Are activated clotting times helpful in the management of anticoagulation with subcutaneous low-molecular-weight heparin?

BACKGROUND: Enoxaparin has recently been shown to be superior to unfractionated heparin in patients with unstable angina/non-ST-elevation myocardial infarction. Theoretical advantages of low-molecular-weight heparin versus unfractionated heparin include a higher ratio of anti-Xa to anti-IIa activity (3:1 for enoxaparin), a more predictable dose response that precludes the need for frequent monitoring, and the convenience of subcutaneous administration. Both activated partial thromboplastin time and activated clotting time (ACT) are used to monitor anticoagulation with heparin, and ACTs are now standard during percutaneous coronary intervention (PCI) with heparin. At doses of up to 90 mg, subcutaneous enoxaparin leads to a modest dose-related increase in activated partial thromboplastin time, but the effect on ACT is unknown. METHODS: Thrombolysis In Myocardial Infarction (TIMI) 11A was a multicenter, dose-ranging trial to evaluate the safety and tolerability of subcutaneous enoxaparin in patients with unstable angina/non-ST-elevation myocardial infarction. We obtained peak (mean 4.3 hours after enoxaparin) and trough (mean 11.5 hours after enoxaparin) anti-Xa levels and ACTs for 26 patients in the TIMI 11A trial. RESULTS: Despite doses of enoxaparin in the range of 89 +/- 19 mg every 12 hours and significant increases in anti-Xa levels even at trough, there was no change in the ACT measured by HemoTec and only a small increase with Hemachron. The correlation of peak Hemachron ACT with peak anti-Xa levels was poor (R = 0.5, P =.08). CONCLUSIONS: In contrast to heparin, ACTs are not useful for assessment of anticoagulation with subcutaneous enoxaparin and should not be relied on in patients receiving enoxaparin who require acute PCI. Studies to determine the optimal dose, safety, and efficacy of enoxaparin in patients undergoing PCI are underway.

Recovery of transmural and subepicardial wall thickening after subendocardial infarction.

OBJECTIVES: This study tested the hypothesis that there is preferential recovery of subepicardial wall thickening after nontransmural myocardial infarction. BACKGROUND: Previous studies have demonstrated gradual recovery of mechanical function after reperfusion in acute myocardial infarction. Because myocardial necrosis is primarily subendocardial, it was hypothesized that recovery of mechanical function would occur primarily in the subepicardial layers. METHODS: Eleven mongrel dogs were instrumented with ultrasonic crystals to measure transmural and outer wall thickening. Animals performed treadmill exercise before and 8 days after nontransmural infarction produced by coronary occlusion for 90 min. RESULTS: Coronary artery occlusion reduced myocardial blood flow to inner layers more than that to outer wall layers (mean [+/- SD] 0.19 +/- 0.35 vs. 0.38 +/- 0.38 ml/g per min, p < 0.05). Infarct size (% of risk region) was also greater in subendocardial layers (33.3 +/- 24.3% inner vs. 8.3 +/- 9.7% outer). Rest transmural wall thickening was 22.4 +/- 7.5% versus 14.4 +/- 6.3% for outer wall layers. During coronary artery occlusion, transmural and outer wall thickening decreased similarly (3.2 +/- 7.7% vs. 0.2 +/- 5.9%). Eight days after reperfusion, thickening of the entire wall recovered to 7.5 +/- 4.7%; however, outer wall thickening had only recovered to 0.0 +/- 5.8%. Myocardial blood flow was abnormal during exercise 8 days after reperfusion, with markedly reduced subendocardial perfusion. However, thickening of the inner and outer layers was similar, with transmural thickening of 8.5 +/- 9.3% and outer wall thickening of 1.6 +/- 6.2%. CONCLUSIONS: Despite preferential blood flow and less necrosis, thickening of the outer layer is not preserved 8 days after subendocardial infarction. The severity of subendocardial injury appears to be the major determinant of regional function after nontransmural infarction.

Inhibition of adenosine-mediated coronary vasodilation exacerbates myocardial ischemia during exercise.

Persisting coronary vasoconstrictor tone that is responsive to exogenous adenosine administration has been demonstrated during myocardial ischemia. Therefore, the role and extent of endogenous adenosine-mediated coronary vasodilation in opposing coronary vasoconstriction within regions of ischemic myocardium was investigated in 10 chronically instrumented exercising dogs. Studies were performed on dogs with left circumflex coronary artery stenosis during treadmill exercise (6.5 km/h, 6% grade), while myocardial blood flow was measured with radioactive microspheres. Blood flow was measured before and again after inhibition of the effects of endogenously produced adenosine through combined inactivation of adenosine and adenosine receptor antagonism by the administration of intracoronary adenosine deaminase (ADA) (5 micrograms.kg-1 x min-1 x 10 min) plus 8-phenyltheophylline (8-PT) (5 mg/kg i.v.), respectively. Coronary perfusion pressure was held equal during both conditions at approximately 41 mmHg with a hydraulic occluder. During exercise in the presence of a coronary stenosis, blood flow was reduced in all layers of myocardium in regions supplied by the stenosed left circumflex coronary artery compared with blood flow in regions of myocardium supplied by the nonstenotic left anterior descending coronary artery. After ADA plus 8-PT, myocardial blood flow (in ml.min-1 x g-1) was further reduced in all layers of myocardium in regions supplied by the stenotic left circumflex coronary artery compared with baseline (subendocardial layer 0.44 +/- 0.09 vs. 0.67 +/- 0.13 ml.min-1 x g-1, mean transmural flow 0.92 +/- 0.13 vs. 1.25 +/- 0.2 ml.min-1 x g-1, both P < 0.05). Blood flow in regions of myocardium supplied by the nonstenotic left anterior descending coronary artery were unchanged following ADA plus 8-PT.(ABSTRACT TRUNCATED AT 250 WORDS)

Endogenous adenosine and coronary vasoconstriction in hypoperfused myocardium during exercise.

OBJECTIVE: The coronary circulation has been shown to remain responsive to vasodilator and vasoconstrictor stimuli during myocardial ischaemia. The aim of this study was to investigate whether endogenous adenosine attenuates coronary vasoconstriction caused by the thromboxane A2 analogue, U46619. METHODS: Nine chronically instrumented dogs were studied during treadmill exercise in the presence of a coronary stenosis which resulted in distal left circumflex coronary artery hypoperfusion. Myocardial blood flow was assessed with radioactive microspheres during exercise prior to and during intracoronary infusion of U46619 (0.01 microgram.kg-1 x min-1), in the absence and the presence of adenosine receptor blockade with intravenous 8-phenyltheophylline (5 mg.kg-1) and intracoronary adenosine deaminase (50 units.kg-1). Distal coronary pressure was maintained constant during the control stenosis and the three interventions, at 49(SEM 3), 50(3), 50(3), and 50(3) mm Hg. RESULTS: During control exercise mean myocardial blood flow was 0.91(0.09) ml.min-1 x g-1 in the stenosis region and 2.54(0.28) in the normal region. With no change in distal coronary pressure, U46619 decreased mean myocardial blood flow to 0.70(0.10) ml.min-1 x g-1 (p < 0.05). Adenosine blockade alone decreased myocardial blood flow in the stenosis region to 0.60(0.07) ml.min-1 x g-1 (p < 0.05 v control stenosis), indicating that endogenous adenosine contributed to coronary vasodilatation in the ischaemic region. However, adenosine blockade did not augment the vasoconstriction in response to U46619 [mean myocardial blood flow 0.49(0.05) ml.min-1 x g-1], indicating that endogenous adenosine did not attenuate the vasoconstriction caused by U46619. CONCLUSIONS: Endogenous adenosine contributed to dilatation of resistance vessels in hypoperfused myocardium of exercising dogs in the absence as well as in the presence of U46619. However, endogenous adenosine did not attenuate the magnitude of the vasoconstrictor response to U46619. These findings are best explained by observations that thromboxane A2 and adenosine act on coronary vascular segments of different size.

Regional differences in sympathetic reinnervation after human orthotopic cardiac transplantation.

BACKGROUND: In the majority of humans > or = 1 year after cardiac transplantation, cardiac norepinephrine (NE) stores reappear, suggesting late sympathetic reinnervation. METHODS AND RESULTS: To determine whether there are regional differences in reinnervation, we measured markers of sympathetic reinnervation of the sinus node (SN) and left ventricle (LV) in five early transplant recipients (< or = 4 months after cardiac transplantation), 45 late transplant recipients (> or = 1 year after cardiac transplantation), and seven normally innervated control patients. SN reinnervation was defined as an increase in heart rate by more than five beats per minute after injection of tyramine into the artery supplying the SN. LV reinnervation was defined as a measurable LV NE release after left main coronary injection of 8 micrograms/kg tyramine. In 13 patients with previously known LV reinnervation, regional LV reinnervation was assessed by NE release after subselective injection of tyramine (4 micrograms/kg) into the proximal left anterior descending and circumflex arteries. Five of five patients < or = 4 months after cardiac transplantation had no change in heart rate and no LV NE release, confirming early, total denervation. In contrast, > or = 1 year after cardiac transplantation, tyramine caused a heart rate increase (eight to 49 beats per minute) in 32 of 45 patients and LV NE release in 33 of 45. Although LV NE release was correlated with the change in heart rate in late cardiac transplantation recipients (r = .61), eight of 45 had only heart rate response, nine had only LV NE release, and four had neither. In late cardiac transplantation recipients with LV reinnervation, tyramine caused NE release from both the anterior descending and circumflex perfusion fields in 10 of 14, but one of 14 patients released NE only after circumflex tyramine and three of 14 only after left anterior descending tyramine stimulation. Tyramine caused a marked heart rate increase and LV NE release in all control patients. CONCLUSIONS: Sympathetic reinnervation after cardiac transplantation is regionally heterogeneous. SN reinnervation is not associated necessarily with LV reinnervation, and LV reinnervation can involve the anterior and posterior walls together or separately.

Endothelial function in well-developed canine coronary collateral vessels.

This study examined responses of coronary collateral blood flow to endothelial-dependent vasodilators. Studies were performed in 13 dogs 4-6 mo after embolic occlusion of the left anterior descending coronary artery (LAD). Collateral flow was determined as the sum of retrograde flow from the cannulated LAD, and continuing tissue flow was measured with microspheres administered during the retrograde flow collection. Agonists were introduced into the left main coronary artery to reach collaterals arising from the left coronary arterial system. The endothelial-dependent vasodilators acetylcholine and bradykinin caused 21 +/- 7 and 25 +/- 8% increases of collateral flow, respectively (each P < 0.05). This was not different from the 28 +/- 8% increase in collateral flow produced by nitroglycerin. To determine whether vasodilator prostaglandins contributed to the increased collateral flow, studies were performed after cyclooxygenase blockade with indomethacin (5 mg/kg iv). Indomethacin caused a 30 +/- 9% decrease of retrograde flow during basal conditions but did not blunt the maximum collateral flow rates produced by acetylcholine, bradykinin, or nitroglycerin. These data demonstrate intact endothelial-dependent vasodilator mechanisms in the well-developed coronary collateral circulation.

Effect of serotonin and thromboxane A2 on blood flow through moderately well developed coronary collateral vessels.

This study was performed to determine whether thromboxane A2 (as the analogue U46619) and serotonin can cause vasoconstriction of moderately well developed coronary collateral vessels. Studies were carried out in seven adult mongrel dogs 2 to 4 months after embolic occlusion of the left anterior descending coronary artery had been performed to stimulate collateral vessel growth. At the time of study this artery was cannulated to determine interarterial collateral flow from measurements of retrograde blood flow. Radioactive microspheres were administered during retrograde flow collection to determine continuing tissue flow for evaluation of microvascular collateral communications. Serotonin (50 micrograms/min) resulted in a 48 +/- 11% decrease in retrograde flow (p less than 0.01), with a 36 +/- 10% decrease in total collateral blood flow (p less than 0.02). Infusion of U46619 (0.01 microgram/kg per min) caused a 38 +/- 13% decrease in retrograde blood flow (p less than 0.01), with a 34 +/- 13% decrease in total collateral flow (p less than 0.05). Serotonin caused a significant increase in tissue flow to the subepicardium of the collateral-dependent region, whereas U46619 caused no change in tissue blood flow. These data demonstrate that both serotonin and thromboxane A2 can cause vasoconstriction of interarterial coronary collateral vessels. The findings suggest that platelet activation in coronary arteries from which collateral vessels originate has potential for causing collateral vasoconstriction, thereby compromising blood flow to the dependent myocardium.

Coronary vasodilator reserve in ischemic myocardium of the exercising dog.

BACKGROUND: Previous work has reported that coronary vasodilator reserve may persist in myocardium rendered ischemic by hypoperfusion. This study investigated the presence and extent of residual coronary vasomotor tone in myocardial regions made acutely ischemic by a flow-limiting coronary stenosis during exercise. METHODS AND RESULTS: Studies were done in chronically instrumented dogs undergoing treadmill exercise in the presence of a coronary stenosis that decreased distal left circumflex coronary artery perfusion pressure to approximately 40 mm Hg. Measurements of myocardial blood flow were made with radioactive microspheres during exercise (6.5 km/hr, 6% grade) before and during intracoronary infusion of the potent coronary vasodilator adenosine (40 micrograms/kg/min). Distal coronary perfusion pressure was held equal before and during intracoronary adenosine infusion (43 +/- 5 versus 42 +/- 5 mm Hg) by adjusting the hydraulic coronary occluder. During exercise in the presence of a coronary stenosis, myocardial blood flow (milliliter per minute per gram) was significantly reduced in all layers of the ischemic posterior region compared with the nonischemic anterior region. During intracoronary adenosine infusion, with no change in coronary perfusion pressure, myocardial blood flow was significantly increased compared with preadenosine flows for both the subendocardial layer flow (1.03 +/- 0.74 versus 0.66 +/- 0.50; p less than 0.05) and mean transmural flow (1.54 +/- 0.59 versus 1.16 +/- 0.36; p less than 0.05). In the presence of a coronary stenosis, regional myocardial segment shortening in the ischemic region during exercise fell significantly to 49 +/- 8% of shortening in the absence of a coronary stenosis but improved modestly during adenosine infusion (65 +/- 7 versus 49 +/- 8%; p less than 0.05). CONCLUSIONS: These results indicate that adenosine-responsive coronary vasodilator reserve persists during exercise-induced myocardial ischemia and suggest that residual microvascular vasoconstrictor tone may affect the extent of myocardial hypoperfusion occurring consequent to a flow-limiting coronary stenosis.

Effect of exercise intensity and duration on regional function during and after exercise-induced ischemia.

BACKGROUND: Transient reversible myocardial dysfunction has been documented after episodes of exercise-induced ischemia. This study was undertaken to determine whether the duration or intensity of exercise affects the severity of postischemic dysfunction in this setting. METHODS AND RESULTS: Ten dogs were instrumented with ultrasonic microcrystals for measurement of wall thickening, with circumflex coronary artery flow probes, and with hydraulic occluders. Dogs performed low-intensity exercise, which was sufficient to increase coronary perfusion 50% above control, and high-intensity exercise, which was sufficient to double coronary blood flow. To investigate the effects of exercise intensity on postischemic dysfunction, we had dogs perform high-intensity exercise for 5 minutes in the presence of a stenosis. On the alternate day, dogs performed low-intensity exercise for 10 minutes in the presence of a stenosis. These two protocols provide equivalent coronary flow debts. Mean transmural blood flow during high-intensity exercise without stenosis (2.61 +/- 0.54 ml/min/g) was significantly higher than that during low-intensity exercise (1.74 +/- 0.61 ml/min/g, p less than 0.002). During high-intensity exercise with coronary artery stenosis, subendocardial blood flow was significantly lower than that during low-intensity exercise with stenosis (0.64 +/- 0.40 versus 1.08 +/- 0.28 ml/min/g, p less than 0.02). This difference in subendocardial perfusion was associated with greater degrees of regional dysfunction during exercise (circumflex wall thickening was 44 +/- 23% of control for high-intensity exercise versus 60 +/- 18% of control for low-intensity exercise, p less than 0.01). In addition, from 10 to 30 minutes after exercise, wall thickening in myocardium perfused by the circumflex coronary artery remained significantly lower after high-intensity exercise than that after low-intensity exercise. To assess the effects of exercise duration on the severity of postischemic dysfunction, we had dogs perform low-intensity exercise in the presence of a coronary stenosis for 10 minutes and low-intensity exercise for only 5 minutes on alternate days. Systolic wall thickening was significantly lower after low-intensity exercise for 10 minutes than after low-intensity exercise for 5 minutes. CONCLUSIONS: High-intensity exercise results in greater degrees of subendocardial hypoperfusion and greater degrees of regional dysfunction both during and after exercise-induced ischemia than does low-intensity exercise. Second, exercise duration also exerts an effect on the severity of postischemic dysfunction, although the magnitude of this effect is less important than the effect of exercise intensity.

Evidence for structural sympathetic reinnervation after orthotopic cardiac transplantation in humans.

BACKGROUND: Cardiac transplantation (CT) causes total cardiac denervation. METHODS AND RESULTS: To test directly for sympathetic reinnervation in humans, we measured the cardiac release of norepinephrine (NE) in response to tyramine (an agent that causes NE release from intact sympathetic nerve terminals) and sustained handgrip exercise (a reflex sympathetic stimulus) in 12 patients less than 5 months after CT, in 50 patients 1 year or more after CT, and in eight patients without CT. Plasma [NE] was measured in the aorta [( NE]Ao) and coronary sinus [( NE]CS) at rest, after tyramine administration (55 micrograms/kg, i.v.), and during sustained handgrip exercise. Cardiac NE release was determined by subtracting [NE]Ao from [NE]CS [( NE]CS-Ao). NE release was defined as [NE]CS-Ao during the intervention-[NE]CS-Ao at rest (delta [NE]CS-Ao). In patients studied within 5 months of CT, no significant NE release occurred after tyramine administration (delta [NE]CS-Ao, 33 +/- 18 pg/ml; range, -98 to 117 pg/ml) or handgrip exercise (delta [NE]CS-Ao, -34 +/- 10 pg/ml; range, -46 to 8 pg/ml; n = 10). Conversely, in 39 of 50 patients studied 1 year or more after CT, tyramine administration caused a significant cardiac NE release (delta [NE]CS-Ao, 500 +/- 59 pg/ml; range, -11 to 1,918 pg/ml), and handgrip exercise caused a significant NE release in 17 of 41 patients (delta [NE]CS-Ao, 189 +/- 34 pg/ml; range, -211 to 949 pg/ml). In normally innervated patients, tyramine caused an even larger NE release (delta [NE]Ao-CS, 1,943 +/- 210 pg/ml; range, 1,152 to 2,977 pg/ml), and handgrip exercise caused a significant NE release in two of seven patients (delta [NE]CS-Ao, 143 +/- 51 pg/ml; range, -15 to 338 pg/ml). CONCLUSIONS: Early after CT, neither tyramine nor handgrip exercise caused a significant cardiac release of NE, suggesting sympathetic denervation. Late after CT, most patients had a significant, but subnormal, NE release in response to pharmacological or reflex stimuli, suggesting that limited sympathetic reinnervation occurs in most patients after orthotopic CT.

Effects of adenosine on human coronary arterial circulation.

Adenosine is a potent vasodilator used extensively to study the coronary circulation of animals. Its use in humans, however, has been hampered by lack of knowledge about its effects on the human coronary circulation and by concern about its safety. We investigated in humans the effects of adenosine, administered by intracoronary bolus (2-16 micrograms), intracoronary infusion (10-240 micrograms/min), or intravenous infusion (35-140 micrograms/kg/min) on coronary and systemic hemodynamics and the electrocardiogram. Coronary blood flow velocity (CBFV) was measured with a 3F coronary Doppler catheter. The maximal CBFV was determined with intracoronary papaverine (4.5 +/- 0.2.resting CBFV). In normal left coronary arteries (n = 20), 16-micrograms boluses of adenosine caused coronary hyperemia similar to that caused by papaverine (4.6 +/- 0.7.resting CBFV). In the right coronary artery (n = 5), 12-micrograms boluses caused maximal hyperemia (4.4 +/- 1.0.resting CBFV). Intracoronary boluses caused a small, brief decrease in arterial pressure (similar to that caused by papaverine) and no changes in heart rate or in the electrocardiogram. The duration of hyperemia was much shorter after adenosine than after papaverine administration. Intracoronary infusions of 80 micrograms/min or more into the left coronary artery (n = 6) also caused maximal hyperemia (4.4 +/- 0.1.resting CBFV), and doses up to 240 micrograms/min caused a minimal decrease in arterial pressure (-6 +/- 2 mm Hg) and no significant change in heart rate or in electrocardiographic variables. Intravenous infusions in normal patients (n = 25) at 140 micrograms/kg/min caused coronary vasodilation similar to that caused by papaverine in 84% of patients (4.4 +/- 0.9.resting CBFV). At submaximal infusion rates, however, CBFV often fluctuated widely. During the 140-micrograms/kg/min infusion, arterial pressure decreased 6 +/- 7 mm Hg, and heart rate increased 24 +/- 14 beats/min. One patient developed 1 cycle of 2:1 atrioventricular block, but otherwise, the electrocardiogram did not change. In eight patients with microvascular vasodilator dysfunction (delta CBFV, less than 3.5 peak/resting velocity after a maximally vasodilating dose of intracoronary papaverine), the dose-response characteristics to intracoronary boluses and intravenous infusions of adenosine were similar to those found in normal patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of coronary stenosis on myocardial blood flow during exercise in the chronically pressure-overloaded hypertrophied left ventricle.

This study was performed to determine if a coronary artery stenosis would result in more-severe perfusion abnormalities in hypertrophied compared with normal canine hearts during exercise. Studies were performed in eight normal control dogs and in seven adult dogs in which a 67% increase in left ventricular mass wa produced by banding the ascending aorta at 9 weeks of age. Myocardial blood flow was measured by the microsphere method during treadmill exercise in the presence of a coronary artery stenosis that decreased distal coronary perfusion pressure to 55 or 42 mm Hg. At a coronary pressure of 55 mm Hg, mean myocardial blood flow was decreased by 23 +/- 5% in normal control dogs but was decreased by 53 +/- 10% in dogs with left ventricular hypertrophy (LVH) (p less than 0.05, comparing normal vs. LVH dogs). Similarly, at a coronary pressure of 42 mm Hg, mean blood flow was decreased by 53 +/- 6% below control in normal dogs but was decreased by 76 +/- 5% below control values in dogs with LVH (p less than 0.01, comparing normal vs. LVH dogs). In both groups of dogs, the stenosis caused a gradient of hypoperfusion, worsening from epicardium to endocardium. However, for each level of stenosis, subendocardial blood flow and the ratio of subendocardial to subepicardial blood flow was less in LVH than in normal canine hearts. These findings demonstrate that the presence of LVH secondary to long-term pressure overload is associated with an increased vulnerability to myocardial hypoperfusion during exercise in the presence of a coronary artery stenosis.

Coronary arteriolar vasoconstriction in myocardial ischaemia: coronary vasodilator reserve during ischaemia.

This study was performed to determine whether vasomotor tone of the coronary resistance vessels limits blood flow to ischaemic myocardium perfused by a stenotic coronary artery during exercise. Studies were performed on dogs in which a hydraulic occluder, in place for greater than or equal to 14 days, allowed production of a coronary stenosis, while distal coronary pressure was monitored with a miniature intra-arterial catheter. Treadmill exercise at 6.5 km h-1 with a 6% grade resulted in a mean heart rate of 209 +/- 4 beats min-1, with mean myocardial blood flow in the normally perfused left ventricular region of 2.90 +/- 0.37 ml min-1 g-1. An arterial stenosis that decreased coronary pressure to 40-42 mmHg resulted in a decrease of myocardial blood flow to 1.07 +/- 0.19 ml min-1 g-1 (P less than 0.01), hypoperfusion being most severe in the subendocardium. Intracoronary administration of the selective alpha 1-adrenergic antagonist, prazosin, resulted in a 50 +/- 14% increase in blood flow with no change in perfusion pressure. This increase in flow in response to prazosin was uniform across the left ventricular wall, from epicardium to endocardium. After administration of the selective alpha 2-adrenergic antagonist, idazoxan, there was a trend toward higher blood flow in the region of myocardium perfused by the stenotic coronary artery, but this change did not achieve statistical significance. These data indicate that residual vasomotor tone may limit blood flow to ischaemic areas of myocardium perfused by a stenotic coronary artery, and that this vasoconstriction is mediated, at least in part, by alpha 1-adrenergic mechanisms.

Effect of atrial natriuretic peptide on coronary collateral blood flow.

This study was carried out to examine the effects of atrial natriuretic peptide on coronary collateral blood flow. Studies were performed in nine adult mongrel dogs 3.4 months after embolic occlusion of the left anterior descending coronary artery had been performed to stimulate collateral vessel growth. At the time of study the anterior descending coronary artery was cannulated to allow estimation of interarterial collateral flow from measurements of retrograde blood flow. Injection of radioactive microspheres during retrograde flow collection allowed simultaneous determination of continuing tissue flow for evaluation of microvascular collateral communications. Atrial natriuretic peptide in doses of 20 and 200 micrograms administered into the left atrium resulted in 17 +/- 3.0% and 34 +/- 4.5% increases in retrograde flow, respectively (each p less than 0.01). Tissue flow in the collateral dependent myocardial region did not change in response to atrial natriuretic peptide. After the larger dose of atrial natriuretic peptide, the administration of nitroglycerin (10 micrograms/kg into the left atrium) caused no further increase of retrograde blood flow, and no further decrease of collateral vascular resistance. These data indicate that atrial natriuretic peptide causes vasodilation of moderately well-developed interarterial coronary collateral vessels.

The role of alpha 1- and alpha 2-adrenergic receptors in mediation of coronary vasoconstriction in hypoperfused ischemic myocardium during exercise.

This study was carried out to test the hypothesis that adrenergic coronary vasoconstriction limits blood flow to hypoperfused regions of myocardium during exercise. The vasoconstrictor influence of alpha-adrenergic receptor subtypes was assessed by use of selective adrenergic blocking agents. Dogs chronically instrumented with a circumflex coronary artery hydraulic occluder and an intra-arterial catheter underwent treadmill exercise in the presence of a coronary stenosis that decreased distal perfusion pressure to 40 mm Hg. Myocardial blood flow was measured with radioactive microspheres (15 microns) before and during selective alpha 1- or alpha 2-adrenergic receptor blockade produced by intracoronary infusion of prazosin (1 microgram/kg/min x 10 min) or idazoxan (1 microgram/kg/min x 10 min), respectively. Coronary perfusion pressure was held equal before and during receptor blockade with the hydraulic occluder. Compared with control exercise, subendocardial blood flow increased during alpha 1-receptor blockade with prazosin from 0.60 +/- 0.14 to 1.12 +/- 0.17 ml/min/g (p less than 0.05), and mean transmural flow increased from 1.07 +/- 0.19 to 1.60 +/- 0.22 ml/min/g (p less than 0.05). In contrast, subendocardial and mean transmural blood flow were not different from control during selective alpha 2-adrenergic receptor blockade with idazoxan (0.48 +/- 0.10 vs. 0.67 +/- 0.14 ml/min/g, p = 0.33, and 0.82 +/- 0.15 vs. 1.02 +/- 0.20 ml/min/g, p = 0.45, respectively). These data indicate that even in the presence of a coronary stenosis that causes substantial myocardial underperfusion during exercise, residual coronary vasoconstrictor tone is present in ischemic myocardium, and this vasoconstriction is mediated predominantly by the alpha 1-adrenergic receptor.

Cumulative deterioration of myocardial function after repeated episodes of exercise-induced ischemia.

To determine whether progressive regional myocardial dysfunction occurs after repetitive episodes of exercise-induced ischemia, 10 dogs were instrumented with ultrasonic microcrystals for determination of regional myocardial wall thickening, circumflex artery electromagnetic flow probes, and hydraulic coronary artery occluders. Dogs performed treadmill exercise in the presence of a coronary artery stenosis, which limited coronary blood flow to control levels. Dogs performed a single 10-min exercise period one day and three identical runs separated by 1-h rest periods on the alternate day. At rest before the first exercise period, circumflex wall thickening was 18.8 +/- 6.7% and increased to 25.5 +/- 10.6% during exercise before the application of coronary stenosis. On the day that three exercise trials were performed, circumflex systolic wall thickening at rest before the third exercise period (9.7 +/- 4.0%) and during exercise without coronary stenosis (17.3 +/- 7.3%) were both significantly lower than during the first exercise period (P less than 0.0125). During exercise with stenosis, circumflex systolic wall thickening fell to 4.6 +/- 4.7% during a single run, and 5.0 +/- 2.0% during the third of three consecutive runs. Wall thickening was significantly lower 2 h after the third consecutive run (9.1 +/- 2.4%) than 2 h after a single period of exercise-induced ischemia (14.8 +/- 7.6%; P 0.0125). Transmural myocardial blood flow to circumflex myocardium during the third period of exercise-induced ischemia (0.93 +/- 0.47 ml.min-1.g-1) was not different than during the single period of exercise (0.84 +/- 0.47 ml.min-1.g-1). It is concluded that repetitive episodes of exercise-induced ischemia result in cumulative postexercise regional myocardial dysfunction.

Intense microvascular constriction after angioplasty of acute thrombotic coronary arterial lesions.

Immediately after balloon dilation of a fresh thrombotic coronary lesion, 5 patients had angina, ST segment elevation, and a striking reduction of blood flow in the dilated artery. A mean (SEM) pressure gradient across the dilated lesion of only 3(1) mm Hg and an average minimum lesion diameter of 1.7 mm indicated that the decline in resting blood flow was not due to obstruction at the site of the original lesion. Neither distal vascular emboli nor side branch occlusions were visible on the angiogram. An increase in distal coronary artery pressure during a subsequent balloon inflation suggested that the site of vasoconstriction was distal to the origin of collateral vessels. The syndrome lasted 48-80 min and was not reversed with nitroglycerin or thrombolytic drugs. Papaverine lessened the syndrome transiently on one occasion. Such microvascular constriction, caused by release of potent vasoconstrictors from the clot, may partly explain the failure of emergency angioplasty to reduce infarct size in acute myocardial infarction.