Ion Channel Disorders and Sudden Cardiac Death

Abstract

Long QT syndrome, short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia are inherited primary electrical disorders that predispose to sudden cardiac death in the absence of structural heart disease. Also known as cardiac channelopathies, primary electrical disorders respond to mutations in genes encoding cardiac ion channels and/or their regulatory proteins, which result in modifications in the cardiac action potential or in the intracellular calcium handling that lead to electrical instability and life-threatening ventricular arrhythmias. These disorders may have low penetrance and expressivity, making clinical diagnosis often challenging. However, because sudden cardiac death might be the first presenting symptom of the disease, early diagnosis becomes essential. Genetic testing might be helpful in this regard, providing a definite diagnosis in some patients. Yet important limitations still exist, with a significant proportion of patients remaining with no causative mutation identifiable after genetic testing. This review aims to provide the latest knowledge on the genetic basis of cardiac channelopathies and discuss the role of the affected proteins in the pathophysiology of each one of these diseases.

Keywords: Brugada syndrome; catecholaminergic polymorphic ventricular tachycardia; channelopathies; ion channel; long QT syndrome; primary electrical disorders; short QT syndrome; sudden cardiac death.

Figure 1

(A) Cardiac action potential and transmembrane ionic currents that participate in each phase. Phase 0: rapid depolarization due to entrance of Na⁺ currents into the cell. Phase 1: early repolarization initiated by outward K⁺ I_to currents. Phase 2: a plateau phase marked by the Ca²⁺ entry into the cell against K⁺ outward repolarizing currents. Phase 3: end of repolarization produced by K⁺ currents upon Ca²⁺ channel-inactivation. Phase 4: resting membrane potential (≈−90 mV) determined by inward-rectifier K⁺ currents. OW: outward currents. IW: inward currents. (B) Excitation-contraction coupling: during action potential, Ca²⁺ entry in phase 2 induces a large release of Ca²⁺ from the sarcoplasmic reticulum through the RyR2 receptor that allows cell contraction. After repolarization, Ca²⁺ is extruded from the cell through the Na⁺/Ca²⁺ exchanger or taken back into the sarcoplasmic reticulum through SERCA2a to allow cell relaxation.

Figure 2

Electrocardiographic findings in the four primary electrical disorders or channelopathies. (A) LQTS, with prolonged QT interval; (B) SQTS, with shortened QT interval; (C) BrS. In this case, ECG at baseline was normal (C1), but the typical pattern, with ST-segment elevation in right precordial leads, was unmasked after a provocative test with sodium-blockers (D2); (D) CPVT. ECG is normal at baseline (D1), but premature ventricular complexes and occurrence of bidirectional tachycardia appear with exercise (D2). Characteristic ECG features of each disorder are circled in red.

Figure 3

Schematic representation of the pathophysiological mechanisms involved in the four main primary electrical disorders. (A) in LQTS, either by a decrease in K⁺ currents (A1) or an increase in Na⁺ currents (A2), AP duration is prolonged, and so is the QTc interval on the ECG (depicted by the bottom horizontal lines: in black normal QT, in red long-QT interval). This situation favors the development of early afterdepolarizations, the trigger of ventricular arrhythmias in LQTS patients (A3). (B) in SQTS, an increase in K⁺ currents accelerates repolarization (B1), and manifests as short QTc interval in the ECG (depicted by the bottom horizontal lines: in black normal QT, in red short-QT interval); in those cases of SQTS caused by loss-of-function mutations in the calcium channel (B2), besides shortening of the AP duration there is transmural gradient in early phases of repolarization, leading to ST-segment elevation like the one seen in BrS (combined phenotype, QT interval depicted by horizontal lines and ST segment elevation by the red arrow). In SQTS, an increased dispersion of repolarization favors the appearance of atrial and ventricular arrhythmias (B3). (C) In BrS, a decrease in Na⁺ currents (C1) or, less commonly, an increase in I_to currents (C2); produces a ionic imbalance in early repolarization, giving rise to the characteristic ST-segment elevation seen in the ECG (depicted by the red arrows). The consequent epicardial and transmural dispersion of repolarization favors ventricular arrhythmias by a mechanism of phase-2 reentry (C3). (D) CPVT is produced by abnormal Ca²⁺ leak from the sarcoplasmic reticulum (D1), which favors the occurrence of delayed afterdepolarizations, which in turn can trigger ventricular arrhythmias (D2). Modified from [6].