Sudden death mechanisms in nonischemic cardiomyopathies: Insights gleaned from clinical implantable cardioverter-defibrillator trials

Sudden cardiac death (SCD) represents a major cause of death among patients with heart failure. Although scar-based, macroreentrant ventricular tachycardia/ventricular fibrillation is the primary etiology for SCD among patients with ischemic cardiomyopathy, a more diverse set of mechanisms and substrates is likely at play for the diverse group of patients characterized by nonischemic dilated cardiomyopathy (NICM). These causes may include scar-based reentry, but also neurohormonal stimulation (sympathetic, parasympathetic, renin-angiotensin-aldosterone), inflammation, and nonarrhythmic processes occurring in the context of a genetic predisposition. In addition to basic and translational science, observations from large randomized clinical trials of implantable cardioverter-defibrillators (ICDs) can also offer insight and support for specific mechanisms of SCD in these patients. This review will discuss the background of SCD in NICM, its potential mechanisms based on experimental and theoretical models, and the evidence for these mechanisms that can be derived from clinical trials of ICD therapy.