Fig. 1. The heart beat is controlled by a hierarchical clock system (brain-heart) that synchronizes functions of cells within the sinoatrial node (SAN). The circadian system that orchestrates the circadian activity of the entire body is located in the suprachiasmatic nucleus (SCN). The master clock in the SCN, through its anatomical connection with the preautonomic motor neurons in the paraventricular nucleus of the hypothalamus (HyP), transmits signals to the parasympathetic and sympathetic nervous system enforcing its endogenous rhythmicity to the heart and other organs. Different sensory mechanisms (purple line) detect the SCN signaling in the lung and heart: carotid body (CB) chemical receptors, high-pressure baroreceptors (HPBR) and low-pressure baroreceptors (LPBR). Changes in the levels of hormonal influences such as atrial-natriuretic peptides (ANP), and mechanical factors such as atrial pressure are correlated with changes in circadian rhythms. Both the sympathetic and parasympathetic nervous systems innervate the sinoatrial node (red and green lines). The brain hierarchical clock system modulates heart rate and rhythm via neurotransmitter release from the vagal and sympathetic nerves to the SAN. Vagal nerve stimulates cholinergic receptors on the cell membrane (Ch-R) by acetylcholine (ACH), and sympathetic nerve stimulates adrenergic receptor (β-AR) also located on the cell membrane by norepinephrine (NE). Even in the absence of neuronal input via receptor stimulation, protein phosphorylation, driven by Ca²⁺ activation of calmodulin-adenylyl cyclase (AC)-dependent protein kinase A (PKA) and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) drives cardiac pacemaker sarcoplasmic reticulum (SR) Ca²⁺ cycling proteins (phospholamban (PLB) interacting with sarcoplasmic reticulum Ca²⁺-ATPase (SERCA), ryanodine receptor (RyR)) and surface membrane ion channels (K⁺ current (I_k), funny current (I_f), Na⁺-Ca²⁺ exchanger (NCX) and L-type current (I_Ca)). Phosphodiesterase (PDE) degrades cAMP and phosphatase (PPT) removes phosphate.