Defects in T-tubular electrical activity underlie local alterations of calcium release in heart failure

Year: 2014

Authors: Crocini C., Coppini R., Ferrantini C., Yan P., Loew L.M., Tesi C., Cerbai E., Poggesi C., Pavone F.S., Sacconi L.

Autors Affiliation: European Lab Nonlinear Spect, I-50019 Florence, Italy; Univ Florence, Dept NeuroFarBa, Div Pharmacol, I-50139 Florence, Italy; Univ Florence, Dept Expt & Clin Med, Div Physiol, I-50134 Florence, Italy; Univ Connecticut, Ctr Hlth, RD Berlin Ctr Cell Anal & Modeling, Farmington, CT 06030 USA; Univ Florence, Dept Phys & Astron, I-50019 Sesto Fiorentino, Italy; CNR, Natl Opt Inst, I-50125 Florence, Italy.

Abstract: Action potentials (APs), via the transverse axial tubular system (TATS), synchronously trigger uniform Ca2+ release throughout the cardiomyocyte. In heart failure (HF), TATS structural remodeling occurs, leading to asynchronous Ca2+ release across the myocyte and contributing to contractile dysfunction. In cardiomyocytes from failing rat hearts, we previously documented the presence of TATS elements which failed to propagate AP and displayed spontaneous electrical activity; the consequence for Ca2+ release remained, however, unsolved. Here, we develop an imaging method to simultaneously assess TATS electrical activity and local Ca2+ release. In HF cardiomyocytes, sites where T-tubules fail to conduct AP show a slower and reduced local Ca2+ transient compared with regions with electrically coupled elements. It is concluded that TATS electrical remodeling is a major determinant of altered kinetics, amplitude, and homogeneity of Ca2+ release in HF. Moreover, spontaneous depolarization events occurring in failing T-tubules can trigger local Ca2+ release, resulting in Ca2+ sparks. The occurrence of tubuledriven depolarizations and Ca2+ sparks may contribute to the arrhythmic burden in heart failure.

Journal/Review: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Volume: 111 (42)      Pages from: 15196  to: 15201

More Information: We thank Dr. Francesco Vanzi for useful discussion about the manuscript. T he research leading to these results received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under Grant Agreements 241577, 241526, and 284464. This research project was also supported by Human Frontier Science Program Research Grant RGP0027/2009, by National Institutes of Health (NIH Grant: R01 EB001963), by the Italian Ministry for Education, University and Research in the framework of the Flagship Project NANOMAX, and by Telethon-Italy (GGP13162).
KeyWords: cardiac disease; voltage imaging; calcium imaging; nonlinear microscopy
DOI: 10.1073/pnas.1411557111

Citations: 67
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