Jeffrey S. Schwartz

Effect of Perfusion Pressure Distal to a Coronary Stenosis on Transmural Myocardial Blood Flow

SUMMARY We tested the hypothesis that reductions of perfusion pressure distal to a flow-limiting coronary artery stenosis can directly impair perfusion of the suibendocardial myocardium. Dogs were instrumented with an electromagnetic flowmeter probe and a variable occluder on the proximal left circumflex coronary artery. Coronary perfusion pressure was measured with a catheter distal to the occluder. Coronary autoregulation was abolished by intraarterial infusion of adenosine to produce maximal coronary vasodilation. The transmural distribution of myocardial blood flow- was measured with radioactive microspheres during unimpeded arterial inflow, when the occluder was progressively narrowed to reduce distal coronary pressure to approximately 70%, 50% and 35% of the control coronary perfusion pressure, and during total coronary occlusion. Heart rate, left ventricular diastolic presure and the fraction of coronary artery flow during systole remained constant throughout the study. Progressive reductions of coronary perfusion pressure were accompanied by direct reductions of the subendocardial/subepicardial blood flow ratio (r= 0.83). Examination of the relationship between myocardial blood flow and coronary perfusion presure showed that blood flow decreased linearly with perfusion pressure, with flow ceasing at a positive pressure (zero-flow pressure). Blood flow data from four transmural myocardial layers from epicardium to endocardium showed that this zero-flow pressure increased progressively from 10 ± 2.1 mm Hg in the subepicardium to 18 ± 2.3 mm Hg in the subendocardium (p < 0.01). Consequently, as coronary pressure was reduced, the zero-flow pressure represented a progressively greater fraction of coronary pressure in the subendocardium than in the subepicardium. This effect appeared to account for the progressive redistribution of blood flow away from the subendocardium that occurred as coronary pressure was decreased. Myocardial vascular resistance did not change as a result of changes in coronary perfusion pressure.

Effect of dilation of the distal coronary bed on flow and resistance in severely stenotic coronary arteries in the dog

Studies were performed to evaluate the hemodynamic response of severely stenotic coronary arteries to dilation of the distal coronary bed. A critical stenosis was produced with an adjustable wire snare on the left anterior descending or circumflex arteries of open chest dogs. Coronary flow, distal coronary pressure and aortic pressure were measured. In one group of experiments, coronary arteriolar dilatation was induced by transient occlusion of the artery distal to the stenosis. After the release of a transient occlusion in vessels without a critical stenosis, flow increased (from 33 +/- 4 to 85 +/- 8 ml/min, P less than 0.01), distal pressure decreased slightly (from 86 +/- 4 to 80 +/- 4 mm Hg, P less than 0.01), and large vessel resistance did not change significantly (from 0.06 +/- 0.02 to 0.08 +/- 0.03 units). After the release of a transient occlusion in vessels with a critical stenosis, flow decreased (from 23 +/- 3 to 12 +/- 2 ml/min, P less than 0.01), distal pressure decreased to persistently low levels (from 63 +/- 2 to 29 +/- 2 mm Hg, P less than 0.01), and large vessel resistance increased (from 1.4 +/- 0.3 to 6.7 +/- 1.8 units, P less than 0.01). In a separate group of experiments, radio-opaque contrast medium was used to dilate the distal coronary bed. In these studies dilation of the distal coronary of arteries with a critical stenosis again resulted in a decrease in coronary blood flow (from 35 +/- 4 to 19 +/- 3 ml/min, P less than 0.01), a decrease in distal coronary pressure (from 84 +/- 6 to 35 +/- 6 mm Hg, P less than 0.01) and an increase in large arterial resistance (from 1.0 +/- 0.2 to 5.5 +/- 1.2 units, P less than 0.02). Therefore, in coronary vessels with severe stenosis, dilation of the distal coronary bed may result in a paradoxical decrease in coronary blood flow.

Role of adenosine in coronary vasodilation during exercise.

This study examined the hypothesis that increases in myocardial blood flow during exercise are mediated by adenosine-induced coronary vasodilation. Active hyperemia associated with graded treadmill exercise and coronary reactive hyperemia were examined in chronically instrumented awake dogs during control conditions, after intracoronary infusion of adenosine deaminase (5 units/kg/min for 10 minutes), and after adenosine receptor blockade with 8-phenyltheophylline. Both adenosine deaminase and 8-phenyltheophylline caused a rightward shift of the dose-response curve to intracoronary adenosine; 8-phenyltheophylline was significantly more potent than adenosine deaminase. Adenosine deaminase caused a 33 ± 7 to 39 ± 3% decrease in reactive hyperemia blood flow following coronary occlusions of 5–20 seconds duration, respectively, while 8-phenyltheophylline produced a 40 ± 6 to 62 ± 8% decrease in reactive hyperemia. Increasing myocardial oxygen consumption during treadmill exercise was associated with progressive increases of coronary blood flow. Neither adenosine deaminase nor 8-phenyltheophylline attenuated the increase in coronary blood flow or the decrease of coronary vascular resistance during exercise. Neither agent altered the relation between myocardial oxygen consumption and coronary blood flow. Thus, although both adenosine deaminase and 8-phenyltheophylline antagonized coronary vasodilation in response to exogenous adenosine and blunted coronary reactive hyperemia, neither agent impaired coronary vasodilation associated with increased myocardial oxygen requirements produced by exercise. These findings fail to support a substantial role for adenosine in mediating coronary vasodilation during exercise.

Effect of coronary arterial pressure on coronary stenosis resistance.

The effects of coronary pressure on coronary stenosis resistance were studied in 13 open-chest dogs. A noncircumferential stenosis was produced in the circumflex coronary artery by placing sutures into either side of the artery and invaginating a portion of the arterial wall by tying the sutures. Coronary pressure both proximal and distal to the stenosis and coronary flow were measured. Coronary pressure was lowered by 1) hemorrhage and 2) placing a snare proximal to the noncircumferential stenosis and tightening the snare. After hemorrhage, mean proximal coronary pressure fell from 100 ± 5 to 56 ± 6 mm Hg (p < 0.01) and resistance across the noncircumferential stenosis increased from 0.56 ± 0.13 to 1.3 ± 0.26 units (p < 0.05). After the snare was tightened, mean proximal coronary pressure fell from 110 ± 4 to 58 ± 4 mm Hg (p < 0.01) and resistance across the noncircumferential stenosis increased from 0.43 0.05 to 1.1 ± 0.25 units (p < 0.02). In a series of experiments, coronary pressure was raised by inflating a balloon in the proximal aorta. After the balloon was inflated, mean proximal coronary pressure increased from 95 ± 7 to 129 5 mm Hg (p < 0.01) and resistance across the noncircumferential stenosis decreased from 2.34 0.56 to 2.05 + 0.46 units (p < 0.05). These changes in stenosis resistance were consistent with passive narrowing and distension of the stenotic segment caused by the changes in coronary pressure. Alterations in coronary pressure may therefore affect the severity of a coronary stenosis.

Early redistribution of thallium-201 after temporary ischemia.

To define the time course of redistribution of thallium-201 (251TI), ischemia was induced in seven pigs by temporary occlusion of the circumflex coronary artery. After 1½ min of occlusion 201T1 and labeled microspheres were injected into the left atrium. Flow was re-established 4 min after occlusion. Prior to reflow, the relative activities of 201TI and microspheres in the ischemic area were similar, but as early as 5 min after reflow the relative 201fT activity was considerably higher than the relative microsphere activity and from 15 to 105 min after reflow, relative 201TI activity (average 69% of that in normal myocardium) continued to be higher than relative microsphere activity (average 6% of normal). Myocardial arteriovenous differences for 201TI were followed sequentially after 201Tl injection in normal dogs and in dogs with temporary coronary occlusions. The results suggested both loss of 201TI from normal myocardium beginning 10 min after 205TI injection and increased extraction of 201TI from the blood pool immedately after release of a transient occlusion. Redistribution of 201TI therefore begins very soon after relief of myocardial ischemia and even a short delay in initiating myocardial imaging may decrease the sensitivity of the technique for detecting transient ischemia.

Clinical myocardial imaging with nitrogen-13 ammonia

Myocardial infarcts may be clearly imaged using intravenous nitrogen-13 as carrier-free ammonia in doses of 10–30 mCi. This positron emitter is well imaged with the Nuclear Chicago HP Anger Camera with heavy collimation. The rapid blood disappearance of the agent gives good image contrast, and the short half-life and high isotope dosage give high-count density images with little radiation absorbed dose (5 mrad∕mCi total body).

Effects of coronary occlusion on flow in the distribution of a neighboring stenotic coronary artery in the dog

Abstract The effect of left anterior descending coronary artery (LAD) occlusion on flow through a severely stenotic left circumflex artery (LC) was studied in 19 openchest dogs. In 8 dogs (Group 1) aortic pressure, distal circumflex pressure, circumflex flow, and heart rate were measured. In the absence of an LC stenosis, LAD occlusion resulted in an increase in LC flow from 32 ± 3 to 41 ± 5 ml/min (p In 11 dogs (Group 2) the LC stenoses were produced so that anterograde flow through the stenotic LC artery did not change significantly after LAD occlusion. However, LAD occlusion resulted in a decrease in flow (measured with radioactive microspheres) to the area supplied by the stenotic LC artery (0.62 ± 0.02 to 0.50 ± 0.09 ml/min/g; p The results of these studies demonstrate mechanisms by which myocardial ischemia may occur in the area supplied by a stenotic coronary artery if a neighboring coronary artery becomes occluded.

Effects of atrial natriuretic peptide in the canine coronary circulation.

Atriopeptin II has been reported to cause profound coronary vasoconstriction in the isolated perfused guinea pig heart and in the blood perfused canine heart. Consequently, this study was carried out to examine possible mechanisms by which vasomotor effects of human atrial natriuretic peptide (ANP) occur in the canine coronary circulation. Bolus dosages of ANP were administered into the left circumflex coronary artery of in situ dog hearts perfused at constant flow rate. ANP produced dose-related coronary vasodilation with a threshold dosage of 2 ng/kg; a dosage of 2 micrograms/kg caused a 27 +/- 4% decrease in coronary vascular resistance. Coronary vasodilation produced by ANP was not altered by beta-adrenergic blockade with propranolol (1 mg/kg i.v.). In addition, neither adenosine receptor blockade with 8-phenyltheophylline (5 mg/kg i.v.) nor cyclooxygenase inhibition with indomethacin (5 mg/kg i.v.) significantly altered the response to intra-arterial ANP. These data demonstrate that in the in vitro blood perfused canine heart, ANP administered intra-arterially results in coronary vasodilation that does not utilize adenosine-dependent or prostaglandin-dependent mechanisms.

Effects of Amiodarone With and Without Polysorbate 80 on Myocardial Oxygen Consumption and Coronary Blood Flow During Treadmill Exercise in the Dog

Since amiodarone has been reported to possess antianginal activity, this study examined the effects, of amiodarone on coronary blood flow and myocardial oxygen consumption during exercise. Studies were performed in 14 chronically instrumented dogs trained to run on a motor-driven treadmill. Left circumflex coronary artery blood flow was measured with an electromagnetic flowmeter while aortic and coronary sinus catheters allowed measurement of myocardial oxygen extraction. During control conditions, graded exercise resulted in progressive increases in heart rate, aortic pressure, and coronary blood flow. Two preparations of amiodarone, 5 mg/kg, one dissolved in sterile water and the other in 10% polysorbate 80, were given intravenously to separate groups of dogs. Amiodarone in sterile water caused no hemodynamic changes at rest. However, the increase in heart rate during exercise was blunted after amiodarone, so that heart rate during the heaviest level of exercise was significantly less than during control exercise. Coronary blood flow and myocardial oxygen consumption were unchanged. Amiodarone with polysorbate 80 also blunted the increase in heart rate during exercise, but in addition caused a significant decrease in aortic pressure both at rest and during exercise. Myocardial oxygen consumption and coronary blood flow were significantly decreased after administration of amiodarone with polysorbate 80 at rest and during all exercise levels. Amiodarone with or without polysorbate 80 did not change myocardial oxygen extraction. These data demonstrate that amiodarone exerts a negative chronotropic effect during exercise. However, the decreased arterial pressure and myocardial oxygen consumption were not due to amiodarone, but was seen only with the combination of amiodarone dissolved in polysorbate 80.

Mechanisms of remote myocardial dysfunction during coronary artery occlusion in the presence of multivessel disease.

Myocardial dysfunction may occur in areas remote from an acutely occluded coronary artery if those areas are served by a critically stenosed vessel. Although subendocardial hypoperfusion of such remote myocardium has been demonstrated in experimental preparations of this situation, this study was undertaken to determine whether actual reductions in subendocardial perfusion below control levels were necessary for such dysfunction to occur. A 20 mg dose of pentobarbital was injected into the left anterior descending artery (LAD) in 14 anesthetized dogs to create a large anterior regional wall motion abnormality without drawing significant collateral flow from the circumflex vascular bed. Circumflex subendocardial flow was found to rise during injections of pentobarbital and occlusion of the LAD (1.12 +/- 0.38 and 1.17 +/- 0.34 ml/min/g, respectively, vs control 0.91 +/- 0.23 ml/min/g; p less than .05) in the absence of circumflex stenosis. In the presence of circumflex stenosis, circumflex subendocardial flow fell during left anterior descending occlusion (0.59 +/- 0.21 vs 0.89 +/- 0.19 ml/min/g control; p less than .01) but did not change during pentobarbital injections in the LAD (0.77 +/- 0.36 ml/min/g). In the absence of circumflex stenosis, circumflex segment shortening increased during injection of pentobarbital or occlusion of the LAD (14.3 +/- 4.9% and 14.4 +/- 3.5%, respectively, vs 12.3 +/- 3.3% control). In the presence of circumflex stenosis, it did not change (12.5 +/- 4.0% pentobarbital, 11.8 +/- 3.6 LAD occlusion vs 13.1 +/- 4.0% control). We concluded that the presence of large regional wall motion abnormalities may increase the oxygen consumption of remaining myocardium and that dysfunction of that myocardium may result from relative hypoperfusion if blood flow cannot increase appropriately.