Microdomain-Specific Modulation of L-Type Calcium Channels Leads to Triggered Ventricular Arrhythmia in Heart FailureNovelty and Significance

Sanchez-Alonso, J L and Bhargava, Anamika and O’Hara, T and Glukhov, A V and Schobesberger, S and Bhogal, N and Sikkel, M B and Mansfield, C and Korchev, Y E and Lyon, A R and Punjabi, P P and Nikolaev, V O and Trayanova, N A and Gorelik, J (2016) Microdomain-Specific Modulation of L-Type Calcium Channels Leads to Triggered Ventricular Arrhythmia in Heart FailureNovelty and Significance. Circulation Research, 119 (8). pp. 944-955. ISSN 0009-7330

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Abstract

Methods and Results: Super-resolution scanning patch-clamp, confocal and fluorescence microscopy were used to explore the distribution of single LTCCs in different membrane microdomains of nonfailing and failing human and rat ventricular myocytes. Disruption of membrane structure in both species led to the redistribution of functional LTCCs from their canonical location in transversal tubules (T-tubules) to the non-native crest of the sarcolemma, where their open probability was dramatically increased (0.034 +/- 0.011 versus 0.154 +/- 0.027, P<0.001). High open probability was linked to enhance calcium-calmodulin kinase II-mediated phosphorylation in nonnative microdomains and resulted in an elevated I-Ca,I-L window current, which contributed to the development of early afterdepolarizations. A novel model of LTCC function in HF was developed; after its validation with experimental data, the model was used to ascertain how HF-induced T-tubule loss led to altered LTCC function and early afterdepolarizations. The HF myocyte model was then implemented in a 3-dimensional left ventricle model, demonstrating that such early afterdepolarizations can propagate and initiate reentrant arrhythmias.

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