Dan M. Roden

Inherited long QT syndromes: a paradigm for understanding arrhythmogenesis.

LQTS as a Paradigm. The inherited long QT syndrome (LQTS) is a familial disease characterized by QT interval changes that often are labile, syncope, and sudden death due to arrhythmias, predominantly in young people. Multiple mutations in five genes encoding structural subunits of cardiac ion channels now have been identified in families with LQTS. Correlations are being described between genotype and specific clinical features in LQTS. However, increasing screening of affected families and sporadic cases has identified incomplete penetrance with highly variable clinical manifestations, even among individuals carrying the same mutations. The identification of LQTS disease genes represents a crucial first step in developing an understanding of the molecular basis for normal cardiac repolarization. This information will be important not only for identifying new therapies in LQTS, but also in further understanding arrhythmias, and their potential therapies, in situations such as heart failure, cardiac hypertrophy, myocardial infarction, or sudden infant death syndrome, where abnormal repolarization has been linked to sudden death. LQTS thus presents a new paradigm to cardiac electrophysiology, in which new molecular information is being brought to bear both on clinical management of patients and on development of a new framework to study the fundamental causes of arrhythmias and new approaches to therapy.

Cisapride-Induced Torsades de Pointes

Cisapride‐Induced Torsades de Pointes. Two cases of torsades de pointes associated with cisapride are presented, both in association with concomitant drug therapy that inhibits cisapride biotransformation. In one case, plasma cisapride was elevated days after the event, strongly supporting a role for accumulation of the drug in causing the arrhythmia. It is emphasized that these adverse drug reactions are not idiosyncratic, hut rather are predictable based on an understanding of the underlying mechanisms.

A randomized, double-blind, placebo-controlled, dose-ranging study of dofetilide in patients with inducible sustained ventricular tachyarrhythmias.

Dofetilide and Ventricular Tachyarrhythmias. Introduction: Dofetilide is a new antiarrhythmic agent with potent Ik blocking properties in vitro. We developed a dose‐ranging, placebo‐controlled study design to define the range of effective doses and to evaluate the clinical electrophysiology of intravenous dofetilide in patients in whom sustained ventricular tachycardia or fibrillation was reproducibly inducible at baseline electrophysiologic testing.

A Rate-Independent Method of Assessing QT-RR Slope Following Conversion of Atrial Fibrillation

Introduction: Following conversion of atrial fibrillation (AF), QT interval transiently and variably prolongs and can trigger Torsades de Pointes (TdP). However, quantitative analysis of risk in this setting is difficult because cycle length variability during AF makes rate‐corrected QT impossible to calculate. In this study, a newly developed method to study heart rate dependence of the QT interval during AF was applied to assess the QT–RR relationships prior to and following cardioversion in patients with AF.

Autonomic tone attenuates drug-induced QT prolongation.

Introduction: The QT interval is a predictor of sudden death. Many drugs prolong the QT, primarily through IKr block. Autonomic tone directly affects heart rate and ventricular repolarization, but its effects in the setting of IKr block are unknown.

Brugada-type ECG pattern and extreme QRS complex widening with propafenone overdose

Brugada-Type ECG Pattern and Extreme QRS Complex Widening with Propafenone Overdose CAN HASDEMIR, M.D.,∗ MURAT OLUKMAN, M.D.,† CEM ULUCAN, M.D.,∗ and DAN M. RODEN, M.D.‡ From the ∗Department of Cardiology and †Department of Pharmacology, Ege University School of Medicine, Izmir, Turkey; and ‡Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

Intracellular Sodium Overload: A System Biology Problem with Implications for Drug Target Identification

Multiple lines of evidence, summarized in the symposium that this Supplement reviews, converge on the concept that abnormal intracellular sodium homeostasis is a key proximate initiator of a range of clinically important cardiac phenotypes, such as serious arrhythmias, contractile dysfunction, and angina. Defining the adaptive and possibly maladaptive responses to acute and chronic sodium loading is a first step in further testing of this hypothesis. The potential complexities involved in attacking a single molecular lesion such as an increase in intracellular sodium are nicely illustrated by Noble’s studies of action potential modeling1,2 that opened the symposium. It is clear that subtle changes in behavior in one component of this complicated system can result in unexpected and occasionally detrimental abnormalities in function of other components of the system. Importantly, these downstream components may be functioning entirely normally in response to a change in their environment. A good example is that a consequence of action potential prolongation (through any one of a number of mechanisms) is physiologic activation or reactivation of inward currents that unfortunately generates the arrhythmogenic triggers and substrate that can lead to torsades de pointes. Given the fact that opening of the cardiac sodium channel is the initiating event in the cardiac cycle, it should come as no surprise that there are multiple potential downstream responses to changes in its behavior. One general conclusion is that wellconstructed computational models may be not only desirable but in fact also necessary to analyze responses of complex systems to even seemingly “simple” changes in the behavior of one component. A second conclusion seems inescapable: multiple molecules act in concert to maintain normal physiology and that individual molecular lesions may lead to system dysfunction through “unexpected” mechanisms. This carries important implications for the general field of drug development. Torsades de pointes in response to IKr block or an increase in myocardial infarction with COX-2 inhibition represent examples of how specificity in drug targeting may lead to unanticipated toxicities though an effect on the complex biologies within which these “specific” drug actions occur.3