Chinmay Patel

Tp-e/QT ratio as an index of arrhythmogenesis☆

An increasing number of basic and clinical studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (T(p-e)) may correspond to the transmural dispersion of repolarization and that amplification of the T(p-e) interval is associated with malignant ventricular arrhythmias. In this review, we outline the utility of the T(p-e) interval and the T(p-e)/QT ratio as an electrocardiographic index of arrhythmogenesis for both congenital and acquired ion channel disease leading to ventricular arrhythmias. In healthy individuals, the T(p-e)/QT ratio has a mean value of approximately 0.21 in the precordial leads and it remains relatively constant between the heart rates from 60 to 100 beats per minute. Interestingly, the T(p-e)/QT ratio is significantly greater in the patients at risk for arrhythmic event such as those with long QT syndrome, Brugada syndrome, short QT syndrome, and also in patients with organic heart disease such as acute myocardial infarction. Functional reentry is the underlying mechanism for arrhythmogenesis associated with an increased T(p-e)/QT ratio.

Short QT Syndrome: From Bench to Bedside

Short QT syndrome (SQTS) is an inheritable primary electric disease of the heart characterized by abnormally short QT intervals on the ECG and an increased propensity to develop atrial and ventricular tachyarrhythmias.1,–,3 It is a relatively recent addition to the list of inherited channelopathies responsible for sudden cardiac death (SCD) in individuals with structurally normal hearts. Cases of SQTS have been reported with presentation as early as in the first year of life, suggesting that it could be one of the etiologies underlying sudden infant death syndrome.4 SQTS was first described as a new clinical entity by Gussak et al in 2000.1 The familial nature and arrhythmic potential of the disease was further highlighted by Gaita et al.5 They described 6 patients of SQTS in 2 unrelated European families with strong family history of sudden death in association with short QT intervals on the ECG. Since its initial introduction in 2000, significant progress has been made in defining the clinical, genetic,6 and ionic basis of the disease as well as approaches to therapy. The purpose of this review is to summarize the available data concerning SQTS from bench to bedside. The definition of a pathophysiologic long QT interval evolved over a period of several decades and it may take some time to define what constitutes a pathophysiologic short QT interval. Several large scale population studies have shown that the corrected QT interval (QTc, using the Bazett formula) of healthy individuals conforms to a gaussian normal distribution, that is, a bell-shaped curve.7,–,10 Based on this distribution, the “normal QTc” interval may be defined as values that fall within 2 standard deviations (SD) from the mean. This approach will categorize 95% of the population as having normal QTc …

Cellular basis for arrhythmogenesis in an experimental model of the SQT1 form of the short QT syndrome

BACKGROUND Short QT syndrome (SQTS) is a primary electrical disease of the heart associated with a high risk of sudden cardiac death. A gain-of-function in I(Kr), due to a mutation in KCNH2, underlies SQT1. OBJECTIVE This study sought to examine the cellular basis for arrhythmogenesis in an experimental model of SQT1 created using PD-118057, a novel I(Kr) agonist. METHODS Transmembrane action potentials were simultaneously recorded from epicardial, M, and endocardial regions of arterially perfused canine left ventricular (LV) wedge preparations, together with a pseudo-electrocardiogram. RESULTS PD-118057 (10 micromol/l) abbreviated the QT interval from 267 +/- 4 to 232 +/- 4 ms and increased transmural dispersion of repolarization (TDR) from 33.7 +/- 2.0 to 49.1 +/- 3.1 ms (P <.001). T-wave amplitude increased from 18.0% +/- 1.4% to 23.1% +/- 1.7% of R-wave amplitude (P =.027). Reversing the direction of activation of the LV wall (epicardial pacing) resulted in an increase in QT interval from 269 +/- 5 to 282 +/- 5 ms and an increase in TDR from 34.1 +/- 2.0 to 57.6 +/- 3.3 ms (P <.001) under baseline conditions. PD-118057 abbreviated the QT interval from 282 +/- 5 to 258 +/- 5 ms and produced a proportional decrease in effective refractory period (ERP). TDR increased from 57.6 +/- 3.3 to 77.6 +/- 4.3 ms (P <.001). Polymorphic ventricular tachycardia (pVT) was induced in 10 of 20 preparations with a single S(2) applied to epicardium. Quinidine (10 micromol/l) increased the ERP and QT interval, did not significantly alter TDR, and prevented induction of pVT in 5 of 5 preparations. CONCLUSION Our results suggest that a combination of ERP abbreviation and TDR amplification underlie the development of pVT in SQT1 and that quinidine prevents pVT principally by prolonging ERP.

Is there a significant transmural gradient in repolarization time in the intact heart? Cellular Basis of the T Wave: A Century of Controversy

The ECG is one of the oldest and most versatile noninvasive cardiac diagnostic tests. It has remained in use essentially in its original form despite dramatic advances in cardiac electrophysiology. In May 1887, Augustus Desire Waller recorded the first human Electrogram using a primitive instrument called a Libbmann capillary electrometer. It had 2 deflections corresponding to ventricular depolarization and repolarization.1 In 1903, Willem Einthoven invented the String Galvanometer—a more sophisticated voltage recording instrument and recorded an Elektrokardiogramm with 5 deflections that he named PQRST.2 Since its initial invention, the body surface ECG has become a commonly used and extremely valuable test for the diagnosis of a variety of cardiac conditions. Despite a century of prolific use and intensive investigation, the cellular basis of ECG waveforms, particularly the T wave, remains a matter of debate.The ECG is one of the oldest and most versatile noninvasive cardiac diagnostic tests. It has remained in use essentially in its original form despite dramatic advances in cardiac electrophysiology. In May 1887, Augustus Desire Waller recorded the first human Electrogram using a primitive instrument called a Libbmann capillary electrometer. It had 2 deflections corresponding to ventricular depolarization and repolarization.1 In 1903, Willem Einthoven invented the String Galvanometer—a more sophisticated voltage recording instrument and recorded an Elektrokardiogramm with 5 deflections that he named PQRST.2

Preclinical assessment of drug-induced proarrhythmias: Role of the arterially perfused rabbit left ventricular wedge preparation☆

Drug-induced torsade de pointes (TdP) is a rare but lethal side effect of many cardiovascular and non-cardiovascular drugs. It has led to black box warnings or even withdrawal of many useful compounds from the market and is one of the major stumbling blocks for new drug development. The critical need for a better test that can predict the TdP liability of a candidate drug has led to the development of multiple preclinical models. Each of these models has it own merits and limitations in preclinical testing for TdP liability; however, most of these models have not been adequately validated, so their precise sensitivity and specificity remain largely unknown. Recent blinded validation studies have demonstrated that the rabbit left ventricular wedge preparation can predict drug-induced TdP with an extremely high sensitivity and specificity. As a matter of fact, the wedge technique was initially developed primarily for studying the electrical heterogeneity of myocardium and the cellular basis of QT prolongation and TdP. Naturally then, the electrophysiological data obtained from the wedge takes into account every critical factor associated with the development of TdP. The TdP scores generated using the wedge technique have been shown to assess the torsadogenic potential of the drugs in a predictable fashion. This review elaborates on the current and prospective role of the rabbit left ventricular wedge preparation in preclinical assessment of drug-induced proarrhythmias including but not limited to TdP.

Pharmacological approach to the treatment of long and short QT syndromes

Inherited channelopathies have received increasing attention in recent years. The past decade has witnessed impressive progress in our understanding of the molecular and cellular basis of arrhythmogenesis associated with inherited channelopathies. An imbalance in ionic forces induced by these channelopathies affects the duration of ventricular repolarization and amplifies the intrinsic electrical heterogeneity of the myocardium, creating an arrhythmogenic milieu. Today, many of the channelopathies have been linked to mutations in specific genes encoding either components of ion channels or membrane or regulatory proteins. Many of the channelopathies are genetically heterogeneous with a variable degree of expression of the disease. Defining the molecular basis of channelopathies can have a profound impact on patient management, particularly in cases in which genotype-specific pharmacotherapy is available. The long QT syndrome (LQTS) is one of the first identified and most studied channelopathies where abnormal prolongation of ventricular repolarization predisposes an individual to life threatening ventricular arrhythmia called Torsade de Pointes. On the other hand of the spectrum, molecular defects favoring premature repolarization lead to Short QT syndrome (SQTS), a recently described inherited channelopathy. Both of these channelopathies are associated with a high risk of sudden cardiac death due to malignant ventricular arrhythmia. Whereas pharmacological therapy is first line treatment for LQTS, defibrillators are considered as primary treatment for SQTS. This review provides a comprehensive review of the molecular genetics, clinical features, genotype-phenotype correlations and genotype-specific approach to pharmacotherapy of these two mirror-image channelopathies, SQTS and LQTS.

Should catheter ablation be the preferred therapy for reducing ICD shocks?: Ventricular tachycardia ablation versus drugs for preventing ICD shocks: role of adjuvant antiarrhythmic drug therapy.

In 1980, Mirowski et al1 implanted the first implantable cardioverter-defibrillator (ICD) in a young female with recurrent ventricular fibrillation and provided an innovative approach to aborted sudden cardiac death (SCD). Although the ICD was considered a treatment of last resort during that incipient stage, subsequent years have witnessed prolific expansion of indications for ICD implantation.2 Several large-scale clinical trials have demonstrated its efficacy for both primary and secondary prevention of SCD in patients with ischemic and nonischemic cardiomyopathy.3,4 ICD therapy in such high-risk patients has been shown to improve survival compared with conventional antiarrhythmic drug therapy alone.3,4 The number of ICD implantations has increased significantly in the last decade, with a concurrent decrease in the use of stand-alone antiarrhythmic drugs for ventricular indications.5–7 Current ICDs have sophisticated programming capabilities, atrial and bipolar leads, and are able to deliver antitachycardia pacing algorithms (ATP) in addition to defibrillating shocks. Response by Kuck on p 705 Typically, patients who receive ICDs are at high risk for recurrent arrhythmia; hence, most patients receive 1 or more ICD therapies for spontaneous arrhythmias after implantation.3 Despite the technological evolution of ICD systems, more than 20% of shocks are due to supraventricular arrhythmia and hence are inappropriate.8–10 The ICD uses ATP or defibrillating shocks to terminate episodes of ventricular tachycardia (VT) or ventricular fibrillation (VF). Although the ICD aborts VT/VF, many patients continue to have symptoms such as dizziness, palpitations, nervousness, flushing, or syncope before receiving an ICD shock.11 When the shock is finally delivered, it is physically and emotionally painful and so noxious that 23% of patients dread shocks and 5% of patients prefer to do without an ICD and “take their chances.”12 A significant prevalence of sadness, depression, and even anxiety disorders have been reported after …In 1980, Mirowski et al1 implanted the first implantable cardioverter-defibrillator (ICD) in a young female with recurrent ventricular fibrillation and provided an innovative approach to aborted sudden cardiac death (SCD). Although the ICD was considered a treatment of last resort during that incipient stage, subsequent years have witnessed prolific expansion of indications for ICD implantation.2 Several large-scale clinical trials have demonstrated its efficacy for both primary and secondary prevention of SCD in patients with ischemic and nonischemic cardiomyopathy.3,4 ICD therapy in such high-risk patients has been shown to improve survival compared with conventional antiarrhythmic drug therapy alone.3,4 The number of ICD implantations has increased significantly in the last decade, with a concurrent decrease in the use of stand-alone antiarrhythmic drugs for ventricular indications.5–7 Current ICDs have sophisticated programming capabilities, atrial and bipolar leads, and are able to deliver antitachycardia pacing algorithms (ATP) in addition to defibrillating shocks.

Pharmacological enhancement of cardiac gap junction coupling prevents arrhythmias in canine LQT2 model.

Gap junctions contribute to the transmural heterogeneity of repolarization in the normal heart and under conditions of prolonged QT interval in the diseased heart. This study examined whether enhancing of gap junction coupling can reduce transmural dispersion of repolarization (TDR) and prevent torsade de pointes (TdP) in a canine LQT2 model. Canine left ventricular wedge preparations were perfused with delayed rectifier potassium current (IKr) blocker d-sotalol to mimic LQT2 and the antiarrhythmic peptide 10 (AAP10) was used as a gap junction coupling enhancer. As compared with the control group, the LQT2 group had significantly augmented TDR and higher incidence of TdP associated with increased nonphosphorylated connexin 43 (Cx43). AAP10 prevented augmentation of TDR and induction of TdP while rescuing Cx43 phosphorylation. There was no significant change in the quantity and spatial distribution of Cx43. These data indicate that gap junction enhancer AAP10 can prevent augmentation of TDR and suppress TdP by preventing dephosphorylation of Cx43 in a LQT2 model.

Role of antiarrhythmic drugs: frequent implantable cardioverter-defibrillator shocks, risk of proarrhythmia, and new drug therapy.

The implantable cardioverter-defibrillator (ICD) is the standard of care in patients with ischemic and nonischemic cardiomyopathy who are at high risk for arrhythmic events and sudden cardiac death. Although an ICD saves life, ICD shocks are emotionally and physically debilitating. Most patients receive adjuvant antiarrhythmic drug therapy to circumvent episodes of recurrent ventricular and supraventricular arrhythmias. Antiarrhythmic drugs including b-blockers, sotalol, amiodarone, and azimilide are effective at reducing the shock burden. This article describes data supporting the need for and potential risks and benefits of adjuvant antiarrhythmic drug therapy and examines the benefits and pitfalls of the same in ICD-implanted patients.

Atrial Fibrillation: Pharmacological Therapy

Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice. Although once considered a nuisance arrhythmia, recent clinical trial evidence suggests that the presence of AF is an important independent predictor of mortality and morbidity. The primary goals of AF treatment are relief of symptoms and prevention of stroke. The value of anticoagulation with warfarin has been proven unequivocally. Control of ventricular rate with atrioventricular nodal blocking agents-the so-called rate control strategy-is least cumbersome and sometimes the best approach. By contrast, efforts to restore and maintain sinus rhythm using antiarrhythmic drugs-the rhythm control approach-although tedious, may be ideal in patients who are young or highly symptomatic and in those with new-onset AF. The relative merits of both treatment strategies are discussed in this article, emphasizing the excellent clinical trial data that support each.