Restenosis after percutaneous transluminal coronary angioplasty--a histopathological study using autopsied hearts

Restenosis was studied histopathologically by serial step sectioning of 22 coronary arteries from 21 patients in whom percutaneous transluminal coronary angioplasty (PTCA) had been performed (9 arteries from patients who had died shortly after PTCA and 13 from those who had died considerably later). Nine of the 13 arteries from the patients who had died long after PTCA were immunohistochemically stained using anti-actin antibody for examination of spindle-shaped cells proliferating in the intima. In the patients who had died shortly after PTCA, all 9 arteries showed fresh thrombus formation. In the patients who had died considerably later after PTCA, however, there was fragmentation of the internal elastic lamina (IEL) in 9 arteries. In each of these 9 arteries, a remarkable proliferation of intimal cells was observed on the intimal side, mainly at the site of the IEL fragmentation. These spindle-shaped cells were identified as smooth muscle cells (SMC) because they stained reddish-brown with Masson's trichrome, and because immunohistochemical staining with anti-actin antibody was also positive. In 2 arteries, proliferation of SMC and elastic fibers was observed on the luminal side of the intima, despite absence of fragmentation in the IEL. Proliferation of SMC in false lumens was identified in 2 patients with medial dissection. From the above findings, the following 4 forms of restenosis after PTCA have been identified: 1. thrombus formation; 2. proliferation of SMC on the intimal side, mainly around fragmentation in the IEL; 3. proliferation of SMC on the luminal side of the intima where there was no fragmentation of the IEL; and 4. proliferation of SMC in dissected false lumen. The proliferation of SMC on the intimal side of the disrupted IEL was thought to have been a result of migration of SMC from the media to the intima, because SMC proliferation was seen around the disrupted region.     

The intima of human coronary arteries

Intimal thickness relative to that of the media (r) was measured in coronary and internal mammary arteries from 300 human subjects. Whereas this ratio remained low (less than 0.17) in the mammary arteries, coronary arteries showed progressive intimal thickening (r = 4.10 by 60 years). The intimal surfaces of 70 pairs of arteries were compared by light, transmission, and scanning electron microscopy. The mammary arteries had a continuous endothelial lining, but the coronary arteries showed incomplete coverage of the thickened intima. In affected vessels the endothelial cells showed loss of attachment to adjacent cells and to the underlying tissue. It was concluded that the progressive intimal thickening of the human coronary artery, which develops early in life and is associated with defects in the internal elastic lamina, is also associated with endothelial cell separation and detachment, with the formation of denuded areas on the intimal surface.     

Proteoglycan distribution in the intima and media of the aortas of young and aging rabbits: an ultrastructural study

Aortas from normal healthy rabbits, approx. 3 months old, were examined by light and transmission electron microscopy. The proteoglycan of the extracellular matrix, which was stained by ruthenium red and appeared as granules by transmission electron microscopy, was quantitated morphometrically in the intima and the superficial media. The intima included areas which were thickened and which contained connective tissue, including proteoglycan, and some smooth muscle cells. In the thickened intima there was a greater proportion of extracellular space which was occupied by proteoglycan, and the proteoglycan was present in higher concentration than in the media. In the aortas of rabbits, approx. 2 years old, the extent of intimal thickening and the concentration of proteoglycan increased in the thickened intima but there was no evidence of extracellular lipid deposition. The endothelial basement membrane contained small proteoglycan granules (heparan sulphate) which decreased in concentration in older animals. It is possible that the accumulation of proteoglycan in the thickened intima increases the susceptibility of the intima to accumulate lipid following an additional stimulus, such as hyperlipaemia, in the initial stages of atherosclerosis.     

Distribution of plasma proteins across the human aortic wall--barrier functions of endothelium and internal elastic lamina

The concentrations of plasma proteins of different molecular weights were measured in layers across the human aortic wall. On a volumetric basis the concentration of low density lipoprotein (LDL) in inner intima, adjacent to the endothelium, was almost twice the concentration in the patient's plasma. With the exception of transferrin, which behaved anomalously, the concentration of each protein was a linear function of is plasma concentration and molecular weight, so that the relative retention of albumin was only 15% of LDL retention and its concentration in inner intima less than one-quarter of the plasma concentration. Between the inner (luminal) and outer layers of intima the concentration of all proteins decreased by about 40%. In aortas in which the internal elastic lamina (IEL) appeared to be intact it provided an almost total barrier to LDL, but for smaller proteins the concentrations in the layer immediately outside it were inversely related to molecular weight; the concentration of LDL was only 0.3% of the intimal concentration whereas albumin was 26% of the intimal concentration. However, in aortas in which the IEL appeared morphologically frayed, fragmented or discontinuous there was an 80% increase in albumin, and a 25-fold increase in LDL in this layer. The differential barrier functions of endothelium and IEL produce bizarrely different macromolecular environments for smooth muscle cells in intima and media.     

Intimal thickening of jugular and femoral veins vs arteries in the rabbit following investment

The authors induced intimal thickening in the jugular and femoral veins and in the common carotid and femoral arteries of rabbits by placement of a polyethylene tube cuff. The comparative effects on the intima were studied by light and electron microscopy. Even in the veins, thickening resulted from the migration of medial smooth muscle cells into the intima with subsequent proliferation. Thickening in the arteries consisted of tightly packed smooth muscle cells and a few elastic fibers, whereas that in the veins was characterized by an abundance of collagen fibers, layers of smooth muscle cells, and a few elastic fibers. Capillaries were often observed in the thickened intima of the veins but not of the arteries.     

Diffuse intimal thickening of coronary arteries in patients with coronary spastic angina

OBJECTIVES: The purpose of this study was to evaluate the extent of atherosclerotic changes in angiographically normal coronary arteries using intravascular ultrasound (IVUS) technique in patients with coronary spastic angina. BACKGROUND: Nitric oxide activity was shown to be decreased in coronary arteries of patients with coronary spastic angina (CSA). Decrease in nitric oxide causes arterial intimal hyperplasia or thickening. However, it remains unclear whether intimal thickening is diffusely present in coronary arteries of patients with CSA. METHODS: The IVUS study was performed in 26 patients with CSA and with normal coronary angiograms and in 31 control subjects in whom age and gender was matched with those in patients with CSA. RESULTS: Compared with control subjects, patients with CSA had significantly larger percent intima + media area (%I + M area), intima + media area and maximal intima + media thickness in all of proximal, middle and distal segments (p<0.01, respectively). Lumen area was comparable between these groups. The presence of spasm was the most powerful independent predictor of increase in percent intima + media area, in multiple-regression analysis with the traditional risk factors as covariates. CONCLUSIONS: Intimal thickening existed entirely in a coronary artery in patients with CSA and with normal angiograms, independently of other traditional risk factors. The diffuse intimal thickening in the spasm coronary arteries is intimately related with coronary spasm.     

Intramural ("small vessel") coronary artery disease in hypertrophic cardiomyopathy

Many patients with hypertrophic cardiomyopathy have signs and symptoms of myocardial ischemia and dysfunction. Although hypertrophy and increased left ventricular pressure can account for such abnormalities, altered small intramural coronary arteries have also been described in such patients. To determine the prevalence and extent as well as the clinical relevance of abnormal intramural coronary arteries, a histologic analysis of left ventricular myocardium obtained at necropsy was performed in 48 patients with hypertrophic cardiomyopathy (but without atherosclerosis of the extramural coronary arteries) and in 68 control patients with either a normal heart or acquired heart disease. In hypertrophic cardiomyopathy, abnormal intramural coronary arteries were characterized by thickening of the vessel wall and a decrease in luminal size. The wall thickening was due to proliferation of medial or intimal components, or both, particularly smooth muscle cells and collagen. Of the 48 patients with hypertrophic cardiomyopathy, 40 (83%) had abnormalities of intramural coronary arteries located in the ventricular septum (33 patients), anterior left ventricular free wall (20 patients) or posterior free wall (9 patients); an average of 3.0 +/- 0.7 abnormal arteries were identified per tissue section. Altered intramural coronary arteries were also significantly more common in tissue sections having considerable myocardial fibrosis (31 [74%] of 42) than in those with no or mild fibrosis (31 [30%] of 102; p less than 0.001). Abnormal intramural coronary arteries were also identified in three of eight infants who died of hypertrophic cardiomyopathy before 1 year of age. In contrast, only rare altered intramural coronary arteries were identified in 6 (9%) of the 68 control patients (0.1 +/- 0.05 abnormal arteries per section; p less than 0.001) and those arteries showed only mild thickening of the wall and minimal luminal narrowing. Moreover, of those patients with abnormal intramural coronary arteries, such vessels were about 20 times more frequent in patients with hypertrophic cardiomyopathy (0.9 +/- 0.2/cm2 myocardium) than in control patients (0.04 +/- 0.02/cm2 myocardium). Hence, abnormal intramural coronary arteries with markedly thickened walls and narrowed lumens are present in increased numbers in most patients with hypertrophic cardiomyopathy studied at necropsy and may represent a congenital component of the underlying cardiomyopathic process.(ABSTRACT TRUNCATED AT 400 WORDS)     

Discontinuities in the internal elastic lamina: a comparison of coronary and internal mammary arteries

The internal elastic lamina (iel.) of the anterior descending branch of the left coronary artery, and the internal mammary artery, were studied in 166 unselected subjects of different ages and races. The coronary artery showed substantial defects in the iel. even in the first few years of life, while the iel. of the mammary artery showed only minimal defects in all age groups. The defects in the iel. were associated with the presence of medial cells in the intima, and the thickness of the intima was correlated with the magnitude of the defects in the iel. (Correlation coefficient 0.95 for the coronary artery and 0.80 for the mammary artery). Small arteries involved in chronic inflammatory or neoplastic disease showed a similar relationship if the vessel were present in an edematous area. These vessels which do not usually show intimal thickening, displayed a thickened intima in the vicinity of defects of the iel. It is suggested that the pronounced difference in the incidence of arteriosclerosis between the coronary and internal mammary arteries is related to these defects in the internal elastic lamina.     

Pathological features of coronary arteries in children with Kawasaki disease in which coronary arterial aneurysm was absent at autopsy. Quantitative analysis

Coronary arteries in six children who had Kawasaki disease but lacked coronary arterial aneurysms were examined. Four children died of myocarditis at the acute stage, and two children died of bacterial sepsis or as a result of an occurrence during cineangiography at the healed stage. Twenty-one children without Kawasaki disease were examined as controls. The six children with Kawasaki disease had no thrombi, recanalization, or stenosis greater than 50% in the major coronary arteries. Three patients had dilatation of the major coronary arteries at the acute stage. Two of the three patients died during the acute stage, and autopsy showed slight dilatation of coronary arteries and abnormal intimal thickening due to panvasculitis. In the third child, who died at the healed stage, dilatation of the coronary arteries detected by two-dimensional echocardiography at the acute stage had disappeared at the healed stage. No dilatation of the major coronary arteries was seen at autopsy. However, abnormal fibrous intimal thickening of the major coronary arteries without inflammatory changes was found. The other three patients had no dilatation of the major coronary arteries at the acute stage. Two patients died at the acute stage, and slight inflammation without abnormal intimal thickening was seen in the intima and the adventitial area. In the third patient, who died during the healed stage, two-dimensional echocardiography revealed no dilatation during the clinical course, and there was no inflammatory changes or abnormal intimal thickening at autopsy.(ABSTRACT TRUNCATED AT 250 WORDS)     

转化生长因子-beta1与冠状动脉内膜增厚及平滑肌细胞增生的关系

目的通过检测扩张性心肌病(DCM)的冠状动脉组织,研究转化生长因子-beta1(TGF-β1)与冠状动脉的内膜增厚的联系。方法解剖20例DCM心脏移植术的受体心脏的冠状动脉,检测冠状动脉壁的中层和内膜层组织的α平滑肌肌动蛋白(α-SMA)和TGF-β1的蛋白表达水平。结果组织形态观察DCM的冠脉均存在不同程度的内膜层增厚,通过免疫组化染色中对α-SMA阳性区域的分析,发现SMC广泛均一地分布在DCM冠脉壁增厚的内膜中。TGF-β1的表达与α-SMA的表达(r=0.498,P<0.05)及内膜/中层面积比(r=0.465,P<0.05)成正相关,且TGF-β1与内膜中α-SMA阳性区域的面积百分比(r=0.615,P<0.01)也成正相关。结论正常冠状动脉壁中TGF-β1的表达与冠状动脉内膜增厚及SMC在内膜中的增生成正相关。     

Intimal thickening of human femoral arteries with special regard to elastin, Part 1. Diffuse intimal thickening due to growth and age

In infants, human femoral arteries display seam-like internal elastic lamina (IEL) covered with endothelium on the luminal side and with smooth muscle cells (SMC) on the medial side. At birth the growth of IEL is finished, correlated with a loss of microfibrils (MF) at the periphery. With the onset of the postnatal vessel growth the joints of IEL seem to be mechanically widened until they have the appearance of gaps with progressing age. After the age of 40 years there are often rod-like crystallites in the IEL, probably composed of cholesterol esters. A small first consecutive lamina (CL) can be seen already in childhood; it enlarges until the 3rd decade of life and is interpreted as a substitute to the "fragmented" IEL. After the 5th decade of life the first CL is arranged within the intima at a certain distance from the IEL and consisting of loosely arranged elastic fibrils. In very old arteries (beyond the 8th decade of life) gaps are rarely seen in the first CL. In individuals over the age of 30 years, the space between IEL and the first CL is occupied by smooth muscle cells (SMC) which are tightly packed. Additional CLs above the first CL can be found in elderly individuals, there CL obviously contribute to the intimal thickening. The ultrastructure of the elastic elements of the vessel wall and their possible function are discussed.     

Diffusion of gamma globulin into the arterial wall identifies localized entry of lipid and cells in atherosclerosis

BACKGROUND: The localization of atheromatous lesions in vulnerable arteries and their relatively rare occurrence in other arteries of the same subject cannot be explained by current theories of the aetiology of atherosclerosis. OBJECTIVE: To determine whether abnormal diffusion of gamma globulin into the arterial wall from the lumen will identify defects of barrier function allowing localized entry of lipid and cells in atherosclerosis. METHODS: Paraffin sections of left anterior descending coronary arteries and corresponding internal thoracic arteries from 80 human subjects aged 1-65 years were stained for gamma globulin by the immunoperoxidase technique. Duplicate sections were stained with orcein to demonstrate the elastin structure. RESULTS: The barrier function of the luminal surface of the thickened intima was associated with the presence of an elastin lamina beneath the endothelial cells. With advancing age, the coronary arteries exhibited breakdown of this barrier function in localized areas with entry into the arterial wall of gamma globulin, lipid and cells. This was rare in the internal thoracic artery. CONCLUSION: Lack of continuity or incomplete formation of this sub-endothelial lamina, which was seen particularly in the coronary artery, was associated with localized entry into the arterial wall of gamma globulin, lipid and cells from the circulating blood and with the development of atheromatous lesions.     

Distribution of intimal and medial thickening in the human right coronary artery: a study of 17 RCAs

OBJECTIVE: To quantify the distribution of intimal and medial thickening in human right coronary arteries (RCAs) obtained at autopsy. BACKGROUND: The shear and tensile stresses created by arterial bifurcation are believed to result in eccentric fibromuscular intimal thickening that leads to atherosclerosis. Vascular curvature has been cited as a cause of atherosclerosis; however, details of the location and extent of intimal and medial thickness in the largely curved human RCA are not adequately documented. METHODS: The right coronary arteries were obtained from 40 postmortem hearts and cut into 20-30 segments, each being 3-4 mm in length. Microscopic sections from the proximal, acute margin, and distal regions of the RCA were digitized around the circumference of the vessel. Seventeen arteries showed insignificant stenosis (<50%) and were selected for detailed examination. RESULTS: Seventy-one percent (12/17) of proximal sections displayed eccentric intimal thickening. Normalized ensemble averaging revealed a preferential thickening on the myocardial side of the artery. At the acute margin region where curvature is most pronounced and at the distal region, 51% (8/17) of the samples showed eccentric thickening, but the ensemble average thickening in these regions showed no preferential location. In these mildly diseased arteries, the thickened intima comprised of mainly smooth muscle cells with an extracellular matrix of collagen and some elastin. A relatively uniform medial smooth muscle layer was seen at all three locations. CONCLUSIONS: The proximal region of the RCA appears to be a site of intrinsic eccentric intimal thickening with maximum thickness on the myocardial side of the artery. Eccentric thickening does occur in the acute margin and distal regions; however, no distinct pattern or location was evident.     

Changes in morphology of elastin fibers during development of the tunica intima of monkey aorta

Summary The normal development of elastin fibers in the thoracic aorta was studied in fetal, young, and adult monkeys. Tissue was examined by scanning electron microscopy (SEM) after NaOH treatment and by transmission electron microscopy (TEM). The NaOH treatment of fixed tissues effectively removed collagen fibers and enabled three-dimensional visualization of the elastin fibers. In intact fetal aortae, the internal elastic lamina (IEL) was situated immediately beneath the endothelium. This IEL consisted of superficial, longitudinally arranged bundles of elastin fibrils and an underlying solid sheet containing round fenestrations. In neonates, diffuse intimal thickening was observed. In the young and young-adult monkeys, the aortae exhibited intimal thickening with slender but split IEL. One of the most important findings of this study was that elastin fibers in the intimal thickening, as well as smooth muscle cells, ran in a longitudinal fashion. This was in contrast with the elastic laminae of the media which were mainly oriented circumferentially. Subendothelial elastin fibers in this intimal thickening combined with longitudinally arranged microfibrils which formed close associations with endothelial stress fibers. In some adult monkey aortae with well-developed intimal thickening, a complex meshwork of slender elastin fibers was also found beneath the endothelium. The development of the intimal elastin fibers is discussed in relation to hemodynamic forces.     

Vascular changes at the prehypertensive phase in the mesenteric arteries from spontaneously hypertensive rats

Morphometric measurements of three categories of mesenteric vessels (representing elastic, muscular and arteriolar vessels) from prehypertensive spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY) were carried out at the light and electron microscope levels. Structural alterations of the blood vessels were already present in the SHR, even though the blood pressure was not yet elevated as compared with age-matched WKY. No change was found in the elastic vessels (superior mesenteric artery). Among the muscular arteries (i.e. large mesenteric arteries), the increase in vessel wall cross-sectional area was due to the increase in the intima, media and adventitia. Increase in media was due to hyperplasia of the smooth muscle cells. The smooth muscle cells were not hypertrophied. Nerve density was also higher in the large mesenteric arteries of SHR. In the arteriolar vessels (i.e. small mesenteric arteries), wall to lumen ratio, as well as media to lumen ratio, were increased in the SHR. The number of smooth muscle cell layers was also increased. In all these vessel types, the cross-sectional area of the lumen under maximal relaxation was similar between SHR and WKY, except in small mesenteric arteries where the lumen was smaller in the SHR. Our results suggest that structural alteration of the blood vessels at the prehypertensive phase may be one of the contributing factors leading to the development of hypertension in the SHR.     

Changes of coronary artery morphology and distribution of smooth muscle cells during progression of coronary atherosclerosis after heart transplantation

To examine the changes in coronary artery morphology and the distribution of smooth muscle cells during the progression of coronary atherosclerosis after cardiac transplantation, intimal and medial tissues were evaluated and the density of smooth muscle cells in the media were measured 30 and 60 days after transplantation by microspectrophotometry from rats receiving both auto- and allo-transplantation. Transplanted animals were given cyclosporine A to prevent graft rejection. Signs of rejection were not seen in the animals receiving auto-transplants. Rejection gradually progressed after transplantation in animals receiving allografts. The intima of the coronary arteries in the allograft group was significantly thickened at both 30 and 60 days after transplantation. The total intimal area in the day 60 group was significantly increased relative to the day 30 group among animals receiving allo-transplantation. The medial area of the coronary arteries in the group receiving allotransplantation was significantly less than that of the auto-transplantation group at both 30 and 60 days after transplantation. Azocarmine G stain revealed that the principal component of the thickened intima was smooth muscle cells. Coronary arteries in the allotransplantation group had disruption of the internal elastic lamina. We therefore hypothesized that the smooth muscle cells (SMCs) in the intima are probably derived from the media. The density of SMCs in the media was measured by microspectrophotometry. The density of SMCs was significantly decreased in the allo-transplantation group relative to the autotransplantation group. We conclude that intimal thickening of the coronary arteries is due to SMC proliferation, the myocytes being from the media through disruption of the internal elastic lamina. This process is similar to the mechanism of the development of atherosclerosis.     

The distribution of oxidatively-modified lysine in the human vasculature

Fifty-seven sections of human vessels, collected in the Pathobiological Determinants of Atherosclerosis in Youth study from individuals aged 25-34, were stained with two monoclonal antibodies to oxidatively-modified lysine. Intensity and extent of immunoreactivity were graded by three pathologists. Aorta from a Watanabe heritable hyperlipidemic (WHHL) rabbit was stained as a positive control. Intimal immunoreactivity in the rabbit was predominantly localized to lesions. Although immunoreactivity in humans was somewhat more intense in atherosclerotic plaques, substantial staining was present in intima with diffuse intimal thickening and coronary veins. Localization of oxidatively-modified lysine in humans did not correlate with localization or severity of atherosclerosis. Localization of immunoreactivity for oxidatively-modified lysine to intimal lesions in the WHHL rabbit may be due to absence of diffuse intimal thickening, which prevents retention of epitopes throughout the intima.     

Adaptive remodeling of internal elastic lamina and endothelial lining during flow-induced arterial enlargement.

Gaps in the internal elastic lamina (IEL) have been observed in arteries exposed to high blood flow. To characterize the nature and consequences of this change, blood flow was increased in the carotid arteries of 56 adult, male, Japanese white rabbits by creating an arteriovenous fistula between the common carotid artery and the external jugular vein. The common carotid artery proximal to the arteriovenous fistula was studied at intervals from 1 hour to 8 weeks after exposure to high flow. In the controls, the IEL showed only the usual, small, physiological holes, 2 to 10 microm in diameter. At 3 days, some of the holes in the IEL had become enlarged, but they could not be detected by scanning electron microscopy, despite manifest endothelial cell proliferation. At 4 days, gaps in the IEL appeared as small, luminal surface depressions, 15 to 50 microm wide. At 7 days, the gaps in the IEL had enlarged and formed circumferential, luminal depressions occupying 15+/-5% of the lumen surface. Endothelial cell proliferation persisted in the gaps while proliferative activity decreased where the IEL remained intact. At 4 weeks, as the artery became elongated and dilated, the gaps in the IEL widened as intercommunicating circumferential and longitudinal luminal depressions occupying 64+/-5% of the lumen surface. At 8 weeks, the rate of elongation and dilatation of the artery slowed and the widening of the gaps in the IEL diminished. Endothelial cells covered the gaps throughout. We conclude that flow-induced arterial dilatation is accompanied by an adaptive remodeling of the intima. The gaps in the IEL permit an increase in lumen surface area while endothelial cell proliferation assures a continuous cell lining throughout.     

Intracoronary ultrasound assessment late after the arterial switch operation for transposition of the great arteries

OBJECTIVES: This research was undertaken to assess the status of the coronary wall morphology late after the arterial switch operation (ASO) for transposition of the great arteries employing intravascular ultrasound (IVUS). BACKGROUND: Long-term patency of the reimplanted coronary arteries is a key issue after ASO. Follow-up studies have demonstrated coronary obstruction in up to 8% of patients that may be related to progressive fibrocellular intimal thickening. METHODS: Twenty-two asymptomatic children were enrolled at a median age of 9.5 years (range 5 to 22 years); IVUS images were obtained in 20 children at cardiac catheterization 5.0 to 21.6 years after the operation (in two cases IVUS study was not feasible due to technical constraints). Quantitative analysis was performed in 37 coronary arteries involving segments with a mean length of 28.4 +/- 1.8 mm. RESULTS: Thirty-three arteries (89%) displayed variable degrees of proximal eccentric intimal proliferation, with the maximal intimal thickening being 0.26 +/- 0.14 mm (range 0.06 to 0.71 mm) at the most thickened site. According to the Stanford classification, all children had coronary artery involvement with 50% having moderate-to-severe lesions (>0.3 mm). No risk factors for such abnormalities were encountered, including age, origin of the coronary arteries, hemodynamics, and follow-up duration after surgery. CONCLUSIONS: Intravascular ultrasound assessment late after the ASO revealed proximal eccentric intimal thickening in most of the studied vessels. This observation suggests the development of early atherosclerosis in the reimplanted coronary arteries, which may have a role in the genesis of late coronary events.