title: Changes in the organization of excitation-contraction coupling structures in failing human heart.
abstract: BACKGROUND
  The cardiac myocyte t-tubular system ensures rapid, uniform cell activation and several experimental lines of evidence suggest changes in the t-tubular system and associated excitation-contraction coupling proteins may occur in heart failure.
  
  
  RESULTS
  The organization of t-tubules, L-type calcium channels (DHPRs), ryanodine receptors (RyRs) and contractile machinery were examined in fixed ventricular tissue samples from both normal and failing hearts (idiopathic (non-ischemic) dilated cardiomyopathy) using high resolution fluorescent imaging. Wheat germ agglutinin (WGA), Na-Ca exchanger, DHPR and caveolin-3 labels revealed a shift from a predominantly transverse orientation to oblique and axial directions in failing myocytes. In failure, dilation of peripheral t-tubules occurred and a change in the extent of protein glycosylation was evident. There was no change in the fractional area occupied by myofilaments (labeled with phalloidin) but there was a small reduction in the number of RyR clusters per unit area. The general relationship between DHPRs and RyR was not changed and RyR labeling overlapped with 51±3% of DHPR labeling in normal hearts. In longitudinal (but not transverse) sections there was an ∼30% reduction in the degree of colocalization between DHPRs and RyRs as measured by Pearson's correlation coefficient in failing hearts.
  
  
  CONCLUSIONS
  The results show that extensive remodelling of the t-tubular network and associated excitation-contraction coupling proteins occurs in failing human heart. These changes may contribute to abnormal calcium handling in heart failure. The general organization of the t-system and changes observed in failure samples have subtle differences to some animal models although the general direction of changes are generally similar.
authors.affiliation: Department of Physiology, Faculty of Medicine and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: David J
authors.initials: DJ
authors.lastname: Crossman
authors.forename: Peter N
authors.initials: PN
authors.lastname: Ruygrok
authors.forename: Peter R
authors.initials: PR
authors.lastname: Ruygrok
authors.forename: Christian
authors.initials: C
authors.lastname: Soeller
authors.forename: Mark B
authors.initials: MB
authors.lastname: Cannell
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000368:Aged; D020746:Calcium Channels, L-Type / Q000378:metabolism; D056966:Excitation Contraction Coupling / Q000502:physiology*; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism / Q000473:pathology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D013194:Staining and Labeling; D014909:Wheat Germ Agglutinins / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D014909:Wheat Germ Agglutinins