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Carotid atherosclerosis, silent ischemic brain damage and brain atrophy: A systematic review and meta-analysis
International Journal of Cardiology 223 (2016) 681–687
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Carotid atherosclerosis, silent ischemic brain damage and brain atrophy: A systematic review and meta-analysis Francesco Moroni a,⁎, Enrico Ammirati a,b, Marco Magnoni a, Fabrizio D'Ascenzo c, Matteo Anselmino c, Nicoletta Anzalone d, Maria Assunta Rocca e, Andrea Falini d, Massimo Filippi e, Paolo G. Camici a a
Cardiothoracic Department, San Raffaele Scientific Institute and Vita-Salute University, Milan, Italy Cardiovascular and Thoracic Department, AO Niguarda Ca' Granda, Milan, Italy c Division of Cardiology, Department of Medical Sciences, “Città della Salute e della Scienza”, University of Turin, Turin, Italy d Department of Neuroradiology, CERMAC, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy e Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy b
a r t i c l e
i n f o
Article history: Received 4 May 2016 Received in revised form 1 August 2016 Accepted 12 August 2016 Available online 13 August 2016 Keywords: Carotid atherosclerosis Leukoaraiosis Silent brain infarction Brain atrophy Meta-analysis
a b s t r a c t Background: The widespread use of brain imaging has led to increased recognition of subclinical brain abnormalities, including white matter hyperintensities (WMH) and silent brain infarctions (SBI), which have a vascular origin, and have been associated to a high risk of stroke, disability and dementia. Carotid atherosclerosis (CA) may be causative in the development of WMH, SBI and eventually brain atrophy. Aim of the present systematic review and meta-analysis was to assess the existing evidence linking CA to WMH, SBI and brain atrophy. Methods: The relation between CA and WMH, SBI and brain atrophy was investigated through the systematic search of online databases up to September 2015 and manual searching of references and related citations. Pooled estimates were calculated by random-effects model, using restricted maximum likelihood method with inverse variance weighting method. Results: Of the 3536 records identified, fifteen were included in the systematic review and 9 were found to be eligible for the meta-analysis. CA was significantly associated with the presence of WMH (Odds Ratio, OR 1.42, confidence interval, CI 1.22–1.66, p b 0.0001) and of SBI (OR 1.89, CI 1.46–2.45, p b 0.0001). No meta-analysis could be performed for the relation between CA and brain atrophy due to the lack of suitable studies. Conclusions: CA was found to be associated to WMH and SBI. While no causative association can be inferred from the available data, the presence of carotid plaque may be considered a significant risk factor for subclinical cerebral damage. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Asymptomatic carotid stenosis is common in the general population, with prevalence estimates being as high as 6% in elderly men and 4.4% in elderly women [1], while presence of carotid artery plaque may be even higher, reaching up to 40% of free living subjects [2]. The widespread use of brain magnetic resonance imaging (MRI) has enabled an increased recognition, especially in elderly subjects, of cerebral alterations in apparently healthy individuals. A causative role for carotid atherosclerosis, however, cannot, to date, be ruled out. MRI detected alterations include white matter hyperintensities (WMH), defined as patchy areas of signal Abbreviations: CA, carotid atherosclerosis; WMH, white matter hyperintensities; SBI, silent brain infarctions; OR, odds ratio; CI, confidence interval; MRI, magnetic resonance imaging; US, ultrasound; FLAIR, fluid attenuation inversion recovery; IMT, intima-media thickness. ⁎ Corresponding author at: Cardiothoracic Department, San Raffaele Scientific Institute and University, Via Olgettina 60, 20132 Milan, Italy. E-mail address: [email protected] (F. Moroni).
http://dx.doi.org/10.1016/j.ijcard.2016.08.234 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
hyperintensity on T2-weighted and/or fluid attenuated inversion recovery (FLAIR) sequences [3,4], and silent brain infarctions (SBI), i.e., focal areas of at least 3 mm in diameter showing high signal intensity on T2-weighted, or having the same signal intensity as cerebrospinal fluid in FLAIR images, and low intensity on T1-weighted images, in the absence of corresponding neurological signs and symptoms and with no clinical history of stroke [5,6]. WMH and SBI are not innocuous, since they have been associated with brain atrophy [7] and confer a significant risk of incident stroke [8], mood and gait disturbances [9], cognitive decline and dementia [8,9]. As a consequence, they could be considered as markers of “brain frailty” [10]. Both types of lesions are thought to have a vascular origin [6,9], but their precise etiology remains controversial. Local microvascular alterations, embolic occlusion of arterioles or chronic cerebral hypoperfusion have all been implicated [6,11]. Advanced age, cardiovascular risk factors, in particular hypertension, atrial fibrillation and patent foramen ovale have been associated with WMH and SBI [6,12–17]. Carotid atherosclerosis, as a source of microemboli [18] or by causing ischemia in case of flow limiting
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stenosis, may contribute to WMH and SBI, and ultimately to brain atrophy [19]. The aim of the present systematic review and meta-analysis was to investigate the association between the presence of carotid atherosclerotic plaques and WMH, SBI or brain atrophy in the general population, largely including asymptomatic subjects. 2. Methods The present study was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statement [20] guidelines for its design, implementation, analysis and reporting. 2.1. Search strategy We searched for studies assessing the relation between carotid atherosclerosis and WMH, SBI or brain atrophy detected with brain MRI. Specific inclusion criteria were: MRI field strength of at least 1.0 Tesla, assessment of WMHs on T2-weighted or FLAIR images and definition of SBI as focal lesions of at least 3 mm in diameter that appeared hyperintense on T2-weighted or FLAIR images and hypointense on T1-weighted images, with no associated neurological symptoms, in compliance with recently defined neuroimaging standards [4]. In the absence of a consensus on how to assess brain WMH involvement [4,21], we did not apply restrictions on the methods used. Similarly, no restriction was applied for brain atrophy evaluation method. We included only studies providing imaging evidence of carotid artery atherosclerosis, defined as carotid involvement by a fully developed atherosclerotic lesion. We did not apply restrictions for the specific definition of plaque and for the modality used for carotid assessment, which could include ultrasound (US), digital subtraction angiography, computed tomography angiography or magnetic resonance angiography. Studies concerned with the association between carotid intimamedia thickness (IMT) and WMH, SBI or cerebral atrophy were excluded, since IMT, while generally considered an early stage of atherosclerotic disease, appears to be biologically distinct from carotid atherosclerosis, and its relation to carotid plaques is incompletely understood [22]. Studies focusing selectively on stroke patients were excluded to avoid the confounding effect of the expected high ischemic burden in these subjects. Since recent evidence suggests that periventricular and deep WMH are to be considered as part of a continuous pathology [3], we excluded those studies selectively reporting on either of the two. Finally, we considered an article regarding brain atrophy suitable for meta-analysis if it provided mean and standard deviation values of standardized total brain volumes both in patients with carotid atherosclerosis and healthy controls. Studies reporting the odds ratio (OR) of patients with carotid atherosclerosis for extensive WMH or for the presence of SBI were included in the quantitative synthesis. If the study reported both adjusted and unadjusted ORs, we included in the analysis the value adjusted for age and sex, and, if available, cardiovascular risk factors. We decided to include age and sex adjusted ORs due to the known effect of both these variables on CA [23] and WMH prevalence and burden [3]. If no OR was available, the article was still included if the OR could be manually calculated from the data reported. Searches were performed of literature published through September the 30th, 2015 using MEDLINE and Embase. Additional records were identified on the gray literature database OpenSIGLE, related article feature on PubMed and hand searching of reference lists. 2.2. Data extraction Data concerning the imaging technique used to assess the presence of carotid artery plaque, MRI field strength, total number and mean age of participants and the proportion of participants with history of cerebrovascular disease were collected from each study. For studies on WMH or SBI, contingency tables and ORs were extracted. For studies on brain volume, mean and standard deviation of standardized total brain volumes were extracted. 2.3. Statistical analysis Continuous variables are reported as mean (standard deviation) or median (1st–3rd quartile). Categorical variables are expressed as percentages. The summary effect size was calculated with the random-effect models, using restricted maximum likelihood method with inverse variance weighting. Between-study heterogeneity was assessed with Q test and I2. Potential publication bias was assessed by inspecting a funnel plot of effect sizes versus standard errors [24], and using rank correlation test [25]. A meta-analysis was carried out if at least three studies were available for the same outcome. All analyses were performed using the metafor package in R [26]. Associations with p b 0.05 were considered significant.
3. Results 3.1. Articles selection The search strategy for Embase is shown in Table 1. For other databases, we applied the same strategy with variations based on database structure. Of the 3536 articles identified, 3426 records were excluded
Table 1 Search strategy for Embase. For other databases, i.e. MEDLINE and OpenSIGLE, we applied variations based on database structure. #1
‘carotid artery disease’/exp
#2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12 #13 #14
‘white matter lesion’/exp ‘leukoaraiosis’/exp white AND matter AND hyperintensit⁎ 2# OR #3 OR 4# ‘brain atrophy’/exp silent OR occult ‘cerebrovascular accident’/exp #7 AND #8 ‘lacunar stroke’/exp #9 OR #10 #5 OR #6 OR #11 #1 AND #12 Filter #13 for “English and Humans”
upon title screening. Abstracts of the remaining 110 records were reviewed, which led to the exclusion of further 42 articles. Full text was evaluated in 68 articles, and 15 were found to match our inclusion and exclusion criteria. Of those, 9 were found suitable for meta-analysis. Fig. 1 summarizes articles' selection process. 3.2. Carotid atherosclerosis and WMH Ten population-based studies explored the relation between carotid atherosclerosis and WMH [27–36]. Of those, six, comprising 5306 subjects, fulfilled the criteria for inclusion in the meta-analysis [27–32]. Table 2 reports data extracted from these studies. Combining all studies, the pooled OR for WMH in patients suffering from carotid atherosclerosis was 1.42 (95% confidence interval [CI]: 1.22–1.66, p b 0.0001), as shown in Fig. 2. No evidence of significant heterogeneity was present (Q-test p = 0.38; I2 = 0.0%). Visual inspection of the funnel plot (Supplementary Fig. 1) showed some potential for publication bias, despite a nonsignificant rank correlation test (p = 0.47). In particular, the study by Fazekas et al. [27] appeared as an outlier in terms of sample size and OR. However, the exclusion of this study led to marginal changes in the results, yielding a pooled OR of 1.40 (95% CI: 1.20–1.63, p b 0.0001; Q-test p = 0.58; I2 = 0.0%). Four additional studies were identified through the systematic search, which could not be included in the quantitative synthesis [33– 36]. Table 3 summarizes the main findings and reasons for exclusion from the meta-analysis. Manolio et al. investigated the association between carotid atherosclerosis and the extent of cerebral WMH involvement assessed using a visual scoring system in a cohort of 3502 subjects older than 65 years of age [33]. These Authors report a significant association between carotid atherosclerosis and the severity of white matter changes that was stronger with increasing stenosis severity and remained significant after adjustment for age and sex [33]. De Leeuw et al. described the relation between the number of atherosclerotic plaques in the carotid arteries bilaterally and brain WMH, assessed semi-quantitatively, in a cohort of 1077 individuals aged 60 to 90 years [36]. They found a significant association between the number of plaques and the severity of WMH in the periventricular white matter, but not in the subcortical region. Such an association remained significant after adjustment for hypertension [36]. Shrestha et al. explored the association between the number of carotid plaques and carotid plaque score, i.e., the sum of the heights of all the plaques detected bilaterally using ultrasound, and the extent of WMH assessed by Fazekas score in a cohort of 179 subjects, with a mean age of 66 years [35]. At multivariable regression, plaque score was independently associated to the severity of WMH both in periventricular and deep white matter [35]. Finally, Landi et al. assessed the association between carotid atherosclerosis and total WMH volume in a cohort of 94 subjects with a mean
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Fig. 1. Study selection flow diagram.
Table 2 Data extracted from the studies evaluating the relation between carotid atherosclerosis and white matter hyperintensities. Author
Year
CA imaging
CA definition
MRI
N
CA and WMH
Reported OR
Calculated OR
Age (years)
Proportion of symptomatic subjects (%)
Fazekas
1988
US
1.5 T
52
19
NA
3.56
58
0
Bots
1993
US
1.5 T
111
8
NA
1.04
74
0
Pico
2002
US
At least a single plaque independently from stenosis, not otherwise specified Focal widening of the carotid wall relative to adjacent segment, with protrusion into the lumen of either calcified deposits or a combination of calcifications and non-calcified material. Localized echo structures N1 mm which encroach the lumen Carotid plaque determining at least 25% stenosis Presence of plaque, not otherwise specified Localized echo structure encroaching the lumen for N1 mm from the media-adventitia interface
1.0 T
640
46
1.35†
1.56
62
0
‡
– 1.25 –
58 61 72
NA§ 0 NA||
Romero Yoshida Brisset
2009 2012 2013
US US US
1.0 T 1.5 T 1.5 T
1971 790 1742
NA 90 NA
1.76 NA 1.37†
Proportion of symptomatic subjects reports the number of subjects with symptomatic cerebrovascular disease. MRI = magnetic resonance imaging; CA = carotid atherosclerosis; WMH = white matter hyperintensities; OR = odds ratio; US = ultrasound. †Adjusted for age, sex and cardiovascular risk factors; ‡Adjusted for age and sex; §Overall manifest cardiovascular disease (including cerebrovascular disease, coronary artery disease, heart failure and peripheral artery disease) 7.5%; ||Overall manifest cardiovascular disease (including cerebrovascular disease, coronary artery disease, heart failure and peripheral artery disease) 6%.
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Fig. 2. Meta-analysis of the studies evaluating the association between carotid atherosclerosis and white matter hyperintensities. OR: odds ratio; CI: confidence interval.
age of 71 years [34]. At multivariable analysis, they found a significant association between age and WMH, but not between carotid stenosis and WMH [34]. A single, prospective study reported an increased risk (OR = 1.76) for severe WMH at 4 years of follow up in patients with carotid atherosclerosis [29].
One further study, not suitable for the meta-analysis, was identified through the search [40]. In particular, at multivariable analysis, Longstreth et al. described a significant association between SBI and ipsilateral carotid plaque with a stenosis of at least 50% in 3244 subjects aged 65 years or more [40].
3.4. Carotid atherosclerosis and brain atrophy 3.3. Carotid atherosclerosis and SBI Seven studies examined the relationship between carotid atherosclerosis and the presence of SBI at brain MRI [30,31,33,37–40]. Two [30,33] referred to subgroups of the population of larger studies, [37, 40] respectively, thus, in order to avoid duplications, only the latter were included in the present analysis. Four studies, including 3586 participants, fulfilled the criteria for the inclusion in the meta-analysis [31, 37–39] (Table 4). They demonstrate a significant association between carotid atherosclerosis and the presence of SBI, with a pooled OR of 1.89 (95% CI: 1.46–2.45, p b 0.0001), as shown in Fig. 3. No evidence of significant heterogeneity was detected (Q-test p = 0.23, I2 = 15.5%). The study by Giele et al. [39] was identified as a potential source of bias, since the definition of carotid atherosclerosis markedly differed from other studies (i.e., presence of a stenosis ≥70% in the work by Giele et al. [39], imaging evidence of carotid plaques in all other studies). After the exclusion of this study from the analysis, a small increase in effect size was observed, with a pooled OR of 1.94 (95% CI: 1.45–2.60, p b 0.0001; Q-test p = 0.15, I2 = 35.3%). Visual inspection of the funnel plot (Supplementary Fig. 2) was not suggestive of publication bias, as was rank correlation test (p = 1).
Only three studies assessing the relationship between carotid atherosclerosis and brain volume were identified [30,33,41], none of which fulfilled the criteria for inclusion in the meta-analysis. Romero et al. observed a highly significant association between the presence of a carotid plaque determining a stenosis ≥25% and lower total brain volume to total cranial volume ratio in 1971 subjects [30]. Manolio et al. described an association between sulcal widening, bifrontal distance and ventricular size, all MRI markers of brain atrophy, and the presence of carotid atherosclerosis, defined as a focal thickening of the intimal-medial layer of the common carotid, carotid bulb or internal carotid artery, in a population of 3502 elderly subjects [33]. The association remained significant after adjustment for age, sex, aspirin use and hypertension. Finally, Muller et al. reported an association between carotid atherosclerosis, with a stenosis of at least 50% in diameter, and lower total brain and cortical gray matter volume, normalized for intracranial volume, in a population-based cohort of 1232 subjects [41]. Interestingly, follow up data at 4 years were available for 663 participants, and showed a significant association between severe, i.e., stenosis ≥70%, or bilateral carotid atherosclerosis and progression of global, cortical and subcortical atrophy [41].
Table 3 Studies concerned with the relation between carotid atherosclerosis and white matter hyperintensities not included in the meta-analysis. Author Manolio
Year
n
Main findings
1999 3502 WMH severity assessed with an Authors' defined visual scoring system increased with increasing stenosis severity. The association remained significant after age and sex adjustment. DeLeeuw 2001 1077 Significant association between number of plaques in the carotid arteries and a semiquantitative measure of WMH severity in the periventricular, but not in the subcortical, white matter. Shresta 2007 179 Plaque score, i.e. the sum of the thickness of all plaques identified bilaterally in the carotid arteries, significantly correlated with WMH assessed with Fazekas score. Landi 2015 94 No association between the degree of stenosis and cerebral WMH in a multivariate analysis including age and cardiovascular risk factors
CA definition
Reasons for exclusion
Focal thickening of the intimal-medial layer Both WMH and CA treated continuously. No variances reported. OR was not reported or of the common carotid, carotid bulb or calculable. internal carotid artery Focal widening of the vessel wall relative to adjacent segments with protrusion into the lumen of calcifications and/or non-calcific material Focal thickening of the carotid wall exceeding 1.1 mm from the media-adventitia interface Focal thickening of carotid wall on B-mode images, in compliance with Society of Radiologists in Ultrasound Consensus Conference [60]
Not reported the number of subject without CA. WMH treated as a continuous variable. Distinction between periventricular and subcortical WMH. CA and WMH treated as continuous variables. Insufficient data for OR calculation. Number of subjects without CA was not reported. Insufficient data to calculate OR.
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Table 4 Data extracted from the studies evaluating the relation between carotid atherosclerosis and silent brain infarctions. Author
Year
CA imaging
CA definition
MRI
N
CA and SBI
Reported OR
Calculated OR
Age (years)
Proportion of symptomatic subjects (%)
Giele Inoue
2003 2006
US US
1.5 T 1.5 T
308 448
1 19
NA NA
0.84 3.28
58 51
0 0
Das† Yoshida
2008 2009
US US
Atherosclerotic stenosis 70% Localized lesion protruding into the lumen of the common carotid or bifurcation Presence of a carotid stenosis of at least 25% Presence of plaque, not otherwise specified
1.0 T 1.5 T
2040 790
NA 93
1.62‡ NA
. 1.84
58 61
0 0
Proportion of symptomatic subjects reports the number of subjects with symptomatic cerebrovascular disease. MRI = magnetic resonance imaging; CA = carotid atherosclerosis; SBI = silent brain infarction; OR = odds ratio; US = ultrasound. †Presence of plaque defined for carotid stenosis of at least 25%; ‡Adjusted for age and sex.
4. Discussion The main finding of the present systematic review and metaanalysis was the demonstration of a significant association between carotid atherosclerosis and a higher risk of both WMH and SBI. The association appears to be particularly robust, since it derives mainly through the analysis of either multivariate OR or from directly calculated OR, which are believed to reduce spurious associations due to reporting bias. Secondarily, we found records concerning the relation between carotid atherosclerosis and brain volumes: surprisingly few studies were identified, [30,33,41], but all appeared to suggest an association between carotid plaque and brain atrophy. As the use of brain MRI has become increasingly widespread, clinicians often have to cope with the incidental finding of silent cerebral alterations, particularly in patients with asymptomatic carotid artery plaques. WMH and SBI are frequently discovered in healthy subjects, and their prevalence depends on age [42–44]. These lesions were shown to associate with brain atrophy, a marker of accumulating cerebral damage [7,45]. Both WMH and SBI appear to have a vascular pathogenesis [6,9,46] and both are strongly associated with cardiovascular risk factors and atrial fibrillation [6,12,13]. However, the precise etiology is yet to be defined. Indeed, local vascular degenerative processes leading to hypoperfusion or acute ischemia with tissue necrosis [9], distal embolization from the heart [13] or from a large vessel [47], or chronic reduction in cerebral perfusion, have all been implicated [19,48]. Carotid atherosclerosis may thus contribute to the pathogenesis of both WMH and SBI as a source of microemboli [49] or through the reduction of cerebral blood flow [50]. While some of the studies eligible for the present systematic review and meta-analysis reported an increasing cerebral involvement proportional to the degree of the carotid stenosis [30,33], many of the studies did not report stenosis severity [27–29,31,32]. In others, patients with hemodynamically significant stenosis, i.e., ≥50%, were absent or under-represented [37,38]. These data support a potential etiologic
role for carotid atherosclerosis in the development of WMH and SBI, but possibly suggest that the presence of a flow limiting stenosis is not required, making the chronic ischemia hypothesis less likely. Furthermore, some reports associated the presence of vulnerability features within the plaque to a higher burden of silent ischemic brain damage, suggesting a direct role for atherothrombosis and subsequent distal embolization [30,51,52]. A recent meta-analysis showed a significant association between atrial fibrillation and presence of SBI, with a pooled OR of 2.62, which supports an embolic origin for these lesions [53]. A direct causative role for carotid atherosclerosis with an embolic mechanism would imply a higher burden of silent ischemic lesions ipsilateral to the site of carotid artery disease. Research in this field, however, yielded mixed results [54–56]. Indeed, the association may be accounted for by the risk factors shared by carotid atherosclerosis, WMH and SBI, including age, hypertension, dyslipidemia, smoking and diabetes [9,12]. A limit of the present work relates to the partial characterization of the study population: indeed, we were not able to take into consideration the potential influence of atrial fibrillation, the presence of PFO or the effect of current treatment, e.g. antiplatelet medications, since the Authors of the studies included in the meta-analysis did not report such characteristics. Carotid atherosclerosis may be considered a marker of higher ischemic vulnerability of the brain. This may allow the clinician to identify subjects at risk of stroke and dementia, and prompt an aggressive correction of cardiovascular risk factors, eventually including the initiation of treatment which were shown to effectively slow the progression of cerebral ischemic damage, including antiplatelet medications, as aspirin [57] or cilostazol [58] and lipid lowering medications such as statins [59]. 5. Conclusions Carotid atherosclerosis appears to be strongly associated to the presence of WMH (OR = 1.42, p b 0.0001) and SBI (OR = 1.89, p b 0.0001). The few available studies concerning the relation between carotid
Fig. 3. Meta-analysis of the studies evaluating the association between carotid atherosclerosis and silent brain infarctions. OR: odds ratio; CI: confidence interval.
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atherosclerosis and brain volumes suggest that carotid plaques and cerebral atrophy may be associated. While any speculation about the causative role of carotid atherosclerosis for WMH, SBI and subsequently brain atrophy cannot be made from the available literature, carotid atherosclerosis can be proposed as a marker for susceptibility to ischemic cerebral damage. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2016.08.234. Founding EA received financial support from the “Giovane Ricercatore 2009 Grant” from Italian Ministry of Health (project code GR-2009-1608780). Conflicts of interest None. References [1] M. de Weerd, J.P. Greving, B. Hedblad, M.W. Lorenz, E.B. Mathiesen, D.H. O'Leary, et al., Prevalence of asymptomatic carotid artery stenosis in the general population: an individual participant data meta-analysis, Stroke 41 (2010) 1294–1297. [2] C. Zhan, M. Shi, Y. Yang, H. Pang, S. Fei, L. Bai, et al., Prevalence and risk factors of carotid plaque among middle-aged and elderly adults in rural Tianjin, China, Sci. Rep. 6 (2016) 23870. [3] J.M. Wardlaw, M.C. Valdes Hernandez, S. Munoz-Maniega, What are white matter hyperintensities made of? Relevance to vascular cognitive impairment, J. Am. Heart Assoc. 4 (2015) 001140. [4] J.M. Wardlaw, E.E. Smith, G.J. Biessels, C. Cordonnier, F. Fazekas, R. Frayne, et al., Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration, Lancet Neurol. 12 (2013) 822–838. [5] K.R. Kovács, D. Czuriga, D. Bereczki, N.M. Bornstein, L. Csiba, Silent brain infarction — a review of recent observations, Int. J. Stroke 8 (2013) 334–347. [6] S.E. Vermeer, W.T. Longstreth Jr., P.J. Koudstaal, Silent brain infarcts: a systematic review, Lancet Neurol. 6 (2007) 611–619. [7] A.P. Appelman, K.L. Vincken, Y. van der Graaf, A.L. Vlek, T.D. Witkamp, W.P. Mali, et al., White matter lesions and lacunar infarcts are independently and differently associated with brain atrophy: the SMART-MR study, Cerebrovasc. Dis. 29 (2010) 28–35. [8] S. Debette, H.S. Markus, The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis, BMJ 341 (2010) c3666. [9] L. Pantoni, Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges, Lancet Neurol. 9 (2010) 689–701. [10] K. Rockwood, X. Song, C. MacKnight, H. Bergman, D.B. Hogan, I. McDowell, et al., A global clinical measure of fitness and frailty in elderly people, CMAJ 173 (2005) 489–495. [11] L. Pantoni, Pathophysiology of age-related cerebral white matter changes, Cerebrovasc. Dis. 13 (Suppl. 2) (2002) 7–10. [12] L.J. Launer, Epidemiology of white matter lesions, Top. Magn. Reson. Imaging 15 (2004) 365–367. [13] F. Gaita, L. Corsinovi, M. Anselmino, C. Raimondo, M. Pianelli, E. Toso, et al., Prevalence of silent cerebral ischemia in paroxysmal and persistent atrial fibrillation and correlation with cognitive function, J. Am. Coll. Cardiol. 62 (2013) 1990–1997. [14] Y. Ueno, Y. Shimada, R. Tanaka, N. Miyamoto, Y. Tanaka, N. Hattori, et al., Patent foramen ovale with atrial septal aneurysm may contribute to white matter lesions in stroke patients, Cerebrovasc. Dis. 30 (2010) 15–22. [15] J. Wieczorek, K. Mizia-Stec, A. Lasek-Bal, P. Wieczorek, A. Hoffmann, S. Nowak, et al., CHA2DS2-Vasc score, age and body mass index as the main risk factors of hyperintense brain lesions in asymptomatic patients with paroxysmal non-valvular atrial fibrillation, Int. J. Cardiol. 215 (2016) 476–481. [16] Y. Tabara, K. Kohara, M. Ochi, Y. Okada, M. Ohara, T. Nagai, et al., Association of office-based frailty score with hypertensive end organ damage in the J-SHIPP cross-sectional study, Int. J. Cardiol. 216 (2016) 25–31. [17] H.K. Kuo, C.Y. Chen, H.M. Liu, C.J. Yen, K.J. Chang, C.C. Chang, et al., Metabolic risks, white matter hyperintensities, and arterial stiffness in high-functioning healthy adults, Int. J. Cardiol. 143 (2010) 184–191. [18] H.S. Markus, A. King, M. Shipley, R. Topakian, M. Cullinane, S. Reihill, et al., Asymptomatic embolisation for prediction of stroke in the asymptomatic carotid emboli study (ACES): a prospective observational study, Lancet Neurol. 9 (2010) 663–671. [19] A.P. Appelman, Y. van der Graaf, K.L. Vincken, A.M. Tiehuis, T.D. Witkamp, W.P. Mali, et al., Total cerebral blood flow, white matter lesions and brain atrophy: the SMARTMR study, J. Cereb. Blood Flow Metab. 28 (2008) 633–639. [20] D. Moher, A. Liberati, J. Tetzlaff, D.G. Altman, Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, PLoS Med. 6 (2009), e1000097. [21] M. Anselmino, F. Gaita, Silent cerebrovascular ischemias following transcatheter atrial fibrillation ablation: definition and cerebral magnetic resonance protocols, J. Cardiovasc. Electrophysiol. 24 (2013), E1.
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Carotid atherosclerosis, silent ischemic brain damage and brain atrophy: A systematic review and meta-analysis Francesco Moroni a,⁎, Enrico Ammirati a,b, Marco Magnoni a, Fabrizio D'Ascenzo c, Matteo Anselmino c, Nicoletta Anzalone d, Maria Assunta Rocca e, Andrea Falini d, Massimo Filippi e, Paolo G. Camici a a
Cardiothoracic Department, San Raffaele Scientific Institute and Vita-Salute University, Milan, Italy Cardiovascular and Thoracic Department, AO Niguarda Ca' Granda, Milan, Italy c Division of Cardiology, Department of Medical Sciences, “Città della Salute e della Scienza”, University of Turin, Turin, Italy d Department of Neuroradiology, CERMAC, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy e Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy b
a r t i c l e
i n f o
Article history: Received 4 May 2016 Received in revised form 1 August 2016 Accepted 12 August 2016 Available online 13 August 2016 Keywords: Carotid atherosclerosis Leukoaraiosis Silent brain infarction Brain atrophy Meta-analysis
a b s t r a c t Background: The widespread use of brain imaging has led to increased recognition of subclinical brain abnormalities, including white matter hyperintensities (WMH) and silent brain infarctions (SBI), which have a vascular origin, and have been associated to a high risk of stroke, disability and dementia. Carotid atherosclerosis (CA) may be causative in the development of WMH, SBI and eventually brain atrophy. Aim of the present systematic review and meta-analysis was to assess the existing evidence linking CA to WMH, SBI and brain atrophy. Methods: The relation between CA and WMH, SBI and brain atrophy was investigated through the systematic search of online databases up to September 2015 and manual searching of references and related citations. Pooled estimates were calculated by random-effects model, using restricted maximum likelihood method with inverse variance weighting method. Results: Of the 3536 records identified, fifteen were included in the systematic review and 9 were found to be eligible for the meta-analysis. CA was significantly associated with the presence of WMH (Odds Ratio, OR 1.42, confidence interval, CI 1.22–1.66, p b 0.0001) and of SBI (OR 1.89, CI 1.46–2.45, p b 0.0001). No meta-analysis could be performed for the relation between CA and brain atrophy due to the lack of suitable studies. Conclusions: CA was found to be associated to WMH and SBI. While no causative association can be inferred from the available data, the presence of carotid plaque may be considered a significant risk factor for subclinical cerebral damage. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Asymptomatic carotid stenosis is common in the general population, with prevalence estimates being as high as 6% in elderly men and 4.4% in elderly women [1], while presence of carotid artery plaque may be even higher, reaching up to 40% of free living subjects [2]. The widespread use of brain magnetic resonance imaging (MRI) has enabled an increased recognition, especially in elderly subjects, of cerebral alterations in apparently healthy individuals. A causative role for carotid atherosclerosis, however, cannot, to date, be ruled out. MRI detected alterations include white matter hyperintensities (WMH), defined as patchy areas of signal Abbreviations: CA, carotid atherosclerosis; WMH, white matter hyperintensities; SBI, silent brain infarctions; OR, odds ratio; CI, confidence interval; MRI, magnetic resonance imaging; US, ultrasound; FLAIR, fluid attenuation inversion recovery; IMT, intima-media thickness. ⁎ Corresponding author at: Cardiothoracic Department, San Raffaele Scientific Institute and University, Via Olgettina 60, 20132 Milan, Italy. E-mail address: [email protected] (F. Moroni).
http://dx.doi.org/10.1016/j.ijcard.2016.08.234 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
hyperintensity on T2-weighted and/or fluid attenuated inversion recovery (FLAIR) sequences [3,4], and silent brain infarctions (SBI), i.e., focal areas of at least 3 mm in diameter showing high signal intensity on T2-weighted, or having the same signal intensity as cerebrospinal fluid in FLAIR images, and low intensity on T1-weighted images, in the absence of corresponding neurological signs and symptoms and with no clinical history of stroke [5,6]. WMH and SBI are not innocuous, since they have been associated with brain atrophy [7] and confer a significant risk of incident stroke [8], mood and gait disturbances [9], cognitive decline and dementia [8,9]. As a consequence, they could be considered as markers of “brain frailty” [10]. Both types of lesions are thought to have a vascular origin [6,9], but their precise etiology remains controversial. Local microvascular alterations, embolic occlusion of arterioles or chronic cerebral hypoperfusion have all been implicated [6,11]. Advanced age, cardiovascular risk factors, in particular hypertension, atrial fibrillation and patent foramen ovale have been associated with WMH and SBI [6,12–17]. Carotid atherosclerosis, as a source of microemboli [18] or by causing ischemia in case of flow limiting
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stenosis, may contribute to WMH and SBI, and ultimately to brain atrophy [19]. The aim of the present systematic review and meta-analysis was to investigate the association between the presence of carotid atherosclerotic plaques and WMH, SBI or brain atrophy in the general population, largely including asymptomatic subjects. 2. Methods The present study was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statement [20] guidelines for its design, implementation, analysis and reporting. 2.1. Search strategy We searched for studies assessing the relation between carotid atherosclerosis and WMH, SBI or brain atrophy detected with brain MRI. Specific inclusion criteria were: MRI field strength of at least 1.0 Tesla, assessment of WMHs on T2-weighted or FLAIR images and definition of SBI as focal lesions of at least 3 mm in diameter that appeared hyperintense on T2-weighted or FLAIR images and hypointense on T1-weighted images, with no associated neurological symptoms, in compliance with recently defined neuroimaging standards [4]. In the absence of a consensus on how to assess brain WMH involvement [4,21], we did not apply restrictions on the methods used. Similarly, no restriction was applied for brain atrophy evaluation method. We included only studies providing imaging evidence of carotid artery atherosclerosis, defined as carotid involvement by a fully developed atherosclerotic lesion. We did not apply restrictions for the specific definition of plaque and for the modality used for carotid assessment, which could include ultrasound (US), digital subtraction angiography, computed tomography angiography or magnetic resonance angiography. Studies concerned with the association between carotid intimamedia thickness (IMT) and WMH, SBI or cerebral atrophy were excluded, since IMT, while generally considered an early stage of atherosclerotic disease, appears to be biologically distinct from carotid atherosclerosis, and its relation to carotid plaques is incompletely understood [22]. Studies focusing selectively on stroke patients were excluded to avoid the confounding effect of the expected high ischemic burden in these subjects. Since recent evidence suggests that periventricular and deep WMH are to be considered as part of a continuous pathology [3], we excluded those studies selectively reporting on either of the two. Finally, we considered an article regarding brain atrophy suitable for meta-analysis if it provided mean and standard deviation values of standardized total brain volumes both in patients with carotid atherosclerosis and healthy controls. Studies reporting the odds ratio (OR) of patients with carotid atherosclerosis for extensive WMH or for the presence of SBI were included in the quantitative synthesis. If the study reported both adjusted and unadjusted ORs, we included in the analysis the value adjusted for age and sex, and, if available, cardiovascular risk factors. We decided to include age and sex adjusted ORs due to the known effect of both these variables on CA [23] and WMH prevalence and burden [3]. If no OR was available, the article was still included if the OR could be manually calculated from the data reported. Searches were performed of literature published through September the 30th, 2015 using MEDLINE and Embase. Additional records were identified on the gray literature database OpenSIGLE, related article feature on PubMed and hand searching of reference lists. 2.2. Data extraction Data concerning the imaging technique used to assess the presence of carotid artery plaque, MRI field strength, total number and mean age of participants and the proportion of participants with history of cerebrovascular disease were collected from each study. For studies on WMH or SBI, contingency tables and ORs were extracted. For studies on brain volume, mean and standard deviation of standardized total brain volumes were extracted. 2.3. Statistical analysis Continuous variables are reported as mean (standard deviation) or median (1st–3rd quartile). Categorical variables are expressed as percentages. The summary effect size was calculated with the random-effect models, using restricted maximum likelihood method with inverse variance weighting. Between-study heterogeneity was assessed with Q test and I2. Potential publication bias was assessed by inspecting a funnel plot of effect sizes versus standard errors [24], and using rank correlation test [25]. A meta-analysis was carried out if at least three studies were available for the same outcome. All analyses were performed using the metafor package in R [26]. Associations with p b 0.05 were considered significant.
3. Results 3.1. Articles selection The search strategy for Embase is shown in Table 1. For other databases, we applied the same strategy with variations based on database structure. Of the 3536 articles identified, 3426 records were excluded
Table 1 Search strategy for Embase. For other databases, i.e. MEDLINE and OpenSIGLE, we applied variations based on database structure. #1
‘carotid artery disease’/exp
#2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12 #13 #14
‘white matter lesion’/exp ‘leukoaraiosis’/exp white AND matter AND hyperintensit⁎ 2# OR #3 OR 4# ‘brain atrophy’/exp silent OR occult ‘cerebrovascular accident’/exp #7 AND #8 ‘lacunar stroke’/exp #9 OR #10 #5 OR #6 OR #11 #1 AND #12 Filter #13 for “English and Humans”
upon title screening. Abstracts of the remaining 110 records were reviewed, which led to the exclusion of further 42 articles. Full text was evaluated in 68 articles, and 15 were found to match our inclusion and exclusion criteria. Of those, 9 were found suitable for meta-analysis. Fig. 1 summarizes articles' selection process. 3.2. Carotid atherosclerosis and WMH Ten population-based studies explored the relation between carotid atherosclerosis and WMH [27–36]. Of those, six, comprising 5306 subjects, fulfilled the criteria for inclusion in the meta-analysis [27–32]. Table 2 reports data extracted from these studies. Combining all studies, the pooled OR for WMH in patients suffering from carotid atherosclerosis was 1.42 (95% confidence interval [CI]: 1.22–1.66, p b 0.0001), as shown in Fig. 2. No evidence of significant heterogeneity was present (Q-test p = 0.38; I2 = 0.0%). Visual inspection of the funnel plot (Supplementary Fig. 1) showed some potential for publication bias, despite a nonsignificant rank correlation test (p = 0.47). In particular, the study by Fazekas et al. [27] appeared as an outlier in terms of sample size and OR. However, the exclusion of this study led to marginal changes in the results, yielding a pooled OR of 1.40 (95% CI: 1.20–1.63, p b 0.0001; Q-test p = 0.58; I2 = 0.0%). Four additional studies were identified through the systematic search, which could not be included in the quantitative synthesis [33– 36]. Table 3 summarizes the main findings and reasons for exclusion from the meta-analysis. Manolio et al. investigated the association between carotid atherosclerosis and the extent of cerebral WMH involvement assessed using a visual scoring system in a cohort of 3502 subjects older than 65 years of age [33]. These Authors report a significant association between carotid atherosclerosis and the severity of white matter changes that was stronger with increasing stenosis severity and remained significant after adjustment for age and sex [33]. De Leeuw et al. described the relation between the number of atherosclerotic plaques in the carotid arteries bilaterally and brain WMH, assessed semi-quantitatively, in a cohort of 1077 individuals aged 60 to 90 years [36]. They found a significant association between the number of plaques and the severity of WMH in the periventricular white matter, but not in the subcortical region. Such an association remained significant after adjustment for hypertension [36]. Shrestha et al. explored the association between the number of carotid plaques and carotid plaque score, i.e., the sum of the heights of all the plaques detected bilaterally using ultrasound, and the extent of WMH assessed by Fazekas score in a cohort of 179 subjects, with a mean age of 66 years [35]. At multivariable regression, plaque score was independently associated to the severity of WMH both in periventricular and deep white matter [35]. Finally, Landi et al. assessed the association between carotid atherosclerosis and total WMH volume in a cohort of 94 subjects with a mean
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Fig. 1. Study selection flow diagram.
Table 2 Data extracted from the studies evaluating the relation between carotid atherosclerosis and white matter hyperintensities. Author
Year
CA imaging
CA definition
MRI
N
CA and WMH
Reported OR
Calculated OR
Age (years)
Proportion of symptomatic subjects (%)
Fazekas
1988
US
1.5 T
52
19
NA
3.56
58
0
Bots
1993
US
1.5 T
111
8
NA
1.04
74
0
Pico
2002
US
At least a single plaque independently from stenosis, not otherwise specified Focal widening of the carotid wall relative to adjacent segment, with protrusion into the lumen of either calcified deposits or a combination of calcifications and non-calcified material. Localized echo structures N1 mm which encroach the lumen Carotid plaque determining at least 25% stenosis Presence of plaque, not otherwise specified Localized echo structure encroaching the lumen for N1 mm from the media-adventitia interface
1.0 T
640
46
1.35†
1.56
62
0
‡
– 1.25 –
58 61 72
NA§ 0 NA||
Romero Yoshida Brisset
2009 2012 2013
US US US
1.0 T 1.5 T 1.5 T
1971 790 1742
NA 90 NA
1.76 NA 1.37†
Proportion of symptomatic subjects reports the number of subjects with symptomatic cerebrovascular disease. MRI = magnetic resonance imaging; CA = carotid atherosclerosis; WMH = white matter hyperintensities; OR = odds ratio; US = ultrasound. †Adjusted for age, sex and cardiovascular risk factors; ‡Adjusted for age and sex; §Overall manifest cardiovascular disease (including cerebrovascular disease, coronary artery disease, heart failure and peripheral artery disease) 7.5%; ||Overall manifest cardiovascular disease (including cerebrovascular disease, coronary artery disease, heart failure and peripheral artery disease) 6%.
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Fig. 2. Meta-analysis of the studies evaluating the association between carotid atherosclerosis and white matter hyperintensities. OR: odds ratio; CI: confidence interval.
age of 71 years [34]. At multivariable analysis, they found a significant association between age and WMH, but not between carotid stenosis and WMH [34]. A single, prospective study reported an increased risk (OR = 1.76) for severe WMH at 4 years of follow up in patients with carotid atherosclerosis [29].
One further study, not suitable for the meta-analysis, was identified through the search [40]. In particular, at multivariable analysis, Longstreth et al. described a significant association between SBI and ipsilateral carotid plaque with a stenosis of at least 50% in 3244 subjects aged 65 years or more [40].
3.4. Carotid atherosclerosis and brain atrophy 3.3. Carotid atherosclerosis and SBI Seven studies examined the relationship between carotid atherosclerosis and the presence of SBI at brain MRI [30,31,33,37–40]. Two [30,33] referred to subgroups of the population of larger studies, [37, 40] respectively, thus, in order to avoid duplications, only the latter were included in the present analysis. Four studies, including 3586 participants, fulfilled the criteria for the inclusion in the meta-analysis [31, 37–39] (Table 4). They demonstrate a significant association between carotid atherosclerosis and the presence of SBI, with a pooled OR of 1.89 (95% CI: 1.46–2.45, p b 0.0001), as shown in Fig. 3. No evidence of significant heterogeneity was detected (Q-test p = 0.23, I2 = 15.5%). The study by Giele et al. [39] was identified as a potential source of bias, since the definition of carotid atherosclerosis markedly differed from other studies (i.e., presence of a stenosis ≥70% in the work by Giele et al. [39], imaging evidence of carotid plaques in all other studies). After the exclusion of this study from the analysis, a small increase in effect size was observed, with a pooled OR of 1.94 (95% CI: 1.45–2.60, p b 0.0001; Q-test p = 0.15, I2 = 35.3%). Visual inspection of the funnel plot (Supplementary Fig. 2) was not suggestive of publication bias, as was rank correlation test (p = 1).
Only three studies assessing the relationship between carotid atherosclerosis and brain volume were identified [30,33,41], none of which fulfilled the criteria for inclusion in the meta-analysis. Romero et al. observed a highly significant association between the presence of a carotid plaque determining a stenosis ≥25% and lower total brain volume to total cranial volume ratio in 1971 subjects [30]. Manolio et al. described an association between sulcal widening, bifrontal distance and ventricular size, all MRI markers of brain atrophy, and the presence of carotid atherosclerosis, defined as a focal thickening of the intimal-medial layer of the common carotid, carotid bulb or internal carotid artery, in a population of 3502 elderly subjects [33]. The association remained significant after adjustment for age, sex, aspirin use and hypertension. Finally, Muller et al. reported an association between carotid atherosclerosis, with a stenosis of at least 50% in diameter, and lower total brain and cortical gray matter volume, normalized for intracranial volume, in a population-based cohort of 1232 subjects [41]. Interestingly, follow up data at 4 years were available for 663 participants, and showed a significant association between severe, i.e., stenosis ≥70%, or bilateral carotid atherosclerosis and progression of global, cortical and subcortical atrophy [41].
Table 3 Studies concerned with the relation between carotid atherosclerosis and white matter hyperintensities not included in the meta-analysis. Author Manolio
Year
n
Main findings
1999 3502 WMH severity assessed with an Authors' defined visual scoring system increased with increasing stenosis severity. The association remained significant after age and sex adjustment. DeLeeuw 2001 1077 Significant association between number of plaques in the carotid arteries and a semiquantitative measure of WMH severity in the periventricular, but not in the subcortical, white matter. Shresta 2007 179 Plaque score, i.e. the sum of the thickness of all plaques identified bilaterally in the carotid arteries, significantly correlated with WMH assessed with Fazekas score. Landi 2015 94 No association between the degree of stenosis and cerebral WMH in a multivariate analysis including age and cardiovascular risk factors
CA definition
Reasons for exclusion
Focal thickening of the intimal-medial layer Both WMH and CA treated continuously. No variances reported. OR was not reported or of the common carotid, carotid bulb or calculable. internal carotid artery Focal widening of the vessel wall relative to adjacent segments with protrusion into the lumen of calcifications and/or non-calcific material Focal thickening of the carotid wall exceeding 1.1 mm from the media-adventitia interface Focal thickening of carotid wall on B-mode images, in compliance with Society of Radiologists in Ultrasound Consensus Conference [60]
Not reported the number of subject without CA. WMH treated as a continuous variable. Distinction between periventricular and subcortical WMH. CA and WMH treated as continuous variables. Insufficient data for OR calculation. Number of subjects without CA was not reported. Insufficient data to calculate OR.
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Table 4 Data extracted from the studies evaluating the relation between carotid atherosclerosis and silent brain infarctions. Author
Year
CA imaging
CA definition
MRI
N
CA and SBI
Reported OR
Calculated OR
Age (years)
Proportion of symptomatic subjects (%)
Giele Inoue
2003 2006
US US
1.5 T 1.5 T
308 448
1 19
NA NA
0.84 3.28
58 51
0 0
Das† Yoshida
2008 2009
US US
Atherosclerotic stenosis 70% Localized lesion protruding into the lumen of the common carotid or bifurcation Presence of a carotid stenosis of at least 25% Presence of plaque, not otherwise specified
1.0 T 1.5 T
2040 790
NA 93
1.62‡ NA
. 1.84
58 61
0 0
Proportion of symptomatic subjects reports the number of subjects with symptomatic cerebrovascular disease. MRI = magnetic resonance imaging; CA = carotid atherosclerosis; SBI = silent brain infarction; OR = odds ratio; US = ultrasound. †Presence of plaque defined for carotid stenosis of at least 25%; ‡Adjusted for age and sex.
4. Discussion The main finding of the present systematic review and metaanalysis was the demonstration of a significant association between carotid atherosclerosis and a higher risk of both WMH and SBI. The association appears to be particularly robust, since it derives mainly through the analysis of either multivariate OR or from directly calculated OR, which are believed to reduce spurious associations due to reporting bias. Secondarily, we found records concerning the relation between carotid atherosclerosis and brain volumes: surprisingly few studies were identified, [30,33,41], but all appeared to suggest an association between carotid plaque and brain atrophy. As the use of brain MRI has become increasingly widespread, clinicians often have to cope with the incidental finding of silent cerebral alterations, particularly in patients with asymptomatic carotid artery plaques. WMH and SBI are frequently discovered in healthy subjects, and their prevalence depends on age [42–44]. These lesions were shown to associate with brain atrophy, a marker of accumulating cerebral damage [7,45]. Both WMH and SBI appear to have a vascular pathogenesis [6,9,46] and both are strongly associated with cardiovascular risk factors and atrial fibrillation [6,12,13]. However, the precise etiology is yet to be defined. Indeed, local vascular degenerative processes leading to hypoperfusion or acute ischemia with tissue necrosis [9], distal embolization from the heart [13] or from a large vessel [47], or chronic reduction in cerebral perfusion, have all been implicated [19,48]. Carotid atherosclerosis may thus contribute to the pathogenesis of both WMH and SBI as a source of microemboli [49] or through the reduction of cerebral blood flow [50]. While some of the studies eligible for the present systematic review and meta-analysis reported an increasing cerebral involvement proportional to the degree of the carotid stenosis [30,33], many of the studies did not report stenosis severity [27–29,31,32]. In others, patients with hemodynamically significant stenosis, i.e., ≥50%, were absent or under-represented [37,38]. These data support a potential etiologic
role for carotid atherosclerosis in the development of WMH and SBI, but possibly suggest that the presence of a flow limiting stenosis is not required, making the chronic ischemia hypothesis less likely. Furthermore, some reports associated the presence of vulnerability features within the plaque to a higher burden of silent ischemic brain damage, suggesting a direct role for atherothrombosis and subsequent distal embolization [30,51,52]. A recent meta-analysis showed a significant association between atrial fibrillation and presence of SBI, with a pooled OR of 2.62, which supports an embolic origin for these lesions [53]. A direct causative role for carotid atherosclerosis with an embolic mechanism would imply a higher burden of silent ischemic lesions ipsilateral to the site of carotid artery disease. Research in this field, however, yielded mixed results [54–56]. Indeed, the association may be accounted for by the risk factors shared by carotid atherosclerosis, WMH and SBI, including age, hypertension, dyslipidemia, smoking and diabetes [9,12]. A limit of the present work relates to the partial characterization of the study population: indeed, we were not able to take into consideration the potential influence of atrial fibrillation, the presence of PFO or the effect of current treatment, e.g. antiplatelet medications, since the Authors of the studies included in the meta-analysis did not report such characteristics. Carotid atherosclerosis may be considered a marker of higher ischemic vulnerability of the brain. This may allow the clinician to identify subjects at risk of stroke and dementia, and prompt an aggressive correction of cardiovascular risk factors, eventually including the initiation of treatment which were shown to effectively slow the progression of cerebral ischemic damage, including antiplatelet medications, as aspirin [57] or cilostazol [58] and lipid lowering medications such as statins [59]. 5. Conclusions Carotid atherosclerosis appears to be strongly associated to the presence of WMH (OR = 1.42, p b 0.0001) and SBI (OR = 1.89, p b 0.0001). The few available studies concerning the relation between carotid
Fig. 3. Meta-analysis of the studies evaluating the association between carotid atherosclerosis and silent brain infarctions. OR: odds ratio; CI: confidence interval.
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