What is Atherosclerosis

Atherosclerosis (literally, ‘hardening of the arteries') is a condition with intimal thickening due to cellular and lipid accumulation provoked by endothelial dysfunction. It is an inflammatory systemic disease that affects the intima of large and medium arteries, including, carotid, aorta, coronary and peripheral arteries.

viles gonzales links between inflammation and thrombogenicity).This intimal lesions are called atheromas, or atheromatous plaques (hereafter called plaques) and can potentially cause serious complications, like cerebral infarction, myocardial infarction and peripheral vascular disease.

The initial step in atherosclerosis is endothelial dysfunction. Hemodynamic stresses, hypertension, hypercholesterolemia and products absorbed from cigarette smoke may be sources of endothelial injury and dysregulation.

Hypercholosterolemia, for instance, provokes endothelial dysfunction because of impaired relaxation. This allows lipid, predominantly in the form of cholesterol-rich low-density lipoproteins (LDLs), to enter the intimal layer of the vessel wall where it becomes oxidized and acts as an inflammatory stimulus.

Subsequent adhesion of monocytes and platelets by endothelial adhesion molecules commits the monocyte to migration into the intima (viles gonzales links between inflammation and thrombogenicity)

After entry into the intima, monocytes differentiate into macrophages, internalize oxidized LDL via scavenger receptors, and give rise to foam cells (P libby inflammation nature). Activated macrophages, in combination with less abundant lymphocytes, release a host of proinflammatory cytokines and reactive oxygen species that serve to maintain and amplify the inflammatory process. Additionally, they are capable of producing a range of proteases with specificity againgst all of the connective tissue matrix proteins (Davies MJ stability). Matrix metalloproteinases (MMPs), proteolytic enzymes that enhance collagen, elastin and proteoglycans degradation. (Quantitation and localization of matrix metalloproteinases and their inhibitors in human carotid endarterectomy tissues., Wengen Chen Review, Eur J nucl Med Mol Im 2009

Emerging role of FDG-PET/CT in assessing atherosclerosis in large arteries

Subsequent foam cell death and release of cholesterol esters give rise to development as well as expansion of the necrotic core of the plaque.

Perpetuating plaque inflammation mediates continuing matrix breakdown and growth of the lipid core, which together reduce the mechanical strength rendering the plaque susceptible to rupture. Plaque rupture implies the process of haemodynamic forces exerted on the plaque by local blood flow, which exceeds its tensile strength. Hereby the underlying prothrombotic vessel exposes to circulating platelets and clotting factors. This results in thrombosis and, potentially, tissue infarction (Virmani pathology of the vulnerable plaque). Thus, inflammation is important during the entire process of atherosclerosis, because of its role in plaque initiation, progression and eventualy rupture. Not all plaques do rupture; a factor that prevents rupture and stabilizes the plaque is a preponderance of vascular smooth muscle cells (VSMCs). Which comprise the major cellular component in the normal vessel and is located in the tunica media. The inflammatory process and, in particular, macrophage-derived cytokines induce VSMCs to migrate into the intima. During migration, they change from a contractile to a synthetic or ‘repair' phenotype. These VSMCs produce fibrous proteins to strengthen the cap, regulate the synthesis of interstitial fibrillar collagens and which are subsequently laid down to form a fibrous cap over the lipid core, render the plaque less prone to rupture. However, besides rendering the plaque from rupture, it results in intima thickening. Sites most frequently affected by carotid atherosclerosis include the proximal internal carotid artery (ICA) and the carotid bifurcation. Intimal thickening possibly leads towards arterial lumen occlusion, a process called negative remodelling. Conceivable resulting in amourosis fugax by carotic arteria stenosis.

In addition to inflammatory inducement of VSMCs migration, inflammation is involved in the potent apoptosis of VSMSc as well, negating for a part its positive effects (5. Boyle JJ, Bowyer DE, Weissberg PL, Bennett MR. Human blood-derived macrophages induce apoptosis in human plaque-derived vascular smooth muscle cells by Fas-ligand/Fas interactions. Arterioscler Thromb Vasc Biol. 2001;21:1402–1407.). Summarizing, plaque stability is determined by the balance between inflammatory driven collagen degradation and the VSMC driven collagen synthesis.

Plaques that are susceptible to rupture and cause clinical events are called vulnerable plaques.

Vulnerable plaques are characterized by a soft, lipid-rich necrotic core with an overlying thin fibrous cap that seperates the core from the lumen. MMPs are among these proteases leading to cap thinning. This cap that is prone to rupture contains less collagen, no or absent vascular smooth muscle cells, and is heavily infiltrated with macrophages (Virmani, pathologie of vulnerable plaque en Davies MJ stability and instability en van der wall). Currently, plaques are defined as vulnerable if they exhibit those features, irrespective of whether rupture has taken place.

Factors that dictate the susceptibility of the cap towards rupture: circumferential wall stress, which is determined by lesion location, size, consistency and thickness; and blood flow characteristics. When the cap is thin, coveres a large necrotic core, consists of macrophage infiltrates, paucity of collagen, is not located near high-grade stenosis and is exposed to high circumferential stress at the luminal border of the plaque, plaque rupture is likely to occur viles gonzales links between inflammation and thrombogenicity, Davies MJ stability and instability .

Typically, a plaque may simultaneously have quiescent (stable) and vulnerable (unstable) regions at any given moment. Macrophages play a pivotal role in the transition from a stable towards a vulnerable plaque and are invariably associated with plaque rupture. Disruption of this fibrous cap allows the thrombogenic lipid core to communicate with the arterial lumen. Leading to direct vascular occlusion by thrombus formation, manifesting clinically as amourosis fugax. Or distal embolization, primarily responsible for subsequent transient ischemic attac (TIA) or, more worrying, for cardiovascular accident (CVA) e.g. cerebral infarction.
(van der wall site of intimal rupture en car activated inflammatory cells, Carr s atherosclerotic plaque rupture, Jander S, Stroke 1998

Inflammation in High-Grade Carotid Stenosis

A Possible Role for Macrophages and T Cells in Plaque Destabilization). Fuster V, Lewis A. Conner Memorial Lecture: mechanisms leading to myocardial infarction—insights from studies of vascular biology. Circulation. 1994; 90:2126–2146.

VSMCs, as mentioned earlier, can cause negative remodeling. A term used to describe plaques that eventually can not expand any further and, therefore, encroach into the lumen of the vessel. In contrast, plaques can develop toward the external part of the artery and preserve luminal diameter, e.g. aneurysms. A process known as positive remodeling. Techniques to visualize plaque deposition use degree of stenosis to determine the severity of the plaque burden. Although the extent of luminal stenosis is an indicator of plaque burden, the likelihood of plaque rupture is largely dictated by inflammation and consequent morphology, mentioned previously. Consequently, atherosclerotic plaques that physically appear threatening may be dormant and plaques that do not appear physically threatening can progress and eventually rupture (Pasterkamp 1998, Wengen chen review).

However, performance of carotid endarterectomy (CEA) is primarily based on patients symptomatology and degree of stenosis. CEA has been proven benificial for symptomatic patients with 70-99% (high-grade) stenosis, and somewhat benificial for symptomatic patients with 50-69% if CEA is performed within two weeks. Six patients with high-grade stenosis need to undergo surgery to prevent that one patient experiences ipsilateral stroke within five years (number needed to treat (NNH) is 6). Patients with 50-69% stenosis degree have a conceivable lower risk of recurrence, NNT is 22. On the other hand, large clinical trials showed a perioperative stroke and mortality rate of 2,3-7,1%, number needed to harm is 14. Comprising that many patients undergo surgery with its attendant risks without taking advantage of it.
Moreover, NNTat three years is even lower for asymptomatic patients with carotid stenosis of 60-99%, namely 33.( Carotid endarterectomy—

An evidence-based review

Report of the Therapeutics and Technology Assessment

Subcommittee of the American Academy of Neurology

S. Chaturvedi,) Whereas 70% of ruptured plaques originating from previously silent plaques, occur in lesions that cause a less than 50% stenosis (Wengen Chen Review, Eur J nucl Med Mol Im 2009

Emerging role of FDG-PET/CT in assessing atherosclerosis in large arteries) This means that CEA is incorrectly withheld in the majority of patients, and is only an option after experiencing adverse clinical events, in stead of being an option to prevent the first events.

This incongruity in absolute risk reduction after CEA emphasizes the need for better risk stratifying methods. To target all affected patients and careful patient selection, so that CEA is not incorrectly withheld.

Therefore, there is need for an imaging modality that can visualize vulnerable plaques instead of plaques that physically appear threatening.

Imaging modalities used to assess atherosclerosis include intra-arterial angiography, doppler ultrasound (DUS), contrast-enhanced computed tomographic angiography CTA, contrast-enhanced electron beam CT, multislice spiral CT, multidetector-row CT angiography, magnetic resonance angiography (MRA) and contrast-enhanced MRA (CEMRA). All focusing on structural alterations in the arterial wall and not taking metabolic alerations into account. (DUS, CTA, MRA and CMRA have all high sensitivities and specificities for diagnosing 70-99% carotid stenosis in symptomatic patiens, but might be substantially less accurate for 50–69% carotid stenosis (Wardlaw 2006 Lancet Non-invasive imaging compared with intra-arterial angiography in the diagnosis of symptomatic carotid stenosis: a meta-analysis). Implying that)

The current gold standard method of evaluating atherosclerosis is x-ray angiography.

It permits an evaluation of the entire carotid artery system, providing high-resolution definition of detection and graduation of luminal stenosis due to plaques. It is able to visualize collateral circulation and can trace ulceration with a very wide range of sensitivity and specificity (Bas wallis de vries rev). Although considered to be the gold standard method, conventional angiography has a limited number of projections. Potentially underestimating degree of carotid stenosis in arteries that have asymmetrical rather than concentric lumens (Elgersma OE buijs PC Wust Radiology 1999 Maximum internal carotid arterial stenosis: assessment with rotational angiography versus conventional intraarterial digital subtraction angiography.). Furthermore, it is highly invasive, has a considerable risk to aggravate morbidity and mortality due to atherosclerosis and gives no or sparse information about positive remodeled lesions, plaque composition or disease activity.

Carotid duplex ultrasound (CDUS) is a non-invasive imaging modality which uses B-mode ultrasound imaging and Doppler ultrasound to determine the extent of stenosis. CDUS detects focal increases and decreases in blood flow velocity indicative of carotid stenosis (Bas wallis de vries)

It is used routinely in the assessment of the carotid artery stenosis. Advantages are its noninvasive safe nature, relatively inexpensive technique and high sensitivity and specificity to detect high grade stenosis. However, it is considerably less accurate for 50-69% stenosis (wardlaw 2006 meta analysis). Moreover, CDUS tends to overestimate the degree of stenosis (Quantification of internal carotid artery stenosis with duplex US: comparative analysis of different flow velocity criteria.

Sabeti S; Schillinger M; Radiology 2004 Aug;232(2):431-9). Another limitation of CDUS is that the accuracy relies strongly upon the ultrasonographer.

Compared to angiography, CDUS can classify plaques as soft, fibrous, or calcified. Furthermore, it can detect surface ulceration and intra-plaque hemorrhage. However, current methods to assess this, still got high inter-observer agreement variability and inter-scanner variability. New computer-assisted image analysis software helps to improve this technique's accuracy. Although, CDUS is able to determine some morphologic characteristics, there is little agreement between CDUS and histological observation (Bas wallis de vries). Therefore, plaque morphology assessed by CDUS provides a paucity of information on risk of rupture.

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