Characterization of the Pace-and-Drive Capacity of the Human Sinoatrial Node: a 3D in silico Study

Abstract

ABSTRACTThe sinoatrial node (SAN) is a complex structure that spontaneously depolarizes rhythmically (“pacing”) and excites the surrounding non-automatic cardiac cells (“drive”) to initiate each heart beat. However, the mechanisms by which the SAN cells can activate the large and hyperpolarized surrounding cardiac tissue are incompletely understood. Experimental studies demonstrated the presence of an insulating border that separates the SAN from the hyperpolarizing influence of the surrounding myocardium, except at a discrete number of sinoatrial exit pathways (SEP). We propose a highly detailed 3D model of the human SAN, including 3D SEPs to study the requirements for successful electrical activation of the primary pacemaking structure of the human heart. A total of 788 simulations investigate the ability of the SAN to pace and drive with different heterogeneous characteristics of the nodal tissue (gradient and mosaic models) and myocyte orientation. A sigmoidal distribution of the tissue conductivity combined with a mosaic model of SAN and atrial cells in the SEP was able to drive the right atrium (RA). Additionally, we investigated the influence of the SEPs by varying their number, length and width. SEPs created a transition zone of transmembrane voltage (TMV) and ionic currents to enable successful pace and drive. Unsuccessful simulations showed a hyperpolarized TMV (−66 mV), which blocked the L-type channels and attenuated the sodium-calcium exchanger. The fiber direction influenced the SEPs that preferentially activated the crista terminalis (CT). The location of the leading pacemaker site (LPS) shifted towards the SEP-free areas. LPSs were located closer to the SEP-free areas (3.46±1.42 mm), where the hyperpolarizing influence of the CT was reduced, compared to a larger distance from the LPS to the areas where SEPs were located (7.17±0.98 mm). This study identified the geometrical and electrophysiological aspects of the 3D SAN-SEP-CT structure required for successful pace-and-drive in silico.SIGNIFICANCEThe human sinoatrial node (SAN) is the intrinsic natural pacemaker of the heart. Despite its remarkable robustness to failure, the electrophysiological properties, and mechanisms by which the SAN overcomes the source-sink mismatch towards the hyperpolarized surrounding cardiac tissue remains a mystery. The SAN is electrically isolated from the hyperpolarized cardiac tissue, except at a discrete number of sinoatrial exit pathways (SEP). Using in silico experiments, we explore the influence of the fiber orientation, the SEPs’ number, geometry and location on the activation of the SAN and the surrounding atrial tissue. We provide the mechanisms in a first 3D model of the human SAN-SEP structure that can successfully drive the working myocardium.