The genetic basis for inherited forms of sinoatrial dysfunction and atrioventricular node dysfunction

Abstract

The sinoatrial node (SAN) and the atrioventricular node (AVN) are the anatomical and functional regions of the heart which play critical roles in the generation and conduction of the electrical impulse. Their functions are ensured by peculiar structural cytological properties and specific collections of ion channels. Impairment of SAN and AVN activity is generally acquired,but in some cases familial inheritance has been established and therefore a genetic cause is involved. In recent years, combined efforts of clinical practice and experimental basic science studies have identified and characterized several causative gene mutations associated with the nodal syndromes. Channelopathies, i.e., diseases associated with defective ion channels, remain the major cause of genetically determined nodal arrhythmias; however, it is becoming increasingly evident that mutations in other classes of regulatory and structural proteins also have profound pathophysiological roles. In this review, we will present some aspects of the genetic identification of the molecular mechanism underlying both SAN and AVN dysfunctions with a particular focus on mutations of the Na, pacemaker (HCN), and Ca channels. Genetic defects in regulatory proteins and calcium-handling proteins will be also considered. In conclusion, the identification of the genetic defects associated with familial nodal dysfunction is an essential step for implementing an appropriate therapeutic treatment.

Novel SCN5A Frameshift Mutation in Brugada Syndrome Associated With Complex Arrhythmic Phenotype

“…In fact, mutations in the SCN5A gene have been found responsible for atrial fibrillation, Long QT syndrome type 3, sick sinus syndrome type 2, idiopathic ventricular fibrillation, and heart block type 1A (Olson et al, 2005). While atrial fibrillation is the most common arrhythmia to overlap with BrS, cases of supraventricular tachycardia have been described (Milanesi et al, 2015). An article by Hasdemir et al (2015) studied 96 patients with AVNRT screened for BrS.…”

Mutations in NaV1.5 Reveal Calcium-Calmodulin Regulation of Sodium Channel

“…Although I Na does not contribute to the action potential of pacemaker cells, its presence in the periphery of the sinoatrial node can modulate impulse conduction and heart rate (Kodama et al, 1997). Hence, loss-of-function mutations in SCN5A can result in a nodal dysfunction (Benson et al, 2003; Lei et al, 2008; Gui et al, 2010; Ziyadeh-Isleem et al, 2014; Chiang et al, 2015; Milanesi et al, 2015).…”

Impaired neuronal sodium channels cause intranodal conduction failure and reentrant arrhythmias in human sinoatrial node

“…These results establish a significant role for Nav channels in maintaining stable intranodal conduction and robust protection of human SAN rhythm, in both HF and non-failing hearts. In the light of our findings, we suggest that impaired intranodal conduction could underlie clinically observed symptoms of familial sick sinus syndrome including sinus bradycardia/arrest in some patients carrying SCN5A mutations 18,31 .…”