|Year : 2022 | Volume
| Issue : 3 | Page : 169-177
Carotid intima–Media thickness: An independent risk factor for stroke prediction – A call for revised framingham score system
Garima Khatri1, Mohan Singh1, Sunita Bika2, Khushboo Joshi1, Nirmala Swami1
1 Department of Anatomy, S.P. Medical College, Bikaner, Rajasthan, India
2 Department of Pathology, S.P. Medical College, Bikaner, Rajasthan, India
|Date of Submission||24-Dec-2021|
|Date of Decision||16-Jun-2022|
|Date of Acceptance||05-Jul-2022|
|Date of Web Publication||20-Sep-2022|
Dr. Garima Khatri
D-7 Nagnechi Scheme, UIT Colony, Bikaner, Rajasthan
Source of Support: None, Conflict of Interest: None
Introduction: Stroke is the second leading cause of death globally, with more than 85% of deaths from stroke occurring in developing countries. It is also reported as the major sequel of head and neck irradiation and has not received the attention it deserves. The contribution of various risk factors to the burden of stroke worldwide is unknown, particularly in countries of low and middle income. We aimed to establish the association of known and emerging risk factors, the carotid intima–media thickness (IMT), with stroke in postradiotherapy patients with head and neck malignancies, also aimed to establish whether carotid IMT (cIMT) is an independent risk factor to predict future stroke. Material and Methods: The study recruited 501 subjects. 151 irradiated patients with head and neck malignancy, formed case group. Three hundred and fifty nonirradiated apparently healthy controls formed control group. Each group was subdivided into four subgroups on the basis of gender and presence or absence of classical atherogenic risk factors, i.e. totally 8 groups were structured. All subjects were measured for their cIMT by color Doppler, b-mode ultrasonography and were also made to complete a questionnaire to assess other cardiovascular risk factors. The Framingham score system was used to predict probability of stroke. Results: Study described higher values of cIMT and total points for risk factors in cases than in controls and the difference was again statistically significant (P = 0.0001). Discussion and Conclusion: CIMT clearly indicated to act as an independent risk factor to predict stroke and is suggested to be worked on to be incorporated in the Framingham score.
Keywords: Cardiovascular risk factors, carotid intima–media thickness, stroke
|How to cite this article:|
Khatri G, Singh M, Bika S, Joshi K, Swami N. Carotid intima–Media thickness: An independent risk factor for stroke prediction – A call for revised framingham score system. J Anat Soc India 2022;71:169-77
|How to cite this URL:|
Khatri G, Singh M, Bika S, Joshi K, Swami N. Carotid intima–Media thickness: An independent risk factor for stroke prediction – A call for revised framingham score system. J Anat Soc India [serial online] 2022 [cited 2022 Sep 29];71:169-77. Available from: https://www.jasi.org.in/text.asp?2022/71/3/169/356495
| Introduction|| |
Stroke is the second leading cause of death globally, with more than 85% of deaths from stroke occurring in developing countries. Stroke has been reported the most common late circulatory disease after radiotherapy of head and neck malignancy. The Indian subcontinent (including India, Pakistan, Bangladesh, Srilanka, and Nepal) has among the highest rates of cardiovascular diseases (CVDs) stroke and coronary heart disease (CHD) contributes significantly to premature mortality and morbidity worldwide. Largely preventable, they demand prevention.
Stroke is the major sequel of head and neck irradiation that has not received the attention it deserves. Radiotherapy as a part of the treatment regime of head and neck tumors increases the survival but also puts the patients at risk of radiation-related side effects. Of these, vascular side effects are serious and may be life-threatening. Radiation-induced thrombosis of carotid arteries and subsequent stroke is the most common complication after radiotherapy of head and neck malignancy. The changes in carotid intima–media thickness (cIMT) are thought to occur in an accelerated manner; however, the time course of the appearance of clinical symptoms remains to be defined.
However, there has been little research to identify the causes of stroke in low-income and middle-income countries. An understanding of the risk factors for stroke in these countries is crucial, to determine priorities and strategies for reversing the rapidly rising rates of stroke mortality in developing countries. The contribution of various risk factors to the burden of stroke worldwide is unknown, particularly in countries of low and middle income. We aimed to establish the association of known risk factors and emerging risk factor, the cIMT, with stroke in postradiotherapy patients with head and neck malignancies. This study will aid in assessing the contribution of this risk factor to the burden of stroke and also explore the differences between risk factors for stroke and CVDs.
It is generally believed that atherosclerosis associated with radiation therapy, while histologically similar to spontaneous atherosclerosis, is clinically distinct because it is limited to the irradiated area and is less likely to be associated with atherogenic risk factors (i.e. aging, male sex, hypertension, cigarette smoking, diabetes, and hypercholesterolemia) and concomitant illnesses (i.e. coronary artery disease and peripheral vascular disease).,
The measurement of the cIMT is feasible with today's high-resolution ultrasound (US) machine. When US beam is at right angle to the carotid walls, two white lines are seen in the vessel, particularly on the far wall. The first-line corresponds to the blood-intima boundary and the second to the outer media-adventitia junction. The IMT is the distance between the two interfaces.,
Considering in view, the poor quality of the lives of cancer patients and the severe emotional trauma of their families, this study aimed first to determine the effect of radiations on cIMT in patients with head and neck malignancy in comparison with non-irradiated matched subjects. Second and more important, we aimed to establish whether cIMT is an independent risk factor to predict future stroke.
We postulated that cIMT increases after radiation therapy and acts as a good independent risk factor for stroke prediction, if this hypothesis is true, it will be an alarming call for recalibration or revision of Framingham and other risk scores for stroke prediction, which should give due place to cIMT as an individual risk factor in their risk score profiles. This will greatly help medical interventions to discriminate between future cases and noncases and help the clinicians to focus on those at highest risk because risk scores are not crystal balls for prophesying, they are for prioritizing preventive treatment.
| Material and Methods|| |
Study design and participants
It was a cross-sectional study which recruited 501 subjects. 151 individuals were irradiated patients of head and neck malignancy, they constituted the case group. Three hundred and fifty individuals were nonirradiated apparently healthy controls formed the control group. Each group was further divided, first on the basis of gender, into two subgroups females and males. Each gender subgroup was then again further classified into two subgroups on the basis of the absence or presence of classical atherogenic risk factors. In this way, a total of 8 subgroups were structured as shown in [Figure 1].
|Figure 1: Classification of study participants into groups (on the basis of presence or absence of irradiations) and subgroups (on the basis of gender and absence or presence of atherogenic risk factors)|
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Distribution of study participants was classified into groups and subgroups:
- Cases (E) (n = 151):
- Females (F) (n = 16):
- Without risk factors (W) (n = 13)
- With risk factors (R) (n = 03)
- Males (M) (n = 135):
- Without risk factors (W) (n = 26)
- With risk factors (R) (n = 109)
i.e. 4 subgroups in cases, namely, EFW (n = 13), EFR (n = 03), EMW (n = 26), EMR (n = 109)
- Controls (C) (n = 350):
- Females (F) (n = 60):
- Without risk factors (W) (n = 44)
- With risk factors (R) (n = 16)
- Males (M) (290):
- Without risk factors (W) (n = 188)
- With risk factors (R) (n = 102),
i.e. four subgroups in controls, namely CFW (n = 44), CFR (n = 16), CMW (n = 188), CMR (n = 102)
Inclusion criteria for cases were that, they must have received radiation therapy to the carotid area for treatment of malignancy, radiotherapy to have occurred at least 1 year before US examination, may or may not have other atherogenic risk factors (i.e. diabetes mellitus, hypertension, hypercholesterolemia, obesity,and cigarette smoking habit), all cases were treated with cobalt therapy.
Inclusion criteria for the control group were that they were nonirradiated apparently healthy individuals with or without any major risk factors for atherosclerosis as mentioned before.
All cases and controls were made to complete a questionnaire to assess their cardiovascular risk factors, had their height, weight, and blood pressure measured and they also provided a blood sample for measurement of HDL, total cholesterol, and random blood sugar levels [Table 1]. Smoking history was assessed. The institutional ethics committee approved the protocol. The study obtained written, informed consent from all participants before enrolment.
All scans were obtained by color Doppler and B mode US technique. All carotid US scans were carried out by one observer using previously standardized program incorporated in software package of the US equipment. Examination was performed after a rest period of 10 min with subjects in supine position and neck extended. Both common carotid arteries were examined along with their full visible length [Figure 2].
|Figure 2: Schematic representation of cIMT on the far wall of CCA. cIMT: Carotid intima–media thickness, CCA: Common carotid artery|
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Sonological examination of common carotid artery (CCA) was done using L and T SEQUINA Color Doppler Scanner with a linear band probe of frequency 6.6–14 MHz. All scans were obtained at 12 MHz. All IMT measurements were made in the longitudinal plane at the point of maximum thickness on the far wall of the CCA along a 1 cm section of the artery, proximal to the carotid bulb [Figure 2]. The position of the carotid bulb is defined as the point at which the far wall deviates away from the parallel plane of the distal CCA. IMT was the distance between the inner echogenic line representing the intima-blood interface and the outer echogenic line representing the adventitia media junction [Figure 3]. After freezing the image, the measurements were made with electronic calipers [Figure 4]. The US images were magnified to improve the accuracy of caliper placement. Measurements were repeated three times, unfreezing the image on each occasion. The mean value of each set of three measurements, representing the mean IMT of each CCA was taken. The hard copy of images was obtained of each examination.
|Figure 3: Illustration of IMC of far the wall of the common carotid artery. The IMC consists of the intima band (Z5), the media band (Z6) and the far wall adventitia band (Z7). The IMT complex is defined as the distance between the blood intima interface line and the media adventitia interface line. IMC: Intima–media complex, IMT: Intima–media thickness|
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|Figure 4: Ultrasound scan showing carotid intima–media thickness on the far wall of common carotid artery|
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The data on cIMT were analyzed among all participants using INDOSTAT software. The mean values were compared using Student's t-test and their significance was assessed using P value. The P < 0.05 showed a significant difference among the cohorts.
| Results|| |
Our study enrolled 501 subjects. 350 individuals were nonirradiated control group [Table 1] and remaining 151 individuals were irradiated patients [Table 1] who underwent radiotherapy for head and neck region and also had CCA exposed to radiation during their treatment. Data obtained were put in [Table 1], [Table 2], [Table 3].
|Table 2: Mean intima-media thickness and mean total points for risk factors in controls and cases|
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|Table 3: Mean intima-media thickness and mean total points for risk factors in different groups under study|
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[Table 1] describes the comparative baseline demographics of the cohorts with the prevalence of classical risk factors of atherosclerosis (i.e. age, hypercholesterolemia, diabetes mellitus, hypertension, and obesity). It makes evident that the values of all the risk factors were higher in groups with risk factors in comparison to groups without risk factors and the differences were statistically significant.
[Table 2] shows higher values of cIMT and total points for risk factors in cases than in controls and the difference was again statistically significant.
[Table 3] manifests comparative biometrics of all the 8 groups for cIMT and total points for risk factors. These total points for risk factors were calculated using a standard Framingham Stroke Risk Score (being standard score, it has not been described here). Another alternative score for CVD risk calculation which is less commonly used in standard books, gives more importance to modifiable risk factors such as physical activity and dietary factors, is described in [Table 4], [Table 5], [Table 6]. Since this score is less commonly used currently but seems to be more relevant in the current scenario of changing lifestyles, especially in the Indian scenario, so we compared this score with Framingham score on a hypothetical subject in discussion section, to prove the rationale of our study.
In [Table 3], when the female group was compared for their mean cIMT, it was found that CFW group (control females without risk factors) showed lower value (0.299 ± 0.049) than the CFR group (control females with risk factors) (0.425 ± 0.025) and the difference was highly significant (i.e. P = 0.0001).
When the baseline data of the above-mentioned groups were applied to the Framingham Stroke Risk Score to calculate stroke probability for 10 years, the mean total points for Risk Factors in CFW group were 3.45 ± 0.76, and in CFR group, it was 7.31 ± 4.55 which was much higher than the former. The difference between the two groups was highly significant (P = 0.0001).
Similarly, when irradiated female groups were compared for the same data, then it was found that EFW group (case females without risk factors) showed lower mean cIMT value (0.689 ± 0.062) than the EFR group (case females with risk factors) (0.85 ± 0.06) and their difference was highly significant (P = 0.0001). In EFW group, Total Points for Risk Factors were recorded 4.0 ± 2.12 which was lower than EFR group (7.66 ± 1.52) and their difference was significant (P = 0.014).
When similar comparisons were made for males, then it is evident from [Table 3] that CMW group (control males without risk factors) showed lower values of mean cIMT (0.313 ± 0.035) and total points for risk factors (2.88 ± 1.18) than the CMR group (control males with risk factors) (0.414 ± 0.036 and 6.99 ± 3.36. respectively). It is also clear from [Table 2] that the difference in data between the two groups was found to be highly significant (P = 0·0001).
In EMW group (case males without risk factors), the value of mean cIMT and total points for risk factors was lower (0.691 ± 0.068 and 3.35 ± 1.74, respectively) than EMR group (case males with risk factors) (0.826 ± 0.191 and 8.21 ± 3.15, respectively). The difference between both the variables was highly significant (P = 0·0001).
[Figure 5], [Figure 6], [Figure 7] show the data of cIMT, total points for risk factors, and cIMT versus total points for risk factors, respectively, in the form of a scatterplot. [Figure 5] and [Figure 6] depict the increasing trends of these variables as we move from controls toward cases. [Figure 7] clearly shows a positive linear correlation between the two plotted variables.
|Figure 5: Scatterogram for mean carotid IMT. IMT: Intima–media thickness|
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|Figure 6: Scatterogram for total points for risk factors as per the Framingham Stroke Risk Score|
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|Figure 7: Scatterogram representing mean IMT versus total points for risk factors in case males with risk factors (EFR). IMT: Intima–media thickness|
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| Discussion|| |
Analysis of our data documents two major findings in support of the aim of this case–control study:
- One is that there is thickening of the intima–media complex of CCA in patients with a history of radiations to the head and neck region compared with matched nonirradiated subjects (P = 0.0001). If there is the presence of any predisposing factors for atherosclerosis, then there is further increase in cIMT and cerebrovascular risk or stroke.,,,,,,,, It was indicated when parameters under consideration of our study were compared for their mean in different groups. [Table 3] shows that cIMT is independent of pressure of other conventional risk factors. [Figure 5] favors this finding. It shows a clear increasing trend as we move from controls toward case groups.
- Second finding surfaced from this study is an interesting one and opens up a new discussion on recalibration of the Framingham risk score for stroke and CVDs. It states that cIMT is not only a good predictor of future stroke but also appears to act as an independent factor for stroke prediction [Figure 7]. This can be easily understood by comparing the data for mean cIMT with that of Total Points for Risk factors, as calculated from the Framingham score, among different groups. [Table 3] apparently shows that the value of latter is more in groups with risk factors and furthermore in irradiated groups.
It is evident from [Figure 5], [Figure 6], [Figure 7] that there is a positive linear relation between Total Points for risk factors as proposed in Framingham Stroke Risk Score, and cIMT, i.e. with increasing total points for risk factors, cIMT also increases, and thus, we can say that risk of stroke increases with increasing cIMT. Hence, this study indicates that besides all the conventional risk factors incorporated in Framingham Stroke Risk Score, cIMT appears to bag an independent position.
Although [Figure 7] shows a positive correlation of cIMT and Framingham Stroke Risk Score, the scatter is wide. A more comprehensive scoring system may generate a better scatter plot.
This study is first to propose and suggest that cIMT appears to act [Figure 7] as a new independent factor for stroke prediction so it should be further worked on to be incorporated in the Framingham Stroke Risk Score.
As we know that stroke is one of the leading causes of serious, long-term disability and mortality in the developed as well as developing countries, this study is an alarming call for an improved scoring system for identifying patients at high risk of stroke, so as to prioritize the preventive treatments. Key to the usefulness of determining the likelihood of stroke by means of a risk score profile is evidence that the modification of several potential risk factors will reduce stroke probability.
Many workers around the world are debating on Framingham and other risk scores such as ASSIGN, QRISK, REYNOLDS, and ABCD.,,, All these scores are working on conventional risk factors for predicting stroke and cardiovascular risk probability, but the ground fact with changing scenario is that besides classic risk factors, there are other determinants which play important role in the prediction of CVDs and stroke and they vary with geographical, environmental and lifestyle differences. If a score is to be globally adopted for preventive action, it should not neglect sections of the population at excess risk, for reasons incompletely identified by classic risk factors and score systems.
WHO in its surveillance study of risk factors for non-communicable diseases has emphasized on risk factors amenable to intervention,, out of which physical inactivity and inappropriate diet are considered important.
The INTERHEART study has also approved of the association of potentially modifiable risk factors with myocardial infarction.
The Framingham risk score profile for stroke and CVDs has one major drawback that it has emphasized more on non-modifiable risk factors (e.g. age and sex) than the modifiable risk factors (e.g. cigarette smoking, high blood pressure, elevated serum cholesterol, diabetes, obesity, sedentary habits, and stress), while the latter is manageable by community action. This drawback can be better understood if we consider a hypothetical case, for example, a male, 30 years of age who is hypertensive (160/100 mm of Hg), diabetic, regular smoker, with a total cholesterol 150 mg/dl and HDL cholesterol value 50 mg/dl, is obese and leads a sedentary life with ridiculous dietary habits. He also exhibits family history of these diseases. In order to estimate CVD or CHD in this patient, we apply two different scoring systems. One is Framingham score and another is the score system [Table 4], [Table 5], [Table 6] put forth in a hospital-based cross-sectional study at Apex Hospital in Kolkata, India. The variation in results of two risk scores is shocking. The Framingham score gives us very low-risk estimation i.e. total points = 3/14 which means only 5% risk of CHD in the next 10 years, the latter score system for the same case manifests a high-risk warning, i.e. total points = 24/24 which means 100% risk of CVD in next 10 years. Such a wide difference in risk estimation is like playing with sensitive lives. This issue needs urgent attention and prompt action.
The role of physical activity and dietary habits seem to be underestimated in Framingham score, may be due to the fact that Framingham Heart Study started long back in 1948 when the use of petrol-driven vehicles was limited and the physical activity of an average person was more. But with the changing lifestyle, the case is reversed. Sedentary life has taken over, leading to high vascular morbidity. This fact is also indicated by the higher vascular morbidity in urban population of India in comparison to the rural population which indicates toward higher physical activity in the lifestyle of latter. Moreover, vigorous aerobic exercise has shown to be protective against ischemic heart diseases rather than the exercises such as long walks (the most convenient form of exercise for many).
A leading newspaper in India,, in 2014, published the scientific picture of Indian heart disease which comes from the American College of Cardiology and states that heart disease is hitting Indians early. Another important fact is that CVD is no more an age-related problem as young patients with CVDs are being spotted in the OPDs in India. Halvor et al. also emphasized the inclusion of individuals younger than 45 years of age so that the potential for primary prevention could be even greater. This also indicates toward the role of modifiable risk factors in a scoring system. The cIMT is a widely used surrogate marker for atherosclerosis and also a strong predictor of future cerebral and cardiovascular events, so a global standard for measuring cIMT is required for better understanding of its usefulness in clinical settings., As Carotid IMT is indicated to play an independent factor for the prediction of future stroke in this study, it is suggested to be incorporated in the Framingham risk score.
In recent studies at Apex Hospital and Urban Health care center in Kolkata, India,, a different score system is used to predict cardiovascular risk in which 60% burden is carried by physical activity and dietary factors and only 40% by general risk factors which seems to stand more appropriate in Asian scenario. In Framingham score, 100% contribution is by general risk factors which do not stand appropriate in the Indian subcontinent. Yusuf et al. in their study of CVD burden in the Indian subcontinent, have clearly elaborated that there were important differences between risk factor profiles of South Asians compared with non-South Asians in INTERHEART STUDY. Many researches are being conducted for genetic correlation and sex specific analysis of cIMT as well as for the prevention of stroke, so as to contribute to stratified medicine approaches.,,
As the survival statistics of Asian, European, American, and other populations at the global level are different, so the same score system cannot be applicable to all.
Our study highlights the criticality of the situation and calls for an urgent need to produce such a comprehensive, flexible, and universal score system for stroke and CVDs which could be applicable to an individual in any corner of the world.
| Conclusion|| |
The main conclusions and recommendations of this study are that, as irradiation triggers atherosclerosis in carotid artery and causes carotid stenosis, it would appear prudent to exercise caution in recommending elective neck irradiation in patients if an alternative is feasible. Carotid IMT appears to act as good predictor and independent factor for stroke prediction so this study also recommends recalibration of Framingham stroke risk scoring system with suggestive follow-up researches to authenticate the incorporation of cIMT as an individual factor to make this score universally applicable to any individual, irrespective of geographical, environmental, and lifestyle differences. This study is an attempt to support INTERSTROKE, and like researches who are working to reduce stroke burden globally.
Departments of Sardar Patel Medical College and Associated Group of Hospitals at Bikaner (Rajasthan), India, supported in technical and administrative issues. We acknowledge the participants, clinical and non-clinical staff of the college and hospital. We thank all the people associated with this research in any which way.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]