Noninvasive arrhythmia risk assessment in guiding pharmacologic therapy for prevention of sudden cardiac death: where do we stand? Where do we go?

Despite reductions in age-adjusted death rates in patients with cardiovascular disease over the past 20 years, approximately 325,000 deaths still occur suddenly and unexpectedly each year. In 20% to 30% of cases, sudden cardiac death (SCD), commonly defined as death within 1 hour after onset of symptoms, occurs without warning. It is generally assumed that this mode of demise is attributable mainly to ventricular tachycardia and fibrillation, although this event can be difficult to document, an inherent limitation in SCD studies. Nevertheless, the scope of this public health problem and the need for progress provide a compelling rationale for development of noninvasive markers to stratify risk for life-threatening arrhythmias and to guide preventive pharmacologic therapy. The present two-part series addresses the advances in noninvasive risk stratification and the evolution of pharmacologic therapy for prevention of SCD, which has progressed beyond targeting ion channels to include myocardial substrate changes, particularly those related to arrhythmogenic postmyocardial infarction remodeling. The first group of reviews focuses on basic mechanisms, conventional antiarrhythmic and nonantiarrhythmic agents for SCD prevention, and the utility of T-wave alternans (TWA) in guiding pharmacologic therapy. Rosen and Janse place the development of antiarrhythmic agents within the framework of the ‘‘vulnerable parameter,’’ first advanced in the Sicilian Gambit nearly two decades ago. The Gambit conference assembled an interdisciplinary group of leading scientists and clinicians in the field of antiarrhythmic drug therapy to stimulate the development and application of agents based on in-depth understanding of cellular and ionic mechanisms and molecular therapeutic targets. Fundamentally, a ‘‘vulnerable parameter’’ reflects an electrophysiological property, phenomenon, or ion channel that is within the causal pathway of arrhythmogenesis and can be altered by pharmacologic therapy to decrease the occurrence of arrhythmia. By definition, a noninvasive therapeutic marker encompasses one or more ‘‘vulnerable parameters’’ or arrhythmia mechanism targets. Guided by these concepts, Rosen and Janse review the history of antiarrhythmic drug development, basic mechanisms, and the ensuing major clinical trials, including Cardiac Arrhythmia Pilot Study (CAPS), Cardiac Arrhythmia Suppression Trial (CAST), and Survival With ORal D-Sotalol (SWORD). Important insights are provided into disappointing findings, particularly those from the CAST trial, along with lessons learned to guide future drug development. The authors also discuss the need for research to expand and modify the library of vulnerable parameters and the relevance of newer markers in this context. The need to go beyond ion channels to include consideration of substrate remodeling in association with myocardial infarction and cardiomyopathic heart disease is also underscored. Overall, their encompassing view of the complexities associated with arrhythmogenesis provides a valuable blueprint for future investigation. Das and Zipes address the clinically challenging problem of antiarrhythmic therapy for prevention of lethal ventricular tachyarrhythmias. They make the important points that although implantable cardioverter–defibrillator (ICD) discharge is the primary therapy for