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

Claudia Crocini,Raffaele Coppini,Elisabetta Cerbai,Cecilia Ferrantini,Chiara Tesi,Leonardo Sacconi,Leslie M Loew,Francesco S Pavone,Corrado Poggesi,Ping Yan

doi:10.1073/pnas.1411557111

Abstract

Action potentials (APs), via the transverse axial tubular system (TATS), synchronously trigger uniform Ca(2+) release throughout the cardiomyocyte. In heart failure (HF), TATS structural remodeling occurs, leading to asynchronous Ca(2+) 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 Ca(2+) release remained, however, unsolved. Here, we develop an imaging method to simultaneously assess TATS electrical activity and local Ca(2+) release. In HF cardiomyocytes, sites where T-tubules fail to conduct AP show a slower and reduced local Ca(2+) 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 Ca(2+) release in HF. Moreover, spontaneous depolarization events occurring in failing T-tubules can trigger local Ca(2+) release, resulting in Ca(2+) sparks. The occurrence of tubule-driven depolarizations and Ca(2+) sparks may contribute to the arrhythmic burden in heart failure.

Highlights

Action potentials (APs), via the transverse axial tubular system (TATS), synchronously trigger uniform Ca2+ release throughout the cardiomyocyte
We demonstrate that T-tubular loss represents just one way by which T-tubule dysfunction leads to asynchronous Ca2+ release across the myocyte
The synchronization of Ca2+ release within ventricular cardiomyocytes is ensured by AP propagation across TATS

Summary

Introduction

Action potentials (APs), via the transverse axial tubular system (TATS), synchronously trigger uniform Ca2+ release throughout the cardiomyocyte. Simultaneous recording of local Ca2+ release and AP in the tubular network is needed to unravel the consequences of these electrical anomalies on intracellular Ca2+ dynamics. To address this challenge, here we augment the previous experimental setup by adding the capability to optically measure Ca2+ transients simultaneously with AP in several tubular elements. Here we augment the previous experimental setup by adding the capability to optically measure Ca2+ transients simultaneously with AP in several tubular elements We apply this method to dissect the spatiotemporal relationship between TATS electrical activity and Ca2+ release in heart failure

Methods

Results

Conclusion