title: Cardiac Resynchronization Therapy Reduces Subcellular Heterogeneity of Ryanodine Receptors, T-Tubules, and Ca2+ Sparks Produced by Dyssynchronous Heart Failure.
abstract: BACKGROUND
  Cardiac resynchronization therapy (CRT) is a major advance for treatment of patients with dyssynchronous heart failure (DHF). However, our understanding of DHF-associated remodeling of subcellular structure and function and their restoration after CRT remains incomplete.
  
  
  RESULTS
  We investigated subcellular heterogeneity of remodeling of structures and proteins associated with excitation-contraction coupling in cardiomyocytes in DHF and after CRT. Three-dimensional confocal microscopy revealed subcellular heterogeneity of ryanodine receptor (RyR) density and the transverse tubular system (t-system) in a canine model of DHF. RyR density at the ends of lateral left ventricular cardiomyocytes was higher than that in cell centers, whereas the t-system was depleted at cell ends. In anterior left ventricular cardiomyocytes, however, we found a similar degree of heterogeneous RyR remodeling, despite preserved t-system. Synchronous heart failure was associated with marginal heterogeneity of RyR density. We used rapid scanning confocal microscopy to investigate effects of heterogeneous structural remodeling on calcium signaling. In DHF, diastolic Ca(2+) spark density was smaller at cell ends versus centers. After CRT, subcellular heterogeneity of structures and function was reduced.
  
  
  CONCLUSIONS
  RyR density exhibits remarkable subcellular heterogeneity in DHF. RyR remodeling occurred in lateral and anterior cardiomyocytes, but remodeling of t-system was confined to lateral myocytes. These findings indicate that different mechanisms underlie remodeling of RyRs and t-system. Furthermore, we suggest that ventricular dyssynchrony exacerbates subcellular remodeling in heart failure. CRT efficiently reduced subcellular heterogeneity. These results will help to explain remodeling of excitation-contraction coupling in disease and restoration after CRT.
authors: From the Nora Eccles Harrison Cardiovascular Research and Training Institute (H.L., J.G.L., T.S., J.H.B., F.B.S.), and Department of Bioengineering (J.G.L., F.B.S.), University of Utah, Salt Lake City; and Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (G.F.T.).
authors: Hui
authors: H
authors: Li
authors: From the Nora Eccles Harrison Cardiovascular Research and Training Institute (H.L., J.G.L., T.S., J.H.B., F.B.S.), and Department of Bioengineering (J.G.L., F.B.S.), University of Utah, Salt Lake City; and Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (G.F.T.).
authors: Justin G
authors: JG
authors: Lichter
authors: From the Nora Eccles Harrison Cardiovascular Research and Training Institute (H.L., J.G.L., T.S., J.H.B., F.B.S.), and Department of Bioengineering (J.G.L., F.B.S.), University of Utah, Salt Lake City; and Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (G.F.T.).
authors: Thomas
authors: T
authors: Seidel
authors: From the Nora Eccles Harrison Cardiovascular Research and Training Institute (H.L., J.G.L., T.S., J.H.B., F.B.S.), and Department of Bioengineering (J.G.L., F.B.S.), University of Utah, Salt Lake City; and Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (G.F.T.).
authors: Gordon F
authors: GF
authors: Tomaselli
authors: From the Nora Eccles Harrison Cardiovascular Research and Training Institute (H.L., J.G.L., T.S., J.H.B., F.B.S.), and Department of Bioengineering (J.G.L., F.B.S.), University of Utah, Salt Lake City; and Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (G.F.T.).
authors: John H B
authors: JH
authors: Bridge
authors: From the Nora Eccles Harrison Cardiovascular Research and Training Institute (H.L., J.G.L., T.S., J.H.B., F.B.S.), and Department of Bioengineering (J.G.L., F.B.S.), University of Utah, Salt Lake City; and Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (G.F.T.). frank.sachse@utah.edu.
authors: Frank B
authors: FB
authors: Sachse
mesh_terms: D000818:Animals; D058406:Cardiac Resynchronization Therapy; D004195:Disease Models, Animal; D004285:Dogs; D056966:Excitation Contraction Coupling; D006333:Heart Failure / Q000209:etiology / Q000473:pathology* / Q000628:therapy*; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000473:pathology; D019837:Ryanodine Receptor Calcium Release Channel; D020257:Ventricular Remodeling
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel
keywords: cardiac resynchronization therapy; excitation–contraction coupling; heart failure; myocyte; remodeling; ryanodine receptors; transverse tubular system