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.
Highlights
“We might mention that, in some of the pathological hearts cut by us, sections of this region appeared to show a definite increase in the amount of fibrous tissue present-a fact of considerable importance...”
FUTURE DIRECTIONS AND CONCLUSION Even after one century of extensive research on the Sinoatrial Node (SAN), the lack of understanding of the human SAN complexity remains a critical barrier to the optimal treatment of heart rhythm disorders
Heterogeneous distribution of fibrosis within and around the SAN pacemaker complex plays a crucial role in proper SAN function by providing (1) structural and functional integrity/stability of the SAN (2) electrical insulation of SAN myocyte clusters and the entire SAN complex, apart from sinoatrial conduction pathways (SACPs), preventing depression of pacemaker automaticity from the hyperpolarizing effect of the surrounding atria (3) mechanical protection from pathophysiological heart rate changes due to stretch and pressure from the contractile force of the atria
Summary
“We might mention that, in some of the pathological hearts cut by us, sections of this region (i.e., the sinoatrial node) appeared to show a definite increase in the amount of fibrous tissue present-a fact of considerable importance...”. The heterogeneous distribution of specialized ion channels, intracellular sodium/calcium handling proteins, gap junction channels and receptors within the SAN pacemaker complex are a few of the critical players shown to be involved in SAN pacemaking that have been addressed in recent reviews (Monfredi et al, 2010; Dobrzynski et al, 2013; Wu and Anderson, 2014) In addition to these molecular mechanisms, the passive, structural features of the SAN complex contributes significantly to its normal functioning. Fibrosis in the sinoatrial node enmeshed within strands of connective tissue or fibrosis, mostly a combination of collagen, elastin and fibroblasts (Lev, 1954; Hudson, 1960; Truex et al, 1967; Sanchez-Quintana et al, 2002) This fibrotic matrix provides mechanical protection (Alings et al, 1995) of the SAN and electrically insulates the SAN pacemaker cells from the surrounding atrial myocardium, thereby efficiently regulating normal sinus rhythm. This review will take a more in depth look at the role of fibrosis in normal SAN function, as well as factors involved in unfavorable fibrosis production observed in patients and animal models with cardiac diseases and SND (Liu et al, 2007; de Jong et al, 2011; Nakao et al, 2012; Glukhov et al, 2013, 2015; Alonso et al, 2014; Jensen et al, 2014; Morris and Kalman, 2014)
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