**5. Factors affecting serum homocysteine level**

Genetic polymorphisms of the metabolic genes, such as methylenetetrahydrofolate reductase (MTHFR), cystathionine-beta-synthase (CBS), DNA methyltransferase (DNMT) and nicotinamide N-methyl-transferase (NNMT), results in increased level of homocysteine [50, 51]. This leads to an increased risk of ischaemic stroke [50, 51]. CBS deficiency is the most common cause of homocysteinemia due to genetic cause [52]. In the mutation in the gene coding for the enzyme MTHFR, cytosine is replaced by thymidine (C → T) at the base position 677 of the gene [53]. The carriers have nearly 70% reduction in the enzymatic activity [53]. Therefore, the carriers have 20% increase of serum homocysteine concentrations [54]. Deficiencies in CBS and MTHFR result in very high serum homocysteine levels [55].

Nutritional and metabolic abnormalities can also result in elevated serum homocysteine [42]. Metabolism of homocysteine involves remethylation to methionine requiring folate and vitamin B12-derived methylcobalamin [56]. Furthermore, in the process of transsulfuration to cystathionine, vitamin B6-derived pyridoxal 5′-phosphate is needed [56]. Nutritional deficiencies in the vitamin B cofactors inhibit the metabolism of homocysteine metabolism, and this causes an elevated level of serum homocysteine [56].

Serum homocysteine level was significantly higher in the patients with people with impaired renal function [57]. In various studies, gender was significantly correlated with serum homocysteine [53, 58]. However, in some other studies, there was no variation in gender [59].

Parkinsonism and antiepileptic medications have been reported to lead to raised serum homocysteine [60–63]. Paradoxically, lipid-lowering medications have also been reported to cause raised serum homocysteine [60, 63]. The patients with diabetes mellitus (DM) have higher homocysteine than nondiabetics irrespective of gender and ethnic group [64, 65]. Malignancy also leads to higher concentration of homocysteine [66].

#### **6. Factors affecting extracranial carotid atherosclerosis**

Atherosclerosis involves inflammation, intimal injury, proliferation of smooth muscle cells and lipid metabolism [67, 68]. In the Framingham study, fasting cholesterol level, systolic blood pressure (SBP), age and status of smoking were significantly associated with the degree of extracranial carotid stenosis in both genders [69]. In the study by Zhu et al., age was correlated positively with CIMT [70]. Hyperlipidaemia, hypertension, DM and smoking were thought to be associated with endothelial dysfunction [71]. In another study, there was positive correlation between incidence of smoking and hypertension with the severity of presentation of extracranial carotid artery stenosis [72].

In a recent study, CIMT and carotid plaques were associated with hypertension, DM and hyperlipidaemia [73]. Male gender has an increased risk of ischaemic stroke in comparison to female gender for all degrees of carotid stenosis [74, 75]. After the age of 85, female gender had a higher risk of stroke [76]. Carotid plaques present in female gender contain reduced level of pro-inflammatory cytokine and more smooth muscle cell content [77]. Female gonadal hormones provide protective effect by causing favourable lipid profile change and by increasing neuronal viability and cerebral blood flow [78, 79]. Oestrogen protects premenopausal women against atherosclerosis [78, 79].

Various ethnic groups have different associations with vascular risk factors [80]. Therefore, these ethnic groups have varying prothrombotic factors and degrees of plaque rupture [80]. Particularly, South Asians have increased serum homocysteine

**143**

*Atherosclerosis at Extracranial Carotid Vessels and Serum Homocysteine*

undergoing coronary artery bypass surgery (CABG) [81].

However, other studies showed conflicting results [86–87].

older women with 0–39% ECAD [92].

mellitus, hypertension and hyperlipidaemia [96].

**8. Homocysteine and carotid plaque**

**7. Homocysteine and extracranial carotid artery stenosis**

levels in comparison to Chinese and European patients [80]. Kim et al. reported that serum homocysteine is a predictor of asymptomatic carotid stenosis in the patients

Kim et al. reported that serum homocysteine in the highest quartile was independently associated with extracranial carotid artery stenosis ≥50% [81]. In another study, raised serum homocysteine was also independently associated with severe extracranial carotid stenosis in both genders [82]. In other studies, serum homocysteine was significantly associated with carotid artery stenosis in internal carotid arteries and external carotid arteries as well as the degree of stenosis [83, 84]. The hypertensive patients who had raised serum homocysteine were reported to have higher risk of developing asymptomatic extracranial carotid artery stenosis [85].

In a community-based study, serum homocysteine >19.3 μmol/L was associated with asymptomatic carotid artery stenosis in the non-smoker participants aged ≥40 without transient ischemic attack and coronary artery disease [21]. In addition, raised serum homocysteine was associated with asymptomatic carotid artery stenosis in the diabetic patients [21]. Wang et al. reported that serum homocysteine level of ≥15 μmol/L was a predictor of extracranial carotid stenosis [20] and serum homocysteine level > 14.4 μmol/L was associated with increased extracranial carotid stenosis ≥25% in the elderly people [88], whereas Samson et al. reported that serum

homocysteine >10 μmol/L was associated with carotid artery stenosis [89].

Every 1 μmol/L increase of total homocysteine level was associated with 1.12 times the risk for developing internal carotid artery (ICA) occlusion after adjustment for stroke subtypes and risk factors [90]. In the study conducted by Wang et al., every 1 μmol/L increase of total homocysteine level was associated with 1.096 times the risk of developing extracranial carotid stenosis [20]. In addition, Mueller et al. identified serum homocysteine as independent predictor of ICA stenosis ≥50%, with OR 1.32 (95% CI: 1.02–1.72) for every rise of 5 μmol/L [91].

In a previous study, elevated serum homocysteine level is associated with a higher prevalence of 40–100% extracranial carotid arterial disease (ECAD) in older patients [92]. In this study, high serum homocysteine levels were seen in 45% of the older male patients with 40–100% ECAD, whereas only in 20% of the older men with 0–39% ECAD [92]. In addition, elevated serum homocysteine levels were found in 40% of the older female patients with 40–100% ECAD versus 18% of the

Elevated serum homocysteine levels were also associated with a higher prevalence of coronary artery disease (CAD) and peripheral artery disease in older patients [93, 94]. In another study, the significant independent predictors of new cerebral infarction in older patients were serum homocysteine, age, smoking,

Moreover, in a previous study, the significant independent predictors of newonset CAD in older patients were serum homocysteine, age, smoking, diabetes

Increased serum homocysteine level was associated with 1.344 higher risk of developing carotid plaque [97]. Plaque area was reported to be increased in the

diabetes mellitus, hypertension and previous cerebral infarcts [95].

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

*Inflammatory Heart Diseases*

level of serum homocysteine [56].

was no variation in gender [59].

homocysteine [66].

**5. Factors affecting serum homocysteine level**

Genetic polymorphisms of the metabolic genes, such as methylenetetrahydrofolate reductase (MTHFR), cystathionine-beta-synthase (CBS), DNA methyltransferase (DNMT) and nicotinamide N-methyl-transferase (NNMT), results in increased level of homocysteine [50, 51]. This leads to an increased risk of ischaemic stroke [50, 51]. CBS deficiency is the most common cause of homocysteinemia due to genetic cause [52]. In the mutation in the gene coding for the enzyme MTHFR, cytosine is replaced by thymidine (C → T) at the base position 677 of the gene [53]. The carriers have nearly 70% reduction in the enzymatic activity [53]. Therefore, the carriers have 20% increase of serum homocysteine concentrations [54].

Deficiencies in CBS and MTHFR result in very high serum homocysteine levels [55]. Nutritional and metabolic abnormalities can also result in elevated serum homocysteine [42]. Metabolism of homocysteine involves remethylation to methionine requiring folate and vitamin B12-derived methylcobalamin [56]. Furthermore, in the process of transsulfuration to cystathionine, vitamin B6-derived pyridoxal 5′-phosphate is needed [56]. Nutritional deficiencies in the vitamin B cofactors inhibit the metabolism of homocysteine metabolism, and this causes an elevated

Serum homocysteine level was significantly higher in the patients with people with impaired renal function [57]. In various studies, gender was significantly correlated with serum homocysteine [53, 58]. However, in some other studies, there

Parkinsonism and antiepileptic medications have been reported to lead to raised serum homocysteine [60–63]. Paradoxically, lipid-lowering medications have also been reported to cause raised serum homocysteine [60, 63]. The patients with diabetes mellitus (DM) have higher homocysteine than nondiabetics irrespective of gender and ethnic group [64, 65]. Malignancy also leads to higher concentration of

Atherosclerosis involves inflammation, intimal injury, proliferation of smooth

In a recent study, CIMT and carotid plaques were associated with hypertension, DM and hyperlipidaemia [73]. Male gender has an increased risk of ischaemic stroke in comparison to female gender for all degrees of carotid stenosis [74, 75]. After the age of 85, female gender had a higher risk of stroke [76]. Carotid plaques present in female gender contain reduced level of pro-inflammatory cytokine and more smooth muscle cell content [77]. Female gonadal hormones provide protective effect by causing favourable lipid profile change and by increasing neuronal viability and cerebral blood flow [78, 79]. Oestrogen protects premenopausal women against atherosclerosis [78, 79].

Various ethnic groups have different associations with vascular risk factors [80]. Therefore, these ethnic groups have varying prothrombotic factors and degrees of plaque rupture [80]. Particularly, South Asians have increased serum homocysteine

muscle cells and lipid metabolism [67, 68]. In the Framingham study, fasting cholesterol level, systolic blood pressure (SBP), age and status of smoking were significantly associated with the degree of extracranial carotid stenosis in both genders [69]. In the study by Zhu et al., age was correlated positively with CIMT [70]. Hyperlipidaemia, hypertension, DM and smoking were thought to be associated with endothelial dysfunction [71]. In another study, there was positive correlation between incidence of smoking and hypertension with the severity of presentation

**6. Factors affecting extracranial carotid atherosclerosis**

of extracranial carotid artery stenosis [72].

**142**

levels in comparison to Chinese and European patients [80]. Kim et al. reported that serum homocysteine is a predictor of asymptomatic carotid stenosis in the patients undergoing coronary artery bypass surgery (CABG) [81].
