Cardiac Channelopathies: Clinical Diagnosis and Promising Therapeutics

Abstract

Cardiac channelopathies, also known as primary electrical heart diseases, are inherited genetic abnormalities of cardiomyocyte electrical behavior. Notable for their absence of structural heart diseases, they include a diverse group of diseases such as long QT syndrome, short QT syndrome, Brugada syndrome, early repolarization syndrome, catecholaminergic polymorphic ventricular tachycardia, and idiopathic ventricular fibrillation, and carry the risk of malignant arrhythmias leading to sudden cardiac death. The genetic and molecular foundations of these diseases are diverse and complex, with evolving research highlighting the multifactorial nature of their pathophysiology and the intricate interplay of various genes in the manifestation of arrhythmias. While advances in diagnostic techniques, such as genetic testing and electrophysiological studies, have improved the identification and management of these conditions, the relationship between specific genetic mutations and sudden cardiac death remains incompletely understood. This review provides an overview of the molecular and genetic mechanisms underlying those inherited arrhythmias, exploring both well-established and emerging data. Additionally, it discusses current diagnostic approaches and management strategies, aiming to enhance the understanding of these conditions and contribute to better sudden cardiac death prevention.

Keywords: cardiac electrophysiology; channelopathies; heart rhythm disorders; inherited arrhythmias; sudden cardiac death.

Figure 1. Overview of most common channelopathies.

This figure presents a comprehensive summary of the 6 most common channelopathies. Each channelopathy is presented with key details including prevalence in the general population, major genes responsible for the development of the disease, clinical assessment with common and channelopathy‐specific diagnostic methods, along with available pharmacological and surgical interventions for the management of these disorders. This figure was created with BioRender.com. AECG indicates ambulator ECG; CMR, cardiac magnetic resonance imaging; EPS, electrophysiological study; ETT, exercise treadmill test; ICD, implantable cardioverter defibrillator; ILR, implantable loop recorder; IV, intravenous; LCSD, left cardiac sympathetic denervation; NSBBs, nonselective β blockers; PDE, phosphodiesterase; RCSD, right cardiac sympathetic denervation; and SCB, sodium channel blockers.

Figure 2. Typical and common arrhythmogenic channelopathies.

Shown are representative ECGs for normal cardiac function and most prevalent arrhythmogenic channelopathies. Panels are annotated to highlight specific abnormal feature characteristic of the respective channelopathy. This figure was created with BioRender.com. BrS indicates Brugada syndrome; CPVT, catecholaminergic polymorphic ventricular tachycardia; ERS, early repolarization syndrome; IVF, idiopathic ventricular fibrillation; LQTS, long QT syndrome; and SQTS, short QT syndrome.