Abstract
A highly organized transverse‐tubule (TT) system is essential to normal Ca2+ cycling and cardiac function. We explored the relationship between the progressive disruption of TTs and resulting Ca2+ cycling during the development of heart failure (HF). Confocal imaging was used to measure Ca2+ transients and 2‐D z‐stack images in left ventricular epicardial myocytes of intact hearts from spontaneously hypertensive rats (SHR) and Wistar‐Kyoto control rats. TT organization was measured as the organizational index (OI) derived from a fast Fourier transform of TT organization. We found little decrease in the synchrony of Ca2+ release with TT loss until TT remodeling was severe, suggesting a TT “reserve” characterized by a wide range of TT remodeling with little effect on synchrony of release but beyond which variability in release shows an accelerating sensitivity to TT loss. To explain this observation, we applied a computational model of spatially distributed Ca2+ signaling units to investigate the relationship between OI and excitation‐contraction coupling. Our model showed that release heterogeneity exhibits a nonlinear relationship on both the spatial distribution of release units and the separation between L‐type Ca2+ channels and ryanodine receptors. Our results demonstrate a unique relationship between the synchrony of Ca2+ release and TT organization in myocytes of intact rat ventricle that may contribute to both the compensated and decompensated phases of heart failure.
Highlights
The transverse tubule (TT) network of a ventricular myocyte is essential for conducting the action potential from the surface of the cell into the cell center (Brette and Orchard 2007)
Our results demonstrate that the TT remodeling that takes place during the transition from hypertension to heart failure are responsible for the increased variability in Ca2+ cycling within the cardiac myocyte
There may be a threshold up to which TT remodeling may occur without resulting in the development of dyssynchronous Ca2+ release and disrupted CICR
Summary
The transverse tubule (TT) network of a ventricular myocyte is essential for conducting the action potential from the surface of the cell into the cell center (Brette and Orchard 2007). These sarcolemmal invaginations play a key role in excitation-contraction (EC) coupling, ensuring that synchronized contraction occurs following synchronous Ca2+ release (Guo et al 2013; Wei et al 2010). Signaling occurs when Ca2+ entry due to an LCC opening initiates a local rise in Ca2+ concentration which induces a coordinated release of the local RyR cluster.
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