**4. Pathophysiology**

*Inflammatory Heart Diseases*

5′-phosphate [6].

the extracranial carotid arteries [7].

intima layer [10–12].

stroke and CAD in the healthy population [5].

**2. Introduction: molecular aspects of homocysteine**

**3. Introduction to extracranial carotid atherosclerosis**

found to be an independent risk factor for vascular diseases with odds ratios (OR) of 1.5 to 1.8 for every increase of 5 μmol/L in serum homocysteine [4]. In a metaanalysis, raised serum homocysteine was an independent predictor of ischaemic

Homocysteine is a sulphur-containing amino acid which is derived from methionine [6]. Methionine is activated by ATP to S-adenosylmethionine (SAM) [6]. In turn, S-adenosylhomocysteine (SAH) is produced from SAM by transmethylation

Cystathionine β-synthase (CBS) has the role of catalysing the condensation of homocysteine together with serine into cystathionine by process of transsulfuration [6]. The conversion of cystathionine into cysteine depends on pyridoxal

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

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

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

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

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

of cardiovascular diseases, such as CAD and ischaemic stroke [15–18].

with moderate asymptomatic carotid stenosis [19].

process [6]. Subsequently, SAH is then hydrolysed into homocysteine [6].

**140**

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

The autoxidation of homocysteine produces oxidative stress [32]. Raised serum 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 hydrogen peroxide which damages the endothelial cell [38].

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

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