Sinus node disease

Sinus node dysfunction (SND), formerly known as sick sinus syndrome, is a condition affecting the sinoatrial node, the heart’s natural pacemaker. It is often age-related, resulting from progressive, degenerative fibrosis of the sinoatrial node tissue and surrounding atrial myocardium. These structural changes impair impulse generation and conduction, leading to various syndromes. Clinically, SND frequently presents as sinus bradycardia, where the heart rate drops below 50 beats per minute. This reduced heart rate can cause symptoms such as dizziness, syncope (sudden loss of consciousness), or, in rare cases, cardiac arrest. Other characteristic ECG changes include chronotropic incompetence (inability to increase heart rate adequately under stress), sinus pause, sinus arrest, various degrees of sinoatrial exit block, atrial fibrillation, and atrioventricular (AV) block.

Genetics plays a critical role, particularly in inherited forms of SND. Although most cases of SND are acquired, there are also familial or idiopathic forms caused by genetic factors. These genetic forms, while less common, are clinically significant as they can manifest earlier in life. The genetic heterogeneity of SND means that a large number of different genes may contribute to its development, complicating diagnosis. Currently, it is estimated that genetic causes can be definitively identified in fewer than 25% of idiopathic or familial SND cases. Most inherited cases follow an autosomal dominant inheritance pattern, while other modes of inheritance, such as X-linked or recessive inheritance, as well as complex genetic mechanisms like digenic traits or copy number variations (CNVs), are rare.

Most familial forms of sinus node dysfunction are inherited in an autosomal dominant manner. Each child of an affected individual has a 50% probability of inheriting the familial pathogenic variant.

Diagnosis is based on clinical and electrocardiographic findings and may be supported by molecular genetic testing. Surface electrocardiography, ambulatory Holter monitoring, exercise testing, and implantable loop recording can document sinus node dysfunction (sinus bradycardia, sinus pauses or arrest, sinoatrial exit block, chronotropic incompetence, or tachycardia-bradycardia syndrome).

Familial cases typically present at significantly younger ages than acquired sinus node dysfunction and may be accompanied by a positive family history of conduction disease, arrhythmia, or pacemaker implantation, prompting molecular genetic investigation. Identification of a pathogenic variant can confirm the underlying genetic cause in an appropriate clinical context.

SND can be classified into isolated and syndromic forms, as well as those associated with cardiomyopathies such as dilated cardiomyopathy (DCM). Isolated forms typically occur without structural cardiac changes and stem fromdisruptions in the electrical signal transmission of the sinoatrial node itself. In contrast, syndromic forms of SND areassociated with other clinical phenomena, often posing additional diagnostic challenges. Syndromic SND is usually part of a broader disease profile involving other systemic or structural anomalies, such as coronary artery disease (CAD) or neurological phenotypes, where SND represents only one aspect of a more complex disorder. In these syndromes, SND can occur alongside other symptoms and complications that indicate an underlying multisystem disorder. This multitude of possible causes makes SND a clinically very heterogeneous disease. 

The degeneration of the sinoatrial node is often exacerbated by age-related changes in heart tissue, but can also occur under other pathological conditions. Besides age-related degeneration, other factors contributing to SND include ischaemia, infiltrative diseases such as sarcoidosis or amyloidosis, infections, cardiac surgeries, and certain medications. Systemic conditions such as hypothyroidism, autonomic dysfunctions, and abnormally increased vagal tone may also play a role.