双羟基黄酮醇对心肌再灌注损伤中局部心肌血流量影响的实验研究

目的:评价双羟基黄酮醇对缺血后冠脉内皮功能的作用以及评价其对致死性心肌缺血再灌注损伤的防治效果。方法:测定意识清醒、无应激状态下绵羊的冠状血管对不同浓度静脉输注的乙酰胆碱的反应,闭塞冠状动脉1 h然后进行7 d的连续再灌注,再灌注的同时进行双羟基黄酮醇或vehicle的治疗,测定缺血状态下和再灌注开始后的血液动力学指数和局部心肌收缩力,评估冠脉血管对乙酰胆碱的反应,并心脏测量梗死面积。结果:(1)双羟基黄酮醇处理后可预防心率上升,显著降低左室舒张末压在再灌注过程中的升高幅度;(2)乙酰胆碱引起的浓度依赖性心率、心搏出量和外周血管传导力的上升并不受到双羟基黄酮醇的处理和心肌缺血/再灌注的影响;(3)双羟基黄酮醇处理后梗死面积显著缩小;(4)双羟基黄酮醇处理可以显著改善危险心肌边缘区域的局部心肌血流。结论:双羟基黄酮醇可显著缩小心肌梗死面积,延长缺血后心肌再灌注中可显著改善内皮功能,可显著减弱危险心肌边缘区局部血流量的进行性损伤。     

Regional perfusion in hearts with acute coronary artery occlusion and subsequent β2- and α1-adrenergic blockade

Summary. Blockade of cardiac adrenoceptor subtypes, coronary or myocardial, might elicit compensatory interaction from remaining unblocked subtypes. An attempt to explore this interplay was made by studying regional myocardial blood flow alterations associated with β₂-adrenergic blockade followed by β₁-adrenergic blockade in anaesthetized cats with acute coronary occlusion. In order to maintain constant needs for perfusion, atrial pacing was established and the aortic blood pressure was kept constant. In myocardium remote from the ischaemic region, β₂-adrenergic blockade produced higher endocardial blood flow whereas no flow changes were observed close to the ischaemic region. With subsequent β₁-adrenergic blockade, blood flow increased endocardially in non-ischaemic regions, but remained unchanged in epicardial tissue. Control experiments without coronary ligation revealed no increase in left ventricular oxygen consumption during the experiments and support the theory that the observed blood flow increase in the coronary ligation group, following drug interventions, was not caused by increased cardiac work. This study indicates that combined β₂- and α₁-adrenergic blockade alters the balance between receptor subtypes. Unopposed β₁-mediated vasodilation is the most likely candidate to explain why endocardial flow was increased.     

Regional myocardial tissue blood flow during β-adrenergic blockade in cat hearts with acute ischaemia

Summary. Selective β₁ or β₂-adrenergic blockade was achieved by practolol or IPS 339, respectively, in cats with acute ligation of a coronary artery. During blockade, heart rate was kept constant by atrial pacing and blood pressure reduction was prevented by aortic clamping. Regional myocardial blood flow was measured by the distribution of 15 μm labelled microspheres. Practolol slightly reduced epicardial blood flow in ischaemic myocardium, while blood flow in border and normally perfused myocardium remained unchanged. Following IPS 339, myocardial tissue flow increased in normally perfused myocardium, on average by 37% in the endocardium and 30% in the epicardium. No changes occurred in the other regions. The flow changes brought about by IPS 339 were unrelated to haemodynamic changes, and the coronary vascular resistance was reduced. These results are indicative of coronary vasodilation related to β₂-adrenergic receptor blockade and was confined to well-oxygenated areas surrounding the acutely ischaemic zone.     

Does α1-adrenergic blockade influence regional blood flow regulation in hearts with coronary artery occlusion?

Summary. The effects of selective α₁-adrenergic blockade with doxazosin on regional myocardial tissue blood flow was studied in anaesthetized cats with acute coronary artery occlusion. Reflex tachycardia was prevented by selective β₁-adrenergic blockade with atenolol and coronary perfusion pressure was kept constant by partial stenosis of the descending aorta. Administration of atenolol reduced cardiac mechanical work-load by its negative inotropic and chronotropic effects, and reduced myocardial tissue blood flow in normally perfused myocardium. This reduction was most pronounced in the endocardial half-layer of the myocardium adjacent to the ischaemic region. Administration of doxazosin in this situation clearly reduced peak systolic and coronary perfusion pressure. But when coronary perfusion pressure was raised to pre-administration values, measurements of regional blood flow revealed no changes either in ischaemic or non-ischaemic myocardium. Also, there was no sign of redistribution of blood flow between endocardial and epicardial tissue in any area. This study, therefore, indicates that α₁-adrenoceptors play a minor role in the regulation of coronary blood flow in normal myocardium as well as ischaemic myocardium.     

A minimally invasive method for induction of myocardial infarction in an animal model using tungsten spirals

Most animal models use surgical thoracotomy with ligation of a coronary artery to induce myocardial infarction. Incision of the chest wall and myocardium affect remodeling after myocardial infarction. The aim of our study was to evaluate a new minimally invasive technique for inducing acute myocardial infarction in pigs. To this end, coronary angiography using a 6-F cardiac catheter was performed in 20 pigs. The cardiac catheter was advanced into the left circumflex artery (LCX) under electrocardiographic monitoring and small tungsten spirals were deployed in the vessel. LCX occlusion was verified by coronary angiography. Two days later, magnetic resonance imaging (MRI) was performed to estimate the extent of infarction. Thereafter, all animals were euthanized and the hearts stained with 2,3,5-triphenyltetrazolium chloride for histologic measurement of infarct size. Tungsten spirals were successfully placed in the LCX in all 20 pigs. About 13 of the 20 animals survived until the end of the experiment. The mean infarct size in the area supplied by the LCX was 4.4 ± 2.3 cm³ at MRI and 4.3 ± 2.2 cm³ at histology (r = 0.99, P < 0.001). No other myocardial regions showed infarction in any of the 13 pigs. Five of nine pigs requiring defibrillation due to ventricular fibrillation died because defibrillation was unsuccessful. One animal each died from pericarditis and pneumonia. Our results show that the minimally invasive method presented here enables reliable induction of myocardial infarction in a fairly straightforward manner. The 25% mortality rate associated with induction of myocardial infarction in our study is comparable to that reported by other investigators.     

Ultrasound Bio-microscopy for Measurement of Coronary Artery Flow and Estimation of Infarct Size in a Mouse Model of Acute Myocardial Infarction

Ultrasound bio-microscopy was used to measure hemodynamic changes in the left main coronary artery after myocardial infarction (MI), and its usefulness in estimating infarct size was evaluated. MI was induced by left anterior descending artery ligation. Diastolic peak velocity (V_d), mean flow velocity (V_mean) and the velocity-time integral (VTI) were measured 2 and 6 h after MI. Serum troponin I levels were assayed 2, 6 and 12 h after MI. At 2 h, V_mean and VTI significantly differed between mice that underwent low and high left anterior descending artery ligation; V_d, V_mean and VTI were correlated with infarct size (r = −0.557, −0.693 and −0.672, respectively; all p < 0.01). Infarct size was more strongly correlated with 2-h ultrasound bio-microscopy measurements than with 2-h serum troponin I level. Measurement of coronary artery blood flow by ultrasound bio-microscopy may be useful for early estimation of infarct size in mice.     

Monitoring Canine Myocardial Infarction Formation and Recovery via Transthoracic Cardiac Strain Imaging

Myocardial elastography (ME) is an ultrasound-based strain imaging method that aims to determine the degree of ischemia or infarction as a result of the change in the elastic properties of the myocardium. A survival canine model (n = 11) was employed to investigate the ability of ME to image myocardial infarction formation and recovery. Infarcts were generated by ligation of the left anterior descending coronary artery. Canines were survived and imaged for 4 days (n = 7) or 4 weeks (n = 4), allowing sufficient time for recovery via collateral perfusion. A radial strain-based metric, percentage of healthy myocardium by strain (PHM_ε), was developed as a marker for healthy myocardial tissue. PHM_ε was strongly linearly correlated with actual infarct size as determined by gross pathology (R² = 0.80). Mean PHM_ε was reduced 1–3 days post-infarction (p < 0.05) at the papillary and apical short-axis levels; full infarct recovery was achieved by day 28, with mean PHM_ε returning to baseline levels. ME was capable of diagnosing individual myocardial segments as non-infarcted or infarcted with high sensitivity (82%), specificity (92%) and precision (85%) (area under the receiver operating characteristic curve = 0.90). The study therefore strengthens the ME premise that it can detect and assess myocardial infarction progression and recovery in vivo and could thus provide an important role in both disease diagnosis and treatment assesssment.     

The role of serotonin (5HT2) receptor blockade in myocardial reperfusion injury: effects of LY53857 in a canine model of myocardial infarction.

The potential protective effects of serotonin receptor antagonism during the process of acute myocardial infarction were studied in anesthetized male dogs, which were subjected to a 90-min left circumflex coronary artery occlusion followed by 5 h of reperfusion. Either vehicle (0.9% NaCl) or the serotonin (5HT2) receptor antagonist LY53857 was infused i.v. at a dose of 0.5 mg/kg, followed by a constant infusion of 2 mg/kg/min beginning 5 min before left circumflex coronary artery occlusion and continuing throughout the duration of the ischemia and subsequent reperfusion. Verification of functional 5HT2 receptor antagonism in the circulating blood of the LY53857-treated dogs was monitored throughout the experiments by periodic assessment of ex vivo platelet reactivity to exogenous serotonin. After 5 h of reperfusion, the hearts were excised and analyzed utilizing histochemical staining with triphenyltetrazolium, which demarcates myocardial infarct size and anatomical area of myocardium at risk of infarction. There was not a significant reduction of infarct size with LY53857 treatment: control infarct/area at risk = 38.6 +/- 4.7%, n = 9 LY53857 infarct/area at risk = 33.4 +/- 3.8%, n = 6. Similarly, when myocardial infarct size was analyzed as a function of myocardial collateral blood flow, there were no significant effects of drug treatment on the relationship between collateral blood flow and infarct size. The effects of 5HT on neutrophil activation were determined by measuring the potential ability of 5HT to enhance the chemotactic peptide-induced production of superoxide. 5HT did not activate human neutrophils in vitro and LY53857 had no effect on neutrophil superoxide production.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute graded hypercapnia increases collateral coronary blood flow in a swine model of chronic coronary artery obstruction

OBJECTIVE: To evaluate the effect of acute hypercapnia on regional myocardial blood flow in a swine model of chronic, single-vessel coronary artery obstruction. Permissive hypercapnia is being used frequently in critical care settings. One possible detrimental effect of hypercapnia is the initiation of coronary "steal" in patients with coronary artery disease. The effects of hypercapnia on collateral coronary blood flow in the setting of coronary obstruction have not been defined. DESIGN: Prospective controlled experimental study. SETTING: Institutional animal research facility. SUBJECTS: Eight juvenile swine weighing 25-30 kg. INTERVENTIONS: Collateral coronary circulation was induced in eight piglets by banding the proximal left anterior descending coronary artery for 8-10 wks followed by total ligation. Graded hypercapnia (mean Paco2, 81 torr [10.80 kPa; Paco2 = 81 torr] and 127 torr [16.93 kPa; Paco2 = 127 torr]) was induced by increasing inspiratory carbon dioxide under isoflurane anesthesia (1 minimum alveolar concentration). MEASUREMENTS AND MAIN RESULTS: Animals were attached to instruments to measure pulmonary and systemic hemodynamics, regional myocardial blood flow, and cardiac output. Regional myocardial blood flow was determined using radiolabeled microspheres. Cardiac output, mean arterial pressure, and coronary perfusion pressure were unchanged at both levels of hypercapnia compared with baseline values. Heart rate was increased at Paco2 [HI] (p < .05). Regional blood flow was increased at both levels of hypercapnia in the collateral-dependent and normally perfused myocardium (p < .05; as high as 56% for subendocardium and as high as 106% for subepicardium at Paco2 [HI]). The intercoronary blood flow ratio remained unaltered. The transmural flow ratio was reduced at Paco2 [HI] (P < .05). During hypercapnia, regional lactate extraction remained unaltered, and regional oxygen extraction was unchanged or reduced despite the increase in oxygen consumption. CONCLUSIONS: In this swine model of chronic single-vessel coronary artery obstruction, acute hypercapnia does not induce coronary steal from collateral-dependent myocardium, but it does increase global coronary blood flow.     

Effect of intraaortic balloon counterpulsation (IABP) on myocardial infarct size and collateral flow in an experimental dog model

To determine the influence of IABP on infarct size and collateral blood flow in each of 12 openchest anaesthetised mongrel dogs two small branches of the left coronary artery were occluded consecutively. The perfusion areas of both branches were comparable in size. IABP was started immediately before ligation of the first branch for a 90-min period followed by a reperfusion period of 90 min. Subsequently the second vessel was also occluded for 90 min as a control without IABP while myocardial oxygen consumption remained constant and was then reperfused. Infarct size was expressed as a percentage of the perfusion area. A difference in infarct size with and without IABP (18±17, 18±10% respectively) could not be observed. However a significant increase of collateral blood flow due to IABP in the subendocardial layer from 8.9±4.8 to 14.9±4.6 ml/100 g/min (p<0.05) was prevalent. In the subepicardial layer the augmentation from 23.7±19.9 to 26.9±15.2 was not significant. Thus, in spite of a small increase of collateral blood flow in the subendocardial layer of the ischemic myocardium the infarct size was not reduced by IABP in our dog model.     

Deleterious influence of hypothyroidism on evolving myocardial infarction in conscious dogs.

To study the influence of hypometabolism on evolving myocardial infarction in a model with intact autoregulation, we investigated 53 awake dogs after coronary artery occlusion. Severe hypothyroidism was induced by the intravenous administration of 131I. Animals were instrumented to obtain hemodynamic measurements, and regional myocardial blood flow was measured with radioactive microspheres. Infarct size was determined by the creatine kinase depletion method, and dysrhythmia analysis was performed from 24-h Holter monitor tapes in animals matched for infarct size. The microarchitecture of hypothyroid myocardium was determined by the electron microscope. Before coronary occlusion, mean systemic pressure in hypothyroid dogs was reduced by 14% and cardiac output reduced by 32%, with no change in left ventricular end-diastolic pressure, first derivative of left ventricular pressure rise, (dP/dt), or heart rate. After coronary occlusion, there was deterioration in hemodynamic measurements in both groups, with lower absolute levels of mean systemic blood pressure and cardiac output obtained in hypothyroid dogs. Hypothyroidism was detrimental to evolving infarction with a 36% increase in infarct size present in hypothyroid dogs (30 +/- 2%) compared to euthyroid controls (22 +/- 3%), P less than 0.05. Dysrhythmias were more severe in hypothyroid dogs. There were no changes in the relationship between regional myocardial blood flow and the extent of infarction after coronary occlusion. Abnormalities in microarchitecture were present in hypothyroid dog myocardium. Severe hypometabolism in this model was associated with alterations in hemodynamics, more severe dysrhythmias and changes in microarchitecture. The combined effect of these alterations resulted in an overall detrimental influence of hypothyroidism on evolving myocardial necrosis in this model.     

Relative rates of oxidation of glucose and free fatty acids by ischaemic and non-ischaemic myocardium after coronary artery ligation in the dog

Abstract. 1. Small regional ischaemic lesions, involving about 7 % of the volume of the whole heart, were produced in the greyhound dog by ligation of a branch of the anterior descending coronary artery. Arteriovenous differences across ischaemic tissue were studied by cannulation of a local vein visibly draining the ischaemic area, whereas arteriovenous differences across the non-ischaemic tissue were obtained by coronary sinus samples. This system permitted study of those ischaemic cells draining into the local vein and perfused by residual collateral circulation. Flow factors were common to all metabolites measured in local venous blood, thereby allowing detection of changes in substrate metabolism relative to each other. As the contribution of local venous blood to coronary sinus blood was negligible, it was possible to use coronary sinus values as non-ischaemic control data for each local venous sample.—2. The contributions of glucose, free fatty acids (FFA) and other substrates (lactate, pyruvate, ketones, triglycerides) to the residual oxidative metabolism of the ischaemic, infarcting dog myocardium were indirectly assessed by calculations of the oxygen extraction ratio (OER), and directly by the rate of ¹⁴CO₂ formation from ¹⁴C-labelled glucose or palmitic acid.—3. Within two hours of arterial ligation, the arteriovenous difference of glucose across the ischaemic tissue was increased relative to that of IT A. Whether calculated from OER or from ¹⁴CO₂ data, there was an increase in the oxidation rate of glucose relative to that of FFA. In absolute terms the oxygen uptake of ischaemic tissue fell almost as much as the flow rate, and the glucose uptake probably fell too. Nevertheless, glucose competed more favourably than did FFA for the residual oxidative metabolism of the ischaemic tissue.—4. In coronary sinus blood, draining predominantly non-ischaemic tissue, formation of ¹⁴CO₂ accounted for about half the uptake of ¹⁴C-glucose and formation of ¹⁴C-lactate was very low. In local venous blood draining predominantly ischaemic tissue, ¹⁴CO₂ formation accounted for about 30–40% and ¹⁴C-lactate for about 10% of the arteriovenous difference of ¹⁴C-glucose. The chemical oxygen extraction ratio of glucose and FFA could account for 90–100% of the residual oxygen uptake of the ischaemic myocardium 60–100 min. post-ligation, with glucose accounting for nearly twice as much oxygen as FFA. Thus an unexpected finding was that a major part of the glucose extracted by the ischaemic myocardium was oxidized, possibly because local venous blood drained the less severely ischaemic areas.—5. The major fate of labelled FFA extracted by the non-ischaemic myocardium also appeared to be oxidation. After arterial ligation, rates of FFA oxidation fell as assessed by both OER calculation and by rates of ¹⁴CO₂ formation. More ¹⁴C-label was recovered in the “mitochondrial” and less in the “microsomal” lipid fractions of the ischaemic tissue.—6. Lactate uptake by the normal myocardium was changed to lactate discharge by the ischaemic myocardium. Initially, tissue glycogen was the major source of the lactate formed, but 60–120 min. after arterial ligation there was less discharge of lactate and circulating ¹⁴C-gIucose became a major source of venous lactate.—7. It was concluded that not only was anaerobic metabolism of glucose accelerated by coronary artery ligation, but the aerobic metabolism of glucose increased relative to that of FFA.     

Moderate normovolaemic haemodilution increases regional myocardial blood flow but has no effect on experimental infarct size

Regional myocardial blood flow was measured with radioactive microspheres before and 1, 3, 6, and 12 h after occlusion of the left anterior descending coronary artery (LAD) in anaesthetized cats. In one group of cats, 1 h after LAD occlusion, moderate normovolaemic haemodilution was started with a dextran 40 solution, which reduced the haematocrit by 20-25% throughout the rest of the experiment. In the other group, the haematocrit was kept at the original level. Infarct size was measured planimetrically 12 h after the coronary ligation, using the tetrazolium staining technique for disclosing the ischaemic myocardium. Haemodilution increased blood flow in the non-ischaemic myocardium and in the so-called 'border zone' comprising both normal, and ischaemic tissue. However, in the severely ischaemic myocardium dependent on collateral blood flow, where there was no admixture of non-ischaemic myocardium, the blood perfusion was not significantly affected by the haemodilution. After 12 h of ischaemia the infarct size in the control group was fully comparable with that in the haemodiluted group: 28 +/- 3 and 27 +/- 4 (percentage of the left ventricle, mean +/- SEM), respectively.     

Improvement in Myocardial Function and Coronary Blood Flow in Ischemic Myocardium after Mannitol

The purpose of this study was to evaluate the effect of hyperosmolality on the performance of, and the collateral blood flow to, ischemic myocardium. The myocardial response to mannitol, a hyperosmolar agent which remains extracellular, was evaluated in anesthetized dogs. Mannitol was infused into the aortic roots of 31 isovolumic hearts and of 15 dogs on right heart bypass, before and during ischemia. Myocardial ischemia was produced by temporary ligation of either the proximal or mid-left anterior descending coronary artery.Mannitol significantly improved the depressed ventricular function curves which occurred with left anterior descending coronary artery occlusion. Mannitol also significantly lessened the S-T segment elevation (epicardial electrocardiogram) occurring during myocardial ischemia in the isovolumic hearts and this reduction was associated with significant increases in total coronary blood flow (P < 0.005) and with increased collateral coronary blood flow to the ischemia area (P < 0.005).THUS, INCREASES IN SERUM OSMOLALITY PRODUCED BY MANNITOL RESULT IN THE FOLLOWING BENEFICIAL CHANGES DURING MYOCARDIAL ISCHEMIA: (a) improved myocardial function, (b) reduced S-T segment elevation, (c) increased total coronary blood flow, and (d) increased collateral coronary blood flow.     

Myocardial strain in sub-acute peri-infarct myocardium

Purpose In the absence of additional ischemic insults, the peri-infarct region surrounding the infarct myocardium can recover function. T2 weighted MRI signal is sensitive to edema and used to detect peri-infarct, salvageable myocardium. The main purpose of this study was to investigate the alterations in myocardial strain in the peri-infarct myocardium as compared to normal and infarct myocardium. Materials and methods Comprehensive MRI of the myocardium was performed in five pigs 6–7 days following coronary artery occlusion–reperfusion myocardial injury. MRI included tagged cine images for myocardial strain, T2weighted (T2w)-images and late gadolinium enhancement (LGE) for assessing myocardial viability. Automated signal intensity thresholds were used to define tissue edema and myocardial infarct. Maximum-shortening strains were analyzed in the infarct, peri-infarct and normal myocardial sectors. The results were correlated with triphenyltetrazolium-chloride (TTC) and hemotoxylin–eosin stained tissue images. Results We found an excellent correlation of LGE with TTC (r = 0.94, P < 0.05). T2w-images markedly overestimated the infarct size (25 ± 3%). Both the healthy and peri-infarct myocardial sectors had higher myocardial strain than infarct myocardial sectors (P < 0.05). Clear demarcation between infarct and non-infarct myocardium was noted on histology. Conclusion Peri-infarct myocardium continues to demonstrate T2 signal enhancement to at least 7 days, but this region has preserved mechanical function. T2-weighted imaging and myocardial strain measurements provide complementary information and both may be useful for characterization of the peri-infarct myocardium. Balázs Ruzsics and Pál Surányi have contributed equally.     

Localization of cardiac myosin-specific antibody in myocardial infarction.

Specific localization of purified antibody against cardiac myosin has been demonstrated in areas of altered myocardial membrane permeability after experimental myocardial infarction. Intravenously administered radioiodine-labeled antimyosin was selectively localized in infarcted myocardium of seven dogs 24 h after coronary occlusion. The mean ratio (+/-SE) of antimyosin antibody in infarcted to normal myocardium in the center of the infarct was 4.2+/-0.4 for endocardial and 2.9+/-0.3 for epicardial layers. By utilizing (Fab')2 fragments of antimyosin obtained by pepsin digestion of purified antibody, the ratio of uptake was increased in eight dogs to 6.1+/-0.6 in the endocardial and 3.3+/-0.4 in the epicardial layers at the infarct center 24 h after occlusion. These ratios were further increased in the infarct center to 13.8+/-1.2 in the endocardial and 7.3+/-0.8 in the epicardial layers when eight dogs were sacrificed 72 h after coronary occlusion. The specificity of antimyosin (Fab')2 localization in infarcted myocardium was demonstrated in four dogs by simultaneous intravenous administration of 125I-labeled antimyosin (Fab')2 and 131I-labeled normal rabbit gamma globulin (Fab')2. Nonspecific trapping of normal rabbit IgG (Fab')2 was observed to be about 38% of total antimyosin (Fab')2 uptake in the central zone of infarction. Regional blood flow was related to antimyosin (Fab')2 uptake in infarcted myocardium by utilizing simultaneous administration of 85Sr-labeled microspheres. An inverse exponential relationship between antimyosin (Fab')2 uptake and regional blood flow was observed (r=0.85). The specific localization of antimyosin antibody or its (Fab')2 components in infarcted myocardium suggests a conceptually new approach to myocardial infarct localization and sizing.     

Effect of diltiazem on infarct size, reperfusion flow and flow reserve: the effect of timing of treatment

This study was performed to determine if improved subendocardial reflow seen with diltiazem pretreatment after left circumflex coronary (LCX) occlusion is due to a direct vasodilatory effect of diltiazem on the reperfused bed or due to an increased flow maximum or reserve. In the first part of this study anesthetized dogs were subjected to saline or diltiazem (infused starting before, 10 min after LCX occlusion or 2 min before reperfusion; 0.18 mg/kg + 0.45 mg/kg/hr i.v. for all groups) treatment with a 90-min LCX occlusion and 5-hr reperfusion and myocardial blood flow and infarct size were determined at the end of the experiment. In the second part, maximal flow using intracoronary adenosine was determined at 1 and 3 hr postreperfusion in the ischemic bed when pretreated with saline or diltiazem. Myocardial infarct size was reduced significantly only in animals pretreated with diltiazem compared to saline-treated animals. At 1-hr postreperfusion, subendocardial flow (microspheres) was significantly higher only with diltiazem pretreatment compared to the saline group (100 +/- 17 vs. 54 +/- 8 ml/min/100 g, respectively) and subendocardial reperfusion flows were negatively correlated to infarct size (r = 0.97, P less than .05). Thus, diltiazem only improves reflow and infarct size when infused before occlusion and this improved reflow does not occur via a direct vasodilator action of diltiazem. When maximal vasodilating doses of adenosine were given, flow in the ischemic region was nearly identical for saline and diltiazem pretreated groups despite higher preadenosine flows in the diltiazem group (higher resting flow occurred at the expense of the existing flow reserve).(ABSTRACT TRUNCATED AT 250 WORDS)     

Infarct evolution in man studied in patients with first-time coronary occlusion in comparison to different species - implications for assessment of myocardial salvage

Background

The time course of infarct evolution, i.e. how fast myocardial infarction (MI) develops during coronary artery occlusion, is well known for several species, whereas no direct evidence exists on the evolution of MI size normalized to myocardium at risk (MaR) in man. Despite the lack of direct evidence, current literature often refers to the "golden hour" as the time during which myocardial salvage can be accomplished by reperfusion therapy. Therefore, the aim of the present study was to investigate how duration of myocardial ischemia affects infarct evolution in man in relation to previous animal data. Consecutive patients with clinical signs of acute myocardial ischemia were screened and considered for enrollment. Particular care was taken to assure uniformity of the patients enrolled with regard to old MI, success of revascularization, collateral flow, release of biochemical markers prior to intervention etc. Sixteen patients were ultimately included in the study. Myocardium at risk was assessed acutely by acute Myocardial Perfusion Single photon emission computed tomography (MPS) and by T2 imaging (T2-STIR) cardiovascular magnetic resonance (CMR) after one week in 10 of the 16 patients. Infarct size was measured by late gadolinium enhancement (LGE) at one week.

Results

The time to reach 50% MI of the MaR (T₅₀) was significantly shorter in pigs (37 min), rats (41 min) and dogs (181 min) compared to humans (288 min). There was no significant difference in T₅₀ when using MPS compared to T2-STIR (p = 0.53) for assessment of MaR (288 ± 23 min vs 310 ± 22 min, T₅₀ ± standard error). The transmural extent of MI increased progressively as the duration of ischemia increased (R² = 0.56, p < 0.001).

Conclusion

This is the first study to provide direct evidence of the time course of acute myocardial infarct evolution in relation to MaR in man with first-time MI. Infarct evolution in man is significantly slower than in pigs, rats and dogs. Furthermore, infarct evolution assessments in man are similar when using MPS acutely and T2-STIR one week later for determination of MaR, which significantly facilitates future clinical trials of cardioprotective therapies in acute coronary syndrome by the use of CMR.     

Sodium bicarbonate versus carbicarb in canine myocardial hypercarbic acidosis

The objective of this study was to compare the in vivo effects of sodium bicarbonate (NaHCO₃) and Carbicarb infusion on regional contractile performance and acid-base status in the setting of hypercarbic acidosis. Animals (N = 9) were anesthetized and paralyzed using sodium pentothal, halothane, and pancuronium bromide, and mechanically ventilated with an air-O₂ mixture so that arterial Po₂ was ≥300 mm Hg. Following beta-adrenergic blockade, alveolar ventilation was gradually reduced over a 50-minute period to increase arterial Pco₂ to 60 to 80 mm Hg. Each of the following solutions was then infused in consecutive order directly into the left anterior descending artery coronary artery for 15 minutes: (1) 8.4% NaHCO₃ at 2 mL/min; (2) 5% sodium chloride at 2 mL/min, equivalent to NaHCO₃ in osmolality; (3) 6.3% Carbicarb at 0.5 mL/min, equivalent to NaHCO₃ in buffer capacity; and (4) 6.3% Carbicarb at 2 mL/min, equivalent to NaHCO₃ in volume. Regional stroke work analog (ultrasonic dimension transducers), interstitial myocardial pH (Khuri electrode), coronary blood flow (doppler flow probe), and hemodynamic/metabolic variables (heart rate, blood pressure, arterial and coronary venous blood gases) were measured at 1, 5, 10, and 15 minutes during each infusion and 10 minutes after the infusion was discontinued, ie, at 25 minutes. Animals were allowed to recover for 45 minutes between interventions. Values at each time point were compared with baseline for statistical significance. Small reductions in interstitial myocardial pH (P < .05) and stroke work (P > .05) were observed within 1 minute of NaNCO₃ administration. Both parameters increased significantly from baseline levels thereafter, ie, interstitial myocardial pH at 5 minutes and stroke work at 15 minutes. Infusion of Carbicarb invariably was associated with an increase (P < .05) in interstitial myocardial pH. Stroke work increased (P < .05) during low-dose Carbicarb administration, but infusion of the higher dose was accompanied by a biphasic response, ie, an increase (P < .05) from 0 to 5 minutes, followed by a gradual decrease that achieved statistical significance 10 minutes after termination of the infusion. End-diastolic length was inversely proportional to changes in stroke work, and coronary blood flow varied directly with changes in coronary venous Pco₂. Myocardial O₂ consumption decreased (P < .05) during Carbicarb infusion, but changes during NaHCO₃ did not reach statistical significance. Our findings lend support to the hypothesis that intramyocardial pH determines myocardial function independent of CO₂ production by buffer therapy. While Carbicarb may restore intramyocardial pH and improve myocardial function more rapidly than NaHCO₃, both buffers neutralize the effects of intracellular acidosis to a similar extent when they enter the myocardium. Our results do not support the argument that NaHCO₃ is detrimental to myocardial contractile function when spontaneous contractile function is present.     

心肌灌注显像对心梗恢复期骨髓细胞移植效果估侧的实验研究

目的应用99Tcm-MIBI心肌灌注显像评价猪急性心梗恢复期自体骨髓细胞移植的治疗效果.方法结扎小型猪冠状动脉前降支创建心肌梗死动物模型,分两组,分别于结扎后2周经前降支注入自身骨髓干细胞和磷酸缓冲液(PBS).结扎后2周及第5周,同时对两组动物行99Tcm-MIBI心肌灌注显像.结果骨髓细胞移植组,移植后3周心肌灌注显像血流灌注较PBS组明显改善,两组显像评分结果有显著性差异[(42.4±5.0)和(29.8±9.5)(P＜0.05)].并与冠造及免疫组化结果一致.结论心肌灌注显像是评价骨髓干细胞移植后,心梗心肌血流灌注和心肌细胞活性的较好方法.骨髓干细胞移植可明显改善心肌血运供应及心肌活力.