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Altered coronary flow responses to vasoactive drugs in the presence of coronary arterial stenosis in the dog
Altered Coronary Flow Responses to Vasoactive Drugs in the Presence of Coronary Arterial Stenosis in the Dog
WILLIAM P. SANTAMORE, PhD
Recent in vitro observations of human coronary arteries have suggested that intraluminal pressure can be a determinant of the resistance to flow through the stenosis. This study examined whether similar pressuredependent changes in stenotic resistance could be observed and analyzed in an open chest, anesthetized, animal model of coronary arterial stenosis. Without stenosis, intracoronary isoproterenol(1 pg) or nitroglycerin (10 pg) increased flow and decreased coronary resistance, whereas methoxamine (500 pg) or vasopressin (0.2 U) decreased flow and increased coronary resistance. After partial arterial constriction, administration of isoproterenol (1 pg) resulted in a decrease in coronary pressure from 61.2 f 2.5 to 39.4 f 2.7 mm Hg (p 10.05), a 23 percent decrease in distal coronary resistance (p 10.05) and a 22 percent decrease in flow associated with an increase in stenotic resistance of 2.34 f 0.97 (p 10.05). Similarly, nitroglycerin caused a decrease in coronary pressure from 55.7 f 3.1 to 42.1 f 3.6 mm Hg (p <0.05), a 29 percent increase in distal coronary resistance and only a 1 percent increase in flow associated with a 38 percent increase in stenotic resistance. Methoxamine caused an increase in coronary pressure from 62.8 f 2.0 to 73.6 f 3.4 mm Hg (p 10.05), an 18 percent increase in distal coronary resistance, an 8 percent decrease in flow and a 10 percent decrease in stenotic resistance. Vasopressin caused an increase in coronary pressure from 61.0 f 1.5 to 99.2 f 7.1 mm Hg (p 10.05), a 239 percent increase in distal coronary resistance but only a 45 percent decrease in flow associated with a decrease in stenotic resistance of 1.33 f 0.91 (p 50.05). Passive changes in the stenotic area caused by coronary pressure changes are postulated as part of the mechanism for the observed changes in stenotic resistance. This hypothesis is strengthened by the changes in stenotic resistance and radiographic analysis obtained from an in vitro carotid arterial preparation. The pressure-dependency of stenotic resistance could be an additional factor in the treatment of patients with coronary artery disease.
PAUL WALINSKY, MD Philadelphia,
Pennsylvania
From the Department of Medicine, Division of Cardiology, Temple University Medical School, and the Division of Cardiology, Jefferson Medical College, Philadelphia, Pennsylvania. This study was supported by an Investigatorship (to Dr. Santamore) from the Southeastern Pennsylvania Heart Association, and by Biomedical Research Support Grant RR 05414 from the National Instittites of Health, Bethesda, Maryland. Manuscript received April 4, 1979; revised manuscript received September 5. 1979, accepted September 12, 1979. Address for reprints: William P. Santamore, PhD, Temple University Medical School, Department of Medicine, Philadelphia, Pennsylvania 19140.
276
February
1960
The American
Journal
Coronary arterial stenosis has a complex influence on blood flow through and beyond the narrowed segment. Factors that have been recognized as determining resistance across a stenosis include the absolute radius, the relative percent of narrowing, the length of the stenosis and the viscosity and velocity of fluid flowing through the ‘stenosis.lm4 A recent in vitro study suggested that stenotic resistance was also dependent on intraluminal pressure. 5 In that study proximal coronary arteries, obtained from fresh postmortem adult hearts, were examined under various flow rates, perfusion pressures and distal resistances. In coronary arteries with eccentric lesions (a plaque on one side not completely surrounding the lumen), the resistance to flow was found to be dependent on the perfusion pressure: lowering the perfusion pressure increased the resistance, whereas increasing the perfusion pressure decreased the re-
of CARDIOLOGY
Volume
45
ALTERED CORONARY
sistance. This study suggested that interventions that lower the distal coronary arterial pressure could increase the hemodynamic resistance of the stenotic segment of the artery, whereas interventions that raise the distal coronary pressure could decrease the hemodynamic resistance of the stenotic segment of the artery. Recently, Schwartz et a1.6 and Walinsky et a1.7 in our laboratory documented an alteration of the normal response to momentary coronary arterial occlusion in the presence of partial coronary arterial constriction. We observed a dependence of stenotic resistance on distal coronary pressure, a finding similar to the in vitro observations on human coronary arteries described previously. It was the objective of this study to expand our initial observations by examining the coronary response to a variety of vasoactive drugs in a canine model of high grade coronary stenosis and to determine the mechanism for the observed changes in stenotic resistance by using an in vitro arterial preparation. Methods Initial Preparation Animal studies were performed in 10 mongrel dogs weighing 29.5 to 34.1 kg. All animals were pretreated with morphine (1 mg/kg), anesthetized with alpha-chloralose (100 mg/kg) and mechanically ventilated. Supplemental doses of alpha-chloralose were given as needed. Arterial blood partial pressures of oxygen (Pop) and carbon dioxide (Pco~) and pH were periodically monitored throughout the experiment by a blood gas analyzer (Instrumentation Laboratory). Respiratory adjustments or intravenous infusions of sodium bicarbonate, or both, were made when necessary to keep blood gases and pH within a physiologic range of pH 7.32 to 7.42, PC02 32 to 42 mm Hg, POT above 70 mm Hg.8 The heart was exposed through a left lateral thoracotomy and suspended in a pericardial cradle. A catheter was advanced in retrograde fashion from the right femoral artery and positioned in the ascending aorta to measure aortic pressure. Depending on the coronary arterial anatomy, an electromagnetic flow probe (Biotronex Laboratory, Inc.) was placed around either the left anterior descending artery or the circumflex artery. If the left anterior descending artery was utilized, the site of isolation varied from the proximal to the mid portion of the artery. If the circumflex artery was utilized, the site of isolation was always proximal to the first major marginal branch. A variable snare type of occluder was placed distal to the flow probe. The snare consisted of a 1 mm wide band of Teflon@ passed around the artery, through stiff tubing, and attached to a machinist’s micrometer. The micrometer and tubing were mounted above the dog in a position that prevented traction from being exerted on the stenosis during the cardiac cycle both before and after drug interventions. The snare could be closed by small precise amounts according to a 0.01 mm micrometer scale. The advantage of a narrow (1 mm) snare occluder was that a higher degree of stenosis could be obtained before resting coronary blood flow was affected.l Distal to the micrometer-adjusted snare occluder, 1-O nylon suture was placed around the coronary artery. The ends of the suture were inserted through a piece of polyethylene tubing, 3 cm in length. Zero flow was obtained by pulling the ends of the suture while pressing on the polyethylene tubing against the coronary vessel. Thus, zero flow could be obtained without changing the setting on the micrometer-adjusted snare oceluder. Distal to the occluder, a 22 gauge catheter was inserted
FLOW RESPONSES-SANTAMORE
AND WALINSKY
either into a diagonal branch or directly into the circumflex artery. The catheter was used for monitoring distal coronary arterial pressure and for all intracoronary injections. In the region perfused by the artery in which instruments were placed a small platinum electrode was inserted into the myocardium to record an intramyocardial electrogram. Aortic pressure, coronary blood flow, coronary pressure distal to the snare and an intramyocardial electrogram were
recorded on an Electronics for Medicine physiologic recorder (model DR8). Mean pressures were obtained electronically. Distal coronary resistance was calculated by dividing mean distal coronary arterial pressure by mean coronary blood flow. Stenotic resistance was calculated by dividing the mean pressure gradient across the stenosis by mean coronary flo~.l,~ The mean pressure gradient across the stenosis was calculated as the mean aortic blood pressure minus mean coronary arterial pressure. At the end of each experiment the electromagnetic flow probe was calibrated by timed collection of blood. The coronary artery distal to the site of insertion of the 22 gauge catheter was occluded. The coronary blood then flowed through the proximal coronary artery and the coronary catheter into a graduated cylinder. Statistical analysis was performed by using the Wilcoxon sign rank testi to compare the control values with the values obtained after injection of the pharmacologic agent. Experimental Procedure: Vasoactive Drugs After the initial preparation, the effects of intracoronary injection of isoproterenol(l pg) and methoxamine (500 pg), each diluted in 1 ml of physiologic saline solution, were examined before and after partial constriction of the coronary artery in six dogs. All injections were made through the catheter used to monitor distal coronary pressure. Before constriction of the coronary artery, isoproterenol (1 pg) was rapidly injected into that artery while all physiologic variables were recorded continuously for a 10 minute period before and after the injection. Next, methoxamine (500 pug)was injected into the coronary artery while the physiologic variables were recorded. Mean distal coronary pressure was then gradually reduced to 60 mm Hg by tightening the snare occluder. Mean distal coronary pressure was reduced to 60 mm Hg because 60 mm Hg has been shown to be close to the limits of autoregulationll and ventricular mechanical integrity.12 All physiologic variables were recorded for at least 15 minutes with the mean coronary pressure at 60 mm Hg to verify stability. Isoproterenol (1 pg) and methoxamine (500 pg) were again administered into the coronary artery by the technique outlined earlier. To avoid any interaction between the drugs, there was a 20 minute period between intracoronary injections. Further, the order in which the drugs were given was alternated. In half the experiments isoproterenol was injected first and in the other half, methoxamine was injected first. In six dogs, after the initial preparation, the effects of intracoronary injections of nitroglycerin (10 pg) and vasopressin (0.2 U), each diluted in 1 ml physiologic saline solution, were examined before and after partial coronary arterial constriction by the methods outlined earlier. Again, to avoid drug interaction, there was at least a 20 minute period between intracoronary injections and the order in which the drugs were given was alternated. In Vitro Carotid Arterial Preparations To test further the dependency intraluminal pressure, an in vitro used. The in vitro carotid arterial exclude alpha and beta adrenergic
February 1980
of stenotic resistance on arterial preparation was preparation was used to stimulation, reflexes, sys-
The American Journal of CARDIOLOGY
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CORONARY
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RESPONSES-SANTAMORE
AND WALINSKY
temic blood pressure changes, pulsatile blood flow and pressure, collateral vessels and platelet plugging as potential causes of the stenotic resistance changes. The carotid artery was used because of its easy removal from the dog and its long length without branches. In each study, the artery was frozen, thawed, suspended in air and kept moist by externally applied saline solution. By design, therefore, only the passive characteristics of arterial stenosis were studied by means of this preparation. In 11 mongrel dogs (11.3 to 40.8 kg) the left and right common carotid arteries were rapidly removed immediately after the anesthetized animal was killed. The arteries were frozen in physiologic saline solution until they were studied. Two types of experimental protocols were performed: constant flow and constant pressure. For the constant flow experiments, the artery was attached between points a and b (Fig. 1) and stretched to its original in vivo length. The artery was kept moist by externally applied physiologic saline solution. A Harvard syringe pump maintained a constant flow rate (22.9 ml/min between a pressure range of 0 to 400 mm Hg) of an isotonic dextran solution (1.7 centipoise). With use of a circumferential snare (previously described), various stenotic resistances between 0.5 and 6.0 mm Hg/ml.min-’ were established, with a high peripheral resistance (20 gauge Longdwel needle). Stenotic resistance was calculated as the pressure gradient across the stenosis (Pl - P2) divided by the flo~.~*s Distal resistance was calculated as distal pressure divided by flow. With the initial stenotic resistance set and the pressures recorded, the distal resistance was halved three times by sequentially opening stopcocks Sl, S2 and S3. At each level of distal resistance, the pressures were recorded. Stopcock Sl was then closed, reestablishing the initial conditions. If stenotic resistance varied more than 5 percent from the control value, the data were discarded. This procedure was repeated 10 times with different initial stenotic resistances for each artery studied in this experimental group. The pressures were recorded on an Electronics for Medicine physiologic recorder. The pressure transducers were carefully calibrated to insure equal sensitivity by simultaneously exposing the pressure transducers to the reservoir pressure, Without flow, both transducers recorded the same pressure level. The absolute pressure value was determined by mea-
CONSTANT
I”
suring the height of the fluid column above the pressure transducers. For the constant pressure experiments, the artery was attached between points a and b (Fig. l), stretched to its original length and kept moist by externally applied physiologic saline solution. The reservoir consisted of a 4 liter bottle filled with physiologic saline solution and suspended at a fixed height above the artery. Using a circumferential snare, stenotic resistances between 0.5 and 6.0 mm Hg/ml.min-i were established with a high peripheral resistance (20 gauge Longdwel needle). With the initial stenotic resistance set, the pressures and flow were recorded. The flow was determined by a 1 minute collection in a graduated cylinder. The peripheral resistance was halved three times by sequentially opening stopcocks Sl, S2, S3. At each level of peripheral resistance, the pressures and flow were recorded. Stopcock Sl was then closed, reestablishing the initial conditions. If the calculated stenotic resistance varied more than 5 percent from the control value, the data were discarded. This procedure was repeated 10 times for each artery.
Radiogr.aphic Analysis Radiographic techniques were used to investigate the stenotic geometric changes that occurred with changes in peripheral resistance. In five dogs, immediately after sacrifice, the left or right common carotid artery was rapidly removed and attached to the constant flow-external constrictor apparatus (Fig. 1). The Dextran solution was replaced with contrast material (Angio-conray@). The circumferential snare was used to establish stenotic resistances between 1.0 and 6.0 mm Hg/ml.min-l. A radiogram was taken (40 kV, 100 mA, 8 seconds, Kodak gray tone imaging film) and the proximal and distal pressures were recorded. The stopcocks Sl, S2 and S3 were then simultaneously opened, lowering the peripheral resistance to approximately one eighth of its initial value. A second radiogram was taken and the pressures recorded. This procedure was repeated only four times for each artery, thereby limiting the total experimental time to less than 15 minutes. High resolution radiograms were obtained by using microangiographic techniques. I9 This involved the use of high resolution film without an image intensifier (Kodak gray tone
FLOW
I
FIGURE 1. Diagram of in vitro constant pressure or constant flow perfusion system. Pl = proximal pressure; P2 = distal pressure; a = proximal and b = distal points of attachment of artery; S 1, S2, S3 = stopcocks: R 1, R2 = 20 gauge Longdwel needles; R3 = short 20 gauge Longdwel needle; and R4 = short 18 gauge Longdwel needle.
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February 1980
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Volume 45
ALTERED CORONARY FLOW RESPONSES-SANTAMORE AND WALINSKY
imaging film, 2,000 line pairs per inch); the use of Angioconray with its high iodine content (800 mg/ml sodium iothalamate); placing the artery close to the film; using fresh arteries; and limiting the experimental time. The radiograms were analyzed by using a dissecting microscope with a calibrated eye piece (magnification X20). Four observers measured the proximal, stenotic and distal diameters of each vessel, before and after the peripheral resistance was lowered. The mean and standard error of the mean were calculated for each diameter measurement. The percent of stenosis was based on the reduction in cross-sectional area9 and was calculated as: percent of stenosis = 100 (1 - DS2/Dp2), where D, is the stenotic diameter and D, is the proximal diameter. Results Vasoactive
Drugs
Methoxamine: Figure 2 (top) shows the typical response to intracoronary methoxamine (500 pg) before
ECG -100 I
1 ’ FLOW (ml/min)
AORTIC PRESSURE CORONARY PRESSURE 7100 PRESSURE
CORONARY FLOW
INJtCTION
= = = =
I
Coronary Hemodynamic Effects of Methoxamine”
I 15 SEEONOS AFTER INJECTION
BEFORE INJECTION AoP COP COR. FLOW DCR
TABLE
Jo
500 fig METHOXAMINE INTRACORONARY
coronary arterial constriction. After administration of methoxamine, coronary flow decreased, whereas distal coronary resistance increased. Figure 2 (bottom) shows for the same experiment the response to methoxamine after partial coronary occlusion. Methoxamine then caused a slight increase in coronary flow, an increase in coronary pressure, an initial increase in distal coronary resistance and a decrease in stenotic resistance. Table I summarizes the effects of intracoronary methoxamine before and after partial coronary occlusion in six dogs. Before occlusion, methoxamine led to a large increase in distal coronary resistance and a decrease in coronary flow. After partial coronary arterial occlusion, methoxamine caused an insignificant decrease in coronary flow. By 15 seconds, coronary flow had decreased from 27.4 f 4.6 to 25.3 f 3.6 ml/min. This decrease in coronary flow was significantly less than the decrease in coronary flow that occurred before coronary arterial constriction (p 10.05). This altered coronary flow response was associated with a coronary pressure increase and a slight, insignificant decrease in stenotic resistance. Vasopressin: Table II summarizes the effects of vasopressin (0.2 U) in six experiments. Before coronary arterial constriction, vasopressin caused a large increase in distal coronary resistance and a decrease in coronary flow. After partial coronary arterial constriction, vaso-
135 135 32.5 4.15
AoP COP COR.FLOW DCR
Coronary Stenotic ResisResistance tance Aortic Coronary Coronary (mm (mm Pressure Pressure Flow Hg/ml Hg/ml (mm Hg) (mm Hg) (mllmin) emin-‘) -min-‘)
= 135 = 135 = 20 = 6.75
Before Occlusion
ECG
Preinjection After iniection 15 skonds 30 seconds 60 seconds 120 seconds
PRESSURE hmHd
INJECTION BEFORE INJECTION AoP COP COR. FLOW DCR SR
= 120 = 60 = 19 = 3.16 = 3.16
122.5 f 4.5
122.5 * 4.5
32.8 f 5.3
4.17 f 0.46
123.5 f 4.4 125.8 f 4.0 127.2 f 5.2 128.3 f 3.3
122.7 f 4.9 125.0 f 4.6 126.7 f 5.7 128.3 f 3.3
24.2 zk 4.2+ 24.5 f 9.8 25.9 * 3.7t 26.9 f 3.9t
5.87 f 0.78+ 5.78 f 0.70+ 5.44 f 0.64+ 5.58 * 0.70+
After Partial Occlusion
500 “g METHOXAMINE INTRACORONARY
Preinjection 15 SECONDS AFTER INJECTION AoP COP COR. FLOW OCR SR
After injection 15 seconds
= 120 = 71 = 24 = 2.96 = 2.04
30 seconds 60 seconds
FIGURE 2. The response in one experiment to intracoronary administration of methoxamine (500 pg) before (lop) and after (bottom)partial coronary arterial constriction. AoP = mean aortic pressure; COP = mean coronary pressure; Cor. Flow = mean coronary blood flow; DCR = distal coronary resistance; ECG = electrocardiogram; and SR = stenotic resistance.
120 seconds
127.8 f 2.9
62.8 f 2.0
27.4 f 4.6
2.79
f 0.43
2.84 f 0.51
128.8 f 2.4 129.3 f 2.6 128.6 f 2.3 130.7 f 2.4
73.6 f 3.4+ 71.4 f 3.0+ 67.8 f 3.0 67.8 f 4.4
25.3 f 3.6 26.0 f 4.5 26.9 f 5.4 24.6 f 7.4
3.29 f 0.40 3.23 f 0.47 3.11 f 0.50 3.72 f 0.77+
2.57 f 0.50 2.67 f 0.44 2.76 f 0.41 3.39 f 0.57
All data values are mean f standard error of mean. + Change from preinjection value significant at p 10.05 by Wilcoxon test. l
February 1980
The American Journal of CARDIOLOGY
Volume 45
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FLOW RESPONSES-SANTAMORE
AND WALINSKY
pressin still caused an increase in distal coronary resistance and a decrease in coronary flow. Coronary pressure increased while stenotic resistance decreased. These studies illustrate that when constriction of distal coronary vasculature is severe, the reduction in stenotic resistance is insufficient to alter effectively the decrease in coronary flow. Isoproterenol: The typical response to intracoronary isoproterenol (1 pg) given before coronary arterial constriction is shown in Figure 3 (top). After the isoproterenol injection, there was a large increase in coronary flow subsequent to the decrease in distal coronary resistance. Heart rate also increased. After partial coronary arterial constriction, there was a strikingly different response to isoproterenol (Fig. 3, bottom). Coronary flow and coronary presssure now decreased and stenotic resistance and heart rate increased. The decrease in coronary flow was associated with a large increase in stenotic resistance. Table III summarizes for six experiments the effects of isoproterenol before and after partial coronary arterial constriction. Before such constriction, isoproterenol resulted in a significant decrease in distal coronary resistance and an increase in coronary flow. Heart rate increased 31 beats/min (p 10.05). After partial coronary arterial constriction, isoproterenol resulted in a decrease in coronary flow that was significantly (p 50.05) dif-
ferent from the normal coronary flow response to isoproterenol. This altered coronary flow response was associated with a large increase in stenotic resistance and a decrease in distal coronary pressure. Heart rate increased 49 beats/min (p 50.05). Nitroglycerin: Table IV summarizes the data from the six nitroglycerin experiments. Before coronary arterial constriction, nitroglycerin led to a transient increase in coronary flow and a decrease in distal coronary resistance. After partial coronary arterial constriction, nitroglycerin caused a decrease in distal coronary resistance and distal coronary pressure, and an increase in stenotic resistance. Although distal coronary resistance decreased, coronary blood flow was unaltered. This coronary flow response was significantly different from the normal coronary flow response to nitroglycerin (p 10.05) and was associated with a large increase in stenotic resistance and a decrease in distal coronary pressure. Stenotic resistance versus distal coronary pressure: Figure 4, combining the data on stenotic resistance and distal coronary pressure in the four experimental groups, shows the changes in stenotic resistance that occurred after administration of a vasoactive drug versus the distal coronary pressure. For all the data shown in Figure 4, the initial value of coronary pressure (abscissa) before the vasoactive drug was between 56
TABLE II
TABLE Ill
Coronary Hemodynamic Effects of Vasopressin’
Coronary Hemodynamic Effects of Isoproterenol’
Aortic Coronary Coronary Pressure Pressure Flow (mm Hg) (mm Hg) (ml/min)
Coronary Resistance (mm Hglml smin-‘)
Stenotic Resistance (mm Hg/ml amin-‘)
Aortic Coronary Coronary Flow Pressure Pressure (mm Hg) (mm Hg) (ml/min)
After injection 15 seconds 30 seconds 60 seconds 120 seconds
Preinjection
120.5 f 5.3
120.5 f5.3
34.2 f 5.8
4.22 f 0.73
122.0 f 5.4 123.0 f 4.5 126.0 f 5.5 131.8 f 6.8
122.0 f 5.4 122.7 f 4.4 124.8 f 5.0 130.7 f 6.3
12.7 f 3.6+ 15.5 f 6.5 16.3 f 7.5 23.0 f 5.9
15.44 f 3.74’ 12.55 f 3.83 23.10 f 9.27 7.87 f 1.75
116.3 f 6.3
61.0 f 1.5
26.1 f 4.9
2.79 f 0.42
2.63 f 0.69
115.5 f 6.9 117.7 f 6.9 119.5 f 6.5 120.2 f 7.3
99.2 f 7.1+ 101.3 f 7.9+ 101.7 f 7.0+ 97.2
14.2 f 3.2+ 13.9 f 3.1+ 15.5 f 3.3 21.3 f 3.8
9.45 f 2.42+ 10.45 f 2.97+ 9.28 f 2.53+ 6.06 f 1.70+
1.30 f 0.31+ 1.12 f 0.22+ 1.24 f 0.44+ 1.21 f 0.41+
After injection 15 seconds 30 seconds 60 seconds 120 seconds
After injection 15 seconds 30 seconds 60 seconds 120 seconds
f
6.3+
All data values are mean f standard error of mean. + Change from preinjection value significant at p SO.05 by Wilcoxon test. l
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February 1980
124.0 f 4.9
124.0 f 4.9
32.2 f 6.9
5.09 f 0.92
121.0 f 6.9 115.6 f 2.9 119.3 f 4.4 122.4 f 4.8
116.8 f 2.1 115.0 f 3.3 118.6 f 4.7 122.0 f 4.8
87.4 f 15.7+ 45.3 f 11.1+ 35.4 f 8.4 36.6 f 7.9
1.70 f 0.30+ 3.42 f 0.53+ 5.47 f 1.35 5.03 f 1.37
After Partial Occlusion
After Occlusion Preinjection
Stenotic Resistance (mm Hg/ml. min-‘)
Before Occlusion
Before Occlusion Preinjection
Coronary Resistance (mm Hg/ml. min-‘)
The American Journal of CARDIOLOGY
Preinjection After injection 15 seconds 30 seconds 60 seconds 120 seconds
124.4 f 3.3
61.2 f 2.5
25.8 rt 4.9
3.05 f 0.35
3.09 f 0.46
18.6 f 2.5 16.6 f 2.8 17.4 f 2.4 21.1 f 2.8
2.40 * 0.29 3.20 f 0.69 2.78 f 0.31 2.16 f 0.47
5.43 f 0.85+ 7.07 f 0.85+ 5.50 f 0.91 4.56 f 0.93
’ All data values are mean f standard error of mean. + Change from preinjection value significant at ~10.05 by Wilcoxon test.
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ALTERED CORONARY
and 64 mm Hg and the initial value of stenotic resistance (ordinate) was between 0.5 and 5.6 mm Hg/ml. min-‘. As coronary pressure decreased after vasodilation, stenotic resistance increased (p 50.01); and, as coronary pressure increased above 60 mm Hg after vasoconstriction, stenotic resistance decreased (p 50.01). In Vitro Arterial Preparation
Constant flow experiments: Table V is based on 86 observations in nine arteries. Stenotic resistance always increased as the distal resistance or distal pressure (P2) decreased; the greater the decrease in distal resistance, the greater the corresponding increase in stenotic resistance. Further demonstrating the dependency of stenotic resistance on intraluminal pressure is the observation that the stenotic resistance changes were bidirectional. Lowering the distal pressure increased the stenotic resistance, whereas increasing the distal pressure decreased the stenotic resistance. At the end of each observation, the peripheral resistance was increased from 0.7 to 4.9 mm Hg/ml.min-l; this caused the stenotic resistance to decrease and return to its control value. Constant pressure experiments: Table VI is based on 31 observations in five arteries. The mean perfusion pressure was 112.4 f 0.2 mm Hg. On the basis of the
FLOW RESPONSES-SANTAMORE
AND WALINSKY
ECG
AORTIC PRESSURE CORONARY PRESSURE CORONARY FLOW INJEkTION
1 UB ISOPROTERENOL INTRACORONARY
I
BEFORE INJECTION AoP COP COR.FLOW DCR
15 SkONDS AFTER INJECTION AoP COP COR. FLOW DCR
= 108 = 106 = 48 = 2.21
= 110 = 98 = 140 = 0.70
100 ECG
FLOW (ml/mln)
CORONARY FLOW
50
AORTIC PRESSURE
CORONARY PRESSURE
TABLE IV
INJEtTlON
Coronary Hemodynamic Effects of Nitroglycerin*
Aortic Coronary Coronary Flow Pressure Pressure (mm Hg) (mm Hg) (ml/min)
Coronary Resistance (mm Hg/ml -min-‘)
Stenotic Resistance (mm Hglml emin-‘)
Before Occlusion Preinjection After injection 15 seconds 30 seconds 60 seconds 120 seconds
121.0 f 2.4
121.0 f 2.4
37.8 f 7.1
4.79 f 1.53
120.0 f 3.5 118.7 f 3.2 120.9 f 2.4 119.6 f 3.0
120.0 f 3.5 118.7 f 3.2 120.9 f 2.4 119.6 f 3.0
55.0 f 11.7+ 38.7 f 7.1 36.9 f 6.2 37.6 f 6.8
3.00 f 0.60+ 4.60 f 1.50 4.42 f 1.19 4.72 f 1.54
After injection 15 seconds 30 seconds 60 seconds 120 seconds
AoP COP COR.FLOW DCR SR
I 15 SiCONDS .AFTER INJECTION AoP COP CDR. FLOW DCR SR
= 109 = 60 = 49 = 1.22 = 1.02
= 121 = 31 = 25 = 1.24 = 3.60
FIGURE 3. The response in one experiment to intracoronary administration of isoproterenol (1 pg) before (top) and after (bottom) partial coronary arterial occlusion. Abbreviations as in Figure 2.
Constant Flow-External Constrictor: Effects of Lowering Distal Resistance on Stenotic Resistance*
112.9 f 6.2
55.7 f 3.1
27.6 f 5.0
2.82 f 0.71
3.29 f 1.15
113.4 f 5.8 113.1 f 6.1 112.4 f 6.7 114.0 f 6.0
42.1 f 3.6+ 51.9 f 4.1 52.4 f 4.3 55.4 f 3.5
27.9 f 5.0 27.9 f 5.0 27.7 f 4.9 25.7 f 4.5
2.00 f 0.48+ 2.47 f 0.64 3.12 f 1.13 3.34 & 1.11
4.54 f 1.94+ 3.33 f 1.11 3.54 f 1.31 3.71 * 1.33
All data values are mean f standard error of mean. + Change from preinjection value significant at p SO.05 by Wilcoxon test. l
BEFORE INJECTION
TABLE V
After Partial Occlusion Preinjection
1 uB ISOPROTERENOL INTRACORDNARY
Distal Resistance (mm Hg/ml -min-‘)
Proximal Pressure (mm Hg)
Distal Pressure (mm Hg)
Stenotic Resistance (mm Hg/ml amin-‘)
4.88 f 0.06 2.52 f 0.03+ 1.36 f 0.01++ 0.71 f 0.01++
153.6 f 1.9 122.6 f 7.7+ 129.7 f 10.8+ 192.6 f 14.1+
111.8 f 1.4 57.7 f 0.6+ 31.1 f 0.2++ 16.3 f 0.3++
1.80 f 0.08 2.86 f 0.34+ 4.29 f 0.47++ 7.70 f 0.62++
* All data values are mean f standard error of mean. + Change from control value significant at p 10.01 by Wilcoxon test. * Change from preceding value (from line above) significant at p 10.05 by Wilcoxon test.
February 1980
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Journal of CARDIOLOGY
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AND WALINSKY
TABLE
VI
Constant Pressure-External Distal Resistance (mm Hg/ml mmin-‘)
Distal Pressure (mm Hg)
Constrictor*
Flow (ml/min)
Stenotic Resistance (mm Hg/ml mmin-‘)
Group A: Flow Increase 5.03 f 0.11 2.47 f 0.07+ 1.27 f- 0.04++ 0.70 f 0.03+*
94.0 f 2.7 74.1 f 3.5+ 49.4 f 4.2++ 30.4 f 3.7+t
18.7 f 0.5 30.1 f 1.51 38.7 * 2.9++ 43.1 f 4.4+
1.08 f 0.17 1.37 f 0.20 1.78 f 0.26+ 2.12 fi28+
Group B: Initial Flow Increase
-4
l
I
CORONARY PRESSURE
FIGURE 4. Distal coronary pressure versus changes in stenotic resistance (SR) that occurred after the administration of the four vasoactive drugs. See text for explanation.
flow response, the data were divided into two groups. In Group A, the flow always increased as the distal resistance decreased. In Group B, the flow initially increased as the distal resistance was decreased. With subsequent lowering of the distal resistance, flow decreased. The decrease in flow was due to the large increase in stenotic resistance. The initial stenotic resistance was significantly higher (p 50.05) and the distal pressure significantly lower (p (0.05) in Group B than in Group A. Thus, the data indicate that a severe stenosis (Group B) was required for flow to decrease as the distal resistance was decreased. Radiographic
Analysis
The radiographic analysis demonstrated that lowering the peripheral resistance caused a significant decrease in stenotic diameter and a significant increase in percent stenosis. Figure 5 shows a typical radiogram obtained from one experiment. Figure 6 summarizes the results of the radiographic analysis. Lowering the peripheral resistance caused a significant reduction in the stenotic and distal diameters and a significant increase in percent of stenosis. These changes were associated with an increase in stenotic resistance from 2.48 f 0.53 to 5.23 f 0.74 mm Hg/ml~min-l (p 10.01). If the stenotic resistance is assumed to be inversely proportional to the diameter to the fourth power, then decreasing the diameter from 0.59 to 0.50 mm would cause an approximate doubling of the stenotic resistance, which is similar to the observed experimental results. Thus, this group of experiments verifies that the changes in stenotic resistance were partially due to changes in stenotic area caused by the reduction of intraluminal pressure.
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4.99
f 0.05 2.45 f 0.03+ 1.22
f
0.02+r
0.73 f 0.02++
77.3 f 2.1 50.1 f 2.2+ 25.1 f
1.5+t
12.2 f 0.9++
15.5 f 0.4 20.4 f 0.8+ 20.8 f 1.4+ 17.0 f 1.6
2.40 f 0.19 3.24 f0.24+ 4 74 f 0.43+* 7.15 f 0.95+t
* All data values are mean f standard error of mean. Change from control value significant at p 10.05 by Wilcoxon test. + Change from preceding value significant at p 10.05 by Wilcoxon test.
Discussion
Coronary flow response to vasoactive drugs: Methoxamine and vasopressin, before coronary arterial constriction, increased distal coronary arterial resistance and decreased coronary flow, a response similar to that reported by others. 14p16After partial coronary arterial occlusion, both methoxamine and vasopressin still increased distal coronary resistance. In the methoxamine experiments, the decrease in stenotic resistance either attenuated the decrease in coronary flow or caused an increase in coronary flow. However, in the vasopressin experiments the decrease in stenotic resistance was insufficient to overcome the large increase in distal coronary resistance, and coronary flow always decreased. Before partial coronary arterial occlusion, intracoronary administration of isoproterenol or nitroglycerin increased coronary blood flow and decreased coronary resistance. This response is similar to the results of other investigators.l7-21 After partial coronary arterial occlusion, intracoronary isoproterenol or nitroglycerin still decreased distal coronary resistance. However, the coronary flow response was attenuated (or even reversed in some experiments) by the large increase in stenotic resistance. Thus, in the presence of severe stenosis, the normal coronary flow response to vasoactive drugs can be attenuated or even reversed. The mechanism for this phenomenon appears to be an interaction between the stenosis and the distal coronary vasculature. Methoxamine and vasopressin, which constricted the distal
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FLOW RESPONSES-SANTAMORE
PROXIMAL 3.28 k.04
STENOTIC 0.59 i.01
AND WALINSKY
DISTAL 3.14 f.02
96.6%
f.2
lllllllllllllllllIllll1lll~l~ll~~llll1;1llllllll;illll~~llllllllllllllllllllllllllllliillllllllllllliilllllll 97.2’%
3.13’ LO4 ‘p
+.1
0.50’ +.01
2.57’ LO2
FIGURE 6. Sketch of artery before (solid line) and after (vertical bars) the peripheral resistance was lowered. Data values on top are the mean f standard error of mean of the proximal, stenotic and distal diameters and percent stenosis obtained before the peripheral resistance was lowered. Data on bottom are the same values obtained after the peripheral resistance was lowered.
FIGURE 5. Typical radiogram obtained before (top) and after (bottom) the peripheral resistance was lowered.
coronary vasculature, also reduced the hemodynamic severity of the stenosis. Because total coronary resistance is the sum of stenotic resistance and distal coronary resistance, if the decrease in stenotic resistance was greater than the increase in distal coronary resistance, then total coronary resistance decreased. This decrease in stenotic resistance altered or even reversed the normal increase in total coronary resistance and decrease in coronary blood flow after the injection of the vasoconstrictors. Conversely, isoproterenol and nitroglycerin, which dilated the distal coronary vasculature, increased the hemodynamic severity of the stenosis. This increase in stenotic resistance altered or even reversed the normal decrease in total coronary resistance and increase in coronary blood flow after the injection of the vasodilators. Thus, the results of this study would indicate that in the presence of severe stenosis, the interaction between the stenosis and distal coronary vasculature will ultimately determine whether a vasoactive agent will increase or decrease coronary blood flow. Stenotic resistance changes induced by changing distal resistance or pressure: Similarly, in the in vitro, carotid arterial preparation, changes in stenotic resistance were also induced by changing the distal resistance or pressure. Increasing the distal resistance or pressure always decreased the stenotic resistance. Conversely, lowering the distal resistance or pressure always increased the stenotic resistance. In the constant pressure experiments, distal resistance was not always associated with a flow increase. With higher initial values for stenotic resistance, flow actually decreased
February
as the distal resistance decreased. This occurred because of the large increase in stenotic resistance. Changes in stenotic resistance versus changes in luminal area: Radiographic analysis demonstrated that the changes in stenotic resistance were due at least in part to changes in luminal area. Lowering the distal pressure or resistance decreased the luminal area. With the snare, an external force is applied to the vessel that is opposed by the intraluminal pressure. Decreasing the intraluminal pressure would tend to collapse the vessel, whereas increasing the intraluminal pressure would tend to expand it.s2 With severe stenosis, only minimal changes in stenotic area will drastically affect flow.ls Thus, in the presence of severe stenosis, these minimal changes in luminal area could cause part of the observed increase in stenotic resistance. An increase in turbulence in blood flowing through the stenosis could also explain part of the increase in stenotic resistance.g However, changes in blood flow turbulence probably occurred secondary to luminal area changes. Lowering the distal pressure decreased the luminal area. If flow remained constant (as in the in vitro constant flow experiments), the flow velocity through the stenosis would increase, leading to increased blood flow turbulence. Several potential mechanisms for the observed changes in stenotic resistance were unsubstantiated by our findings. Platelet plugging has been shown over long periods of time to influence flow through a stenosis.2s However, the rapid response observed after administration of vasoactive drugs, the decrease in stenotic resistance after vasoconstrictors and the increase in stenotic resistance after isoproterenol and nitroglycerin preclude platelet plugging as a mechanism for the responses observed in this study.24 Systemic arterial pressure was unchanged. Finally, any potential changes in collateral blood supply would occur in the distal
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coronary vasculature and therefore could not account for the observed changes in stenotic resistance. Previous studies on stenotic resistance changes: Several in vivo studies have demonstrated changes in stenotic resistance that were postulated to be caused by changes in geometry of the stenosis. Kreuzer and Schenk25 demonstrated an increase in stenotic resistance in the iliac artery caused by distal vasodilation. They believed that vasodilation altered the degree of stenosis by increasing the unstenosed cross-sectional luminal area. Previously7 we demonstrated an increase in stenotic resistance caused by momentary coronary arterial occlusion. Schwartz et a1.6 observed similar changes in stenotic resistance and postulated that the increase in stenotic resistance was due to a passive decrease in the stenotic area secondary to the reduction in intraluminal pressure. In unsedated dogs in which instruments are chronically in place, Gould26 observed dynamic increases in the hemodynamic severity of coronary arterial stenosis after coronary vasodilation. The increase in stenotic resistance after coronary vasodilation was probably due to the dilation of the epicardial artery adjacent to the stenosis, which caused more severe relative percent narrowing and a larger divergence angle. However, Lipscomb and Hooten, using stenotic models, found that the pressure gradient across the coronary stenosis was not affected by varying the exit angle of the stenosis from 10 to 90”. More studies appear necessary to determine the exact mechanism or mechanisms involved in the increase in stenotic resistance after a reduction in the distal pressure.6.72526 Obviously, experimental arterial stenosis is only a model or imitation of human arterial stenosis. However, a recent in vitro study suggested that in man stenotic resistance is also dependent on intraluminal pressure.5
In that study proximal coronary arteries obtained from fresh postmortem human hearts were examined at various flow rates and levels of perfusion pressure and distal resistance. In coronary arteries with eccentric lesions (a plaque on one side not completely surrounding the lumen), the resistance to flow was found to be dependent on the perfusion pressure. At lower perfusion pressures the resistance increased, whereas at higher perfusion pressures the resistance decreased. These results are similar to ours. Clinical implications of this study: In the presence of severe stenosis distal coronary vasodilation might paradoxically decrease blood flow by increasing the hemodynamic severity of the stenosed arterial segment. In light of Logan’s observations,” this phenomenon would probably occur only in patients with eccentric lesions. Patients with hard, fixed concentric lesions would probably not exhibit this characteristic. Further, this study indicates that vasodilation can cause a severe reduction in distal coronary pressure. The reduction in coronary pressure could lead to a maldistribution of myocardial blood flow and therefore the reduction in coronary pressure may be a factor in the production of subendocardial ischemia. This study also implies a very important role for collateral vessels: Such vessels not only would help to maintain myocardial blood flow, but also would help to maintain distal coronary pressure and to stabilize the hemodynamic status of the stenosed arterial segment. Obviously, the foregoing arguments are speculative and additional studies are required to relate these experimental results to the clinical situation. Conceivably, however, the interaction between stenosis and the distal coronary vasculature after administration of vasoactive drugs could be an additional factor in the therapy of patients with coronary arterial disease.
References 1. Shipley RE, Gregg DE. The effect of external constriction of a blood vessel on blood flow. Am J Physiol 1944; 141:289-96. 2. Young DF, Cholvin NR, Kirkeeide RL, Roth AC. Hemodynamics of arterial stenosis at elevated flow rates. Circ Res 1977; 41:
11. Rubio R, Berne RM. Regulation of coronary blood flow. Prog
Cardiovasc Dis 1975; 18:105-22. 12. Forrester JS, Tyberg JV, Wyatt HL, Goldner S, Parmley WW,
99-107.
3. Mates RE, Gupta RL, Bell AC, Klocke FJ. Fluid dynamics of coronary artery stenosis. Circ Res 1978; 42:152-62. 4. Berguer R, Hwang NHC. Critical arterial stenosis: a theoretical and experimental solution. Ann Surg 1974; 180:39-50. 5. Logan SE. On the fluid mechanics of human coronary artery stenosis. IEEE Trans Biomed Eng 1975; 22:327-35. 6. Schwartz JS, Carlyle PF, Cohn JN. Effect of dilation of the distal coronary arteries in the dog. Am J Cardiol 1979; 43:219-24. 7. Wallnsky P, Santamore WP, Wiener L, Brest AN. Dynamic changes in the hemodynamic severity of coronary artery stenosis in a canine model. Cardiovasc Res 1979; 13:113-l 18. 8. Arfors KE, Arturson 0, Malmberg P. Effect of prolonged chloralose anesthesia on acid-base balance and cardiovascular function in dogs. Acta Physiol Stand 1971; 81:47-53. 9. Gould KL, Lipscomb K, Calvert C. Physiologic basis for assessing critical coronary stenosis. Am J Cardiol 1974; 33:87-94. 10. Guilford JP. Fundamental Statistics in Psychology and Education. New York: McGraw-Hill, 1965; 255-6.
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13. 14. 15.
16.
17.
18.
Swan HJC. Pressure-length loops: a new method for simultaneous measurement of segmental and total cardiac function. J Appl Physiol 1974; 37171 l-78. Bellman S. Microangiography. Acta Radio1 [Suppl] 1953; 102: l-104. Nakano J. Studies on the cardiovascular effects of synthetic vasopressin. J Pharmacol Exp Ther 1967; 157:19-30. Heyndricky GR, Boettcher DH, Vatner SF. Effects of angiotensin, vasopressin, and methoxamine on cardiac function and blood flow distribution in conscious dogs. Am J Physiol 1978; 231:157987. Corliss RJ, McKenna DH, Sialer S, O’Brien GS, Rowe GG. Systemic and coronary hemodynamic effects of vasopressin. Am J Med Sci 1968; 256:293-g. McClenathan JH, Guyton RA, Breyer RH, Newman GE, Michaelis LL. The effects of isoproterenol and dopamine on regional myocardial blood flow after stenosis of circumflex coronary artery. J Thorac Cardiovasc Surg 1977; 73:43 l-5. Vatner SF, McRitchie RJ, Maroko PR, Patrick TA, Braunwald E. Effects of catecholamines, exercise and nitroglycerin on the normal
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19.
20.
21. 22.
23.
ischemic myocardium in conscious dogs. J Clin Invest 1974; 54: 563-75. Richards AF, Seabra-Gomes R, Parker DJ. Effects of tachycardia and isoprenaline on coronary blood flow: observations on pathogenesis of myocardial infarction. Br Heart J 1976; 37:881-2. Malindzak GS Jr, Green HD, Stagg PL. Effects of nitroglycerin on flow after partial constriction of the coronary artery. J Appl Physiol 1970; 29: 17-22. Fam WM, McGregor M. Effect of nitroglycerin and dipyridamole on regional coronary resistance. Circ Res 1968; 22:649-59. Rubinow SI, Keller JR Flow of a viscous fluid through an elastic tube with applications to blood flow. J Theor Biol 1972; 35: 299-313. Felts JD, Crowell EB Jr, Rowe GG. Platelet aggregation in partially
24.
25. 26.
27.
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AND WALINSKY
obstructed vessels and its elimination with aspirin. Circulation 1976; 54:365-70. Yu SE, Latour JG. Potentiation by LY-and inhibition by b-adrenergic stimulations of rat platelet aggregation. Thromb Haemostas 1977; 371413-22. Kreuzer W, Schenk WJ Jr. Effects of local vasodilatation on blood flow through arterial stenosis. Eur Surg Res 1973; 5:233-42. Gould KL. Pressure-flow characteristics of coronary stenosis in unsedated dogs at rest and during coronary vasodilation. Circ Res 1978; 43~242-53. Lipscomb K, Hooten S. Effect of stenotic dimensions and blood flow on the hemodynamic significance of model coronary arterial stenosis. Am J Cardiol 1978; 42:781-92.
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WILLIAM P. SANTAMORE, PhD
Recent in vitro observations of human coronary arteries have suggested that intraluminal pressure can be a determinant of the resistance to flow through the stenosis. This study examined whether similar pressuredependent changes in stenotic resistance could be observed and analyzed in an open chest, anesthetized, animal model of coronary arterial stenosis. Without stenosis, intracoronary isoproterenol(1 pg) or nitroglycerin (10 pg) increased flow and decreased coronary resistance, whereas methoxamine (500 pg) or vasopressin (0.2 U) decreased flow and increased coronary resistance. After partial arterial constriction, administration of isoproterenol (1 pg) resulted in a decrease in coronary pressure from 61.2 f 2.5 to 39.4 f 2.7 mm Hg (p 10.05), a 23 percent decrease in distal coronary resistance (p 10.05) and a 22 percent decrease in flow associated with an increase in stenotic resistance of 2.34 f 0.97 (p 10.05). Similarly, nitroglycerin caused a decrease in coronary pressure from 55.7 f 3.1 to 42.1 f 3.6 mm Hg (p <0.05), a 29 percent increase in distal coronary resistance and only a 1 percent increase in flow associated with a 38 percent increase in stenotic resistance. Methoxamine caused an increase in coronary pressure from 62.8 f 2.0 to 73.6 f 3.4 mm Hg (p 10.05), an 18 percent increase in distal coronary resistance, an 8 percent decrease in flow and a 10 percent decrease in stenotic resistance. Vasopressin caused an increase in coronary pressure from 61.0 f 1.5 to 99.2 f 7.1 mm Hg (p 10.05), a 239 percent increase in distal coronary resistance but only a 45 percent decrease in flow associated with a decrease in stenotic resistance of 1.33 f 0.91 (p 50.05). Passive changes in the stenotic area caused by coronary pressure changes are postulated as part of the mechanism for the observed changes in stenotic resistance. This hypothesis is strengthened by the changes in stenotic resistance and radiographic analysis obtained from an in vitro carotid arterial preparation. The pressure-dependency of stenotic resistance could be an additional factor in the treatment of patients with coronary artery disease.
PAUL WALINSKY, MD Philadelphia,
Pennsylvania
From the Department of Medicine, Division of Cardiology, Temple University Medical School, and the Division of Cardiology, Jefferson Medical College, Philadelphia, Pennsylvania. This study was supported by an Investigatorship (to Dr. Santamore) from the Southeastern Pennsylvania Heart Association, and by Biomedical Research Support Grant RR 05414 from the National Instittites of Health, Bethesda, Maryland. Manuscript received April 4, 1979; revised manuscript received September 5. 1979, accepted September 12, 1979. Address for reprints: William P. Santamore, PhD, Temple University Medical School, Department of Medicine, Philadelphia, Pennsylvania 19140.
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Journal
Coronary arterial stenosis has a complex influence on blood flow through and beyond the narrowed segment. Factors that have been recognized as determining resistance across a stenosis include the absolute radius, the relative percent of narrowing, the length of the stenosis and the viscosity and velocity of fluid flowing through the ‘stenosis.lm4 A recent in vitro study suggested that stenotic resistance was also dependent on intraluminal pressure. 5 In that study proximal coronary arteries, obtained from fresh postmortem adult hearts, were examined under various flow rates, perfusion pressures and distal resistances. In coronary arteries with eccentric lesions (a plaque on one side not completely surrounding the lumen), the resistance to flow was found to be dependent on the perfusion pressure: lowering the perfusion pressure increased the resistance, whereas increasing the perfusion pressure decreased the re-
of CARDIOLOGY
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45
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sistance. This study suggested that interventions that lower the distal coronary arterial pressure could increase the hemodynamic resistance of the stenotic segment of the artery, whereas interventions that raise the distal coronary pressure could decrease the hemodynamic resistance of the stenotic segment of the artery. Recently, Schwartz et a1.6 and Walinsky et a1.7 in our laboratory documented an alteration of the normal response to momentary coronary arterial occlusion in the presence of partial coronary arterial constriction. We observed a dependence of stenotic resistance on distal coronary pressure, a finding similar to the in vitro observations on human coronary arteries described previously. It was the objective of this study to expand our initial observations by examining the coronary response to a variety of vasoactive drugs in a canine model of high grade coronary stenosis and to determine the mechanism for the observed changes in stenotic resistance by using an in vitro arterial preparation. Methods Initial Preparation Animal studies were performed in 10 mongrel dogs weighing 29.5 to 34.1 kg. All animals were pretreated with morphine (1 mg/kg), anesthetized with alpha-chloralose (100 mg/kg) and mechanically ventilated. Supplemental doses of alpha-chloralose were given as needed. Arterial blood partial pressures of oxygen (Pop) and carbon dioxide (Pco~) and pH were periodically monitored throughout the experiment by a blood gas analyzer (Instrumentation Laboratory). Respiratory adjustments or intravenous infusions of sodium bicarbonate, or both, were made when necessary to keep blood gases and pH within a physiologic range of pH 7.32 to 7.42, PC02 32 to 42 mm Hg, POT above 70 mm Hg.8 The heart was exposed through a left lateral thoracotomy and suspended in a pericardial cradle. A catheter was advanced in retrograde fashion from the right femoral artery and positioned in the ascending aorta to measure aortic pressure. Depending on the coronary arterial anatomy, an electromagnetic flow probe (Biotronex Laboratory, Inc.) was placed around either the left anterior descending artery or the circumflex artery. If the left anterior descending artery was utilized, the site of isolation varied from the proximal to the mid portion of the artery. If the circumflex artery was utilized, the site of isolation was always proximal to the first major marginal branch. A variable snare type of occluder was placed distal to the flow probe. The snare consisted of a 1 mm wide band of Teflon@ passed around the artery, through stiff tubing, and attached to a machinist’s micrometer. The micrometer and tubing were mounted above the dog in a position that prevented traction from being exerted on the stenosis during the cardiac cycle both before and after drug interventions. The snare could be closed by small precise amounts according to a 0.01 mm micrometer scale. The advantage of a narrow (1 mm) snare occluder was that a higher degree of stenosis could be obtained before resting coronary blood flow was affected.l Distal to the micrometer-adjusted snare occluder, 1-O nylon suture was placed around the coronary artery. The ends of the suture were inserted through a piece of polyethylene tubing, 3 cm in length. Zero flow was obtained by pulling the ends of the suture while pressing on the polyethylene tubing against the coronary vessel. Thus, zero flow could be obtained without changing the setting on the micrometer-adjusted snare oceluder. Distal to the occluder, a 22 gauge catheter was inserted
FLOW RESPONSES-SANTAMORE
AND WALINSKY
either into a diagonal branch or directly into the circumflex artery. The catheter was used for monitoring distal coronary arterial pressure and for all intracoronary injections. In the region perfused by the artery in which instruments were placed a small platinum electrode was inserted into the myocardium to record an intramyocardial electrogram. Aortic pressure, coronary blood flow, coronary pressure distal to the snare and an intramyocardial electrogram were
recorded on an Electronics for Medicine physiologic recorder (model DR8). Mean pressures were obtained electronically. Distal coronary resistance was calculated by dividing mean distal coronary arterial pressure by mean coronary blood flow. Stenotic resistance was calculated by dividing the mean pressure gradient across the stenosis by mean coronary flo~.l,~ The mean pressure gradient across the stenosis was calculated as the mean aortic blood pressure minus mean coronary arterial pressure. At the end of each experiment the electromagnetic flow probe was calibrated by timed collection of blood. The coronary artery distal to the site of insertion of the 22 gauge catheter was occluded. The coronary blood then flowed through the proximal coronary artery and the coronary catheter into a graduated cylinder. Statistical analysis was performed by using the Wilcoxon sign rank testi to compare the control values with the values obtained after injection of the pharmacologic agent. Experimental Procedure: Vasoactive Drugs After the initial preparation, the effects of intracoronary injection of isoproterenol(l pg) and methoxamine (500 pg), each diluted in 1 ml of physiologic saline solution, were examined before and after partial constriction of the coronary artery in six dogs. All injections were made through the catheter used to monitor distal coronary pressure. Before constriction of the coronary artery, isoproterenol (1 pg) was rapidly injected into that artery while all physiologic variables were recorded continuously for a 10 minute period before and after the injection. Next, methoxamine (500 pug)was injected into the coronary artery while the physiologic variables were recorded. Mean distal coronary pressure was then gradually reduced to 60 mm Hg by tightening the snare occluder. Mean distal coronary pressure was reduced to 60 mm Hg because 60 mm Hg has been shown to be close to the limits of autoregulationll and ventricular mechanical integrity.12 All physiologic variables were recorded for at least 15 minutes with the mean coronary pressure at 60 mm Hg to verify stability. Isoproterenol (1 pg) and methoxamine (500 pg) were again administered into the coronary artery by the technique outlined earlier. To avoid any interaction between the drugs, there was a 20 minute period between intracoronary injections. Further, the order in which the drugs were given was alternated. In half the experiments isoproterenol was injected first and in the other half, methoxamine was injected first. In six dogs, after the initial preparation, the effects of intracoronary injections of nitroglycerin (10 pg) and vasopressin (0.2 U), each diluted in 1 ml physiologic saline solution, were examined before and after partial coronary arterial constriction by the methods outlined earlier. Again, to avoid drug interaction, there was at least a 20 minute period between intracoronary injections and the order in which the drugs were given was alternated. In Vitro Carotid Arterial Preparations To test further the dependency intraluminal pressure, an in vitro used. The in vitro carotid arterial exclude alpha and beta adrenergic
February 1980
of stenotic resistance on arterial preparation was preparation was used to stimulation, reflexes, sys-
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temic blood pressure changes, pulsatile blood flow and pressure, collateral vessels and platelet plugging as potential causes of the stenotic resistance changes. The carotid artery was used because of its easy removal from the dog and its long length without branches. In each study, the artery was frozen, thawed, suspended in air and kept moist by externally applied saline solution. By design, therefore, only the passive characteristics of arterial stenosis were studied by means of this preparation. In 11 mongrel dogs (11.3 to 40.8 kg) the left and right common carotid arteries were rapidly removed immediately after the anesthetized animal was killed. The arteries were frozen in physiologic saline solution until they were studied. Two types of experimental protocols were performed: constant flow and constant pressure. For the constant flow experiments, the artery was attached between points a and b (Fig. 1) and stretched to its original in vivo length. The artery was kept moist by externally applied physiologic saline solution. A Harvard syringe pump maintained a constant flow rate (22.9 ml/min between a pressure range of 0 to 400 mm Hg) of an isotonic dextran solution (1.7 centipoise). With use of a circumferential snare (previously described), various stenotic resistances between 0.5 and 6.0 mm Hg/ml.min-’ were established, with a high peripheral resistance (20 gauge Longdwel needle). Stenotic resistance was calculated as the pressure gradient across the stenosis (Pl - P2) divided by the flo~.~*s Distal resistance was calculated as distal pressure divided by flow. With the initial stenotic resistance set and the pressures recorded, the distal resistance was halved three times by sequentially opening stopcocks Sl, S2 and S3. At each level of distal resistance, the pressures were recorded. Stopcock Sl was then closed, reestablishing the initial conditions. If stenotic resistance varied more than 5 percent from the control value, the data were discarded. This procedure was repeated 10 times with different initial stenotic resistances for each artery studied in this experimental group. The pressures were recorded on an Electronics for Medicine physiologic recorder. The pressure transducers were carefully calibrated to insure equal sensitivity by simultaneously exposing the pressure transducers to the reservoir pressure, Without flow, both transducers recorded the same pressure level. The absolute pressure value was determined by mea-
CONSTANT
I”
suring the height of the fluid column above the pressure transducers. For the constant pressure experiments, the artery was attached between points a and b (Fig. l), stretched to its original length and kept moist by externally applied physiologic saline solution. The reservoir consisted of a 4 liter bottle filled with physiologic saline solution and suspended at a fixed height above the artery. Using a circumferential snare, stenotic resistances between 0.5 and 6.0 mm Hg/ml.min-i were established with a high peripheral resistance (20 gauge Longdwel needle). With the initial stenotic resistance set, the pressures and flow were recorded. The flow was determined by a 1 minute collection in a graduated cylinder. The peripheral resistance was halved three times by sequentially opening stopcocks Sl, S2, S3. At each level of peripheral resistance, the pressures and flow were recorded. Stopcock Sl was then closed, reestablishing the initial conditions. If the calculated stenotic resistance varied more than 5 percent from the control value, the data were discarded. This procedure was repeated 10 times for each artery.
Radiogr.aphic Analysis Radiographic techniques were used to investigate the stenotic geometric changes that occurred with changes in peripheral resistance. In five dogs, immediately after sacrifice, the left or right common carotid artery was rapidly removed and attached to the constant flow-external constrictor apparatus (Fig. 1). The Dextran solution was replaced with contrast material (Angio-conray@). The circumferential snare was used to establish stenotic resistances between 1.0 and 6.0 mm Hg/ml.min-l. A radiogram was taken (40 kV, 100 mA, 8 seconds, Kodak gray tone imaging film) and the proximal and distal pressures were recorded. The stopcocks Sl, S2 and S3 were then simultaneously opened, lowering the peripheral resistance to approximately one eighth of its initial value. A second radiogram was taken and the pressures recorded. This procedure was repeated only four times for each artery, thereby limiting the total experimental time to less than 15 minutes. High resolution radiograms were obtained by using microangiographic techniques. I9 This involved the use of high resolution film without an image intensifier (Kodak gray tone
FLOW
I
FIGURE 1. Diagram of in vitro constant pressure or constant flow perfusion system. Pl = proximal pressure; P2 = distal pressure; a = proximal and b = distal points of attachment of artery; S 1, S2, S3 = stopcocks: R 1, R2 = 20 gauge Longdwel needles; R3 = short 20 gauge Longdwel needle; and R4 = short 18 gauge Longdwel needle.
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imaging film, 2,000 line pairs per inch); the use of Angioconray with its high iodine content (800 mg/ml sodium iothalamate); placing the artery close to the film; using fresh arteries; and limiting the experimental time. The radiograms were analyzed by using a dissecting microscope with a calibrated eye piece (magnification X20). Four observers measured the proximal, stenotic and distal diameters of each vessel, before and after the peripheral resistance was lowered. The mean and standard error of the mean were calculated for each diameter measurement. The percent of stenosis was based on the reduction in cross-sectional area9 and was calculated as: percent of stenosis = 100 (1 - DS2/Dp2), where D, is the stenotic diameter and D, is the proximal diameter. Results Vasoactive
Drugs
Methoxamine: Figure 2 (top) shows the typical response to intracoronary methoxamine (500 pg) before
ECG -100 I
1 ’ FLOW (ml/min)
AORTIC PRESSURE CORONARY PRESSURE 7100 PRESSURE
CORONARY FLOW
INJtCTION
= = = =
I
Coronary Hemodynamic Effects of Methoxamine”
I 15 SEEONOS AFTER INJECTION
BEFORE INJECTION AoP COP COR. FLOW DCR
TABLE
Jo
500 fig METHOXAMINE INTRACORONARY
coronary arterial constriction. After administration of methoxamine, coronary flow decreased, whereas distal coronary resistance increased. Figure 2 (bottom) shows for the same experiment the response to methoxamine after partial coronary occlusion. Methoxamine then caused a slight increase in coronary flow, an increase in coronary pressure, an initial increase in distal coronary resistance and a decrease in stenotic resistance. Table I summarizes the effects of intracoronary methoxamine before and after partial coronary occlusion in six dogs. Before occlusion, methoxamine led to a large increase in distal coronary resistance and a decrease in coronary flow. After partial coronary arterial occlusion, methoxamine caused an insignificant decrease in coronary flow. By 15 seconds, coronary flow had decreased from 27.4 f 4.6 to 25.3 f 3.6 ml/min. This decrease in coronary flow was significantly less than the decrease in coronary flow that occurred before coronary arterial constriction (p 10.05). This altered coronary flow response was associated with a coronary pressure increase and a slight, insignificant decrease in stenotic resistance. Vasopressin: Table II summarizes the effects of vasopressin (0.2 U) in six experiments. Before coronary arterial constriction, vasopressin caused a large increase in distal coronary resistance and a decrease in coronary flow. After partial coronary arterial constriction, vaso-
135 135 32.5 4.15
AoP COP COR.FLOW DCR
Coronary Stenotic ResisResistance tance Aortic Coronary Coronary (mm (mm Pressure Pressure Flow Hg/ml Hg/ml (mm Hg) (mm Hg) (mllmin) emin-‘) -min-‘)
= 135 = 135 = 20 = 6.75
Before Occlusion
ECG
Preinjection After iniection 15 skonds 30 seconds 60 seconds 120 seconds
PRESSURE hmHd
INJECTION BEFORE INJECTION AoP COP COR. FLOW DCR SR
= 120 = 60 = 19 = 3.16 = 3.16
122.5 f 4.5
122.5 * 4.5
32.8 f 5.3
4.17 f 0.46
123.5 f 4.4 125.8 f 4.0 127.2 f 5.2 128.3 f 3.3
122.7 f 4.9 125.0 f 4.6 126.7 f 5.7 128.3 f 3.3
24.2 zk 4.2+ 24.5 f 9.8 25.9 * 3.7t 26.9 f 3.9t
5.87 f 0.78+ 5.78 f 0.70+ 5.44 f 0.64+ 5.58 * 0.70+
After Partial Occlusion
500 “g METHOXAMINE INTRACORONARY
Preinjection 15 SECONDS AFTER INJECTION AoP COP COR. FLOW OCR SR
After injection 15 seconds
= 120 = 71 = 24 = 2.96 = 2.04
30 seconds 60 seconds
FIGURE 2. The response in one experiment to intracoronary administration of methoxamine (500 pg) before (lop) and after (bottom)partial coronary arterial constriction. AoP = mean aortic pressure; COP = mean coronary pressure; Cor. Flow = mean coronary blood flow; DCR = distal coronary resistance; ECG = electrocardiogram; and SR = stenotic resistance.
120 seconds
127.8 f 2.9
62.8 f 2.0
27.4 f 4.6
2.79
f 0.43
2.84 f 0.51
128.8 f 2.4 129.3 f 2.6 128.6 f 2.3 130.7 f 2.4
73.6 f 3.4+ 71.4 f 3.0+ 67.8 f 3.0 67.8 f 4.4
25.3 f 3.6 26.0 f 4.5 26.9 f 5.4 24.6 f 7.4
3.29 f 0.40 3.23 f 0.47 3.11 f 0.50 3.72 f 0.77+
2.57 f 0.50 2.67 f 0.44 2.76 f 0.41 3.39 f 0.57
All data values are mean f standard error of mean. + Change from preinjection value significant at p 10.05 by Wilcoxon test. l
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pressin still caused an increase in distal coronary resistance and a decrease in coronary flow. Coronary pressure increased while stenotic resistance decreased. These studies illustrate that when constriction of distal coronary vasculature is severe, the reduction in stenotic resistance is insufficient to alter effectively the decrease in coronary flow. Isoproterenol: The typical response to intracoronary isoproterenol (1 pg) given before coronary arterial constriction is shown in Figure 3 (top). After the isoproterenol injection, there was a large increase in coronary flow subsequent to the decrease in distal coronary resistance. Heart rate also increased. After partial coronary arterial constriction, there was a strikingly different response to isoproterenol (Fig. 3, bottom). Coronary flow and coronary presssure now decreased and stenotic resistance and heart rate increased. The decrease in coronary flow was associated with a large increase in stenotic resistance. Table III summarizes for six experiments the effects of isoproterenol before and after partial coronary arterial constriction. Before such constriction, isoproterenol resulted in a significant decrease in distal coronary resistance and an increase in coronary flow. Heart rate increased 31 beats/min (p 10.05). After partial coronary arterial constriction, isoproterenol resulted in a decrease in coronary flow that was significantly (p 50.05) dif-
ferent from the normal coronary flow response to isoproterenol. This altered coronary flow response was associated with a large increase in stenotic resistance and a decrease in distal coronary pressure. Heart rate increased 49 beats/min (p 50.05). Nitroglycerin: Table IV summarizes the data from the six nitroglycerin experiments. Before coronary arterial constriction, nitroglycerin led to a transient increase in coronary flow and a decrease in distal coronary resistance. After partial coronary arterial constriction, nitroglycerin caused a decrease in distal coronary resistance and distal coronary pressure, and an increase in stenotic resistance. Although distal coronary resistance decreased, coronary blood flow was unaltered. This coronary flow response was significantly different from the normal coronary flow response to nitroglycerin (p 10.05) and was associated with a large increase in stenotic resistance and a decrease in distal coronary pressure. Stenotic resistance versus distal coronary pressure: Figure 4, combining the data on stenotic resistance and distal coronary pressure in the four experimental groups, shows the changes in stenotic resistance that occurred after administration of a vasoactive drug versus the distal coronary pressure. For all the data shown in Figure 4, the initial value of coronary pressure (abscissa) before the vasoactive drug was between 56
TABLE II
TABLE Ill
Coronary Hemodynamic Effects of Vasopressin’
Coronary Hemodynamic Effects of Isoproterenol’
Aortic Coronary Coronary Pressure Pressure Flow (mm Hg) (mm Hg) (ml/min)
Coronary Resistance (mm Hglml smin-‘)
Stenotic Resistance (mm Hg/ml amin-‘)
Aortic Coronary Coronary Flow Pressure Pressure (mm Hg) (mm Hg) (ml/min)
After injection 15 seconds 30 seconds 60 seconds 120 seconds
Preinjection
120.5 f 5.3
120.5 f5.3
34.2 f 5.8
4.22 f 0.73
122.0 f 5.4 123.0 f 4.5 126.0 f 5.5 131.8 f 6.8
122.0 f 5.4 122.7 f 4.4 124.8 f 5.0 130.7 f 6.3
12.7 f 3.6+ 15.5 f 6.5 16.3 f 7.5 23.0 f 5.9
15.44 f 3.74’ 12.55 f 3.83 23.10 f 9.27 7.87 f 1.75
116.3 f 6.3
61.0 f 1.5
26.1 f 4.9
2.79 f 0.42
2.63 f 0.69
115.5 f 6.9 117.7 f 6.9 119.5 f 6.5 120.2 f 7.3
99.2 f 7.1+ 101.3 f 7.9+ 101.7 f 7.0+ 97.2
14.2 f 3.2+ 13.9 f 3.1+ 15.5 f 3.3 21.3 f 3.8
9.45 f 2.42+ 10.45 f 2.97+ 9.28 f 2.53+ 6.06 f 1.70+
1.30 f 0.31+ 1.12 f 0.22+ 1.24 f 0.44+ 1.21 f 0.41+
After injection 15 seconds 30 seconds 60 seconds 120 seconds
After injection 15 seconds 30 seconds 60 seconds 120 seconds
f
6.3+
All data values are mean f standard error of mean. + Change from preinjection value significant at p SO.05 by Wilcoxon test. l
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124.0 f 4.9
124.0 f 4.9
32.2 f 6.9
5.09 f 0.92
121.0 f 6.9 115.6 f 2.9 119.3 f 4.4 122.4 f 4.8
116.8 f 2.1 115.0 f 3.3 118.6 f 4.7 122.0 f 4.8
87.4 f 15.7+ 45.3 f 11.1+ 35.4 f 8.4 36.6 f 7.9
1.70 f 0.30+ 3.42 f 0.53+ 5.47 f 1.35 5.03 f 1.37
After Partial Occlusion
After Occlusion Preinjection
Stenotic Resistance (mm Hg/ml. min-‘)
Before Occlusion
Before Occlusion Preinjection
Coronary Resistance (mm Hg/ml. min-‘)
The American Journal of CARDIOLOGY
Preinjection After injection 15 seconds 30 seconds 60 seconds 120 seconds
124.4 f 3.3
61.2 f 2.5
25.8 rt 4.9
3.05 f 0.35
3.09 f 0.46
18.6 f 2.5 16.6 f 2.8 17.4 f 2.4 21.1 f 2.8
2.40 * 0.29 3.20 f 0.69 2.78 f 0.31 2.16 f 0.47
5.43 f 0.85+ 7.07 f 0.85+ 5.50 f 0.91 4.56 f 0.93
’ All data values are mean f standard error of mean. + Change from preinjection value significant at ~10.05 by Wilcoxon test.
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and 64 mm Hg and the initial value of stenotic resistance (ordinate) was between 0.5 and 5.6 mm Hg/ml. min-‘. As coronary pressure decreased after vasodilation, stenotic resistance increased (p 50.01); and, as coronary pressure increased above 60 mm Hg after vasoconstriction, stenotic resistance decreased (p 50.01). In Vitro Arterial Preparation
Constant flow experiments: Table V is based on 86 observations in nine arteries. Stenotic resistance always increased as the distal resistance or distal pressure (P2) decreased; the greater the decrease in distal resistance, the greater the corresponding increase in stenotic resistance. Further demonstrating the dependency of stenotic resistance on intraluminal pressure is the observation that the stenotic resistance changes were bidirectional. Lowering the distal pressure increased the stenotic resistance, whereas increasing the distal pressure decreased the stenotic resistance. At the end of each observation, the peripheral resistance was increased from 0.7 to 4.9 mm Hg/ml.min-l; this caused the stenotic resistance to decrease and return to its control value. Constant pressure experiments: Table VI is based on 31 observations in five arteries. The mean perfusion pressure was 112.4 f 0.2 mm Hg. On the basis of the
FLOW RESPONSES-SANTAMORE
AND WALINSKY
ECG
AORTIC PRESSURE CORONARY PRESSURE CORONARY FLOW INJEkTION
1 UB ISOPROTERENOL INTRACORONARY
I
BEFORE INJECTION AoP COP COR.FLOW DCR
15 SkONDS AFTER INJECTION AoP COP COR. FLOW DCR
= 108 = 106 = 48 = 2.21
= 110 = 98 = 140 = 0.70
100 ECG
FLOW (ml/mln)
CORONARY FLOW
50
AORTIC PRESSURE
CORONARY PRESSURE
TABLE IV
INJEtTlON
Coronary Hemodynamic Effects of Nitroglycerin*
Aortic Coronary Coronary Flow Pressure Pressure (mm Hg) (mm Hg) (ml/min)
Coronary Resistance (mm Hg/ml -min-‘)
Stenotic Resistance (mm Hglml emin-‘)
Before Occlusion Preinjection After injection 15 seconds 30 seconds 60 seconds 120 seconds
121.0 f 2.4
121.0 f 2.4
37.8 f 7.1
4.79 f 1.53
120.0 f 3.5 118.7 f 3.2 120.9 f 2.4 119.6 f 3.0
120.0 f 3.5 118.7 f 3.2 120.9 f 2.4 119.6 f 3.0
55.0 f 11.7+ 38.7 f 7.1 36.9 f 6.2 37.6 f 6.8
3.00 f 0.60+ 4.60 f 1.50 4.42 f 1.19 4.72 f 1.54
After injection 15 seconds 30 seconds 60 seconds 120 seconds
AoP COP COR.FLOW DCR SR
I 15 SiCONDS .AFTER INJECTION AoP COP CDR. FLOW DCR SR
= 109 = 60 = 49 = 1.22 = 1.02
= 121 = 31 = 25 = 1.24 = 3.60
FIGURE 3. The response in one experiment to intracoronary administration of isoproterenol (1 pg) before (top) and after (bottom) partial coronary arterial occlusion. Abbreviations as in Figure 2.
Constant Flow-External Constrictor: Effects of Lowering Distal Resistance on Stenotic Resistance*
112.9 f 6.2
55.7 f 3.1
27.6 f 5.0
2.82 f 0.71
3.29 f 1.15
113.4 f 5.8 113.1 f 6.1 112.4 f 6.7 114.0 f 6.0
42.1 f 3.6+ 51.9 f 4.1 52.4 f 4.3 55.4 f 3.5
27.9 f 5.0 27.9 f 5.0 27.7 f 4.9 25.7 f 4.5
2.00 f 0.48+ 2.47 f 0.64 3.12 f 1.13 3.34 & 1.11
4.54 f 1.94+ 3.33 f 1.11 3.54 f 1.31 3.71 * 1.33
All data values are mean f standard error of mean. + Change from preinjection value significant at p SO.05 by Wilcoxon test. l
BEFORE INJECTION
TABLE V
After Partial Occlusion Preinjection
1 uB ISOPROTERENOL INTRACORDNARY
Distal Resistance (mm Hg/ml -min-‘)
Proximal Pressure (mm Hg)
Distal Pressure (mm Hg)
Stenotic Resistance (mm Hg/ml amin-‘)
4.88 f 0.06 2.52 f 0.03+ 1.36 f 0.01++ 0.71 f 0.01++
153.6 f 1.9 122.6 f 7.7+ 129.7 f 10.8+ 192.6 f 14.1+
111.8 f 1.4 57.7 f 0.6+ 31.1 f 0.2++ 16.3 f 0.3++
1.80 f 0.08 2.86 f 0.34+ 4.29 f 0.47++ 7.70 f 0.62++
* All data values are mean f standard error of mean. + Change from control value significant at p 10.01 by Wilcoxon test. * Change from preceding value (from line above) significant at p 10.05 by Wilcoxon test.
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TABLE
VI
Constant Pressure-External Distal Resistance (mm Hg/ml mmin-‘)
Distal Pressure (mm Hg)
Constrictor*
Flow (ml/min)
Stenotic Resistance (mm Hg/ml mmin-‘)
Group A: Flow Increase 5.03 f 0.11 2.47 f 0.07+ 1.27 f- 0.04++ 0.70 f 0.03+*
94.0 f 2.7 74.1 f 3.5+ 49.4 f 4.2++ 30.4 f 3.7+t
18.7 f 0.5 30.1 f 1.51 38.7 * 2.9++ 43.1 f 4.4+
1.08 f 0.17 1.37 f 0.20 1.78 f 0.26+ 2.12 fi28+
Group B: Initial Flow Increase
-4
l
I
CORONARY PRESSURE
FIGURE 4. Distal coronary pressure versus changes in stenotic resistance (SR) that occurred after the administration of the four vasoactive drugs. See text for explanation.
flow response, the data were divided into two groups. In Group A, the flow always increased as the distal resistance decreased. In Group B, the flow initially increased as the distal resistance was decreased. With subsequent lowering of the distal resistance, flow decreased. The decrease in flow was due to the large increase in stenotic resistance. The initial stenotic resistance was significantly higher (p 50.05) and the distal pressure significantly lower (p (0.05) in Group B than in Group A. Thus, the data indicate that a severe stenosis (Group B) was required for flow to decrease as the distal resistance was decreased. Radiographic
Analysis
The radiographic analysis demonstrated that lowering the peripheral resistance caused a significant decrease in stenotic diameter and a significant increase in percent stenosis. Figure 5 shows a typical radiogram obtained from one experiment. Figure 6 summarizes the results of the radiographic analysis. Lowering the peripheral resistance caused a significant reduction in the stenotic and distal diameters and a significant increase in percent of stenosis. These changes were associated with an increase in stenotic resistance from 2.48 f 0.53 to 5.23 f 0.74 mm Hg/ml~min-l (p 10.01). If the stenotic resistance is assumed to be inversely proportional to the diameter to the fourth power, then decreasing the diameter from 0.59 to 0.50 mm would cause an approximate doubling of the stenotic resistance, which is similar to the observed experimental results. Thus, this group of experiments verifies that the changes in stenotic resistance were partially due to changes in stenotic area caused by the reduction of intraluminal pressure.
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4.99
f 0.05 2.45 f 0.03+ 1.22
f
0.02+r
0.73 f 0.02++
77.3 f 2.1 50.1 f 2.2+ 25.1 f
1.5+t
12.2 f 0.9++
15.5 f 0.4 20.4 f 0.8+ 20.8 f 1.4+ 17.0 f 1.6
2.40 f 0.19 3.24 f0.24+ 4 74 f 0.43+* 7.15 f 0.95+t
* All data values are mean f standard error of mean. Change from control value significant at p 10.05 by Wilcoxon test. + Change from preceding value significant at p 10.05 by Wilcoxon test.
Discussion
Coronary flow response to vasoactive drugs: Methoxamine and vasopressin, before coronary arterial constriction, increased distal coronary arterial resistance and decreased coronary flow, a response similar to that reported by others. 14p16After partial coronary arterial occlusion, both methoxamine and vasopressin still increased distal coronary resistance. In the methoxamine experiments, the decrease in stenotic resistance either attenuated the decrease in coronary flow or caused an increase in coronary flow. However, in the vasopressin experiments the decrease in stenotic resistance was insufficient to overcome the large increase in distal coronary resistance, and coronary flow always decreased. Before partial coronary arterial occlusion, intracoronary administration of isoproterenol or nitroglycerin increased coronary blood flow and decreased coronary resistance. This response is similar to the results of other investigators.l7-21 After partial coronary arterial occlusion, intracoronary isoproterenol or nitroglycerin still decreased distal coronary resistance. However, the coronary flow response was attenuated (or even reversed in some experiments) by the large increase in stenotic resistance. Thus, in the presence of severe stenosis, the normal coronary flow response to vasoactive drugs can be attenuated or even reversed. The mechanism for this phenomenon appears to be an interaction between the stenosis and the distal coronary vasculature. Methoxamine and vasopressin, which constricted the distal
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PROXIMAL 3.28 k.04
STENOTIC 0.59 i.01
AND WALINSKY
DISTAL 3.14 f.02
96.6%
f.2
lllllllllllllllllIllll1lll~l~ll~~llll1;1llllllll;illll~~llllllllllllllllllllllllllllliillllllllllllliilllllll 97.2’%
3.13’ LO4 ‘p
+.1
0.50’ +.01
2.57’ LO2
FIGURE 6. Sketch of artery before (solid line) and after (vertical bars) the peripheral resistance was lowered. Data values on top are the mean f standard error of mean of the proximal, stenotic and distal diameters and percent stenosis obtained before the peripheral resistance was lowered. Data on bottom are the same values obtained after the peripheral resistance was lowered.
FIGURE 5. Typical radiogram obtained before (top) and after (bottom) the peripheral resistance was lowered.
coronary vasculature, also reduced the hemodynamic severity of the stenosis. Because total coronary resistance is the sum of stenotic resistance and distal coronary resistance, if the decrease in stenotic resistance was greater than the increase in distal coronary resistance, then total coronary resistance decreased. This decrease in stenotic resistance altered or even reversed the normal increase in total coronary resistance and decrease in coronary blood flow after the injection of the vasoconstrictors. Conversely, isoproterenol and nitroglycerin, which dilated the distal coronary vasculature, increased the hemodynamic severity of the stenosis. This increase in stenotic resistance altered or even reversed the normal decrease in total coronary resistance and increase in coronary blood flow after the injection of the vasodilators. Thus, the results of this study would indicate that in the presence of severe stenosis, the interaction between the stenosis and distal coronary vasculature will ultimately determine whether a vasoactive agent will increase or decrease coronary blood flow. Stenotic resistance changes induced by changing distal resistance or pressure: Similarly, in the in vitro, carotid arterial preparation, changes in stenotic resistance were also induced by changing the distal resistance or pressure. Increasing the distal resistance or pressure always decreased the stenotic resistance. Conversely, lowering the distal resistance or pressure always increased the stenotic resistance. In the constant pressure experiments, distal resistance was not always associated with a flow increase. With higher initial values for stenotic resistance, flow actually decreased
February
as the distal resistance decreased. This occurred because of the large increase in stenotic resistance. Changes in stenotic resistance versus changes in luminal area: Radiographic analysis demonstrated that the changes in stenotic resistance were due at least in part to changes in luminal area. Lowering the distal pressure or resistance decreased the luminal area. With the snare, an external force is applied to the vessel that is opposed by the intraluminal pressure. Decreasing the intraluminal pressure would tend to collapse the vessel, whereas increasing the intraluminal pressure would tend to expand it.s2 With severe stenosis, only minimal changes in stenotic area will drastically affect flow.ls Thus, in the presence of severe stenosis, these minimal changes in luminal area could cause part of the observed increase in stenotic resistance. An increase in turbulence in blood flowing through the stenosis could also explain part of the increase in stenotic resistance.g However, changes in blood flow turbulence probably occurred secondary to luminal area changes. Lowering the distal pressure decreased the luminal area. If flow remained constant (as in the in vitro constant flow experiments), the flow velocity through the stenosis would increase, leading to increased blood flow turbulence. Several potential mechanisms for the observed changes in stenotic resistance were unsubstantiated by our findings. Platelet plugging has been shown over long periods of time to influence flow through a stenosis.2s However, the rapid response observed after administration of vasoactive drugs, the decrease in stenotic resistance after vasoconstrictors and the increase in stenotic resistance after isoproterenol and nitroglycerin preclude platelet plugging as a mechanism for the responses observed in this study.24 Systemic arterial pressure was unchanged. Finally, any potential changes in collateral blood supply would occur in the distal
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coronary vasculature and therefore could not account for the observed changes in stenotic resistance. Previous studies on stenotic resistance changes: Several in vivo studies have demonstrated changes in stenotic resistance that were postulated to be caused by changes in geometry of the stenosis. Kreuzer and Schenk25 demonstrated an increase in stenotic resistance in the iliac artery caused by distal vasodilation. They believed that vasodilation altered the degree of stenosis by increasing the unstenosed cross-sectional luminal area. Previously7 we demonstrated an increase in stenotic resistance caused by momentary coronary arterial occlusion. Schwartz et a1.6 observed similar changes in stenotic resistance and postulated that the increase in stenotic resistance was due to a passive decrease in the stenotic area secondary to the reduction in intraluminal pressure. In unsedated dogs in which instruments are chronically in place, Gould26 observed dynamic increases in the hemodynamic severity of coronary arterial stenosis after coronary vasodilation. The increase in stenotic resistance after coronary vasodilation was probably due to the dilation of the epicardial artery adjacent to the stenosis, which caused more severe relative percent narrowing and a larger divergence angle. However, Lipscomb and Hooten, using stenotic models, found that the pressure gradient across the coronary stenosis was not affected by varying the exit angle of the stenosis from 10 to 90”. More studies appear necessary to determine the exact mechanism or mechanisms involved in the increase in stenotic resistance after a reduction in the distal pressure.6.72526 Obviously, experimental arterial stenosis is only a model or imitation of human arterial stenosis. However, a recent in vitro study suggested that in man stenotic resistance is also dependent on intraluminal pressure.5
In that study proximal coronary arteries obtained from fresh postmortem human hearts were examined at various flow rates and levels of perfusion pressure and distal resistance. In coronary arteries with eccentric lesions (a plaque on one side not completely surrounding the lumen), the resistance to flow was found to be dependent on the perfusion pressure. At lower perfusion pressures the resistance increased, whereas at higher perfusion pressures the resistance decreased. These results are similar to ours. Clinical implications of this study: In the presence of severe stenosis distal coronary vasodilation might paradoxically decrease blood flow by increasing the hemodynamic severity of the stenosed arterial segment. In light of Logan’s observations,” this phenomenon would probably occur only in patients with eccentric lesions. Patients with hard, fixed concentric lesions would probably not exhibit this characteristic. Further, this study indicates that vasodilation can cause a severe reduction in distal coronary pressure. The reduction in coronary pressure could lead to a maldistribution of myocardial blood flow and therefore the reduction in coronary pressure may be a factor in the production of subendocardial ischemia. This study also implies a very important role for collateral vessels: Such vessels not only would help to maintain myocardial blood flow, but also would help to maintain distal coronary pressure and to stabilize the hemodynamic status of the stenosed arterial segment. Obviously, the foregoing arguments are speculative and additional studies are required to relate these experimental results to the clinical situation. Conceivably, however, the interaction between stenosis and the distal coronary vasculature after administration of vasoactive drugs could be an additional factor in the therapy of patients with coronary arterial disease.
References 1. Shipley RE, Gregg DE. The effect of external constriction of a blood vessel on blood flow. Am J Physiol 1944; 141:289-96. 2. Young DF, Cholvin NR, Kirkeeide RL, Roth AC. Hemodynamics of arterial stenosis at elevated flow rates. Circ Res 1977; 41:
11. Rubio R, Berne RM. Regulation of coronary blood flow. Prog
Cardiovasc Dis 1975; 18:105-22. 12. Forrester JS, Tyberg JV, Wyatt HL, Goldner S, Parmley WW,
99-107.
3. Mates RE, Gupta RL, Bell AC, Klocke FJ. Fluid dynamics of coronary artery stenosis. Circ Res 1978; 42:152-62. 4. Berguer R, Hwang NHC. Critical arterial stenosis: a theoretical and experimental solution. Ann Surg 1974; 180:39-50. 5. Logan SE. On the fluid mechanics of human coronary artery stenosis. IEEE Trans Biomed Eng 1975; 22:327-35. 6. Schwartz JS, Carlyle PF, Cohn JN. Effect of dilation of the distal coronary arteries in the dog. Am J Cardiol 1979; 43:219-24. 7. Wallnsky P, Santamore WP, Wiener L, Brest AN. Dynamic changes in the hemodynamic severity of coronary artery stenosis in a canine model. Cardiovasc Res 1979; 13:113-l 18. 8. Arfors KE, Arturson 0, Malmberg P. Effect of prolonged chloralose anesthesia on acid-base balance and cardiovascular function in dogs. Acta Physiol Stand 1971; 81:47-53. 9. Gould KL, Lipscomb K, Calvert C. Physiologic basis for assessing critical coronary stenosis. Am J Cardiol 1974; 33:87-94. 10. Guilford JP. Fundamental Statistics in Psychology and Education. New York: McGraw-Hill, 1965; 255-6.
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13. 14. 15.
16.
17.
18.
Swan HJC. Pressure-length loops: a new method for simultaneous measurement of segmental and total cardiac function. J Appl Physiol 1974; 37171 l-78. Bellman S. Microangiography. Acta Radio1 [Suppl] 1953; 102: l-104. Nakano J. Studies on the cardiovascular effects of synthetic vasopressin. J Pharmacol Exp Ther 1967; 157:19-30. Heyndricky GR, Boettcher DH, Vatner SF. Effects of angiotensin, vasopressin, and methoxamine on cardiac function and blood flow distribution in conscious dogs. Am J Physiol 1978; 231:157987. Corliss RJ, McKenna DH, Sialer S, O’Brien GS, Rowe GG. Systemic and coronary hemodynamic effects of vasopressin. Am J Med Sci 1968; 256:293-g. McClenathan JH, Guyton RA, Breyer RH, Newman GE, Michaelis LL. The effects of isoproterenol and dopamine on regional myocardial blood flow after stenosis of circumflex coronary artery. J Thorac Cardiovasc Surg 1977; 73:43 l-5. Vatner SF, McRitchie RJ, Maroko PR, Patrick TA, Braunwald E. Effects of catecholamines, exercise and nitroglycerin on the normal
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19.
20.
21. 22.
23.
ischemic myocardium in conscious dogs. J Clin Invest 1974; 54: 563-75. Richards AF, Seabra-Gomes R, Parker DJ. Effects of tachycardia and isoprenaline on coronary blood flow: observations on pathogenesis of myocardial infarction. Br Heart J 1976; 37:881-2. Malindzak GS Jr, Green HD, Stagg PL. Effects of nitroglycerin on flow after partial constriction of the coronary artery. J Appl Physiol 1970; 29: 17-22. Fam WM, McGregor M. Effect of nitroglycerin and dipyridamole on regional coronary resistance. Circ Res 1968; 22:649-59. Rubinow SI, Keller JR Flow of a viscous fluid through an elastic tube with applications to blood flow. J Theor Biol 1972; 35: 299-313. Felts JD, Crowell EB Jr, Rowe GG. Platelet aggregation in partially
24.
25. 26.
27.
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obstructed vessels and its elimination with aspirin. Circulation 1976; 54:365-70. Yu SE, Latour JG. Potentiation by LY-and inhibition by b-adrenergic stimulations of rat platelet aggregation. Thromb Haemostas 1977; 371413-22. Kreuzer W, Schenk WJ Jr. Effects of local vasodilatation on blood flow through arterial stenosis. Eur Surg Res 1973; 5:233-42. Gould KL. Pressure-flow characteristics of coronary stenosis in unsedated dogs at rest and during coronary vasodilation. Circ Res 1978; 43~242-53. Lipscomb K, Hooten S. Effect of stenotic dimensions and blood flow on the hemodynamic significance of model coronary arterial stenosis. Am J Cardiol 1978; 42:781-92.
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