Biochemical and electrophysiological alterations underlying ventricular arrhythmias in the failing heart

Our understanding of the electrophysiological and biochemical mechanisms underlying malignant ventricular arrhythmias in the setting of heart failure has been limited, in large part because of the lack of experimental preparations of heart failure that demonstrate spontaneously occurring ventricular arrhythmias. Recent 3-dimensional cardiac mapping studies in experimental preparations of heart failure, as well as the failing human heart, have demonstrated that focal non-reentrant mechanisms may underlie ventricular tachycardia occurring spontaneously or induced by programmed electrical stimulation. This non-reentrant activation may be due to triggered activity arising from delayed after depolarization. Alterations of calcium homeostasis in the failing heart involving a number of ionic channels and membrane transporters may contribute to increased levels of intracellular calcium and the activation of a transient inward current. Modulation of calcium flux by alpha- and beta-adrenergic stimulation may impact significantly on development of arrhythmias in the failing heart. Activation of the renin-angiotensin system and the generation of free radicals may also contribute. A thorough understanding of the underlying electrophysiological and biochemical alterations responsible for arrhythmogenesis in the failing heart will be critical for the development of therapeutic agents to prevent sudden death in patients with congestive heart failure.