Regulation of cardiac pacemaking activities in health and disease

The human heart beats 60-80 times a minute, which can amount to more than 3 billion heartbeats in one's lifetime. Each heartbeat is initiated by the sinoatrial node (SAN), a highly complex structure consisting of specialized cells that spontaneously fire action potentials (APs), propagating throughout the heart. Its automaticity is orchestrated by ion channels and transporters that contribute to the membrane and Ca²⁺ clocks, collectively known as the 'coupled clock'. Their activity is tightly regulated by autonomic and hormonal signalling pathways, most prominently β-adrenergic receptor (β-AR) signalling, which increases heart rate via activation of adenylyl cyclase (AC) and subsequent production of 3',5'-cyclic adenosine monophosphate (cAMP). In contrast, parasympathetic signalling through muscarinic M₂ receptors reduces cAMP levels and activates inwardly rectifying K⁺ currents, thereby slowing pacemaker activity. The current topical review discusses recent literature encompassing the mechanisms of SAN regulation in health and disease, including cardiac arrhythmia syndrome such as catecholaminergic polymorphic ventricular arrhythmia, autoimmune cardiac ion channelopathies, and SAN dysfunction in heart failure (HF). SAN dysfunction in HF frequently manifests as bradyarrhythmia, a complication that significantly increases the morbidity and mortality of HF patients and confers an increased risk of sudden cardiac death. Recent studies support the previously unrecognized roles of mitochondrial-sarcoplasmic reticulum connectomics in SAN dysfunction commonly seen with HF. In addition, the roles of distinct AC isoforms that are preferentially expressed and compartmentalized in the SAN to serve a specialized function will be discussed. Finally, the review will consider recent advances in the development of biological pacemakers.