Correlation of morphological variables in the coronary atherosclerotic plaque with clinical patterns of ischemic heart disease

The frequency and severity of "morphological" variables (fibrosis, proteoglycan accumulation, atheroma, intimal vascularization, calcification, acute intimal hemorrhage, and both adventitial and intimal lymphoplasmacellular infiltrates) in atherosclerotic plaques were related to plaque type, percentage of lumen reduction, plaque length, and intimal and medial thickness in 3,640 coronary artery sections sampled at the site of maximal lumen reduction in 8 selected segments from 100 cases of acute myocardial infarct, 50 of chronic angina, 208 of unexpected sudden coronary death with or without prodromata, and from 97 normal subjects dying accidentally. Morphological variables were occasionally observed in 1,519 sections with no lumen reduction. They were found only in sections from ischemic patients. With increasing luminal stenosis and intimal thickness, progression of the coronary plaque seemed to start as a fibrous change followed by proteoglycan accumulation in the deeper portion of the fibrous intima. Proteoglycan deposits appeared as a recurrent phenomenon. In them, atheroma or calcification develop. Intimal hemorrhage was a less frequent variable. It was found mainly in a vessel supplying an infarcted area. Lymphoplasmacellular inflammation correlated mainly with proteoglycan accumulation and atheroma, both showing a parallel increase with increasing intimal thickness and lumen reduction. No correlation was found between plaque variables and sex, age, heart weight, and infarct size. Significant variations in the distribution of plaque variables were observed among hearts of patients in the ischemic groups and between them and controls. In particular, inflammatory reaction was significantly more frequent and severe in ischemic groups than in controls, independent of the degree of coronary stenosis. Coagulative myocytolysis (contraction band necrosis), found in the majority of ischemic patients, correlated with the inflammatory reaction in supplying vessels. A peculiar tropism of mononuclear cell infiltrates for adventitial nerve structures was found. As a result, we question whether this inflammation may trigger coronary spasm and/or coagulative myocytolysis ("active" plaque vs "inactive" plaque).     

人冠状动脉壁组织结构增龄性变化的研究

目的：探讨人冠状动脉壁随年龄变化的形态学改变，为心血管病临床提供形态学资料。方法：33例经福尔马林固定后的正常男性尸体，在左冠状动脉前室间支（以下简称冠状动脉）起始部横断取材，常规石蜡包埋切片，HE和Verhoeff氏铁苏木精染色，光镜观察及图像定量分析。结果：随年龄增长，冠状动脉内膜面积与中膜面积均逐渐增大。各年龄组，心肌侧内膜厚度均大于胸壁侧。内膜面积与内弹力膜周长等价圆面积的百分数与腔面积／截面积值之间呈线性负相关。结论：冠状动态壁最重要的年龄变化是内膜增厚，这种增厚是不均匀的，其中心肌侧内膜厚度大于胸壁侧。评价冠状动脉狭窄程度，内膜面积占内弹力膜周长等价圆面积的百分数是一良好指标。     

Structural Changes Within the Media of Coronary Arteries Related to Intimal Thickening

From observations on 454 coronary arteries from subjects ranging in age from prematurely newborn to 90 years, six structural patterns of medial smooth muscle are interpreted as representing, or related to, the proliferation and/or migration of medial smooth muscle into intima. By measuring the extent of inner medial circumference occupied by four of the six patterns, it was possible to calculate a numerical value designated the medial proliferatice and / or migratory activity (MP-MA) of each artery. During the first three decades, nonatherosclerotic diffuse intimal thickening was the characteristic intimal process, and during this phase of the arterial maturation span, the MP-MA of the arteries was significantly related to the degree of intimal thickening. Following a peak MP-MA level by the end of the third decade, there was a progressive decrease in the MP-MA level as the incidence and severity of atherosclerotic intimal thickening increased. At advanced stages of atherosclerotic intimal thickening, which were associated with thinning of adjacent media, intimal-medial structural patterns indicating a relationship between medial smooth muscle proliferative activity and the expanding atherosclerotic plaque were also apparent. The observations support the concept that the movement of medial smooth muscle into intima is a critical step preceding and during the evolution of the atherosclerotic plaque.     

锁骨下动脉、颈总动脉和椎动脉分叉处血流动力学数值模拟

目的:探讨锁骨下动脉、颈总动脉和椎动脉分叉处的血流动力学特性,分析该处发生血管狭窄引起大脑供血不足的 血流动力学原因。方法:采用内蒙古民族大学附属医院神经内科提供的CT数据,应用医学建模软件MIMICS20.0将患者 二维CT数据进行三维血管重建,经过网格划分及边界条件设置后导入计算流体力学软件FLUENT14.5中。计算和分析 不同血液入口速度的锁骨下动脉、颈总动脉和椎动脉分叉处的血流动力学特性。结果:在血液入口速度不同的情况下,锁 骨下动脉、颈总动脉和椎动脉分叉处的血液流场分布、血液压力分布和血管壁面切应力分布有显著变化。在血液入口速 度增大时,锁骨下动脉分叉处和颈总动脉分叉处的血液流速快、血管壁压力大,颈总动脉内侧血管壁面切应力大,但锁骨 下动脉分叉处和颈总动脉分叉处血管壁面切应力数值和变化幅度小,属于低切应力区。结论:通过血流动力学数值模拟 研究,分析锁骨下动脉、颈总动脉和椎动脉分叉处易发生粥样斑块病变导致大脑供血不足的血流动力学原因。     

A sequential ultrastructural study of different arteries in the hypertensive rat

Hypertensive vascular disease was induced in rats using weekly injections of deoxycorticosterone and substituting 1% sodium chloride for tap water to drink. The emphasis of the study was on the progression and comparative aspects of alterations produced in the large clastic vessels and the coronary artery.One of the carliest alterations was observed in the intima of all vascular segments. These were characterized by endothelial cell enlargement and a gradual subendothelial accumulation of granular material leading to intimal thickening. In the later stages of the disease, mononuclear cells, fibrin and smooth muscle cells were present within the intima, with the exception of the coronary artery; only smooth muscle cells were seen in the intimal portion of this vessel.Early changes in the media consisted of smooth muscle hypertrophy and widened lamellar units, resulting in increased thickness of the vessel wall. These alterations progressed to include variation in the shape of smooth muscle cells, increasing disorganization of the cellular arrangement, focal cytoplasmic necrosis, and the loss of entire smooth muscle cells.A definite regional difference in susceptibility of individual mural components to hypertensive damage was noted. The most striking feature of this difference was demonstrated by the relatively early, severe involvement of the media of the coronary artery, in contrast to the other arteries examined.These alterations may be initiated by increased intraluminal pressure. In the case of the coronary artery, failure of this vessel to adapt effectively to increased mural tension by structural re-modelling of the arterial wall, may exacerbate these alterations.     

The natural history of collagen and alpha-actin expression after coronary angioplasty.

BACKGROUND: Restenosis after percutaneous transluminal coronary angioplasty (PTCA) is a result of remodeling and deposition of new mass. The new mass is formed by invading and replicating cells and by extracellular matrix (ECM), of which collagens constitute the dominating component. Smooth muscle actin is an important element in cell contraction. We tested the hypothesis that the accumulation of collagen and actin correlates with the development of postinjury luminal narrowing. METHODS AND RESULTS: Thirty-five pigs underwent balloon angioplasty and were killed 0, 1, 4, 7, 14, 28, and 56 days later. Tissue samples from the left circumflex artery were in paraffin, sectioned, and immunostained for Collagen Types I and III and alpha1-smooth muscle actin. Collagen accumulation was measured separately in intima, media, and adventitia using computerized semiautomatic planimetry. The injury produced a strong healing response, with a marked accumulation of collagen in all three vessel wall layers. However, the accumulation in adventitia began surprisingly early (1 to 4 days after PTCA) and stopped at Day 7, i.e., before luminal narrowing occurred (14 to 28 days after PTCA in our model). Furthermore, a conspicuous accretion of collagen occurred in the injured area of the medial layer. This response attenuated 14 days after PTCA. Neointimal collagen accumulation took place parallel to neointima formation 2 to 4 weeks after injury. Extramedial smooth muscle actin occurred predominantly from Days 4 to 14 in neointima. Only small quantities of actin were observed in the (neo-)adventitia. Furthermore, adventitial actin was a temporary phenomenon that disappeared between Days 14 and 28. CONCLUSION: Adventitial and medial collagen deposition apparently occurs before luminal narrowing, indicating that the bulk of new mass in adventitia and media is not the cause of vessel remodeling, but possibly stabilizes the vessel wall and impairs compensatory outward remodeling. The accumulation of actin-positive cells and collagen takes place in neointima parallel to luminal narrowing, which suggests that a contraction within the neointimal mass may contribute to the remodeling process.     

A pathological study of dissecting aneurysm in individuals under forty years of age including a case of a 13 years old boy

The author has investigated grossly and microscopically 12 cases (5 males and 7 females) of dissecting aneurysm in individuals under 40 years of age, autopsied during the last 6 years at the Tokyo-to Medical Examiner Office. They composed of 6 cases of Marfan's syndrome, 3 cases of obesity, and one case each of pregnancy, aortitis syndrome, and male pseudohermaphroditism, respectively. The 6 cases other than Marfan's syndrome were also thought to belong to the Marfan group from the gross and microscopic examinations of the aorta. As to the cases of dissecting bleeding of the aorta, Erdheim's idiopathic cystic medial necrosis was as a rule authentical up to date, but the author has never observed the bleeding within the cysts which were said to be formed due to accumulation of metachromatic ground substance. On the contrary, the medial bleeding occurred always in the weakened area in where the elastic fibers were disrupted and disappeared accompanying with the diminution of metachromatic substance. The author assumed that the diminution of metachromatic substance might be the most important etiologic factor of dissecting bleeding of the media and the extension of dissection might occur along such weakened foci of the media.     

A PATHOLOGICAL STUDY OF DISSECTING ANEURYSM IN INDIVIDUALS UNDER FORTY YEARS OF AGE INCLUDING A CASE OF A 13 YEARS OLD BOY

The author has investigated grossly and microscopically 12 cases (5 males and 7 females) of dissecting aneurysm in individuals under 40 years of age, autopsied during the last 6 years at the Tokyo-to Medical Examiner Office. They composed of 6 cases of Marfan's syndrome, 3 cases of obesity, and one case each of pregnancy, aortitis syndrome, and male pseudohermaphroditism, respectively. The 6 cases other than Marfan's syndrome were also thought to belong to the Marfan group from the gross and microscopic examinations of the aorta. As to the cases of dissecting bleeding of the aorta, Erdheim's idiopathic cystic medial necrosis was as a rule authentical up to date, but the author has never observed the bleeding within the cysts which were said to be formed due to accumulation of metachromatic ground substance. On the contrary, the medial bleeding occurred always in the weakened area in where the elastic fibers were disrupted and disappeared accompanying with the diminution of metachromatic substance. The author assumed that the diminution of metachromatic substance might be the most important etiologlc factor of dissecting bleeding of the media and the extension of dissection might occur along such weakened foci of the media.     

Strain-dependent vascular remodeling phenotypes in inbred mice

We have recently established a mouse model of arterial remodeling in which flow in the left common carotid artery of FVB mice was interrupted by ligation of the vessel near the carotid bifurcation, resulting in a dramatic reduction of the lumen as a consequence of a reduction in vessel diameter and intimal lesion formation. In the present study we applied this model to various inbred strains of mice. Wide variations in the remodeling response with regard to reduction in vessel diameter, intimal lesion formation, lumen area, and medial hypertrophy were found. On carotid artery ligation SJL/J mice revealed the most extensive inward remodeling leading to an approximate 78% decrease in lumen area while lumen narrowing in FVB/NJ mice was largely due to extensive neointima formation as a result of smooth muscle cell (SMC) proliferation. Significant positive remodeling in the contralateral right carotid artery with a >20% increase in lumen area was observed in SM/J and A/J mice. An in vitro comparison of growth properties of SMC isolated from FVB/NJ mice and a strain that exhibited very little SMC proliferation (C3H/HeJ) demonstrated accelerated growth of SMC from FVB/NJ following serum stimulation. In vivo, SMC proliferation in the FVB/NJ strain was preceded by a 37% loss of medial SMC occurring within the 2 days after ligation, however, cell death was not detectable in C3H/HeJ mice. These findings suggest that the mechanisms leading to lumen narrowing in the vascular remodeling process are genetically controlled.     

Expression of lumican in thickened intima and smooth muscle cells in human coronary atherosclerosis

Lumican is a member of a small leucine-rich proteoglycan family. Members of this family play an important role in cell migration and proliferation during embryonic development, tissue repair, and tumor growth. Lumican is reported to be overexpressed during the wound-healing process in the cornea and ischemic and reperfused heart. Recently, we found that lumican mRNA and its protein are expressed in cultured vascular smooth muscle cells (VSMCs) from the rat aorta. However, the expression and role of lumican in human atherosclerotic tissues are not clearly elucidated. In the present study, we aimed to clarify whether lumican is expressed in VSMCs and its localization in human coronary atherosclerotic tissues. The lumican protein and its mRNA were expressed in a small number of VSMCs in the media of normal coronary artery, but the lumican protein was not localized in the medial stroma. In contrast, the lumican protein and its mRNA were expressed in most of VSMCs that migrated into the thickened intima, but not in infiltrating foamy macrophages. The lumican protein was prominently localized in the thickened intimal stroma. The lumican protein and its mRNA were also expressed in VSMCs in the inner layer of the media and its protein was localized in medial stromal tissues. These findings indicate that the lumican protein is mainly synthesized by intimal and medial VSMCs in coronary atherosclerosis and that lumican contributes to collagen fibrillogenesis of coronary atherosclerosis.     

Hypoplasia of left vertebral artery with intimal fibromuscular dysplasia in a Korean woman

We found a case of hypoplasia of vertebral artery with fibromuscular dysplasia in an 82-yr-old Korean female cadaver during a routine dissection course. In the present case, intracranial hypoplasia in left vertebral artery and bilateral origin of posterior inferior cerebellar artery at the vertebrobasilar junction were recognized. Histopathologically, left vertebral artery showed intimal type of fibromuscular dysplasia both in its extracranial and intracranial courses. These results indicate that the association of fibromuscular dysplasia and hypoplasia does exist in the vertebral artery, although the etiologies are not verified yet.     

Early changes of experimentally induced cerebral aneurysms in rats. Light-microscopic study.

The changes of the anterior cerebral artery/olfactory artery junction, one of the favorite sites of aneurysm formation, in rats treated with unilateral ligation of the common carotid artery and renal hypertension were investigated by light microscopy. The initial changes of aneurysm occurred not at the apex itself, but on the distal side of the major branch adjacent to the apex, at the intimal pad and the neighboring distal portion. Here the internal elastic lamina showed various degenerative changes and disappearance. The neighboring distal portion adjacent to the intimal pad showed a shallow depression associated with a thinning of the media due to a decrease of medial smooth muscle cells in number even in some control animals. Such degenerative changes of the internal elastic lamina and medial smooth muscle cells caused by hemodynamic stress due to branching structure, including intimal pads, augmented by the experimental treatment, are supposed to be the basis for aneurysm formation.     

The initiation of intimal thickening in human arteries

To obtain more detailed information about the relationship of intimal thickening to defects in the elastin structure of the arterial wall, the internal elastic lamina and subsequent elastin formation in the intima was studied by very oblique sectioning of paraffin sections of the arterial wall, and by scanning electron microscopy of formic acid digested preparations. Comparison was made in the same subject between the internal thoracic artery (a vessel showing only slight intimal thickening) and the anterior descending coronary (which usually develops advanced intimal thickening). There was no evidence of penetration of the normal fenestrations of the internal elastic lamina by medial smooth muscle cells. This took place through major defects of this lamina and resulted in a change from transverse to longitudinal orientation of these cells and the accompanying elastin fibers of the intima. A further condensation of elastin (greater for the internal thoracic) occurred in the intima subjacent to the endothelial cells.     

Vascular collagen fibril morphology in type IV Ehlers-Danlos syndrome

Morphometric analysis of transmission electron micrographs of blood vessel, skin and dura mater collagen fibers were performed on postmortem tissues taken from 28-year-old female with Ehlers-Danlos type IV syndrome (EDS IV). Vascular tissue from this patient was compared to 5 age- and sex-matched controls (age range 26-28 years). Our study revealed significant variation in collagen fibril diameter in the walls of almost all the vessels studied. In general, the EDS IV tissue showed a net decrease in average collagen fibril cross sectional area in arterial wall samples. This decrease was significant (p less than .05) across the entire wall of the renal artery, in the media of the carotid artery, and in the media and adventitia of the common iliac artery. Samples from the vena cava show significant increases in collagen fibril cross sectional area across the vessel wall (p less than .005). The only areas studied which did not show significant changes were the intimal and adventitial regions of the common carotid artery. The observed changes may be contributory to the decreased arterial wall strength typical of the syndrome.     

Method for maximising measurements of muscular pulmonary arteries.

Using a digitiser for assessing the media and intima of muscular pulmonary arteries, we have previously shown that the most sensible measurements are those of medial and intimal area and that artery size should be defined in terms of the total length of internal elastic lamina. These measurements do not vary with the collapse or constriction of the artery. A cross sectional cut and a well defined internal elastic lamina are essential for measurement using our technique. This study explores methods for obtaining the above three measurements for cross sectionally cut arteries with an ill defined internal elastic lamina, with a view to increasing the number of arteries measured. The methods were tested on three subjects, using arteries for which the true values of the three variables were known. Acceptable estimates of medial and intimal area could be obtained by simply delineating the boundaries of the intima and media and ignoring the crinkles in the elastic laminae. It was also found that muscular pulmonary arteries may not be uniformly collapsed or constricted round the circumference of their walls and that the overall degree of collapse or constriction seemed to be affected by the size of the artery. An acceptable estimate of the total length of an internal elastic lamina was most readily obtained by multiplying the length of the boundary between intima and media by a crinkle factor based on an optical assessment of the amount of crinkling in that internal elastic lamina.     

Injury and repair of smaller muscular and elastic arteries

Summary 26 rabbits of the Danish country strain were subjected to mechanical dilatation injury of the left femoral and carotid arteries with Fogarty's embolectomy catheters F2 and F3 respectively. The rabbits were killed 2, 7, 14 and 28 days after the dilatation injury and the arteries examined histologically. Initially both of the arteries exhibited necrosis of the media and infiltration of the vessel wall with neutrophils and mononuclear cells. From day 7, intimal thickening was observed in both types of arteries, progressing in thickness during the later stages. However, thrombosis occurred in the majority of the carotid arteries, whereas this was only infrequently seen in the femoral arteries. In all of the dilated arteries, the elastic laminas were stretched or fragmented and never regained their normal appearance. In the carotid artery, giant cells accumulated around the fragmented elastin and calcified areas, located primarily at the intima-medial border. These changes were never observed in the femoral artery. At the twenty-eight days stage, proliferation of the smooth muscle cells more or less led to restitution of the media in the femoral artery, whereas the carotid artery showed medial restitution only to a lesser extent. The similarities between the injured carotid artery and human temporal arteritis, and the utility of the model as an animal model for the study of temporal arteritis are underlined.     

Administration of chronic intravenous platelet-activating factor induces pulmonary arterial atrophy and hypertension in rabbits

Platelet-activating factor (PAF), a lipid mediator of inflammation, was given by continuous intravenous infusion to rabbits for 2, 4, and 8 weeks, and morphologic and hemodynamic findings were correlated. Pulmonary arterial pressure (PAP), cardiac output, and right atrial pressure were measured, and total pulmonary resistance was calculated. In cross-sections of intraparenchymal pulmonary arteries, internal elastic lamina circumference and intimal and medial areas were measured. The ratio of the weight of the right ventricle to the weight of the left ventricle plus septum, and alveolar/artery ratios were also obtained. In bronchoalveolar lavage fluid, total and differential cell counts were determined. After 2 weeks of PAF treatment, PAP rose by 4 mm Hg. The increase in PAP became significant by 4 weeks and remained so at 8 weeks of treatment. Total pulmonary resistance nearly doubled by 2 weeks and continued to be elevated throughout 8 weeks of PAF treatment. Cardiac output fell significantly to 0.26 liters/minute at 2 weeks of PAF treatment and remained low at 4 weeks. By 8 weeks of treatment, it normalized. The significant rise in total pulmonary resistance at 2 and 4 weeks correlated with the rise in PAP and the fall in cardiac output. The alveolar/artery ratio was increased at 2 weeks of treatment and progressively increased at 4 and 8 weeks, reaching statistical significance at 8 weeks. In intra-acinar arteries, after 2 weeks of treatment, there was a reduction in total cross-sectional area (within the external elastic lamina), medial area, and internal elastic lamina circumference measured by computerized image analysis of 5-microns thick Verhoeff Van Gieson-stained sections. Changes in total area, medial area, and internal elastic lamina circumference persisted after 4 and 8 weeks of treatment. In preacinar arteries, similar changes occurred that were significant only after 8 weeks of treatment. Other findings apparent at 2 weeks of treatment included right ventricular hypertrophy and a marked decline in the number of macrophages and lymphocytes recovered from bronchoalveolar lavage fluid. We conclude that chronic intravenous infusion of PAF in rabbits induces remodeling of pulmonary arteries, specifically reduction of the internal elastic lamina, with consequent narrowing of arterial lumens producing increased pulmonary vascular resistance and pulmonary hypertension. We attribute the increase in alveolar/artery without evident vessel obliteration, to a shortening of arterial length, which is of insufficient magnitude to overcome the effect of vessel narrowing on vascular resistance.     

Pathological changes in cerebral arteries following experimental subarachnoid hemorrhage: role of blood platelets

The role of blood platelets in producing early intimal changes in cerebral arteries following subarachnoid hemorrhage (SAH) was examined by using 18 cats. Experimental SAH was produced by a rupture of the proximal portion of the right middle cerebral artery. Following SAH, the scanning electron microscope revealed that structural alterations in the intimal layer of major cerebral arteries occurred as early as 2 hours and became more severe by 48 hours. Vascular alterations, which were predominantly detected in the ruptured vessel, consisted of endothelial cell corrugation, detachment, crater formation, intimal adhesion of platelets and red blood cells, intimal thrombi, and reendothelialization. When cats were pretreated prior to SAH with an anti-platelet-aggregating agent, OKY-1581, the intimal blood elements and thrombi were clearly reduced, and reendothelialization was not observed. However, endothelial cell changes in the OKY-1581-treated group were very similar to those occurring in the nontreated group. While these results suggest that bioactive substances contained within blood platelets, such as growth factors, serotonin, and norepinephrine, have little effect on producing endothelial cell injury, platelets may be important in the initiation of reendothelialization following vessel injury.     

Experimental cerebral atherosclerosis in the rabbit. Scanning electron microscopic study of the initial lesion site.

The development and initial lesion sites of cerebral atherosclerosis were studied in hypertensive rabbits fed 0.5 g/day cholesterol in their diet. The earliest lesions developed at remarkably localized areas of the basilar artery-posterior cerebral artery Y-bifurcation (area A) and vertebral arteries-basilar artery confluence (area B). These findings were obtained from a thorough scanning electron microscopic survey of the dorsal surface of the cerebral artery segment covering from the vertebral arteries to the posterior cerebral arteries. By light microscopy intimal lesions were mainly composed of accumulations of foam cells and smooth muscle cells. Electron microscopically foam cells accumulated in the intima resembled those of a monocyte-macrophage lineage. Early lesions involving only a few endothelial cells with adherent leukocytes occurred at the dividing and confluent portions of the endothelial arrays formed in areas A and B, respectively. The results indicate that hypertension coupled with hypercholesterolemia induces atherosclerosis in particular vulnerable regions of the cerebral arteries.     

丹参酮ⅡA纳米球对兔颈动脉球囊损伤后内膜增殖的抑制

制备丹参酮ⅡA纳米球．以用于观察局部灌注后对损伤血管内膜增殖的抑制。通过超声乳化法制备了PLGA包载的、载药量为1．55％土0．016％（mg／mg），平均粒径为119nm的丹参酮ⅡA纳米球，将其和空白纳米粒分别局部灌注于球囊损伤后的兔颈动脉内，对内膜增殖的情况进行分析。结果发现：28d丹参酮ⅡA纳米粒组与空白纳米粒组和动脉损伤模型组相比，内膜面积明显减少（P〈0．01）；空白纳米粒组与模型组的内膜面积比较，无明显变化（P=0．302）；内膜面积／中膜面积作为内膜增殖指数的指标，丹参酮ⅡA纳米粒组比动脉损伤模型组减少了39．7％。本实验成功地研制了丹参酮ⅡA纳米粒，局部灌注于内膜剥脱后的血管内，不仅证实了其组织相容性，而且显示出良好的局部摄取，以及显著抑制损伤血管内膜增殖的效应。