title: Left ventricular diastolic dysfunction during demand ischemia: rigor underlies increased stiffness without calcium-mediated tension. Amelioration by glycolytic substrate.
abstract: OBJECTIVE
  The goal of this study was to determine the subcellular mechanism(s) underlying increased left ventricular (LV) diastolic chamber stiffness (DCS) during angina (demand ischemia).
  
  
  BACKGROUND
  Increased DCS may result from increased diastolic myocyte calcium concentration and/or rigor. Therefore, we assessed the effects of direct alterations of both calcium-activated tension and high-energy phosphates on increased DCS.
  
  
  METHODS
  Demand ischemia was reproduced in isolated, isovolumic, red-cell perfused rabbit hearts by imposing low-flow ischemia and pacing tachycardia. This resulted in increased DCS. Interventions were performed after LV end-diastolic pressure had increased approximately 7 mm Hg. Initially, to determine the effects of altered calcium concentration or myofilament calcium responsiveness, hearts received either: 1) 5 or 14 mmol/L calcium chloride; 2) 8 mmol/L egtazic acid; 3) 5 mmol/L butane-dione-monoxime (BDM); or 4) 50 mmol/L ammonium chloride (NH4Cl). Then, to assess the contribution of decreased high-energy phosphate supply, hearts received 5) glucose (25 mmol/L) and insulin (400 microU/ml).
  
  
  RESULTS
  1) Calcium chloride, 5 and 14 mmol/L, increased LV systolic pressure by 42% and 70%, respectively (p < 0.001), indicating increased calcium-activated tension, but did not further increase DCS, implying intact diastolic calcium resequestration. 2) Egtazic acid reduced LV systolic pressure by 30% (p < 0.001), indicating reduced intracellular calcium, but failed to reduce increased DCS. 3) Butane-dione-monoxime and NH4Cl chloride affected contractile function (i.e., a calcium-driven force) but did not alter increased DCS. 4) Glucose and insulin, which increase high-energy phosphates during ischemia, reduced increased DCS by 50% (p < 0.001).
  
  
  CONCLUSIONS
  Increased DCS during demand ischemia was insensitive to maneuvers altering intracellular calcium concentration or myofilament calcium-responsiveness, that is, evidence against an etiology of calcium-activated tension. In contrast, increased glycolytic substrate ameliorated increased DCS, supporting a primary mechanism of rigor-bond formation.
authors: Boston University School of Medicine, Masachusetts 02118, USA. nxv11@po.cwru.edu
authors: N
authors: N
authors: Varma
authors: F R
authors: FR
authors: Eberli
authors: C S
authors: CS
authors: Apstein
mesh_terms: D000787:Angina Pectoris / Q000503:physiopathology*; D000818:Animals; D002118:Calcium / Q000502:physiology*; D004195:Disease Models, Animal; D006019:Glycolysis / Q000502:physiology*; D006439:Hemodynamics; D066298:In Vitro Techniques; D011817:Rabbits; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology*
chemical_list: D002118:Calcium