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(Circulation. 1995;91:2058-2070.)
© 1995 American Heart Association, Inc.
Articles |
Gradual Onset of Myocardial Ischemia Results in Reduced Myocardial Infarction
Association With Reduced Contractile Function and Metabolic Downregulation
From the Department of Medicine, Cardiology Division, University of California, San Diego, and Research Service, Veterans Administration Medical Center, San Diego, Calif.
Correspondence to Bruce R. Ito, PhD, Gensia Inc, 9360 Towne Centre Dr, San Diego, CA 92121.
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.
Methods and 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 (M
O2)
followed by
linear decreases in both variables (r=.98 to .99) as flow
fell to the 10% level. The relation of
MO2 to function was linear
(r=.99) over the entire flow range. Although %SS,
MO2, 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 of coronary stenosis.
Key Words: myocardium • metabolism
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