Coronary Reactive Hyperemia

Detta är en avhandling från Clinical Sciences, Lund University

Sammanfattning: Introduction: The mechanism of post ischemic reactive hyperemia is still unknown but now thought to be multifactorial and perhaps involving purinergic signalling. Purines such as ATP and ADP have recently been discovered to play a vital role in the regulation of vascular tone. We postulated that ADP could play a vital role in the mechanism of coronary post ischemic reactive hyperemia and that increased concentrations of plasma ADP could also stimulate a negative feed back loop governing release of ATP from red blood cells as well as an increased release of t-PA. It was also hypothesized that hypothermia may have effects on coronary reactive hyperemia and that rapidly induced hypothermia prior to reperfusion in an infarction model could reduce myocardial infarct size.

Material and Methods: All studies were performed in a closed chest porcine model in which coronary reactive hyperemia was studied after a ten minute occlusion of the LAD distal to the first diagonal branch, and blood flow measured in the distal LAD with a Doppler flow wire. Blood samples were collected in a peripheral artery, in the Coronary Sinus and in a central vein. Hypothermia was induced with an endovascular catheter and cold saline solution. In the infarction model in conjunction with hypothermia, the occlusion of the LAD was maintained for 40 minutes before reperfusion. Risk area was analyzed by SPECT and final infarct size by MRI. Results: (1) The P2Y13 receptor on red blood cells is stimulated by ADP and when activated attenuates ATP release from red blood cells to plasma. (2) Activation of the coronary endothelial P2Y1 receptors causes hyperemia in coronary arteries. (3) Inhibition of coronary P2Y1 receptors reduces peak blood flow during reactive hyperemia by 46 %. (4) Coronary t-PA release during ischemia and reperfusion is mediated through P2Y1 receptors. (5) Mild systemic hypothermia reduces peak flow in coronary arteries by a 43 % reduction in peak reactive hyperemia. (6) Rapidly induced hypothermia during anterior myocardial infarction before reperfusion reduces final infarct size compared with rapidly induced hypothermia in conjunction with or after reperfusion. (7) Rapidly induced hypothermia before reperfusion in the setting of anterior myocardial infarction in pigs abolishes microvascular obstruction. Conclusions: ADP is important in both regulation of microvascular circulation as well as stimulating a large part of the increased blood flow seen during reactive hyperemia and the subsequent release of t-PA. Additional research on reactive hyperemia, now with the use of hypothermia, led to the conclusion that mild hypothermia also attenuates the blood flow seen in coronary reactive hyperemia. Further research in the infarction model, using hypothermia as adjunctive treatment resulted in a nearly halved final infarct size and an abolishment of microvascular obstruction in the animals treated with hypothermia compared to controls. This may be due to a reduction of the reperfusion injury and our research indicates that a major part of the myocardial reperfusion injury may occur during the short period of reactive hyperemia which is within the same timeframe in which the initiation of myocardial tissue swelling can be seen, an increased release of t-PA, ATP and ADP can be measured, and microvascular obstruction develops as visualized by MRI.