Carotid intima-media thickness and apolipoproteins in patients of ischemic stroke in a rural hospital setting in central India: A cross-sectional study

Introduction

Stroke is one of the leading causes of morbidity and mortality in the world today.[1] There has been a constant effort on the part of medical researchers to analyze this problem and search for factors that aid in its prevention. Carotid intima-media thickness (CIMT) measurement has emerged as one of the noninvasive methods of choice for determining preclinical (asymptomatic) atherosclerotic changes.[23] CIMT is a marker of subclinical atherosclerosis, a strong predictor of subsequent cardiovascular and cerebrovascular morbidity.[45] Measurement of CIMT, the anatomic extent of atherosclerosis and its progression helps in identifying high risk subjects, who are candidates of primary prevention.

The development of sonography technology has allowed the noninvasive evaluation of atherosclerosis in the carotid arteries. The initial manifestation of carotid atherosclerosis is characterized by a subtle increase in vascular IMT, the progression of which leads to plaque formation and vascular narrowing. Reflecting systemic atherosclerosis, increased CIMT is associated with a higher risk for stroke.

Early detection of atherosclerosis is desirable for the primary and or secondary prevention of atherosclerotic events like stroke and myocardial infarction. Similarly, the risk of stroke increases with increasing CMIT.

Atherosclerosis is the leading cause of occlusive arterial disease in patients over 40 years old; the highest incidence occurs in the sixth and seventh decades of life. The strongest predictors of CIMT, after adjusting for age and sex, were total cholesterol and smoking status besides ethnicity (African American versus white).[26] Apolipoprotein B (ApoB) and apolipoprotein A-I (ApoA-I) are identified as risk factors for cardiovascular and possibly cerebrovascular diseases. It has been documented in certain studies that ApoA-I is inversely related to the CIMT; this is specifically significant in cases of documented cerebrovascular diseases. An increase in ApoB and a decrease in ApoA-I indicate an increased risk for atherosclerotic complications.[7]

Apolipoproteins are good predictors of subsequent cerebrovascular events, and improve on predictions by conventional risk factors alone. Their use is simple and accurate and could be included in routine screening of cerebrovascular status.

Thus, the present study was carried out to measure CIMT and ApoB/ApoA-I ratio and demonstrate the correlation between them in patients of more than 18 years of age with ischemic stroke proven by computerized tomography (CT) in a resource-constrained setting in central rural India.

Materials and Methods

Results

We used STROBE (Strengthening the reporting of observational studies in epidemiology) statement to report this study. We screened 207 consecutive patients of clinically suspected stroke and included 106 patients whose diagnosis was confirmed as an ischemic stroke by CT [Figure 1].

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Figure 1

Study profile of the patients in the study

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The baseline characteristics were recorded with respect to clinical profile, risk factor profile, and biochemical profile. The mean age of the patients was 61 years and 66% were male. The patients’ population had several high risk features, including prehypertension (28% of patients), stage 1 hypertension (31 % of patients), stage 2 hypertension (29.2% of patients), and diabetes (19% of patients). The mean total cholesterol was 193.90 mg/dl, mean HDL-C was 33.8 mg/dl, mean LDL-C was 129.1 mg/dl, and mean triglycerides’ value was 222.1 mg/dl. The mean time for presentation to enrolment was 23.4 hours. The correlation between CIMT and HDL-C was found to be significant (Pearson correlation coefficient 0.244) at the 0.05 level (two-tailed) but there was no significant correlation between CIMT and ApoB , ApoA-I, ApoB/ApoA-I ratio, total cholesterol, LDL-C, and triglycerides [Table 1].

Table 1 Baseline characteristics of study patients

Carotid intima-media thickness

The mean CIMT was 0.83 mm ranging from a minimum of 0.45 mm to a maximum of 1.096 mm. The mean expected CIMT was 0.67 mm calculated to the age of study patients [Table 2]. The difference between the measured and the expected CIMT of the study patients for their age was significant with P < 0.005. Mean CIMT in male patients was 0.82 + 0.13 (95% CI, 0.79- 0.85) while in female patients it was 0.81 + 0.16 (95% CI, 0.75- 0.87). There was no statistical difference in mean CIMT in males and females (P= 0.75) [Table 3 and Figure 2]. There was statistically significant linear correlation of the intima-media thickness with age.

Table 2 Relation between measured and expected carotid intima-media thickness of the study population

Table 3 Carotid intima-media thickness of the study population

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Figure 2

Box plot showing the relationship of carotid intima-media thickness in study patients according to gender

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Apolipoproteins

The mean ApoB was 113.8 mg/dl and it was > 90 mg/dl in 75% of patients, of whom 69 patients (87%) had increased CIMT > 0.7 mm while 15 patients with normal ApoB < 90 mg/dl had increased CIMT. The association of ApoB > 90 mg/dl with increased CIMT > 0.7 mm was significant at 5% level with P<0.001. Thus patients with increased ApoB have increased CIMT and this association was significant [Table 4].

Table 4 Relation of carotid intima-media thickness with ApoB, ApoA-I and ApoB/ApoA-I ratio

Of the 61 patients (58%) with abnormal ApoA-I < 100 mg/dl, 56 patients (92%) had increased CIMT > 0.7 mm while 28 patients (62%), with normal ApoA-I had increased CIMT > 0.7 mm. The association of decreased ApoA-I with CIMT > 0.7 mm was statistically significant with P<0.001. Thus patients with decreased ApoA-I had increased CIMT and this association was significant [Table 4].

There was an increased ApoB:ApoA-I ratio > 0.8 in 63 patients (59%), of whom 53 patients (84%) had increased CIMT > 0.7 mm while 35 patients (81%), with a normal ApoB:ApoA-I ratio < 0.8, had increased CIMT > 0.7 mm. The association of the ApoB:ApoA-I ratio > 0.8 with increased CIMT > 0.7 mm was not significant statistically (P=0.71). Though 84% of patients with a normal ApoB:ApoA-I ratio also had increased CIMT, the association was not statistically significant [Table 4].

Of the 56 patients (53%) with abnormal total cholesterol, 48 patients (86%) had CIMT > 0.7 mm while 36 patients (72%), with normal cholesterol had CIMT > 0.7 mm. The association of abnormal total cholesterol with CIMT > 0.7 mm was not statistically significant (P=0.08 with 95% CI 0.81-6.89). Similarly statistically significant association was not found with increased LDL-C (P=0.08 with 95% CI 0.81-6.89) but the association of abnormal triglycerides (P=0.0006 with 95% CI 1.76-16.79) and HDL-C < 40 mg/dl (P= 0.000001 with 95% CI 3.94-180.39) with increased CIMT > 0.7 mm compared to those with normal levels of triglycerides and HDL-C was statistically significant (P<0.001) [Table 5].

Table 5 Relation of carotid intima-media thickness with total cholesterol, LDL-C, HDL-C and triglycerides

Discussion

In the present study, the most significant finding we observed was that there is a statistically significant increase in the intimal-medial thickness of common carotid artery in patients with CT-proven ischemic stroke. A statistically significant association was found between the increase in the CIMT in patients with ischemic stroke and abnormal increased ApoB, decreased ApoA-I levels. Our data showed that the ApoB:ApoA-I ratio was not associated with stroke and with the change in CIMT ratio in patients of ischemic stroke.

Chien et al, found similar results in a community-based cohort study composed of 2,190 participants free of cardiovascular disease at baseline. A total of 94 cases of stroke were documented during the median 10.5-year follow-up. The multivariate RRs associated with a change of one standard deviation of maximal CIMT were 1.47 (95% CI, 1.28–1.69) and for internal carotid IMT were 1.52 (95% CI, 1.31–1.76) for stroke. The study reported a significant association between CIMT and incidence of stroke in Chinese adults,[9] whereas in a case- control study, which was aimed to assess association of increased CIMT and plaque score with acute ischemic stroke in patients with type 2 diabetes, it was found that CIMT and plaque scores in patients with diabetes and acute ischemic stroke were significantly greater than in patients with diabetes who were stroke-free. The crude odds ratios suggested that CIMT and plaque score are risk factors for acute ischemic stroke in patients with type 2 diabetes. Sex, current smoking habit, history of hypertension, and HDL-C levels differed significantly between the case and control groups. However, when after adjustment for cerebrovascular risk factors, CIMT and plaque score did not remain significantly associated with acute ischemic stroke.[10]

Cupini et al, concluded after a multinomial logistic regression procedure from a case-control study on 292 adult patients with an acute first-ever ischemic stroke that CIMT values and atrial fibrillation are the only independent factors able to discriminate between lacunar and nonlacunar patients.[11]

In another cohort study 1,289 Japanese men aged 60-74 years without a previous stroke or coronary heart disease have been followed-up for 4.5-years and examined for the association of CIMT and plaque characteristics with the risk of stroke. The combination of CIMT and internal carotid IMT as assessed by ultrasonography was found as a better predictor of the risk of stroke than was CIMT alone.[12]

Brenner et al, reported in a cross-sectional study on 470 white ischemic stroke patients that measured CIMT, osteopontin (OPN)-443C allele, and monocyte chemoattractant protein-1 (MCP-1) were associated with increased CIMT. The OPN and MCP-1 genes, coding for two cytokines with known roles in atherosclerosis, may contribute to increase CIMT.[13]

In this study, we did not found an increased ApoB:ApoA-I ratio in patients with ischemic stroke. Lima et al, also reported in their study that the ApoB:ApoA-I ratio was important for identifying an increased trend for coronary and cerebral atherosclerosis, in spite of the fact that heterogeneous distribution of ApoB and ApoA-Ilevels was observed among the different groups. In spite of the increased trend for the ApoB/ApoA-I ratio in ischemic stroke and CAD groups, the studied variables cannot be considered in an isolated way and additional studies are required to extend the evaluation of the ApoB/apoA-I ratio in different populations and in different types of atherosclerosis events.[14] In several studies, similar results have been seen with either only ApoB or ApoA-I or their ratio being found significant, while Angelantonio et al, concluded from their study that lipid assessment in vascular disease can be simplified by measurement of either total and HDL-C levels or apolipoproteins without the need to fast and without regard to triglyceride as they found that hazard ratios for ischemic stroke were 1.02 (95% CI, 0.94-1.11) with triglyceride, 0.93 (95% CI, 0.84-1.02) with HDL-C, and 1.12 (95% CI, 1.04-1.20) with non-HDL-C.[15] Chien et al, found in a community-based cohort consisting of 3602 adults in the Taiwan, after multiple Cox proportional hazard regression models controlling for age and sex, that individuals with ApoA-I at the highest quartile were more likely to have a stroke event than those at the lowest quartile level (relative risk [RR]_2.02, P for trend_0.010). The corresponding risk of stroke predicted by ApoB was also significant (RR_1.88, P for trend_0.020). After adjustment for age, sex, hypertension, and diabetes status, the interaction between hypertension and ApoA-I level remained significant in predicting stroke events in men but not in women (RR_1.71, P_0.033 in men; RR_2.29, P_0.071 in women).[16]

Gardener et al, reported that ApoB was associated with risk of plaque (OR per SD = 1.29, 95% CI 1.03-1.60), ApoA-1 was associated with a decrease in multiple plaques (OR per SD = 0.76, 95% CI 0.60-0.97), while lipoprotein A was associated with an increased risk of multiple plaques (OR per SD = 1.31, 95% CI 1.03-1.66). The ApoB/ApoA-I ratio had the strongest relation with carotid plaque (OR per SD = 1.35, 95% CI 1.08-1.69). Among the common lipid parameters, LDL-C has the strongest relation with carotid plaque. Other lipid precursor proteins such as ApoB and ApoA-I may be stronger predictors of subclinical atherosclerosis, however, and better targets for treatment to reduce plaque formation and risk of cerebrovascular disease.[17]

We found that patients with increased ApoB > 90 mg/dl and decreased ApoA-I < 100 mg/dl have increased CIMT more than 0.7 mm significant at 5% level of significance with P<0.001. We also found statistically significant (P<0.001) association between triglycerides and low HDL-C < 40 mg/dl with increased CIMT > 0.7 mm compared to those with normal levels but the association was not statistically significant with total cholesterol >200 mg/dl and increased LDL-C > 130 mg/dl with increased CIMT > 0.7 mm.

Thus for the present study we concluded that apolipoproteins are good predictor of subsequent cerebrovascular events, and improves on predictions by conventional risk factors alone. It is simple and accurate and could be included in routine screening of high risk patients.

CIMT has been recently recognized as a surrogate marker for evaluating therapeutic interventions in atherosclerotic disease. Therefore, to prevent ischemic stroke in high risk patients, control of hypertension, hyperglycemia, smoking, and low HDL-C, together with monitoring of CIMT, may be important.

Limitations of our study were that it was a cross-sectional study, and it had an inherent selection bias as CIMT was measured only in patients of known ischemic stroke and did not include age-related healthy controls. It was not population based, as all participants were members of a single healthcare scheme, but it did represent a typical community population. In future, the relationship between CIMT and ischemic stroke must be examined in all patients with strokes (TIA, acute, and chronic) and without strokes (healthy controls).

The study had few strengths as well. Our study is one of the few studies available demonstrating the association of the CIMT with apolipoproteins in patients of ischemic stroke in central rural India. The interobserver variability CIMT was low (coefficient of variation 3%).[18] Therapeutic interventions with antihypertensive drugs, control of hyperglycemia, lipid-lowering agents, and life style modification in high risk patients can slow the progression of CIMT.

Conclusion

In patients with CT-proven ischemic stroke, there is an increase in intima-media thickness of common carotid-internal artery compared to the CIMT expected for the age, with increased apolipoprotein B and decreased apolipoprotein A-I.