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Abstract

Atherosclerosis leads to narrowing of vessels and acute coronary syndrome resulting in ischemic events due to either vasospasm or decreased blood flow. Atherosclerosis and acute coronary syndrome are more common in diabetes mellitus. Hyperglycemia and hypercholesterolemia in diabetes predispose the arteries to plaque development. Smoking, hypertension, male sex, and family history or genetic susceptibility are other predisposing factors for plaque development. Depending on the size, morphology, and symptoms of the patients, plaques can be classified as stable and unstable plaques. Unstable plaques are characterized by the presence of thin fibrous cap, necrotic core, and proliferation of vascular smooth muscle cells, angiogenesis and calcification. Plaque formation initiates with fatty streak and progresses through atheroma, atheromatous plaque to fibroatheromatous plaque. Fibroatheromatous plaques with thick fibrous cap are stable plaques. Thinning of the fibrous cap makes a plaque unstable, prone to rupture and thrombus formation. Mechanisms such as increased inflammation, foam cell deposition, impaired repair mechanism, endothelial cell dysfunction, vascular smooth muscle cell proliferation, angiogenesis, intra-plaque hemorrhage, and calcification which facilitate the plaque rupture are increased in diabetes mellitus. Thus, diabetes mellitus increases the prevalence of plaque formation and rupture. Diabetes mellitus affects various cellular and molecular effectors involved in plaque development and rupture. Understanding these cellular and molecular effectors and involved mechanisms in association with diabetes mellitus is essential for the development of potential therapeutic strategies. This review is a critical overview on the effect of hyperglycemia in diabetes mellitus on the pathogenesis of plaque formation and rupture.

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... Plaque formation starts with the inflammation in the fatty streak and deposition of excess lipids in the arterial intima as shown in Figure 1. Lipid deposition in the arterial intima is associated with inflammation, hyperglycemia, hyperlipidemia, and dys regulation of the angiotensin system [1][2][3]. Formation of the minimallyoxidized lipid (oxLDL) by the oxidation of deposited lipids results in the stimulation of the innate and adaptive immune responses. ...
... Chronically, fat deposition, inflammation, immune responses, secretion of pro-inflammatory cytokines, and Vascular Smooth Muscle Cells (VSMCs) proliferation leads to the increase in plaque size and renders the stable plaque into an unstable one followed by plaque rupture due to intraplaque hemorrhage, increased inflammation, and thinning of the fibrous cap [1,4,5]. Plaque rupture alleviates to thrombus formation and precipitates ischemic events including adverse cardiac events (myocardial infarction, angina), brain injury (ischemic stroke) and peripheral vascular disease [3]. Behavioral factors and some pathological conditions like Diabetes mellitus, smoking, hypertension, male sex, family history of atherosclerosis, or genetic susceptibility, add nuances to the disease presentation [3]. ...
... Plaque rupture alleviates to thrombus formation and precipitates ischemic events including adverse cardiac events (myocardial infarction, angina), brain injury (ischemic stroke) and peripheral vascular disease [3]. Behavioral factors and some pathological conditions like Diabetes mellitus, smoking, hypertension, male sex, family history of atherosclerosis, or genetic susceptibility, add nuances to the disease presentation [3]. The pivotal role of various inflammatory cytokines (interleukin (IL)-6, IL1β, IL-8, tumor necrosis factor-α, interferon-γ) damage and pathogen-associated molecular patterns (HMGB-1, RAGE, ENRAGE, S100 proteins, and lipopolysaccharides), surface receptors including TREM-1, TLR-2, and TLR-4 in the atherosclerotic condition has already been discussed in detail by others [1,3,[6][7][8][9][10]. ...
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Atherosclerosis is a chronic inflammatory disease of the vasculature that results in hardening of the vessel wall and narrowed lumen. Development of the atherosclerotic plaque starts from the deposition of the lipids in the fatty streak followed by its progression to atheroma, atheromatous plaque, and fibroatheroma. Diabetes mellitus (hyperglycemia), hypertension, smoking, obesity (hypercholesterolemia, dyslipidemia), male sex, family history of atherosclerosis, or genetic susceptibility are the risk factors for atherosclerosis. Chronic inflammation, immune cells infiltration, a bacterial or viral infection of the plaque, intraplaque hemorrhage, and endothelial and vascular smooth muscle dys regulation renders a stable plaque (rich in VSMC and collagen with few inflammatory cells) unstable (few VSMCs, more macrophages, and less collagen) which are prone to rupture. The role of various mediators of inflammation (damage associated molecular proteins), pro inflammatory cytokines (interleukin-1β,-6,-8, tumor necrosis factor-α etc.), and surface receptors (triggering receptors expressed on myeloid cell 1, Toll-like receptors, receptor for glycation end products etc.) in the pathogenesis of plaque development and rupture has been discussed in the literature. The mechanistic aspects of plaque progression have been discussed mainly at the protein level. The epigenetic regulation of atherosclerosis is a current area of interest to researchers. However, regulation of the development, progression, and rupture of the atherosclerotic plaque at the transcriptional level has not been studied in detail. This review emphasizes the role of transcription factors associated with atherosclerotic plaque progression and rupture.
... Thus attenuating TREM-1 expression may attenuate inflammation and vessel stenosis and a decreased TREM-1 expression in the TAK-242 group compared to the ethanol group (9.62 ±1.42 vs 10.62 ± 3.40) suggest that TAK-242 not only decreases TLR-4 expression but also TREM-1 though not significant (Figure 3). TLR-4 and TREM-1 are expressed mainly on macrophages and these cells are recruited during acute inflammation to clear off the debris, but sustained recruitment of these immune cells may lead to chronic inflammation [23,26,40,41]. The recruitment of immune cells is facilitated by MCP-1 and proinflammatory cytokines including IL-6, IL-8, and TNF-α [42]. ...
... MMP expression is associated with matrix degradation and expression levels of TGF-β, whose expression is increased in early as well as late AVF, regulates matrix remodeling by ECM deposition [17]. Proinflammatory cytokines including IL-6, IL-8, and TNF-α regulate the expression of MMPs [9,40,41]; thus, targeting inflammatory mediators is of interest to modify the anastomosis microenvironment favorable for AVF maturation. An attenuated expression of mediators of inflammation with patent lumen and presence of flow in outflow vein in TAK-242 group is suggestive of the beneficial role of inhibiting TLR-4 in attenuating early thrombosis playing a critical role in AVF nonmaturation. ...
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Arteriovenous fistula (AVF) is the preferred vascular access in hemodialysis patients; however, it is afflicted with a high failure rate. Chronic inflammation, excessive neointimal hyperplasia (NIH), vessel stenosis, early thrombosis, and failure of outward remodeling are the major causes of AVF maturation failure. Inflammatory mediator toll-like receptor (TLR)-4 plays a critical role in NIH, arterial thrombosis, and stenosis. We investigated the effect of TLR-4 inhibition on early thrombosis. Yucatan miniswine were used to create AVF involving femoral artery and femoral vein and treated with TLR-4 inhibitor TAK-242 with ethanol as the vehicle. The vessels were assessed after 12 weeks using histomorphometry, immunostaining, ultrasound, angiography, and optical coherence tomography. Inhibition of TLR-4 attenuated inflammation and early thrombosis in 50% of animals, and blood flow was present through AVF in 25% of animals. Thus, targeting TLR-4 to attenuate inflammation and early thrombosis might be a therapeutic approach to keep AVF patent and maintain blood flow through the outflow vein.
... The development of atherosclerosis is associated with risk factors including hypercholesterolemia, hyperglycemia, hypertension, smoking, male sex, and a family history. Inflammation in the stable plaque results in unstable plaque characterized by a thin fibrous cap, necrotic core, and proliferation of vascular smooth muscle cells, angiogenesis, and calcification, which is prone to rupture, leading to ischemic events [5,6]. Mediators of inflammation, including high mobility group box 1 (HMGB-1), receptor for advanced glycation end products (RAGE), toll-like receptors (TLRs), triggering receptor expressed on myeloid cells-1 (TREM-1), proinflammatory cytokines including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and immune cells such as macrophages, have been found to be involved in the pathogenesis of atherosclerosis [5,[7][8][9][10]. ...
... Development of atherosclerosis and targets of therapeutic importance using nanoparticles: The pathogenesis of atherosclerosis starts with fatty streak with increased deposition and oxidation of lipids and infiltration of immune cells results in the formation of atheroma, fibroatheroma, and atheromatous plaque (stable) followed by the unstable plaque that is prone to rupture. Nanomaterials might be used to target various factors involved in the pathogenesis of atherosclerosis including lipid metabolism (1), vascular smooth muscles (2), endothelial cells (3), macrophages (4), angiogenesis (5), and thrombus (6) to deliver the growth factors, genes, proteins, and drugs. Neointimal tissue and extracellular membrane components are other potential targets as discussed in the text. ...
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Nanotechnology could offer a new complementary strategy for the treatment of vascular diseases including coronary, carotid, or peripheral arterial disease due to narrowing or blockage of the artery caused by atherosclerosis. These arterial diseases manifest correspondingly as angina and myocardial infarction, stroke, and intermittent claudication of leg muscles during exercise. The pathogenesis of atherosclerosis involves biological events at the cellular and molecular level, thus targeting these using nanomaterials precisely and effectively could result in a better outcome. Nanotechnology can mitigate the pathological events by enhancing the therapeutic efficacy of the therapeutic agent by delivering it at the point of a lesion in a controlled and efficacious manner. Further, combining therapeutics with imaging will enhance the theranostic ability in atherosclerosis. Additionally, nanoparticles can provide a range of delivery systems for genes, proteins, cells, and drugs, which individually or in combination can address various problems within the arteries. Imaging studies combined with nanoparticles helps in evaluating the disease progression as well as the response to the treatment because imaging and diagnostic agents can be delivered precisely to the targeted destinations via nanocarriers. This review focuses on the use of nanotechnology in theranostics of coronary artery and peripheral arterial disease.
... The pathogenesis of atherosclerosis is multifactorial involving the deposition of lipids in the intima, foam cell formation, and mediators of inflammation mediating plaque formation with narrowing and hardening of the arteries. Chronic inflammation within the plaque and apoptosis of vascular smooth muscle cells (VSMCs) render it vulnerable to rupture and the rupture of the plaque due to a weak fibrous cap precipitates thrombus and emboli formation [1][2][3][4][5][6][7][8]. Along with these, VSMCs also play an important role in plaque formation and vulnerability. ...
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Plaque formation, thrombosis, and embolism are the underlying causes of acute cardiovascular events such as myocardial infarction and stroke while early thrombosis and stenosis are common pathologies for the maturation failure of arteriovenous fistula (AVF). Chronic inflammation is a common underlying pathogenesis mediated by innate and adaptive immune response involving infiltration of immune cells and secretion of pro- and anti-inflammatory cytokines. Impaired immune cell infiltration and change in vascular smooth muscle cell (VSMC) phenotype play a crucial role in the underlying pathophysiology. However, the change in the phenotype of VSMCs in a microenvironment of immune cell infiltration and increased secretion of cytokines have not been investigated. Since change in VSMC phenotype regulates vessel remodeling after intimal injury, in this study, we investigated the effect of macrophages and pro-inflammatory cytokines, IL-6, IL-1β, and TNF-α, on the change in VSMC phenotype under in vitro conditions. We also investigated the expression of the markers of VSMC phenotypes in arteries with atherosclerotic plaques and VSMCs isolated from control arteries. We found that the inhibition of cytokine downstream signaling may mitigate the effect of cytokines on the change in VSMCs phenotype. The results of this study support that regulating or targeting immune cell infiltration and function might be a therapeutic strategy to mitigate the effects of chronic inflammation to attenuate plaque formation, early thrombosis, and stenosis, and thus enhance AVF maturation.
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Advances in tissue engineering and regenerative medicine and cell therapy research have led to potential therapeutic products to provide structural/mechanical or metabolic function for various medical conditions characterized by organ and/or tissue damage. To date, artificial skin; musculoskeletal tissue (bone and ligaments); cornea tissue; heart valve allografts; hematopoietic stem and progenitor cells derived from peripheral and cord blood; reproductive tissue; cellular therapies; human cellular- and tissue-based products for implantation, transplantation, infusion, or transfer into a human recipient have been developed. Strategic investment in science, engineering, and allied disciplines is a critical determinant for advancing both basic and translational research in organ/tissue replacement, repair, restoration, and regeneration of products for the clinic and marketplace. For engineered tissue and regenerative medicine products as well as other human medical products, important considerations include: cell/tissue and/or biomolecule sourcing, processing, and characterization; detection and avoidance of adventitious agents; product consistency and stability; and quality assurance procedures. Preclinical investigation and regulatory evaluation, e.g., toxicity and immunogenicity testing for local/systemic and acute/chronic responses, as well as assessment of in vivo remodeling determines the effectiveness of tissue engineered products. This chapter aims not only to set out the current state of human cellular- and tissue-based products but also to showcase successful commercialization of products, and their clinical adoption and governmental regulation. An overview on the ethical perspective associated with various determinant and product-specific risks related to translation of tissue based products are deliberated in different sections with the focus on new and different research directions such as bio-printing and stem cell technology.
Chapter
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Vascularization is an exciting and complex mechanism involving angiogenesis and arteriogenesis. The metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) are associated with multiple metabolic toxicities, which result in reactive oxygen species (ROS) due to an elevated tension of oxidative-redox stress and an accelerated atherosclerosis termed atheroscleropathy. This atheroscleropathy is associated with accelerated angiogenesis within the vulnerable, thin-cap fibro-atheroma, prone to rupture resulting in acute coronary syndromes (ACS). The resulting intimopathy with its neovascularization due to angiogenesis of the adventitial vasa vasorum (Vv) is prone to intraplaque hemorrhage (IPH). These IPH are associated with destabilization of the vulnerable plaques resulting in plaque erosion and plaque rupture resulting in ACS. In atheroscleropathy the adventitial Vv invades the plaque in a malignant-like fashion and concurrently is associated with chronic inflammation, as macrophages are being deposited within the shoulder regions of these vulnerable plaques. These angiogenic Vv provide a custom delivery vascular network for multiple detrimental substrates, which further accelerates the growth of these vulnerable plaques and atheroscleropathy. There exists a vascularization paradox in MS and T2DM, in that, angiogenesis within the plaque is induced and arteriogenesis is impaired. This review will attempt to provide a database of knowledge regarding the vascularization process (angiogenesis and arteriogenesis) and its mechanisms to better understand the increased cardiovascular risk and the increased morbidity and mortality associated with MS and T2DM.
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An emerging body of evidence suggests that vascular remodeling in diabetic patients involves a perturbation of the balance between cell proliferation and cell death. Our aim was to study whether arteries and vascular smooth muscle cells (VSMCs) isolated from diabetic patients exhibit resistance to apoptosis induced by several stimuli. Internal mammary arteries (IMAs) were obtained from patients who had undergone coronary artery bypass graft surgery. Arteries from diabetic patients showed increasing levels of Bcl-2 expression in the media layer, measured by immunofluorescence and by Western blotting. Human IMA VSMCs from diabetic patients showed resistance to apoptosis, measured as DNA fragmentation and caspase-3 activation, induced by C-reactive protein (CRP) and other stimuli, such as hydrogen peroxide and 7beta-hydroxycholesterol. The diabetic cells also exhibited overexpression of Bcl-2. Knockdown of Bcl-2 expression with Bcl-2 siRNA in cells from diabetic patients reversed the resistance to induced apoptosis. Consistent with the above, we found that pretreatment of nondiabetic VSMCs with high glucose abolished the degradation of Bcl-2 induced by CRP. Moreover, cell proliferation was increased in diabetic compared with nondiabetic cells. This differential effect was potentiated by glucose. We conclude that the data provide strong evidence that arterial remodeling in diabetic patients results from a combination of decreased apoptosis and increased proliferation.
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Neovascularisation of atherosclerotic plaques correlates with increased plaque instability and subsequent risk of vascular complications. Diabetics have widespread atherosclerotic involvement of the arterial tree and a more aggressive form of the disease culminating in increased plaque instability. This results in a greater incidence of ischaemic sequelae than in non-diabetics. Previous studies have examined neovascularisation as a marker of plaque instability in both the carotid and coronary territories and revealed a greater degree in both symptomatic and diabetic patients. This is the first study to examine intimal neovascularisation in lower limb peripheral arterial disease. Arterial specimens were taken from 20 patients, ten of whom were type 2 diabetics, undergoing major lower limb amputation for unreconstructable critical ischaemia. Sections were stained with H&E for morphological assessment and inflammatory cell characterisation. Additional sections underwent immunohistochemical staining for CD31 and von-Willebrand Factor (vWF) and the number of intimal vessels per four 40x magnification fields assessed. There was a more prominent inflammatory infiltrate in diabetic subjects compared to non-diabetic controls. Diabetic patients had a greater degree of intimal neovascularisation compared to controls with a median of 11.5 and 2.0 vessels per field respectively (P<0.05). Sub-group analysis revealed that diabetic patients medicating with HMG-CoA Reductase inhibitors (Statins) had a greater degree of neovascularisation compared to those not taking this class of medication. Diabetic patients with critical limb ischaemia requiring amputation demonstrate a greater degree of plaque intimal neovascularisation and inflammatory infiltrate compared to their non-diabetic counterparts. This may explain the greater plaque instability and subsequent cardiovascular complications seen in these patients.
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Sustained proinflammatory responses in rheumatoid arthritis, atherosclerosis, and diabetic retinopathy, as well as in cancer, are often associated with increased angiogenesis that contributes to tissue disruption and disease progression. High mobility group B1 (HMGB1) has been recognized as a proinflammatory cytokine and more recently, as a proangiogenic factor. HMGB1 can either be passively released from necrotic cells or actively secreted in response to angiogenic and inflammatory signals. HMGB1 itself may signal through the receptor for advanced glycation end products (RAGE), and via toll-like receptors, TLR2 and TLR4. Activation of these receptors results in the activation of NFkappaB, which induces the upregulation of leukocyte adhesion molecules and the production of proinflammatory cytokines and angiogenic factors in both hematopoietic and endothelial cells, thereby promoting inflammation. Interestingly, HMGB1 seems to be involved in a positive feedback mechanism, that may help to sustain inflammation and angiogenesis in several pathological conditions, thereby contributing to disease progression. Endothelial cells express HMGB1, as well as the receptors RAGE, TLR2, and TLR4, and in diverse pathologies HMGB1 and its receptors are overexpressed. Furthermore, HMGB1-induced signaling can activate NFkappaB, which can subsequently induce the expression of HMGB1 receptors. Thus, HMGB1 can mediate amplification of inflammation and angiogenesis through increased secretion of HMGB1 and increased expression of the receptors it can interact with. In this review, we discuss signaling cascades that HMGB1 can induce via TLRs and RAGE, as well as its contribution to pathologies involving endothelial cells.
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Objective: To determine the relationship between increased triggering receptor expressed on myeloid cells (TREM)-1 and plaque stability in atherosclerotic carotid stenosis. Methods: The mRNA transcripts and protein for TREM-1, MMP-1, MMP-9, collagen type I (COL1A1) and collagen type III (COL3A1) were analyzed by qPCR and immunofluorescence in both tissues and VSMCs isolated from atherosclerotic carotid plaques of symptomatic and asymptomatic patients with carotid stenosis. Results: The TREM-1, MMP-1 and MMP-9 mRNA transcripts were significantly increased (TREM-1, p < 0.01; MMP-1, p < 0.01 and MMP-9, p < 0.001) while COL1A1 and COL3A1 mRNA transcripts were decreased (p < 0.001) in VSMCs isolated from carotid plaques of symptomatic (S) than asymptomatic (AS) patients. Stimulation of cells with TNF-α further increased the mRNA transcripts of TREM-1, MMPs, COL1A1 and COL3A1. Modulation of TREM-1 by treatment with TREM-1 decoy receptor rTREM-1/Fc, and either TREM-1 antibodies or TREM-1 siRNA attenuated the TNF-α-induced expression of MMP-1 and MMP-9 (p < 0.01) and COL1A1 and COL3A1 (p < 0.01) in S compared to AS VSMCs isolated from carotid plaques. Inhibition of NF-kB (BAY 11-7085), JNK (SP600125) and PI3K (LY294002) signaling pathways decreased the expression of TREM-1 (p < 0.01), MMP-1 (p < 0.001) and MMP-9 (p < 0.01) in TNF-α-treated VSMCs isolated from S carotid plaques compared to AS patients. Conclusion: Increased expression of TREM-1 in S compared to AS patients involving MMP-1 and MMP-9 suggest a potential role of TREM-1 in plaque destabilization. Selective blockade of TREM-1 may contribute to the development of new therapies and promising targets for stabilizing vulnerable atherosclerotic plaques.
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Background: Vascular complications are the leading cause of morbidity and mortality among patients with type 1 and type 2 diabetes mellitus. These vascular abnormalities result of a chronic hyperglycemic state, which leads to an increase in oxidative stress and inflammatory responses. Aim: This review addresses the relationships among endothelial dysfunction, hypercoagulability and inflammation and their biomarkers in the development of vascular complications in type 1 and type 2 diabetes. Results: Inflammation, endothelial dysfunction, and hypercoagulability are correlated to each other, playing an important role in the development of vascular complications in diabetic patients. Moreover, it has been observed that several endothelial, inflammatory and pro-coagulant biomarkers, such as VWF, IL-6, TNF-α, D-dimer and PAI-1, are increased in diabetic patients who have microvascular and macrovascular complications, including nephropathy or cardiovascular disease. Conclusion: It is promising the clinical and laboratory use of endothelial, inflammatory and pro-coagulant biomarkers for predicting the risk of cardiovascular and renal complications in diabetic patients and for monitoring these patients.
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Vascular calcification (VC) is the deposition of calcium/phosphate in the vasculature, which portends a worse clinical outcome and predicts major adverse cardiovascular events. VC is an active process initiated and regulated via a variety of molecular signalling pathways. There are mainly two types of calcifications: the media VC and the intima VC. All major risk factors for cardiovascular disease (CVD) have been linked to the presence/development of VC. Besides the risk factors, a genetic component is also operative to determine arterial calcification. Several events take place before VC is established, including inflammation, trans-differentiation of vascular cells and homing of circulating pro-calcific cells. Diabetes is an important predisposing factor for VC. Compared with non-diabetic subjects, patients with diabetes show increased VC and higher expression of bone-related proteins in the medial layer of the vessels. In this review we will highlight the mechanisms underlying vascular calcification in diabetic patients.
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Background: Research targeting glycosylated hemoglobin A1c (HbA1c) to <6.5% to prevent coronary heart disease (CHD) events has conflicting results. We previously observed the haptoglobin (Hp) Hp2-2 genotype is associated with a ∼10-fold increased CHD risk among individuals with HbA1c ≥6.5%, and thus might be useful in identifying those at high risk of CHD who would benefit from maintaining HbA1c <6.5%. Objectives: This study sought to model whether HbA1c ≥ 6.5% in the Hp2-2 genotype is associated with CHD in a prospective case-control study nested within the Health Professionals Follow-Up Study (HPFS). Methods: HbA1c concentration and Hp genotype were determined for 695 incident cases of CHD from 1994 to 2010 and matched control participants. Logistic regression models calculated relative risk (RR) and 95% CI, for the first and second halves of follow-up, adjusting for confounding variables. A dataset from the Nurses' Health Study served as a replication cohort. Results: The prevalence of the Hp2-2 genotype in HPFS was 39%. Compared with HbA1c <6.5%, the RR of CHD for HbA1c ≥6.5% for the Hp2-2 genotype over full follow-up was 3.07 (95% CI: 1.37 to 6.86) to 3.88 (95% CI: 1.31 to 11.52) during the first half of follow-up and 2.16 (95% CI: 0.61 to 7.61) in the second half. The corresponding RRs for the Hp1-1 + Hp2-1 genotypes were: full follow-up, 2.19 (95% CI: 1.14 to 4.24); first half, 1.60 (95% CI: 0.73 to 3.53); and second half, 4.72 (95% CI: 1.26 to 17.65). Conclusions: In 2 independent cohorts, the risk of CHD associated with HbA1c ≥6.5% is pronounced in the Hp2-2 genotype, particularly in early cases. The Hp2-2 genotype may identify individuals at greatest CHD risk from hyperglycemia.
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Although degradation of extracellular matrix (ECM) by matrix metalloproteinases (MMPs) is thought to be involved in unstable carotid plaques in atherosclerosis, the mechanisms for the expression of MMPs are poorly understood. Here, we demonstrate that collagen loss in vascular smooth vessel cells (VSMCs) isolated from unstable plaques was induced by epidermal growth factor (EGF) through the activation of p38-MAPK and JNK-MAPK pathways. The expressions of MMP-1 and MMP-9 were down-regulated by inhibitors of p38-MAPK and JNK-MAPK signaling pathways. In addition, we examined whether Ets-1 (v-ets erythroblastosis virus E26 oncogene homologue 1), an important regulator of different genes, is involved in destabilizing vulnerable plaques in patients with carotid stenosis. We demonstrate that EGF induces Ets-1 expression and decreases interstitial and basement membrane collagen in vascular smooth muscle cells (VSMCs) from patients with carotid stenosis. Increased expression of MMP-1 and -9 and decreased collagen mRNA transcripts were also found in Ets-1 overexpressed VSMCs. Transfection with both dominant-negative form of Ets-1 (Ets-DN) and siRNA, blocked EGF induced MMP-1, and MMP-9 expressions and increased the mRNA transcripts for Col I (α1) and Col III (α1) in S compared to the AS group. Inhibitors of p38 MAPK (SB202190) and JNK MAPK (SP600125) signaling pathways decreased the expression of Ets-1, MMP-1 and MMP-9 and increased collagen type I and III expression in EGF treated VSMCs. This study provides a mechanistic insight into the role of Ets-1 in the plaque destabilization in patients with carotid stenosis involving p38 MAPK, and JNK signaling pathways. Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology.
Article
Advanced glycation end-products (AGEs) comprise a group of non-enzymatic post-translational modifications of proteins and are elevated in diabetic tissues. AGE-modification impairs the digestibility of collagen in vitro but little is known about its relation to collagen-degrading proteinases in vivo. N(ε)-carboxymethyllysine (CML) is a stable AGE that forms on lysyl side-chains in the presence of glucose, probably via a transition metal-catalysed mechanism. Here, rats with streptozotocin-induced diabetes and non-diabetic controls were treated for 8 weeks with placebo or the Cu(II)-selective chelator, triethylenetetramine (TETA), commencing 8 weeks after disease induction. Actions of diabetes and drug treatment were measured on collagen and collagen-degrading proteinases in kidney tissue. The digestibility and CML content of collagen, and corresponding levels of mRNAs and collagen, were related to changes in collagen-degrading-proteinases. Collagen-degrading proteinases, cathepsin L (CTSL) and matrix metalloproteinase-2 (MMP-2) were increased in diabetic rats. CTSL-levels correlated strongly and positively with increased collagen-CML levels and inversely with decreased collagen digestibility in diabetes. The collagen-rich mesangium displayed a strong increase of CTSL in diabetes. TETA treatment normalised kidney collagen content and partially normalised levels of CML and CTSL. These data provide evidence for an adaptive proteinase response in diabetic kidneys, affected by excessive collagen-CML formation and decreased collagen digestibility. The normalisation of collagen and partial normalisation of CML- and CTSL-levels by TETA treatment supports the involvement of Cu(II) in CML formation and altered collagen metabolism in diabetic kidneys. Cu(II)-chelation by TETA may represent a treatment option to rectify collagen metabolism in diabetes independent of alterations in blood glucose levels. Copyright © 2015. Published by Elsevier B.V.
Article
Objective: Diabetes mellitus (DM) type II is increasing rapidly worldwide. Patients with DM II have a greater atherosclerotic burden and higher risk of developing cardiovascular complications. Inflammation has been proposed as the main cause for the high risk of atherosclerotic disease in DM II. In this study, we compared markers of inflammation and fibrous repair in plaques from subjects with and without DM II. Approach and results: Carotid endarterectomy specimens were obtained from 63 patients with and 131 without DM. Plaque structure, connective tissue proteins, inflammatory cells, and markers were analyzed by immunohistochemistry, ELISA, Mesoscale, and Luminex technology. Carotid plaques from diabetics had lower levels of extracellular matrix proteins, elastin, and collagen, which are critical for plaque stability. Plaques from diabetics had reduced levels of platelet-derived growth factor and matrix metalloproteinase-2, both important for tissue repair. No differences were observed in inflammatory markers in plaques from diabetic and nondiabetic patients. Conclusion: This study suggests that atherosclerotic plaques in subjects with DM II are more prone to rupture because of impaired repair responses rather than to increased vascular inflammation. Although this study did not have a mechanistic design, our findings suggest that targeting impaired repair responses in carotid plaques may help to increase our understanding of atherosclerotic plaque development and vulnerability in patients with DM II.
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Atherosclerosis causes clinical disease through luminal narrowing or by precipitating thrombi that obstruct blood flow to the heart (coronary heart disease), brain (ischemic stroke), or lower extremities (peripheral vascular disease). The most common of these manifestations is coronary heart disease, including stable angina pectoris and the acute coronary syndromes. Atherosclerosis is a lipoprotein-driven disease that leads to plaque formation at specific sites of the arterial tree through intimal inflammation, necrosis, fibrosis, and calcification. After decades of indolent progression, such plaques may suddenly cause life-threatening coronary thrombosis presenting as an acute coronary syndrome. Most often, the culprit morphology is plaque rupture with exposure of highly thrombogenic, red cell-rich necrotic core material. The permissive structural requirement for this to occur is an extremely thin fibrous cap, and thus, ruptures occur mainly among lesions defined as thin-cap fibroatheromas. Also common are thrombi forming on lesions without rupture (plaque erosion), most often on pathological intimal thickening or fibroatheromas. However, the mechanisms involved in plaque erosion remain largely unknown, although coronary spasm is suspected. The calcified nodule has been suggested as a rare cause of coronary thrombosis in highly calcified and tortious arteries in older individuals. To characterize the severity and prognosis of plaques, several terms are used. Plaque burden denotes the extent of disease, whereas plaque activity is an ambiguous term, which may refer to one of several processes that characterize progression. Plaque vulnerability describes the short-term risk of precipitating symptomatic thrombosis. In this review, we discuss mechanisms of atherosclerotic plaque initiation and progression; how plaques suddenly precipitate life-threatening thrombi; and the concepts of plaque burden, activity, and vulnerability.
Article
Coronary artery calcification is a well-established predictor of future cardiac events; however, it is not a predictor of unstable plaque. The intimal calcification of the atherosclerotic plaques may begin with smooth muscle cell apoptosis and release of matrix vesicles and is almost always seen microscopically in pathological intimal thickening, which appears as microcalcification (≥0.5 μm, typically <15 μm in diameter). Calcification increases with macrophage infiltration into the lipid pool in early fibroatheroma where they undergo apoptosis and release matrix vesicles. The confluence of calcified areas involves extracellular matrix and the necrotic core, which can be identified by radiography as speckled (≤2 mm) or fragmented (>2, <5 mm) calcification. The calcification in thin-cap fibroatheromas and plaque rupture is generally less than what is observed in stable plaques and is usually speckled or fragmented. Fragmented calcification spreads into the surrounding collagen-rich matrix forming calcified sheets, the hallmarks of fibrocalcific plaques. The calcified sheets may break into nodules with fibrin deposition, and when accompanied by luminal protrusion, it is associated with thrombosis. Calcification is highest in fibrocalcific plaques followed by healed plaque rupture and is the least in erosion and pathological intimal thickening. The extent of calcification is greater in men than in women especially in the premenopausal period and is also greater in whites compared with blacks. The mechanisms of intimal calcification remain poorly understood in man. Calcification often occurs in the presence of apoptosis of smooth muscle cells and macrophages with matrix vesicles accompanied by expression of osteogenic markers within the vessel wall.
Article
Atherosclerosis is a chronic inflammatory disease with activation of both the innate and adaptive arms of the immune system. Dendritic cells (DCs) are potent activators of adaptive immunity and have been identified in the normal arterial wall and within atherosclerotic lesions. Recent evidence points to a functional role for DCs in all stages of atherosclerosis because of their myriad functions including lipid uptake, antigen presentation, efferocytosis, and inflammation resolution. Moreover, DC-based vaccination strategies are currently being developed for the treatment of atherosclerosis. This review will focus on the current evidence as well as the proposed roles for DCs in the pathogenesis of atherosclerosis and discuss future therapeutic strategies.
Article
Objective—The mechanisms promoting the focal formation of rupture-prone coronary plaques in vivo remain incompletely understood. This study tested the hypothesis that coronary regions exposed to low endothelial shear stress (ESS) favor subsequent development of collagen-poor, thin-capped plaques. Approach and Results—Coronary angiography and 3-vessel intravascular ultrasound were serially performed at 5 consecutive time points in vivo in 5 diabetic, hypercholesterolemic pigs. ESS was calculated along the course of each artery with computational fluid dynamics at all 5 time points. At follow-up, 184 arterial segments with previously identified in vivo ESS underwent histopathologic analysis. Compared with other plaque types, eccentric thin-capped atheromata developed more in segments that experienced lower ESS during their evolution. Compared with lesions with higher preceding ESS, segments persistently exposed to low ESS (<1.2 Pa) exhibited reduced intimal smooth muscle cell content; marked intimal smooth muscle cell phenotypic modulation; attenuated procollagen-I gene expression; increased gene and protein expression of the interstitial collagenases matrix-metalloproteinase-1, -8, -13, and -14; increased collagenolytic activity; reduced collagen content; and marked thinning of the fibrous cap. Conclusions—Eccentric thin-capped atheromata, lesions particularly prone to rupture, form more frequently in coronary regions exposed to low ESS throughout their evolution. By promoting an imbalance of attenuated synthesis and augmented collagen breakdown, low ESS favors the focal evolution of early lesions toward plaques with reduced collagen content and thin fibrous caps—2 critical determinants of coronary plaque vulnerability.
Article
Macrophages orchestrate the inflammatory response in inflamed tissues, and recent work indicates that these cells can alter their phenotypes and functions accordingly in response to changes in the microenvironment. Initial work in models of cardiovascular disease used immunologic markers to characterize macrophage phenotypes present in atherosclerotic plaque, and these studies have lately been extended through the use of markers that are more specific for atherosclerosis and metabolic disease. Together, these studies have led to a novel view of the function of macrophages in the development of atherosclerosis that suggests dynamic plasticity. Understanding this plasticity and the ensuing macrophage heterogeneity could lead to novel strategies of pharmacological intervention to combat chronic inflammation in metabolic diseases. Most importantly, revealing the functional characteristics of individual macrophage phenotypes will lead to a better understanding of their contribution to lesion development and plaque stability.
Article
The aim of the present study was to compare the characteristics of nonculprit coronary plaques between diabetes mellitus (DM) and non-DM patients using 3-vessel optical coherence tomography (OCT) imaging. DM patients have a higher recurrent cardiovascular event rate. Patients who had undergone 3-vessel OCT imaging were identified from the Massachusetts General Hospital OCT Registry. Characteristics of nonculprit plaques were compared between DM and non-DM patients. A total of 230 nonculprit plaques were identified in 98 patients. Compared with non-DM patients, DM patients had a larger lipid index (LI) (averaged lipid arc × lipid length; 778.6 ± 596.1 vs. 1358.3 ± 939.2, p < 0.001) and higher prevalence of calcification (48.4% vs. 72.2%, p = 0.034) and thrombus (0% vs. 8.3%, p = 0.047). DM patients were divided into 2 groups based on glycated hemoglobin (A(1C)) levels of ≤7.9% and ≥8.0%. LI was significantly correlated with diabetic status (778.6 ± 596.1 [non-DM] vs. 1,171.5 ± 708.1 [A(1C) ≤7.9%] vs. 1,638.5 ± 1,173.8 [A(1C) ≥8%], p value for linear trend = 0.005), and fibrous cap thickness was inversely correlated with the A(1C) level (99.4 ± 46.7 μm [non-DM] vs. 91.7 ± 29.6 μm [A(1C) ≤7.9%] vs. 72.9 ± 22.7 μm [A(1C) ≥8%], p value for linear trend = 0.014). Patients with A(1C) ≥8% also had the highest prevalence of thin-cap fibroatheroma (TCFA) and macrophage infiltration. Compared with non-DM patients, DM patients have a larger LI and a higher prevalence of calcification and thrombus. The LI was larger and TCFA and macrophage infiltration were frequent in patients with A(1C) ≥8%.
Article
Mesenteric vascular hypertrophy occurs in experimental diabetes. The present study examines whether this medial hypertrophy originates via cellular hyperplasia or hypertrophy of smooth muscle cells or an increase in collagen content. Male Sprague–Dawley diabetic (streptozotocin, 50 mg/kg, i.v.) rats were compared with control rats after 3 weeks in order to study mesenteric and aortic smooth muscle cell size and degree of cellular polyploidy. Collagen content in the mesenteric vessels was examined via staining with Sirius red. Further groups of control and diabetic animals were studied after 7 and 14 days of diabetes to assess proliferation in the various layers of the vessel wall using incorporation of [3H]thymidine (0.5 mCi/kg, i.p.). Smooth muscle cell size was measured by a Coulter counter and polyploidy assessed using flow cytometry measurement of cellular DNA content. Diabetic smooth muscle cell size was reduced in both the aorta and the mesenteric vessels and polyploidy was increased in these cells. The collagen content of diabetic mesenteric media was proportionally increased. At day 7, diabetic mesenteric endothelial and adventitial layers showed increased [3H]thymidine labeling of cells and this was not observed in the media of these vessels. These findings indicate that increased endothelial and adventitial cell proliferation are early events in diabetes associated vascular hypertrophy. Furthermore, an increase in extracellular matrix within the media is an important feature of diabetes associated vascular hypertrophy.
Article
Atherosclerosis is a chronic disease of the arterial wall, and a leading cause of death and loss of productive life years worldwide. Research into the disease has led to many compelling hypotheses about the pathophysiology of atherosclerotic lesion formation and of complications such as myocardial infarction and stroke. Yet, despite these advances, we still lack definitive evidence to show that processes such as lipoprotein oxidation, inflammation and immunity have a crucial involvement in human atherosclerosis. Experimental atherosclerosis in animals furnishes an important research tool, but extrapolation to humans requires care. Understanding how to combine experimental and clinical science will provide further insight into atherosclerosis and could lead to new clinical applications.
Article
Sustained inflammation may stimulate a reparative process increasing early reparative type III collagen synthesis, promoting atherosclerotic plaque progression. We evaluated inflammation, neovascularization, intra-plaque hemorrhage (IPH), and collagen deposition in human aortic atherosclerotic plaques from patients with and without diabetes mellitus (DM). Plaques were procured at autopsy from lower thoracic and abdominal aorta from DM (n = 20) and non-DM (n = 22) patients. Inflammation and neovascularization were quantified by double-label immunochemistry and the IPH grade was scored using H&E-stained sections. Type I and type III collagens were quantified using Picro-Sirius red stain with polarization microscopy and computerized planimetry. In non-DM plaques, 27%, 40%, and 33% had mild, moderate and severe inflammation in the fibrous cap and shoulder compared with 2%, 30% and 68% in DM plaques (p < 0.001). The geometric mean neovessel count was increased in DM versus non-DM plaques (140 [95% CI: 119-165] versus 59 [95% CI: 51-70]; p < 0.001). The IPH grade was increased in DM verses non-DM plaques (0.82 ± 0.11 versus 0.29 ± 0.11; p < 0.001) (percentage grade). The density of type III was increased in DM plaques (0.16 ± 0.01 versus 0.06 ± 0.01; p < 0.001) with a non-significant reduction in type I density in DM when compared with non-DM (0.28 ± 0.03 versus 0.33 ± 0.03; p = 0.303) (content per mm²). The increase in type III collagen content correlated with total neovessel content (r = 0.58; p < 0.001) in DM plaques. In conclusion, our study suggests that enhanced type III collagen deposition was associated with inflammation, neovascularization and IPH, and may be a contributing factor in DM plaque progression.
Article
Patients with diabetes mellitus are at increased risk of cardiovascular morbidity and mortality. Atherothrombosis, defined as atherosclerotic lesion disruption with superimposed thrombus formation, is the most common cause of death among these patients. Following plaque rupture, adherence of platelets is followed by local activation of coagulation, the formation of a cross-linked fibrin clot and the development of an occlusive platelet rich fibrin mesh. Patients with diabetes exhibit a thrombotic risk clustering which is composed of hyper-reactive platelets, up regulation of pro-thrombotic markers and suppression of fibrinolysis. These changes are mainly mediated by the presence of insulin resistance and dysglycaemia and an increased inflammatory state which directly affects platelet function, coagulation factors and clot structure. This prothrombotic state is related to increased cardiovascular risk and may account for the reduced response to antithrombotic therapeutic approaches, underpinning the need for adequate antithrombotic therapy in patients with diabetes to reduce their cardiovascular mortality.
Article
Diabetes is a risk factor for the development of atherothrombosis and venous thromboembolism (VTE). We investigated whether plasma from patients with type 2 diabetes has an imbalance of pro- versus anti-coagulation resulting in hypercoagulability despite normal conventional coagulation tests. We analyzed blood samples from 60 patients with type 2 diabetes and 60 gender- and age-matched healthy subjects (controls) for the levels of pro- and anti-coagulant factors, for thrombin generation and for the numbers of cell-derived circulating microparticles bearing such pro-coagulant triggers as tissue factor and negatively charged phospholipids. The levels of pro- or anti-coagulants as measured with conventional coagulation tests or single factor measurements were similar to those of the control population. In contrast, the median (range) of the height of the thrombin peak (taken as an index of thrombin generation) was higher in patients [205 nM (126-352)] than controls [151 nM (41-289)], P < 0.001. The median numbers of circulating microparticles were higher for patients [5,041/μl (1,821-13,132)] than for controls [1,753/μl (554-13,308)], P < 0.001 and their values were correlated with the height of the thrombin peak (ρ = 0.66, P < 0.001). In conclusion, plasma from patients with type 2 diabetes possesses an imbalance of pro- versus anti-coagulation resulting in hypercoagulability that can be detected by thrombin generation tests, but not by the measurement of the single pro- or anti-coagulant factors. This hypercoagulability is associated with increased numbers of circulating microparticles bearing endogenous pro-coagulant triggers. These findings might explain the relatively high risk of atherothrombosis and VTE described in these patients.
Article
Advanced glycation end products (AGEs) play an important role in collagen deposition in diabetic cardiomyopathy. TRB3, a mammalian homolog of Drosophila tribbles, functions to increase glucose intolerance and regulates cell proliferation. We demonstrated that AGEs induce collagen type I expression but inhibit collagen type III expression, accompanied by increased TRB3 expression. Furthermore, the collagen type I induced byAGEs was down-regulated after inhibition of ERK and p38-MAPK, the collagen type III reduced by AGEs was up-regulated after inhibition of ERK. The expression of collagen types I and III regulated by AGEs through MAPK was partly reversed after treatment with TRB3 siRNA. It suggests that the TRB3/MAPK signaling pathway participates in the regulation of collagen types I and III by AGEs and may provide new therapeutic strategies for diabetic cardiomyopathy.
Article
Diabetes mellitus is one of the major risk factors for cardiovascular disease which is the leading cause of death in the U.S. Increasing prevalence of diabetes and diabetic atherosclerosis makes identification of molecular mechanisms by which diabetes promotes atherogenesis an important task. Targeting common pathways may ameliorate both diseases. This review focuses on well known as well as newly discovered mechanisms which may represent promising therapeutic targets.
Article
Purpose: Plaque rupture is often the precipitating event in acute coronary syndromes. We hypothesized that a similar process occurs in stenotic carotid plaques in association with ischemic neurologic symptoms. Our purpose was to examine several morphologic features of stenotic carotid plaques and to determine which characteristics are more commonly associated with plaques obtained from patients with symptomatic carotid artery disease than with those from patients with asymptomatic carotid artery disease. Methods: Forty-four carotid endarterectomy specimens (from 25 asymptomatic and 19 symptomatic patients) were analyzed with pentachrome staining and light microscopy. The asymptomatic patients and symptomatic patients had similar mean percent stenosis (77% vs 74%). Other risk factors, including hypertension, diabetes mellitus, coronary artery disease, smoking history, serum cholesterol, and triglyceride levels, were similar between groups. Results: Patients with symptomatic carotid artery disease were found to have more frequent plaque rupture, fibrous cap thinning, and fibrous cap foam-cell infiltration when compared with the asymptomatic group. Plaque rupture was seen in 74% of symptomatic plaques and in only 32% of plaques from asymptomatic patients (p = 0.004). Fibrous cap thinning was noted in 95% of symptomatic plaques and in 48% of asymptomatic plaques (p = 0.003). Infiltration of the fibrous cap with foam cells was also significantly more common in the symptomatic plaques (84% vs 44% of asymptomatic plaques; p = 0.006). In addition, intraplaque fibrin was more common in symptomatic plaques than in asymptomatic (100% vs 68%; p = 0.008). No significant differences were found between the two groups with respect to plaque hemorrhage, the presence of a necrotic core, luminal thrombus, smooth muscle cell infiltration, eccentric shape, and plaque type (fibrous, necrotic, or calcified). Conclusions: As in the coronary artery system, rupture of the atherosclerotic plaque may play an important role in the pathogenesis of ischemic stroke caused by carotid artery stenosis. The process of inflammation, involving foam-cell infiltration of the fibrous cap, may contribute to rupture of the atherosclerotic plaque.
Article
Very high prevalence rates of coronary artery disease have been reported among Indians. The aim of this study was to determine the relative importance of isolated hypercholesterolemia, isolated hypertriglyceridemia, isolated high low-density lipoprotein and isolated low high-density lipoprotein in coronary artery disease among South Indian type 2 diabetic subjects. The study group comprised of 17,885 type 2 diabetic patients attending our institute. A history of documented myocardial infarction was considered as the diagnostic criteria for coronary artery disease. Isolated hypercholesterolemia was defined as serum cholesterol over 200 mg/dL with normal serum triglyceride levels (< or = 200 mg/dL); isolated hypertriglyceridemia was defined as serum triglyceride level over 200 mg/dL with normal serum cholesterol levels (< or = 200 mg/dL). Isolated low high-density lipoprotein was defined as one below 35 mg/dL with normal serum triglyceride levels. Isolated high low-density lipoprotein cholesterol was defined as one over 150 mg/dL with normal serum triglyceride levels. Normolipidemia was defined as serum cholesterol and serum triglyceride both upto 200 mg/dL, high-density lipoprotein 35 mg/dL or above and low-density lipoprotein upto 150 mg/dL. The prevalence of coronary artery disease was significantly high among patients with isolated hypercholesterolemia (4.1%; p < 0.001), isolated high low-density lipoprotein (4.5%; p < 0.001) and isolated low high-density lipoprotein (3.9%; p = 0.005) compared to normolipidemic individuals (2.8%), but not in those with isolated hypertriglyceridemia (3.4%). The odds ratios for coronary artery disease increased with each quartiles of isolated cholesterol, isolated low-density lipoprotein cholesterol and total cholesterol to high-density lipoprotein ratio and reached statistical significance in the last quartile (p < 0.05). There was no significant increase in the odds ratios for coronary artery disease in relation to quartiles of isolated triglycerides. For isolated low high-density lipoprotein, when the last quartile was taken as the reference, the odds ratio for coronary artery disease in the first quartile reached statistical significance (p = 0.03). Multivariate regression analysis revealed age (odds ratio 1.06; p < 0.001), male sex (odds ratio 1.7; p < 0.001), hypercholesterolemia (odds ratio 1.26; p = 0.07) and high low-density lipoprotein levels (odds ratio 1.22; p = 0.043) to be strongly associated with coronary artery disease. Among South Indian type 2 diabetic subjects, serum isolated hypercholesterolemia and high low-density lipoprotein cholesterol but not isolated hypertriglyceridemia appear to be associated with coronary artery disease.
Article
Children have both macrophages and macrophages that are filled with lipid droplets (foam cells) at susceptible sites of arteries. Such changes are minimal and may not develop further. However, in some adolescents, small pools of dead foam cell remnants and lipid droplets (extracellular lipid) are added to the foam-cell accumulations at the susceptible sites. The pools are the precursor of a much larger confluent accumulation of extracellular lipids (the lipid core)-the hallmark of the atheromas of young adults. As soon as a lesion with a lipid core is present, calcium granules of microscopic size are found among the packed extracellular particles and droplets and in smooth-muscle cells isolated among them. Disintegration of arterial structure at the core facilitates tears at the surface, hematoma, and thrombosis. As a response, layers of reparative fibromuscular tissue are added and may predominate in a lesion. Over time, calcium lumps and plates form through accretion of adjacent extracellular calcium granules. In adults past the fourth decade of life, the greater part of the former lipid core of a lesion may be calcified and there may be osseous metaplasia. The effect of therapeutic reduction of high levels of blood cholesterol on lesions was studied in rhesus monkeys. Drastic reduction of blood cholesterol levels for 312 years resulted in the disappearance of macrophages, macrophage foam cells and lymphocytes, and reduction of extracellular lipid from advanced lesions. Calcium deposits remained in the arterial wall and were not visibly changed.
Article
Complications of atherosclerosis are the most common cause of death in Western societies. Among the many risk factors identified by epidemiological studies, only elevated levels of lipoproteins containing apolipoprotein (apo) B can drive the development of atherosclerosis in humans and experimental animals even in the absence of other risk factors. However, the mechanisms that lead to atherosclerosis are still poorly understood. We tested the hypothesis that the subendothelial retention of atherogenic apoB-containing lipoproteins is the initiating event in atherogenesis. The extracellular matrix of the subendothelium, particularly proteoglycans, is thought to play a major role in the retention of atherogenic lipoproteins. The interaction between atherogenic lipoproteins and proteoglycans involves an ionic interaction between basic amino acids in apoB100 and negatively charged sulphate groups on the proteoglycans. Here we present direct experimental evidence that the atherogenicity of apoB-containing low-density lipoproteins (LDL) is linked to their affinity for artery wall proteoglycans. Mice expressing proteoglycan-binding-defective LDL developed significantly less atherosclerosis than mice expressing wild-type control LDL. We conclude that subendothelial retention of apoB100-containing lipoprotein is an early step in atherogenesis.
Article
Observational studies of necrotic core progression identify intraplaque hemorrhage as a critical factor in atherosclerotic plaque growth and destabilization. The rapid accumulation of erythrocyte membranes causes an abrupt change in plaque substrate characterized by increased free cholesterol within the lipid core and excessive macrophage infiltration. Neoangiogenesis is associated closely with plaque progression, and microvascular incompetence is a likely source of intraplaque hemorrhage. Intimal neovascularization is predominantly thought to arise from the adventitia, where there are a plethora of pre-existing vasa vasorum. In lesions that have early necrotic cores, the majority of vessels invading from the adventitia occur at specific sites of medial wall disruption. A breech in the medial wall likely facilitates the rapid in-growth of microvessels from the adventitia, and exposure to an atherosclerotic environment stimulates abnormal vascular development characterized by disorganized branching and immature endothelial tubes with "leaky" imperfect linings. This network of immature blood vessels is a viable source of intraplaque hemorrhage providing erythrocyte-derived phospholipids and free cholesterol. The rapid change in plaque substrate caused by the excessive accumulation of erythrocytes may promote the transition from a stable to an unstable lesion. This review discusses the potential role of intraplaque vasa vasorum in lesion instability as it relates to plaque rupture.
Article
Vascular calcification is common in diabetes but the pathogenesis is poorly understood. To investigate the pathogenesis, we first examined the histology of inferior epigastric arteries from diabetic and non-diabetic patients undergoing a renal transplant. To examine the role of hyperglycaemia, bovine vascular smooth muscle cells (BVSMCs) were incubated with normal (5 mM) or high glucose (25 mM) for 48 or 72 h. The results demonstrated that diabetic patients, compared with non-diabetic patients, had significantly greater calcification and increased expression of the bone matrix proteins osteopontin, type I collagen, bone sialoprotein and alkaline phosphatase (ALP). The in vitro studies demonstrated that high glucose increased the expression of the osteoblast transcription factor core binding factor alpha subunit 1 (Cbfa1) and its downstream protein osteocalcin by 1.9-fold and 1.8-fold, respectively, and ALP activity by 1.5-fold. These findings were blunted in the presence of an inhibitor to protein kinase C. High glucose also significantly enhanced calcification in BVSMC in a time-dependent manner (2.20 +/- 0.50 vs 1.35 +/- 0.55 micromol/mg, day 7; 5.04 +/- 1.35 vs 3.12 +/- 0.92 micromol/mg, day 14; P < 0.05). High glucose also induced the secretion of bone morphogenetic protein-2, a known osteoinductive factor, and further increased the secretion normally seen during calcification by 43% at day 7 and 57% at day 14. These results demonstrate that vascular calcification in patients with diabetes is a cell-mediated process characterized by a phenotypic change of VSMCs to osteoblast-like cells with increased bone matrix protein expression, and that hyperglycaemia may directly induce these changes.
Article
The term “ P athologic I ntimal T hickening” (PIT) was recently introduced to define an early stage of atherosclerosis described in human coronary lesions found at autopsies of sudden death victims.1 This descriptive identifier is based on the AHA type III (intermediate) lesion and, as originally presented by Stary and collegues, it’s believed to be the morphological and chemical bridge to more advanced plaques.2 The precise histological features and clinical relevance of PIT remains unsettled, and use of the term is still far from widespread. In short, PIT identifies a lesion with an extracellular lipid pool with intimal smooth muscle cell loss typically adjacent to the medial wall in addition to varying degrees of macrophage infiltration near the lumen. These morphological features indicate a progressive lesion in the earlier stages of atherosclerosis, although there is yet the presence of a necrotic core. As recently studied by Nakashima and colleagues in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , it may provide a key in settling the chicken-versus-egg debate of atherosclerotic plaque progression: does lipid come first, or do macrophages?3 Is PIT the precursor lesion of fibroatheroma? The study in this issue uses 3-dimensional histology to attempt to address some of these issues, and, in doing so, may raise as many questions as it answers. See page 1159 Although there are many detailed autopsy studies describing various lesion morphologies, little is known how human atherosclerosis progresses from early to more advanced plaques, marked by the formation of a necrotic core. This important question remains, in part, from a lack of direct experimental testing in prospective models of human disease. Moreover, potentially relevant finding in animals are difficult to associate with humans because the pathologic change of atherosclerosis in man cannot be definitely equated with animals. Although …
Article
The aim of the present study was to evaluate the ability of optical coherence tomography (OCT) for assessment of the culprit lesion morphology in acute myocardial infarction (AMI) in comparison with intravascular ultrasound (IVUS) and coronary angioscopy (CAS). Optical coherence tomography is a new intravascular imaging method with a high resolution of approximately 10 microm. This may allow us to assess the vulnerable plaques in detail in vivo. We enrolled 30 patients with AMI, and analyzed the culprit lesion by OCT, CAS, and IVUS. The average duration from the onset of symptom to OCT imaging was 3.8 +/- 1.0 h. The incidence of plaque rupture observed by OCT was 73%, and it was significantly higher than that by CAS (47%, p = 0.035) and IVUS (40%, p = 0.009). Furthermore, OCT (23%) was superior to CAS (3%, p = 0.022) and IVUS (0%, p = 0.005) in the detection of fibrous cap erosion. The intracoronary thrombus was observed in all cases by OCT and CAS, but it was identified in 33% by IVUS (vs. OCT, p < 0.001). Only OCT could estimate the fibrous cap thickness, and it was 49 +/- 21 microm. The incidence of thin cap fibroatheroma (TCFA) was 83% in this population by OCT. Optical coherence tomography is a feasible imaging modality in patients with AMI and allows us to identify not only plaque rupture, but also fibrous cap erosion, intracoronary thrombus, and TCFA in vivo more frequently compared with conventional imaging techniques.
Article
Vascular calcification is associated with increased risk of cardiovascular events that are the most common cause of death in patients with end-stage renal disease. Clinical and experimental studies indicate that hyperphosphatemia is a risk factor for vascular calcification and cardiovascular mortality in these patients. Our previous studies demonstrated that phosphate transport through the type III sodium-dependent phosphate cotransporter, Pit-1, was necessary for phosphate-induced calcification and osteochondrogenic phenotypic change in cultured human smooth muscle cells (SMC). BMP-2 is a potent osteogenic protein required for osteoblast differentiation and bone formation that has been implicated in vascular calcification. In the present study, we have examined the effects of BMP-2 on human SMC calcification in vitro. We found that treatment of SMC with BMP-2 enhanced elevated phosphate-induced calcification, but did not induce calcification under normal phosphate conditions. mRNAs for BMP receptors, including ALK2, ALK3, ALK6, BMPR-II, ActR-IIA and ActR-IIB were all detected in human SMCs. Mechanistically, BMP-2 dose-dependently stimulated phosphate uptake in SMC (200 ng/ml BMP-2 vs. vehicle: 13.94 vs. 7.09 nmol/30 min/mg protein, respectively). Real-time PCR and Western blot revealed the upregulation of Pit-1 mRNA and protein levels, respectively, by BMP-2. More importantly, inhibition of phosphate uptake by a competitive inhibitor of sodium-dependent phosphate cotransport, phosphonoformic acid, abrogated BMP-2-induced calcification. These results indicate that phosphate transport via Pit-1 is crucial in BMP-2-regulated SMC calcification. In addition, BMP-2-induced Runx2 and inhibited SM22 expression, indicating that it promotes osteogenic phenotype transition in these cells. Thus, BMP-2 may promote vascular calcification via increased phosphate uptake and induction of osteogenic phenotype modulation in SMC.
Intraplaque haemorrhages as the trigger of plaque vulnerability
  • J B Michel
  • R Virmani
  • E Arbustini
  • G Pasterkamp
  • JB Michel
Michel JB, Virmani R, Arbustini E, Pasterkamp G (2011) Intraplaque haemorrhages as the trigger of plaque vulnerability. Eur Heart J 32: 1977-1985, 1985a, 1985b, 1985c.