Femoral Arteries. John D. Folts, Ph.D., Donald E. Detmer, M.D., and Robert Nadler ..... New York, Grune & Stratton, 1975; 277. PP. 21. Rah GHR, Johnson GJ, ...
Peripheral Vascular Hemodynamics
Possible Platelet Thrombi Formation in Dog and Human Femoral Arteries John D. Folts, Ph.D., Donald E. Detmer, M.D., and Robert Nadler, M.S. Atheroscler-osis is a ubiquitous condition that commonnly produces zvessel stenioand progresses ultimately to viascular occlusioll. It is thought by many that platelets collect on sites ofatheroscler-osis and exacer-bate its p-ogression. WVe havie previously shown that platelet thrombi can form within 10 minutes in the stencosed cor-onzary arteries of a dog anzd canl produce acute cyclical r-eduction in bloodflow measured with an electromagneticflowmeter (EMXF). This isfollowied by sudden restor-ationi offlouw as the platelet thr-ombus br-eaks loose and is carr ied distally (Circulation 54:365-3 70, 1976). In five dogs, blood flozw? was measured simultaneously in afemoral a rteiy stenosed 70,c exposed proximally wtith anl E1MIF, and monitored distally over intact skin with a Doppler ultrasoniic flowmeter (DUF). Cyclical reductions in blood flow zwere detected by both the E1VIF and the DUEF, presumably due to platelet thromiibiforming in the stenosed femoral artery and then breaking loose and moving distally. These flouw reductions could be consistently abolished with aspirin (ASA). In ten patients with angiographically proven substantial stenoses of the femoral or popliteal arter-ies who were not taking ASA, the popliteal bloodflow vlelocity was measured with a DUF. Six of the ten patients showed cyclical blood flouw velocity reductions durinig 30 minutes of observation. These flouw velocity reductions were similar to those observed in the stenosed dog femor-al arter-ies. One hour after taking 600 mg ASA orally, five of the six patients no longer showed flow velocity reductions. Eight male control subjects who were niot on ASA and had no known stenoses had nioflouw velocity reductions when stuldied with the DETF. Since many factors, such as cigarette smoking, diabetes, anid elevated plasma lipids, are knowpin to increase human platelet agg-egation, we postulate that platelet thrombi may form in stenosed peripher-al arter-ies, hasten the devielopment of atheroscler-osis, and reduce blood flow. This postulate would be compatible with the increased incidence and accelerated development of clinically significant atheroscler-osis noted in such patients. Claudication may be more than just the response to "increased demand"; thrombus degeneration may lead to the elaboration of vasospastic substances. If these findings are confilrmed by further investigations, the potentialfor- successful therapeutic intervetntioni may be quite significanit. sis
From the Departments of Medicine anid Sur-gerY, University 531792.
of
W1'isconsin Medical School, Aladisoni,
isconsin
Presented at the 4th Inter-niational Confer-enice of Cardiovascular System Dynamics Society, Aliami Beach, Flor-ida, November; 1980.
Address for reprints: J.D. Folts, M.D.,
Texas Heart Institute Journal
L'Unizversits
of Wisconsin ledical School, Mladison,
Wisconsin 53792. 19
CIRCUMFLEX BED EPICARDIAL ECG CIRCUMFLEX BLOOD PRESSURE DISTAL TO OBSTRUCTION mm Hg.
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sis. 1l6.7 This model uses an electromagnetic flowmeter placed on the coronary artery to measure coronary blood flow. The stenosis is produced by placing an encircling plastic cylinder 4 mm in length around the artery producing stenosis. l.67 These cylinders are constructed of Lexan and are made with a range of internal diameters as previously described.""6'7 Depending on the diameter of the artery to be studied, a cylinder is then selected to produce varying degrees of stenosis. By using this technique, we observed the phenomenon shown in Figure 1. Cyclic reductions in coronary flow have been shown to be caused by platelet thrombi gradually forming in the stenosed
IT HAS been postulated by several investigators that platelet thrombus formation in stenosed coronary or cerebral arteries may lead to sudden coronary death'"3 or transient ischemic attacks and stroke. -1.5 The roughened, damaged endothelium with exposed collagen and elastin common to atherosclerotic plaques with stenosis of 70% to 95% could provide the necessary conditions for a platelet thrombus to form temporarily and then be washed away and carried downstream. We have developed an animal model of coronary thrombosis in which we can demonstrate that platelet thrombi periodically occur in the area of fixed mechanical steno-
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Hemodynamic and hemostatic effects of a platelet thrombus forming in a stenosed circumflex coronary Circumflex coronary artery blood pressure, measured with a 21 gauge catheter placed in the artery distal to the stenosis, is declining in panels B and C as the thrombus forms in the narrowed lumen. Circumflex coronary blood flow is also declining due to the thrombus developing at the stenosis, which gradually cuts off the flow, as shown in panels B and C. In panel D at the dotted vertical line, the pressure gradient between the aorta and the distal coronary artery has reached 75 mm Hg, and this pressure differential blows the thrombus through the stenosis, thus restoring blood flow. (Reprinted by permission of Circulation 1976; 54:367 and MehtaJ (ed) Platelets and Prostaglandins in Cardiovascular Disease. Mt. Kisco, New York, Futura Publishing Co., 1981.)
Fig.
1
artery.
20
Vol. 9, No. 1, March 1982
Comparison of femoral volume flow (EMF) with flow velocity (Doppler) in a 70% stenosed femoral artery
Fig. 2 Technique for measuring blood flow with electromagnetic and Doppler flow probes placed proximal and distal, respectively, to a mechanical stenosis of the femoral artery.
lumen, adding to the amount of stenosis and causing the coronary flow to decline. Then, as the pressure gradient builds up, the thrombus is forced through the stenosis and carried distally by the sudden restoration of flow (Fig. 1). We have also demonstrated that this technique can be used to produce stenosis and platelet thrombosis in carotid arteries.8 By using noninvasive techniques, preliminary examinations suggest the possible presence of platelet thrombi formation in some patients with severe peripheral vascular disease. A series of experiments were designed to compare the cyclical blood flow changes produced in stenosed dog femoral arteries and measured with an electromagnetic flowmeter placed proximally on an exposed femoral artery, and with a Doppler ultrasonic flowmeter placed on the skin distal to the stenosis and over the intact femoral artery. The Doppler ultrasonic flowmeter was then applied to two groups of patients to determine if there were any transient reTexas Heart Institute Journal
ductions in blood flow in those with known significant stenosis.
Methods Animal Studies Five anesthetized dogs were prepared as shown in Figure 2. The proximal portion of the femoral artery was dissected out, and an electromagnetic flowmeter probe of appropriate size was placed around the femoral artery. A 75% stenosis was produced with the plastic cylinder shown in the upper right hand corner of Figure 2 (used on coronary arteries as previously described). 6'7 A flat 9.3 M Hz Doppler ultrasonic flow velocity probe was placed on the intact skin over the underlying femoral artery, distal to the area of stenosis (Fig. 2). Blood flow velocity was measured with a Parks Model 806 Doppler velocity flowmeter and recorded on a Sanborn 296 strip chart recorder. The volume blood flow was measured with a 21
Statham SP2202 electromagnetic flowmeter on a Brush-Gould strip chart recorder. Blood flow was monitored continuously by Doppler for 1 hour, after which 20 mg/kg of aspirin was administered intravenously. Human Studies: Volunteers
Using the following criteria, ten male volunteers, average age 48 + 8 years, were selected for study. They had normal ankle to arm systolic pressure ratios, no known peripheral vascular disease, no claudication symptoms or rest pain, no history of taking any known platelet inhibiting medications, including aspirin, for eight days prior to study; and finally, they had to be willing to lie quietly for 45 minutes during the study. Human Studies: Patients
Using the following criteria, ten male patients, average age 57 + 9 years, were pre-
3: Fig. Areroga of a pain
22
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Protocol for Human Studies The patient or volunteer was placed in a comfortable supine position, either on an examining table or in a hospital bed. The ultrasonic probe was placed over the popliteal artery, the area of the loudest audible signal over the artery was found, and the probe was held in place at the same angle to the skin. If the sound began to fade, the probe was moved slightly in a lateral direction to assure that it was still over the artery.
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selected: They had to have an angiographically proven discrete stenotic lesion of 70% to 90% in the femoral or popliteal artery (representative example, Fig. 3); no history of taking any known platelet inhibiting agent, including aspirin, for seven days prior to study; and the presence of either rest pain or pain after walking one block or less. They also had to be willing to lie quietly for 45 minutes during the study.
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Vol. 9, No. 1, March 1982
The patient was monitored for 45 minutes. If any gradual decline in audible signal and recorded flow velocity was observed, followed by a rapid restoration of flow signal, the patient was given two 300 mg aspirin tablets, and the study was repeated 1 hour later. Results Animal Studies In all five dogs, cyclical reductions in femoral artery blood flow were detected (representative example in Fig. 4). The flow velocity changes detected simultaneously with the electromagnetic probe and with the Doppler flowmeter placed distal to the electromagnetic flowprobe recorded at a faster paperspeed (Fig. 4). In all five dogs, the cyclical flow reductions, believed to be due to platelet thrombi formation, were abolished with 20 mg/kg of aspirin.
Arterial Blood Press. mm Hg Femoral Art. B lood Flow ml/Min
I 00
There were no reductions in flow in any of the volunteer subjects studied. Human Studies: Patients A single episode that showed a gradual decline in blood flow velocity folloNwed by a rapid rise back to control velocity levels was observed in four of the ten patients studied for 45 minutes (Fig. 5). In two patients, there were two episodes of declining flow followed by an abrupt return to control levels. In five of the six patients with cyclic flow reductions, there were no changes observed in the flows velocity when the patients were restudied 1 hour after the administration of 600 mg of aspirin. In the sixth patient with cyclic flow, one small flow reduction was noted in blood flow velocity after aspirin ingestion. One patient returned for surgical intervention, and at the
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Femoral Blood Flow
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Fig. 4 Record of simultaneous measurements of blood flow in a stenosed dog femoral artery. The top two tracings are blood pressure and blood flow measured with an electromagnetic flowmeter and recorded on a Brush-Gould recorder at a slow paper speed. The bottom tracing is blood flow velocity measured with a Doppler flowmeter and recorded on a Sanborn 296, two-channel recorder at a paper speed 10 times faster than the Gould recorder. The horizontal arrows mark identical 36-second recording periods for both recorders. The vertical arrow marks the point at which the platelet thrombus breaks loose and is carried distally.
Texas Heart Institute Journal
23
DOPPLER FLOWM ETER
HUMAN POPLITEAL ARTERY BLOOD FLOW VELOCITY
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BEFORE 600 MG ASA
HUMAN POPLITEAL ARTERY BLOOD FLOW VELOCITY
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AFTER 600 MG ASA Fig. 5 Blood flow velocitv measured in a stenosed human popliteal artery. The top panel shows blood flow velocity declining, and then at point X, flow suddenly jumps back up to control level. The bottom tracing shows blood flow velocitv in the same patient 1 hour after the patient was given 600 mg of aspirin.
time of profundoplasty, he showed similar flow reductions with electromagnetic flowmeter measurement proximal to the obstruction (Fig. 6). Profundoplasty obliterated this phenomenon (Fig. 6).
others have confirmed that periodic platelet thrombi occur in the area of stenosis. 10.11 We assume that since the cyclical flow reductions in the stenosed femoral artery are abolished at the same time that flow reductions in the stenosed coronary artery are abolished by platelet inhibitors, the mechanisms are the same. In addition, the cyclical reductions in coronary flow in the stenosed dog coronary artery have been shown to be caused primarily by platelet thrombus formation and not vasospasm. 12.13 The flow changes observed in some of the patients with known peripheral vascu-
Discussion Our studies of coronary artery platelet thrombus formation have clearly established that, in the dog, cyclical blood flowT reductions are due to platelet thrombi formation in the stenosed lumen. 6I '9 By using this model of coronary artery stenosis,
HUMAN FEMORAL ARTERIAL 200BLOOD FLOW (ml/min) l00PREOPERATIVELY 01 1AI,IlII
