Coronary artery embolization in closed-chest canines using flexible radiopaque plugs

A new technique induces localized myocardial infarction in closed-chest dogs by placing discrete plugs in coronary arteries without using cumbersome coaxial catheters or guide wires. Flexible plugs, essential to this method, are formed by extruding a dental impression polymer, rendered radiopaque with sodium iodide, into spaghetti-like strands. Segments of these strands can be injected through a catheter into a selected coronary artery. Contact with blood or saline causes plugs to swell. The mean increase in plug diameter due to swelling was 27 +/- 20%. Eight anesthetized dogs were embolized via carotid approach [6 left anterior descending (LAD), 1 left circumflex (LCX), and 1 LAD and LCX]. Plug positions were monitored fluoroscopically. One animal died at 2 days postembolization. The remaining seven dogs were killed after 14-37 days. Autopsies showed complete vessel occlusion and localized infarction. Infarcts resulting from coronary artery occlusion with one, two, or three plugs involved 2-26% of the left ventricular mass.     

Plasma endothelin levels during myocardial ischemia and reperfusion

Endothelin, an endothelium-derived vasoconstrictive peptide, has a strong potency of coronary artery constriction. However, the role of endogeneous endothelin under pathophysiological conditions has not yet been known. In this study, we examined plasma endothelin concentration in dogs with myocardial ischemia and reperfusion. Anesthetized open-chest dogs underwent either 45 minutes occlusion of the left anterior descending coronary artery followed by 3 hours reperfusion, or 4-10 hours of continuous occlusion. Plasma concentration of endothelin from the central vein was measured by the highly sensitive enzyme-immunoassay. Plasma endothelin concentration increased 2.2-fold with the peak level at 60 minutes after release of the ligated artery, but occlusion per se caused no remarkable change. These data suggest that reperfusion of the occluded artery might be needed to increase the plasma concentration of endothelin in case of myocardial infarction.     

Effect of ethanol on myocardial infarct size in a canine model of coronary artery occlusion-reperfusion

This study was conducted to determine if elevated blood alcohol prior to acute coronary artery occlusion affects myocardial infarct size in an in vivo canine model. Seven pentobarbital anesthetized open-chest dogs received 10 min Iv infusion of ethanol (0.08 g/kg/min). Ten min after ethanol, the left anterior descending coronary artery (LAD) was occluded distal to its first major branch for 60 min. The LAD was then reperfused for 5 h. Following electrically induced ventricular fibrillation, the area at risk of infarction was delineated with dye. The area of infarction was identified by staining with triphenyl tetrazolium chloride. Eleven untreated control experiments were also conducted. Mean blood ethanol concentration was 155 ± 26 mg/dl just prior to LAD occlusion and 47 ± 3 mg/dl after 4 h reperfusion. Ethanol infusion had no effect on systemic hemodynamic variables during ischemia. In ethanol treated animals, the area at risk was 19.7 ± 3.0% of the left ventricle, and the infarct size was 20.9 ± 4.8% of the area at risk. In control experiments, the area at risk was 23.0 ± 4.1% of the left ventricle (p > 0.05), and the infarct size was 21.6 ± 3.8% of the area at risk (p > 0.05). Collateral blood flow to ischemic region did not differ between the two groups, and the relationships between infarct size and collateral flow were similar for control and untreated hearts. Acute ethanol exposure prior to coronary artery occlusion and subsequent reperfusion does not affect myocardial infarct size in the heart of the anesthetized dog.     

ST段抬高性和非ST 段抬高性急性心肌梗死患者的冠状动脉病变特点比较

目的:比较ST段抬高性和非ST段抬高性急性心肌梗死患者的冠状动脉病变特点。方法:选取100例在我院接受24h动态心电图和冠状动脉造影检查的急性心肌梗死患者,根据心电图结果分为观察组和对照组各50例。对照组为ST段抬高性心肌梗死(STEMI)患者,观察组为非ST段抬高性心肌梗死(NSTEMI)患者,比较两组患者冠状动脉病变的差异。结果:对照组LAD(左前降支)闭塞血管比例(52.00%)显著高于观察组(18.00%),差异具有统计学意义(P0.05)。对照组LCX(回旋支)闭塞血管比例(8.00%)显著低于观察组(50.00%),差异具有统计学意义(P0.05)。对照组RCA(右冠脉主干)闭塞血管比例(40.00%)和观察组(30.00%)比较,差异无统计学意义(P0.05)。对照组单支病变比例(46.00%)明显高于观察组(12.00%),对照组三支病变比例(20.00%)明显低于观察组(48.00%)比较,差异均具有统计学意义(P0.05)。对照组二支及正常血管比例与观察组比较,差异均无统计学意义(P0.05)。对照组罪犯血管狭窄程度在76%-90%、91%-99%及完全闭塞的比例与观察组比较差异均具有统计学意义(P0.05)。罪犯血管狭窄程度在50%及50%-75%时,两组差异无统计学意义(P0.05)。两组并发症发生情况比较,差异无统计学意义(P0.05)。结论:1NSTEMI罪犯血管闭塞以LCX多见,STEMI罪犯血管闭塞以LAD多见;2NSTEMI以三支血管病变较多见,STEMI以单支病变较多见。     

二维斑点追踪技术评价犬心梗后自体骨髓CD34＋干细胞移植对心肌功能的影响

目的应用二维斑点追踪成像超声心动图（2D-STE）,评价犬心梗后自体骨髓CD34＋干细胞移植对心肌功能的影响。方法 12只杂种犬行冠脉左前降支结扎术,导致前壁心肌梗死,随机分为两组,A组为对照组,结扎术后两周二次开胸手术,经心肌注射磷酸盐缓冲液（PBS）1 mL;B组为治疗组,结扎术后两周二次开胸手术,经心肌注射含自体骨髓CD34＋干细胞的磷酸盐缓冲液1 mL。应用STE对12只犬结扎术前、术后左室短轴基底段及心尖段心室节段径向应变（RS）、圆周方向应变（CS）以及局部心肌旋转（Rot）进行分析,并对对照组和治疗组治疗后的RS、CS及Rot变化进行比较。结果心肌梗死后梗死节段的RS、CS以及Rot均下降,治疗后治疗组梗死段RS及Rot较对照组好转。结论 STE能够评价左室短轴局部心肌的收缩功能,心肌梗死后梗死段短轴各方向应变减低,自体骨髓CD34＋干细胞移植能够提高局部心肌的收缩功能。     

A3 adenosine receptor agonist IB-MECA reduces myocardial ischemia-reperfusion injury in dogs

We examined the effect of the A3 adenosine receptor (AR) agonist IB-MECA on infarct size in an open-chest anesthetized dog model of myocardial ischemia-reperfusion injury. Dogs were subjected to 60 min of left anterior descending (LAD) coronary artery occlusion and 3 h of reperfusion. Infarct size and regional myocardial blood flow were assessed by macrohistochemical staining with triphenyltetrazolium chloride and radioactive microspheres, respectively. Four experimental groups were studied: vehicle control (50% DMSO in normal saline), IB-MECA (100 microg/kg iv bolus) given 10 min before the coronary occlusion, IB-MECA (100 microg/kg iv bolus) given 5 min before initiation of reperfusion, and IB-MECA (100 microg/kg iv bolus) given 10 min before coronary occlusion in dogs pretreated 15 min earlier with the ATP-dependent potassium channel antagonist glibenclamide (0.3 mg/kg iv bolus). Administration of IB-MECA had no effect on any hemodynamic parameter measured including heart rate, first derivative of left ventricular pressure, aortic pressure, LAD coronary blood flow, or coronary collateral blood flow. Nevertheless, pretreatment with IB-MECA before coronary occlusion produced a marked reduction in infarct size ( approximately 40% reduction) compared with the control group (13.0 +/- 3.2% vs. 25.2 +/- 3.7% of the area at risk, respectively). This effect of IB-MECA was blocked completely in dogs pretreated with glibenclamide. An equivalent reduction in infarct size was observed when IB-MECA was administered immediately before reperfusion (13.1 +/- 3.9%). These results are the first to demonstrate efficacy of an A3AR agonist in a large animal model of myocardial infarction by mechanisms that are unrelated to changes in hemodynamic parameters and coronary blood flow. These data also demonstrate in an in vivo model that IB-MECA is effective as a cardioprotective agent when administered at the time of reperfusion.     

Mitochondrial ATP dependent potassium channels mediate non-ischemic preconditioning by tachycardia in dogs

Brief episodes of tachycardia without myocardial ischemia prior to a coronary occlusion decrease myocardial infarct size in dogs. This non-ischemic preconditioning is mediated by adenosine. Because ischemic preconditioning is mediated through ATP dependent potassium channels, particularly the mitochondrial ones, we studied whether non-ischemic preconditioning is also mediated through these channels. In anesthetized dogs heart rate was kept constant at 120 cycles/min and aortic pressure changes were damped. Myocardial infarction was induced by occlusion of the anterior descending coronary artery for 60 min and reperfusion for 270 min. In a control group the infarct size (necrotic volume/risk region volume × 100) was 15.8 ± 1.5%. Preconditioning with five periods of tachycardia, 5 min in duration each at 213 cycles/min with intervening periods of 5 min of basal heart rate at 120 cycles/min, reduced the infarct size by 45.6% (p < 0.05) with respect to the control group. This effect was completely reverted by the blockade of ATP dependent potassium channels with glibenclamide or 5 hydroxydecanoate (a specific blocker of mitochondrial ATP dependent potassium channels) prior to preconditioning. These effects were not due to differences in collateral flow, risk region size or hemodynamic variables between the groups. These results show that mitochondrial ATP dependent potassium channels mediate non-ischemic preconditioning by tachycardia in dogs.     

The Pathogenesis of Human Myocardial Infarction

Coronary arteriography, dissection of the coronary arteries and histopathological examination of the heart were carried out in 150 autopsies to study the effect of coronary narrowing and occlusion, of the presence of collaterals, and of coronary artery predominance on the development of myocardial infarction. The thrombosis rate was related to the severity of coronary sclerosis. The development of collaterals was not enhanced by coronary sclerosis and occlusion, and collaterals did not protect the myocardium against reinfarction. Coronary occlusion was regularly demonstrable in recent myocardial infarct cases. The association of atrial and posterior ventricular infarcts was explained by occlusion of their common arterial branch. The interdependence between coronary sclerosis, thrombosis and myocardial infarction in human autopsy material emphasizes the importance of mural coronary artery disease in the genesis of coronary occlusion and myocardial infarction, and it is at variance with statistical data and experimental results.     

Morphological bases of myocardial revascularization by laser radiation

The mechanism of myocardial revascularization was studied in 30 dogs with the aid of impulse carbonic acid laser after ligation of the anterior descending branch of the left coronary artery. In the control group, 4 dogs died of myocardial infarction. In 26 animals laser canals were formed. The walls of the canals comprised cardiomyocytes with the manifestations of a coagulation thermal necrosis. Morphological studies disclosed the aseptic productive nature of the inflammatory reaction and the absence of marked leukocytic infiltration of the tissues adjacent to the area of necrosis. The laser canals were lined with endothelium by the 10th-14th day after operation, they were not obliterated or sclerosed. Morphological, laboratory, and radionuclide studies attest to adequate perfusion of the myocardium with the aid of the laser canals preventing the development of myocardial ischemia and infarction.     

Anti-arrhythmic effect of tetrodotoxin in the late stage of experimental myocardial infarct]

The action of tetrodotoxin (TT), blocking the fast sodium current, on arrhythmias that occurred 24 hours after occlusion of the coronary artery was studied in 10 dogs. TT injected intravenously in doses of 0.5--3.0 micrograms/kg significantly decreased the number of ventricular extrasystoles, and completely restored sinum rhythm in 4 animals. The maximum antiarrhythmic effect was noted 3 to 5 minutes after TT adminstration. It is suggested that arrhythmias and the antiarrhythmic effect of the drugs in the late stage of myocardial infarction are connected with the fast inward sodium current.     

冠脉结扎和介入两种方法制备犬心肌梗死模型的比较

目的观察开胸结扎冠状动脉与闭胸明胶海绵栓塞法制备急性心肌梗死（AMI）动物模型的特点。方法分别经开胸结扎犬冠状动脉左前降支主干及闭胸冠脉栓塞的方法阻断冠脉血流;采用单级肢体导联和胸导联方式,在阻断前后监测心电图波形变化;造模72h后取心肌组织行病理切片染色。结果经心电图和病理验证,两种方法均可成功制备犬心梗模型,开胸冠脉结扎犬死亡率较高,而冠脉栓塞成活率高。结论相较开胸冠脉结扎法,闭胸栓塞法制备心梗模型对动物损伤小,成活率高,具推广价值。     

Early time course of myocardial electrical impedance during acute coronary artery occlusion in pigs, dogs, and humans.

Changes in myocardial electrical impedance (MEI) and physiological end points have been correlated during acute ischemia. However, the importance of MEI's early time course is not clear. This study evaluates such significance, by comparing the temporal behavior of MEI during acute total occlusion of the left anterior descending coronary artery in anesthetized humans, dogs, and pigs. Here, interspecies differences in three MEI parameters (baseline, time to plateau onset, and plateau value normalized by baseline) were evaluated using Kruskal-Wallis ANOVA and post hoc tests (P < 0.05). Noteworthy differences in the MEI time to plateau onset were observed: In dogs, MEI ischemic plateau was reached after 46.3 min (SD 12.9) min of occlusion, a significantly longer period compared with that of pigs and humans [4.7 (SD 1.2) and 4.1 min (SD 1.9), respectively]. However, no differences could be observed between both animal species regarding the normalized MEI ischemic plateau value (15.3% (SD 4.7) in pigs, vs. 19.6% (SD 2.6) in dogs). For all studied MEI parameters, only swine values resembled those of humans. The severity of myocardial supply ischemia, resulting from coronary artery occlusion, is known to be dependent on collateral flow. Thus, because dogs possess a well-developed collateral system (unlike humans or pigs), they have shown superior resistance to occlusion of a coronary artery. Here, the early MEI time course after left anterior descending coronary artery occlusion, represented by the time required to reach ischemic plateau, was proven to reflect such interspecies differences.     

The effect of propranolol on blood viscosity changes induced by experimental coronary occlusion

The effect of propranolol treatment was investigated in the myocardial ischemia-induced hyperviscosity state in anesthetized dogs. In untreated control dogs, low shear blood viscosity rose progressively, following an acute occlusion of the left anterior descending coronary artery; this effect was partially but significantly reduced by intravenously administered propranolol (0.2 mg/kg). The effect of the in vitro addition of propranolol was also determined upon viscosity of blood samples obtained at hourly intervals from dogs subjected to similar coronary ligation. The in vitro addition of propranolol did not produce a similar reversal of the hyperviscosity state observed in the blood obtained from dogs after coronary ligation.     

The effect of dietary supplementation of fish oil on experimental myocardial infarction

The effect of altering the abundance of precursors and inhibitors of prostaglandin formation by dietary supplements of fish oil was investigated in dogs with experimentally induced myocardial infarction. Prior to induction, 10 male mongrel dogs were fed standard dog chow supplemented with 25% of the total calories as menhaden oil for 36 to 45 days. The fatty acid composition of the lipids in plasma and platelets changed to reflect the increased intake of polyunsaturated fatty acids of the n-3 type. Thrombosis and subsequent infarction was induced by electrical stimulation of the left circumflex coronary artery of ambulatory dogs that were monitored by telemetry. Upon stimulation of control animals, the frequency of ectopic beats rose from less than 10% at the beginning to about 80% after 19 hours. In contrast, the oil-fed dogs maintained a more normal ECG pattern, showing less than 30% ectopic beats after 19 hours. In these animals, the size of infarction (measured by formazan formation) was 3% of the left ventricle compared to 25% in the control animals. The results suggest that dietary supplementation with fish oil may be beneficial in reducing myocardial damage associated with coronary artery thrombosis.     

Reduction of experimental myocardial infarct size with hyperosmolar mannitol.

Hypertonic mannitol previously has been shown to improve cardiac function, increase collateral flow, and decrease epicardial ST segment elevation following coronary occlusion in anesthetized or awake dogs. The present study quantitates by morphologic techniques, the effect of hypertonic mannitol on infarct size. Ischemic injury was produced by proximal occlusion of the circumflex artery for 40 min and necrosis was assessed after 48 hr of reflow. One group of dogs was given isotonic saline and the other hypertonic mannitol beginning the infusions just prior to, during, and for a short period after the release of the circumflex coronary artery occlusion. Serum osmolality increased by approximately 40 mOsm in the mannitol group. The administration of hypertonic mannitol was associated with a 40-50% reduction in infarct size ventricular fibrillation during occlusion and following release of the circumflex coronary artery occlusion was greater in mannitol-treated dogs although the difference was not statistically significant. Thus, the data obtained in this study extend previous observations and provide direct evidence that hypertonic mannitol can reduce infarct size in dogs with temporary circumflex artery occlusion and reflow.     

Endogenous intoxication of the body in acute myocardial infarct during lymph stimulation]

It was stated experimentally in dogs that the elevation of the lymph toxicity was more expressed than that of the blood in acute myocardial infarction. The shortening of the half-life period of paramecia evidenced the above mentioned fact. The injection of the lymphogogue preparations (obsidan, heparin, rheogluman) after coronary artery occlusion resulted in distinct rise of blood and lymph toxicity in early periods because of the "washing out" of toxic products from the ischemic myocardium, followed by normalization that had been more quicker than in controls.     

Diazepam administered prior to coronary artery occlusion increases latency to ventricular fibrillation

Few studies have addressed the antiarrhythmic potential of pretreatment with diazepam in acute myocardial infarction. Thus, the effect of diazepam pretreatment prior to coronary artery occlusion was examined in conscious pigs. Animals were instrumented with aortic catheters to measure arterial pressure, a pulmonary artery catheter for drug administration, and a snare around the left anterior descending coronary artery for permanent occlusion one week later. Diazepam (1 mg/kg iv bolus) or vehicle was administered 10 minutes prior to occlusion. Eight of 14 animals receiving diazepam (57%) and 13 of 22 receiving vehicle animals (59%) developed ventricular fibrillation following coronary occlusion. However, the latency to ventricular fibrillation was significantly shorter (7 +/- 1 min) in animals receiving vehicle compared to animals receiving diazepam (11 +/- 1 min). Significant increases in heart rate were seen up to 5 hours after coronary occlusion only in animals receiving vehicle. The results indicate that diazepam pretreatment can increase ventricular fibrillation latency and prevent heart rate increases following acute myocardial infarction.     

Electrophysiological action of ethacizin in acute myocardial ischemia in dogs

The effects of ethacizin on delayed activation of the ischemic myocardium by acute left anterior descending coronary artery occlusion were studied in dogs. Ethacizin, administered intravenously at a dose of 0.5 or 1 mg/kg depressed the conduction of excitation in the ischemic myocardium and significantly increased the incidence of ventricular fibrillation. Electrophysiological effects of ethacizin in acute myocardial ischemia, as well as its antiarrhythmic activity at the advanced stages of experimental myocardial infarction might be related to an intensive influence of ethacizin on fast inward sodium current in the myocardial fibers.     

Plasma endothelin-1 concentrations in the coronary sinus in dogs with artificially induced myocardial infarction.

We have previously reported the marked increase in plasma levels of endothelin-1 in patients with acute myocardial infarction (AMI). To investigate the effects of severe myocardial ischemia on the production of endothelin-1, plasma concentrations of endothelin-1 were measured by a sandwich-type enzyme immunoassay that we developed recently in both the coronary sinus and the aorta of dogs with artificially induced AMI. Dogs were anesthetized and chests were opened. The proximal left anterior descending coronary artery was completely occluded by ligation for 1 h and then was reperfused for 1 h. Throughout the experiment (at the end of occlusion for 1 h, at the beginning of reperfusion, at the end of reperfusion for 1 h), plasma endothelin-1 levels were not significantly altered either in the coronary sinus or in the aorta. The present findings indicate that severe myocardial ischemia itself does not affect the production of endothelin-1 in the coronary circulation of dogs.     

Histopathological Study of Healing After Allogenic Mesenchymal Stem Cell Delivery in Myocardial Infarction in Dogs

In this histological study, we assessed the role of mesenchymal stem cells (MSCs) in the healing process that takes place during the subacute phase of myocardial infarction in dogs. Seven days after occlusion of the left anterior descending coronary artery, adult mongrel dogs received 100 × 10⁶ 4′-6-diamidino-2-phenylindole (DAPI)-labeled allogenic bone marrow–derived MSCs by the transendocardial (TE, n=6) and intracoronary (IC, n=4) routes; control dogs (n=6) received no infusion. The dogs were euthanized at 21 days after occlusion. Hearts were excised and sliced from apex to base into four transverse sections, which were divided into nine segments. Paraffin sections from each segment were stained with hematoxylin and eosin, trichrome, picrosirius red, and antibodies against several extracellular matrix components. Frozen sections were immunostained for host cardiac phenotypical markers and analyzed by epifluorescence and deconvolution fluorescence microscopy (DFM). We found less unresolved necrotic myocardium and more extracellular matrix deposition in MSC-treated dogs than in controls 2 weeks after cell delivery. By DFM, no DAPI+ MSC nuclei were observed within native cardiac cells. MSCs delivered during the subacute phase of acute myocardial infarction positively affect healing, apparently by mechanisms other than differentiation into mature native cardiac cells. (J Histochem Cytochem 57:167–176, 2009)