Blood flow reductions in stenosed canine coronary arteries: vasospasm or platelet aggregation?

Abstract

SUMMARY In 67 dogs with a 60-80% coronary stenosis produced by an external constricting plastic ring, blood flow measured with an electromagnetic flowmeter showed cyclical flow reductions of varying magnitude and duration, and then an abrupt return to control flow. In 45 dogs, heparin did not prevent these flow reductions, but ibuprofen (Motrin) or indomethacin abolished them. With incremental doses of each of these drugs, the cyclical flow reductions and the platelet function in vitro were diminished proportionately. In 10 more dogs, during low flow, pinching or poking the narrowed vessel suddenly restored normal flow. Topical application of papaverine and nitroglycerin proximal to the stenosis did not abolish the cyclic flow reduction, although a transient fall in systemic pressure indicated that they had been absorbed.Seven dogs had the constricting cylinder and flow probe chronically implanted for 4-6 weeks. A single oral dose of aspirin, 20 mg/kg, abolished their cyclic flow reductions for 2-4 days.In five dogs with 70% stenosis in the circumflex coronary artery, coronary arteriography was performed before coronary flow reduction and when coronary blood flow was low. This showed that there was a considerable additional reduction in the size of the mechanically constricted lumen during spontaneous flow reduction. In one dog, a nonopacified mass was dislodged from the area of constriction in 67 msec and this restored the lumen to its control diameter. Similar rapid clearing was filmed in two more dogs. In no case was vasospasm observed. These results suggest that obstruction from platelets aggregated in the narrowed lumen caused the cyclic flow reductions.CORONARY ARTERY DISEASE is the major cause of sudden death in the United States.' Although significant narrowing of the coronary arteries is frequent in those who die suddenly, many do not show a recent coronary thrombus or other evidence of exacerbation of their disease.2 Those resuscitated after cardiac arrest often do not have myocardial infarction,3 so the cause of sudden coronary death remains to be defined.While studying the physiologic consequences of controlled coronary artery stenosis in dogs, we noted a cyclic phenomenon, in which there were periodic decreases in coronary flow over a 5-10-minute period, usually with a sudden return to control flow; but sometimes, flow stopped, leading to ventricular fibrillation and sudden death.4 5 These cyclic phenomena could be abolished with aspirin, 20 mg/kg, and Folts et al.5 postulated that they were caused by placelet thrombi that formed in the narrowed lumen. An alternative hypothesis might be that they were caused by vasospasm. We designed a series of experiments to determine if these randomly occurring cyclic flow reductions could be inhibited by platelet inhibitors or by drugs that reduce vasospasm. left thoracotomy was performed through the fifth intercostal space and the heart was exposed. The proximal left circumflex coronary artery was dissected for 20 mm and the adventia was stripped away so that a...

Thromboresistance of Balloon-Injured Porcine Carotid Arteries After Local Gene Transfer of Human Tissue Factor Pathway Inhibitor

“…17,18 The nadir of flow during periods of cyclic flow reduction, often to zero flow, coincides with the presence of obstructive platelet-rich thrombi, 15,16 as is also apparent in our study, in which obstructive thrombi were seen in all cases of zero flow. The platelet dependency of CFVs is stressed by their exquisite sensitivity to antiplatelet agents.…”

“…CFVs in stenosed arteries reflect the dynamic process of growth and embolization of platelet-rich thrombi, with the rate of flow reduction being proportional to the rate of platelet accumulation in the narrowed lumen, 15,16 and have been observed in patients during the course of acute coronary syndromes. 17,18 The nadir of flow during periods of cyclic flow reduction, often to zero flow, coincides with the presence of obstructive platelet-rich thrombi, 15,16 as is also apparent in our study, in which obstructive thrombi were seen in all cases of zero flow.…”

Oral Contraceptives and Hormone Replacement Therapy Do Not Increase the Incidence of Arterial Thrombosis in a Nonhuman Primate Model

“…48 Evidence indicates that reductions in blood flow are due to the interactions of platelets with the vessel wall and with each other, leading to vascular occlusion. 49 The technique, developed originally in dogs, has been used in other species, including monkeys. 34,50 Although this model does not require the presence of atherosclerotic plaque and does not directly mimic what happens during plaque rupture, it, like other injury thrombosis models, causes intimal injury and exposes subintimal components to circulating blood in a setting of altered blood flow.…”

Vascular responses to platelet activation in normal and atherosclerotic primates in vivo.

“…34 - 35 In contrast, in arteries with denuded endothelium, platelets produce contraction that appears to be mediated by thromboxane and serotonin. 35 Several studies indicate that aggregation of platelets can reduce blood flow, 8 11 demonstrated a cyclic reduction in coronary blood flow in dogs caused by periodic formation of platelet aggregates at the site of endothehal injury followed by spontaneous dissolution. This cyclic flow reduction is mediated by a cyclooxygenase-dependent pathway, and active vasoconstriction did not seem to contribute to the reduction in flow because nitrogh/cerin failed to affect the cyclic reductions in blood flow.…”

“…8 Reductions in flow result from intracoronary deposition of platelets that may trigger vasoconstriction, largely mediated by TxA 2 , serotonin, 9 and ADP 10 that are released by activated platelets. It is not clear, however, whether reductions in flow are mediated by mechanical obstruction by aggregated platelets, 11 or whether platelet-induced vasoconstriction may contribute to reductions in blood flow.…”