title: Gradual onset of myocardial ischemia results in reduced myocardial infarction. Association with reduced contractile function and metabolic downregulation.
abstract: BACKGROUND
  With moderate reductions in coronary blood flow, adjustments in myocardial metabolism can occur with a normalization of the imbalance between the decreased O2 delivery and tissue O2 demand. This state of "downregulated" metabolism is associated with reduced function and minimal irreversible injury and has been linked to myocardial hibernation. We hypothesized that (1) this process would occur when perfusion was reduced to severely ischemic levels, but only when flow declined at a slow rate rather than abruptly, and (2) this would result in blunted ischemia and reduced myocardial injury for a given period of low blood flow.
  
  
  RESULTS
  The left anterior descending coronary artery in anesthetized open-chest pigs was cannulated and perfused with arterial blood by an extracorporeal perfusion pump. Regional function (percent segment shortening, %SS) was measured with sonomicrometry and a regional coronary vein cannulated for blood gas analysis and lactate measurements. Coronary blood flow (CBF) was reduced to 10% of control either in a step fashion (Fast Ischemia group) or gradually in a linear manner over 70 minutes (Ramp Ischemia group). In all animals, CBF was held for 60 minutes at this 10% level and then followed by 2 hours of reperfusion. In the Ramp Ischemia group, the linear fall in CBF resulted in an initial maintenance of both %SS and myocardial oxygen consumption (MVO2) followed by linear decreases in both variables (r = .98 to .99) as flow fell to the 10% level. The relation of MVO2 to function was linear (r = .99) over the entire flow range. Although %SS, MVO2, CBF, coronary pressure, and hemodynamics during the 10% flow period were not different between groups, the increases in coronary venous lactate and PCO2 and fall in pH were blunted in the Ramp Ischemia group compared with the Fast Ischemia group. With reperfusion, a significant decrease in end-diastolic length was present only in the Fast Ischemia group. Additionally, although the region at risk was not different, infarction was markedly reduced in the Ramp Ischemia group (6.6 +/- 1.9%) compared with the Fast Ischemia group (31.4 +/- 6.9%).
  
  
  CONCLUSIONS
  These data are consistent with the hypothesis that the downregulation of myocardial metabolism with gradually decreased flow to severe levels results in reduced myocardial injury for a given period of low flow. We propose that the rate at which blood flow decreases with myocardial underperfusion is a novel determinant of infarct injury. This may have clinical implication in situations in which there is a time-dependent component to the decrease in coronary blood flow in acute ischemic events, ie, thrombus formation at a site or coronary stenosis.
authors.affiliation: Department of Medicine, University of California, San Diego.
authors.forename: B R
authors.initials: BR
authors.lastname: Ito
mesh_terms: D000818:Animals; D003326:Coronary Circulation / Q000502:physiology*; D015536:Down-Regulation; D006439:Hemodynamics / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D009200:Myocardial Contraction / Q000502:physiology*; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010101:Oxygen Consumption / Q000502:physiology*; D013552:Swine; D013997:Time Factors
chemical_list: D007773:Lactates; D019344:Lactic Acid