Canine and human sinoatrial node: differences and similarities in the structure, function, molecular profiles, and arrhythmia

Abstract

The sinoatrial node (SAN) is the primary pacemaker in canine and human hearts. The SAN in both species has a unique three-dimensional heterogeneous structure characterized by small pacemaker myocytes enmeshed within fibrotic strands, which partially insulate the cells from aberrant atrial activation. The SAN pacemaker tissue expresses a unique signature of proteins and receptors that mediate SAN automaticity, ion channel currents, and cell-to-cell communication, which are predominantly similar in both species. Recent intramural optical mapping, integrated with structural and molecular studies, has revealed the existence of up to five specialized SAN conduction pathways that preferentially conduct electrical activation to atrial tissues. The intrinsic heart rate, intranodal leading pacemaker shifts, and changes in conduction in response to physiological and pathophysiological stimuli are similar. Structural and/or functional impairments due to cardiac diseases including heart failure cause SAN dysfunctions (SNDs) in both species. These dysfunctions are usually manifested as severe bradycardia, tachy-brady arrhythmias, and conduction abnormalities including exit block and SAN reentry, which could lead to atrial tachycardia and fibrillation, cardiac arrest, and heart failure. Pharmaceutical drugs and implantable pacemakers are only partially successful in managing SNDs, emphasizing a critical need to develop targeted mechanism-based therapies to treat SNDs. Because several structural and functional characteristics are similar between the canine and human SAN, research in these species may be mutually beneficial for developing novel treatment approaches. This review describes structural, functional, and molecular similarities and differences between the canine and human SAN, with special emphasis on arrhythmias and unique causal mechanisms of SND in diseased hearts.

Introduction

The sinoatrial node (SAN), described as the primary cardiac pacemaker, is the source of intrinsic electrical activation consistently driving the coordinated rhythmic contractions of the mammalian heart [1], [2]. It initiates the heartbeat via a combination of pacemaker cells, which generate spontaneous cellular electrical signals, and specialized conduction pathways, which conduct the electrical impulses from pacemaker cells to adjacent atrial tissue [3], [4]. The SAN has the unique ability to match the heart rate (HR) with physiological demands, thereby modulating healthy cardiac function and output. It goes without saying that abnormal SAN function can inappropriately accelerate or slow the HR, which may result in fatal cardiac arrhythmias. Abnormal SAN function can predispose to heart disease including atrial fibrillation (AF) and heart failure (HF) in humans; on the flip side, preexisting heart disease including AF and HF can induce SAN dysfunction (SND) in human, which can result in syncope and sudden cardiac death [5], [6]. Currently, SND in both human and canine is often treated with pharmaceutical interventions and implantable pacemakers with variable success rates [7], [8], [9].

Given the central and critical role that the SAN plays in maintaining the HR and cardiac function, understanding the complex mechanisms involved in SAN function is of utmost importance to diagnose and treat SND in canine and human patients. In fact, the current demographics predict that the number of human SND patients will continue to increase from 78,000 in 2012 to nearly 172,000 by 2060 as a main indication for permanent artificial pacemaker implantation [9]. The prevalence and severity of SND in both canines [7] and humans emphasize the need for more detailed studies that identify and describe structural and functional aspects of the SAN that can be efficiently targeted to treat and/or prevent worsening SND. However, despite several decades of impressive progress in our understanding of the workings of the SAN, we are yet to completely describe its intriguing three-dimensional (3D) complexity [10], [11], [12].

Most of the seminal findings have come from studies using animal models ranging from rabbit, mouse, cat, dog, and pig [13]. More recently, direct examinations of the structure and function of the human SAN ex vivo are possible owing to the increased availability of explanted human hearts for research purposes [11], [14]. Although small animal models such as mouse and rabbit [15], [16], [17] have significantly contributed toward our understanding of the SAN, they have multiple limitations primarily due to faster intrinsic heart rhythm and two-dimensional SAN structure compared with the 3D human SAN. In contrast, the canine SAN closely resembles its human counterpart in many critical aspects, including 3D architecture, ultrastructural characteristics, and function [4]. Studies using an integrated approach of combining structural, molecular, and functional analyses demonstrate that mechanisms known to cause SND in canines and human are predominantly similar [18], [19], [20]. Hence, studies on the SAN in these two species may prove to be mutually beneficial to understand naturally occurring disease-causing mechanisms, explore novel treatment options including pharmaceutical and/or genetic manipulations, and test outcomes of implantable pacemakers. Of note, the studies on control canine SAN mentioned throughout this review were mainly completed in young adult (∼1–4 years old) mongrel canines (∼18–25 kg) [19], [20], [21], [22], [23]. This review will focus on critical structural and molecular and functional characteristics of the SAN that are common and different between the canine and human SAN, with special emphasis on arrhythmias and unique causal mechanisms of SND in diseased hearts, to identify novel therapeutic modalities.