Changes of regional myocardial blood flow during and after acute focal experimental ischaemia.

The regional blood flow through the myocardium of the left ventricle was measured in 11 dogs after ligation of the left anterior descending coronary artery, by means of a local injection of 133Xe depot and precordial detection of its washout 2 hours after ligation. Immediately after ligation the blood flow in the ischaemic area declined considerably but at the same time there was a significant increase of blood flow in the non-ischaemic left ventricular myocardium. The regional flow in the ischaemic and non-ischaemic area increased insignificantly for 2 hrs. These changes were not due to alterations in coronary artery pressure, as the mean arterial pressure declined significantly during the first hour. After temporary ischaemia by ligation of the left anterior descending coronary artery for 2--4 minutes, an intensive reactive hyperaemia developed in the ischaemic region (the blood flow reached 221% of control values on the average) which was the more intensive, the greater the drop of blood flow in the ischaemic area after ligation.     

Hyperglycemia reduces coronary collateral blood flow through a nitric oxide-mediated mechanism

We tested the hypothesis that hyperglycemia alters retrograde coronary collateral blood flow by a nitric oxide-mediated mechanism in a canine Ameriod constrictor model of enhanced collateral development. Administration of 15% dextrose to increase blood glucose concentration to 400 or 600 mg/dl decreased retrograde blood flow through the left anterior descending coronary artery to 78 +/- 9 and 82 +/- 8% of baseline values, respectively. In contrast, saline or L-arginine (400 mg x kg(-1) x h(-1)) had no effect on retrograde flow. Coronary hypoperfusion and 1 h of reperfusion decreased retrograde blood flow similarly in saline- or L-arginine-treated dogs (76 +/- 11 and 89 +/- 4% of baseline, respectively), but these decreases were more pronounced in hyperglycemic dogs (47 +/- 10%). L-arginine prevented decreases in retrograde coronary collateral blood flow during hyperglycemia (100 +/- 5 and 95 +/- 6% of baseline at blood glucose concentrations of 400 and 600 mg/dl, respectively) and after coronary hypoperfusion and reperfusion (84 +/- 14%). The results suggest that hyperglycemia decreases retrograde coronary collateral blood flow by adversely affecting nitric oxide availability.     

Coronary three-vessel disease with occlusion of the right coronary artery: What are the most important factors that determine the right territory perfusion?

With progressive occlusion of a coronary main artery, some anastomotic vessels are recruited in order to supply blood to the ischemic region. This collateral circulation is an important factor in the preservation of the myocardium until reperfusion of the area at risk. An accurate estimation of collateral flow is crucial in surgical bypass planning as it alters the blood flow distribution in the coronary network and can influence the outcome of a given treatment for a given patient. The evaluation of collateral flow is frequently achieved using an index based on pressure measurements. It is named collateral flow index (CFI) and defined as: (P_w − P_v)/(P_ao − P_v), where P_w is the pressure distal to the thrombosis, P_ao the aortic pressure and P_v the central venous pressure. In the present work, we study patients with severe coronary disease (stenoses on the left branches and total occlusion of the right coronary artery). Using a mathematical model that describes the coronary hemodynamics in that situation, we demonstrate that the dependence of the collateral circulation to the pressure values is not as simple as it is commonly believed: using pressures alone as an index of collateral flow is likely to result in misinterpretation of the collateral flow contribution, because collateral flow depends on many other factors related to the status of the native stenosed arteries and to the microvascular resistances (capillary and collateral resistances, and the proportion between them).     

The early consequences of myocardial ischaemia and their modification

This paper attempts to review our studies on the early haemodynamic, metabolic and electrophysiological consequences of acute coronary artery ligation in an experimental model which allows the simultaneous assessment of blood flow and sampling of blood from both normal and acutely ischaemic zones of myocardium. 1. Using local coronary venous sampling, it has been observed that the major metabolic changes which occur in the ischaemic zone during the first 30 min after coronary artery ligation are increases in PCO2, decreases in pH and oxygen content, a shift in lactate handling from extraction to production and an efflux of K+. These changes were not observed in coronary sinus blood draining essentially nonischaemic zones of myocardium. 2. The major haemodynamic change produced by coronary artery ligation was cardiac depression (decreased stroke volume and cardiac work), unchanged LV dP/dt with an elevated filling pressure. 3. Acute ligation of the anterior descending branch of the left coronary artery, l.a.d., resulted in bursts of ventricular ectopic activity which was especially marked 10-20 min after ligation and which frequently resulted in ventricular fibrillation. The incidence of arrhythmias could be modified by the species of dog used, the anaesthetic employed, the arterial oxygen tension and the administration of several antiarrhythmic drugs. The possible relevance observed in the ischaemic myocardium, to the genesis of these arrhythmias is discussed. 4. The changes in the ST-segment of epicardial leads produced by short (3 min) occlusions of the l.a.d. were studied in mongrel dogs. Evidence is presented which suggests that the evolution of ST-segment elevation is linked to the efflux of K+ from ischaemic myocardial cells.     

Modification of the size of developing infarcts in the ligated dog heart by betahistine-HCL

The effectiveness of beta-histine-HCL in modifying the size of developing myocardial infarcts was tested in the surgically ligated dog. Branches of the left coronary artery were ligated and a 6-hour continuous intravenous infusion of 0.24 mg/kg/min of beta-histine was administered from 0 to 120 min after ligation. The effect of this treatment was evaluated histologically in studies on acute ischemia by the use of the hematoxylin-basic fuchsin-picric acid stain for early myocardial ischemia. The treatment was also evaluated grossly in a study on chronic ischemia where the dogs were permitted to survive for 30 days before sacrifice. In these experiments the size of infarcts found in the beta-histine-treated animals was compared with those found in the saline controls. Both studies showed that the control ligations produced a large uniform area of ischemia or infarction that was greatly reduced or prevented by immediate treatment with beta-histine. Also, beta-histine was capable of significantly reducing the size of developing infarcts for up to 120 min after ligation.     

Plasticity of blood vessels of the heart and lungs in collateral circulation under conditions of high altitude]

The combination of the collateral blood flow in the heart and lungs with effects of Alpine hypoxia and pronounced additional loads was found to allow the detecting of plastical capacities of these organs in a sufficiently full volume. The experiments were performed in 273 dogs by microscopic, macro-microscopic, macroscopic and partly functional methods. The collateral coronary blood flow (after ligation of the anterior interventricular artery) under Alpine conditions (3200 m over the sea level) combined with compensatory hyperfunction of the heart (due to stenosing of the aorta arc), gets worse as compared with the conditions of the valley. In these experiments in mountains the extra- and intraorganic anastomoses are more pronounced, the capacity of the coronary artery branches being less pronounced than in the valley. The muscle fibres grow thicker, the heart weight enlarges, the diffusion distances of capillaries increase and the ratio of the arterial bed capacity and the heart weight decreases. Under Alphine conditions (as compared with the valley) the collateral blood flow of lungs deteriorates (after ligation of two lobar branches of the pulmonary artery or of the lobar vein) against the background of additional loads (stenosing of the aorta arc or pulmonectomy). Deterioration of the collateral bloodflow is related with the combination of conditions of the alphine hypoxia with additional loads resulting in a weakening or even block of compensatory reactions of pulmonary or bronchial arteries and veins.     

小型猪急性心肌梗死模型的建立及其评价

目的探索结扎小型猪冠状动脉左前降支（LAD）建立急性心肌梗死模型及进行血流评价的方法。方法小型猪20头全麻下开胸暴露心脏,预阻断LAD（第二对角支）15min,后予结扎,术中心电图动态监测,术后进行冠状动脉造影,心肌酶学监测以确定模型建立情况,冠状动脉造影以及^13N-NH3 PET心肌血流测定评价手术后血流改变。结果20头小型猪中有16头存活4周,成活率80％,开胸手术中1头因麻醉意外死亡,3头死于术后呼吸不畅。结扎后心电图呈动态变化,24h后血清心肌酶谱（CK,CK—MB,cTnI）较术前明显增高,差异有统计学意义（P〈0．05）,冠状动脉造影显示LAD血流中断,TIMI分级为0级,^13N—NH3 PET检查显示手术后缺损面积百分比（27．0±5．0）较手术前（4．0±3．2）有显著性差异,证实心梗模型建立成功。结论本实验中开胸手术成功率高,术后血流评价方法可用于手术前后冠脉血流和心肌血流的比较以及对心肌梗死后治疗效果进行评价。     

犬心肌缺血早期血小板聚集功能和冠脉侧支循环的改变

本实验在18只麻醉开胸犬观察了急性心肌缺血早期血小板聚集功能和冠脉侧支循环功能的变化。实验结果如下:阻断冠脉后心肌缺血区血液中血小板聚集率(PAgR)增大,血小板计数(PC)减少。缺血50min时,PAgR增大58.7±5.6％,PC减少39.5±23.6％,与对照值有明显差异(均为P<0.01)。与此同时,在控制血压条件下,心肌缺血早期单位压力差下冠脉侧支血流量的变化与对照值无明显差异,而根据Wyatt等公式计算的流经缺血区末梢血管的有效侧支血流量明显降低,缺血50min时较对照值降低23.5±9.7％(P<0.05)。PAgR变化与有效侧支血流量改变呈明显负相关(r=-0.887,P<0.01);冠脉侧支指数与梗塞范围呈明显负相关(r=-0.847,P<0.01)。阻断冠脉前静脉注射血小板聚集功能抑制剂阿斯匹林,可明显减轻上述各项参数的异常变化。这些结果提示,心肌缺血早期血小板聚集功能的异常变化虽然对冠脉侧支血管的血流阻力影响较小,但却使流经缺血区末梢血管的有效侧支血流量明显减小,进而扩大梗塞范围。     

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。     

血管内皮生长因子对猪心肌侧枝血管生成的作用

为检测血管内皮生长因子165（VEGF165)能否促进冠状动脉侧枝血管形成,实验在成功制作小型猪慢性心肌缺血模型后,将以复制缺陷复组腺病毒为载体的人VEGF165互补脱氧核糖核酸[(cDNA)Ad-VEGF165]直接注入左回旋支（LCX）分布的缺血心肌内,以心电图门控单光子发射计算机断层摄影和离体太动脉造影检测冠状动脉侧枝形成,心肌灌注和功能变化,结果显示,与对照组和自身给预Ad-VEGF165前比较,给予Ad-VEGF165四周后心肌缺血面积（P＜0．01）和最大缺血程度（P＜0．01）明显减小,左心室射血分数（P＜0．01）TCX区局部心室壁运动（P＜0．05）明显改善,治疗组侧枝血管生成明显多于对照组（P＜0．05）,表明Ad-VEGF165能诱导心肌侧肢血管形成并改善心肌灌注与运动功能。     

Coronary ligation reduces maximum sustained swimming speed in Chinook salmon, Oncorhynchus tshawytscha

The maximum aerobic swimming speed of Chinook salmon (Oncorhynchus tshawytscha) was measured before and after ligation of the coronary artery. Coronary artery ligation prevented blood flow to the compact layer of the ventricular myocardium, which represents 30% of the ventricular mass, and produced a statistically significant 35.5% reduction in maximum swimming speed. We conclude that the coronary circulation is important for maximum aerobic swimming and implicit in this conclusion is that maximum cardiac performance is probably necessary for maximum aerobic swimming performance.     

Coronary physiology before and after chronic total occlusion treatment: what does it tell us?

Studies performed in the last two decades demonstrate that after successful percutaneous coronary intervention (PCI) of a chronically occluded coronary artery, the physiology of the chronic total occlusion (CTO) vessel and dependent microvasculature does not normalise immediately but improves significantly over time. Generally, there is an increase in fractional flow reserve (FFR) in the CTO artery, a decrease in collateral blood supply and an increase in FFR in the donor artery accompanied by an increase in blood flow and decrease in microvascular resistance in the myocardium supplied by the CTO vessel. Analogous to these physiological changes, positive remodelling of the distal CTO artery also occurs over time, and intravascular imaging can be helpful for analysing distal vessel parameters. Follow-up coronary angiography with physiological measurements after several weeks to months can be helpful and informative in a subset of patients in order to decide upon the necessity for treatment of residual coronary artery stenosis in the vessel distal to the CTO or in the contralateral donor artery, as well as in deciding whether stent optimisation is indicated. We suggest that such physiological guidance of CTO procedures avoids unnecessary overtreatment during the initial procedure, guides interventions at follow-up, and improves our understanding of what PCI in CTO means.

     

Changes in the myocardial area at risk, infarct size, and collateral flow following nicardipine infusion in dogs.

The area at risk of infarction after an acute occlusion of the left anterior descending coronary artery was defined in anesthetized dogs using the distribution of 99mTc-labelled albumin microaggregates and Monastral blue dye. In thirteen dogs, it was determined that these two particulate labels identified identical areas of unperfused myocardium. In a second group of dogs (n = 12), the risk areas determined at 10 (99mTc-labelled macroaggregates) and at 180 min (Monastral blue dye) were found to be identical, with no change in collateral blood flow, indicating the absence of a spontaneous change in underperfused myocardium over this time. In a third group of dogs (n = 17) nicardipine was infused (10 micrograms.kg-1.min-1 for 5 min, followed by 8 micrograms.kg-1.min-1 for 165 min). This resulted in a significant and sustained fall (32 +/- 4 mmHg; 1 mmHg = 133.32 Pa) in mean arterial blood pressure but no significant change in collateral blood flow was found, except for a marginal increase in the center of the ischemic zone. Area at risk and infarct sizes were also not significantly different between the latter two groups (18.2 +/- 4.1 vs. 21.6 +/- 4.0% of left ventricle). In this model, the magnitude of the area at risk appears to be determined early after a coronary occlusion and appears to be unmodified by treatment with nicardipine begun after the occlusion.     

A technique for measurement of retrograde coronary blood flow in intact anesthetized dogs.

A technique for measurement of retrograde coronary blood flow in intact anesthetized dogs is described. Occlusion of the coronary artery is produced by the inflation of a small rubber balloon at the tip of a no. 9 cardiac catheter placed under fluorescopy in a branch of the left coronary artery. Blood which bleeds back from the occluded coronary artery through the no. 9 catheter is diverted into a small reservoir of 1-ml capacity. The time to fill this reservoir is recorded electrically. Retrograde coronary blood flow is calculated from the time required to fill this reservoir. Results indicate good repeatability of meadurements. The technique seems to be a simple, adequate, and convenient means for assessing agents for possible vasodilator action on the collateral circulation in intact animals.     

Systemic blood flow to the lung after bronchial artery occlusion in anesthetized sheep.

To compare the effectiveness of different embolizing agents in reducing or redistributing bronchial arterial blood flow, we measured systemic blood flow to the right lung and trachea in anesthetized sheep by use of the radioactive microsphere method before and 1 h after occlusion of the bronchoesophageal artery (BEA) as follows: injection of 4 ml ethanol (ETOH) into BEA (group 1, n = 5), injection of approximately 0.5 g polyvinyl alcohol particles (PVA) into BEA (group 2, n = 5), or ligation of BEA (group 3, n = 5). After occlusion, angiography showed complete obstruction of the bronchial vessels. There were no changes in tracheal blood flow in any of the groups. Injection of ETOH produced a 75 +/- 14% (SD) reduction in flow to the middle lobe (P less than 0.02) and a 75 +/- 13% reduction to the caudal lobe (P less than 0.01), whereas injection of PVA produced a smaller reduction in flow to these two lobes (41 +/- 66 and 51 +/- 54%, respectively). After BEA ligation there was a 52 +/- 29% reduction in flow to the middle lobe and a 53 +/- 38% reduction to the caudal lobe (P less than 0.05). This study has significant implications both clinically and experimentally; it illustrates the importance of airway collateral circulation, in that apparently complete radiological obstruction of the BEA does not necessarily mean complete obstruction of systemic blood flow. We also conclude that, in experimental studies in which the role of the bronchial circulation in airway pathophysiology is examined, ETOH is the agent of choice.     

Effects of experimental coronary ligation of pH and lactate concentration in cardiac lymph.

Changes in pH and lactate concentration in the cardiac lymph and arterial blood were studied after ligation of the left coronary artery of the dog. After the coronary ligation, pH of the cardiac lymph dropped significantly accompanied by a rise in the lactate concentration, while the pH and lactate concentration of the arterial blood did not change throughout the experiments. This fall in pH in the cardiac lymph may reflect changes in the interstitial fluid of the ischemic myocardium.     

Beraprost sodium enhances neovascularization in ischemic myocardium by mobilizing bone marrow cells in rats

Beraprost sodium, an orally active prostacyclin analogue, has vasoprotective effects such as vasodilation and antiplatelet activities. We investigated the therapeutic potential of beraprost for myocardial ischemia. Immediately after coronary ligation of Sprague-Dawley rats, beraprost (200 microg/kg/day) or saline was subcutaneously administered for 28 days. Four weeks after coronary ligation, administration of beraprost increased capillary density in ischemic myocardium, decreased infarct size, and improved cardiac function in rats with myocardial infarction. Beraprost markedly increased the number of CD34-positive cells and c-kit-positive cells in plasma. Also, four weeks after coronary ligation of chimeric rats with GFP-expressing bone marrow, bone marrow-derived cells were incorporated into the infarcted region and its border zone. Treatment with beraprost increased the number of GFP/von Willebrand factor-double-positive cells in the ischemic myocardium. These results suggest that beraprost has beneficial effects on ischemic myocardium partly by its ability to enhance neovascularization in ischemic myocardium by mobilizing bone marrow cells.     

Matching coronary blood flow to myocardial oxygen consumption.

At rest the myocardium extracts approximately 75% of the oxygen delivered by coronary blood flow. Thus there is little extraction reserve when myocardial oxygen consumption is augmented severalfold during exercise. There are local metabolic feedback and sympathetic feedforward control mechanisms that match coronary blood flow to myocardial oxygen consumption. Despite intensive research the local feedback control mechanism remains unknown. Physiological local metabolic control is not due to adenosine, ATP-dependent K(+) channels, nitric oxide, prostaglandins, or inhibition of endothelin. Adenosine and ATP-dependent K(+) channels are involved in pathophysiological ischemic or hypoxic coronary dilation and myocardial protection during ischemia. Sympathetic beta-adrenoceptor-mediated feedforward arteriolar vasodilation contributes approximately 25% of the increase in coronary blood flow during exercise. Sympathetic alpha-adrenoceptor-mediated vasoconstriction in medium and large coronary arteries during exercise helps maintain blood flow to the vulnerable subendocardium when cardiac contractility, heart rate, and myocardial oxygen consumption are high. In conclusion, several potential mediators of local metabolic control of the coronary circulation have been evaluated without success. More research is needed.     

Prolonged transient acidosis during early reperfusion contributes to the cardioprotective effects of postconditioning

We have previously reported that the prolonged transient acidosis during early reperfusion mediates the cardioprotective effects in canine hearts. Recently, postconditioning has been shown to be one of the novel strategies to mediate cardioprotection. We tested the contribution of the prolonged transient acidosis to the cardioprotection of postconditioning. Open-chest anesthetized dogs subjected to 90-min occlusion of the left anterior descending coronary artery and 6-h reperfusion were divided into four groups: 1) control group; no intervention after reperfusion (n = 6); 2) postconditioning (Postcon) group; four cycles of 1-min reperfusion and 1-min reocclusion (n = 7); 3) Postcon + sodium bicarbonate (NaHCO(3)) group; four cycles of 1-min reperfusion and 1-min reocclusion with the administration of NaHCO(3) (n = 8); and 4) NaHCO(3) group; administration of NaHCO(3) without postconditioning (n = 6). Infarct size, the area at risk (AAR), collateral blood flow during ischemia, and pH in coronary venous blood were measured. The phosphorylation of Akt and extracellular signal-regulated kinase (ERK) in ischemic myocardium was assessed by Western blot analysis. Systemic hemodynamic parameters, AAR, and collateral blood flow were not different among the four groups. Postconditioning induced prolonged transient acidosis during the early reperfusion phase. Administration of NaHCO(3) completely abolished the infarct size-limiting effects of postconditioning. Furthermore, the phosphorylation of Akt and ERK in ischemic myocardium induced by postconditioning was also blunted by the cotreatment of NaHCO(3). In conclusion, postconditioning mediates its cardioprotective effects possibly via prolonged transient acidosis during the early reperfusion phase with the activation of Akt and ERK.     

Retrograde coronary venous perfusion at low pressure

The effectiveness of localized retrograde coronary venous perfusion (RCVP) in preventing or reversing myocardial ischemia after acute ligation of a coronary artery is described. Ten domestic pigs (Group I) underwent aorto left anterior coronary vein grafting with RCVP at systemic pressure. In another set of ten pigs (Group II), the coronary vein was similarly grafted, but the proximal end of the graft was perfused with oxygenated blood by means of an external pump at reduced pressure and flow. In both groups, RCVP successfully reversed the mechanical or electrical effects produced by 2 to 5 minutes of acute arterial ligation. After several hours, Group I animals showed evidence of acute ischemia and developing infarction. Group II animals, however, were maintained for 7 hours or more with regional RCVP and no evidence of ischemia. Retrograde coronary venous perfusion at reduced pressure may be more effective than perfusion at systemic pressure in providing myocardial blood flow.