Electroimmunology and cardiac arrhythmia

Abstract

Conduction disorders and arrhythmias remain difficult to treat and are increasingly prevalent owing to the increasing age and body mass of the general population, because both are risk factors for arrhythmia. Many of the underlying conditions that give rise to arrhythmia - including atrial fibrillation and ventricular arrhythmia, which frequently occur in patients with acute myocardial ischaemia or heart failure - can have an inflammatory component. In the past, inflammation was viewed mostly as an epiphenomenon associated with arrhythmia; however, the recently discovered inflammatory and non-canonical functions of cardiac immune cells indicate that leukocytes can be arrhythmogenic either by altering tissue composition or by interacting with cardiomyocytes; for example, by changing their phenotype or perhaps even by directly interfering with conduction. In this Review, we discuss the electrophysiological properties of leukocytes and how these cells relate to conduction in the heart. Given the thematic parallels, we also summarize the interactions between immune cells and neural systems that influence information transfer, extrapolating findings from the field of neuroscience to the heart and defining common themes. We aim to bridge the knowledge gap between electrophysiology and immunology, to promote conceptual connections between these two fields and to explore promising opportunities for future research.

Fig. 1 |. Electrophysiological concepts of conduction and arrhythmogenesis.

a | The physiological cardiac action potential can be divided into different phases. Depolarization due to rapid Na⁺ influx (phase 0). Transient K⁺ channels open and cause K⁺ efflux (phase 1). The plateau phase is facilitated by Ca²⁺ influx and counterbalanced by K⁺ efflux (phase 2). Closing of the Ca²⁺ channels causes rapid repolarization, but K⁺ channels remain open until the membrane potential returns to −90 mV (phase 3). Resting membrane potential, with Na⁺ and Ca²⁺ channels closed, but K⁺ channels open, holding the membrane potential at −90 mV (phase 4). b | Triggered activity usually results from prematurely activated cardiac tissue, causing early or late afterdepolarizations. c | Increased automaticity from dominant pacemaker cells is usually triggered by abnormal impulse function and can lead to tachyarrhythmias by increasing the rate of action potential discharge due to sympathetic stimulation, whereas decreased pacemaker rates slow the heart rate. d | A depolarizing impulse (red arrow) encounters an anatomical obstacle and circles around it. The electrical impulse constantly ‘runs around’ the block, along the excitable tissue gap. If the wavefront never reaches the refractory tail, a re-entrant loop forms, causing sustained arrhythmia. ECG, electrocardiogram; LV, left ventricular.

Fig. 2 |. Leukocyte-released cytokines shape the arrhythmogenic substrate.

Structural remodelling can be facilitated by leukocyte-released cytokines (such as tumour necrosis factor) by decreasing connexin (Cx) protein expression, hampering the intercellular conduction between cardiomyocytes and non-cardiomyocytes (such as leukocytes), ultimately affecting the cardiomyocyte action potential morphology, or by activating fibroblasts to become myofibroblasts, resulting in collagen deposition, shaping an arrhythmogenic substrate. Electrical remodelling by leukocyte-released cytokines usually refers to effects on ion channel expression (such as the sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2a (SERCA2a)), leading to abnormal Ca²⁺ handling in cardiomyocytes. Both structural and electrical remodelling increase conduction heterogeneity and arrhythmogenicity. PLN, phospholamban; RYR2, ryanodine receptor 2; SR, sarcoplasmic reticulum.

Fig. 3 |. Macrophage–cardiomyocyte interactions.

a Macrophages are coupled to cardiomyocytes via connexin 43-containing gap junctions, which allow cation exchange that contributes to the steady-state cardiomyocyte action potential and improves atrioventricular node conduction. b | In the diseased heart, macrophages undergo phenotypic changes (for example, tissue-resident macrophages die and are replaced by monocyte-derived macrophages, which have distinct features) and are recruited in enormous numbers to the site of injury, affecting the cardiomyocyte action potential by modulating repolarization and conduction velocity and increasing conduction heterogeneity.

Fig. 4 |. Autoimmune channelopathies.

a | Autoantibodies released by plasma cells can either inhibit ventricular ion channels such as hERG and K_v1.4, producing long QT syndrome, or activate ventricular ion channels such as K_v7.1, producing short QT syndrome. b | In pacemaker cells, blockade of Ca²⁺ channel subunits by autoantibodies can generate atrioventricular block or sinus bradycardia.