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

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

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 older women with 0–39% ECAD [92].

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

Moreover, in a previous study, the significant independent predictors of newonset CAD in older patients were serum homocysteine, age, smoking, diabetes mellitus, hypertension and hyperlipidaemia [96].

### **8. Homocysteine and carotid plaque**

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

patients with raised serum homocysteine level [98, 99]. Furthermore, the presence of complicated atheromatous plaque was significantly associated with serum homocysteine level [98].

The patients with serum homocysteine level > 15 μmol/L had increased risk of presence of carotid plaque and plaque in bilateral common carotid artery (CCA) [100]. An increase in serum homocysteine was independently associated with plaque morphology and larger plaque area [101].

The patients with serum homocysteine level of ≥8.6 μmol/L had higher risk of developing echolucent plaques [101]. In another study, the patients with raised serum homocysteine level had 1.28 times risk of developing advanced carotid plaques after adjustment for age and gender [102]. Advanced carotid plaques were defined as ulcerated plaque and plaques with incomplete fibrous cap [102]. These advanced carotid plaques resulted in a higher ischaemic stroke risk [102]. In the study by Zhang et al., raised serum homocysteine acted synergistically with hypertension; therefore there was a greater risk of having plaque in bilateral CCA [100]. Alvarez et al. reported that in the patients with carotid stenosis of more than 70% and were receiving surgical management, high homocysteine level was present in the patients with extracranial cerebrovascular diseases [103].

### **9. Homocysteine and carotid intima-media thickness**

An increase in homocysteine level was significantly associated with an increase in CIMT carotid intima-media thickness [104]. In a study on the patients with primary hypertension, serum homocysteine level was independently associated with CIMT [105]. A significant positive correlation between homocysteine and intima-media thickness was reported [106]. In another study conducted among the patients with Parkinson's disease receiving treatment, there was positive correlation with statistical significance between CIMT and serum homocysteine level [107]. The patients with raised serum homocysteine as well as hypertension had higher risk of increased CIMT [100].
