Yee Guan Yap

Drug induced QT prolongation and torsades de pointes

In 1966, Francois Dessertenne described a specific electrocardiographic form of polymorphic ventricular tachycardia, which he termed “torsades de pointes” (TdP).w1 w2 The word “torsades” refers to an ornamental motif imitating twisted hairs or threads as seen on classical architectural columns, and “pointes” referred to points or peaks.w1 w2 In the seminal article, Dessertenne made no attempt to suggest the mechanism of TdP and, until recently, there has been considerable conjecture as to the pathophysiology of this arrhythmia. Since the original work by Dessertenne, it has been well recognised that many conditions may cause prolonged or abnormal repolarisation (that is, QT interval prolongation and/or abnormal T or T/U wave morphology), which is associated with TdP. If TdP is rapid or prolonged, it can lead to ventricular fibrillation and sudden cardiac death (fig 1). Essentially, TdP may be caused by either congenital or acquired long QT syndrome (LQTS). In recent years, there has been considerable renewed interest in the assessment and understanding of ventricular repolarisation and TdP. There are several reasons for this. Firstly, the cloning of cardiac ion channels has improved the understanding of the role of ionic channels in mediating cardiac repolarisation, the pathophysiological mechanism of LQTS (congenital and acquired forms), and the pathogenesis of TdP. Secondly, modern molecular techniques have unravelled the mutations in genes encoding cardiac ion channels that cause long QT syndrome, although the genetic defects in about 50% of patients are still unknown. Thirdly, there has been considerable enthusiasm for the development and use of class III antiarrhythmic drugs, which prolong repolarisation and cardiac refractoriness. Unfortunately, drugs that alter repolarisation have now been recognised to increase the propensity for TdP. Finally, an increasing number of drugs, especially non-cardiac drugs, have been recognised to delay cardiac repolarisation and to share the ability with class III …

QT dispersion does not represent electrocardiographic interlead heterogeneity of ventricular repolarization.

QT Dispersion and Repolarization Heterogeneity. Introduction: QT dispersion (QTd, range of QT intervals in 12 ECG leads) is thought to reflect spatial heterogeneity of ventricular refractoriness. However, QTd may be largely due to projections of the repolarization dipole rather than “nondipolar” signals.

Drug-induced Brugada syndrome

Brugada syndrome is an inherited cardiac arrhythmia condition characterized by (i) coved ST-elevation and J point elevation of at least 2 mm in at least two of the right precordial ECG leads (V1-V3) and (ii) ventricular arrhythmias, syncope, and sudden death. Patients with Brugada syndrome or suspected mutation carriers can have normal ECG recordings at other times. In these cases, a diagnostic challenge with a sodium channel blocker such as ajmaline, flecainide, or pilsicainide may induce the full-blown type 1 ECG pattern and support the diagnosis. However, recently, many other pharmacological agents not related to class I anti-arrhythmic agents have been reported to induce Brugada ECG patterns including tricyclic antidepressants, fluoxetine, lithium, trifluoperazine, antihistamines, and cocaine. As published reports of the drug-induced Brugada sign have become increasingly prevalent, there is growing interest in the mechanisms responsible for this acquired ECG pattern and its clinical significance. It is possible that drug-induced Brugada syndrome may be due to an individual susceptibility that favours drug-induced ECG abnormalities, possibly as a result of an increase in a latent ion channel dysfunction similar to that in drug-induced long QT syndrome. However, further evidence is needed to confirm this postulation. In this paper, we will review the cases and evidence of drug-induced Brugada syndrome reported in the literature.

Comparison of Formulae for Heart Rate Correction of QT Interval in Exercise Electrocardiograms

The study investigated the differences in five different formulae for heart rate correction of the QT interval in serial electrocardiograms recorded in healthy subjects subjected to graded exercise. Twenty‐one healthy subjects (aged 37 ± 10 years, 15 male) were subjected to graded physical exercise on a braked bicycle ergometer until the heart rate reached 120 beats/min. Digital electrocardiograms (ECG) were recorded on baseline and every 30 seconds during the exercise. In each ECG, heart rate and QT interval were measured automatically (QT Guard package, Marquette Medical Systems, Milwaukee, WI, USA). Bazett, Fridericia, Hodges, Framingham, and nomogram formulae were used to obtain QTc interval values for each ECG. For each formula, the slope of the regression line between RR and QTc values was obtained in each subject. The mean values of the slopes were tested by a one‐sample t‐test and the comparison of the baseline and peak exercise QTc values was performed using paired t‐test. Bazett, Hodges, and nomogram formulae led to significant prolongation of QTc intervals with exercise, while the Framingham formula led to significant shortening of QTc intervals with exercise. The differences obtained with the Fridericia formula were not statistically significant. The study shows that the practical meaning of QTc interval measurements depends on the correction formula used. In studies investigating repolarization changes (e.g., due to a new drug), the use of an ad‐hoc selected heart rate correction formula is highly inappropriate because it may bias the results in either direction.

Comparative Reproducibility of QT, QT Peak, and T Peak-T End Intervals and Dispersion in Normal Subjects, Patients with Myocardial Infarction, and Patients with Hypertrophic Cardiomyopathy

Abnormal repolarizaiion is associated with arrhythmogenesis. Because of controversies in existing methodology, new computerized methods may provide more reliable tools for the noninvasive assessment of myocardial repolarization from the surface electrocardiogram (ECC). Measurement of the interval between the peak and the end of the T wave (TpTe interval) has been suggested for the detection of repolarization abnormalities, but its clinical value has not been fully studied. The intrasubject reproducibility and reliability of automatic measurements of QT, QT peak, and TpTe interval and dispersion were assessed in 70 normal subjects, 49 patients with acute myocardial infarction (5th day; MI), and 37 patients with hypertrophic cardiomyopathy (HC). Measurements were performed automatically in a set of 10 ECCs obtained from each subject using a commercial software package (Marquette Medical Systems, Milwaukee, WI, U.S.A.). Compared to normal subjects, all intervals were significantly longer in HC patients (P < 0.001 for QT and QTp; p < 0.05 for TpTe); in MI patients, this difference was only significant for the maximum QT and QTp intervals (P < 0.05). In both patient groups, the QT and QTp dispersion was significantly greater compared to normal subjects (P < 0.05) but no consistent difference was observed in the TpTe dispersion among all three groups. In all subjects, the reproducibility of automatic measurement of QT and QTp intervals was high (coefficient of variation, CV, 1%‐2%) and slightly lower for that of TpTe interval (2%–5%; p < 0.05). The reproducibility of QT, QTp, and TpTe dispersion was lower (12%–24%, 18%–28%, 16%–23% in normal subjects, MI and HC patients, respectively). The reliability of automatic measurement of QT, QTp, and TpTe intervals is high but the reproducibility of the repeated measurements of QT, QTp and TpTe dispersion is comparatively low.

Initial energy setting, outcome and efficiency in direct current cardioversion of atrial fibrillation and flutter

OBJECTIVES The purpose of this study was to design a more efficient protocol for the electrical cardioversion of atrial arrhythmias. BACKGROUND Guidelines for electrical cardioversion of atrial arrhythmias recommend starting with low energy shocks, which are often ineffective. METHODS We recorded the sequence of shocks in 1,838 attempts at cardioversion for atrial fibrillation (AF) and 678 attempts at cardioversion for atrial flutter. These data were used to calculate the probability of success for each shock of a standard series and the probability of success with a single shock at each intensity. In 150 cases, a rhythm strip with the time of each shock allowed us to calculate the time expended on unsuccessful shocks. RESULTS We analyzed the effects of 5,152 shocks delivered to patients for AF and 1,238 shocks delivered to patients for atrial flutter. The probability of success on the first shock in AF of > 30 days duration was 5.5% at < 200 J, 35% at 200 J and 56% at 360 J. In atrial flutter, an initial 100 J shock worked in 68%. In AF of >30 days duration, shocks of < 200 J had a 6.1% probability of success; this fell to 2.2% with a duration >180 days. In those with AF for >180 days, the initial use of a 360 J shock was associated with the eventual use of less electrical energy than with an initial shock of < or =100 J (581 +/- 316 J vs. 758 +/- 433 J, p < 0.01, Mann-Whitney U test). CONCLUSIONS An initial energy setting of > or =360 J can achieve cardioversion of AF more efficiently in patients than traditional protocols, particularly with AF of longer duration.

Acquired Long QT Syndrome

Chapter 1. Introduction.Chapter 2. Mechanisms of Acquired QT Prolongation and Torsades de Pointes.Chapter 3. Measurement of QT Interval and Repolarization Assessment.Chapter 4: Introduction to Drug-Induced Long QT Syndrome.Chapter 5: Risk of QT Prolongation and Torsades de Pointes with Antiarrhythmic Drugs.Chapter 6: Risk of QT Prolongation and Torsades de Pointes with Antihistamines.Chapter 7: Risk of QT Prolongation and Torsades de Pointes with Psychotrophic Drugs.Chapter 8: Risk of QT Prolongation and Torsades de Pointes with Antimicrobial and Antimalarial Drugs.Chapter 9: Risk of QT Prolongation and Torsades de Pointes with Prokinetics and Miscellaneous.Chapter 10: Acquired Long QT Syndrome Secondary to Cardiac Conditions.Chapter 11: Acquired Long QT Syndrome Secondary to Noncardiac Conditions.Chapter 12: Preclinical and Clinical Assessment of the Risk of QT Prolongation and Torsades de Pointes with New Active Substances.Chapter 13: Conclusion and Perspective of Drug-Induced Repolarization Changes

What Should We Expect From the Next Generation of Antiarrhythmic Drugs

The Next Generation of Antiarrhythmic Drugs. Five drugs currently constitute approximately 70% of the world market for antiarrhythmic medications. Since the publication of studies documenting that certain Class I drugs may increase mortality in high‐risk postinfarction patients, basic science and clinical studies have focused on Class III antiarrhythmic drugs. However, drugs that prolong repolarization and cardiac refractoriness are sometimes associated with potentially lethal torsades de pointes. Amiodarone, a multichannel blocker, may he the exception to this observation, but it nevertheless fails to reduce total mortality compared with placebo in high‐risk patients following myocardial infarction. However, Class HI agents remain the focus of drug development efforts because they lack the negative hemodynamic effects, affect both atrial and ventricular tissue, and can be administered as either parenteral or oral preparations. Developers of newer antiarrhythmic agents have focused on identifying antiarrhythmic medications with the following characteristics: appropriate modification of the arrhythmia substrate, suppression of arrhythmia triggers, efficacy in pathologic tissues and states, positive rate dependency, appropriate pharmacokinetics, equally effective oral and parenteral formulations, similar efficacy in arrhythmias and their surrogates, few side effects, positive frequency blocking actions, and cardiac‐selective ion channel blockade. New and investigational agents that more closely approach these goals include azimilide, dofetilide, dronedarone, ersentilide, ibutilide, tedisamil, and trecetilide. In the near future, medications will increasingly constitute only part of an antiarrhythmic strategy. Instead of monotherapy, they will often be used in conjunction with an implanted device. Combination therapy offers many potential advantages. Long‐term goals of antiarrhythmic therapy include upstream approaches, such as identification of the biochemical intermediaries of the process and, eventually, of molecular and genetic lesions involved in arrhythmogenesis.

Prognostic value of blood pressure measured during hospitalization after acute myocardial infarction: an insight from survival trials.

Background The prognostic value of blood pressure measured during hospitalization after acute myocardial infarction (MI) has not been investigated, particularly with regard to arrhythmic death. Methods A total of 3311 placebo patients (2612 men, median age 64 years; range 23–92) from the EMIAT, CAMIAT, SWORD, TRACE and DIAMOND–MI studies with left ventricular ejection fraction less than 40% or asymptomatic ventricular arrhythmia surviving more than 45 days after MI were pooled. Systolic and diastolic blood pressures and pulse pressures were measured soon after MI (median 6 days, range 0–53 days). Mortality up to 2 years was examined using Cox regression. Results At the 2-year follow-up, after adjustment for age, sex, smoking, previous MI, hypertension, heart rate, New York Heart Association functional class, baseline treatments, study effect and diastolic blood pressure, reduced systolic blood pressure measured during hospitalization after acute MI significantly increased the risk of all-cause mortality [hazard ratio (HR) for 10% increase in systolic blood pressure 0.80, 95% confidence interval (CI) 0.71–0.90; P < 0.001] and arrhythmic mortality (HR 0.73, 95% CI 0.61–0.86; P = 0.001). Reduced diastolic blood pressure significantly increased the risk of all-cause mortality (HR 0.87, 95% CI 0.77–0.98; P = 0.02) and arrhythmic mortality (HR 0.80, 95% CI 0.68–0.93; P = 0.005). Conclusion In post-MI patients with left ventricular ejection fraction less than 40% or asymptomatic ventricular arrhythmia, reduced blood pressure measured during hospitalization after MI significantly predicts all-cause mortality and arrhythmic mortality, and can be reliably used to identify patients who are at risk of dying after MI.

Optimising the dichotomy limit for left ventricular ejection fraction in selecting patients for defibrillator therapy after myocardial infarction

Background: The selection of patients for prophylactic implantable cardioverter-defibrilator (ICD) treatment after myocardial infarction (MI) remains controversial. Aim: To determine the optimum left ventricular ejection fraction (LVEF) dichotomy limit for ICD treatment in patients with a history of MI. Methods and results: Data from the placebo arms of four randomised trials were pooled to create a cohort of 2828 patients (2206 men, mean (SD) age 65 (11) years) with reduced left ventricular function after MI. The median LVEF was 33% (range 6–40%). LVEF significantly predicted mortality. Each 10% reduction in LVEF <40% conferred a 42% increase in all-cause mortality, a 39% increase in arrhythmic cardiac mortality and a 49% increase in non-arrhythmic cardiac mortality over the 2-year period of follow-up (p<0.001 for all modes of mortality). As the LVEF progressively decreased from ⩽40% to ⩽10%, the data show a U-shaped relationship between the dichotomy limit for LVEF used and the number of patients who must be treated to prevent one arrhythmic death in 2 years. At an LVEF of 16–20%, more patients are likely to die from arrhythmic than non-arrhythmic cardiac deaths, whereas in those with LVEF ⩽10% all deaths were non-arrhythmic. However, the total number of deaths substantially decreased with lower LVEF. Conclusion: A trade-off exists between the sensitivity and positive predictive accuracy across a range of LVEF, and no single dichotomy limit is completely satisfactory. In patients with LVEF ⩽10% ICD treatment was not beneficial as all patients in this subgroup died from non-arrhythmic causes. The use of a single dichotomy limit for LVEF alone is not sufficient in selecting patients for ICD treatment in the primary prevention of cardiac arrest.