Myocardial and microcirculatory kinetics of BR14, a novel third-generation intravenous ultrasound contrast agent

OBJECTIVES: This study sought to investigate the myocardial and microvascular kinetics of BR14, a novel third-generation ultrasound contrast agent. BACKGROUND: BR14 produces persistent myocardial opacification after the administration of a single intravenous bolus when the left ventricular cavity contrast has considerably diminished. The mechanism of this finding is unknown. METHODS: Nine open-chest dogs with non-critical stenosis of a single coronary artery were given intravenous bolus injections of BR14 during coronary hyperemia. Time versus acoustic intensity (AI) plots were generated from the normal and stenosed beds and myocardial blood flow (MBF) was measured with radiolabeled microspheres. Intravital microscopy was performed on an exteriorized cremaster muscle in 11 wild-type mice to study the microvascular kinetics of the agent. RESULTS: At peak contrast enhancement, the ratio between AI in the stenosed and normal bed was 0.44+/-0.23, which was similar to the radiolabeled microsphere-derived MBF ratio between the two beds (0.45 +/-0.20). At 400 s after injection, the AI ratio between the two beds approximated unity (0.99+/-0.07) despite no changes in MBF, indicating redistribution of the agent. The myocardial kinetics of BR14 was best characterized by a modified lagged normal density function. Only about 3% of administered microbubbles were estimated to be retained in the myocardium. Intravital microscopy showed that most of these bubbles were retained only transiently (2 to 3 s) within capillaries. CONCLUSIONS: BR14 demonstrates redistribution because of transient retention within capillaries. Therefore, similar to (201)Tl, it could potentially be used to detect both coronary stenosis and myocardial viability after a single injection during stress.     

Basis for detection of stenosis using venous administration of microbubbles during myocardial contrast echocardiography: bolus or continuous infusion?

Objectives. This study sought to determine the basis of detection of stenosis by myocardial contrast echocardiography using venous administration of microbubbles and to define the relative merits of bolus injection versus continuous infusion.Background. The degree of video intensity (VI) disparity in myocardial beds supplied by stenosed and normal coronary arteries can be used to quantify stenosis severity after venous administration of microbubbles. However, the comparative merits of administering microbubbles as a bolus injection or continuous infusion has not been studied.Methods. Coronary stenoses of varying severity were created in either the left anterior descending or the left circumflex coronary artery in 18 dogs. Imagent US (AF0150) was given as a bolus injection in 10 dogs (Group I) and as both a bolus injection and a continuous infusion in 8 dogs (Group II). For bolus injections, peak VI was derived from time–intensity plots. During continuous infusion, microbubble velocity and microvascular cross-sectional area were derived from pulsing interval versus VI plots. Myocardial blood flow (MBF) was determined using radiolabeled microspheres.Results. During hyperemia, VI ratios from the stenosed versus normal beds correlated with radiolabeled microsphere–derived MBF ratios from those beds for both bolus injections (r = 0.81) and continuous infusion (r = 0.79). The basis for detection of stenosis common to both techniques was the decrease in myocardial blood volume distal to the stenosis during hyperemia. The advantage of continuous infusion over bolus injection was the abolition of posterior wall attenuation and the ability to quantify MBF.Conclusions. Both bolus injection and continuous infusion provide quantitative assessment of relative stenosis severity. Compared with bolus injection, continuous infusion also allows quantification of MBF and data acquisition without attenuation of any myocardial bed.     

在静息血流无限制的慢性冠状动脉狭窄中静息心肌收缩功能与血流储备的关系

目的 :评价静息心肌收缩功能与血流储备的关系。　　方法 :以安放“水膨胀”式缩窄器的方法建立 11只慢性多支冠状动脉 (冠脉 )狭窄闭胸犬。术后 7～ 10天在静息状态下以二维超声心动图测定室壁增厚百分率 (% WT) ,同时以放射性微球测定心肌血流量 (MBF)和 MBF储备。　　结果 :在 40个心室壁运动异常的心肌节段与 42个心室壁收缩功能正常的心肌节段之间 ,静息心室壁和心内膜下血流均无明显差异 ,但后者的心室壁和心内膜下血流储备均明显低于前者。静息状态 % WT与 MBF储备密切相关 (P<0 .0 0 1)。　　结论 :在静息状态血流无限制的慢性冠脉狭窄犬 ,% WT异常心肌节段的 MBF储备明显降低 ,静息状态 % WT与MBF储备密切相关 ,表明局部收缩功能异常可能是由于反复“需氧增多”性心肌缺血所致。     

Does the extent of the zone at risk after coronary artery occlusion influence the percentage of the zone that evolves to infarction?

To examine whether the extent of the zone at risk for infarction after coronary artery occlusion influences the percentage of the zone that evolves to necrosis in the absence of intervention, 99mTc-labeled albumin microspheres were injected into the left atrium 1 min after coronary occlusion in 34 dogs. Six hours after occlusion, the left ventricle was cut into 3-mm-thick slices for triphenyltetrazolium chloride staining and autoradiography. The extent of myocardial necrosis and hypoperfused zone was measured by planimetry and expressed as a percentage of the total volume of the left ventricle. The extent of myocardial necrosis and hypoperfused zone varied widely from 8 to 40% and 14 to 43% of the left ventricle, respectively. However, there was a close correlation between infarct size (IS, percent of left ventricle) and the extent of hypoperfused zone (HZ, percent of left ventricle): IS = 0.89x (HZ) - 0.21 (r = 0.909, SEE = 3.02, p less than 0.01). The ratio of infarct size to the extent of hypoperfused zone was 87.9 +/- 2.3%. Dogs with large hypoperfused zones (greater than or equal to 30% of the left ventricle) had a significantly greater ratio of infarct size to the extent of the hypoperfused zone (95.3 +/- 2.4%, n = 11, p less than 0.05) than dogs with small hypoperfused zones (less than 30% of the left ventricle; 84.3 +/- 3.0%, n = 23). Moreover, the ratio was greater than or equal to 90% in all but one dog (91%) with large hypoperfused zones, but in only 10 of 23 dogs (43%) with small hypoperfused zones (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Spontaneous redistribution after reperfusion: A unique property of AIP 201, an ultrasound contrast agent

Objectives. We sought to determine the mechanism of spontaneous redistribution of AIP 201 microbubbles after reperfusion from a single left heart injection performed during coronary occlusion.Background. AIP 201, an ultrasound contrast agent consisting of 10-μm sized microbubbles, has demonstrated spontaneous myocardial redistribution in preliminary studies.Methods. Myocardial video intensity (VI) and radiolabeled microsphere-derived myocardial blood flow (MBF) were measured serially after reperfusion in seven dogs undergoing an AIP 201 injection during coronary occlusion. The behavior of these bubbles was also assessed in the rat spinotrapezius muscle using intravital microscopy (IM), both with and without ultrasound. The effect of ultrasound on these bubbles was also determined in vitro.Results. A spontaneous and gradual increase in myocardial VI was noted after reperfusion, which was related to the magnitude of increase in MBF to that region (r = 0.82, p < 0.001). On IM, most of the microbubbles were seen entrapped in small arterioles. Some larger arterioles had aggregates of microbubbles that periodically became dislodged and moved downstream. This behavior was not affected in vivo by ultrasound. In vitro, however, microbubble aggregation was noted only during ultrasound exposure.Conclusions. The magnitude of redistribution of AIP 201 microbubbles to the reperfused myocardium is related to changes in MBF and occurs from their dislodgement from microbubble aggregates entrapped in large arterioles. In vitro microbubble aggregation seen during ultrasound exposure was not reproduced in vivo. These results may have important implications for studying the effects of interventions in acute coronary syndromes and after coronary artery bypass graft surgery.     

Effects of dipyridamole-induced vasodilation on myocardial uptake and clearance kinetics of thallium-201

Myocardial thallium-201 (201Tl) uptake and clearance after intravenous administration of dipyridamole (150 micrograms/kg) were determined in 12 open-chest anesthetized dogs with a partial coronary artery stenosis. 201Tl (1.5 mCi) was injected intravenously and myocardial biopsy specimens were obtained 10 min, 60 min, and 2 hr after injection. Serial changes in 201Tl activity in the normal zone and in the zone of partial stenosis were correlated with microsphere-determined regional blood flow and distal coronary pressure. Another nine dogs with equivalent stenosis not given dipyridamole before 201Tl served as controls. In the 12 dogs given dipyridamole, 201Tl activity at 10 min in the zone of stenosis was reduced to 42 +/- 5% of initial normal zone activity (p less than .001) and remained at 44 +/- 3% of initial normal zone activity at 2 hr. There was a good correlation (.81) between the percent reduction in myocardial 201Tl activity and the percent reduction of peak hyperemic flow as determined by measuring the percentage difference in peak coronary flow after a transient 10 sec occlusion under control and stenotic conditions. In contrast, 201Tl clearance was rapid in the normal zone, with 201Tl activity decreasing to 55 +/- 3% of initial normal zone activity by 2 hr. A redistribution pattern was produced because of the disparate clearance rates from hyperperfused and relatively hypoperfused myocardial regions. The relative 201Tl defect decreased from 58% to 11% from 10 min to 2 hr. In the normal zone dipyridamole increased epicardial flow from 1.03 +/- 0.09 (SEM) to 3.52 +/- 0.36 ml/min/g (p less than .0001) and endocardial flow from 1.19 +/- 0.09 to 2.96 +/- 0.20 ml/min/g (p = .0001). In the zone of partial stenosis the increase in epicardial flow after dipyridamole was less marked (1.01 +/- 0.10 to 1.55 +/- 0.15 ml/min/g; p = .009) and endocardial flow decreased (0.84 +/- 0.11 to 0.64 +/- 0.15 ml/min/g; p = .04). Coronary perfusion pressure distal to the stenotic zone fell from 65 +/- 3 to 50 +/- 3 mm Hg after dipyridamole. In the nine control dogs with equivalent stenosis, 201Tl uptake and washout were not significantly different in the stenotic zone compared with the normal zone. These data indicate that dipyridamole-induced vasodilation in the presence of a partial stenosis results in diminished uptake and delayed clearance compared with increased uptake and more rapid clearance in normally perfused myocardium producing an initial 201Tl defect with delayed redistribution.(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparative effects of propranolol, timolol and metoprolol on myocardial infarct size after experimental coronary artery occlusion

The effects of equiblocking doses of three beta-adrenergic blocking agents, propranolol, timolol and metoprolol, on myocardial infarct size were evaluated in 28 dogs after acute experimental coronary artery occlusion. Heart rate, arterial pressure and arterial free fatty acid concentration were measured in an attempt to evaluate their effects on the extent of myocardial injury. The zone at risk of infarction in each dog 1 minute after left anterior coronary artery occlusion was assessed by injecting highly radioactive albumin microspheres into the left atrium, and the hypoperfused zone was determined by autoradiography. After 15 minutes, the dogs were randomized into four groups: control dogs (n = 7), propranolol-treated dogs (1.2 mg/kg intravenously, n = 7), timolol-treated dogs (0.2 mg/kg intravenously, n = 7) and metoprolol-treated dogs (1.2 mg/kg intravenously, n = 7). After 6 hours, the dogs were killed. The left ventricle was sliced and stained with triphenyl-tetrazolium chloride for measurement on infarct size. The same slices were then autoradiographed for measurement of the hypoperfused zone. The percent of hypoperfused zone that evolved to infarction (the ratio of infarct size to hypoperfused zone) was 90.4 +/- 1.9% in the control group, 72.4 +/- 2.4% in the propranolol-treated dogs (p less than 0.05 versus control group); 57.9 +/- 4.4% in the timolol-treated dogs (p less than 0.01 versus control group; p less than 0.05 versus propranolol) and 54.4 +/- 3.7% in the metoprolol-treated dogs (p less than 0.01 versus control group; p less than 0.05 versus propranolol). Thus, propranolol, timolol and metoprolol reduced myocardial infarct size in dogs by 20, 36 and 40%, respectively, after experimental coronary artery occlusion. Metoprolol and timolol protected the ischemic myocardium more effectively than did propranolol.     

Exercise-induced regional dysfunction with subcritical coronary stenosis

The hypothesis was tested that regional myocardial contractile dysfunction can detect subtle regional coronary blood flow maldistribution induced by exercise. In seven dogs, left ventricular pressure (micromanometer), regional systolic wall thickening (WTh, sonomicrometry), and myocardial blood flow (MBF, microspheres) were measured when mild degrees of coronary artery stenosis were produced during treadmill exercise. During exercise without coronary stenosis, WTh increased by 21 +/- 12% (SD), and transmural MBF increased uniformly. In each dog, two levels of coronary stenosis were produced during exercise by adjusting the coronary hydraulic cuff: (1) St-Ex I, where WTh during exercise failed to increase significantly (average change 0 +/- 7%), and (2) St-Ex II, where WTh during exercise decreased moderately from the resting control value (average -20 +/- 8%). In the potentially ischemic zone coronary hyperemia occurred with each run: resting subendocardial MBF was 1.09 +/- 0.30 mg/g/min, and it was 3.04 +/- 0.83 during control exercise, 2.48 +/- 0.75 during St-Ex I, and 1.55 +/- 0.59 ml/g/min during St-Ex II (p less than .01 compared with control exercise and control area). The subendocardial-subepicardial blood flow ratio fell from 1.32 +/- 0.27 during control exercise to 1.07 +/- 0.20 (p less than .05) during St-Ex I, and to 0.64 +/- 0.15 (p less than .01) with St-Ex II. Changes in the subendocardial electrogram and reactive hyperemia occurred more consistently during St-Ex II than St-Ex I. Thus, failure of regional function to increase during exercise detected slight maldistribution of regional MBF, whereas reduction of regional function during exercise of 10% or more below the resting value was a reliable marker of a regional flow defect and was always associated with other evidence of ischemia. Therefore, regional dysfunction during exercise can detect subcritical but functionally significant coronary stenosis, which may allow regional wall motion to be used for detecting coronary artery disease at a relatively early stage.     

Salvage of ischemic myocardium by prostacyclin during experimental myocardial infarction

The effects of prostacyclin (PGI2) on infarct size and regional myocardial blood flow were studied in 28 anesthetized dogs subjected to 5 hours of coronary occlusion. A region of myocardial hypoperfusion was defined by injection of dye into the left atrium just before sacrifice. Infarct size was determined by planimetry of left ventricular slices after incubation in triphenyl tetrazolium chloride. The animals received either PGI2 in Tris buffer solution (20 to 40 ng/kg per min, n = 14) or Tris buffer alone (control, n = 14) beginning 10 minutes after anterior descending coronary artery occlusion. During PGI2 infusion, mean arterial pressure decreased by 8%, but heart rate was unchanged. Infarct size was significantly less (p less than 0.005) in PGI2-treated dogs compared with the control group, both as percent of left ventricle (8.1 versus 17.7%) and as percent of the hypoperfused zone (39.8 versus 77.3%). No significant changes in regional myocardial blood flow occurred over the 5 hour infusion period in either group. Thus, under the conditions of this study, prostacyclin appeared to protect ischemic myocardium by a direct flow-independent mechanism.     

Detection sensitivity of coronary artery stenosis by 99mTc-sestamibi and 201T1 in canine models of partial and subcritical stenosis.

This study was designed to assess the sensitivity of the monocationic 99mTc-hexakis-2-methoxy, 2-methylpropylisonitrile (99mTc-sestamibi) as compared to 201T1 in the detection of regional myocardial blood flow deficits in dogs with different degrees of stenosis with or without dipyridamole. Regional myocardial distribution of 99mTc-sestamibi and 201Tl was determined in mongrel dogs under different levels of left arterial descending coronary artery (LAD) stenosis (30-45, 60-70 and 100% flow reduction) as monitored with electromagnetic flow probes and radiolabeled microspheres. Both 99mTc-sestamibi and 201Tl distribute in direct proportion to blood flow at all levels of stenosis (r2 = 0.90-0.99). Quantitatively, both tracers underestimate the resting flow stenosis. The regional myocardial distribution for both 99mTc and 201Tl was also determined in subcritically stenosed mongrel dogs. This was produced by placing a balloon cuff around the LAD, infusing dipyridamole to peak hyperemic flow and immediately stenosing the LAD to basal flow. Stenosed to normal zone flow ratios were 0.68 +/- 0.01 compared to 99mTc and 201Tl ratios of 0.73 +/- 0.04 and 0.80 +/- 0.05, respectively. These data suggest that 99mTc is at least as sensitive as 201Tl in the detection of different degrees of critical and subcritical coronary artery stenosis.     

Myocardial protection with autoperfusion during prolonged coronary artery occlusion

Passive transcatheter coronary arterial perfusion, i.e., autoperfusion, has been introduced for clinical use to ameliorate short episodes of myocardial ischemia during percutaneous transluminal coronary angioplasty. The primary goal of this study was to evaluate the cardioprotective effect of autoperfusion after prolonged coronary artery occlusion. Accordingly, in 24 anesthetized dogs, either the left anterior descending or left circumflex coronary artery was occluded for 6 hours. The dogs were randomized to a control group subjected to coronary artery occlusion alone (n = 13) or to a group treated with transcatheter autoperfusion (n = 11). The hypoperfused zone, i.e., risk area and infarct size, were measured by autoradiography and triphenyltetrazolium chloride staining, respectively. The hypoperfused zone was 30 +/- 2% and 29 +/- 2% in the control and treated (NS) groups, respectively. When infarct size was expressed as a percent of the hypoperfused zone, it was 84 +/- 5% in the control group and 25 +/- 9% in the group treated with transcatheter autoperfusion (p less than 0.001), showing a reduction of 70%. In addition, an in vitro study showed pressure-dependent flow during autoperfusion as reflected by close linear relationship between perfusion pressure and flow (Flow = 0.54 X Pressure + 16.16, r = 0.99, n = 16). These data suggest that although passive coronary arterial perfusion for 6 hours after coronary occlusion does not prevent myocardial necrosis, it markedly reduces myocardial infarction in the canine model.     

Coronary hemodynamics and subendocardial perfusion distal to stenoses

We compared distal coronary hemodynamics and regional myocardial perfusion in anesthetized dogs in the presence of a single or two coronary artery stenoses in series. After application of either a single or two stenoses on the left anterior descending coronary artery, regional myocardial blood flow was measured with radioactive microspheres. Moderate degrees of single-vessel stenosis (no change in resting coronary blood flow but reduction in reactive hyperemic response of 70%) resulted in no significant change in regional myocardial perfusion at rest despite a pressure drop across the stenosis of 24 +/- 3 mm Hg. When two such stenoses were applied in series, there was a 91% decrease in reactive hyperemia, a significant reduction in resting diastolic coronary blood flow and a 51 +/- 7 mm Hg pressure drop across the two stenoses. Alone, each stenosis produced no change in regional myocardial perfusion; however, together the two stenoses resulted in a significant decrease in subendocardial blood flow and a redistribution of transmural perfusion within the ischemic zone favoring the subepicardium (endo/epi from 0.95 +/- 0.03 to 0.72 +/- 0.03). The results indicate that whereas resting subendocardial perfusion is not significantly affected by moderate degrees of a single coronary artery stenosis, multiple stenoses of the same severity may dramatically reduce subendocardial perfusion.     

Assessment of regional myocardial blood flow with myocardial contrast echocardiography: an experimental study

OBJECTIVES: The aim of this study was to verify the accuracy of using myocardial contrast echocardiography (MCE), to quantify regional myocardial blood flow (MBF), and to evaluate myocardial viability in comparison to that measured by radiolabeled microsphere and pathologic examination. METHODS: Epicardial MCE was obtained in five myocardial ischemic dogs with constant microbubble intravenous infusion. After the video intensity (VI, y) versus pulsing interval plots derived from each myocardial pixel were fitted to an exponential function: y = A(1 - e(-beta t)), the MBF was calculated as the product of A (microvascular cross-sectional area or myocardial blood volume) and beta (mean myocardial microbubble velocity). The MBF was also obtained by radiolabeled microsphere method. RESULTS: The MBF derived by radiolabeled microsphere method in the normal, ischemic, and infarcted region was 1.5 +/- 0.3, 0.7 +/- 0.3, and 0.3 +/- 0.2 ml/min per gram, respectively; P < 0.01. The product of A and beta in those regions was 52.5 +/- 15.1, 24.4 +/- 3.9, and 3.7 +/- 3.8, respectively; P < 0.01. The normalized product of A and beta correlated well with normalized MBF (r = 0.81, P = 0.001). CONCLUSION: Our initial study demonstrated that MCE has an ability to assess MBF in ischemic myocardium in the experimental model. It may provide a potential capability to detect viable myocardium noninvasively after total persistent coronary occlusion in the clinical setting.     

Relation of myocardial salvage to size of myocardium at risk in dogs

Infarct size varies in untreated animals subjected to coronary artery occlusion at the same anatomic site. The relation between the hypoperfused zone and the magnitude of myocardial salvage when different pharmacologic interventions are used remains to be established. Thus, in 95 anesthetized dogs, 1 minute after left anterior descending coronary occlusion, technetium-99m-labeled albumin microspheres (8 mCi) were injected into left atrium for the assessment of the hypoperfused zone. Fifteen minutes after coronary occlusion 42 dogs were randomized into a control group and 53 into a treated group. In the treated group, 6 dogs received nifedipine, 0.35 micrograms/kg followed by 2.4 micrograms/kg/hour; 7 received diltiazem, 0.2 mg/kg followed by 0.9 mg/kg/hour; 13 received bepridil, 2.5 mg/kg; 9 received cytochrome C, 2.5 mg/kg; 8 received rutosides, 200 mg/kg; and 10 received nifedipine plus cytochrome C. All drugs were administered intravenously. At 6 hours the dogs were killed and their hearts were cut into 3-mm-thick slices. Infarct size was determined by triphenyltetrazolium chloride staining; the hypoperfused zone was delineated by autoradiography. The dogs were retrospectively subgrouped as follows: those with small hypoperfused zones, i.e., less than 15% of the left ventricle (controls n = 8, treated n = 7) and those with large hypoperfused zones, i.e., more than 15% of the left ventricle (controls n = 34, treated n = 46). In dogs with large hypoperfused zones, treatment salvaged 42 +/- 3% of the myocardium destined to undergo necrosis, whereas in those with small hypoperfused zones 78 +/- 10% of myocardium was salvaged (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional myocardial blood flow quantitatively measured using O-15 water and dynamic positron emission tomography

This study was performed to measure regional myocardial blood flow (MBF) quantitatively using dynamic positron emission tomography (PET) and O-15 water. The subjects consisted of two normal volunteers, four patients with normal coronary angiograms (CAG), two patients with angina pectoris (3-vessel disease) and three patients with myocardial infarction. O-15 water (15-20 mCi) was injected via the cubital vein in a bolus, and dynamic PET was performed. MBF was calculated according to the method of Iida. The region of interest (ROI) was selected on the left ventricular wall (septum, anterior and lateral walls) and MBF was calculated in each ROI. In normal volunteers, MBF was 1.07 to 1.17 ml/g/min. It was 0.96 to 1.02 ml/g/min in patients with normal CAG, and 0.53 to 0.64 ml/g/min in patients with angina pectoris in the ischemic area. In patients with myocardial infarction, MBF was so diminished in the infarcted area as detected by 2-DE or ECG that the absolute value was almost 0 ml/g/min. In patients with angina pectoris, there was no definite defect on the MBF image, but we could estimate the severity of coronary stenosis by quantifying the MBF. The clinical advantages of this method include estimation of the severity of coronary arterial stenosis in the resting state.     

Comparative effects of nicardipine, a new calcium antagonist, on size of myocardial infarction after coronary artery occlusion in dogs

To examine whether nicardipine, a dihydropyridine derivative, limits size of myocardial infarction, and to compare the protective effects of nicardipine administered before and early and late after coronary artery occlusion, 99mTc-labeled albumin microspheres were injected into the left atrium during 5 min temporary coronary artery occlusion to determine the extent of the hypoperfused zone (the area at risk). The coronary arteries were then reperfused for 45 min before 6 hr permanent coronary artery occlusion. Fifteen minutes before permanent occlusion, dogs were randomly assigned to a control group (n = 11), a pretreatment group (n = 9), which received at this point 10 micrograms/kg of nicardipine as a loading dose followed by a continuous infusion of 8 micrograms/kg/hr for 6 hr, an early treatment group (n = 9), in which nicardipine treatment was initiated 15 min after occlusion, or a late treatment group (n = 8), in which nicardipine administration was delayed for 3 hr. Six hours after coronary artery occlusion, the hearts were excised and the left ventricle of each was cut into 3 mm thick slices and stained with triphenyltetrazolium chloride. The extent of myocardial necrosis was measured by planimetry of the unstained areas. Thereafter, the same slices were autoradiographed and the extent of the hypoperfused zone was measured by planimetry of the "cold spot." The extent of the hypoperfused zone was identical among the four groups. In the control group, the ratio of the extent of myocardial necrosis to the extent of the hypoperfused zone was 95.8 +/- 3.8% (mean +/- SEM). However, it was significantly smaller in the pretreatment group (59.9 +/- 13.3%, p less than .05) and the early treatment group (49.0 +/- 10.6%, p less than .01) than in the control group. In the late treatment group, this value was not different from that in the control group (86.5 +/- 7.1%). There was a close inverse correlation between reduction of infarct size and the extent of the hypoperfused zone in the pretreatment and early treatment groups. Thus, nicardipine administered before or early after coronary artery occlusion limited infarct size by 37% to 49%, whereas when administration was delayed for 3 hr infarct size was not reduced. Furthermore, nicardipine had more striking effects on the ischemic myocardium of dogs with small hypoperfused zones than on that of dogs with large hypoperfused zones.     

Effect of exercise on the relationship between myocardial blood flow and systolic wall thickening in dogs with acute coronary stenosis

Relationships between regional myocardial perfusion and transmural function, both during treadmill exercise and at rest, were examined in conscious dogs with varying degrees of coronary stenosis produced by a hydraulic occluder. In 13 dogs we measured myocardial blood flow with microspheres (10-12 microns in diameter) and regional systolic wall thickening (%). During exercise with coronary stenosis, myocardial blood flow was characterized by nonuniform distribution, and associated with regional dysfunction. The relationships between normalized myocardial blood flow and normalized %wall thickening during exercise with coronary stenosis were linear, with significantly different slopes (mean myocardial blood flow: y = 1.23x - 0.16, r = 0.93; subendocardial myocardial blood flow: y = 1.50x - 0.02, r = 0.86; subepicardial myocardial blood flow: y = 0.83x - 0.18, r = 0.87). To fill the gap between available subendocardial and subepicardial data during exercise with coronary stenosis and control points, however, would require nonlinear components. In 10 of the dogs, coronary stenosis at rest was also produced to compare regional myocardial blood flow - %wall thickening relations at rest with those during steady state exercise. The absolute mean myocardial blood flow - %wall thickening relation during exercise with coronary stenosis (y = 11.6x - 1.9, r = 0.90) was significantly shifted rightward from the resting relation (y = 25.3x -2.1, r = 0.80). However, when changes in %wall thickening were plotted vs. myocardial blood flow per beat, the relationships at rest and exercise were nearly superimposable. Likewise, relations between normalized myocardial blood flow and changes in %wall thickening at rest and exercise were not significantly different. We conclude: %wall thickening during exercise is directly related to changes in mean myocardial blood flow but is related in nonlinear fashion to changes in subepicardial and subendocardial myocardial blood flow; %wall thickening may provide a reliable index of the relative transmural flow distribution during exercise as well as at rest; during brief bouts (5-8 minutes) of exercise with coronary stenosis, the relationship between stabilized regional contractile dysfunction and level of myocardial blood flow per beat is the same as that during coronary stenosis at rest.     

Does antiplatelet therapy enhance myocardial salvage after coronary reperfusion?

The aim of this study was to test the hypothesis that either the cyclooxygenase inhibitor aspirin or the thromboxane A2 receptor antagonist sulotroban exerts a direct myocardial effect that enhances myocardial salvage afforded by reperfusion. Accordingly, 21 anesthetized dogs underwent suture occlusion of the left anterior descending coronary artery. At 2.5 h after occlusion, all dogs received intravenous streptokinase (20,000 U/kg body weight over 30 min) and were randomized to the following groups: group I (n = 7) received no additional treatment, group II (n = 7) received aspirin (5 mg/kg intravenously) and group III (n = 7) received sulotroban (10 mg/kg followed by 10 mg/kg per h intravenously). At 3 h after occlusion, the dogs underwent coronary reperfusion for the next 3 h. Myocardial infarct size as a percent of the hypoperfused zone was similar among dogs in group I (42 +/- 8%), group II (41 +/- 10%) and group III (45 +/- 11%). The incidence and the extent of myocardial hemorrhage were similar in all three study groups. Infarct size as a percent of the hypoperfused zone was significantly smaller in dogs without hemorrhage irrespective of treatment (35 +/- 9% versus 63 +/- 5%, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Relation between anterograde blood flow through a coronary artery and the size of the perfusion bed it supplies: experimental and clinical implications

The relation between anterograde blood flow through a coronary artery and the size of the perfusion bed it supplies is not known. Accordingly, the left circumflex coronary artery was cannulated and perfused with arterial blood in 12 open chest mongrel dogs. In Group I dogs (n = 7), the goal was to correlate the size of the perfusion bed with the magnitude of anterogradely derived myocardial blood flow. The size of the perfusion bed was measured with use of two-dimensional myocardial contrast echocardiography, whereas anterograde myocardial blood flow was determined by injecting radiolabeled microspheres directly into the artery. In Group II dogs (n = 5), the goal was to study the effects of altering coronary blood flow on both anterogradely and collateral vessel-derived myocardial flow within the perfusion bed. In these dogs, microspheres were injected directly into both the coronary artery and the left atrium at each flow rate. In Group I dogs, the left circumflex perfusion bed size, as defined by myocardial contrast echocardiography, decreased at lower anterograde myocardial blood flow rates. The change in perfusion bed size occurred at the lateral zones. There was a linear relation between the normalized perfusion bed size and the normalized anterograde myocardial blood flow: y = 0.45x + 54.2 (p less than 0.001, r2 = 0.77). These results were substantiated in Group II dogs, in which the size of the perfusion bed was approximated with use of radiolabeled microspheres. The size of the perfusion bed was most affected when anterograde myocardial blood flow decreased to less than approximately 33% of normal. At the lowest flow rates, there was a linear relation between anterograde blood flow versus the fraction of the left circumflex flow derived anterogradely: y = 2.41x + 0.22 (p less than 0.001, r2 = 0.90). The lower the level of anterograde flow, the greater was the blood flow derived from remote vessels. It is concluded that the size of the area perfused by a coronary artery is significantly influenced by the magnitude of anterograde blood flow through that artery. These findings may have important implications in experimental and clinical models of myocardial ischemia.