FRANGINI M.D. Introduction: An insertable loop recorder (ILR) in patients with infrequent syncope or palpitations may be useful to decide management strategies, including clinical observation, medical therapy, pacemaker, or implantable cardioverter defibrillator (ICD). We sought to determine the diagnostic utility of the Reveal® ILR (Medtronic, Inc., Minneapolis, MN, USA) in pediatric patients. Methods: Retrospective review of clinical data, indications, findings, and therapeutic decision in 27 consecutive patients who underwent ILR implantation from 1998,2007. Results: The median age was 14.8 years (2,25 years). Indications were syncope in 24 patients and recurrent palpitations in three. Overall, eight patients had structural heart disease (six congenital heart disease, one hypertrophic cardiomyopathy, one Kawasaki), five had previous documented ventricular arrhythmias with negative evaluation including electrophysiology study, and three patients had QT prolongation. Tilt testing was performed in 10 patients, of which five had neurocardiogenic syncope but recurrent episodes despite medical therapy. After median three months (1,20 months), 17 patients presented with symptoms and the ILR memory was analyzed in 16 (no episode stored in one due to full device memory), showing asystole or transient atrioventricular (AV) block (2), sinus bradycardia (6), or normal sinus rhythm (8). Among asymptomatic patients, 3/10 had intermittent AV block or long pauses, automatically detected and stored by the ILR. In 19 of 20 patients, ILR was diagnostic (95%) and five subsequently underwent pacemaker implantation, while seven patients remained asymptomatic without ILR events. Notably, no life-threatening events were detected. The ILR was explanted in 22 patients after a median of 22 months, two due to pocket infection, 12 for battery depletion and eight after clear documentation of nonmalignant arrhythmia. Conclusions: The ILR in pediatrics is a useful adjunct to other diagnostic studies. Patient selection is critical as the ILR should not be utilized for malignant arrhythmias. A diagnosis is attained in the majority of symptomatic patients, predominantly bradyarrhythmias including pauses and intermittent AV block. [source] New-Onset QT Prolongation and Torsades De Pointes Accompanied by Left Ventricular Dysfunction Secondary to Acute PancreatitisPACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 8 2003PIROOZ S. MOFRAD A 70-year-old woman presented with acute pancreatitis and new-onset QT prolongation with subsequent torsades de pointes. Coronary catheterization was performed and was unremarkable. After persistent QT prolongation, despite temporary atrial pacing, a permanent dual chamber cardioverter defibrillator was implanted. In addition to the QT prolongation, significant depression in the left ventricular function was noted. Both resolved once the pancreatitis abated. (PACE 2003; 26:1765,1768) [source] Steady-State versus Non-Steady-State QT-RR Relationships in 24-hour Holter RecordingsPACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 3 2000GILLES LANDE The aim of the present study was to investigate the QT-RR interval relationship in ambulatory ECG recordings with special emphasis on the physiological circumstances under which the QT-RR intervals follow a linear relation. Continuous ECG recordings make it possible to automatically measure QT duration in individual subjects under various physiological circumstances. However, identification of QT prolongation in Holter recordings is hampered by the rate dependence of QT duration. Comparison of QT duration and QT interval rate dependence between different individuals implies that the nature of the QT-RR relationship is defined in ambulatory ECG. Holter recordings were performed in healthy volunteers at baseline and after administration of dofetilide, a Class III antiarrhythmic drug. After dofetilide, beat-to-beat automated QT measurements on Holter tapes were compared with manually measured QT intervals on standard ECGs matched by time. The QT-RR relationship was analyzed at baseline in individual and group data during three different periods: 24-hour, daytime, and nighttime. Data were collected under steady-state or non-steady-state conditions of cycle length and fitted with various correction formulae. Our study demonstrated an excellent agreement between manually and automated measurements. The classic Bazett correction formula did not fit the QT-RR data points in individual or group data. When heart beats were selected for a steady rhythm during the preceding minute, QT-RR intervals fit a linear relationship during the day and night periods, but not during the 24-hour period in both individual and group data. In contrast, in the absence of beat selection, data fit a more complex curvilinear relationship irrespective of the period. Our study provides the basis for comparison of QT interval durations and QT-RR relationships between individuals and between groups of subjects. [source] The effects of droperidol and ondansetron on dispersion of myocardial repolarization in childrenPEDIATRIC ANESTHESIA, Issue 10 2010DISHA MEHTA BSc Summary Objectives:, To compare the effects of droperidol and ondansetron on electrocardiographic indices of myocardial repolarization in children. Aim:, To refine understanding of the torsadogenic risk to children exposed to anti-emetic prophylaxis in the perioperative period. Background:, QT interval prolongation is associated with torsades des pointes (TdP), but is a poor predictor of drug torsadogenicity. Susceptibility to TdP arises from increased transmural dispersion of repolarization (TDR) across the myocardial wall, rather than QT interval prolongation per se. TDR can be measured on the electrocardiogram as the time interval between the peak and end of the T wave (Tp-e). Tp-e may therefore provide a readily available, noninvasive assay of drug torsadogenicity. The perioperative period is one of high risk for TdP in children with or at risk of long QT syndromes. Droperidol and ondansetron are two drugs commonly administered perioperatively, for prophylaxis of nausea and vomiting, which can prolong the QT interval. This study investigated their effects on myocardial repolarization. Methods:, One hundred and eight ASA1-2 children undergoing elective day-case surgery were randomized to receive droperidol, ondansetron, both or neither. Pre- and post-administration 12-lead electrocardiogram (ECGs) were recorded. QT and Tp-e intervals were measured and compared within and between groups, for the primary endpoint of a 25 ms change in Tp-e. Results:, Eighty children completed the study. There were no demographic or baseline ECG differences between groups. QT intervals lengthened by 10,17 ms after allocated treatments, with no between-group differences. Values remained within normal limits for all groups. Tp-e intervals increased by 0,7 ms, with no between-group differences. There were no instances of dysrhythmia. Conclusions:, Droperidol and ondansetron, in therapeutic anti-emetic doses, produce equivalent, clinically insignificant QT prolongation and negligible Tp-e prolongation, suggesting that neither is torsadogenic in healthy children at these doses. [source] Assessment of Microvolt T-Wave Alternans in High-Risk Patients with the Congenital Long-QT SyndromeANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 4 2009Jörn Schmitt M.D. Background: Microvolt T-wave alternans (MTWA) has been used for arrhythmogenic risk stratification in cardiac disease conditions associated with increased risk of sudden cardiac death. Macroscopic T-wave alternans has been observed in patients with congenital long-QT syndrome (LQTS). The role of MTWA testing in patients with LQTS has not been established. Objective: To determine the diagnostic value of MTWA testing in high-risk patients with LQTS. Methods and results: We assessed MTWA in 10 consecutive LQTS index patients who survived cardiac arrest or had documented torsade de pointes tachycardia and 6 first-degree family members with congenital LQTS which had been genotyped in 13 of 16 subjects (7 index patients, 6 family members). No LQTS-causing mutation was identified in 3 index patients with overt QT prolongation. MTWA was assessed during standardized bicycle exercise testing using the spectral method and yielded negative (n = 8) or indeterminate (n = 2) results in index patients, respectively. Similarly, all first-degree family members tested MTWA negative except for one indeterminate result. Two genotype positive family members could not be tested (two children,4 and 9 years of age). Conclusion: In patients with congenital LQTS, free from structural heart disease and with a history of life-threatening cardiac arrhythmias, assessment of MTWA does not yield diagnostic value. Hence, determination of MTWA in lower risk LQTS patients without spontaneous arrhythmic events is likely not to be useful for arrhythmia risk stratification. [source] Automated QT Measurement and Application to Detection of Moxifloxacin-Induced ChangesANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 2009David W. Mortara Ph.D. Background: Concern for drug-induced QT prolongation has caused significant investment in QT measurement to safety-test new compounds. Manual methods are expensive and time-consuming. Reliable automatic methods would be highly desirable. Methods: Twelve-lead Holter recordings were annotated beat-to-beat by an automatic algorithm for global QRS onset and T offset. T offset was established from the time of peak T downslope plus a rate-dependent offset, analogous to the "tangent method," wherein T offset is determined by extrapolating the T downslope to an intersection with the baseline. Results and Conclusions: Variances of the beat-to-beat QT measurements were in the range 2.5,3.4 ms over three distinct databases, including a large heart failure database. Application to a moxifloxacin/placebo control database of 29 subjects showed excellent results. [source] Methodology of QT-Interval Measurement in the Modular ECG Analysis System (MEANS)ANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 2009Jan A. Kors Ph.D. Background: QT prolongation as can be induced by drugs, signals the risk of life-threatening arrhythmias. The methodology of QT measurement in the modular ECG analysis system (MEANS) is described. Methods: In the simultaneously recorded leads of the standard 12-lead electrocardiogram (ECG), the QRS complexes are detected by a spatial velocity function. They are typed as dominant or nondominant, and a representative complex per lead is obtained by averaging over the dominant complexes. QRS onset and T end are determined by a template technique, and QT is measured. MEANS performance was evaluated on the 125 ECGs of the common standards for quantitative electrocardiography (CSE) multilead database, of which the waveform boundaries have been released. Results: MEANS detected correctly all 1445 complexes of the CSE library, with one false-positive detection due to a sudden baseline jump. All dominant complexes were correctly typed. The average of the differences between MEANS and reference was less than 2 ms (=1 sample) for both QRS onset and T end, and 2.1 ms for QT duration. The standard deviation of the differences was 3.8, 8.4, and 10.4 ms, respectively. Conclusions: A standard deviation of 10.4 ms for QT measurement seems large when related to the regulatory requirement that a prolongation as small as 5 ms should be detected. However, QT variabilities as encountered in different individuals will be larger than when measured in one individual during pharmacological intervention. Finally, if the U wave is part of the total repolarization, then T and U form a continuum and the end of T becomes questionable. [source] Dofetilide-Induced Long QT and Torsades de PointesANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 3 2007Mehmet K. Aktas M.D. Dofetilide, a new class III antiarrhythmic agent, has been approved as an antiarrhythmic agent for the treatment of atrial fibrillation and atrial flutter. Dofetilide selectively inhibits the rapid component of the delayed rectifier potassium current resulting in a prolongation of the effective refractory period. Like other drugs that affect potassium currents, the prolonged QT interval occurring in the patients treated with dofetilide can be complicated by torsades de pointes. We report four cases of dofetilide-induced QT prolongation and torsades de pointes. We discuss the risk factors for the development of dofetilide-induced long QT and torsades de pointes and review the current literature. [source] Comparing Methods of Measurement for Detecting Drug-Induced Changes in the QT Interval: Implications for Thoroughly Conducted ECG StudiesANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 2 2004Nkechi E. Azie M.D. Background:,The aim of this study was to compare the reproducibility and sensitivity of four commonly used methods for QT interval assessment when applied to ECG data obtained after infusion of ibutilide. Methods:,Four methods were compared: (1) 12-lead simultaneous ECG (12-SIM), (2) lead II ECG (LEAD II), both measured on a digitizing board, (3) 3-LEAD ECG using a manual tangential method, and (4) a computer-based, proprietary algorithm, 12SLÔ ECG Analysis software (AUT). QT intervals were measured in 10 healthy volunteers at multiple time points during 24 hours at baseline and after single intravenous doses of ibutilide 0.25 and 0.5 mg. Changes in QT interval from baseline were calculated and compared across ECG methods, using Bland,Altman plots. Variability was studied using a mixed linear model. Results:,Baseline QT values differed between methods (range 376,395 ms), mainly based on the number of leads incorporated into the measurement, with LEAD II and 3-LEAD providing the shortest intervals. The 3-LEAD generated the largest QT change from baseline, whereas LEAD II and 12-SIM generated essentially identical result within narrow limits of agreement (0.4 ms mean difference, 95% confidence interval ± 20.5 ms). Variability with AUT (standard deviation 15.8 ms for within-subject values) was clearly larger than with 3-LEAD, LEAD II, and 12-SIM (9.6, 10.0, and 11.3 ms). Conclusion:,This study demonstrated significant differences among four commonly used methods for QT interval measurement after pharmacological prolongation of cardiac repolarization. Observed large differences in variability of measurements will have a substantial impact on the sample size required to detect QT prolongation in the range that is currently advised in regulatory guidance. [source] Electrophysiological Effects of the Anti-Cancer Drug Lapatinib on Cardiac RepolarizationBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 1 2010Hyang-Ae Lee Although lapatinib is associated with a risk of QT prolongation, the effects of the drug on cellular cardiac electrical properties and on action potential duration (APD) have not been studied. To evaluate the potential effects of lapatinib on cardiac repolarization, we investigated its electrophysiological effects using a whole-cell patch,clamp technique in transiently transfected HEK293 cells expressing human ether-à-go-go (hERG; to examine the rapidly activating delayed rectifier K+ current, IKr), KCNQ1/KCNE1 (to examine the slowly activating delayed rectifier K+ current, IKs), KCNJ2 (to examine the inwardly rectifying K+ current, IK1), or SCN5A (to examine the inward Na+ current, INa) and in rat cardiac myocytes (to examine the inward Ca2+ current, ICa). We also examined its effects on the APD at 90% (APD90) in isolated rabbit Purkinje fibres. In ion channel studies, lapatinib inhibited the hERG current in a concentration-dependent manner, with a half-maximum inhibition concentration (IC50) of 0.8 ± 0.09 ,m. In contrast, at concentrations up to 3 ,m, lapatinib did not significantly reduce the INa, IK1 or ICa amplitudes; at 3 ,m, it did slightly inhibit the IKs amplitude (by 19.4 ± 4.7%; p < 0.05). At 5 ,m, lapatinib induced prolongation of APD90 by 16.1% (p < 0.05). These results suggest that the APD90 -prolonging effect of lapatinib on rabbit Purkinje fibres is primarily a result of inhibition of the hERG current and IKs, but not INa, IK1 or ICa. [source] Case ascertainment and estimated incidence of drug-induced long-QT syndrome: study in Southwest FranceBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2008Mariam Molokhia WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Drug-induced long-QT syndrome (LQTS) is a potentially fatal condition that has led to a number of postmarketing withdrawals in recent years. , However, many cases may not survive long enough to reach hospital, and only a small proportion are reported to pharmacovigilance agencies. , The extent to which genetic determinants of susceptibility to LQTS are specific to particular drugs, or common to several classes of drug, remains to be determined. WHAT THIS STUDY ADDS , We estimated population prevalence of drug-induced LQTS in the Midi-Pyrenees region, southwest France, using five different institutions and assessed feasibility of tracing potential cases (in addition to pharmacovigilance data), using hospital data and rigorous case definition. , These methods can be adapted to a wider region, used to augment pharmacovigilance reporting, and offer researchers the opportunity to study genetic susceptibility to drug-induced LQTS. AIMS The aim of this study was to investigate the incidence and reporting rate of drug-induced long-QT syndrome (LQTS) in France [defined by evidence of torsades de pointes (TdP), QT prolongation and exposure to a relevant drug] and to assess feasibility of case collection for drug-induced LQTS. METHODS A retrospective population-based study was carried out in Southwest France in five institutions: three main hospitals, one private clinic and one cardiac emergency unit, searched from 1 January 1999 to 1 January 2005 (population coverage of 614 000). The study population consisted of 861 cases with International Classification of Diseases-10 diagnostic codes for ventricular tachycardia (I147.2), ventricular fibrillation (I149.0) and sudden cardiac death (I146.1) from hospital discharge summaries, supplemented by cases reported to national or regional pharmacovigilance systems, and voluntary reporting by physicians, validated according to internationally defined criteria for drug-induced LQTS. RESULTS Of 861 patients coded with arrhythmias or sudden cardiac death, there were 40 confirmed surviving acquired cases of drug-induced LQTS. We estimated that the incidence of those who survive to reach hospital drug-induced LQTS is approximately 10.9 per million annually in France (95% confidence interval 7.8, 14.8). CONCLUSIONS Many cases of drug-induced LQTS may not survive before they reach hospital, as the reporting rate for drug-induced LQTS identified through the cardiology records and also reported to pharmacovigilance systems for the Midi-Pyrenees area is 3/40 (7.5%). Using the methods outlined it is possible to assemble cases to study genetic susceptibility to drug-induced LQTS and adapt these methods more widely. [source] Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2008Ruth Dixon WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Drugs that inhibit the human cardiac delayed rectifier potassium current may lead to prolongation of the cardiac QT interval and are associated with a fatal, polymorphic, ventricular tachycardia known as torsades de pointes. , Lamotrigine is indicated in the treatment of epilepsy and the prevention of mood episodes in patients with bipolar disorder. , Lamotrigine inhibits the human cardiac delayed rectifier potassium current in vitro, and it has been hypothesized that QT prolongation may contribute to the risk of sudden unexpected death in epilepsy patients. WHAT THIS STUDY ADDS , This is the first reported thorough QT/QTc study with lamotrigine conducted to International Conference on Harmonization guidelines. , The mean QTc interval was not prolonged by lamotrigine in healthy subjects, as assessed by the standard heart rate correction methods (Fridericia's and Bazett's). , The in vitro inhibition of the delayed rectifier potassium current does not translate into an effect on QT in man. AIM To characterize the effects of lamotrigine on QT interval in healthy subjects. METHODS Healthy subjects received a single oral dose of moxifloxacin (400 mg) or placebo in crossover design, followed by a dose-escalating regimen of lamotrigine (n = 76) over a 77-day period, or matched placebo (n = 76). Blood samples were taken for determination of moxifloxacin and lamotrigine concentrations and digital 12-lead ECGs were recorded. The relationships between individual QT values and respective individual moxifloxacin or lamotrigine concentrations were explored using population pharmacokinetic,pharmacodynamic (PK,PD) modelling. RESULTS Moxifloxacin was associated with a maximum mean increase from baseline in QTcF of 14.81 ms [90% confidence interval (CI) 13.50, 16.11] 2.5 h after dosing. Steady-state exposure to lamotrigine (50, 150 or 200 mg b.d.) was not associated with an increase in QTc interval. Small reductions in QTcF (maximum mean difference from placebo ,7.48 ms, 90% CI ,10.49, ,4.46) and small increases in heart rate (maximum mean difference from placebo 5.94 bpm, 90% CI 3.81, 8.06) were observed with lamotrigine 200 mg b.d. vs. placebo. No effect of lamotrigine on QRS duration or blood pressure was observed. No outliers with QTcF > 450 ms, or with an increase from baseline of >60 ms were observed in the lamotrigine group. PK,PD modelling indicated statistically significant decreases in individually corrected QT intervals for lamotrigine and statistically significant increases in individually corrected QT intervals for moxifloxacin over the concentration ranges studied. CONCLUSIONS Therapeutic doses of lamotrigine (50,200 mg b.d.) were not associated with QT prolongation in healthy subjects. [source] Dexrazoxane protects the heart from acute doxorubicin-induced QT prolongation: a key role for IKsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2010J Ducroq Introduction:, Doxorubicin, an anthracycline widely used in the treatment of a broad range of tumours, causes acute QT prolongation. Dexrazoxane has been shown to prevent the QT prolongation induced by another anthracycline, epirubicin, but has not yet been reported to prevent that induced by doxorubicin. Thus, the present study was designed to test whether the acute QT effects induced by doxorubicin could be blocked by dexrazoxane and to explore the mechanism. Results were compared with those obtained with a reference human ether-a-go-go (hERG) channel blocker, moxifloxacin. Methods:, The effects of moxifloxacin (100 µM) and doxorubicin (30 µM), with or without dexrazoxane (from 3 to 30 µM), have been evaluated on the QTc interval in guinea-pig isolated hearts and on IKr (rapid component of the delayed rectifier current) and IKs (slow component of the delayed rectifier current) currents stably expressed in human embryonic kidney 293 cells. Results:, Moxifloxacin (100 µM), a potent hERG blocker, prolonged QTc by 22%, and this effect was not prevented by dexrazoxane. Doxorubicin (30 µM) also prolonged QTc by 13%, did not significantly block hERG channels and specifically inhibited IKs (IC50: 4.78 µM). Dexrazoxane significantly reduced the doxorubicin-induced QTc prolongation and prevented doxorubicin-induced inhibition of IKs. Conclusion and implications:, Doxorubicin acutely prolonged the QT interval in guinea-pig heart by selective IKs blockade. This effect was prevented by dexrazoxane. This result is important because it illustrates the danger of neglecting IKs in favour of hERG screening alone, for early preclinical testing for possible induction of torsade de pointes. This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010 [source] Potentiation of E-4031-induced torsade de pointes by HMR1556 or ATX-II is not predicted by action potential short-term variability or triangulationBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2007G Michael Background and purpose: Torsade de pointes (TdP) can be induced by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether IKs blockade or enhancement of INa could potentiate TdP induced by IKr blockade and to investigate whether short-term variability (STV) or triangulation of action potentials preceded TdP. Experimental approach: Experiments were performed in open-chest, pentobarbital-anaesthetized, ,1 -adrenoceptor-stimulated, male New Zealand White rabbits, which received three consecutive i.v. infusions of either the IKr blocker E-4031 (1, 3 and 10 nmol kg,1 min,1), the IKs blocker HMR1556 (25, 75 and 250 nmol kg,1 min,1) or E-4031 and HMR1556 combined. In a second study rabbits received either the same doses of E-4031, the INa enhancer, ATX-II (0.4, 1.2 and 4.0 nmol kg,1) or both of these drugs. ECGs and epicardial monophasic action potentials were recorded. Key results: HMR1556 alone did not cause TdP but increased E-4031-induced TdP from 25 to 80%. ATX-II alone caused TdP in 38% of rabbits, as did E-4031; 75% of rabbits receiving both drugs had TdP. QT intervals were prolonged by all drugs but the extent of QT prolongation was not related to the occurrence of TdP. No changes in STV were detected and triangulation was only increased after TdP occurred. Conclusions and implications: Giving modulators of ion channels in combination substantially increased TdP but, in this model, neither STV nor triangulation of action potentials could predict TdP. British Journal of Pharmacology (2007) 152, 1215,1227; doi:10.1038/sj.bjp.0707513; published online 29 October 2007 [source] Prediction of the risk of Torsade de Pointes using the model of isolated canine Purkinje fibresBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2005Pascal Champeroux 1Torsade de Pointes (TdP) is a well-described major risk associated with various kinds of drugs. However, prediction of this risk is still uncertain both in preclinical and clinical trials. We tested 45 reference compounds on the model of isolated canine Purkinje fibres. Of them, 22 are clearly associated and/or labelled with a risk of TdP, and 13 others are drugs with published clinical evidence of QT prolongation, with only one or two exceptional cases of TdP. The 10 remaining drugs are without reports of TdP and QT prolongation. 2The relevance of different indicators such as APD90 increase, reverse use dependency, action potential triangulation or effect on Vmax was evaluated by comparison with available clinical data. Finally, a complex algorithm called TDPscreenÔ and based on two subalgorithms corresponding to particular electrophysiological patterns was defined. 3This latter algorithm enabled a clear separation of drugs into three groups: (A) drugs with numerous or several reports (>2 cases) of TdP, (B) drugs causing QT prolongation and/or TdP only, the latter at a very low frequency (2 cases), (C) drugs without reports of TdP or QT prolongation. 4The use of such an algorithm combined with a database accrued from reference compounds with available clinical data is suggested as a basis for testing new candidate drugs in the early stages of development for proarrhythmic risk prediction. British Journal of Pharmacology (2005) 144, 376,385. doi:10.1038/sj.bjp.0706070 [source] The antihistamine fexofenadine does not affect IKr currents in a case report of drug-induced cardiac arrhythmiaBRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2002Constanze R Scherer The human HERG gene encodes the cardiac repolarizing K+ current IKr and is genetically inactivated in inherited long QT syndrome 2 (LQTS2). The antihistamine terfenadine blocks HERG channels, and can cause QT prolongation and torsades de pointes, whereas its carboxylate fexofenadine lacks HERG blocking activity. In the present study the ability of fexofenadine to block the K897T HERG channel variant was investigated. The underlying single nucleotide polymorphism (SNP) A2960C was identified in a patient reported to develop fexofenadine-associated LQTS. K897T HERG channels produced wild-type-like currents in Xenopus oocytes. Even at a concentration of 100 ,M, fexofenadine did not inhibit wild-type or K897T HERG channels. Coexpression of wild-type and K897T HERG with the ß-subunit MiRP1, slightly changed current kinetics but did not change sensitivity to terfenadine and fexofenadine. Western blot analysis and immunostaining of transiently transfected COS-7 cells demonstrated that overall expression level, glycosylation pattern and subcellular localization of K897T HERG is indistinguishable from wild-type HERG protein, and not altered in the presence of 1 ,M fexofenadine. We provide the first functional characterization of the K897T HERG variant. We demonstrated that K897T HERG is similar to wild-type HERG, and is insensitive to fexofenadine. Although the polymorphism changes PKA and PKC phosphorylation sites, regulation of K897T HERG by these kinases is not altered. Our results strongly indicate that QT lengthening and cardiac arrhythmia in the reported case of drug-induced LQT are not due to the K897T exchange or to an inhibitory effect of fexofenadine on cardiac IKr currents. British Journal of Pharmacology (2002) 137, 892,900. doi:10.1038/sj.bjp.0704873 [source] Phase 1 pharmacokinetic and drug-interaction study of dasatinib in patients with advanced solid tumorsCANCER, Issue 6 2010Faye M. Johnson MD Abstract BACKGROUND: The recently developed the Src and Abelson (Abl) kinase inhibitor dasatinib has antitumor effects in epithelial and mesenchymal tumors. Preclinical data have indicated that dasatinib is metabolized primarily through cytochrome P450 3A4 (CYP3A4) and may cause QT prolongation. In light of its improved tolerability, the authors were interested in the safety of a once-daily dasatinib regimen. METHODS: The authors conducted a phase 1 trial of dasatinib in 29 patients with advanced solid tumors. Segment 1 of the trial was short term and sequential and was designed to determine whether the coadministration of the potent CYP3A4 inhibitor ketoconazole had an effect on the pharmacokinetics of dasatinib. Segment 2 was designed to evaluate the safety of dasatinib as dosing was increased. QT intervals were monitored closely in both segments. Efficacy was assessed in Segment 2 using both positron emission tomography and computed tomography. RESULTS: Hematologic toxicities were markedly less than those observed in patients with leukemia, whereas nonhematologic toxicities were similar. The authors determined that the maximum recommended dose was 180 mg once daily based on the incidence of pleural effusion. Coadministration of ketoconazole led to a marked increase in dasatinib exposure, which was correlated with an increase in corrected QT (QTc) values of approximately 6 msec. No adverse cardiac events were observed. CONCLUSIONS: The dose-limiting toxic effect for dasatinib was pleural effusion. The pharmacokinetic and cardiac studies indicated that coadministration of dasatinib with potent CYP3A4 inhibitors or agents that prolong the QTc interval should be avoided if possible. Close monitoring for toxicity and dose reduction should be considered if the coadministration of such agents cannot be avoided. Cancer 2010. © 2010 American Cancer Society. [source] Domperidone versus cisapride in the treatment of infant regurgitation and increased acid gastro-oesophageal reflux: a pilot studyACTA PAEDIATRICA, Issue 4 2009Badriul Hegar Abstract Aim: Although domperidone is used frequently to treat infant regurgitation, efficacy data are scarce. Cisapride was previously used in the same indication. Methods: Domperidone and cisapride were compared in an investigator-blinded, prospective comparative trial by evaluating (a) the frequency of regurgitation, (b) acid reflux and (c) cardiac side effects in infants regurgitating >4 times/day since >2 weeks and with reflux-associated symptoms of discomfort, after conservative treatment failure. Results: Within the first treatment week, the frequency of regurgitation decreased in both groups, more rapidly in the cisapride group: the median regurgitation decreased from 6.22 to 3.50 in the cisapride group versus from 4.80 to 3.70 in the domperidone group. The decrease in regurgitation was still significant after 1 month: cisapride from 6.22 to 1.55 versus domperidone from 4.80 to 1.25. However, the natural decrease in the incidence of regurgitation induced by age should also be considered. The median reflux index decreased after 1 month in the cisapride group from 3.60 to 1.75 versus from 2.70 to 2.45 in the domperidone group. One child treated with cisapride developed a significant QT prolongation. Conclusion: The decrease in regurgitation was comparable in both groups, although acid reflux decreased more in the cisapride group. Cisapride induced QT prolongation in one infant. [source] | ||||||||||||||||||||||||||||