title: Action potential propagation in transverse-axial tubular system is impaired in heart failure.
abstract: The plasma membrane of cardiac myocytes presents complex invaginations known as the 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 in remodeled tubular networks. Here we develop an ultrafast random access multiphoton microscope that, in combination with a customly synthesized voltage-sensitive dye, is used to simultaneously measure action potentials (APs) at multiple sites within the sarcolemma with submillisecond temporal and submicrometer spatial resolution in real time. We find that the tight electrical coupling between different sarcolemmal domains is guaranteed only within an intact tubular system. In fact, acute detachment by osmotic shock of most tubules from the surface sarcolemma prevents AP propagation not only in the disconnected tubules, but also in some of the tubules that remain connected with the surface. This indicates that a structural disorganization of the tubular system worsens the electrical coupling between the TATS and the surface. The pathological implications of this finding are investigated in failing hearts. We find that AP propagation into the pathologically remodeled TATS frequently fails and may be followed by local spontaneous electrical activity. Our findings provide insight on the relationship between abnormal TATS and asynchronous calcium release, a major determinant of cardiac contractile dysfunction and arrhythmias.
authors.affiliation: National Institute of Optics-National Research Council (INO-CNR), 50125 Florence, Italy. coni@lens.unifi.it
authors.forename: Leonardo
authors.initials: L
authors.lastname: Sacconi
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ferrantini
authors.forename: Jacopo
authors.initials: J
authors.lastname: Lotti
authors.forename: Raffaele
authors.initials: R
authors.lastname: Coppini
authors.forename: Ping
authors.initials: P
authors.lastname: Yan
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Loew
authors.forename: Chiara
authors.initials: C
authors.lastname: Tesi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cerbai
authors.forename: Corrado
authors.initials: C
authors.lastname: Poggesi
authors.forename: Francesco S
authors.initials: FS
authors.lastname: Pavone
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002462:Cell Membrane / Q000502:physiology*; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar