Abstract 376: Functional Significance of Anatomically Heterogeneous Distribution of Transversal-axial Tubule System in Mouse and Human Atrial Myocardium

Abstract

Background: In cardiac myocytes, efficient and synchronous excitation-contraction coupling (ECC) occurs through a specialized network of membrane invaginations called transverse-axial tubule system (TATS). In contrast to an extensive TATS in ventricular myocytes, atrial cells show a significantly heterogeneous organization of TATS, varying from a ventricular-like organized TATS to absent/irregular TATS. However, anatomical distribution of atrial TATS and its functional significance remains unknown. We hypothesized that atrial myocytes with a different TATS organization have a specific anatomical location within the atria that determines their impact on atrial ECC and contraction. Methods and Results: In order to avoid the potential bias associated with cell isolation, we applied a mosaic imaging protocol at the whole-mount isolated mouse atrial preparation stained with a membrane dye RH-237. We developed an algorithm that can automatically remove the outer membrane and analyze TATS organization. This analysis showed that myocytes located within the inter-caval region (ICR, i.e., between the superior and inferior vena cava and between the crista terminalis in atrioventricular junction) have a lower TATS organization than cells located within the right atrial appendage (RAA): 0.21±0.01 A.U. vs. 0.50±0.02 A.U. in ICR vs. RAA, respectively, P<0.01. Fluorescent optical mapping of Ca 2+ transients from isolated mouse atrial preparations revealed that ICR region has a longer Ca 2+ transient rise up time compared to RAA (7.8±0.3 ms vs. 6.3±0.3 ms, P<0.01). Moreover, a similar region-specific TATS organization was found in human non-failing (donor) atrial tissue samples. The analysis of TATS density in specimens selected from ICR and RAA regions of the human hearts (n=4) showed a significantly lower density of TATS in ICR compared to RAA region (5.8±0.2% vs. 10.6±0.4%, P<0.01). Conclusion: Our findings show a region-specific structural and functional differences of myocytes from RAA and ICR regions of mouse and human heart that could represent a general organization of the mammalian atria. It may have important implications into establishment of different functional roles of cells with a specific TATS structure in atrial physiology and pathology.