Abstract

The sinoatrial node (SAN) is the primary pacemaker of the heart and is responsible for generating the intrinsic heartbeat. Within the SAN, spontaneously active pacemaker cells initiate the electrical activity that causes the contraction of all cardiomyocytes. The firing rate of pacemaker cells depends on the slow diastolic depolarization (SDD) and determines the intrinsic heart rate (HR). To adapt cardiac output to varying physical demands, HR is regulated by the autonomic nervous system (ANS). The sympathetic and parasympathetic branches of the ANS innervate the SAN and regulate the firing rate of pacemaker cells by accelerating or decelerating SDD–a process well-known as the chronotropic effect. Although this process is of fundamental physiological relevance, it is still incompletely understood how it is mediated at the subcellular level. Over the past 20 years, most of the work to resolve the underlying cellular mechanisms has made use of genetically engineered mouse models. In this review, we focus on the findings from these mouse studies regarding the cellular mechanisms involved in the generation and regulation of the heartbeat, with particular focus on the highly debated role of the hyperpolarization-activated cyclic nucleotide-gated cation channel HCN4 in mediating the chronotropic effect. By focusing on experimental data obtained in mice and humans, but not in other species, we outline how findings obtained in mice relate to human physiology and pathophysiology and provide specific information on how dysfunction or loss of HCN4 channels leads to human SAN disease.

Highlights

  • Anatomy and Structure of the Sinoatrial Node and Sinoatrial Node NetworkThe sinoatrial node (SAN) is a spindle-shaped structure located at the posterior side of the right atrium of the heart (Figure 1)

  • The SAN network is composed of different cell types comprising spontaneously active pacemaker cells that are interspersed with fibroblasts and embedded within a matrix of fibrous connective tissue, predominately consisting of elastin and collagen (Monfredi et al, 2010; Ho and Sanchez-Quintana, 2016)

  • It is known that the functional interactions of individual pacemaker cells in this cellular network with each other and with the other cell types in the network are of general importance for electrical synchronization to a common electrical rhythm of the sinus node

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Summary

Introduction

Anatomy and Structure of the Sinoatrial Node and Sinoatrial Node NetworkThe sinoatrial node (SAN) is a spindle-shaped structure located at the posterior side of the right atrium of the heart (Figure 1). CAMP binds to a variety of target proteins in the cell, which results in acceleration of SDD and the firing rate of pacemaker cells and HR increase (positive chronotropic effect).

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