Genetic Complexity of Sinoatrial Node Dysfunction

Abstract

The pacemaker cells of the cardiac sinoatrial node (SAN) are essential for normal cardiac automaticity. Dysfunction in cardiac pacemaking results in human sinoatrial node dysfunction (SND). SND more generally occurs in the elderly population and is associated with impaired pacemaker function causing abnormal heart rhythm. Individuals with SND have a variety of symptoms including sinus bradycardia, sinus arrest, SAN block, bradycardia/tachycardia syndrome, and syncope. Importantly, individuals with SND report chronotropic incompetence in response to stress and/or exercise. SND may be genetic or secondary to systemic or cardiovascular conditions. Current management of patients with SND is limited to the relief of arrhythmia symptoms and pacemaker implantation if indicated. Lack of effective therapeutic measures that target the underlying causes of SND renders management of these patients challenging due to its progressive nature and has highlighted a critical need to improve our understanding of its underlying mechanistic basis of SND. This review focuses on current information on the genetics underlying SND, followed by future implications of this knowledge in the management of individuals with SND.

Inhibition of adenylyl cyclase 1 by ST034307 inhibits IP3-evoked changes in sino-atrial node beat rate

“…Additionally, sinus node dysfunction (or sick sinus syndrome) comprises a group of progressive non-curable diseases where the heart rate is inappropriately bradycardic or tachycardic, resulting in increased morbidity rates ( Alonso et al, 2014 ). In familial sinus node dysfunction, multiple different mutated proteins have been implicated including key Ca 2+ handling proteins such as RyR2, calsequestrin and Cav1.3, alongside HCN4 ( Wallace et al, 2021 ). The crucial importance of Ca 2+ handling and signalling to pacemaker function and apparent importance in sinus node dysfunction makes this an important potential target for the modulation of pacemaker activity in patients with sinus node dysfunction as well as patients with heart failure and AF.…”

Identifying digenic disease genes via machine learning in the Undiagnosed Diseases Network

“…107,108 In fact, many previously considered monogenic diseases are now being classified as oligogenic or multigenic with a range of phenotypes depending upon which genes and how many carry variants. 109,110 We also believe that there is the potential to integrate information from large-scale screens of genetic and synthetic lethal interactions in human cell lines and model organisms. [111][112][113][114][115][116] In summary, we have developed DiGePred, a method for identifying gene pairs with digenic disease potential, and generated predictions for all pairs of human genes.…”

Cross-talk between cAMP and Ca2+ signalling in cardiac pacemaker cells involves IP3-evoked Ca2+ release and stimulation of adenylyl cyclase 1

“…Sinus node dysfunction (or sick sinus syndrome) comprises a group of progressive non-curable diseases where the heart rate is inappropriately bradycardic or tachycardic, resulting in increased morbidity rates (Alonso et al ., 2014). In familial sinus node dysfunction, multiple different mutated proteins have been implicated including key Ca 2+ handling proteins such as RyR2, calsequestrin and Cav1.3, alongside HCN4 (Wallace et al ., 2021). The crucial importance of Ca 2+ handling and signalling to pacemaking and apparent importance in sinus node dysfunction makes this an important potential target for the modulation of pacemaking in patients with sinus node dysfunction as well as patients with heart failure and atrial fibrillation.…”