**3. Introduction to extracranial carotid atherosclerosis**

Cardiovascular diseases due to atherosclerosis include ischaemic stroke, transient ischaemic attack (TIA), CAD and peripheral vascular disease [7]. One of the causes of ischaemic stroke is the atherosclerosis involving the extracranial carotid arteries [8, 9]. Ischaemic stroke occurs secondary to ischemia caused by flowlimiting carotid artery stenosis or by embolism due to plaque rupture [8]. 20–30% of ischaemic strokes in the Western countries are caused by stenosis or occlusion of the extracranial carotid arteries [7].

Atherosclerosis is initiated by endothelial dysfunction [10, 11]. This endothelial abnormality is mainly caused by free radicals, homocysteine, lipoproteins, free radicals and infectious agents [10, 11]. In addition, atherosclerosis develops by activation and proliferation of smooth muscle cells [10, 11]. This leads to thickening of the arterial wall [10, 11]. Moreover, there is infiltration of macrophages which result in fatty streak and plasma-derived extracellular lipid accumulation in the thickened intima layer [10–12].

Beginning in the mid-1980s, subclinical atherosclerosis was assessed by measurement of carotid intima-media thickness with ultrasound carotid Doppler [13]. Later, other parameters such as carotid plaques were used to evaluate for atherosclerosis [14]. These parameters of subclinical atherosclerosis are useful in assessment of cardiovascular diseases, such as CAD and ischaemic stroke [15–18].

The frequency of ipsilateral strokes was higher in the patients with progressive asymptomatic carotid stenosis than those without asymptomatic carotid stenosis [19]. A rate of 5.3% of developing ipsilateral strokes was observed in the patients with moderate asymptomatic carotid stenosis [19].

The presence of extracranial carotid artery stenosis was found to be negatively associated with ideal baseline cardiovascular health in several studies [20, 21]. An assessment of carotid intima-media thickness (CIMT) is a good indicator of coronary atherosclerosis [22, 23]. In addition, CIMT is an independent predictor of cardiovascular mortality [22, 23]. Moreover, reduced frequency of subclinical atherosclerosis is associated with ideal cardiovascular health profile [24]. Several large population studies showed that there was an association between increased CIMT with future cardiovascular events [25]. In the Multi-Ethnic Study of Atherosclerosis (MESA), Zhang et al. reported

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*Atherosclerosis at Extracranial Carotid Vessels and Serum Homocysteine*

that measurement of CIMT with magnetic resonance imaging (MRI) was more consistently associated with incident cardiovascular diseases (especially stroke)

The presence of carotid plaque helps in the identification of the patients with coronary atherosclerosis [14]. The baseline plaque area is believed to be more than 3.4 times more powerful than the Framingham risk Equation [27]. The patients with plaque scores in the highest quartile had 3.4 times higher risk of stroke, myocardial infarction and overall mortality in the last 5 years than those in the lowest quartile [27]. Measurement of plaque area is a sensitive parameter to assess atherosclerosis [28]. In a recent study by Kaspar et al., ultrasound-based carotid plaque analysis techniques are more promising for future research studies on generalised

Raised serum homocysteine results in endothelial dysfunction as manifested by changes in endothelial cell structure and function [29, 30]. The hypothesised mechanisms were pro-inflammatory effects (expression of tumour necrosis factor-α and inducible nitric oxide (NO) synthase), oxidative stress and impaired endotheliummediated platelet inhibition [31–33]. In addition, raised serum homocysteine leads

The autoxidation of homocysteine produces oxidative stress [32]. Raised serum

Homocysteine is important in vascular function and atherosclerosis [39]. Ozone activates thioretinaco to produce thioretinaco ozonide which is the active site for oxidative phosphorylation [40]. In addition, ozone has been discovered to be present in human atherosclerotic plaques, thus emphasising the important role of ozone and cholesterol ozonolysis in atherosclerosis [41]. Aggregates of microorganisms, homocysteinylated and oxidised low-density lipoproteins (LDL) and lipoprotein autoantibodies in regions of high pressure lead to obstruction of the vasa vasorum [39, 42, 43]. This in turn results in ischaemia and rupture into arterial intima to

Endothelial cell hyperplasia and fibrin deposition in the walls of arterioles may worsen the degree of obstruction of the vasa vasorum by lipoprotein aggregates [1]. Homocysteine activates the proliferation of endothelial cells by inhibiting the nitric oxide production by platelets and endothelial cells [37, 44]. Subsequently, production of glutathione peroxidase is suppressed, and this results in a rise of amount of arachidonic acid from platelets to produce more reactive oxygen species [37]. Homocysteine initiates the coagulation process by tissue factor pathway [45]. Homocysteine activates platelet production of the thromboxane A2, a vasoconstrictor and pro-aggregant [46]. Moreover, homocysteine causes thrombosis by inhibiting tissue plasminogen activator binding domain of annexin II [47]. Homocysteine suppresses the activation of protein C and thrombomodulin surface expression [48]

homocysteine-related pathologies such as atherosclerosis and thrombosis are believed to be due to oxidative stress [34–37]. Hydroxyl free radicals due to raised serum homocysteine level remove electrons from other molecules including DNA, proteins, lipids and carbohydrates in all the cellular components [34–37]. In addition, the hydroxyl free radicals stimulate lipid oxidation and accumulate intracellular cholesterol [33]. Raised serum homocysteine level increases the adhesion between the endothelial cells and neutrophils, resulting in release of extracellular

to a decrease in nitric oxide bioavailability and inflammation [30].

hydrogen peroxide which damages the endothelial cell [38].

form the vulnerable plaque [39, 42, 43].

as well as increases the adhesion of platelets [49].

*DOI: http://dx.doi.org/10.5772/intechopen.89826*

than ultrasound carotid [26].

atherosclerosis [25].

**4. Pathophysiology**

*Atherosclerosis at Extracranial Carotid Vessels and Serum Homocysteine DOI: http://dx.doi.org/10.5772/intechopen.89826*

that measurement of CIMT with magnetic resonance imaging (MRI) was more consistently associated with incident cardiovascular diseases (especially stroke) than ultrasound carotid [26].

The presence of carotid plaque helps in the identification of the patients with coronary atherosclerosis [14]. The baseline plaque area is believed to be more than 3.4 times more powerful than the Framingham risk Equation [27]. The patients with plaque scores in the highest quartile had 3.4 times higher risk of stroke, myocardial infarction and overall mortality in the last 5 years than those in the lowest quartile [27]. Measurement of plaque area is a sensitive parameter to assess atherosclerosis [28]. In a recent study by Kaspar et al., ultrasound-based carotid plaque analysis techniques are more promising for future research studies on generalised atherosclerosis [25].
