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.

Keywords: Atrial fibrillation; Fibrosis; Pacemakers; Sick sinus syndrome; Sinoatrial node dysfunction.

Figure 1:. Structural and functional characteristics of the canine and human sinoatrial node (SAN) pacemaker complex.

(A) 3 dimensional model of the canine SAN based on structural and functional data from intramural optical mapping. Compact SAN (red) is isolated from the surrounding atrial myocardium (green) by bifurcating coronary arteries (blue) and fibrotic insulation (purple). Preferential sinoatrial conduction pathways (SACPs) are depicted by yellow bundles and arrows that electrically connect SAN to the atrium. (B) 3-dimensional reconstruction of the human SAN showing intranodal pacemaker compartments and 5 SACPs. (C) Histological features of the canine and human SAN pacemaker complex revealed by Masson’s trichrome staining. (D) Immunostaining identifies the SAN by negative connexin 43 (Cx43) expression. [(A) Data modified from Fedorov et al. Am J Physiol Heart Circ Physiol 2012 [37]; (B) (C) and (D) Figures modified from Li et al. Sci Transl Med 2017 (Human) [11] and Lou et al. Circulation 2014 (Canine) [19]]. BB: Bachmann bundle; CT: crista terminalis; EAS: earliest atrial activation site; FP: fat pad; IAS: interatrial septum; PV: pulmonary veins; RA: right atrium; RAA: right atrial appendage; RAFW: right atrial free wall; SAN: sinoatrial node; SVC: superior vena cava.

Figure 2:. Atrial activation pattern is determined by the sinoatrial conduction pathway (SACP) during sinus rhythm.

(A) 3-dimensional view of the sinoatrial node (SAN) complex (B) Intranodal and atrial activation patterns revealed by high resolution optical maps. (C) Traces of SAN and atrial Electrocardiograms (ECG) or optical action potentials (OAP) from canine and human during sinus rhythm. (D) Schematic representation of canine and human SAN depicting shift in leading pacemaker sites and earliest atrial activation site at baseline and after adenosine (Ado). Blocked arrows indicate nonfunctional mid-lateral conduction pathway in canine heart failure (HF) preparations. [(A-D) Sinoatrial node figures and traces were modified from Li et al. Sci Transl Med 2017 (Human) [11] and Lou et al. Circulation 2014 (Canine) [19]]. CT: crista terminalis; EAS: earliest atrial activation site; IAS: interatrial septum; IVC: inferior vena cava; LAA: left atrial appendage; LP: leading pacemaker; OAP: optical action potential; PV: pulmonary veins; RA: right atrium; RAA: right atrial appendage; RAFW: right atrial free wall; SACPs: sinoatrial conduction pathway; SACTsr: sinoatrial conduction time during sinus rhythm; SAN: sinoatrial node; SCL: sinus cycle length; SVC: superior vena cava.

Figure 3:. Pacing induced automaticity depression and sinoatrial node (SAN) exit blocks during adenosine (Ado) perfusion in failing canine and human hearts.

(A) Sinoatrial node optical action potential (OAP) and atrial electrocardiogram (ECG) recordings during and after pacing showing 2:1 SAN entrance block and subsequent exit blocks in a canine heart failure (HF) model. (B) Atrial and SAN OAPs during and after pacing showing exit blocks. [Data modified from (A) Lou et al. Circulation 2014 [19] and (B) Li et al. Sci Transl Med 2017 [11]]. SACT: sinoatrial conduction time; (c)SNRTi/d: (corrected) sinus node recovery time, indirect/direct.

Figure 4:. Sinoatrial node (SAN) reentry could lead to both tachycardia and bradycardia in experimental chronic canine myocardial infarction (MI) and heart failure (HF) models.

(A) In vivo electrocardiogram (ECG) recordings reveal maximum atrial pauses in post-MI canines at rest and ex vivo atrial ECG and SAN optical action potential (OAP) representing tachycardia and bradycardia due to SAN macro- and micro-reentry, respectively. (B) (Left) SAN model and epicardial activation map of fast-slow SAN macro-reentry in a canine model of chronic experimental MI. (Right) Micro-reentry within SAN and exit block in sinoatrial conduction pathways (SACPs) in HF model. [(A) Data modified from Glukhov et al. Circ Arrhythm Electrophysiol 2013 [22] (B-D) Data and models modified from Lou et al. Circulation 2014 [19]]. CT: crista terminalis; Endo: endocardium; Epi: epicardium; SACPs: sinoatrial conduction pathway; SVC: superior vena cava.

Figure 5:. Fibrosis and structural remodeling of the canine and human sinoatrial node (SAN) pacemaker complex.

(A) Graph showing increasing percentage of age-related fibrous tissue volume to the total SAN volume, mean value, and standard deviation. (B) Histological Masson’s trichrome staining of human SAN with lateral SAN conduction pathways (SACP) outlined. (C) A sister section to panel (B) immunostained for connexin 43 (Cx43; green) and vimentin (red) showing increasing gradient of Cx43 expression from SAN to atria. (D) Summary data and Masson’s trichrome staining of fibrosis (blue) in the canine SAN pacemaker complex and SACP in control vs. heart failure (HF). [(A) From Shiraishi et al 1992 [42] (used with permission); (B,C) Data modified from Csepe et al Prog Biophys Mol Biol. 2016 [14] (D) Data adapted from Lou et al Circulation. 2014 [19]]. CT: crista terminalis.

Figure 6:. Heterogeneous protein expression in the sinoatrial node (SAN) vs. adjacent atrial tissue.

(A) Protein expression of hyperpolarization-activated cyclic nucleotide-gated channel (HCN) 1, 2 and 4 isoforms (left) and adenosine A1 receptor (A1R) and G protein-coupled inwardly rectifying potassium channel (GIRK4) (right), and summary data below show that these proteins are significantly higher in the SAN relative to atrial tissues; (B) Left, immunoblots showing protein expression pattern of A1R in the SAN compartments and in the atrial myocardium of control canine hearts ; right, summary of these data shows that A1R expression is significantly upregulated in the SAN compartments in heart failure (HF). [(A) Li et al. Circ Arrhythm Electrophysiol. 2015 [58] and Li et al. Sci Transl Med 2017 [11]; (B) Data modified from Lou et al. Circulation 2014 [19] (left)]. CT: crista terminalis; GAPDH: Glyceraldehyde 3-phosphate dehydrogenase; IAS: interatrial septum; RAFW: right atrial free wall.