Characterization of the pace-and-drive capacity of the human sinoatrial node: A 3D in silico study

The 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 (SEPs). 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) at varying rates induced by gradual If block. Additionally, we investigated the influence of the SEPs by varying their number, length, and width. SEPs created a transition zone of transmembrane voltage and ionic currents to enable successful pace and drive. Unsuccessful simulations showed a hyperpolarized transmembrane voltage (−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 toward 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 with 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

Cardiac cell modelling: Observations from the heart of the cardiac physiome project

In this manuscript we review the state of cardiac cell modelling in the context of international initiatives such as the IUPS Physiome and Virtual Physiological Human Projects, which aim to integrate computational models across scales and physics. In particular we focus on the relationship between experimental data and model parameterisation across a range of model types and cellular physiological systems. Finally, in the context of parameter identification and model reuse within the Cardiac Physiome, we suggest some future priority areas for this field

Molecular mapping of the rabbit atrioventricular node

The atrioventricular node (AVN) of the heart is responsible for the important conduction delay between atrial systole and ventricular systole. The anatomical architecture and functional properties of the AVN are complex. Ionic currents have been characterised in the AVN at both the whole tissue level and single cell level. However, little is known about the molecular basis of these ionic currents. There were two aims of this research: 1) to generate an accurate three-dimensional reconstruction of the rabbit AVN conduction axis and 2) to use real time PCR and in situ hybridisation to measure levels of mRNA for specific ion channels and membrane proteins in the rabbit AVN and surrounding atrial and ventricular tissue. Neurofilament-M (NF-M) immunolabelling revealed a tract of cells extending from the posterior nodal extension through the compact node to the common bundle. The PNE appeared to correspond to the slow pathway. Loosely packed atrial muscle comprised the anterior region of the AVN conduction axis closest to the enclosed part of the AVN and most likely represents the fast pathway. Lower nodal cells extended from the common bundle to the lower extremities of the compact node and PNE. Significant differences in the mRNA levels between the PNE and atrial muscle for the pacemaker channel HCN4, INa channels Navl. 1 and Na, 1.5, the Ica,L channel Cav 1.3, the I to channel ß-subunit KChIP2 and Cx43 were found HCNI, Nav 1.1, Cav 1.3 and NF-M mRNA were significantly higher in the PNE, compact node and common bundle compared to the atrium and ventricle. Kir 2.1 mRNA was significantly higher in the ventricular muscle compared to the PNE and atrial muscle. Atrial natriuretic peptide (ANP) mRNA, was significantly higher in the atrial muscle compared to other tissues. For mRNAs for the Ito channels, Kv 4.2 and Kv 4.3, the delayed rectifier K+ channels, Kv 1.5, ERG, K, LQTI and minK, the inward rectifier K+ channels, Kir 2.2, Kir6.2 and ß-subunit SUR2A, and the Ca2+ handling proteins, RYR2, RYR3, NCXI and SERCA2a, there were no significant differences between tissues. In situ hybridisation staining revealed further complexity of the AVN conduction axis tissue. A region of loosely packed atrial tissue immediately adjacent to the nodal tissue was KChIP2 negative and Nav1.5 negative, and the lower nodal cells were both Cav 1.2 and Cav 1.3 positive. This study has described a complex architecture of the AVN and added further complexity by providing a detailed account of ion channel expression throughout this tissue

Structural and functional properties of subsidiary atrial pacemakers in a goat model of sinus node disease

Background: The sinoatrial/sinus node (SAN) is the primary pacemaker of the heart. In humans, SAN is surrounded by the paranodal area (PNA). Although the PNA function remains debated, it is thought to act as a subsidiary atrial pacemaker (SAP) tissue and become the dominant pacemaker in the setting of sinus node disease (SND). Large animal models of SND allow characterization of SAP, which might be a target for novel treatment strategies for SAN diseases.Methods: A goat model of SND was developed (n = 10) by epicardially ablating the SAN and validated by mapping of emergent SAP locations through an ablation catheter and surface electrocardiogram (ECG). Structural characterization of the goat SAN and SAP was assessed by histology and immunofluorescence techniques.Results: When the SAN was ablated, SAPs featured a shortened atrioventricular conduction, consistent with the location in proximity of atrioventricular junction. SAP recovery time showed significant prolongation compared to the SAN recovery time, followed by a decrease over a follow-up of 4 weeks. Like the SAN tissue, the SAP expressed the main isoform of pacemaker hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) and Na+/Ca2+ exchanger 1 (NCX1) and no high conductance connexin 43 (Cx43). Structural characterization of the right atrium (RA) revealed that the SAN was located at the earliest activation [i.e., at the junction of the superior vena cava (SVC) with the RA] and was surrounded by the paranodal-like tissue, extending down to the inferior vena cava (IVC). Emerged SAPs were localized close to the IVC and within the thick band of the atrial muscle known as the crista terminalis (CT).Conclusions: SAN ablation resulted in the generation of chronic SAP activity in 60% of treated animals. SAP displayed development over time and was located within the previously discovered PNA in humans, suggesting its role as dominant pacemaker in SND. Therefore, SAP in goat constitutes a promising stable target for electrophysiological modification to construct a fully functioning pacemaker

Simulation of action potential propagation based on the ghost structure method

In this paper, a ghost structure (GS) method is proposed to simulate the monodomain model in irregular computational domains using finite difference without regenerating body-fitted grids. In order to verify the validity of the GS method, it is first used to solve the Fitzhugh-Nagumo monodomain model in rectangular and circular regions at different states (the stationary and moving states). Then, the GS method is used to simulate the propagation of the action potential (AP) in transverse and longitudinal sections of a healthy human heart, and with left bundle branch block (LBBB). Finally, we analyze the AP and calcium concentration under healthy and LBBB conditions. Our numerical results show that the GS method can accurately simulate AP propagation with different computational domains either stationary or moving, and we also find that LBBB will cause the left ventricle to contract later than the right ventricle, which in turn affects synchronized contraction of the two ventricles

Modeling the heart

Quantitative prediction over multiple space and time scales using computer models of the electrical activity in the mammalian heart, based on membrane and intracellular ion transport and binding dynamics, digital histology, and three-dimensional cardiac anatomy and architecture