458Action potential propagation in transverse-axial tubular system is impaired in heart failure

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The plasma membrane of cardiac myocytes presents complex invaginations known as transverse-axial tubular system (TATS). Despite TATS's crucial role in excitation-contraction coupling and morphological alterations found in pathological settings, TATS's electrical activity has never been directly investigated. Here we develop an ultrafast random access multi-photon microscope that, in combination with a novel voltage sensitive dye, is used to simultaneously measure action potentials (APs) at multiple sites within the sarcolemma with sub-ms temporal and sub-μm spatial resolution. We find that the TATS APs are identical in amplitude and time-course to those of the surface sarcolemma (SS); this uniformity implies tight electrical coupling between the two membrane domains. Acute detachment by osmotic shock of most tubules from SS prevents AP propagation not only in the disconnected tubules, but also in some of the tubules that remain connected with SS. This indicates that structural integrity of the TATS is crucial to maintain a functional electrical coupling between the TATS and SS. The pathological implications of this finding are investigated in failing hearts. We find that AP propagation into the remodeled TATS frequently fails and may be followed by local spontaneous electrical activity. Our findings shed new light on the relationship between abnormal TATS and asynchronous calcium release, a major determinant of cardiac contractile dysfunction and arrhythmias.

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