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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-10, Vol.111 (42), p.15196-15201
• Main Authors: Crocini, Claudia, Coppini, Raffaele, Ferrantini, Cecilia, Yan, Ping, Loew, Leslie M., Tesi, Chiara, Cerbai, Elisabetta, Poggesi, Corrado, Pavone, Francesco S., Sacconi, Leonardo
• Format: Article
• Language: English
• Subjects: Action Potentials - physiology; Animals; Biological Sciences; Calcium; Calcium - metabolism; Calcium Signaling - physiology; Cardiomyocytes; Cells, Cultured; Depolarization; Dysrhythmias; Electric potential; Fluorescence; Green Fluorescent Proteins - metabolism; Heart; Heart failure; Heart Failure - metabolism; Heart Ventricles - cytology; Heart Ventricles - metabolism; Kinetics; Male; Muscle Cells - cytology; Myocardial Contraction - physiology; Myocardium; Myocytes, Cardiac - metabolism; plasma membrane; Rats; Rats, Wistar; Receptors; Renovations; Rodents; Sarcoplasmic Reticulum - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1411557111

Significance The plasma membrane of cardiac myocytes contains complex invaginations known as transverse tubules (T-tubules). In heart failure, T-tubule loss is a major contributor to Ca ²⁺ transient abnormalities, leading to weaker and slower contraction. Current therapeutic strategies are often based on attempts to accelerate Ca ²⁺ transients. Here, we demonstrate that T-tubular loss represents just one way by which T-tubule dysfunction leads to asynchronous Ca ²⁺ release across the myocyte. In fact, we report that defects in T-tubular electrical activity may contribute to Ca ²⁺-mediated arrhythmogenesis not only by favoring asynchronous Ca ²⁺ release, but also by generating voltage-associated Ca ²⁺ sparks. This work provides the first description to our knowledge of these novel proarrhythmogenic events that could help guide future therapeutic strategies. 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.