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

Year: 2012

Authors: Sacconi L., Ferrantini C., Lotti J., Coppini R., Yan P., Loew L.M., Tesi C., Cerbai E., Poggesi C., Pavone FS.

Autors Affiliation: National Institute of Optics–National Research Council (INO-CNR), 50125 Florence, Italy; European Laboratory for Non-Linear Spectroscopy (LENS), University of Florence, 50019 Sesto Fiorentino, Italy; Department of Physiology, University of Florence, 50134 Florence, Italy; Interuniversity Center of Molecular Medicine and Applied Biophysics (CIMMBA), University of Florence, 50139 Florence, Italy; Department of Preclinical and Clinical Pharmacology, University of Florence, 50139 Florence, Italy; Richard D. Berlin Center for Cell Analysis and Modeling (CCAM), University of Connecticut Health Center, Farmington, CT 06030 USA; Department of Physics, University of Florence, 50019 Sesto Fiorentino, Italy; International Center of Computational Neurophotonics (ICON), 50019 Sesto Fiorentino, Italy

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.


Volume: 109 (15)      Pages from: 5815  to: 5819

More Information: We thank Dr. Victoria Barygina for confocal imaging; Drs. Emanuela Masini, Niccol Mugelli, and Maddalena Fazi for surgery assistance during coronary artery legation; and Drs. Antonio Zaza, Giovanni Cecchi, Philip W. Brandt, Feliciano Protasi, and Francesco Vanzi for useful discussion about the manuscript. The research leading to these results received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under Grant Agreements 241577, 241526, and 228334. This research project was also supported by Human Frontier Science Program Research Grant RGP0027/2009; by National Institutes of Health Grant R01 EB001963; and by the Ente Cassa di Risparmio di Firenze (a private foundation).
DOI: 10.1073/pnas.1120188109

Citations: 79
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