Genetics and Sinus Node Dysfunction.

Sinus node dysfunction (SND) is commonly encountered in the clinic. The clinical phenotype ranges from asymptomatic sinus bradycardia to complete atrial standstill. In some cases, sinus bradycardia is associated with other myocardial conditions such as congenital abnormalities, myocarditis, dystrophies, cardiomyopathies as well as fibrosis or other structural remodeling of the SA node.1-8 Although there are many etiologies for symptomatic slow heart rates, the only effective treatment available today is the implantation of a pacemaker. The predominant ion channel currents contributing to the pacemaker activity in the sinoatrial node (SAN) include currents flowing through hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels,9 Ltype Ca, Ttype Ca,10 delayed rectifier K,11,12 and acetylcholine (ACh)-activated13,14 channels. However, their relative contribution remains a matter of debate and the cellular mechanisms contributing to abnormal sinus node function leading to bradycardia are not fully elucidated. Sodium channel current (INa), encoded by SCN5A, is responsible for the cardiac action potential (AP) upstroke and therefore has an important role in initiation and propagation of the cardiac action potential. Although it is largely absent in the sinus node, it plays an important role at the periphery of the sinus node in transmitting electrical activity from the sinus node to the rest of the atria. Mutations in genes encoding structural anchoring proteins (ANK2, Caveolin3, AKAP9) have been associated with the development of atrial as well as ventricular arrhythmias.15, 16, 17 Sinus node dysfunction has been associated with a variety of atrial tachyarrhythmias, atrial fibrillation (AF) in particular. In recent years, numerous publications have focused on the genetic basis for ion channels and structural protein remodeling, providing further insights in the mechanisms of sinus node dysfunction and its role in AF. In this review, we will focus on the genetic aspects of the various forms of sinus node dysfunction and their relation to AF.