Vasculogenesis and angiogenesis: Extracellular matrix remodeling in coronary collateral arteries and the ischemic heart

Heart failure secondary to ischemic cardiomyopathy is the primary cause of cardiovascular mortality. The promise of the collateral circulation lies in its potential to alter the course of the natural history of coronary heart disease. The collateral circulation of the heart is responsible for supplying blood and oxygen to the myocardium at ischemic risk following severe stenosis and reduced vasoelasticity function of a major coronary artery. In response to flow, stress, and pressure, collateral vessels are restructured and remodeled. Vascular remodeling by its very nature implies synthesis and degradation of extracellular matrix components in the vessel wall. Under normal physiological conditions proteinases that break down the specialized matrix are tightly regulated by antiproteinases. The balance between proteinase and antiproteinase influences is discoordinated during collateral development which leads to adaptive changes in the structure, function, and regulation of extracellular matrix components in the vessel wall. The role of extracellular matrix components in coronary collateral vessel formation in a canine model of chronic coronary artery occlusion has been demonstrated. The role of matrix proteinases and antiproteinases in the collateral vessel play a significant role in the underlying mechanisms of collateral development. This review presents new and significant information regarding the role of extracellular matrix proteinases and antiproteinases in vascular remodeling, function, and collateral development. Such information will have a significant impact on the understanding of the basic biology of the vascular extracellular matrix turnover, remodeling, and function as well as on elucidating potential avenues for pharmacological approaches designed to increase collateral formation and optimize myocardial blood flow in the treatment of ischemic heart disease. J. Cell. Biochem. 65:388–394. © 1997 Wiley-Liss, Inc.     

The role fo collateral circulation in the course of coronary heart disease: 10-year clinical and angiographic follow-up

The paper presents the results of a 10-year prospective follow-up of 59 patients with coronary heart disease (CHD) concurrent with functional classes II-IV angina pectoris. Coronarography was made in all the patients whose coronary arteries and collateral blood flow were assessed. The experimental group comprised 37 patients with CHD and collateral circulatory insufficiency. The control group included 22 patients with effective collateral circulation. The experimental group showed a worse prognosis than did the control one. Myocardial infarction developed in 54 and 27% of cases, coronary heart disease mortality was 29.7 and 9% in the experimental and control groups, respectively. Effective collateral circulation is a prerequisite of successful surgical myocardial infarction.     

Effects of exercise training on coronary collateralization and control of collateral resistance

Coronary collateral vessels serve as a natural protective mechanism to provide coronary flow to ischemic myocardium secondary to critical coronary artery stenosis. The innate collateral circulation of the normal human heart is typically minimal and considerable variability occurs in extent of collateralization in coronary artery disease patients. A well-developed collateral circulation has been documented to exert protective effects upon myocardial perfusion, contractile function, infarct size, and electrocardiographic abnormalities. Thus therapeutic augmentation of collateral vessel development and/or functional adaptations in collateral and collateral-dependent arteries to reduce resistance into the ischemic myocardium represent a desirable goal in the management of coronary artery disease. Tremendous evidence has provided documentation for the therapeutic benefits of exercise training programs in patients with coronary artery disease (and collateralization); mechanisms that underlie these benefits are numerous and multifaceted, and currently under investigation in multiple laboratories worldwide. The role of enhanced collateralization as a major beneficial contributor has not been fully resolved. This topical review highlights literature that examines the effects of exercise training on collateralization in the diseased heart, as well as effects of exercise training on vascular endothelial and smooth muscle control of regional coronary tone in the collateralized heart. Future directions for research in this area involve further delineation of cellular/molecular mechanisms involved in effects of exercise training on collateralized myocardium, as well as development of novel therapies based on emerging concepts regarding exercise training and coronary artery disease.     

The pig as a model for myocardial ischemia and exercise

The pig has been well characterized as an appropriate model for the study of coronary physiology, the coronary collateral circulation and exercise physiology. We compared both Yucatan miniature swine and young farm pigs in experiments involving myocardial ischemia, infarction and exercise. The Yucatan pig was vigorous, docile and proved to be an appropriate model of coronary physiology and exercise in man. The exercise capacity of the Yucatan pig was greater than that of the similar weight Hampshire pig, apparently because of the higher hematocrit and larger heart size. Both breeds were able to increase their maximal oxygen consumption (VO2 max) by approximately 25% after 10 weeks of training. Experiments measuring maximal coronary capacity suggest that the vascular capacity was similar to that of man, but less than that of the dog. Acute occlusion of the coronary artery in pigs infarcted most of the tissue of the vascular bed at risk. The collateral circulation of the pig is less than one fourth that of the dog and is similar to that of man. Slow occlusion of the left circumflex coronary artery produces an ischemic vascular bed which is collaterally dependent with only 5% infarction. Collateral flow is sufficient to meet resting conditions, but during exercise, severe ischemia is unmasked. This ischemia is present for up to 16 weeks following occlusion. The observation of limited infarction in conjunction with limited collateral vessel development suggests that this is a good model for investigating the growth and development of coronary collateral circulation in man.     

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.     

lp-PLA2、RBP与冠心病病变程度相关性及其疾病诱发的危险因素分析

摘要 目的：研究脂蛋白磷脂酶A2（lp-PLA2）、视黄醇结合蛋白（RBP）与冠心病（CAD）病变程度的相关性及冠心病病变发生的危险因素。方法：以2019年12月至2021年12月在本院诊治的冠心病患者140例作为研究对象,所有患者均进行冠状动脉造影检查,并根据冠状动脉侧支循环形成情况进行分级。所有患者都给予血清lp-PLA2、RBP检测并进行相关性、危险因素分析。结果：在140例患者中,冠状动脉侧支循环未形成40例（对照组）,冠状动脉侧支循环形成100例（研究组）,研究组中Ⅰ级40例,Ⅱ级38例,Ⅲ级22例。研究组的血清lp-PLA2、RBP含量都高于对照组（P<0.05）;不同分级患者的血清lp-PLA2、RBP含量对比也有明显差异（P<0.05）。在冠心病患者中,Spearsman相关分析显示血清lp-PLA2、RBP含量与侧支循环形成分级存在正相关性（P<0.05）。logistic回归分析显示血清lp-PLA2、RBP含量均为影响冠心病患者侧支循环形成分级的危险因素（P<0.05）。ROC曲线分析显示血清lp-PLA2、RBP含量预测冠心病患者侧支循环分级的曲线下面积为0.891、0.805。结论：随着冠状动脉侧支循环形成,冠心病患者的血清lp-PLA2、RBP含量明显增加,lp-PLA2、RBP与侧支循环形成分级存在相关性,也是影响侧支循环分级的危险因素,也可预测侧支循环分级状况。     

Effects of the collateral circulation of the heart

Collateral circulation minimizes the myocardial injury which results from narrowing of a coronary artery. A large collateral circulation has disadvantages, however. It may divert so much of the limited blood flow through the adjacent nonarteriosclerotic coronary artery that the blood supply of the normal muscle supplied by that artery may be inadequate during heavy exercise. In the presence of a large collateral circulation, both the normal and ischemic regions of the heart may be extremely vulnerable to small arteriosclerotic changes narrowing the patent artery near the aorta. The effective increase in flow which results from arteriolar vasodilatation produced by drugs may be much greater in the presence of a small collateral circulation than a large one.     

Minimal effect of collateral flow on coronary microvascular resistance in the presence of intermediate and noncritical coronary stenoses

Depending on stenosis severity, collateral flow can be a confounding factor in the determination of coronary hyperemic microvascular resistance (HMR). Under certain assumptions, the calculation of HMR can be corrected for collateral flow by incorporating the wedge pressure (P(w)) in the calculation. However, although P(w) > 25 mmHg is indicative of collateral flow, P(w) does in part also reflect myocardial wall stress neglected in the assumptions. Therefore, the aim of this study was to establish whether adjusting HMR by P(w) is pertinent for a diagnostically relevant range of stenosis severities as expressed by fractional flow reserve (FFR). Accordingly, intracoronary pressure and Doppler flow velocity were measured a total of 95 times in 29 patients distal to a coronary stenosis before and after stepwise percutaneous coronary intervention. HMR was calculated without (HMR) and with P(w)-based adjustment for collateral flow (HMR(C)). FFR ranged from 0.3 to 1. HMR varied between 1 and 5 and HMR(C) between 0.5 and 4.2 mmHg·cm(-1)·s. HMR was about 37% higher than HMR(C) for stenoses with FFR < 0.6, but for FFR > 0.8, the relative difference was reduced to 4.4 ± 3.4%. In the diagnostically relevant range of FFR between 0.6 and 0.8, this difference was 16.5 ± 10.4%. In conclusion, P(w)-based adjustment likely overestimates the effect of potential collateral flow and is not needed for the assessment of coronary HMR in the presence of a flow-limiting stenosis characterized by FFR between 0.6 and 0.8 or for nonsignificant lesions.     

Influence of coronary collateral flow on coronary diagnostic parameters: An in vitro study

Functional severity of coronary stenosis is often assessed using diagnostic parameters. These parameters are evaluated from the combined pressure and/or flow measurements taken at the site of the stenosis. However, when there are functional collaterals operating downstream to the stenosis, the coronary flow-rate increases, and the pressure in the stenosed artery is altered. This effect of downstream collaterals on different diagnostic parameters is studied using a physiological representative in vitro coronary flow-loop.The three diagnostic parameters tested are fractional flow reserve (FFR), lesion flow coefficient (LFC), and pressure drop coefficient (CDP). The latter two were discussed in recent publications by our group (Banerjee et al., 2008, Banerjee et al., 2007, 2009). They are evaluated for three different severities of stenosis and tested for possible misinterpretation in the presence of variable collateral flows. Pressure and flow are measured with and without downstream collaterals. The diagnostic parameters are then calculated from these readings.In the case of intermediate stenosis (80% area blockage), FFR and LFC increased from 0.74 to 0.77 and 0.58 to 0.62, respectively, for no collateral to fully developed collateral flow. Also, CDP decreased from 47 to 42 for no collateral to fully developed collateral flow. These changes in diagnostic parameters might lead to erroneous postponement of coronary intervention. Thus, variability in diagnostic parameters for the same stenosis might lead to misinterpretation of stenosis severity in the presence of operating downstream collaterals.     

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。     

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 coronary circulation in exercise training

Exercise training (EX) induces increases in coronary transport capacity through adaptations in the coronary microcirculation including increased arteriolar diameters and/or densities and changes in the vasomotor reactivity of coronary resistance arteries. In large animals, EX increases capillary exchange capacity through angiogenesis of new capillaries at a rate matched to EX-induced cardiac hypertrophy so that capillary density remains normal. However, after EX coronary capillary exchange area is greater (i.e., capillary permeability surface area product is greater) at any given blood flow because of altered coronary vascular resistance and matching of exchange surface area and blood flow distribution. The improved coronary capillary blood flow distribution appears to be the result of structural changes in the coronary tree and alterations in vasoreactivity of coronary resistance arteries. EX also alters vasomotor reactivity of conduit coronary arteries in that after EX, α-adrenergic receptor responsiveness is blunted. Of interest, α- and β-adrenergic tone appears to be maintained in the coronary microcirculation in the presence of lower circulating catecholamine levels because of increased receptor responsiveness to adrenergic stimulation. EX also alters other vasomotor control processes of coronary resistance vessels. For example, coronary arterioles exhibit increased myogenic tone after EX, likely because of a calcium-dependent PKC signaling-mediated alteration in voltage-gated calcium channel activity in response to stretch. Conversely, EX augments endothelium-dependent vasodilation throughout the coronary arteriolar network and in the conduit arteries in coronary artery disease (CAD). The enhanced endothelium-dependent dilation appears to result from increased nitric oxide bioavailability because of changes in nitric oxide synthase expression/activity and decreased oxidant stress. EX also decreases extravascular compressive forces in the myocardium at rest and at comparable levels of exercise, mainly because of decreases in heart rate and duration of systole. EX does not stimulate growth of coronary collateral vessels in the normal heart. However, if exercise produces ischemia, which would be absent or minimal under resting conditions, there is evidence that collateral growth can be enhanced. While there is evidence that EX can decrease the progression of atherosclerotic lesions or even induce the regression of atherosclerotic lesions in humans, the evidence of this is not strong due to the fact that most prospective trials conducted to date have included other lifestyle changes and treatment strategies by necessity. The literature from large animal models of CAD also presents a cloudy picture concerning whether EX can induce the regression of or slow the progression of atherosclerotic lesions. Thus, while evidence from research using humans with CAD and animal models of CAD indicates that EX increases endothelium-dependent dilation throughout the coronary vascular tree, evidence that EX reverses or slows the progression of lesion development in CAD is not conclusive at this time. This suggests that the beneficial effects of EX in CAD may not be the result of direct effects on the coronary artery wall. If this suggestion is true, it is important to determine the mechanisms involved in these beneficial effects.     

中性粒细胞与淋巴细胞比值和冠心病的关系

炎性作用在心血管疾病中的作用越来越重要,尤其是炎性标记物与冠心病之间的相互作用及关系,近年来被广泛研究,大多研究结果呈现一致性。中性粒细胞与淋巴细胞比值是近些年新兴的炎症标记物,其简易、普及、易获取的特点受到了广泛学者的肯定。NLR与动脉粥样硬化相关,相关研究显示动脉僵硬度、钙化积分与NLR密切相关,另外,高NLR者更易发现易损斑块。NLR可预测急性冠脉综合征的短期及长期心血管事件发生率及死亡率,以及预测稳定性心绞痛预后情况及侧支循环是否丰富。在冠脉造影的应用中,发现NLR不仅与冠脉病变严重程度密切相关,能预测完全闭塞病变的发生,及预测无复流的发生。在已有心血管危险因素的基础上,NLR可作为新成员,为冠心病的发现及其预后的风险评价提供依据。     

Porcine coronary collateral formation in the absence of a pressure gradient remote of the ischemic border zone

In the current paradigm on coronary collateral development, it is assumed that these vessels develop consequentially from increased fluid shear stress (FSS) through preexisting collateral arteries. The increased FSS follows from an increase in pressure gradient between the region at risk and well-perfused surroundings. The objective of this study was to test the hypothesis that, in the heart, collateral connections can form in the absence of an increased FFS and consequentially at any depth and region within the ventricular wall. In Yorkshire pigs, gradual left circumflex coronary artery occlusion was obtained over 6 wk by an ameroid constrictor, whereas the control group underwent a sham operation. Hearts were harvested and subsequently processed in an imaging cryomicrotome, resulting in 40-μm voxel resolution three-dimensional reconstructions of the intramural vascular vessels. Dedicated software segmented the intramural vessels and all continuous vascular pathways containing a collateral connection. In the ameroid group, 192 collaterals, 22-1,049 μm in diameter, were detected with 62% within the subendocardium. Sixty percent of collaterals bridged from the left anterior descending artery to left circumflex coronary artery. A novel result is that 25% (n = 48) of smaller-radius collaterals (P = 0.047) connected with both origin and terminus in the nontarget area where perfusion was assumed uncompromised. In the porcine heart, collateral vessels develop not only in ischemic border zones with increased FSS but also away from such border zones where increased FSS is unlikely. The majority of collaterals were located at the subendocardium, corresponding to the region with highest prevalence for ischemia.     

Anomalous course and branches of human coronary arteries

132 hearts obtained from cadavers were dissected in order to study anomalies in the course and branches of human coronary arteries. Only in 1 heart was a deviation of the circumflex branch of the left coronary artery taking a course inferior to the coronary sulcus observed. The right coronary artery travelled the entire length of the coronary sulcus on the back of the heart and gave both a posterior ventricular and a collateral branch. Circumflex branches of the right and left coronary arteries did not anastomose.     

Use and limitations of magnetic resonance phase-contrast assessment of coronary flow reserve in a model of collateral dependence

Phase-contrast magnetic resonance imaging (PC-MRI) is useful for assessing coronary artery flow reserves (CFR) in man and acute animal models with intermediate coronary lesions. The present study examines the use of PC-MRI for assessing CFR in a model with critical stenosis and collateral dependence. PC-MRI quantitative flow measurements from the proximal left anterior descending (LAD) and left circumflex (LCX) coronary arteries were compared with myocardial tissue perfusion reserve measurements (microsphere techniques) after placement of a 2.25-mm ameroid constrictor on the proximal LCX in a porcine model; measurements were obtained at implantation (n = 4) and at 3 to 4 weeks (n = 4) and 6 weeks (n = 5) postimplantation. CFR is defined as the ratio of maximal hyperemic flow to baseline flow. Hyperemia was induced using intravenous adenosine (140 mg/kg/min). Collateral dependence in the LCX distri bution was evidenced by angiographic findings of critical stenosis with minimal myocardial histological changes and normal baseline myocardial perfusion (microsphere techniques). In this setting, PC-MRI CFR was correlated with microsphere measures of perfusion reserve. Collateral dependence was confirmed by Evan's blue dye injection. This study provides angiographic, myocardial perfusion, and histological correlates associated with PC-MRI epicardial CFR changes during chronic, progressive coronary artery constriction. It also demonstrates the disparity between epicardial and myocardial measures of coronary flow reserve with collateral dependence and the caveats for PC-MRI use in models of progressive coronary constriction.     

Effects of exercise on collateral development in myocardial ischemia in pigs

To study the effects of exercise on collateral development in myocardial ischemia, we induced coronary arterial stenosis of the left circumflex coronary artery (LCCA) in 18 of 30 pigs. During that surgery, we identified the coronary bed at risk. Nine of these pigs were then subjected to 5 mo of exercise training on a treadmill. After exercise training, we determined regional collateral and myocardial blood flow using radiolabeled microspheres. At autopsy, all animals had complete occlusion of the LCCA. Infarct size in the exercise-trained pigs was significantly less than in the sedentary pigs (5.9 +/- 1.0 vs. 11.7 +/- 1.0% of the left ventricle). The exercise-trained animals had a greater increase in collateral flow, 35.1 +/- 3.0 vs. 28.7 +/- 4.1 ml X min-1 X 100 g-1, in the noninfarcted jeopardized zone of the LCCA bed. The major findings of the study were the following: 1) chronic coronary artery stenosis progressing to occlusion stimulated development of the collateral circulation and salvaged tissue in the jeopardized myocardium of an animal model with sparse collaterals; 2) development of the collateral circulation and tissue salvage is increased by exercise training; 3) collaterals develop primarily in or near the ischemic zone; and 4) all collateral beds develop a circumferential flow gradient following occlusion.     

Progression of myocardial injury during coronary occlusion in the collateral-deficient heart: a non-wavefront phenomenon

It is widely accepted that, during acute coronary occlusion, ischemic cell death progresses from the subendocardium to the subepicardium in a wavefront fashion. This concept, which implies that the subendocardium is the most susceptible myocardial region to ischemic injury, was established using a canine model with an extensive system of subepicardial coronary collaterals. In humans, particularly in those with coronary artery disease, there is a wide range in the distribution and functional capacity of the collateral circulation, which may affect the pattern of infarct evolution. Using an ovine model with a limited system of preformed subendocardial coronary collaterals, we characterized the effect of increasing lengths of ischemia on regional blood flow and infarct size in three regions of the ventricular wall: subendocardium, midmyocardium, and subepicardium. Our results demonstrate that the myocardium and microvasculature in these three regions are equally susceptible to injury after 45 min of ischemia. When ischemic time is increased to 1 h, infarct size in the midmyocardium (90 +/- 2%) is greater than in the subendocardium (76 +/- 4%, P = 0.004) and subepicardium (84 +/- 3%, P = 0.13). Microvascular dysfunction as assessed as a percentage of baseline flow is also greater in the midmyocardium (14 +/- 5%) compared with the subendocardium (20 +/- 3%, P = 0.23) and subepicardium (51 +/- 9%, P = 0.007). These findings suggest that, in subjects with a limited system of coronary collateral circulation, the midmyocardium is the most susceptible myocardial region to ischemia and the subendocardium is the most resistant. Myocardial viability during coronary occlusion appears to be primarily determined by the distribution and functional capacity of the collateral circulation.     

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.     

Acetaminophen and myocardial infarction in dogs

The hypothesis that acetaminophen can reduce necrosis during myocardial infarction was tested in male dogs. Two groups were studied: vehicle- (n=10) and acetaminophen-treated (n=10) dogs. All dogs were obtained from the same vendor, and there were no significant differences in their ages (18 +/- 2 mo), weights (24 +/- 1 kg), or housing conditions. Selected physiological data, e.g., coronary blood flow, nonspecific collateral flow, epicardial temperature, heart rate, systemic mean arterial pressure, left ventricular developed pressure, the maximal first derivative of left ventricular developed pressure, blood gases, and pH, were collected at baseline and during regional myocardial ischemia and reperfusion. There were no significant differences in coronary blood flow, nonspecific collateral flow, epicardial temperature, heart rate, systemic mean arterial pressure, or blood gases and pH between the two groups at any of the three time intervals, even though there was a trend toward improved function in the presence of acetaminophen. Infarct size, the main objective of the investigation, was markedly and significantly reduced by acetaminophen. For example, when expressed as a percentage of ventricular wet weight, infarct size was 8 +/- 1 versus 3 +/- 1%(P <0.05) in vehicle- and acetaminophen-treated hearts, respectively. When infarct size was expressed as percentage of the area at risk, it was 35 +/- 3 versus 13 +/- 2% (P <0.05) in vehicle- and acetaminophen-treated groups, respectively. When area at risk was expressed as percentage of total ventricular mass, there were no differences in the two groups. Results reveal that the recently reported cardioprotective properties of acetaminophen in vitro can now be extended to the in vivo arena. They suggest that it is necessary to add acetaminophen to the growing list of pharmaceuticals that possess cardioprotective efficacy in mammals.