Significant QT Research Articles

Maternal methadone may cause arrhythmias in neonates

Methadone treatment is a well recognised cause of QT interval lengthening in adults. In this case report, we present for the first time, clinically significant QT interval lengthening in a neonate secondary to maternal methadone treatment. Neonatal paediatricians should be aware of this important and potentially serious clinical phenomenon. Bradycardia, tachycardia or an irregular heart rate in an infant born to a mother on methadone treatment should not be ignored and a 12-lead electrocardiogram should be performed. Furthermore, there is also a need for a prospective study of QTc intervals in infants born to mothers receiving methadone.

QT hysteresis in long-QT syndrome children with exercise testing

Congenital long QT syndrome (LQTS) is an inherited ion channel disorder resulting in abnormal cardiac repolarization that can cause syncope and sudden death associated with a prolonged rate-corrected QT interval and polymorphic ventricular tachycardia. Several studies in adults showed that LQTS patients have altered QT adaptation to heart rate changes compared with normal subjects which forming a "hysteresis loop" in the QT-circle length plot. This study was to observe the QT interval changing during exercise testing in children long QT syndrome (LQTS) patients, explore the new diagnosis methods of LQTS. The subjects were divided into 3 groups according to 1993 LQTS diagnostic criteria. Group 1: LQTS group (n = 17) who scored > or = 4 points indicating definite LQTS. Group 2: Middle group (n = 16), patients who have prolonged QT interval but scored 1.5 to 3.5. Group 3: Normal control group (n = 18). The average age of all study population is (12.3 +/- 5.8) years. No case had beta-adrenergic antagonists administration before exercise testing. All subjects were underwent tread mill exercise testing and electrocardiograph in whole exercise testing and recovery were recorded. QT and heart rate changing during whole exercise testing period were recorded. DeltaQT, the QT interval at 1, 2, 4, 6 minutes into recovery subtract from the QT interval at a similar heart rate during exercise, were calculated. In all three groups, QT intervals were shortening with the increasing of heart rate, but QTc had no significant change. DeltaQT at 1 minute ((45 +/- 11) ms), 2 minutes ((37 +/- 15) ms), 4 minutes ((23 +/- 12) ms) into recovery in LQTS group were significantly greater than that of the other two groups (P < 0.05, P < 0.01, P < 0.01, respectively). There was no DeltaQT significant difference between middle group and normal control group at recovery time. During the recovery phase in LQTS group, the QT interval remained shortened despite a decelerating heart rate, forming a hysteresis "loop" in the curve relating the QT interval to the cycle length. In children LQTS patients, there is significant QT hysteresis loop in the relation of QT interval with heart rate during recovery of exercise testing, which could be useful to the early diagnosis for LQTS.

Modulation of Ventricular Repolarization in Patients with Transient Left Ventricular Apical Ballooning: A Case Control Study

Even though diffuse T wave inversion and prolongation of the QT interval in the surface electrocardiogram (ECG) have been consistently reported in patients with transient stress-induced left ventricular apical ballooning (AB), ventricular repolarization has not yet been systematically investigated in this clinical entity. AB, an emerging syndrome that mimics acute ST-segment elevation myocardial infarction (MI), is characterized by reversible left ventricular wall motion abnormalities in the absence of obstructive coronary heart disease and significant QT interval prolongation. We prospectively enrolled 22 consecutive patients (21 women, median age 65 years) with transient left ventricular AB. A total of 22 age-, gender-, body-mass-index-, and left-ventricular-function-matched patients with acute anterior ST-segment elevation MI undergoing successful direct percutaneous coronary intervention for a proximal occlusion of the LAD, as well as 22 healthy volunteers served as control groups. Beat-to-beat QT interval and QT interval dynamicity were determined from 24-hour Holter ECGs, recorded on the third day after hospital admission. There were no significant differences in baseline clinical characteristics, except higher peak enzyme release in MI patients. Compared with MI patients, AB patients exhibited significantly prolonged mean QT intervals and rate-corrected QT intervals (QT: 418 +/- 37 vs 384 +/- 33 msec, P < 0.01; QTcBazett: 446 +/- 40 vs 424 +/- 35 msec, P < 0.05; QTcFridericia: 437 +/- 35 vs 412 +/- 31 msec, P < 0.05). Mean RR intervals tended to be higher in AB patients, without reaching statistical significance (877 +/- 96 vs 831 +/- 102 msec, P = NS). The linear regression slope of QT intervals plotted against RR intervals was significantly flatter in AB patients at both day- and nighttime (QT/RR slopeday: 0.18 +/- 0.04 vs 0.22 +/- 0.06, P < 0.01; QT/RR slopenight: 0.12 +/- 0.03 vs 0.17 +/- 0.05, P < 0.01). The present study is the first to demonstrate significant differences of QT interval modulation in patients with transient left ventricular AB and acute ST-segment elevation MI. Even though transient AB is associated with a significant QT interval prolongation, rate adaptation of ventricular repolarization (i.e., QT dynamicity) is not significantly altered, suggesting a differential effect of autonomic nervous activity on the ventricular myocardium in transient AB and in acute MI.

Bradycardia‐Mediated Ventricular Electrical Remodeling

Bradycardic states are associated with myocardial electrical remodeling predisposing to potentially lethal ventricular tachydysrhythmias. We used a novel model of complete heart block (CHB) in the rabbit to test the hypothesis that ventricular activation rate is the primary determinant of early bradycardic electrical remodeling. Chronic endocardial right ventricular demand (VVI) pacing was applied at either the near-physiologic rate of 280 beats/min or at the bradycardic rate of 140 beats/min, beginning immediately after transcatheter radiofrequency AV node ablation. A third group of animals underwent sham ablation and served as non-paced, normal sinus rhythm controls. The major finding of this study was that electrical remodeling was established within 8 days of CHB induction in the bradycardic animals, but was not observed in either of the other 2 groups. Bradycardic animals had significant QT interval prolongation and biventricular downregulation of the delayed rectifier K+ currents, IKr and IKs. The Ca2+-independent transient outward K+ current, I(to), and the inwardly rectifying K+ current, I(K1), were unaffected. This paper highlights these findings in the context of a literature-based review of heart rate-dependent remodeling of the mammalian myocardium, summarizing the current state of knowledge and describing future challenges.

The Impact of Posture on Cardiac Repolarization: More Than Heart Rate?

The effect of standing on heart rate and QT is well known but its impact on QTc is less clear. Serial supine and standing 12-lead ECGs (seven pairs each day) were recorded from 54 healthy volunteers each day of a three-day period. ECGs were captured digitally and over-read by a cardiologist. A statistically significant shortening of RR (216 ms), QT (40 ms), and decreases in QTc-F (Fridericia) and QTc-LR (Framingham) were demonstrated on standing (8.3 and 6.9 ms, respectively). In contrast, QTc-B (Bazett's) significantly increased by 9.6 ms. Two subject-individualized correction methods were derived using each subject's supine measurements. Both showed significant decreases in QTc of approximately 13-14 ms upon standing. Using the bin analysis method, comparisons between positions using 25 ms interval RR bins revealed significant QT shortening of up to 15 ms upon standing. We have demonstrated a postural effect on cardiac repolarization independent of heart rate using two individualized correction methods, as well as QTc-F and QTc-LR, and the bin method. Characterization of postural differences in QT/QTc (other than QTc-B) may provide a safe and inexpensive physiological control to validate the ECG methodology used in clinical trials to assess potential drug-induced QT interval changes.

Gender and Age Effects on Ventricular Repolarization Abnormality in Japanese General Carriers of a G643S Common Single Nucleotide Polymorphism for the KCNQ1 Gene

The KCNQ1 single nucleotide polymorphism (SNP), G643S, is known to be associated with secondary long QT syndrome (LQTS) and to cause a mild reduction in KCNQ1 current. However, the precise incidence and its association with QT intervals remain unknown in the greater cohort of the population in Japan. The genotype was screened at codon 643 of KCNQ1 in 992 residents of a farming community. Eighty-eight individuals (female/male =52/36, 8.9%) were found to have a heterozygous G643S SNP. Matching both gender and age, we randomly selected 243 control (G643G) cases and compared the electrocardiogram parameters in both groups; QT, QTf (QT corrected by Fridericia's formula) intervals, the peak and the end of the T wave (Tpe) interval, and the Tpe/QT ratio. The latter 2 reflect the transmural dispersion of ventricular repolarization (TDR). In G643S carriers, both Tpe and Tpe/QT were significantly longer than in non-carriers, without significant QT prolongation. Both genders showed a tendency for an increase in QTf with aging. In females, both Tpe and Tpe/QT showed a similar significant increase with age, which was not observed in males. In elderly females, G643S might be an independent risk factor for secondary LQTS by causing a greater TDR.

Comparative Evaluation of HERG Currents and QT Intervals following Challenge with Suspected Torsadogenic and Nontorsadogenic Drugs

The purpose of the present study was to comparatively evaluate human HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic drugs. Various concentrations of 14 different drugs were initially evaluated in terms of their relative potency to block I(HERG) in stably transfected human embryonic kidney cells. Four general categories of drugs were identified: high-potency blockers (IC50 < 0.1 microM) included lidoflazine, terfenadine, and haloperidol; moderate-potency blockers (0.1 microM < IC50 < 1 microM) included sertindole, thioridazine, and prenylamine; low-potency blockers (IC50 > 1 microM) included propafenone, loratadine, pyrilamine, lovastatin, and chlorpheniramine; and ineffective blockers (IC50 > 300 microM) included cimetidine, pentamidine, and arsenic trioxide. All measurements were performed using similar conditions and tested acute drug effects only (<30 min of drug exposure per measurement). Since two of the drugs that were ineffective I(HERG) blockers, arsenic trioxide and pentamidine, have been associated with cardiac repolarization delays (QT interval lengthening) and torsades de pointes ventricular arrhythmias in patients, we chose to evaluate them further using the isolated perfused rabbit heart model. Neither arsenic trioxide nor pentamidine had any significant effect on QT intervals in this model, even at relatively high (micromolar) concentrations. Similar results were obtained for loratadine in this model. When the hearts were challenged with a known torsadogenic drug such as cisapride, significant QT lengthening was rapidly induced. These results demonstrate that arsenic trioxide and pentamidine are essentially devoid of direct acute effects on cardiac repolarization or inhibition of I(HERG).

Acquired QT Prolongation Associated with Esophagitis and Acute Weight Loss:How to Evaluate a Prolonged QT Interval

When the physician is confronted with a patient having significant QT prolongation, it is critical to determine whether the patient harbors a genetic defect and a transmissible form of long QT syndrome (LQTS) or whether the QT prolongation has an acquired cause. The distinction has profound ramifications for the type of care provided to the patient and family. We report the case of a previously healthy 14-year-old boy who presented with a 10-day history of painful swallowing, a 10-lb weight loss, and chest pain. A 12-lead electrocardiogram (ECG) showed marked QT prolongation. Endoscopy and culture identified a Herpes simplex esophageal ulcer. After treatment with acyclovir, the patient recovered completely. Three weeks after the resolution of his symptoms and recovery from his acute weight loss, a follow-up ECG showed complete normalization of the QT interval. This case illustrates yet another potential mechanism for acquired QT prolongation. We also provide a diagnostic algorithm for the careful evaluation of a prolonged QT interval.

Atypical Proarrhythmia with Dofetilide: Monomorphic VT and Exercise‐Induced Torsade de Pointes

Proarrhythmia with dofetilide has most typically taken the form of torsade de pointes (TdP) and generally occurs early with therapy, such that in-hospital initiation of dofetilide with 3 days of continuous electrocardiogram monitoring is recommended. This article reports two unusual variants of ventricular proarrhythmia with dofetilide: (1) nonsustained runs of monomorphic ventricular tachycardia shortly after taking the first dose of dofetilide, confirmed by rechallenge; and (2) TdP that followed the development of isolated ventricular premature beats during an exercise test in a patient with neither excessive QT prolongation on dofetilide nor any ectopy whatsoever during in-hospital telemetric monitoring but with significant QT interval prolongation after the postectopic pause. These cases demonstrate that clinicians must be alert to the appearance of proarrhythmia with dofetilide at times other than early during drug initiation if the electrophysiological milieu is altered during nonhospital activity and/or of a pattern other than TdP.

Cholestatic liver disease modulates susceptibility to ischemia/reperfusion-induced arrhythmia, but not necrosis and hemodynamic instability: The role of endogenous opioid peptides

Acute cholestasis is associated with cardiovascular complications, which mainly manifest during stressful conditions. The goal of this study is to evaluate susceptibility of 7-day bile duct-ligated rats to ischemia/reperfusion-induced injury. Sham-operated and cholestatic rats, treated with daily normal saline, L-NAME (a non-selective NO synthase inhibitor) naltrexone, or both L-NAME and naltrexone were subjected to 30 min of ischemia followed by 2 h of reperfusion. Cholestatic rats demonstrated significant bradycardia, hypotension (P < 0.01), and QT prolongation (P < 0.001). The incidence of premature ventricular contractions (P < 0.01), incidence and duration of ventricular tachycardia (P < 0.05), but not ventricular fibrillation, were significantly lower in cholestatic rats. There was no significant difference in hemodynamic instability and infarct size between the groups. L-NAME corrected QT prolongation in cholestatic rats (P < 0.05), with no effect on heart rate, blood pressure and arrhythmia. Naltrexone restored normal heart rate (P < 0.05), blood pressure (P < 0.05) and susceptibility to arrhythmia (P < 0.05) in cholestatic animals, with no significant effect on QT interval. L-NAME and naltrexone co-administration corrected bradycardia (P < 0.05), hypotension (P < 0.05), QT prolongation (P < 0.05) and abolished resistance of cholestatic rats against arrhythmia (P < 0.05). This study suggests that short-term cholestasis is associated with resistance against ischemia/reperfusion-induced arrhythmia, which depends on availability of endogenous opioids.

Assessment of the effect of a single oral dose of telithromycin on sotalol‐induced qt interval prolongation in healthy women

Telithromycin belongs to ketolides, a new class of macrolide antibiotics. Macrolides are known to have the potential to prolong QT interval duration. Previous studies have shown that telithromycin did not induce significant QT interval prolongation in healthy subjects compared with placebo. The main objective of this study was to demonstrate the absence of amplification of QT interval prolongation induced by sotalol, when telithromycin and sotalol were co-administered. The secondary objective was to correlate the QT interval changes induced by the study drugs to plasma concentrations during the elimination phase. Twenty-four women received sotalol (160 mg) together with placebo or telithromycin (800 mg) in a two-period, double-blind, randomized study. Electrocardiograms were recorded at rest. Comparison of maximal corrected QT interval (QTc(max)) with sotalol in the presence or absence of telithromycin was performed. The relation between sotalol concentration and QTc was studied using linear regression. Mean difference (95% CI) between QTc(max) with sotalol-placebo and QTc(max) with sotalol-telithromycin was -15.5 ms (-27.7 to -3.2 ms). QTc(max) interval prolongation was lower (P < 0.05) with sotalol-telithromycin than with sotalol-placebo, in relation to decreased sotalol plasma concentrations. Regression analysis showed that the relationship between sotalol plasma concentration and QTc interval duration was not modified by telithromycin co-administration. Our results do not support a potential synergistic effect on QT interval prolongation between sotalol and telithromycin. The decrease of mean QTc interval in subjects taking telithromycin and sotalol may be explained by a decrease of sotalol concentration.

Brugada‐like ECG abnormalities during thioridazine overdose

A previously healthy 58-year-old woman was comatose when admitted to our emergency department. Physical evaluation showed muscular rigidity, opisthotonus, external-rotation of upper limbs in response to painful stimulation and neck stiffness. Arterial blood pressure (120/80 mmHg) and temperature (36.5 °C) were unremarkable. The ECG showed sinus rhythm with significant QT lengthening (Figure 1A). A CT scan of the brain and evaluation of spinal fluid were normal. The patient was intubated and mechanically ventilated. Figure 1 (A) Sinus rhythm with significant QT lengthening; (B) Brugada-like pattern; (C) Normal ECG A few hours after admission, we learnt that the patient's husband was being treated with haloperidol and risperidone. The ECG recorded the day after evolved into a Brugada-like pattern (Figure 1B). Over the next 72 h, both the ECG and the clinical abnormalities resolved (Figure 1C), and she was extubated on day 3. She denied deliberate ingestion of psychoactive drugs. Later we learned that the patient's husband was also receiving thioridazine. Thioridazine, measured by HPLC-UV and FL, in a blood sample drawn from the patient on day 4 was 1.48 µg ml−1 (therapeutic levels for our laboratory are up to 2 µg dl−1). No haloperidol or risperidone was detectable in the same sample. In the literature there are several reports of Brugada-like ECG abnormalities during tryciclic antidepressant intoxication [1, 2], but such abnormalities have not been reported during neuroleptic overdose.

Effect of simvastatin on left ventricular mass in hypercholesterolemic rabbits.

Epidemiological studies showed that hypercholesterolemia is associated with higher left ventricular mass. Endothelin signaling is activated in hyperlipidemic animals and may contribute to progressive ventricular hypertrophy. Simvastatin has been shown to inhibit endothelin-1. However, the behavior of simvastatin on ventricular hypertrophy in hyperlipidemic animals is not well understood. In this study, we evaluated the hemodynamic, biochemical, and morphological responses to simvastatin in cholesterol-fed (1%) rabbits. The left ventricular weight increased 8 wk after cholesterol feeding compared with that in normocholesterolemic rabbits. Simvastatin at a clinical therapeutic dose (1.2 mg x kg(-1) x day(-1)) significantly decreased left ventricular weight by 14% and left ventricular myocyte sizes by 14% as isolated by enzymatic dissociation. Hypercholesterolemia upregulated ventricular preproendothelin-1 mRNA as assessed by real-time quantitative RT-PCR and elevated production of cardiac endothelin-1 concentration. The increased endothelin-1 responses can be inhibited after simvastatin administration. Left ventricular mass indexed by body weight positively correlated with tissue endothelin-1 levels (P = 0.0003). In Langendorff-perfused rabbit hearts, hyperlipidemia led to significant QT prolongation compared with normocholesterolemia, which can be reversed by administering simvastatin. In contrast, simvastatin-induced beneficial effects were reversed by the addition of mevalonate. The addition of bosentan, a nonspecific endothelin receptor blocker, improved the response in hypercholesterolemic rabbits and did not have additional beneficial effects in simvastatin-treated rabbits. The results of the present study suggest that the antihypertropic and electrocardiographic effects of simvastatin at a clinical therapeutic dose are mediated through inhibition of tissue endothelin-1 expression, which is linked to mevalonate metabolism, and result in an amelioration of cardiomyocyte hypertrophy development by an atherogenic diet.

Evaluation of six-lead electrocardiograms obtained from dogs in a sitting position or sternal recumbency

To compare 6-lead ECG traces in clinically normal conscious dogs in a sitting position and sternal recumbency to that of right lateral recumbency. 31 healthy dogs with no history of cardiac disease. Six-lead ECGs were recorded for dogs in right lateral recumbency, a sitting position, and sternal recumbency. Q-, R-, and S-wave amplitudes as well as QRS-complex duration were measured in all leads. Additionally, P-wave amplitude and duration, PR interval, ST-segment elevation or depression, and OT interval were measured in lead II. Compared with measurements in right lateral recumbency, the sitting position resulted in increased Q-wave amplitude (lead III), increased R-wave amplitude (leads I and aVL), decreased R-wave amplitude (leads III and aVF), increased S-wave amplitude (lead aVR), decreased S-wave amplitude (lead aVL), increased P-wave amplitude (lead II), and a leftward shift in the mean electrical axis. Compared with measurements in right lateral recumbency, sternal recumbency resulted in decreased Q-wave amplitude (leads I, II, and aVF), increased R-wave amplitude (leads 11, III, and aVF), decreased R-wave amplitude (lead aVR), increased S-wave amplitude (lead aVR), increased P-wave amplitude (lead II), and decreased ST-segment depression (lead II). Compared with right lateral recumbency, the sitting position or sternal recumbency did not result in significant differences in PR interval, QT interval, or QRS-complex duration. Significant changes are found in ECG measurements in the sitting position and sternal recumbency, compared with right lateral recumbency. In dogs, many ECG reference range values for right lateral recumbency are not valid for ECGs obtained in the sitting position or sternal recumbency.

QT interval prolongation related to psychoactive drug treatment: a comparison of monotherapy versus polytherapy

BackgroundSeveral antipsychotic agents are known to prolong the QT interval in a dose dependent manner. Corrected QT interval (QTc) exceeding a threshold value of 450 ms may be associated with an increased risk of life threatening arrhythmias. Antipsychotic agents are often given in combination with other psychotropic drugs, such as antidepressants, that may also contribute to QT prolongation. This observational study compares the effects observed on QT interval between antipsychotic monotherapy and psychoactive polytherapy, which included an additional antidepressant or lithium treatment.MethodWe examined two groups of hospitalized women with Schizophrenia, Bipolar Disorder and Schizoaffective Disorder in a naturalistic setting. Group 1 was composed of nineteen hospitalized women treated with antipsychotic monotherapy (either haloperidol, olanzapine, risperidone or clozapine) and Group 2 was composed of nineteen hospitalized women treated with an antipsychotic (either haloperidol, olanzapine, risperidone or quetiapine) with an additional antidepressant (citalopram, escitalopram, sertraline, paroxetine, fluvoxamine, mirtazapine, venlafaxine or clomipramine) or lithium. An Electrocardiogram (ECG) was carried out before the beginning of the treatment for both groups and at a second time after four days of therapy at full dosage, when blood was also drawn for determination of serum levels of the antipsychotic.Statistical analysis included repeated measures ANOVA, Fisher Exact Test and Indipendent T Test.ResultsMean QTc intervals significantly increased in Group 2 (24 ± 21 ms) however this was not the case in Group 1 (-1 ± 30 ms) (Repeated measures ANOVA p < 0,01). Furthermore we found a significant difference in the number of patients who exceeded the threshold of borderline QTc interval value (450 ms) between the two groups, with seven patients in Group 2 (38%) compared to one patient in Group 1 (7%) (Fisher Exact Text, p < 0,05).ConclusionsNo significant prolongation of the QT interval was found following monotherapy with an antipsychotic agent, while combination of these drugs with antidepressants caused a significant QT prolongation. Careful monitoring of the QT interval is suggested in patients taking a combined treatment of antipsychotic and antidepressant agents.

Short QT syndrome: pharmacological treatment

ObjectivesThe purpose of this study was to evaluate the efficacy of various antiarrhythmic drugs at prolonging the QT interval into the normal range and preventing ventricular arrhythmias in patients with short QT syndrome. BackgroundShort QT syndrome is a recently described genetic disease characterized by short QT interval, high risk of sudden death, atrial fibrillation, and short refractory periods. MethodsSix patients with short QT syndrome, five of whom had received an implantable cardioverter-defibrillator (ICD) and one child, were tested with different antiarrhythmic drugs, including flecainide, sotalol, ibutilide, and hydroquinidine, to determine whether they could prolong the QT interval into the normal range and thus prevent symptoms and arrhythmia recurrences. ResultsClass IC and III antiarrhythmic drugs did not produce a significant QT interval prolongation. Only hydroquinidine administration caused a QT prolongation, which increased from 263 ± 12 ms to 362 ± 25 ms (calculated QT from 290 ± 13 ms to 405 ± 26 ms). Ventricular programmed stimulation showed prolongation of ventricular effective refractory period to ≥200 ms, and ventricular fibrillation was no longer induced. ConclusionsThe ability of quinidine to prolong the QT interval has the potential to be an effective therapy for short QT patients. This is particularly important because these patients are at risk of sudden death from birth, and ICD implant is not feasible in very young children.

Antiarrhythmic and proarrhythmic properties of QT-prolonging antianginal drugs.

In recent years there has been a major reorientation of drug therapy for cardiac arrhythmias, its changing role, and above all, a radical change in the class of arrhythmia drugs because of their impact on mortality. The decline in the use of sodium-channel blockers has led to an ex panding use of beta-blockers and simple or complex class III agents for controlling cardiac arrhythmias. Success with these agents in the context of their side effects has spurred the development of compounds with simpler ion-channel blocking properties that have less complex adverse reactions. The resulting so-called pure class III agents, such as dofetilide or ibutilide, were found to have antifibrillatory effects in atrial fibrillation and flutter and in ventricular tachyarrhythmias. Such agents are effective and have diversity, but they have come into therapeutics with a price: the sometimes-fatal torsades de pointes. The drug amiodarone, a complex compound that was synthesized as an antianginal agent, has been an exception in this regard. Its therapeutic use is associated with a negligibly low incidence of torsades de pointes, even though the drug produces significant bradycardia and QT lengthening to 500 to 700 msec. Recent electrophysiologic studies suggest that this paradox is likely due to the differential block of ion channels in endocardium, epicardium, midmyocardial (M) cells, and Purkinje fibers in the ventricular myocardium. There is also clinical evidence suggesting that amiodarone reduces the "torsadogenic" effects of pure class III agents. Ranolazine was also synthesized for the development of antianginal properties that stem from a partial inhibition of fatty acid oxidation; it too has been found to have electrophysioloigic properties. These are somewhat similar to those of amiodarone on ion channels in endocardium, epicardium, M cells, and Purkinje fibers in the ventricular myocardium, but the drug does not prolong the QT interval to the same extent as amiodarone does. Thus, the drug produces modest increases in repolarization as judged by its effects on the action potential duration (APD) without the potential for the development of torsades de pointes. By virtue of its suppressant action on early afterdepolarizations and triggered activity in Purkinje fibers and M cells, the drug appears to have a powerful potential for reducing the torsadogenic proclivity of conventional class III antiarrhythmic compounds. The rationale for the therapeutic niche for amiodarone, and especially in the case of ranolazine, in the prevention of drug-induced torsades de pointes is discussed.

Syncope in children and adolescents and the congenital long QT syndrome

From a population-based epidemiologic cohort of children and adolescents who sought medical attention for syncope (n = 151), screening 12-lead electrocardiograms were obtained from 118 patients (79 female) to determine the frequency of significant QT prolongation. The distribution of heart rate corrected QT intervals (QTc) was compared with age- and sex-matched controls. Only one patient had QTc >470 ms.

Effect of epicardial or biventricular pacing to prolong QT interval and increase transmural dispersion of repolarization

Background— The present study examined pacing site–dependent changes in QT interval and transmural dispersion of repolarization (TDR) and their potential role in the development of torsade de pointes (TdP). Methods and Results— In humans, the QT interval, JT interval, and TDR were measured in 29 patients with heart failure during right ventricular endocardial pacing (RVEndoP), biventricular pacing (BiVP), and left ventricular epicardial pacing (LVEpiP). In animal experiments, pacing site–dependent changes in ventricular repolarization were examined with a rabbit left ventricular wedge preparation in which action potentials from endocardium and epicardium could be simultaneously recorded with a transmural ECG. In humans, LVEpiP and BiVP led to significant QT and JT prolongation. LVEpiP also enhanced TDR. Frequent R-on-T extrasystoles generated by BiVP and LVEpiP but completely inhibited by RVEndoP occurred in 4 patients, of whom 1 developed multiple episodes of nonsustained polymorphic ventricular tachycar...

A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs

Many antipsychotic drugs produce QT interval prolongation on the electrocardiogram (ECG). Blockade of the human cardiac K + channel known as human ether- a- go- go-related gene (HERG) often underlies such clinical findings. In fact, HERG channel inhibition is now commonly used as a screen to predict the ability of a drug to prolong QT interval. However, the exact relationship between HERG channel blockade, target receptor binding affinity and clinical QT prolongation is not known. Using patch-clamp electrophysiology, we examined a series of seven antipsychotic drugs for their ability to block HERG, and determined their IC 50 values. We then compared these results to their binding affinities ( K i values) for the dopamine D 2 receptor, the 5-HT 2A receptor and, where available, to clinical QT prolongation data. We found that sertindole, pimozide and thioridazine displayed little (<10-fold) or no selectivity for dopamine D 2 or 5-HT 2A receptors relative to their HERG channel affinities. This lack of selectivity likely underlies the significant QT interval prolongation observed with administration of these drugs. Of the other drugs tested (ziprasidone, quetiapine, risperidone and olanzapine), olanzapine displayed the greatest selectivity for dopamine D 2 and 5-HT 2A receptor binding (100–1000-fold) compared to its HERG channel IC 50. We also compared these HERG channel IC 50 values to QT interval prolongation and plasma drug levels obtained in a recent clinical study. We found that the ratio of total plasma drug concentration to HERG IC 50 value was indicative of the degree of QT prolongation observed. Target receptor affinity and expected clinical plasma levels are important parameters to consider for the interpretation of HERG channel data.