Significance of the intima-media thickness of carotid and thoracic aorta in coronary artery disease in the South Indian population.

BACKGROUND: Ultrasound detected intima-media thickness (IMT) of the carotid artery and thoracic aorta are possible screening tests to assess the risk of coronary artery disease (CAD) in asymptomatic individuals.
OBJECTIVE: Aim of the study was to assess the utility of carotid and aortic IMT as a predictor of CAD and to assess the extent of IMT with severity of CAD in a South Indian population. PATIENTS AND METHODS: A cross-sectional and analytical study was carried out among 40 cases, who had angiographic evidence of CAD against 30 healthy control subjects with a normal treadmill test. At plaque-free regions, the carotid IMT was evaluated by B-mode ultrasonography and thoracic aorta IMT was evaluated by trans-esophageal echocardiography (TEE). The significance of difference in means between two groups was analyzed using one-way ANOVA F-test and the significance of difference in proportions by Chi-square test. Multiple comparisons were done by Bonferroni t test. The correlation between IMT and severity of CAD was assessed by Spearman's method.
RESULTS: There were 38 males and 2 females among cases with age 51.7 ± 8.3 years, and 28 males and 2 females among control subjects with age 52.2 ± 7.1 years. Increased carotid IMT was noted among 24 cases and 2 control subjects, and the association was significant for CAD [P < 0.001, Chi-square = 20.89, odds ratio (OR) = 21.00, and 95% confidence interval (CI) = 4.78-89.59]. Similarly, 19 cases and one control subject had abnormal IMT with positive correlation for CAD (P < 0.001, Chi-square = 16.39, OR = 28.24, and 95% CI = 4.06-163.21). There was no association between IMT and diabetes, hypertension, or smoking; however, IMT was significantly associated with age and dyslipidemia. Also, there was no correlation between extent of IMT and severity of CAD.
CONCLUSIONS: IMT of the carotid and thoracic aorta is strongly associated with risk of CAD in a South Indian population, and may be used as a non-invasive screening tool for coronary atherosclerosis in resource-limited settings. The presence of dyslipidemia influenced IMT and may be used as a tool to follow patients on hypolipidemic drugs.

INTRODUCTION

Cardiovascular disease remains the leading cause of death worldwide. Studies have demonstrated that Asians have different patterns of cardiovascular events.[1] People of Indian Asian descent worldwide have increased risks of vascular disease, which was more in the brain and heart.[23] In a cross sectional study, it was shown that migrants of Indian Asian descent have 1.5-fold increased risk of ischemic heart disease (IHD) and stroke compared to Europeans.[4] Previously, we have shown the risk factors for IHD, which included diabetes, hypertension, dyslipidemia, and smoking.[56] In India, prevalence of coronary artery disease (CAD) is nearly 10 times higher at present compared to 40 years ago.[7] Although prevalence of peripheral arterial disease (PAD) has not been extensively studied in Indian Asians, incidence of PAD was lower than Europeans with reduction rate of 50-75%.[8-10] However, extent of CAD was not measured in these studies.

Atherosclerosis is a fundamental cause of vascular disease and is a systemic disease. Coronary atherosclerosis is often clinically silent with serious morbidity or mortality as its first manifestation. Furthermore, presence of subclinical markers in subjects without evidence of clinical cardiovascular disease is associated with significant risk for CAD.[11] Hence, it is mandated to institute the primary prevention strategies. One among strategies includes the measurement of intima-media thickness (IMT) of carotid and other peripheral vessels. These are well established non-invasive techniques in the terms of cost effectiveness, reproducibility, procedural effect, sensitivity, accuracy, and availability.[1213] Several studies have documented the relationship between carotid IMT and CAD.[14-16] The American Heart Association (AHA) and Third Adult Treatment Panel of the National Cholesterol Education Program (NCEP ATP III) have endorsed the carotid IMT as a tool in risk assessment of IHD.[1718] However, literature relating the precise relationship between thoracic aorta IMT and CAD are scarce.[1619] To our knowledge, there is no report with relation to such factors among the South Indian population.

High resolution B-mode ultrasonography enables accurate assessment of vessel wall characteristics of the carotid arteries. This technique facilitates the evaluation of IMT, lumen diameter and extent of carotid plaques.[20] Similarly atherosclerotic process in aorta can be detected by transesophageal echocardiography (TEE).[16] The objectives of our study were to: 1) assess the utility of carotid and aortic IMT as a predictor of CAD, 2) elicit the relationship between IMT and risk factors such as age, diabetes, hypertension, dyslipidemia and smoking, and 3) assess the extent of IMT with severity of CAD in a South Indian population.

PATIENTS AND METHODS

A cross sectional and analytical study was carried out in the Government General Hospital, Madras Medical College, Chennai, India after informed consent from patient and institutional ethical clearance according to Helsinki Declaration guidelines.

Study population

The study population included 40 patients who underwent elective coronary angiography, and had evidence of CAD with at least one coronary diameter stenosis ≥30%. High risk of cardiovascular events and small coronary artery diameter among Indian population, made us to consider CAD in individuals with coronary diameter ≥30%.[21-25]

Healthy age- and sex-matched control subjects[26] without evidence of cardiac diseases or symptoms were included. Control subjects had a normal treadmill test (TMT). Subject groups were then evaluated for carotid IMT and aortic IMT by Doppler ultrasound and TEE, respectively. The subject groups with age less than 40 years, pregnancy, acute and systemic illnesses were excluded. Among subject groups, history of medical and surgical conditions with smoking habit was included. Blood samples were obtained on the day of admission after overnight fasting for analysis of total cholesterol (TC), triglyceride (TGA), high density cholesterol (HDL), and blood sugar. Low density cholesterol (LDL) was calculated.

Definition of risk factors

Hypertension was defined as the current use of anti-hypertensive drugs or two readings of blood pressure ≥ 140/90 mmHg. Diabetes was defined as the use of hypoglycemic drugs or fasting plasma glucose of >126 mg/dL on two occasions. Subject groups with smoking pack-years ≥20 years were considered as smokers in our study.

Coronary angiography

Coronary angiography was performed according to standard angiographic techniques. CAD is defined as luminal narrowing of 30% as assessed by quantitative coronary arteriography. Coronary segments were analyzed in one angiographic view and frames of analysis were selected by one investigator. Coronary segments were classified into four categories based on their location. The left main coronary artery was analyzed separately. Proximal parts of anterior descending left circumflex and right coronaries were considered as proximal segments. In analysis, the mid parts of the three main coronary arteries were included as mid segments. All the segments distal to the mid segments and >1.5 mm in diameter were regarded as distal segments. Quantitative analysis of coronary angiograms was analyzed with cardiovascular measurement system and 3.0 (Medis, Nuenen) coronary catheter diameter was used as a calibration standard.

Treadmill test

TMT was performed by using the Standard Bruce protocol on the control group to rule out presence of ischemic heart disease. Bruce multistage maximal treadmill protocol has 3 minutes period to allow achievement of steady state before work load is increased.

Patients were instructed not to eat or drink caffeinated beverages for 3 hours before testing and to wear comfortable shoes and loose fitting cloths. Unusual physical exertion was avoided before testing. Adequate skin preparation was done to obtain high quality recordings. The areas of electrode application were rubbed with alcohol pad to remove oil and rubbed with free sand paper to reduce skin resistance to 5000 ohms. All standard precautions and measures were taken.

The heart rate, blood pressure, and electrocardiogram (EKG) were recorded at the end of each stage of exercise, immediately before and after stopping exercise at the onset of an ischemic response and for each minute for at least 5 to 10 minutes in the recovery phase. Minimum of 3 leads were displayed continuously on the monitor during the rest. The development of 0.1 mV (1 mm) of greater of J point depression measured from PQ junction with a relatively flat ST segment slope, depressed 0.1 mV or more 80 milliseconds after the J point (ST 80) in 3 consecutive beats with a stable baseline is considered to be an abnormal response. When ST 80 measurement is difficult, to determine at rapid heart rate (> 130 beats/min), ST 60 measurement is used. Hypertensive response during TMT was considered when systolic blood pressure more than 214 mmHg.

Ultrasound

The measurement of posterior wall of right and left common carotid artery below the bulb is done in a plaque free region with probe in a longitudinal plane by using high resolution B-mode ultrasound. A mean of three measurements is taken in 1 cm segment in a non-neighboring fashion on both sides. The frequency of probe used is 7.5 MHz. Multiplane TEE with 5 MHz probe using Aloka Prosound 4000 system was used to assess aortic IMT. The measurement of IMT was done in a plaque free region in upper esophageal views by taking a mean of measurements at ascending aorta, arch and descending aorta. Abnormal/increased carotid IMT value was considered as ≥ 0.89 mm and abnormal/increased aortic IMT was taken as ≥ 1 mm.

Statistical analysis

Statistical analysis was carried out for subject groups after categorizing each variable. Continuous variables are listed as the mean and standard deviation. The significance of difference in means between two groups was analyzed using the one-way ANOVA F-test and the significance of difference in proportions by Chi-square test. Multiple comparisons were done by Bonferroni t-test. The correlation between IMT and severity of CAD was assessed by Spearman's method. The statistical analysis was carried out the software package, STATPAGES.[27]

RESULTS

Demographic and clinical characteristics

There were 38 males and 2 females among cases, and 28 males and 2 females among control subjects. The mean ages of cases and control subjects were 51.7 ± 8.3 and 52.2 ± 7.1 years, respectively. Among cases, 16 diabetics (40%), 19 hypertensives (48%), and 15 smokers (38%) were noted. The mean values of LDL cholesterol, HDL cholesterol, and TGA in mg/dl among cases and control subjects were 123.1 ± 12.9 and 116 ± 9.9, 42.07 ± 3.6 and 46.9 ± 4.03, 156.6 ± 21.5, and 134.1 ± 47.9, respectively.

Carotid IMT

Increased carotid IMT was noted among 24 cases (60%) and 2 control subjects (7%) and the association was significant (P < 0.001, Chi-square = 20.89, odds ratio (OR) = 21.00, and 95% confidence interval (CI) = 4.78-89.59; [Table 1]. As the age advanced, IMT increased in carotid arteries (P = 0.035) as shown in Table 2. Among cases, IMT was compared between each individual factor such as diabetics versus (Vs) non-diabetics, hypertensives Vs normotensives and smokers Vs non-smokers [Table 3].

Table 1

IMT between cases and control subjects

Table 2

Mean and association of IMT with age groups in cases, control, subjects, n=70

Table 3

Comparison of IMT for Each factor among cases, n=40

The correlations between increased IMT and diabetes, hypertension, and smoking were not significant. Since control subjects were free from these factors, they were excluded for this analysis. However, comparison between IMT and dyslipidemia was carried out among subject groups (cases and control subjects, n = 70), illustrated in Table 4. Carotid IMT was significantly increased in patients with abnormal lipids. Moreover, TGA was more strongly associated with abnormal IMT than LDL and HDL cholesterols.

Table 4

Comparison of IMT among subject groups including cases and control subjects, n=70

Additionally, we categorized our cases into three groups depending on the vessel involvement such as single vessel disease (SVD), double vessel disease (DVD) and triple vessel disease (TVD). However, the association between carotid IMT and severity of CAD was not significant [Table 5].

Table 5

Association of IMT with severity of CAD, n=40

Aortic IMT

Aortic IMT was significantly associated with CAD (P < 0.001, Chi-square = 16.39, OR = 28.24, and 95% CI = 4.06-163.21) as shown in Table 1. Aortic IMT increased significantly with age (P = 0.018) as given in Table 2. Similar to carotid IMT, aortic IMT did not associate with diabetes, hypertension and smoking [Table 3]. However, aortic IMT increased significantly in dyslipidemic individuals [Table 4]. Again, TGA had a stronger association with increased IMT than LDL and HDL cholesterols. Also, severity of CAD could not be associated with aortic IMT [Table 5].

DISCUSSION

In the present study, we evaluated the relationship between IMT of carotid and thoracic aorta with CAD in a South Indian population. There is a higher risk for cardiovascular events not only among native Indians but also among immigrant Indians.[1-3] Also, coronary artery diameter is smaller in Indian population, compared with Western population.[2425] Hence, in our study we included CAD risk in an individual with coronary diameter ≥30% based on the previous studies.[21-23] Atherosclerosis is a generalized progressive process, though it may involve any vessels, medium and large sized arteries are the main culprits. Besides guiding the management of atherosclerosis, early detection of subclinical CAD and prevention of future ischemic events are our most important tasks.

IMT is the earliest sign to appear in atherosclerosis and represents an in vivo variable that can be measured non-invasively from childhood to advanced age. There was strong association between IMT of carotid, aortic,[28] and lower extremities vessels,[29] since it is a generalized process.

The risk factors for increased IMT included age, male gender, obesity, hypertension, diabetes, dyslipidemia, and smoking.[2630-32] In our study, we could not find any association for diabetes, hypertension, and smoking with carotid and aortic IMT. However, there were significant associations between age and dyslipidemia, and carotid and aortic IMT. According to Doruk et al., in a healthy population, age was not associated with carotid IMT, which was contradicted by many observations including our study.[33]

In a comparative study, it was observed that carotid IMT was significantly increased in South Indian rural population compared to an Australian urban population.[30] The high carbohydrate diet among rural Indians may lead to an abnormal lipid profile, which has a strong association with increased IMT.[30] Also, treatment for dyslipidemia by anti-hyperlipidemic drugs significantly reduces carotid IMT.[34]

Rare disorders, such as familial Mediterranean fever and rheumatoid arthritis, were associated with increased IMT in carotid arteries and may be due to subclinical inflammation.[3536] Recently, it was shown that factor VII (FVII) was associated with carotid IMT and strength of association was modified by other cardiovascular risk factors.[37] Inflammation due to any cause is a risk factor for IMT including atherosclerosis.

Several epidemiological and autopsy studies have clearly evaluated the association between carotid IMT and CAD.[14153238] Non-invasive measurement of carotid IMT by using high-resolution B-mode ultrasound scan has been suggested as a surrogate marker for coronary atherosclerosis for use in clinical trials.[2038] Patients being evaluated for chest pain had carotid artery disease which was significantly related to severe CAD.[39]

Similarly, there was an association between thoracic aorta IMT and CAD.[19] TEE is a unique ultrasound tool that allows improved visualization of aorta because of its proximity to esophagus. In addition to carotid and aortic vessels, peripheral arteries such as femoral and popliteal with increased IMT have an increased incidence of CAD.[2631324041]

However, in another study of IMT of brachial and popliteal arteries, these vessels do not seem to play a role in detecting CAD.[4041] In contrast, high cardio-ankle vascular index implies the progression of carotid and coronary atherosclerosis.[42] From this fact, we hypothesize that atherosclerosis starts from central towards peripheral vessels and hence, carotid and thoracic aorta show atherosclerotic changes earlier than more peripheral vessels.

Although there is sufficient evidence to show that there is a strong association between carotid IMT and CAD and stroke,[14314344] there are some conflicting reports.[45-47] IMT increases with advancing CAD:[31] patients with a mean IMT >1.15 mm had a 94% likelihood of CAD, and the coexistence of CAD in those with severe aortic arch stenosis was noted in 16.6% of patients with TVD.[43] However, weak correlation of carotid IMT extent and severity of disease was observed in some other studies.[45-47] Similarly, we did not find association between carotid and aortic IMT with severity of CAD.[45] For every 0.03 mm increase in carotid IMT, the relative risk for fatal CAD was 2.2 and the relative risk for non-fatal CAD was 3.1.[15] Moreover, the progression rate of carotid IMT by serial measurement is more predictive for CAD than single measurement of IMT.[15]

The predictive value of IMT at the common carotid, bifurcation and internal carotid artery had similar risk of CAD on comparison to the combined IMT of these three sites.[48]

The pathology of atherosclerosis is the same in all arteries including aorta, coronary and carotid; however, the extent of lesion is not. Atherosclerotic plaque thickness >4 mm in the aortic arch is a significant predictor of recurrent brain infarction and other vascular events.[49] In Indians, there is a greater prevalence of CAD even with reduced carotid IMT.[3] In our study, IMT of thoracic aorta correlated significantly with coronary atherosclerosis.[19] The descending thoracic aorta IMT correlated better than that of the ascending thoracic aorta IMT.[19] The measurement of thoracic aorta IMT with carotid IMT is a sensitive tool for understanding the extent of coronary atherosclerosis than measuring thoracic aorta IMT alone.[19]

Atherosclerosis is not uncommon in young Indians where CAD occurs prematurely.[50] However, most patients do not develop clinical symptoms.[51] Hence, management strategies that use clinical risk factor assessment to identify high risk individuals for CAD have been recommended. Though traditional CAD risk factors including hypertension, diabetes, dyslipidemia, smoking, and others are useful, these markers do not determine the atherosclerotic process at the level of arterial wall and are neither sensitive nor specific. Measurement of IMT provides information about atherosclerotic change at the arterial wall level and provides a more rational approach to prevention or early treatment of CAD.[52] The normal carotid IMT reliably excludes the cause of CAD.[13]

CONCLUSIONS

We conclude that IMT of the carotid and thoracic aorta is strongly associated with the risk of CAD, and can be used as a non-invasive marker of coronary atherosclerosis. Age is directly related to IMT. Abnormal lipid profile was associated with increased IMT and may be used as a tool to follow patients on hypolipedemic drugs. In our study, the presence of diabetes, hypertension, and smoking did not affect IMT. Also, IMT was influenced by inflammation and the association of anti-inflammatory drugs and IMT needs to be ascertained.

Our study may have significant clinical and public health implications. In India, epidemiologic transition is progressing rapidly. Uncontrolled risk factors of atherosclerosis impose future burden of vascular diseases in India and our health system should implement earlier stratification of risk factor management policies. However, quantitative B-mode ultrasound of carotid arteries requires training and should therefore be done in established centers. Before implementing the routine measurement of IMT in clinical practice, methodological standardization for IMT measurement and normal values need to be proposed.

Strength and limitation

The major strength of our study is being the rigid inclusion and exclusion criteria with measurement of both aortic and carotid IMT in comparison with CAD and its severity. The limitation includes the small subject group.