Is Obesity a Risk Factor for Carotid Atherosclerotic Disease?—Opportunistic Review

Obesity is a risk factor for coronary atherosclerosis. However, the influence of adipose tissue in carotid atherosclerosis is not completely understood. No systematic review/meta-analysis was previously performed to understand if obesity is a risk factor for carotid atherosclerosis. This paper aims to provide an opportunistic review of the association between obesity and carotid atherosclerosis and define the role of the different adipose tissue depots in the characteristics of carotid stenosis. The databases PubMed and Cochrane Library were searched on 15–27 April and 19 May 2021. A total of 1750 articles published between 1985 and 2019 were identified, 64 were preselected, and 38 papers (35,339 subjects) were included in the final review. The most frequent methods used to determine obesity were anthropometric measures. Carotid plaque was mostly characterized by ultrasound. Overall obesity and visceral fat were not associated with the presence of carotid plaque when evaluated separately. Waist-hip ratio, however, was a significant anthropometric measure associated with the prevalence of carotid plaques. As it reflected the ratio of visceral and subcutaneous adipose tissue, the balance between these depots could impact the prevalence of carotid plaques.


Introduction
The worldwide prevalence of obesity has increased in the past decades. Obesity is an independent risk factor for atherosclerosis, stroke, and cardiovascular disease [1][2][3]. Cardiovascular outcomes and mortality are more dependent on fat distribution than on the total amount of adipose tissue [1]. Previous studies demonstrated that a higher ratio of visceral adipose tissue (VAT) to subcutaneous adipose tissue (SAT) was associated with an increased risk of poor cardiovascular outcomes [1]. VAT is metabolically active and secret adipokines that cause vascular inflammation and insulin resistance [2]. Conversely, SAT is associated with a neutral or even beneficial metabolic impact [2].
Increased abdominal VAT/SAT ratio was inversely correlated with the extent and severity of coronary artery plaques, higher total mortality, and incidence of major adverse cardiac events (MACE) [1,2].
The influence of obesity on carotid atherosclerosis disease remains unclear [4]. No previous systematic review/metanalyses evaluated the relationship between obesity on carotid atherosclerosis.

Data Sources and Search
The PubMed and Cochrane Library databases were searched on 15-27th of April and 19 May 2021. The query was as follows: ('Carotid artery stenosis OR 'Carotid artery atherosclerosis') AND ('visceral adipose tissue' OR 'visceral fat' OR 'fat tissue' OR 'Obesity' OR 'subcutaneous adipose tissue' OR 'subcutaneous fat').
This review was conducted according to established methods for reviews in cardiovascular medicine (PRISMA criteria).

Inclusion and Exclusion Criteria
Studies were included in the current opportunistic review if they met the following criteria: (1) correlating general obesity, VAT, or SAT with the prevalence of carotid artery plaque, (2) evaluating the influence of general obesity, VAT/SAT on carotid artery symptomatology, (3) retrospective or prospective observational clinical studies, (4) performed in humans, (5) full-text available, (6) studies published in English, French, Spanish, and Portuguese.
Other studies were excluded for the following reasons: (1) analyzing intima-media thickness, (2) performed in children, (3) studies reported only as abstracts or with incomplete data, letters, reviews, case reports, nonclinical studies, (4) reviews or meta-analysis.
If the studies had overlapping subjects, the one with the largest sample size was included in the final analysis.
No attempt was made to contact the authors of the included studies to enquire about missing or incomplete data. No studies were excluded because of concerns about missing data.

Data Extraction-Outcomes-Definitions
After removing the duplicated articles, two authors (J.F. and A.C.) independently selected the full-text articles after screening the title and abstract. Disagreements were resolved by consensus.
For each study, the subsequent data were collected: first author, year of publication, country of the research center, type of study design, total number of patients, age, men (percentages), aims, inclusion and exclusion criteria, and main conclusions (Tables 1-3).
Concerning the adipose tissue, the following information was recorded: the method used to determine the overall obesity, the VAT, and SAT ( Table 3).

Asymptomatic
Measures of adiposity were not significantly different in patients with higher plaques score Ultrasound Focal plaques were identified as wall thickness that was increased compared with the surrounding IMT

NA Asymptomatic
There were no differences in BMI, total fat mass, percent body fat, total abdominal adipose tissue, and SAT in those with versus without carotid plaques. In those with plaques, VAT was a significant, independent predictor of plaque area after adjusting for age, sex, ethnicity, education, household income, family history of CVD, smoking, and percent body fat Ultrasound Plaque was defined as a focal wall thickening of at least 1.5 mm The degree of plaque at the six segments was graded according to the following criteria: grade 0, no observable plaque, grade 1, one small plaque < 30% of vessel diameter, grade 2, one medium plaque between 30% and 50% of the vessel diameter or multiple small number plaques, and grade 3, one large plaque > 50% vessel diameter or multiple plaques with at least one medium plaque Asymptomatic A high WHR was independently associated with the presence of plaque Terzis et al. [16] Ultrasound Plaque was defined as a focal structure encroaching into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value, or a thickness of 1.5 mm as measured from the media-adventitia interface to the intima-lumen interface

NA Asymptomatic
The presence of atheromatous plaques was independently associated with BMI    Obesity is an independent risk factor for carotid plaque destabilization The quality of each study was assessed by one author (J. F.) using the MINORS (methodological index for non-randomized studies) criteria (see supplement material) [41]. Each item was scored as 0 (not reported), 1 (reported but inadequate), or 2 (re-ported and adequate). The global ideal score is 16 for non-comparative studies and 24 for comparative studies [41]. The final classification is presented in Table 1.

Results
A total of 1750 articles were found, and after removing duplicates, 1201 articles were left, as shown in Figure 1 [42][43][44][45][46][47][48][49]. The quality of each study was assessed by one author (J. F.) using the MINORS (methodological index for non-randomized studies) criteria (see supplement material) [41]. Each item was scored as 0 (not reported), 1 (reported but inadequate), or 2 (reported and adequate). The global ideal score is 16 for non-comparative studies and 24 for comparative studies [41]. The final classification is presented in Table 1.
The 38 studies included in this opportunistic review were published in 1985 (one article) and between 2001 and 2019. The studies were conducted in 32 different countries, the majority in Europe (18 papers), eight studies in North America, eight in Asia, two in South America, and two in Africa (Table 1).
Analyzing the studies included in this opportunist review by regions, there was a higher number of papers describing a positive association between obesity and carotid plaque characteristics in the research work performed in Asia and Africa. However, just two papers were identified from Africa. The majority of papers included were from Europe, where 10 papers found a relationship and an equal number did not.
The authors used different methods to determine the quantity of adipose tissue and to characterize the atherosclerotic plaque. The most frequent method used to determine obesity was anthropometric measures: Thirty-three articles assessed overall obesity with BMI, 19 evaluated visceral obesity with WC, and 11 estimated the relationship between the visceral and subcutaneous adipose tissue with WHR (Table 2). Six authors used medical imaging to quantify the VAT and SAT: Four authors used CT scans [3,8,26,31], one author used ultrasound [40], and another MRI [28]. Other methods were used: bioimpedance (three papers) [9,17,37]; dual-energy X-ray absorptiometry (two) [3,36]; and DXA (one) [8] ( Table 2). In one paper, omental, mesenteric, mesocolon, and perirenal fat were dissected after the autopsy and weighed [33]. The VAT was the sum of the omental, mesenteric, mesocolon, and perirenal fat [33].
The carotid plaque was evaluated with ultrasound in 19 articles, with doppler ultrasound in 12 papers, and with MRI in three articles (Table 3).
Two articles analyzed the histological composition of the carotid plaque (number of macrophages, foam cells, cap characteristics, and the quantity of lipids and calcium) [4,19]. One study determined the area of the cadavers of the largest atheroma plaque in the carotid artery of cadavers to calculate the stenosis index [33].
The carotid plaque was defined in most papers as a focal structure encroaching the vessel lumen or as a widening in the intima media-thickness (Table 3). However, there was no homogeneity in the definition, and different publications used different measures of intima-media thickness to define a plaque (Table 3). Sixteen articles only analyzed asymptomatic carotid plaques, six papers studied both symptomatic and asymptomatic, and two articles symptomatic. Fourteen articles did not specify if the carotid artery caused symptomatology. (Table 3). This opportunistic review included 1533 symptomatic and 19,799 asymptomatic patients.
The oldest study included in this review included 477 patients who performed angiography or Doppler ultrasound and concluded that obesity was significantly more frequent in patients with internal artery occlusion or stenosis than in controls. Obesity was defined according to medical charts [5].
Two papers totaling 268 patients found that the prevalence of carotid plaques was associated with overall obesity determined by BMI [16,34].
However, one paper with 750 individuals concluded that the prevalence of carotid artery plaques was inversely related to BMI (Figure 2) [7].

Overall Obesity and the Characteristics of the Carotid Plaques
Three papers suggested that overall obesity could be associated with carotid plaque instability ( Figure 3) [4, 24,36].
(1). Histological analysis of carotid plaques (390) concluded that obesity, defined as BMI ≥ 30 kg/m 2 was an independent risk factor for carotid plaque destabilization, particularly in males [4]. Obesity was correlated with the presence of unstable carotid plaques, characterized by a high degree of inflammation, thinning, and rupture of the cap [4]. (2). One study analyzed the plaque echogenicity by gray-scale median using ultrasound and concluded that low gray-scale median values were related to high BMI [24]. Plaques with a low gray-scale median had a higher probability of causing embolization and symptoms. This research included 179 diabetic patients [24]. (3). One research paper found that obesity (BMI > 30.0 kg/m 2 ) was associated with increased carotid plaque necrotic core volume and calcification independently of diabetes mellitus status [36]. The carotid plaque composition was assessed by magnetic resonance imaging. Obesity was determined by BMI [36]. The study included 78 patients with short-duration Type 2 diabetes mellitus and 91 sex-and aged-matched control subjects [36]. One of these was a prevalence study conducted on 474 healthy residents in Northeast China [27]. This study sought to determine the risk factors associated with carotid atherosclerosis identified by ultrasound. However, there was no definition of atherosclerotic plaque [27]. The prevalence was significantly higher in obese females than in the control females. Obesity was defined as BMI ≥ 28 kg/m 2 [27]. The study included 231 males, and no association was found for this gender [27].
Another study conducted on 144 women with systemic lupus erythematous found that the prevalence of carotid artery plaque was significantly associated with obesity, determined by BMI [11].
The oldest study included in this review included 477 patients who performed angiography or Doppler ultrasound and concluded that obesity was significantly more frequent in patients with internal artery occlusion or stenosis than in controls. Obesity was defined according to medical charts [5].
Two papers totaling 268 patients found that the prevalence of carotid plaques was associated with overall obesity determined by BMI [16,34].
However, one paper with 750 individuals concluded that the prevalence of carotid artery plaques was inversely related to BMI (Figure 2) [7].

Overall Obesity and the Characteristics of the Carotid Plaques
Three papers suggested that overall obesity could be associated with carotid plaque instability ( Figure 3) [4, 24,36].
(1). Histological analysis of carotid plaques (390) concluded that obesity, defined as BMI ≥ 30 kg/m 2 was an independent risk factor for carotid plaque destabilization, particularly in males [4]. Obesity was correlated with the presence of unstable carotid plaques, characterized by a high degree of inflammation, thinning, and rupture of the cap [4]. (2). One study analyzed the plaque echogenicity by gray-scale median using ultrasound and concluded that low gray-scale median values were related to high BMI [24]. Plaques with a low gray-scale median had a higher probability of causing embolization and symptoms. This research included 179 diabetic patients [24]. (3). One research paper found that obesity (BMI > 30.0 kg/m 2 ) was associated with increased carotid plaque necrotic core volume and calcification independently of diabetes mellitus status [36]. The carotid plaque composition was assessed by magnetic resonance imaging. Obesity was determined by BMI [36]. The study included 78 patients with short-duration Type 2 diabetes mellitus and 91 sex-and aged-matched control subjects [36].
1 Figure 3. Summary of the studies that correlate overall obesity with the characteristics of the carotid atherosclerotic plaques.
This opportunistic review identified three articles that found that obesity did not correlate with calcium score or carotid plaque score ( Figure 3) [8,26,37]. (1). No association was found between BMI and calcium mass score of the carotid arteries determined with a CT scan [26]. This study was performed on 1315 diabetic patients [26]. (2). One study found that the measures of adiposity (BMI, the systemic fat mass, and the fat-free mass determined with DXA) were not significantly different in patients with higher plaques score [8]. For each segment, the degree of plaque was graded as follows: 0 = no plaque; 1 = 1 small plaque. <30% of vessel diameter; 2 = 1 medium plaque between 30% of vessel diameter or multiple small plaques; and 3 = 1 large plaque >50% of the vessel diameter or multiple plaques with at least 1 medium plaque [8].
The grades were summed across the right and left carotid arteries to create an overall measure of the extent of focal plaque [8]. This study included 52 patients [8].
(3). One paper found an inverse correlation between BMI and plaque score, defined as the total plaque thickness for the visualization sites in the IMT measurement on the right and left size [37]. The study was performed on 352 rheumatoid arthritis patients [37].
Two different papers did not find any relation between BMI and the severity of atherosclerotic plaque (Figure 3) [19,23].
(1). A histological study analyzed the relationship between obesity and the severity of atherosclerosis carotid plaque [19]. The atherosclerotic lesions were described according to the American Heart Association classification [19]. BMI did not independently predict the risk of developing advanced carotid atherosclerotic lesions (including 185 cadavers of men and women) [19]. (2). No association was found between obesity (BMI > 27 kg/m 2 ) and carotid stenosis ≥ 50% (determined with NASCET criteria) in 533 patients [23]. In this study, there was no association between obesity and symptomatic carotid stenosis [23].
Another paper concluded that obesity (determined by BMI) was associated with the progression of carotid atherosclerosis, studied with magnetic resonance [29]. This research project determined the change in the carotid artery wall in 106 hyperlipidemic participants during the course of treatment with statins ( Figure 3) [29].

Visceral Adipose Tissue and the Prevalence of Carotid Plaque
Nineteen articles analyzed the relationship between VAT and carotid stenosis. Eight papers performed in 12,444 patients showed no association between waist circumference (WC) and the presence of carotid plaques [9,13,15,16,22,25,35,39,40]. Three studies, however, found that the presence of plaque was associated with WC in 1271 subjects ( Figure 4) [7,21].
Three other studies that included 5 700 subjects found that WHR was associated with the prevalence of carotid plaques (Figure 4) [15,35,38].
WHR was significantly related to the presence of carotid artery plaque in African Caucasian women, whereas none of the obesity measures were associated with carotid artery plaque in black women [18]. The study was limited to 203 African black and African Caucasian women who met the American College of Rheumatology criteria for rheumatoid arthritis (Figure 4) [18].
In two research works, there was no association between WHR and the presence of carotid plaques (1205 subjects) (Figure 4) [9,28].
A research work analyzed the relationship between new anthropometric measures that reflected the quantity of abdominal adipose tissue and the carotid plaque [39]. The anthropometric measures were the A Body Shape Index (ABSI) and Body Roundness Index (BRI) [39]. ABSI was independently associated with the presence of carotid atherosclerotic plaque. The study included 468 subjects with arterial hypertension [39].
Four articles used CT scans to quantify the VAT and another used MRI [3,8,26,28,31]. The VAT area determined with a CT scan in 980 healthy Japanese was independently associated with cervical plaque [31]. In three studies with 2161 subjects, the VAT area determined with a CT scan was not associated with the presence of carotid plaques [3,8,26]. One paper published the relationship between VAT and SAT as determined by MRI and the presence of carotid plaque [28]. The study included 191 subjects, and no relation was found between the variables (Figure 4) [28].
One paper concluded that VAT measured with bioelectrical impedance was associated with a higher prevalence of atherosclerotic carotid plaques [37]. This study was limited to 352 patients with rheumatoid arthritis (Figure 4) [37]. sociated with cervical plaque [31]. In three studies with 2161 subjects, the VAT area determined with a CT scan was not associated with the presence of carotid plaques [3,8,26]. One paper published the relationship between VAT and SAT as determined by MRI and the presence of carotid plaque [28]. The study included 191 subjects, and no relation was found between the variables (Figure 4) [28].
One paper concluded that VAT measured with bioelectrical impedance was associated with a higher prevalence of atherosclerotic carotid plaques [37]. This study was limited to 352 patients with rheumatoid arthritis (Figure 4) [37].

Visceral Adipose Tissue and the Characteristics of the Carotid Plaque
A research work of 112 subjects found that increased fat mass (determined with bioimpedance) correlates with carotid plaque vulnerability, as expressed by the gray scale median score ( Figure 5) [17].
A research work determined WC in 657 patients with symptoms of cerebral ischemia and carotid stenosis of ≥50% [20]. The author concluded that patients with and without abdominal obesity did not significantly differ either in the degree of carotid stenosis or in the degree of its clinical manifestation [20]. Haberka also reached a similar conclusion determining the central obesity with WC and ultrasound [8]. In this study, the amount of visceral fat was not related to carotid stenosis severity ( Figure 5) [40].
A study in 774 men without atherosclerosis showed that abdominal obesity, as indicated by high WHR and high WC, was associated with accelerated progression of carotid atherosclerosis independent of overall obesity and other risk factors in middle-aged men with no prior atherosclerotic diseases ( Figure 5) [6].
An autopsy study with 240 deceased subjects concluded that VAT was not associated with carotid artery stenosis index [33]. The VAT was the sum of the weight of the omental, mesenteric, mesocolon and perirenal fat [33]. The largest atheroma plaque in the carotid artery was determined [33]. The stenosis index was calculated by subtracting the lumen area from the outer area, dividing the difference by the outer area, and multiplying the result by 100 ( Figure 5) [33].
One paper showed that subjects with the highest amount of VAT were more prone to have more than one carotid plaque compared to participants showing the highest values of SAT or other conventional anthropometric indices [28]. The quantity of VAT and SAT was quantified by MRI in 191 subjects ( Figure 5) [28]. mesenteric, mesocolon and perirenal fat [33]. The largest atheroma plaque in the carotid artery was determined [33]. The stenosis index was calculated by subtracting the lumen area from the outer area, dividing the difference by the outer area, and multiplying the result by 100 ( Figure 5) [33].
One paper showed that subjects with the highest amount of VAT were more prone to have more than one carotid plaque compared to participants showing the highest values of SAT or other conventional anthropometric indices [28]. The quantity of VAT and SAT was quantified by MRI in 191 subjects ( Figure 5) [28].

Figure 5.
Overview of the studies that analyze the association between visceral obesity and the characteristics of the carotid atherosclerotic plaques.

Figure 5.
Overview of the studies that analyze the association between visceral obesity and the characteristics of the carotid atherosclerotic plaques.

Discussion and Conclusions
To the best of our knowledge, this is the first opportunistic review analyzing the relationship between obesity and carotid artery disease.
The general assumption emerging from our analysis suggests no association between overall obesity (determined with BMI) or visceral obesity (determined in the majority of the studies with WC) and the presence of carotid plaque. However, three studies (5700 patients) found that WHR was associated with the prevalence of carotid plaques [15,35,38]. BMI is not always a measure of fatness. Individuals with more muscle mass may be incorrectly classified as obese [67]. BMI has poor specificity for excess adiposity, and it does not characterize the excess of centrally distributed obesity [68]. Low BMI values may also be associated with the loss of lean body mass (muscle) [68]. In contrast with BMI, WC and WHR specifically address abdominal obesity and correlate better with overall atherosclerotic disease prevalence [68]. WC and WHR may correlate better with body fatness [67] and may more accurately reflect the additional risk conferred by obesity [68]; actually, they are more associated with mortality and cardiovascular events than BMI [68].
Although WC is well-described as a measure of VAT and a marker of obesity's associated metabolic risks, WHR has superior performance in estimating atherosclerotic risk [68]. One possible explanation is that WHR is an indexed value (to lower body girth) and provides a more precise assessment of relative central adiposity across the spectrum of body size, compared with WC [68]. WHR is considered the main anthropometric measure of central obesity [15,35,38]. Another explanation is that increased hip circumference may protect against atherosclerosis [68]. Fat in the lower body may function as a protective reservoir against ectopic (abdominal) adiposity [68]. WHR is independently associated with prevalent atherosclerosis and provides better dis-crimination than either BMI or WC [68].
There is a correlation between the WHR and the ratio of VAT-to-SAT cross-sectional area (quantified by CT images taken in the abdominal region) [69]. VAT is an endocrine organ that can secrete adipokines, including cytokines and chemokines [70,71]. VAT is associated with cardiovascular disease and can be used as a cardiometabolic risk marker, while SAT has a beneficial metabolic impact in the opposite direction [71]. Abdominal visceral fat correlates with the prevalence of coronary artery disease and mortality. Subcutaneous fat may play a protective role against the development of coronary artery disease by improving insulin sensitivity or the secretion of adipokines. The VAT/SAT ratio is a unique parameter relevant to vascular inflammation or poor cardiovascular outcomes [71,72]. VAT/SAT ratio is associated with a higher total mortality and incidence of MACE, independently of traditional vascular risk factors, and with the presence of obstructive coronary artery disease [2].
In this review, we found a relationship between obesity and other characteristics of carotid atherosclerotic plaque. Overall obesity (738 patients) [4, 24,36] and an increase in fat mass (112 patients) [17] were associated with carotid plaque instability. Obesity and visceral fat (880 patients) are correlated with the progression of carotid atherosclerosis [6,29]. However, no study related obesity to carotid artery symptomatology.
Studies conducted with cardiac patients found that obesity was also positively associated with the progression of coronary plaque [72,73]. Excess VAT is correlated with higher serum levels of fasting glucose, triglycerides, lower HDL cholesterol, greater prevalence of hypertension, tobacco use, and artery inflammation [72,73]. The systemic inflammation causes endothelial dysfunction, formation, and progression of atherosclerotic plaques [73,74]. Importantly, inflammation is also responsible for atherosclerotic plaque instability [43]. These biological facts could also explain why in this opportunistic review, we found that obesity did not correlate with calcium score, carotid plaque score [8,26,37], or the severity of atherosclerotic plaque [19,20,23,40].
None of the studies included in this review found any relationship between SAT and carotid plaques [3,8,26,28,31,40]. Further studies to characterize the subcutaneous fat should be developed.

Strengths and Limitations
A key strength of this review is the standardized data extraction, the quality assessment procedures, and searches conducted by two authors. This manuscript covers a broader range of patients and countries from 1985 to 2019 (most articles were published in the last 10 years). It includes published research in English, French, Portuguese, and Spanish language journals. The main limitation of this revision is that it did not conduct a metaanalysis. The articles included are not homogenous. There are different definitions of carotid plaque and obesity. The authors included different subjects and used different methods to determine obesity and carotid plaque. The opportunistic review included observational studies, and its bias was not entirely avoided.
Another bias of this study is the inability to determine the impact of obesity on atherosclerotic plaque independently of the cardiovascular risk. Obesity can increase the prevalence of certain factors such as dyslipidemia which contributes to atherosclerosis. However, there was no description of cardiovascular risk factors in all included papers.
Another limitation is that two research questions were not answered: (i). We did not find the relation between VAT and symptomatic carotid artery disease (ii). neither was the role played by subcutaneous tissue in carotid stenosis.

Implications for Practice
The results of the current investigation provide key information for practice. First, the importance of determining the WHR to infer the relation between VAT and SAT. The BMI, more frequently used in clinical activity, can erroneously represent the cardiovascular risk. Secondly, it may be useful to address obese patients to increase lean body mass. This study also has an impact on future research. The authors should use rigorous methods to determine obesity to homogenize the results, and facilitate the comparisons accurately. The role of subcutaneous tissue in carotid atherosclerosis still needs more investigations to clearly determine its role in vascular diseases. The relationship between obesity, subcutaneous fat, and carotid symptomatology should be more deeply investigated. Behavioral and pharmacological interventions could be developed to decrease the VAT/SAT ratio. Studies focused on obesity and inflammation could be important in atherosclerosis control.

Concluding Remarks
Considering the data analyzed, obesity and visceral obesity were not associated with the presence of carotid plaque. The ratio between VAT and SAT could influence the prevalence of carotid plaques. Obesity could be related to carotid plaque instability and progression, but its association with carotid symptomatology has not been proved and should be investigated in future studies.