T-tubule remodeling and increased heterogeneity of calcium release during the progression to heart failure in intact rat ventricle

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.

Adverse transverse-tubule remodeling in a rat model of heart failure is attenuated with low-dose triiodothyronine treatment

“…In the present study, confocal microscopy of isolated cardiomyocytes stained with WGA or di-8-ANEPPS to visualize T-tubules showed significant reduction in the periodicity of these structures similar to that described by others in animal and human failing myocytes (Singh et al 2017; Ibrahim et al 2012; Hong et al 2012; Schobesberger et al 2017; Pinali et al 2017). Novel to this study was the observation that T3 treatment commenced immediately after MI prevented these T-tubule changes or altered the course of this remodeling.…”

“…Cells were then incubated with di-8-ANEPPS (5 uM in HBSS/BDM; Biotium Inc., Fremont, CA) for 20 min. at 37 °C as published by others (Hong et al 2014; Singh et al 2017; Schobesberger et al 2017; Caldwell et al 2014; Reynolds et al 2016). Cells were washed and immediately imaged with a 63x objective under oil immersion using a Leica confocal microscope (DMI6000 SP5) housed in an enclosed unit heated to 37 °C.…”

“…In heart failure, transverse tubules (TT) in the remodeled cardiomyocyte appear dilated and decreased in number while longitudinal tubules increase with greater distances between sarcoplasmic reticulum (SR) and TT (Hong and Shaw 2017; Hasenfuss 1998). Advances in super-resolution cell imaging have confirmed these TT changes in heart failure that lead to diminished synchronous and slowed Ca 2+ release resulting in impaired excitation-contraction coupling and contractile dysfunction (Hong et al 2014; Hong et al 2010; Singh et al 2017; Ibrahim et al 2012). Adverse remodeling of TT has been documented in many animal models of HF and recently confirmed in failing human hearts (Hong et al 2012; Schobesberger et al 2017; Seidel et al 2017; Pinali et al 2017).…”

Dyadic Plasticity in Cardiomyocytes

“…Evidence of t-tubule plasticity is further supported by examinations of cardiac disease. A large number of studies have reported remodeling of t-tubules in left ventricular cardiomyocytes during heart failure with an array of etiologies, spanning myocardial infarction (Louch et al, 2006; Swift et al, 2008; Lyon et al, 2009; Biesmans et al, 2011; Chen et al, 2012; Wagner et al, 2012; Øyehaug et al, 2013; Frisk et al, 2016; Sanchez-Alonso et al, 2016; Figure 2B), aortic stenosis (Wei et al, 2010; Ibrahim et al, 2013; Pinali et al, 2013), tachycardia (He et al, 2001; Balijepalli et al, 2003), hypertension (Song et al, 2006; Singh et al, 2017), chronic ischemia (Heinzel et al, 2008), and diabetes (Stølen et al, 2009; Ward and Crossman, 2014). Despite the range of species and disease models employed in these studies, there is general agreement that overall t-tubule density is reduced, and commonly accompanied by a re-emergence of longitudinally-oriented tubules (Figures 1C, 2B).…”

Letter by Nikolova et al Regarding Article, “Heart Failure With Preserved Ejection Fraction in Perspective”

“…8,9 In the continuum to heart failure progression, in heart failure with reduced ejection fraction and even with HFpEF, TTs exhibit worsening luminal dilation and microdomain loss. 5,6,9 Moreover, adverse TT changes have been proposed to serve as a prognostic tool in left ventricular assist device patients that can predict the potential for left ventricle functional recovery with mechanical unloading. 10 As it is impractical to assay TT integrity via invasive endomyocardial biopsies, cBIN1 (cardiac bridging integrator 1) is emerging as a noninvasive test that reflects TT remodeling and thus has the potential to change the paradigm of HFpEF diagnosis and prognosis.…”