Emerging Arrhythmic Risk of Autoimmune and Inflammatory Cardiac Channelopathies

Cardiac arrhythmias are associated with high morbidity and mortality.1 Specifically, malignant arrhythmias are a recognized leading cause of sudden cardiac death (SCD) in the Western countries. It has been estimated that every day >1000 SCDs occur in the United States.1, 2 Although structural heart diseases, particularly coronary artery disease and heart failure,2, 3 are the prevalent underlying causes of cardiac arrhythmias and SCD, structural alterations are not identified at the postmortem examination in 5% to 15% of patients, increasing up to 40% in subjects aged <40 years.1, 2 The discovery that, in the absence of structural heart defects, mutations in the genes encoding for cardiac ion channels and/or associated regulatory proteins can promote arrhythmias led to the recognition of a new group of inherited arrhythmogenic diseases, accounting for a significant proportion of the unexplained cases.4 The term cardiac channelopathies has been used to designate a collection of genetically mediated syndromes, including long‐QT syndrome (LQTS), short‐QT syndrome (SQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), early repolarization syndrome (ERS), idiopathic ventricular fibrillation (IVF), and progressive cardiac conduction disease.5 All these disorders are caused by the dysfunction (loss or gain of function) of specific cardiomyocyte ion channels, resulting in a disruption of the cardiac action potential (AP). 4 Such electrical abnormalities lead to an increased susceptibility to develop arrhythmias, syncope, seizures, or SCD, precipitated by episodes of polymorphic ventricular tachycardia (torsade de pointes [TdP]) or ventricular fibrillation (VF), typically in the presence of a structurally normal heart.4 Thus, although the term cardiac channelopathies does not per se imply a genetic origin, it currently coincides with that of inherited cardiac channelopathies.1, 5 Accumulating recent evidence demonstrated that factors other than genetic mutations can promote arrhythmias by causing a selective cardiac ion channel dysfunction in the absence of any structural heart defect. In addition to a well‐recognized list of drugs directly interfering with cardiac ion channel function,6 immunologic and inflammatory factors can cause cardiac channelopathies.7, 8 In fact, besides the established role of cardiac inflammation, often of autoimmune origin, in promoting arrhythmias in the presence of an autopsy/biopsy‐proven inflammatory cell tissue infiltration,9, 10, 11, 12, 13 it is increasingly recognized that systemically released autoantibodies and cytokines can be per se arrhythmogenic, regardless of evident histologic changes in the heart.14, 15, 16 Several arrhythmogenic autoantibodies targeting calcium, potassium, or sodium channels in the heart have been identified, and the term autoimmune cardiac channelopathies has been proposed.7 Moreover, evidence exists that inflammatory cytokines, mainly tumor necrosis factor (TNF)‐α, interleukin‐1, and interleukin‐6, can modulate expression and/or function of ion channels, both by directly acting on cardiomyocytes8, 17 and/or inducing systemic effects (fever). 17 A careful consideration of these, to date, largely overlooked factors is highly relevant because they are potentially involved in several unexplained arrhythmias/SCD that are negative for genetic factors.2 In patients with unexplained cause of death after a comprehensive postmortem genetic testing of blood/tissue samples (the so‐called “molecular autopsy”), a genetic cause is demonstrated in no more than ≈30% of cases.2 As such, a novel and more comprehensive classification of cardiac channelopathies is herein proposed, distinguishing the “classic” inherited forms, related to genetic mutations, from the acquired forms, including drug‐induced and more recently recognized autoimmune and inflammatory/fever‐induced cardiac channelopathies (Figure 1). In this review, we focus on autoimmune and inflammatory/fever‐induced channelopathies and their emerging impact on arrhythmic risk, providing both basic and clinical perspectives. Open in a separate window Figure 1 Classification of arrhythmogenic cardiac channelopathies. Besides the “classic” inherited forms of cardiac channelopathies related to genetic mutations, a wider spectrum of acquired forms includes not only drug‐induced, but also autoimmune and inflammatory/fever‐induced, cardiac channelopathies.