Mean blood flow in the ischemic segment, examined in the dog model, was similar between the control (autoreperfusion alone) and treatment (AO perfusion) groups during both balloon occlusion and at the initial (30 min) autoreperfusion period (p > 0.05) (Figure 4). However, after AO perfusion, the mean blood flow in the treatment group was double that of the control group (p < 0.01), whether expressed as absolute blood flow (AO mean = 0.92 ± 0.35 ml/g/min; autoreperfusion = 0.43 ± 0.19 ml/g/min) or the ratio of blood flow of the ischemic segment to the normal segment in the same animals. The improvement in flow after AO hyperoxemic reperfusion was similar in subepicardial and subendocardial tissues (p > 0.05).
The clinical importance of microvascular integrity during postinfarction myocardial reperfusion is now well recognized. The presence of a “no reflow” region portends a relatively high clinical event rate. 5,6,13,14 The fact that such regions often exist despite TIMI III angiographic flow after angioplasty or thrombolytic therapy has been emphasized only recently. 5 However, Hori et al. 15 demonstrated more than a decade ago that resting blood flow was reduced experimentally by microsphere embolization only when >70% of total embolization of a myocardial region was performed, despite significant ischemic changes in function and lactate production at even 10% embolization.
In the present study, TIMI III angiographic flow in the infarct vessel was observed during all periods of reperfusion in all animals. Nevertheless, it is likely that microvascular ischemia was present during reflow. LVEF and electrocardiographic abnormalities (both ST segment deviation and premature ventricular contraction frequency) were significantly improved with AO hyperoxemic reperfusion but not with either autoreperfusion or active normoxemic reperfusion. The most likely explanation for these effects is that oxygen delivery during reflow is inadequate to correct the residual ischemia in all segments of the infarct zone.
Experimental studies have demonstrated that hypoxia has profound effects on endothelial morphology and function. 16–23 An increase in endothelial permeability and loss of barrier function results in edema of both endothelial cells and adjacent tissue, and the associated transformation to a globular shape as well as expression of adhesion molecules would be expected to impede blood flow. Low velocity flow 24,25 and hypoxia 26 each can result in leukocyte activation which may further amplify problems with local tissue flow. The results of the current study demonstrated that microvascular blood flow, immediately after AO reperfusion, was twice that observed with ordinary reperfusion (autoreperfusion).
The level of improvement in microvascular blood flow noted in our study is similar to that noted in other studies of the effects of enhanced oxygenation of reperfused tissues. Capillary density was doubled after hyperbaric oxygen (HBO) treatment of reperfused striated skeletal muscle, 27 and tissue blood flow was markedly increased by HBO during reperfusion of skin flaps. 28
AO hyperoxemic perfusion has been shown to prevent low flow myocardial ischemia. 29 In reperfused regions of myocardium with relatively low blood flow, it is possible that delivery of oxygen at high partial pressures in plasma may attenuate endothelial cell hypoxia and reverse a potentially self-propagating cycle (ischemia and responses to ischemia) that compromises microvascular flow. The possibility exists that diffusion of oxygen at high partial pressures between perfused and occluded capillaries 30 may also provide some benefit. This proposed effect may help explain the reduction in infarct size associated with hyperoxemic reperfusion 12,31,32 and in the sustained improvement in LVEF noted 1 hr after termination of AO treatment in the present study and in the AO porcine reperfusion model. 12 The results of a recent clinical trial of AO reperfusion immediately after angioplasty and stenting of the infarct coronary artery on left ventricular function 33 are consistent with this hypothesis. Echocardiographic regional wall motion score index improved at each time period examined (1 day, as well as 1 and 3 months after reperfusion) and was sufficiently great to explain the chronic improvement in LVEF at 3 months (7% mean absolute increase compared to postangioplasty, before AO reperfusion).
Our results support the hypothesis that inadequate reperfusion at the tissue level commonly occurs despite TIMI III reflow. AO hyperoxemia improved left ventricular function and electrocardiographic evidence of ischemia, very likely as a result of augmentation of oxygen delivery in plasma. Marked improvement in myocardial blood flow after AO infusion was found, which may explain the improvement in LV function after treatment.
This work was supported by grants from TherOx, Inc., and the National Institutes of Health (HL56436).
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