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Prevalence and risk factors of asymptomatic carotid artery stenosis in Indian population: An 8-year follow-up study
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/neuroindia.NI_523_16
Background: Asymptomatic carotid artery stenosis (ACAS) is a marker for cerebrovascular disease, coronary atherosclerosis, and death. Keywords: Asymptomatic, carotid stenosis, vascular risk factors, family history of stroke, migraine, periodontitis
Atherosclerosis is a major contributor to mortality worldwide and is the leading cause of morbidity in the population aged greater than 45 years in most countries. However, both predisposing genetic factors and environmental conditions modify occurrence of the disease, leading to a marked variation in the prevalence of atherosclerosis among various countries and various regions within the same country.[1] Atherosclerosis of internal carotid artery (ICA) is a major risk factors for stroke [2] and is the causative factor in approximately 30% of all ischemic strokes.[3] Asymptomatic carotid artery stenosis (ACAS) of more than 50% has a 2–6% annual risk of stroke.[4] To combat the disease morbidity and mortality, it is important to screen high-risk individuals for significant ACAS and treat them with medications, intervention, or surgery, or to monitor them with serial surveillance. There are very few studies addressing ACAS in India. The present study aimed to investigate the prevalence of asymptomatic CAS in Indian individuals more than 40 years of age.
We prospectively recruited 1500 consecutive asymptomatic individuals of age more than 40 years from the Department of Neurology, Nizam's Institution of Medical Sciences (NIMS) Hyderabad, India. NIMS is one of the prominent tertiary care centers and university teaching hospitals from South India. Participants were selected from patients' attendants, as well as patients attending the Neurology outpatient department with nonvascular diseases such as carpal tunnel syndrome and lumbar radiculopathy. Every day, 2 individuals were selected for the study on a “ first come first served” basis. The study period was from June 2003 to December 2014. This study was approved by the Institutional Ethics Committee. Data from all the participants were collected through face-to-face interviews and a detailed medical record review by a junior neurologist, whereas vascular risk factor evaluation and clinical examination was done by a senior neurologist. Inclusion and exclusion criteria Individuals with no present or past history of stroke or transient ischemic attack (TIA), and age more than 40 years were included in the study. Individuals with present or past history of cardiovascular disease (angina, myocardial ischemia), cerebrovascular disease (stroke or TIA), vascular diseases of the eye, peripheral vascular diseases, and age below 40 years were excluded from the study. Risk factor assessment Data were obtained directly from the participants using standardized data collection instruments. Standard techniques were used to measure weight, height, serum blood sugar, lipid profile (total cholesterol, triglycerides, high-density lipoprotein, very low-density lipoprotein, low-density lipoprotein) and blood pressure. History of smoking and consumption of alcohol was recorded. Hypertension was defined according to the Joint National Committee (JNC) VI-VII guidelines; alcoholics were defined as those in whom alcohol consumption was >50 g/day; dyslipidemia was defined according to the National Institutes of Health (NIH), USA guidelines; and smokers were defined as participants who smoked daily. Ex-smokers and occasional smokers were classified as nonsmokers. Diabetes was diagnosed according to the World Health Organization (WHO) criteria. Participants with body weight >30 kg/m 2 were considered obese.[1] Family history of stroke in first-degree and second-degree relatives was collected from participants through a questionnaire. History of migraine or headache, infection in teeth, or bleeding in teeth was collected from all the participants. Estimation of carotid artery stenosis Doppler evaluation was performed on a high-resolution duplex ultrasound system, ATL (Advance Technical Laboratories) HDI 3000 duplex, using a probe at scanner frequency of 7–10 MHz. Evaluation of carotid arteries was performed in longitudinal and transverse planes with anterior, lateral, and posterior approaches with the participants in supine position. The common carotid artery (CCA), carotid bifurcation, internal carotid artery (ICA), and external carotid artery (ECA) were studied in all the participants. The carotid artery disease was detected and classified according to the established criteria, in which plaque characteristics (homogenous, heterogeneous, and calcific) were noted, and the degree of stenosis was calculated.[5] In the present study, degree of ICA stenosis was dichotomized and classified into mild (1–49% diameter reduction) and significant (≥50% diameter reduction) stenosis. The ultrasonography examination was performed by a qualified radiologist, experienced in neurosonology, and the findings were confirmed by the stroke neurologist certified in neurosonology by the American Society of Neuroimaging. Follow-up and therapy All the participants were followed up from January 2006 to December 2014. Out of 1500 participants, follow-up was complete for 1078 (71.8%) participants. Participants with significant stenosis were prescribed aspirin 150 mg/day and atorvastatin 10–40 mg/day. Statistical analysis Statistical analysis was performed with the Statistical Package for Social Sciences (SPSS) 14.0 Windows software (SPSS Inc.). Continuous variables were presented as mean ± standard deviation (SD). Student's t-test was performed to test the differences in continuous variables, and chi square test was done to study the association in proportions. We assessed odds ratio (OR) and the resulting 95% confidence interval (CI) for mild and significant stenosis. Multiple logistic regression was assessed before and after adjustment for potential confounders (age, sex, hypertension, diabetes, alcoholism, smoking, migraine, two risk factors, three risk factors, family history of stroke, and periodontitis). All tests were two-sided, and P value of <0.05 was considered statistically significant.
Of the 1500 participants, 1016 (67.7%) were men and 484 were women. The mean age of the cohort was 58.1 ± 10.6 years, and the age range was 40–98 years. On assessment of vascular risk factors, 539 participants (35.9%) were hypertensive, 348 (23.2%) were diabetic, 261 (17.4%) had dyslipidemia, 112 (7.4%) had a history of migraine, 171 (11.4%) had a history of periodontitis, and 121 (8%) had a family history of stroke or coronary artery disease. Out of the 1500 participants, 448 (29.8%) had one vascular risk factor, 290 (19.3%) had two, 129 (7.9%) had three, and 58 (3.8%) had more than three risk factors [Table 1].
Carotid stenosis less than 50% (mild stenosis) was seen in 238 (15.8%) participants, and significant stenosis (>50% stenosis) was seen in 78 (5.2%) participants. Among the 78 (5.2%) participants with significant stenosis, 45 (3%) had 50–69% stenosis, 25 (1.6%) had 70–99% stenosis, and 8 (0.5%) had total occlusion. Bilateral significant stenosis was observed in 16 (1%) patients. Significant stenosis was detected in 58 (24.2%) of 239 participants aged >70 years, whereas it was found in only 20 of 1261 (1.5%) of participants <70 years of age. The carotid plaque structure was studied in all the participants. A total of 261 (17.4%) participants had homogeneous plaques, 22 (1.4%) had heterogeneous plaques, 128 (8.5%) had fibrofatty plaques, 106 (7%) had calcified plaques, and 20 (1.3%) had ulcerated plaques [Table 2].
The participants with normal arteries and mild and significant stenosis were compared for their risk factors [Table 3]. A significant association of >50% stenosis was noted with increasing age (P = 0.001), diabetes (P = 0.01), smoking (P = 0.009), dyslipidemia (P = 0.007), history of migraine (P = 0.0008), history of periodontitis (P = 0.0008), and family history of stroke (P = 0.0003). There was an additive effect of various risk factors, and prevalence of significant stenosis was highest among subjects with more than 3 risk factors [35.8% (P < 0.0001)].
OR was calculated for each risk factor, and after adjustment using multiple logistic regression analysis, long-standing diabetes (>15 years) had the strongest association with significant stenosis (OR = 6.2; 95% CI = 3.41–11.3) followed by long-duration smoking (OR = 5.2; 95% CI = 3.41–11.3). Dyslipidemia and family history of stroke had an OR of 4.0, whereas history of migraine and periodontitis had 3.5 times higher risk of having significant stenosis [Table 4]. The risk of having significant carotid stenosis increased drastically with the number of risk factors, and the presence of more than 3 risk factors carried an OR of 31.5 (95% CI = 15.6–54.3) [Table 4].
Follow up Follow up was available for 1015 (71.3%) participants with mild stenosis and 63 (80.7%) with significant stenosis; remaining participants were lost to follow-up. In the follow-up over 8 years, 14 (1.4%) participants with mild stenosis and 3 (4.7%) participants with significant stenosis developed stroke.
Asymptomatic carotid stenosis is a silent harbinger of stroke. Identification of carotid stenosis in an asymptomatic population can help in preventing major cerebrovascular diseases. The present study found significant asymptomatic carotid stenosis in 5.2% of Indian participants. The frequency of asymptomatic carotid stenosis in our study falls somewhat in the middle of the frequency spectra from various countries.[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22] Asymptomatic significant stenosis was lower in some areas of the world such as 1.2% from Austria,[7] 1.3% in Australia.,[8] 1.4% in Netherlands,[9] 1.5% from Taiwan,[10] and 2.1% from France.[11] The prevalence of asymptomatic significant carotid stenosis was reported as being 5.4% in the Dutch population,[6] 3.9% in Italians,[12] 4.6% from USA,[5] and 4.2% from Russia.[13] A significantly higher prevalence was observed from Sweden (13.6% by Lindgren et al.,[14] and 22.5% by Lernfelt et al.,[15]) and Germany (Hillen et al.,[16] 15.1%). Ethnicity and the underlying genetic makeup with modification from external aspects such as diet, lifestyle, and stress may contribute to this varied range. Carotid endarterectomy and carotid stenting is recommended in individuals with >70% occlusion. In our study, only 1.6% of asymptomatic participants had carotid stenosis >70%. This finding is similar to the findings of other studies from most Western countries.[7],[8],[9],[12],[13],[16],[17],[18],[20],[21] Most authors have suggested that the prevalence of asymptomatic carotid stenosis of more than 70% was 0.4–4.0%. Our study identified total occlusion of the extracranial carotid artery in 0.5% of asymptomatic participants, which was lower in comparison to some other studies. Other studies have identified total occlusion in 5% among Australians,[22] 7.2% in the Dutch population,[23] and 2.7% from a study in the USA.[24] The conventional risk factors for atherosclerosis, and hence, carotid stenosis have been well-studied in various populations; however, they account for only approximately 50–70% of all risk factors. The other less studied risk factors include infection and inflammation. Conventional risk factors Age In the present study, we dichotomized our participants into those with age ≥70 and <70 years. Significant ICA stenosis was found in 58/239 (24.2%) of participants with age >70 years. Other studies have shown a similar prevalence of asymptomatic carotid stenosis in individuals with age >70 years, namely, O'Leary et al.,[26] (9.1%), Hillen et al.,[16] (17.3%), Mananmi et al.,[27] (18.1%), and Lernfelt et al.,[15] (28.2%). Age is one of the major risk factors for atherosclerosis.[1] With increasing age, decrease in fibrous plaques and an increase in atheromatous plaques were observed. Ageing also leads to a reduction in the smooth muscle cell content within the carotid plaque. There is a slight increase in inflammatory cells, especially macrophages, with age. In addition, there is a change in the type of matrix metalloproteases (MMP), with a positive correlation of MMP-9 and negative correlation of MMP-2 with age. Plaque phenotypic differences were most prominent in the youngest age group, in contrast to a consistent lipid laden plaques in the elderly.[28] Kaul et al., noted an independent association of age with atherosclerosis.[1] In the present study, we found that age >70 years had an independent association with significant ICA stenosis (OR = 2.0; 95% CI = 1.48–2.74), which is similar to the findings of Roh et al., (OR = 1.11; 95% CI = 1.10–1.13).[3] Gender In our study, we found a higher prevalence of asymptomatic carotid stenosis among women (7.4%) compared to men (4.0%), although the difference was not statistically significant. However, some studies have found significant association of >50% stenosis among men.[21],[29] Mathiesen et al., noted a prevalence of 3.8% in men and an independent association of significant carotid stenosis with the male gender.[21] Hypertension Existing studies have shown a significant association of systolic blood pressure with carotid atherosclerosis.[12] In our study, we found that 56.4% of the participants with significant stenosis had hypertension, whereas other studies have noted 88.9% of such individuals to have hypertension.[30] Liapis et al., noted that a higher blood pressure was associated with ICA stenosis and a future risk of stroke.[31] In our study, we noted hypertension had an independent association with ICA stenosis (OR = 1.8; 95% CI = 1.11–2.96), and our findings were similar to that of Roh et al., (OR = 1.69; 95% CI = 1.25–2.28).[3] Duration of hypertension increased the risk of atherosclerosis, and in our study, chronic hypertension (>15 years) had 2.5 times higher risk of causing ICA stenosis. Diabetes Diabetes is a major risk factor for cerebrovascular and cardiovascular events. Our study noted a prevalence of 55.1% in patients with significant stenosis. Other studies have noted similar findings; 45% by Mustafa et al.,[30] 77% by Mirharifi et al.,[32] and 52.8% by De Angelis et al.[33] In our study, diabetes was found to have a robust independent association with ICA stenosis (OR = 2.3; 95% CI = 1.45–3.89), similar to the findings observed in previous studies by Roh et al.,[3] (OR = 1.41; 95% CI: 1.00–1.99), De Angelis et al.,[33] (OR = 3.1; 95% CI: 2.03–4.88),[33] and Fabris et al.[34] (OR = 5.3; 95% CI: 2.01–14.2). The current study showed a marked increase in the risk (6.2 times) of developing ICA stenosis with diabetes of more than 15 year duration (OR = 6.2; 95% CI: 3.41–11.3). Smoking Smoking is a well-established risk factor for carotid artery stenosis.[1],[35] Various clinical and experimental studies have shown that smoking can disrupt the vasomotor tone of vessels and trigger atherogenesis, as well as thrombosis in multiple vascular beds.[1] In our study, we found a significant association of smoking with carotid stenosis and identified smoking to have an independent association with carotid stenosis (OR = 3.6; 95% CI = 2.18–6.03). Chronic smoking (>15 years) almost doubled the risk of carotid stenosis with an OR of 5.2. In our study, alcoholism and obesity had no significant association with ICA stenosis. However, some studies have noted significant association between them.[36],[37] Dyslipidemia Atherosclerosis is accelerated by dyslipidemia. Studies have established dyslipidemia as a risk factor for cardiovascular disease and ischemic stroke.[1] Our study also noted dyslipidemia as an independent risk factor for significant carotid stenosis with the highest OR of 4.0. Inflammation and Infection as risk factors for internal carotid artery stenosis The current study also noted a significant association of history of migraine or headache with carotid stenosis, which is an interesting finding that has also been noted by others.[38],[39] Herial et al., noted that ipsilateral headache was associated with high-grade ICA stenosis.[40] Association of migraine with stroke has been well-established in numerous studies, especially in migraine with aura.[41] The mechanisms include diffuse vasoconstriction, abnormal platelet function, and endothelial activation. It is postulated that inflammation triggered by migraine may play an important role and contribute to atherosclerosis. This has been advocated by studies which have shown an association of migraine with increased intima and media thickness in carotid arteries.[38] In our study, a history of periodontal disease was significantly associated with carotid stenosis, which has been observed in other studies also.[42],[43],[44],[45] Several scientists have suggested that periodontitis acts as a long-duration low grade infection, which can frequently spread to the blood stream and cause recurrent mild bacteremia. This in turn can trigger a state of chronic inflammation and hasten the atherosclerotic process.[42],[43] Existing studies have shown a 1.5 to 2.5-fold increased risk of acquiring atherosclerotic cardiovascular and cerebrovascular diseases in patients with periodontal diseases.[44],[45] Desvarieux et al., noted teeth loss as a sign of past periodontitis, which had a significant association with the prevalence of carotid artery plaque.[46] However, some studies have found no significant association between periodontal disease and atherosclerosis.[47],[48] In the present study, we noted that a family history of stroke had a significant association with carotid stenosis, similar to the observation made by others studies.[49],[50] Recent studies have found that a history of early onset coronary artery disease in siblings had a higher risk compared to parental history.[51],[52] Our study established family history of stroke as an independent risk factor for carotid stenosis. Combination of risk factors can worsen atherogenecity, and the risk may exceed the additive effect. In our study, a combination of three risk factors had a 31.9% (95%CI: 15.6-54.3) higher chance of causing ICA stenosis. In our study, stroke occurred in 1.4% (annual stoke risk of 0.17%) of participants with mild stenosis and in 4.7% (annual stroke risk of 0.6%) of participants with significant stenosis during the 8 year follow-up. In a previous study, the annual stroke risk for asymptomatic carotid stenosis was shown to be approximately 1% for stenosis <75% and 3.3% for stenosis >75%.[53] O'Holleran reported that the 60% of the people with more than 75% stenosis had a stroke or TIA during 5 years of follow-up.[54] There is considerable variation in the risk of TIA or stroke in various studies on ACAS. Among patients with asymptomatic carotid stenosis who participated in randomized control trials for assessing the efficacy of carotid endarterectomy, the 5-year risk of stroke was 11.0–11.8% among those with more than 70% stenosis who did not undergo any intervention.[55],[56] In our study, we recorded a very low risk of stroke compared to other studies, probably because all participants with significant stenosis were treated with aspirin and statins, and kept under strict surveillance, thereby reducing their risk of stroke. Our study has a few limitations. All participants were assessed by carotid Doppler ultrasound, the sensitivity and specificity of which is less when compared to digital subtraction angiography. The family history of stroke was based on the participants' knowledge and may have been underreported. History of migraine or headache and periodontal disease was collected through face-to-face questionnaire and was not based on clinical evidence at that time, and hence may have been over- or underreported.
To the best of our knowledge, this is the first study assessing the prevalence of ACAS and its association with various vascular risk factors from the Indian subcontinent. Our study has established that conventional risk factors such as hypertension, diabetes, smoking, and dyslipidemia are independently associated with significant extracranial CAS. History of migraine, periodontal disease, and family history of stroke were also found to be independent risk factors for significant extracranial CAS. Finally, it may be worthwhile to screen for extracranial carotid artery atherosclerosis in individuals >40 years, especially those with vascular risk factors. Financial support and sponsorship This study was supported by a grant from Indian Council of Medical Research, New Delhi, Lr no. SWG/Neuro/8/2001-NCD-1 dated 08-09-2003. Conflicts of interest There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4]
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