Embryological development of pacemaker hierarchy and membrane currents related to the function of the adult sinus node: implications for autonomic modulation of biopacemakers

Abstract

The sinus node is an inhomogeneous structure. In the embryonic heart all myocytes have sinus node type pacemaker channels (I (f)) in their sarcolemma. Shortly before birth, these channels disappear from the ventricular myocytes. The response of the adult sinus node to changes in the interstitium, in particular to (neuro)transmitters, results from the interplay between the responses of all of its constituent cells. The response of the whole sinus node cannot be simply deduced from these cellular responses, because all cells have different responses to specific agonists. A biological pacemaker will be more homogeneous. Therefore it can be anticipated that tuning of cycle length may be problematic. It is discussed that efforts to create a biological pacemaker responsive to vagal stimulation, may be counterproductive, because it may have the potential risk of 'standstill' of the biological pacemaker. A normal sinus node remains spontaneously active at high concentrations of acetylcholine, because it has areas that are unresponsive to acetylcholine. The same is pertinent to other substances with a negative chronotropic effect. Such functional inhomogeneity is lacking in biological pacemakers.

β-Adrenergic Stimulation Synchronizes a Broad Spectrum of Action Potential Firing Rates of Cardiac Pacemaker Cells toward a Higher Population Average

“…Cholinergic receptor stimulation causes some SAN cells to become silent, which contributes to a rate decrease as proposed by Fenske et al [9]. Still other areas may be unresponsive to acetylcholine [44]. Using small tissue pieces dissected from rabbit SA node, Opthof et al [45] found that SA node pieces bordering the left atrium were quiescent when dissected, but became activated to fire APs in the presence of adrenaline or acetylcholine.…”

Augmentation of myocardial If dysregulates calcium homeostasis and causes adverse cardiac remodeling

“…It is well documented that I f and the expression of the main ventricular HCN isoforms 2 and 4 are significantly increased in ventricular moycytes of heart failure patients 5,11,28 . These changes are considered reminiscent of the immature myocytic phenotype, based on the fact that during pathological remodeling several early genes reappear in reverse order compared to embryonic development 29 . To mimic maladaptive upregulation of HCN4 in our model, the cTNI promoter was used to activate hHCN4 transcription from the intermediate-late phase of fetal development on 30 , leading to augmented levels in the myocardium throughout postnatal and adult stages, normally characterized by low HCN4 expression 6 .…”

Neurohumoral Control of Sinoatrial Node Activity and Heart Rate: Insight From Experimental Models and Findings From Humans

“…The SAN is heavily innervated, with a complex network of nerve fibers and ganglia whose density is much higher than the surrounding myocardium (Roberts et al, 1989;Chow et al, 2001;Newton et al, 2014;Pauza et al, 2014;Stoyek et al, 2015;Inokaitis et al, 2016). Yet the SAN is not ubiquitously innervated and this, along with variable receptor densities throughout the node, make it functionally heterogeneous (MacKaay et al, 1980;Opthof, 2007). Sympathetic control will dominate in heavily innervated regions and areas with high receptor density, whereas these regions may be silenced by parasympathetic control, such that areas with fewer receptors or little innervation would then determine rate.…”