SUMMARY In 35 open chest anesthetized dogs coronary and aortic blood flow were measured with electromagnetic flowmeters while aortic and distal coronary blood pressure and an epicardial ECG were recorded. A fixed amount of stenosis (60-80%) was produced in the coronary artery by an externally applied plastic cylinder. In 24 of the 35 dogs the coronary blood flow showed cyclical reductions to near zero, with a sudden spontaneous return to near control levels. During reduced flow the epicardial ECG showed ST-segment depression suggestive of ischemia, and ventricular premature beats were often noted. Six animals died acutely during episodes of reduced flow.MANY STUDIES OF MYOCARDIAL INFARCTION AND SUDDEN DEATH from coronary heart disease have been reported. The significance of acute occlusive thrombi as a precipitating cause is widely debated.' 2 Acute coronary occlusion by thrombi were found in 21%' to 88%4 of those infarcted hearts examined at autopsy. These data vary with the investigative technique and material examined. In many patients with coronary artery disease and sudden death no acute thrombus or other mechanism for producing acute coronary insufficiency is demonstrated at post mortem examination and an episode of transient ischemia precipitating arrhythmia is often postulated.Platelet aggregation is involved in the formation of arterial thrombi and is not prevented by coumarin or heparin anticoagulant therapy.5 Mechanical damage of platelets can induce platelet aggregation in vitro6 and thrombosis occurs in areas of turbulent flow.7 It has been postulated that the turbulent flow produced at the sites of atherosclerotic plaques may play a role in thrombus formation by inducing platelet aggregation.' It has also been postulated that sudden coronary death may result from platelet aggregates in the epicardial arteries of man.8'9We present experimental evidence here that a fixed stenosis in a narrowed coronary artery promotes periodic in vivo platelet aggregation which transiently increases obstruction and decreases coronary blood flow. The possible significance of these observations to coronary disease in man is discussed.Material and Methods Thirty-five healthy adult mongrel dogs of both sexes were anesthetized with morphine sulfate (3 mg/kg) followed one hour later by sodium pentobarbital (30 mg/kg). Respiration was maintained using a positive pressure respirator, and the heart was exposed through a left thoracotomy at the fifth intercostal space in the usual fashion. After 35 mg/kg of aspirin were given intravenously the cyclical reductions in coronary blood flow were abolished and the in vitro platelet aggregations were reduced from a control of 62.1 ± 15 units (Born technique) to an average of 23.7 ± 12 units. Histologic sections of the narrowed coronary artery obtained when coronary flow was reduced show an amorphous mass in the lumen which was thought to be a platelet aggregate. Perhaps a similar process of platelet aggregation occurs in the stenosed coronary arteries in man, producing acute coronary...

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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...

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