Fibrosis: a structural modulator of sinoatrial node physiology and dysfunction

Abstract

Heart rhythm is initialized and controlled by the Sinoatrial Node (SAN), the primary pacemaker of the heart. The SAN is a heterogeneous multi-compartment structure characterized by clusters of specialized cardiomyocytes enmeshed within strands of connective tissue or fibrosis. Intranodal fibrosis is emerging as an important modulator of structural and functional integrity of the SAN pacemaker complex. In adult human hearts, fatty tissue and fibrosis insulate the SAN from the hyperpolarizing effect of the surrounding atria while electrical communication between the SAN and right atrium is restricted to discrete SAN conduction pathways. The amount of fibrosis within the SAN is inversely correlated with heart rate, while age and heart size are positively correlated with fibrosis. Pathological upregulation of fibrosis within the SAN may lead to tachycardia-bradycardia arrhythmias and cardiac arrest, possibly due to SAN reentry and exit block, and is associated with atrial fibrillation, ventricular arrhythmias, heart failure and myocardial infarction. In this review, we will discuss current literature on the role of fibrosis in normal SAN structure and function, as well as the causes and consequences of SAN fibrosis upregulation in disease conditions.

Keywords: aging; atrial fibrillation; exit block; fibrosis; heart failure; sinoatrial node; sinoatrial reentry; sinus node dysfunction.

Figure 1

(A) Left: Drawing of the posterior human atrial anatomy from (Keith and Flack, 1907), with SAN outlined in red. Right: Histological cross section of the SAN (red outline) connected to the atria by a SACP (yellow outline). The SAN is seen to be isolated from the atria by sup-epicardial fat and connective tissue. Modified from Fedorov et al. (2010b, 2012) with permission. (B) 1—Scanning electron micrograph of the SAN and nodal artery (NA) of a cross section through the CT after digestion of the nodal cells. The collagenous sheaths of endomysial fibrosis formed a complex network in the gaps between the nodal cells, whereas occasional perimysial septums were seen between them. 2—Scanning electron micrograph of non-macerated SAN cells (N), which are encased in dense and coarse endomysial sheaths (yellow arrows) in a specimen from a 75 year old. 3—Scanning electron micrograph of a cross section through the CT, after digestion, from a specimen of 70 years shows a diffuse notable excess of endomysial sheaths (yellow arrows) indicating focal interstitial reactive fibrosis. Vascular space (V) corresponds to a coronary vein. 4—Scanning electron micrograph of non-macerated cross section through the body of the CT shows mainly longitudinal fibers (H) with intermingling oblique (O) or lateral (L) fibers. From Sanchez-Quintana et al. (2002) with permission. (C) Graph showing percentage of fibrous connective tissue volume to the total SAN volume, mean value, and standard deviation. From Shiraishi et al. (1992); used with permission. (D) Fibrosis in the SAN is increased in HF vs. control dog. Left: A structural model of the control canine SAN complex and SACPs. Middle: histological sections showing upregulated fibrotic and fatty content in SAN complex (black outline) and SACP in HF (bottom, blue box) compared to control (top, green box). Right: A structural model of the heart failure SAN complex and SACPs, showing upregulated intranodal fibrosis (blue fibrotic strands). Modified from Lou et al. (2014) with permission. Abbreviations: CT, crista terminalis; Endo, endocardium; Epi, epicardium; HF, heart failure; IAS, interatrial septum; PV, pulmonary veins; RAA, right atrial appendage; RV, right ventricle; SACP, sinoatrial conduction pathway; SAN, sinoatrial node; SVC and IVC, superior and inferior vena cava.

Figure 2

(A) Example of Tachy-Brady arrhythmia often observed in structurally remodeled hearts with upregulated intranodal fibrosis. Atrial Fibrillation or Tachycardia leads to Bradycardia (long pauses) due to SAN exit block, followed by recovery of sinus rhythm or new Tachycardia event. ECG (black) and Optical Action Potentials (green and blue). Modified from Lou et al. (2013) with permission. (B) Enlarged epicardial view of 3D canine SAN model based on structural and functional data from optical mapping experiments. The SAN is demarcated from the atrium (green) by 3 bifurcating coronary arteries (light blue) and connective tissue (light purple). The yellow bundles show SACPs that electrically connect the SAN to the atrium. (C) Macro-reentry between the SAN and atria that occurred in the structurally remodeled canine heart after cessation of atrial tachypacing. Path of macro-reentry correlated with fibrotic strands within SAN. (D) SAN micro-reentry transformed from the previous macro-reentry is shown. Fibrosis strands were the structural substrates anchoring micro-reentry to this area. (B–D) modified from Glukhov et al. (2013) with permission. Abbreviations as seen in Figure 1.