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

Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15196-201. doi: 10.1073/pnas.1411557111. Epub 2014 Oct 6.


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.

Keywords: calcium imaging; cardiac disease; nonlinear microscopy; voltage imaging.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Calcium / metabolism*
  • Calcium Signaling / physiology
  • Cells, Cultured
  • Green Fluorescent Proteins / metabolism
  • Heart Failure / metabolism*
  • Heart Ventricles / cytology
  • Heart Ventricles / metabolism
  • Male
  • Muscle Cells / cytology*
  • Myocardial Contraction / physiology
  • Myocytes, Cardiac / metabolism*
  • Rats
  • Rats, Wistar
  • Sarcoplasmic Reticulum / metabolism


  • Green Fluorescent Proteins
  • Calcium