Intimal Plaque Research Articles

Standard Morphologic Evaluation of the Heart in the Laboratory Dog and Monkey

The nonrodent species most commonly utilized in preclinical safety studies are the purpose-bred beagle dog and cynomolgus macaque (Macaca fascicularis). Potential effects of a new chemical entity (NCE) on the heart pose serious concerns; consequently in vivo testing is focused on detection of functional alterations as well as morphological changes. Macroscopic and microscopic evaluation of the heart is based on a standard survey of key structures to properly assess presence of spontaneous and potential drug-induced lesions. Evaluation of historical controls to determine type and frequency of background change is valuable, as studies with non-rodent species generally have a small sample size. Archived control dog and monkey data were retrospectively reviewed, including terminal body weight (BW), heart weight (HW), and archival glass slides of heart. Control dogs had minimal background changes that included myxomatous or cartilagenous change in the cardiac skeleton and a variable degree of vacuolation in Purkinje fibers. Control monkey hearts commonly contained inflammatory cell infiltrates, myocyte anisokaryosis, and handling artifacts, while myocyte degeneration, squamous plaques, pigment, and intimal plaques were occasionally observed. These findings highlight the utility of consistently recorded and readily accessible archived control data when attempting to discern background spontaneous changes and artifacts from test-article induced changes.

Relationship Between Oxidative Stress Parameters and Atherosclerotic Signs in the Carotid Artery of Stable Renal Transplant Patients

Reactive oxygen species (ROS) may participate in atheroma plaque formation, which may be noninvasively diagnosed by Doppler ultrasound of carotid artery. We sought to determine the relationship between the presence of carotid artery lesions and oxidative parameters to identify factors that may influence these lesions in renal transplant patients. Fifty renal transplanted patients with stable renal function and without diabetes mellitus were studied for more than 1 year posttransplantation. Echo Doppler examination of the carotid artery was performed to assess the intimal media thickness (IMT), atheroma plaques, calcification, and stenosis. Data were collected on oxidative parameters: malondialdehyde (MDA), glutathione peroxidase (GPx), catalase, superoxide dismutase (SOD), glutathione reductase (GR), and lipid profile. The serum GPx level among patients without atheroma plaques, calcification, or stenosis was higher than in those with ultrasound signs. The LDL cholesterol fraction was lower in patients with no ultrasound signs of atherosclerotic lesions; total cholesterol values showed the same behavior. In conclusion, transplanted patients with atheromatous plaques, calcification, and carotid stenosis have a greater degree of hypercholesterolemia and lower antioxidant activity (lower GPx). Recipient age was the principal risk factor for the presence of increased IMT, atheroma plaque, calcification, and/or stenosis of carotid artery in renal transplant patients.

Endostatin binds biglycan and LDL and interferes with LDL retention to the subendothelial matrix during atherosclerosis

Retention of lipoproteins to proteoglycans in the subendothelial matrix (SEM) is an early event in atherosclerosis. We recently reported that collagen XVIII and its proteolytically released fragment endostatin (ES) are differentially depleted in blood vessels affected by atherosclerosis. Loss of collagen XVIII/ES in atherosclerosis-prone mice enhanced plaque neovascularization and increased the vascular permeability to lipids by distinct mechanisms. Impaired endothelial barrier function increased the influx of lipoproteins across the endothelium; however, we hypothesized that enhanced retention might be a second mechanism leading to the increased lipid content in atheromas lacking collagen XVIII. We now demonstrate a novel property of ES that binds both the matrix proteoglycan biglycan and LDL and interferes with LDL retention to biglycan and to SEM. A peptide encompassing the alpha coil in the ES crystal structure mediates the major blocking effect of ES on LDL retention. ES inhibits the macrophage uptake of biglycan-associated LDL indirectly by interfering with LDL retention to biglycan, but it has no direct effect on the macrophage uptake of native or modified lipoproteins. Thus, loss of ES in advanced atheromas enhances lipoprotein retention in SEM. Our data reveal a third protective role of this vascular basement membrane component during atherosclerosis.

In vivo detection of macrophages in a rabbit atherosclerotic model by time-resolved laser-induced fluorescence spectroscopy

Accumulation of numerous macrophages in the fibrous cap is a key identifying feature of plaque inflammation and vulnerability. This study investigates the use of time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) as a potential tool for detection of macrophage foam cells in the intima of atherosclerotic plaques. Experiments were conducted in vivo on 14 New Zealand rabbits (6 control, 8 hypercholesterolemic) following aortotomy to expose the intimal luminal surface of the aorta. Tissue autofluorescence was induced with a nitrogen pulse laser (337 nm, 1 ns). Lesions were histologically classified by the percent of collagen or macrophage foam cells as well as thickness of the intima. Using parameters derived from the time-resolved fluorescence emission of plaques, we determined that intima rich in macrophage foam cells can be distinguished from intima rich in collagen with high sensitivity (>85%) and specificity (>95%). This study demonstrates, for the first time, that a time-resolved fluorescence-based technique can differentiate and demark macrophage content versus collagen content in vivo. Our results suggest that TR-LIFS technique can be used in clinical applications for identification of inflammatory cells important in plaque formation and rupture.

Matrix Metalloproteinase-9 Modulation by Resident Arterial Cells Is Responsible for Injury-Induced Accelerated Atherosclerotic Plaque Development in Apolipoprotein E–Deficient Mice

Although matrix metalloproteinase-9 (MMP-9) has been implicated in atherosclerotic plaque instability, the exact role it plays in the plaque development and progression remains largely unknown. We generated apolipoprotein E (apoE)-deficient (apoE-/-) MMP-9-deficient (MMP-9-/-) mice to determine the mechanisms and the main cell source of MMP-9 responsible for the plaque composition during accelerated atherosclerotic plaque formation. Three weeks after temporary carotid artery ligation revealed that while on a Western-type diet, apoE-/- MMP-9-/- mice had a significant reduction in intimal plaque length and volume compared with apoE-/- MMP-9+/+ mice. The reduction in plaque volume correlated with a significantly lower number of intraplaque cells of resident cells and bone marrow-derived cells. To determine the cellular origin of MMP-9 in plaque development, bone marrow transplantation after total-body irradiation was performed with apoE-/- MMP-9+/+ and apoE-/- MMP-9-/- mice, which showed that only MMP-9 derived from resident arterial cells is required for plaque development. MMP-9 is derived from resident arterial cells and is required for early atherosclerotic plaque development and cellular accumulation in apoE-/- mice.

Effect of inhibitors of myeloperoxidase on the development of aortic atherosclerosis in an animal model

Our earlier studies have shown that some steroids increase myeloperoxidase enzyme (MPO) release from human granulocytes, and that MPO plasma levels are significantly lower in postclimacteric people. Moreover, we have proven that MPO inhibits production of atherogenic free radical superoxide anion and MPO-inhibitors increase superoxide release. The aim of the present study was to investigate the effect of MPO-inhibitors on the early phase of aortic atherosclerosis, namely the extent of intimal plaques and the thickening of the medial layer. Adult male rabbits were fed with lipid rich food (cholesterol: 1.3%, peanut oil: 8%) for 8 weeks. During this period MPO-inhibitors were also given (4-aminobenzoicacid-hydrazide/ABAH/-13.3 mg/kg/day or indometacin-5 mg/kg/day). All animals developed intimal lipid plaques (raised fatty streaks). The relative plaque-covered areas of the aortas were compared and the media thickness of the aorta was measured on plaque-free as well as plaque-containing areas. The medial smooth muscle density and peroxidase activity of the aortic media were also determined. The media thickness increased ( p<0.05) in the cholesterol+ABAH as well as in the cholesterol+indometacin groups up to 375.7 (±60.5) and 442.5 (±123.4) μm, respectively, compared to the control group (cholesterol feeding alone) where it measured only 308.4 (±51.67) μm. The medial peroxidase activity decreased significantly in the indometacin treated group and showed a decreasing tendency using ABAH. In parallel to this there was a tendency of increase in the relative plaque covered areas. The smooth muscle density showed no significant modifications, while inhibitors of the MPO seemed to enhance aortic medial thickness, i.e. the grade of a pre-atherosclerotic lesion, in our animal model. Collectively, the anti-atherogenic effect of certain steroid hormones might be realized through the impact on MPO activity.

Chronic-arginine supplementation improves endothelial cell vasoactive functions in hypercholesterolemic and atherosclerotic monkeys

Chronic exposure to L-arginine results in regression of atherosclerotic lesions and reversal of endothelial dysfunction. We investigated whether chronic L-arginine supplementation induces regression of atherosclerotic lesions and reversal of endothelial dysfunction in atherogenic rhesus monkeys and the mechanism which leads to these effects. About 12 male rhesus monkeys were fed 1% cholesterol and 18 g butter for 6 months to create an experimental model of hypercholesterolaemia and atherosclerosis (Group I) and 12 monkeys were fed standard stock diet for 6 months (Group II). After, 6 months these two groups were further divided into 2 sub-groups which in addition to their respective diets were fed 2.5% L-arginine in drinking water for additional 6 months (Group III and Group IV). Systemic nitric oxide (NO) formation was assessed as plasma nitrite and cGMP formation every 3 months. Oxygen free radical (OFR) generation and malondialdehyde production as an index of lipid peroxidation were determined. Changes in isometric tension were compared in isolated ring segments of thoracic aorta from normal and hypercholesterolemic animals. Cholesterol feeding progressively reduced plasma nitrite and cGMP generation (p < 0.05). Dietary L-arginine partly restored the levels of plasma nitrite and cGMP (p < 0.05) but did not change plasma cholesterol levels. L-arginine significantly reduced aortic intimal thickening, blocked the production of carotid and coronary intimal plaques and completely preserved endothelium-dependent vasodilator function. Further, L-arginine significantly inhibited generation of the reactive oxygen species (ROS) generation and lipid peroxidation. Chronic oral supplementation with L-arginine blocks the progression of plaques via restoration of nitric oxide synthase substrate availability and reduction of vascular oxidative stress.

Adventitial dysfunction: an evolutionary model for understanding atherosclerosis

Endothelial and smooth muscle dysfunctions are widely implicated in the pathogenesis of atherosclerosis. Modern mechanical and pharmacologic treatments aim to remodel abnormalities of the vessel intima and media. We hypothesize that adventitial dysfunction comprises the dominant source of atherosclerosis by originating many endothelial and smooth muscle abnormalities. The autonomic nervous system innervates the adventitia, and autonomic dysfunction induces many end-organ dysfunctions including inflammation and thrombosis. The link between diabetes and atherosclerosis may operate through adventitial autonomic neuropathy. Smoking may promote atherosclerosis by inducing adventitial autonomic dysfunction related to nicotine-mediated compensatory upregulation of sympathetic bias independent of endothelial injury induced by purported tobacco toxins. While hypertension is thought to cause atherosclerosis, the two conditions may instead represent independent consequences of autonomic dysfunction. The link between aging and atherosclerosis may operate through adventitial dysfunction induced by autonomic dysregulations. Exercise may ameliorate atherosclerosis by restoring adventitial autonomic function, thereby normalizing adventitial regulation of medial and intimal biology. Feed-forward adventitial vascular baroreceptor and chemoreceptor dysregulation may further exacerbate atherosclerosis as intimal plaque interferes with these sensors. Since penetrating external physical injury likely represented a dominant selective force during evolution, the adventitia may be preferentially equipped with sensors and response systems for vessel trauma. The convergent response of adrenergia, inflammation, and coagulation, which is adaptive for physical trauma, may be maladaptive today when different stressors trigger the cascade. Endoluminal therapies including atherectomy, angioplasty, and stent deployment involve balloon expansion that traumatizes all layers of the vessel wall. These interventions may paradoxically reinitiate the cascade of atherogenesis that begins with adventitial dysfunction and leads to restenosis. Methods to reduce adventitial trauma, a maladaptive trigger of adventitial dysfunction, may reduce the risk of restenosis. We envision novel mechanical and biopharmaceutical solutions that target the adventitia to prevent or treat atherosclerosis including novel drug delivery strategies, exo-stents that wrap vessels, and neuromodulation of vessels.

Association of serum lipoprotein(a) with ultrasonographically determined early atherosclerotic changes in the carotid and femoral arteries in kidney transplanted patients

Objectives To evaluate the association of serum lipoprotein(a) [Lp(a)] with carotid intimal media thickness (IMT) and carotid femoral plaque occurrence in kidney transplant patients. Patients and methods Fifty-four subjects included 29 group 1 normal healthy persons and 25 group 2 kidney transplant patients underwent carotid IMT measurements and carotid femoral plaque assessment by B-mode ultrasonography. Also we measured cholesterol, triglyceride, HDL-C, LDL-C and Lp(a) as well as BUN and creatinine. Results There was a significant difference between Lp(a) in the two groups ( P = .016). There was a significant difference between carotid IMT of the two groups ( P < .001). Moreover there was a significant difference between the plaque scores of kidney transplant patients and the normal group ( P = .05). There were no correlations between carotid IMT and plaque score in normal subjects or in kidney transplant patients ( P > .05). There was a significant correlation between carotid IMT with age in Group 1 ( P = .035). No correlation between carotid IMT and serum Lp(a) was seen in the two groups. No significant correlations between plaque score and serum Lp(a) were observed. There was no correlation between duration of transplant and thickening of intimal media complex in this group. In this group a positive correlation was demonstrated between carotid IMT with serum LDL-C ( P < .001). Conclusions Age was the most important factor associated with thickening of intimal media complex in normal subjects and in plaque formation in the renal transplant group. Serum LDL-C may be associated with thickening of intimal media complex in kidney transplant patients. Serum Lp(a) may not be a significant factor in thickening of the intimal media complex or plaque occurrence in kidney transplant patients.

Donor intracranial bleeding is associated with advanced transplant coronary vasculopathy: Evidence from intravascular ultrasound

Objectives We evaluated the impact of spontaneous intracranial bleeding (ICB) in the donor on transplant coronary vasculopathy using serial intravascular ultrasound examinations. Materials and methods Between January 1995 and December 2000, 72 recipients underwent cardiac transplantation from donors who had experienced spontaneous ICB (ICB group). Their findings using serial intravascular ultrasound analysis at baseline (within 1 month) and 1 year after transplantation were compared with 90 recipients who had undergone transplantation from trauma donors (trauma group). Results Compared with the Trauma group, the ICB group showed increased coronary intimal thickness (0.55 ± 0.33 vs 0.39 ± 0.3 mm; P = .034), plaque volume (3.84 ± 2.5 vs 2.28 ± 1.65 mm 3; P = .015) and plaque burden (7.4 vs 2%) at 1 year after transplantation. Conclusions Donor spontaneous ICB is associated with significantly increased coronary vasculopathy.

Incidence and time course of intimal plaque formation in the right coronary artery after radiofrequency current application detected by intracoronary ultrasound

Despite the current clinical use of radiofrequency (RF) catheter ablation in infants and children, the late effects of RF current application at immature myocardium remain unclear. The purpose of this study was to investigate incidence and time course of coronary lesions after RF current application at developing myocardium in an animal model. In 10 pigs, 6 weeks of age (13+/-2 kg), RF current (500 kHz) was delivered by temperature guidance (75 degrees C) using a steerable electrode catheter (4 mm tip electrode) over 30-second periods. RF lesions were created at the lateral right atrial wall at the tricuspid valve annulus and the lateral left atrial and ventricular wall at the mitral valve annulus. Subsequent coronary angiography and intracoronary ultrasound (ICUS) of the right coronary artery (RCA) and the left circumflex artery (CX) were performed 3, 6, 9 and 12 months after RF current application. Quantitative coronary angiography did not exhibit any significant stenosis of the vessels during the study period. Intimal lesions of the RCA were documented for the first time at the 6-month study in 3 animals by ICUS (mean plaque area 2.2+/-0.2 mm(2), mean area stenosis 30.4+/-4.0%). There was no significant change in lesion length, area stenosis and plaque area at the 9- and 12-month studies. All 3 coronary artery lesions were confirmed in close proximity to myocardial RF lesions by histological examination 12 months after RF delivery. No intimal plaque formation of the CX was observed. Affection of the RCA as a late sequel after RF current application at the lateral right atrial wall occurred in 3 out of 8 long-term surviving pigs. Three to six months seem to be the time frame for the development of intimal lesions after RF delivery. In this experimental setting, angiography failed to detect these intimal changes. The potential risk of coronary affection may be important for catheter ablation procedures at the right atrial myocardium in infants and small children.

The Role of Vascular Endothelial Growth Factor in Restenosis

In 1996, the late Jeffrey Isner proposed the use of vascular endothelial growth factor (VEGF) gene delivery in patients undergoing percutaneous transluminal angioplasty as a strategy to limit the risk of restenosis.1VEGF promotes endothelial cell function and is a potent stimulator of endothelial cell migration and survival. Because normal endothelium inhibits smooth muscle cell proliferation, it was hypothesized that accelerating the reendothelialization of the balloon-injured site would diminish the severity of restenosis. Indeed, reports in animal models demonstrate that local administration of VEGF-A or VEGF-C leads to accelerated reendothelialization and a reduction in intimal thickening.2–5 However, the utility of VEGF or other proangiogenic factors for the treatment of restenosis is questioned by reports that have documented extensive vascular networks in atherosclerotic plaques6 and balloon-injured coronary arteries.7 Thus, the delivery of proangiogenic agents might exacerbate the growth of vascular lesions, analogous to the concept that angiogenesis contributes to tumor growth. These concerns are supported by studies showing that treatment of apolipoprotein E (ApoE)-deficient mice with an angiogenesis inhibitor reduced intimal neovascularization and plaque growth,8 and administration of VEGF enhanced atherosclerotic plaque progression, which was associated with increased capillary density.9 See pp 2424, 2430, 2436, 2444 This controversy has been rekindled by 3 articles appearing in the present issue of Circulation .10–12 Although many of the previous studies focused on the effects of exogenously administered angiogenic growth factors on vascular lesions, these new studies analyze the role of endogenous angiogenic growth factor signaling in neointima formation after acute vascular injury. Specifically, these studies tested whether VEGF-Traps (Figure), inhibitors of endogenous VEGF signaling, have a positive or negative effect on the process of intimal hyperplasia. On the basis of these new studies, we can conclude that VEGF inhibits restenosis,10 VEGF promotes restenosis,12 …

Decorin promotes aortic smooth muscle cell calcification and colocalizes to calcified regions in human atherosclerotic lesions.

Ectopic calcification localized to the intima of atherosclerotic plaque is a risk marker for cardiovascular events and increases the risk of aortic dissection during angioplasty. A variety of extracellular matrix molecules such as collagen type 1, bone sialoprotein, and osteopontin are known to regulate the biomineralization of bone and ectopic vascular calcification. In the present study, it was investigated whether decorin, a small leucine-rich proteoglycan expressed in bone and atherosclerotic plaque, is involved in arterial calcification. Calcification was induced in cultured bovine aortic smooth muscle cell (BASMC) by the addition of beta-glycerophosphate or inorganic phosphate. Northern and Western analysis revealed that decorin expression was strongly upregulated in mineralizing BASMC. Furthermore, overexpression of decorin using a retroviral expression vector resulted in a 3- to 4-fold elevation of calcium deposited on the BASMC monolayer. Increased calcification in response to decorin could also be mimicked by adding exogenous decorin to the cultures. In addition, human coronary atherosclerotic lesions taken from sudden-death patients showed marked colocalization of calcium deposits with decorin. Decorin induces calcification of arterial smooth muscle cell cultures and colocalizes to mineral deposition in human atherosclerotic plaque, suggesting that decorin functions as promoter of intimal calcification.

Angiotensin II receptors from peritransplantation through first-year post-transplantation and the risk of transplant coronary artery disease

ObjectivesWe evaluated whether the angiotensin II (Ang II) receptors from perioperation through one-year post-transplantation predict the transplant coronary artery disease (TCAD) progression. BackgroundThe role of Ang II receptors (type 1: AT1R; type 2: AT2R) in TCAD is uncertain. MethodsWe investigated 28 heart donors and the corresponding recipients. The levels of AT1R and AT2R messenger ribonucleic acid (mRNA) were examined in lymphocytes from the donor spleen and in the donor heart at one-week and one-year posttransplantation to determine their association with the progression of TCAD, measured as changes in maximal intimal thickness (CMIT) and plaque volume (CPV) by intravascular ultrasound (IVUS) examinations. ResultsThe AT1R mRNA in lymphocytes from the donor spleen (CMIT: r = 0.73, p < 0.0001; CPV: r = 0.69, p < 0.0001) and in the donor hearts at one-week (CMIT: r = 0.52, p = 0.005; CPV: r = 0.56, p = 0.002) and at one-year (CMIT: r = 0.63, p < 0.0001; CPV: r = 0.43, p = 0.004) post-transplantation along with AT2R mRNA in the donor hearts at one-year post-transplantation (CMIT: r = 0.3, p < 0.0001; CPV: r = 0.53, p = 0.009) were univariate predictors, whereas AT1R mRNA in lymphocytes and in the donor hearts at one-year post-transplantation proved to be multivariate predictors of the progression of TCAD. ConclusionsThese data suggest a role for Ang II receptors in the pathogenesis of TCAD and support a novel concept that TCAD may have its origin in the donor per se and may be modulated by the recipient's inherent biological factors.

Phytoestrogen α-Zearalanol Inhibits Atherogenesis and Improves Lipid Profile in Ovariectomized Cholesterol-Fed Rabbits

Although favorable effects of estrogen replacement therapy on atherosclerosis have been recognized, the benefit versus risk of estrogen replacement on overall cardio- vascular health remains controversial. The main adverse effect jeopardizing the clinical usage of estrogen is the increased risk of breast and endometrial cancer. Zearalenone (ZEN) is a universal endogenous hormone possessing estrogen-like effects and facilitating plant growth. alpha-Zearalanol (alpha-ZAL), a new phytoestrogen, is a reductive product of ZEN. Our preliminary evidence suggested that alpha-ZAL is anti-atherosclerotic. The aim of this study was to examine the effect of alpha-ZAL on atherosclerotic formation and serum lipid profile. Adult female nulliparous rabbits were ovariectomized or sham-operated and fed a high-cholesterol diet with different doses of alpha-ZAL or 17beta-estradiol for 12 wk. The aortic intimal atherosclerotic plaque was significantly larger in the cholesterol-fed group compared to control and sham groups. alpha-ZAL and 17beta-estradiol treatments significantly reduced plaque formation and improved serum profile of lipid (TC, TG, HDL-C, and LDL-C) and lipoprotein (ApoAl and ApoB). Both alpha-ZAL and 17beta-estradiol reconciled ovariectomy-induced uterine atrophy, although alpha-ZAL was significantly less potent than 17beta-estradiol in stimulating uterine growth. Our findings indicate that the phytoestrogen alpha-ZAL has an important anti-atherogenic property, analogous to that of estrogen.

Exercise increases endostatin in circulation of healthy volunteers.

Physical inactivity increases the risk of atherosclerosis. However, the molecular mechanisms of this relation are poorly understood. A recent report indicates that endostatin, an endogenous angiostatic factor, inhibits the progression of atherosclerosis, and suggests that reducing intimal and atherosclerotic plaque tissue neovascularization can inhibit the progression atherosclerosis in animal models. We hypothesize that exercise can elevate the circulatory endostatin level. Hence, exercise can protect against one of the mechanisms of atherosclerosis. We examined treadmill exercise tests in healthy volunteers to determine the effect of exercise on plasma levels of endostatin and other angiogenic regulators. Oxygen consumption (VO2) was calculated. Plasma levels of endostatin, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) were determined using ELISA. The total peak VO2 (L) in 7 male subjects was 29.5 +/- 17.8 over a 4-10 minute interval of exercise. Basal plasma levels of endostatin (immediately before exercise) were 20.3 +/- 3.2 pg/ml, the plasma levels increased to 29.3 +/- 4.2, 35.2 +/- 1.8, and 27.1 +/- 2.2 ng/ml, at 0.5, 2, and 6 h, respectively, after exercise. There was a strong linear correlation between increased plasma levels of endostatin (%) and the total peak VO2 (L) related to exercise (R2 = 0.9388; P < 0.01). Concurrently, VEGF levels decreased to 28.3 +/- 6.4, 17.6 +/- 2.4, and 26.5 +/- 12.5 pg/ml, at 0.5, 2, and 6 h, respectively, after exercise. There were no significant changes in plasma bFGF levels in those subjects before and after exercise. The results suggest that circulating endostatin can be significantly increased by exercise in proportion to the peak oxygen consumption under physiological conditions in healthy volunteers. These findings may provide new insights into the molecular links between physical inactivity and the risk of angiogenesis dependent diseases such as atherosclerosis.

頚部頚動脈狭窄病変に対する頚部超音波検査―ＰＴＡ／ＳＴＥＮＴ治療の安全性の予測―

The recent advancement of ultrasonographic imaging equipment has provided accurate visualization and characterization of the intimal plaques of the cervical carotid arteries. Because the soft plaques may easily cause embolic occlusion of the distal cerebral arteries during manipulation of the stenotic carotid arteries, it is important to predict the character of the carotid plaques for the safe PTA/STENT procedures. In this study, we examined patients who underwent carotid endarterectomy (CEA) with ultrasonographic imagings preoperatively. The macroscopic findings of the obtained carotid artery plaques and the preoperative ultrasonographic findings were compared to elucidate the diagnostic ability and clinical usefulness of the ultrasonography in this disorder. Twelve patients with 14 lesions who underwent CEA were examined preoperatively by ultrasonography (TOSHIBA SSA370A, linear probe of 7.5 MHz). There were 10 men and 2 women, aged from 64 to 73 years. Ultrasonographic findings of the plaques could be classified as “hyper,” “iso,,” “low,” or “mixed,” intensity by the character, and as “smooth,” or “irregular,” plaques by the configuration. The perioperative macroscopic findings of the plaques were characterized as “fragile,” or “tough.,” The ultrasonography showed 3 lesions with low intensity and 4 lesions with mixed intensity, including low intensity. These 7 lesions were fragile in the macroscopic findings. Five lesions showing iso intensity by the ultrasonography did not include fatty degeneration or internal bleeding of the plaques and were judged as tough plaques. The ultrasonography was able to detect an ulcer of plaque. Micro embolisms such as the fat in plaque or the thrombus can occur in the operation, and it is said that the complications of the cerebral embolisms caused by them are a serious problem of PTA. The exclusion of the high-risk group by ultrasonography examination is the most important factor in doing PTA/STENT safely. From the findings by ultrasonography and the perioperative macroscopy, we can classify “safety,” or “danger,” in each plaque to perform PTA/STENT. We judged the fragile plaques too dangerous for PTA/STENT. We can fully satisfy the character diagnosis of the carotid plaques by ultrasonography in estimating the safeness for the intravascular operation. The probability that complications by micro embolisms occur will be high when performing PTA/STENT in low-intensity plaques. We should exclude such cases from indication of PTA/STENT in future.

Calcification in atherosclerosis: bone biology and chronic inflammation at the arterial crossroads.

Dystrophic or ectopic mineral deposition occurs in many pathologic conditions, including atherosclerosis. Calcium mineral deposits that frequently accompany atherosclerosis are readily quantifiable radiographically, serve as a surrogate marker for the disease, and predict a higher risk of myocardial infarction and death. Accelerating research interest has been propelled by a clear need to understand how plaque structure, composition, and stability lead to devastating cardiovascular events. In atherosclerotic plaque, accumulating evidence is consistent with the notion that calcification involves the participation of arterial osteoblasts and osteoclasts. Here we summarize current models of intimal arterial plaque calcification and highlight intriguing questions that require further investigation. Because atherosclerosis is a chronic vascular inflammation, we propose that arterial plaque calcification is best conceptualized as a convergence of bone biology with vascular inflammatory pathobiology.

Hepatic artery thrombosis in pediatric liver transplantation

PurposeChildren have been reported to be at greater risk for hepatic artery thrombosis when compared to adults due to small arterial size, nonuse of intraoperative microscope, and postoperative hypercoagulable state. MethodsWe evaluated arterial anastomosis type, intraoperative field magnification, and hepatic artery complications and how they were managed. All patients underwent ultrasound, anticoagulation consisted of 41 mg aspirin once a day, and 35 patients received alprostadil (PGE) for the first 7 days after transplantation. No patients were administered intravenous heparin following liver transplantation. ResultsOf the 74 livers transplanted, 36 grafts (48.6%) were whole organ transplants and 38 grafts (51.4%) were partial livers. We observed HAT in 1 of 74 (1.35%) transplants in our pediatric liver transplant population. The only patient with HAT was a young girl with a history of biliary atresia. The occurrence of a hepatic artery thrombosis on day 7 was caused by the migration of an intimal plaque dissection within the artery graft. She was emergently taken back into the operating room for graft revision. This individual currently has a survival time of 426 days following her last transplant. ConclusionHepatic artery thrombosis may be minimized in pediatric liver transplantation without the use of microsurgery. Anticoagulation utilizing ASA and alprostadil is sufficient to avoid HAT. Accurate use of ultrasound is crucial to avoid this complication. Graft and patient salvage is possible with expedient surgical treatment; microsurgery, anticoagulant therapy, site of arterial inflow, and recipient size and weight.

Effects of cerivastatin on human arterial smooth muscle cell growth and extracellular matrix expression at varying glucose and low-density lipoprotein levels.

Statins exert pleiotropic effects on several other cellular functions besides lipid-lowering. Previously, it was found that cerivastatin is a very potent inhibitor of human arterial smooth muscle cell (haSMC) growth. However, because increased extracellular matrix (ECM) synthesis also accounts mainly for intimal plaque formation, the effects of cerivastatin on ECM expression was examined in this study. Furthermore, the influence of varying glucose and low-density lipoprotein (LDL) levels on cerivastatin-treated haSMCs was analyzed to mimic the conditions in patients with diabetes or hypercholesterolemia. The haSMCs were treated with 0.001-5.0 microM cerivastatin in the presence of 5.5-18.9 m glucose and 10-1000 microg/ml LDL. After 3 days, the messenger RNA (mRNA) expression of eight ECM proteins was analyzed and, after 7 days, mitotic and mitochondrial activities and thrombospondin (TSP)-1 protein expression were analyzed. TSP-1 and TSP-2 mRNA expression was inhibited highly significantly at cerivastatin doses >or=0.01 microM with maximums of 72% and 35%, respectively, at high glucose levels. The mRNA signals of the third glycoprotein fibronectin were not influenced. Furthermore, collagen-1 mRNA was inhibited highly significantly up to 71% and biglycan mRNA was similarly inhibited up to 45%. The mRNA expression of the matrix-stimulating transforming growth factor (TGF)-beta1 and matrix metalloproteinase (MMP)-2 was not altered significantly, whereas mRNA expression of the tissue inhibitor of metalloproteinase (TIMP)-2 was stimulated clearly up to 150%. Mevalonate, but not LDL replacement, reversed the effects. Immunofluorescence staining showed an unaltered TSP-1 pattern with cerivastatin doses up to 0.1 microM whereas higher doses impaired TSP-1 excretion. The effects of cerivastatin on haSMC growth and mRNA expression of the eight ECM components were not diminished by the increase in LDL and glucose levels. Since accelerated SMC growth and ECM formation contribute mainly to intimal thickening, cerivastatin may be protective against the development of atherosclerotic and restenotic lesions by its direct cellular effects. Increased LDL and glucose levels, as in diabetes, do not mitigate the beneficial effects of cerivastatin on cell growth and ECM formation in vitro.