Characterization of an Extensive Transverse Tubular Network in Sheep Atrial Myocytes and its Depletion in Heart Failure

Abstract

Background-In ventricular myocytes, the majority of structures that couple excitation to the systolic rise of Ca 2ϩ are located at the transverse tubular (t-tubule) membrane. In the failing ventricle, disorganization of t-tubules disrupts excitation contraction coupling. The t-tubule membrane is virtually absent in the atria of small mammals resulting in spatiotemporally distinct profiles of intracellular Ca 2ϩ release on stimulation in atrial and ventricular cells. The aims of this study were to determine (i) whether atrial myocytes from a large mammal (sheep) possess t-tubules, (ii) whether these are functionally important, and (iii) whether they are disrupted in heart failure. Methods and Results-Sheep left atrial myocytes were stained with di-4-ANEPPS. Nearly all control cells had an extensive t-tubule network resulting in each voxel in the cell being nearer to a membrane (sarcolemma or t-tubule) than would otherwise be the case. T-tubules decrease the distance of 50% of voxels from a membrane from 3.35Ϯ0.15 to 0.88Ϯ0.04 m. During depolarization, intracellular Ca 2ϩ rises simultaneously at the cell periphery and center. In heart failure induced by rapid ventricular pacing, there was an almost complete loss of atrial t-tubules. The distance of 50% of voxels from a membrane increased to 2.04Ϯ0.08 m, and there was a loss of early Ca 2ϩ release from the cell center. Conclusion-Sheep atrial myocytes possess a substantial t-tubule network that synchronizes the systolic Ca 2ϩ transient. In heart failure, this network is markedly disrupted. This may play an important role in changes of atrial function in heart failure. (Circ Heart Fail. 2009;2:482-489.)

Tachycardia-induced silencing of subcellular Ca2+ signaling in atrial myocytes

“…Recent work in human right atrial tissue has shown the presence of TTs, albeit less abundant than in other large mammals (cow, horse, sheep) (33). A denser TT system leads to more DHPR-RyR2 pairs at the junctional SR (jSR), thus facilitating (near-) simultaneous CaT activation throughout the cell (34). In the present study, ss and cc CaT amplitudes were the same in CTL cells.…”

Reduced density and altered regulation of rat atrial L-type Ca2+current in heart failure

“…Evidence from animal models of heart diseases that predispose to AF indicates that disease-associated remodeling of the atria, presumably due to mechanical overload of the atrial wall, creates an arrhythmic substrate in which AF is more likely to arise and be sustained (10,13,22,29,30,32,34,48). In addition to atrial enlargement, fibrosis and conduction abnormalities that establish a substrate for reentry, cellular remodeling involving cellular hypertrophy, changes in membrane structure, and abnormal expression and function of ion channels and transporters are also likely to contribute to the genesis of AF (4,10,13,15,16,18,22,26,29,30,32,34,35,38,48,51).…”

“…Evidence from animal models of heart diseases that predispose to AF indicates that disease-associated remodeling of the atria, presumably due to mechanical overload of the atrial wall, creates an arrhythmic substrate in which AF is more likely to arise and be sustained (10,13,22,29,30,32,34,48). In addition to atrial enlargement, fibrosis and conduction abnormalities that establish a substrate for reentry, cellular remodeling involving cellular hypertrophy, changes in membrane structure, and abnormal expression and function of ion channels and transporters are also likely to contribute to the genesis of AF (4,10,13,15,16,18,22,26,29,30,32,34,35,38,48,51).Atrial L-type Ca 2ϩ current (I CaL ) is reduced in heart disease, both in animal models (4,13,29,38) and in myocytes from human dilated atria (19,33). The loss of I CaL has been suggested to have a number of sequelae that contribute to the genesis of AF, including 1) changes in action potential configuration and the rate dependence of refractoriness, 2) abnormalities in Ca 2ϩ handling and the triggering of episodes of AF, and 3) hypocontractility and dilatation of the atria (15,29,33,35,42).…”

Transverse tubules are a common feature in large mammalian atrial myocytes including human

“…Furthermore, immunohistochemistry suggests the presence of t tubules in the cow atria (34). In sheep, atrial cell-triggered Ca 2ϩ release occurs simultaneously at the cell center and periphery (11), and in the dog atria Ca 2ϩ signals are similar in subsarcolemmal and central regions (43). In the rat atrium, the rudimentary t-tubule system is more apparent in larger diameter myocytes (25,40) consistent with the hypothesis that atrial myocytes with a comparatively large width require t tubules to allow rapid propagation of the Ca 2ϩ transient to the cell interior.…”