The applicants'long-term aim is to gain insights in structure-function relationships underlying excitation- contraction (EC) coupling in normal and diseased heart cells. In this study, the way that cellular architecture and calcium (Ca) handling proteins involved in EC coupling are modified in dyssynchronous heart failure (DHF) will be examined. Further studies will be used to establish to what extent these modifications can be reversed by cardiac resynchronization therapy (CRT). These investigations will be conducted on canine models of both DHF and CRT. Left ventricular cells from anterior and lateral locations will be studied because previous studies indicated a very different phenotype of those cells in DHF.
In specific aim 1, three-dimensional reconstructions of the transverse tubular system (t-system) and associated ryanodine receptor (RyR) clusters will be obtained with scanning confocal microscopy. The discovery of non-junctional RyRs is a novel finding in mammalian ventricular cells. The extent to which the number of junctional RyR clusters exceeds non-junctional clusters will be established in control cells. In the proposed studies the extent and nature of structural and functional remodeling during DHF will be established. These studies are based on the hypothesis that reconstructed structures in control myocytes are significantly altered in cells from DHF ventricles. In particular, the hypothesis that the t-system is more reduced in lateral than anterior cells will be tested. The structure of t-tubules and RyRs in intact tissue will be compared with isolated cells. Preliminary data indicate that in cells from intact tissue the t-system is far more extensive than in isolated cells. The hypothesis that there remain significant numbers of non-junctional RyRs in cells in tissue will be tested. The extent to which DHF related changes in structure in intact tissue parallels the changes that were observed in isolated cells will also be investigated.
In specific aim 2, the microscopic changes in Ca transients that produce contractions as a consequence of alterations in the t-system and proteins associated with EC coupling will be established. This includes measuring Ca movements in normal and DHF cells with extremely rapid two-dimensional confocal microscopy. We will test the hypothesis that Ca transients in DHF are significantly disorganized compared to controls. In addition spontaneous release events that have been suggested to be arrhythmogenic and reflect the distribution of junctional and non-junctions RyR clusters will be measured.
In specific aim 3, we will test the hypothesis that CRT partially or completely reverses the effects of DHF on cellular architecture and Ca transients. Both, structural and functional alterations observed in DHF cells are expected to be partially or completely reversed in both cell types as a result of CRT. However, number and/or size of RyR clusters are not expected to be restored. Finally, we will investigate the hypothesis that the probability of spontaneous release events in CRT cells is increased due to up-regulation of adrenergic receptors.

Public Health Relevance

The way that dyssynchronous heart failure remodels cellular architecture and proteins involved in excitation- contraction coupling is incompletely understood. Furthermore, there is very little information on the restoration of these structures and functions by cardiac resynchronization therapy. Our studies are designed to gain insights into these processes.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Lathrop, David A
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University of Utah
Biomedical Engineering
Schools of Engineering
Salt Lake City
United States
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Seidel, Thomas; Navankasattusas, Sutip; Ahmad, Azmi et al. (2017) Sheet-Like Remodeling of the Transverse Tubular System in Human Heart Failure Impairs Excitation-Contraction Coupling and Functional Recovery by Mechanical Unloading. Circulation 135:1632-1645
Lichter, J; Li, Hui; Sachse, Frank B (2016) Measurement of Strain in Cardiac Myocytes at Micrometer Scale Based on Rapid Scanning Confocal Microscopy and Non-Rigid Image Registration. Ann Biomed Eng 44:3020-3031
Abdullah, Osama M; Seidel, Thomas; Dahl, MarJanna et al. (2016) Diffusion tensor imaging and histology of developing hearts. NMR Biomed 29:1338-49
Seidel, T; Edelmann, J-C; Sachse, F B (2016) Analyzing Remodeling of Cardiac Tissue: A Comprehensive Approach Based on Confocal Microscopy and 3D Reconstructions. Ann Biomed Eng 44:1436-1448
Diakos, Nikolaos A; Selzman, Craig H; Stehlik, Josef et al. (2015) Reply: does size matter? In search of a physiological definition of myocardial atrophy. J Am Coll Cardiol 65:2156-7
Shibayama, Junko; Yuzyuk, Tatiana N; Cox, James et al. (2015) Metabolic remodeling in moderate synchronous versus dyssynchronous pacing-induced heart failure: integrated metabolomics and proteomics study. PLoS One 10:e0118974
Li, Hui; Lichter, Justin G; Seidel, Thomas et al. (2015) Cardiac Resynchronization Therapy Reduces Subcellular Heterogeneity of Ryanodine Receptors, T-Tubules, and Ca2+ Sparks Produced by Dyssynchronous Heart Failure. Circ Heart Fail 8:1105-14
Lichter, Justin G; Carruth, Eric; Mitchell, Chelsea et al. (2014) Remodeling of the sarcomeric cytoskeleton in cardiac ventricular myocytes during heart failure and after cardiac resynchronization therapy. J Mol Cell Cardiol 72:186-95
Diakos, Nikolaos A; Selzman, Craig H; Sachse, Frank B et al. (2014) Myocardial atrophy and chronic mechanical unloading of the failing human heart: implications for cardiac assist device-induced myocardial recovery. J Am Coll Cardiol 64:1602-12
Torres, Natalia S; Sachse, Frank B; Izu, Leighton T et al. (2014) A modified local control model for Ca2+ transients in cardiomyocytes: junctional flux is accompanied by release from adjacent non-junctional RyRs. J Mol Cell Cardiol 68:1-11

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