title: Cell geometry and contractile abnormalities of myocytes from failing human left ventricle.
abstract: OBJECTIVE
  Systolic and diastolic dysfunction of the failing human heart may be due to changes in myocyte function, or to extracellular influences such as necrosis, fibrosis or repositioning of viable cells. In order to determine the contribution of cellular factors we have characterised the contraction amplitudes, and contraction and relaxation velocities of single myocytes isolated from failing human left ventricle.
  
  
  METHODS
  Myocytes were enzymatically isolated from the left ventricles of 42 subjects, superfused at 32 degrees C and paced at 0.2 Hz. Using a video/edge tracking system we obtained contraction amplitude and contraction and relaxation velocities as well as times to peak contraction (TTP) and to 50% and 90% relaxation (R50 and R90). Concentration-response curves to Ca2+ were constructed for each cell.
  
  
  RESULTS
  There was little difference in contraction amplitude at any Ca2+ concentration between cells from failing and non-failing hearts at this low frequency. At maximally activating Ca2+ concentrations (6-20 mM) there was a 30% slowing of relaxation velocity in myocytes from patients with both mild-moderate (P < 0.001) and severe (P < 0.001) congestive heart failure. Contraction and relaxation times were increased in myocytes from failing hearts [TTP: 0.46 +/- 0.02 s (n = 34 patients) vs. 0.35 +/- 0.02 s (n = 6), P < 0.01 and R50: 0.25 +/- 0.02 s (n = 34) vs. 0.16 +/- 0.02 s (n = 6), P < 0.001]. Impaired relaxation was seen with most etiologies, including ischemic and dilated cardiomyopathies and mitral valve disease. Myocytes from failing hypertrophied ventricles were more severely affected than those from failing non-hypertrophied hearts for both contraction and relaxation velocities. Cells from failing hypertrophied ventricles had a significantly larger area than from non-failing or failing non-hypertrophied ventricles, although cell length and sarcomere length were similar between groups. Larger myocytes did not show a more pronounced change in relaxation velocity than normally sized cells from the same hypertrophied ventricle.
  
  
  CONCLUSIONS
  Significant impairment of relaxation can be observed in ventricular myocytes from failing human heart under conditions where contraction amplitude appears normal. The defect is not confined to one etiology of disease, but is exacerbated during hypertrophy. An increase in cell size, although observed in myocytes from hypertrophied ventricle, does not itself account for changes in relaxation. Cellular changes contribute to diastolic dysfunction in the failing human heart.
authors.affiliation: Department of Cardiac Medicine, National Heart and Lung Institute, London, UK.
authors.forename: F
authors.initials: F
authors.lastname: del Monte
authors.forename: P
authors.initials: P
authors.lastname: O'Gara
authors.forename: P A
authors.initials: PA
authors.lastname: Poole-Wilson
authors.forename: M
authors.initials: M
authors.lastname: Yacoub
authors.forename: S E
authors.initials: SE
authors.lastname: Harding
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002118:Calcium / Q000494:pharmacology; D048429:Cell Size; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000473:pathology*; D006801:Humans; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology*
chemical_list: D002118:Calcium