Mechanisms underlying ischemic diastolic dysfunction: relation between rigor, calcium homeostasis, and relaxation rate.
Increased diastolic chamber stiffness (upward arrow DCS) during ischemia may result from increased diastolic calcium, rigor, or reduced velocity of relaxation. We tested these potential mechanisms during severe ischemia in isolated red blood cell-perfused isovolumic rabbit hearts. Ischemia (coronary flow reduced 83%) reduced left ventricular (LV) contractility by 70%, which then remained stable. DCS progressively increased. When LV end-diastolic pressure had increased 5 mmHg, myofilament calcium responsiveness was altered with 50 mmol/l NH(4)Cl or 10 mmol/l butanedione monoxime. These affected contractility (i.e., a calcium-mediated force) but not upward arrow DCS. Second, quick length changes reversed upward arrow DCS, supporting a rigor mechanism. Third, ischemia increased the time constant of isovolumic pressure decline from 47 +/- 3 to 58 +/- 3 ms (P < 0.02) but concomitantly abbreviated the contraction-relaxation cycle, i.e., pressure dissipation occurred earlier without diastolic tetanization. Finally, to assess any link between rate of relaxation and upward arrow DCS, hearts were exposed to 10 mmol/l calcium. Calcium doubled contractility and accelerated relaxation velocity, but without affecting upward arrow DCS. Thus upward arrow DCS developed during ischemia despite severely reduced contractility via a rigor (and not calcium mediated) mechanism. Calcium resequestration capacity was preserved, and reduced relaxation velocity was not linked to upward arrow DCS.
Varma
Niraj
N
Boston University School of Medicine, Boston 02118, USA. nxv11@po.cwru.edu
Morgan
James P
JP
Apstein
Carl S
CS
D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D003931:Diacetyl / Q000031:analogs & derivatives* / Q000494:pharmacology; D003971:Diastole; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000503:physiopathology*; D010477:Perfusion; D011817:Rabbits; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology*
D004791:Enzyme Inhibitors; D000643:Ammonium Chloride; C004717:diacetylmonoxime; D003931:Diacetyl; D002118:Calcium