Synergism between Enhanced Late Inward Currents and Tissue Fibrosis in the Initiation of Spontaneous Ventricular Tachyarrhythmias

Sudden cardiac death (SCD) death is a major worldwide public health problem that often arises in patients with diverse cardiac diseases associated with enhanced cardiac tissue fibrosis and altered cardiac sarcolemmal ionic current conductances. It is now clear that the major cause of SCD is ventricular tachycardia (VT) degenerating to ventricular fibrillation (VF), although bradyarrhythmias may also promote the fatal event albeit, to a much lesser extent than the VT/VF [1]. SCD occurs in approximately 180,000-250,000 cases annually in the United States, and an estimated 4-5 million cases worldwide [2]. The prevalence of cardiovascular diseases potentially associated with lethal ventricular arrhythmia is estimated at approximately 13 million US individuals, which is about 5% of the middleaged population [3]. Sarcolemmal ion channels of cardiac myocytes are responsible for the genesis of cardiac action potential (AP) and their genetic (channelopathy) or disease-induced alterations promote arrhythmogenic changes including triggered activity caused either by early or delayed after depolarizations (EAD and DAD respectively) predisposing the heart to life-threatening VT/VF. Four major classes of genetically-based ion channel abnormalities have been described that predispose the heart to VT/VF; the long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT) [4]. Initially it was thought that patients at increased risk of VT/VF with genetic abnormalities in sarcolemmal ionic currents (i.e. channelopathies) had structurally normal hearts. However recent studies based on post-mortem histological analysis of patients with Na channelopathy (i.e. BrS), provided compelling evidence that these patients had focal areas of increased ventricular tissue fibrosis and reduced gap junctional connexin-43 (Cx43) indicating the potential dual contributions of fibrosis and channelopathy to the development of VT/VF [5]. Diverse etiological factors including myocardial infarction or drug-induced altered ion channel conductances are also thought to interact with cardiac tissue fibrosis to promote VT/VF [6]. In this article, I will make the case for the presence of a synergism between ionic current abnormality caused by enhanced late Na current so to mimic LQT3 and enhanced late Ca current as a surrogate of LQT8 (Timothy syndrome) and increased ventricular tissue fibrosis in the promotion of VT/VF. The cellular basis of the synergism is then briefly discussed.