Sinus node dysfunction: current understanding and future directions

Abstract

The sinoatrial node (SAN) is the primary pacemaker of the heart. Normal SAN function is crucial in maintaining proper cardiac rhythm and contraction. Sinus node dysfunction (SND) is due to abnormalities within the SAN which can affect the heartbeat frequency, regularity, and the propagation of electrical pulses through the cardiac conduction system. As a result, SND often increases the risk of cardiac arrhythmias. SND is most commonly seen as a disease of the elderly given the role of degenerative fibrosis as well as other age-dependent changes in its pathogenesis. Despite the prevalence of SND, current treatment is limited to pacemaker implantation, which is associated with substantial medical costs and complications. Emerging evidence has identified various genetic abnormalities that can cause SND, shedding light on the molecular underpinnings of SND. Identification of these molecular mechanisms and pathways implicated in the pathogenesis of SND is hoped to identify novel therapeutic targets for the development of more effective therapies for this disease. In this review article, we examine the anatomy of the SAN and the pathophysiology and epidemiology of SND. We then discuss in detail the most common genetic mutations correlated with SND and provide our perspectives on future research and therapeutic opportunities in this field.

Epigenetic and Genetic Mechanisms Underlying Cardiovascular Diseases and Neurodevelopmental Disorders

“…In addition, studies have shown that the increase of pyruvate kinase M2 (PKM2) protein expression in PAH can promote the phosphorylation of ERK1/2 and further upregulate the expression of key glycolytic enzymes LDHA and GLUT1, thereby participating in vascular remodeling in PAH. However, increasing shikonin decreased the protein level of PKM2, decreased the phosphorylation level of ERK1/2 and the expression level of GLUT1 protein, and inhibited the progression of PAH (Li et al, 2023). A hypoxia-induced adaptive response is initiated by HIF-1, which increases or represses the expression of genes regulating vascular tone, autophagic response, cell metabolism, and proliferation.…”

Selection of patients with symptomatic vagal-induced sinus node dysfunction: Who will be the best candidate for cardioneuroablation?

“…The relationship between symptoms and emotional or psychological distress, physical activity, positional changes, medical measures, and typical triggers (cough, prolonged upright posture, urination, and defecation) should be explored along with pulse rate change, if measured during an episode ( Kusumoto et al, 2019 ). In addition, family history provides data on irreversible genetic abnormalities, including familial SND, inherited cardiomyopathies, or inheritable arrhythmic conditions associated with SND (catecholaminergic polymorphic ventricular tachycardia and long QT syndrome) that are often attributed to gene mutation ( Manoj et al, 2022 ). Physical examination and a detailed history help exclude systemic diseases, drug effects, and surgical trauma.…”

“…Observing the heart rate response through pharmacologic interventions is not frequently warranted in clinical practice, but the evaluation of the intrinsic heart rate might be helpful if there is a question regarding intrinsic versus extrinsic SND. As an anticholinergic agent, atropine can simulate the effect of vagal denervation, manifesting an acceleration of both spontaneous depolarization of sinoatrial node pacemaker cells and atrioventricular conduction, which increases heart rate ( Manoj et al, 2022 ). Thus, dysfunction of the sinus node in a patient with bradyarrhythmia, which might be attributed to vagal overactivity, could restore partly or completely when vagal neural control was largely eliminated using atropine.…”

Use of machine learning and Poincaré density grid in the diagnosis of sinus node dysfunction caused by sinoatrial conduction block in dogs

“…The pacing cells synchronize to generate an impulse of sufficient strength to propagate through sinoatrial conduction pathways to excite the atrial myocardium 3,4 . Additionally, the sinus node and conduction pathways contain fibrous tissue 5 and connexin 45 2,6 and no connexin 43 7 resulting in low conductance. The slowed conduction from the sinus node to the atria permits charge to build and overcome the source‐sink difficulty 2,8 .…”

“…Additionally, the sinus node and conduction pathways contain fibrous tissue 5 and connexin 45 2,6 and no connexin 43 7 resulting in low conductance. The slowed conduction from the sinus node to the atria permits charge to build and overcome the source‐sink difficulty 2,8 . However, these features that assure enough current to overcome the source‐sink challenge are also those that are vulnerable to alterations that slow impulse propagation leading to sinus node dysfunction (Figure 1).…”