Human sinoatrial node structure: 3D microanatomy of sinoatrial conduction pathways
Introduction
The sinoatrial node (SAN) is the primary pacemaker of the heart and responsible for initiating and regulating cardiac rhythm (Keith and Flack, 1907, Lewis et al., 1910, James, 1961, Boineau et al., 1988, Opthof, 1988, Boyett et al., 2000, Chandler et al., 2009, Fedorov et al., 2009, Fedorov et al., 2010a). SAN automaticity and conduction depends on the unique heterogeneous distribution of intracellular ion channels, Ca2+ handling proteins and autonomic receptors within the SAN (Monfredi et al., 2010, Dobrzynski et al., 2013, Wu and Anderson, 2014) as well as the unique structure of the SAN complex (Fedorov et al., 2012). The specialized microanatomy allows the small SAN to pace the large atria efficiently by maintaining a balanced source-sink relationship (Joyner et al., 1986). Multiple factors affecting SAN structure could lead to sinus node dysfunction (SND) (Csepe et al., 2015), when the SAN inadequately paces the atria, which may result in a number of cardiac diseases such as heart failure, atrial fibrillation, malignant ventricular arrhythmias, and eventually cardiac arrest (Luu et al., 1989, Sumitomo et al., 2007, Faggioni et al., 2013, Hjortshoj et al., 2013, Alonso et al., 2014, Jensen et al., 2014). SND is the predominant prognosis for electric pacemaker implantation, which is currently the only available treatment (Jensen et al., 2014, Mangrum et al., 2000, Packer et al., 2009, Greenspon et al., 2012). Despite over a century of research on the SAN, limited knowledge of the relationship between the human SAN microarchitecture and SAN function remains a critical barrier to properly understanding SND mechanisms and developing new alternatives to implantable pacemaker therapy.
Since the discovery of the SAN by Keith and Flack in 1907, multiple studies have investigated the SAN structure and its role in the formation and regulation of sinus rhythm in human and different animal hearts (Keith and Flack, 1907, James, 1961, Opthof, 1988, Boyett et al., 2000, Fedorov et al., 2009, Fedorov et al., 2010a, Boineau et al., 1989, Beau et al., 1995, Sanchez-Quintana et al., 2005, Chandler et al., 2011). Located at the junction of the superior vena cava (SVC) and the right atrium, the human SAN structure consists of a compact mass of specialized cardiomyocytes enmeshed in a dense matrix of collagen, fibroblasts and fatty tissue (Csepe et al., 2015). In general, the macrostructural features of the SAN, such as SAN size, the relationship between increased collagen tissue percent with age (Lev and 1954, Alings et al., 1995), the defined SAN artery, and the banana-shaped 3D structure of the SAN, are generally accepted and agreed upon (James, 1961, Sanchez-Quintana et al., 2005, Chandler et al., 2011, Lev and 1954, Truex et al., 1967, Shiraishi et al., 1992) (Fig. 1). However, due to the complexities of this 3D structure, several microstructural features remain disputed and/or undefined.
Among the debates over human SAN microstructure are the contradictory hypotheses of how the SAN is electrically connected to the atria. One hypothesis is that the SAN is electrically insulated from the surrounding atria by a structural border of fibrosis, fat layers and myocyte discontinuity, and that functional and structural connection between the SAN and atria is limited to discrete SAN conduction pathways (SACPs) (James, 1961, Opthof, 1988, Fedorov et al., 2009, Fedorov et al., 2010a, Boineau et al., 1978, Bromberg et al., 1995, Schuessler and 2003). An alternative hypothesis is that SAN and atrial cells are extensively connected by diffuse inter-digitations of the SAN border with the atrial myocardium, and that no discrete pathways exist (Chandler et al., 2009, Sanchez-Quintana et al., 2005, Chandler et al., 2011, Anderson et al., 1998, Sanchez-Quintana et al., 2002). These discrepancies may be explained by methodological limitations of previous SAN studies, such as restricting analyses of SAN structure to 2D instead of utilizing a 3D computational model, insufficient spatial resolution of 3D structural studies, and/or conducting structural studies without functional mapping of SAN conduction.
The importance of the functional-structural SAN to atria connection lies in its fundamental role in the mechanism of atrial activation from SAN pacemaker activity (Fedorov et al., 2012, Joyner et al., 1986, Csepe et al., 2015) and the maintenance of normal sinus rhythm in the human heart. New methodologies need to be developed to resolve the discrepancy of the SAN-atrial connections. In the present study, we developed an integrated approach including high-resolution optical mapping, serial histological sectioning and computational 3D fiber tracking to provide for the first time a detailed description of the functionally-identified SAN structure and a 3D reconstruction of the specialized SACP microstructure in human hearts with and without SND.
Section snippets
Optical mapping of coronary-perfused human atrial preparations
Explanted human hearts were obtained from Lifeline of Ohio in accordance with The Ohio State University Institutional Review Board. Patient-specific data can be found in Table 1. Explanted human hearts were cardioplegically-arrested and cooled to 4 °C in the operating room following cross-clamping of the aorta. Hearts were stored in cold cardioplegic solution (4 °C) during transport, dissection and cannulation. Human atrial preparations were isolated as previously described (Fedorov et al.,
Functional identification of SAN pacemaker complex
Near infrared optical mapping revealed that during baseline conditions, SAN #1 had stable sinus rhythm (61 BPM) with the leading pacemaker in the central region of the SAN tail (Fig. 2A). SAN activation preferentially traveled superiorly from the leading pacemaker at 11.8 ± 3.1 cm/s and slowed to 6.5 ± 1.6 cm/s before exiting SAN through lateral SACP to excite the atria in the superior CT (atrial breakthrough in Fig. 2A). While additional septal and inferior lateral exit and entrance SACPs were
3D histological reconstructions and structural models of the human SAN
Over a century ago, the anatomic structure of the SAN was discovered by Keith and Flack (Keith and Flack, 1907). Since this discovery, animal model and human studies have investigated how cardiac rhythm is initiated and regulated by the SAN (Keith and Flack, 1907, Lewis et al., 1910, James, 1961, Boineau et al., 1988, Opthof, 1988, Boyett et al., 2000, Chandler et al., 2009, Fedorov et al., 2010a). One of the critical components of efficient SAN function as the leading pacemaker of the human
Conclusion
We developed a new integrated approach that allowed us to provide the first 3D structural delineation of human SACPs connecting the human SAN to the atria. We suggest that SACPs are a necessary structural component of proper SAN function and a major contributor for source–sink relationship. Structural remodeling of SACPs due to aging and different cardiac diseases may lead to discontinuous myofiber tracts in SACP regions and ultimately exit block and SND. Future application of this approach
Editors' note
Please see also related communications in this issue by Vigmond and Stuyvers (2016) and George and Poelzing (2016).
Conflicts of interest
There are no conflicts of interest.
Acknowledgments
We sincerely thank the Lifeline of Ohio Organ Procurement Organization for providing the explanted hearts; Dr. Qing Lou and Mr. Benjamin Canan and Mr. Eric Schultz for help with tissue processing.
This work was supported by NIH HL115580 (VVF), HL113084 (PMLJ), HL084583, HL083422, HL114383 (PJM), National Heart Foundation of New Zealand (JZ) #1666 and by funding from the Dorothy M. Davis Heart and Lung Research Institute.
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