Association between Aortic Atheroma and Cerebral Small Vessel Disease in Patients with Ischemic Stroke

Subjects

Subjects for this study were drawn from consecutive patients with acute ischemic stroke who were registered in the Yonsei Stroke Registry [15]. The Yonsei Stroke Registry is a prospective hospital-based registry of patients with cerebral infarction or transient ischemic attack within 7 days after symptom onset [16]. During admission, all patients were evaluated according to the standard stroke evaluation that includes brain imaging (computed tomography and/or magnetic resonance imaging [MRI]), vascular imaging studies (digital subtraction angiography, MR angiography, or computed tomography angiography), plain chest X-ray, 12-lead electrocardiography and cardiac echocardiography including TEE. Stroke subtype was determined according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification [17,18]. Briefly, large artery atherosclerosis is defined as significant (≥50%) stenosis of the large artery relevant to the acute infarction. The presence of complex aortic plaque (CAP) was considered as one form of large artery atherosclerosis. Cardioembolism is defined as at least one potential cardiac source of embolism based on the TOAST classification. A patient with lacunar infarction should have one of the classic clinical lacunar syndromes and a relevant subcortical hemispheric or brain stem lesion with diameter <1.5 cm [16]. Besides above method of the TOAST classification, we reclassified the TOAST classification. In that reclassification, CAPs were not considered as large artery atherosclerosis. The Institutional Review Board of Severance Hospital, Yonsei University Health System, approved this study and waived the need for patient informed consent because of the retrospective design and observational nature of the study.

Transesophageal echocardiography

TEE was performed within 2 weeks of initial stroke or transient ischemic attack. TEE was a component of standard evaluation for patients in the study hospital [16] and was performed in all patients except for those with altered consciousness, progressing brain herniation, poor systemic condition, tracheal intubation, failure to introduce an esophageal transducer, or lack of informed consent. Detailed method of performing TEE was described in supplemental methods [19]. Maximal thickness of plaques was used in this study. AAs were classified as CAP or simple aortic plaque (SAP). CAPs consisted of plaques protruding into the lumen by ≥4 mm and mobile lesions located in the proximal aorta. SAPs were plaques <4 mm in the proximal aorta or plaques of any size located in the descending aorta [20]. Patients who had both CAP and SAP were categorized into the CAP group because CAP is a more advanced form of AA and is regarded a potential cause of stroke. Two cardiologists who are experts in echocardiography interpreted the TEE results. In cases of discrepancy, the final decision was made by consensus [3,19].

Risk factors and definitions of variables

The clinical variables including risk factors (hypertension, diabetes mellitus, hyperlipidemia, current smoking, coronary artery disease, the patient’s prior medication and metabolic syndrome) were described as based on previous studies. The detail definition of clinical variables was elucidated in supplementary methods.

MRI protocol and cerebral small vessel diseases

All MRI examinations were performed on a 3.0T MRI machine (Achieva 3.0T; Philips Medical Systems, Best, Netherlands or MAGNETOM 3.0T Trio; Siemens, Germany). Parameters of diffusion-weighted imaging were time repetition/time echo=2,600-6,500/42-70 ms, 2-mm inter-slice gap, field of view=230×230 mm, and slice thickness=5 mm. Two b-values (0, 1,000) in six different directions of diffusion gradient (x, y, z, xy, yz, zx) were calculated. The fluid-attenuated inversion recovery image was performed with time repetition/time echo=9,000/120 ms, pixel spacing=0.449 mm/0.449 mm, field of view=230×230 mm, and slice thickness=5 mm. The gradient recalled echo images were obtained at time repetition/time echo=600/16 ms, pixel spacing=0.449 mm/0.449 mm, field of view=250×250 mm, and slice thickness=5 mm.

Cerebral SVDs, including CMBs, WMHs, PVSs, and ALIs, were defined according to MRI findings (Figure 1). All lesions of SVDs should not be located in acute infarctions on diffusion-weighted imaging (Supplementary Figure 1, 2) [21]. CMBs were indicated as punctate hypointense lesion less than 10 mm in size and located in brain parenchyma [22]. For this study, CMBs were classified as strictly lobar or non-lobar. Strictly lobar CMBs were defined as CMBs located only in the lobar location, whereas non-lobar CMBs were found in the non-lobar location, with or without one or more lobar CMBs. Strictly lobar CMBs were defined when a patient had possible or probable cerebral amyloid angiopathy (CAA), as defined previously [23]. We also assessed the severity of WMHs. The extent of WMHs was determined on the fluid-attenuated inversion recovery images of periventricular white matter or deep white matter according to Fazekas’ scoring system [24]. A Fazekas score ≥2 in periventricular white matter and/or ≥2 in deep white matter was regarded as high-grade WMHs. PVSs were defined as punctate and/or linear hyperintense lesion in the basal ganglia on T2-weighted images. PVSs were <3 mm in size and were classified with the following scale: grade 0, no PVS; grade 1, 1-10 PVSs; grade 2, 11-20 PVSs; grade 3, 21-40 PVSs; and grade 4, ≥40 PVSs. High-grade PVSs were defined when lesions of grade 2-4 were found in the basal ganglia and centrum semiovale [25]. ALIs were defined when the patients had no history of symptoms or signs of previous stroke. The imaging criterion of ALIs was one or more cavitary lesions with high-signal lesions on fluid-attenuated inversion recovery and T2-weighted images and low signal intensities on T1-weighted images. Size limitation of ALIs was ≥3 mm and <15 mm [26]. According to a previous study, total SVD score was calculated by summation of 1 point for the presence of each of CMBs, high-grade WMHs, high-grade PVSs, or ALIs. The range of total SVD score was therefore 0-4 [27]. Two investigators who were blinded to the patient’s clinical information independently assessed the presence of SVD lesions. Interobserver agreement (kappa values) for presence of CMBs, high-grade WMHs, high-grade PVSs, and ALIs was 0.92, 0.84, 0.88, and 0.82, respectively. If there was disagreement, a final decision was reached by consensus.

Figure 1.

Illustrative imaging findings of cerebral small vessel diseases. (A) Cerebral microbleeds (arrows), (B) high-grade white matter hyperintesities (arrows), (C) high-grade perivascular spaces (arrows), and (D) asymptomatic lacunar infarction (arrows).

Arterial stiffness

Arterial stiffness was evaluated by brachial-ankle pulse wave velocity (baPWV). The baPWV was measured using an automated device (VP-1000; Colin Co. Ltd, Komaki, Japan) while the patients were in the supine position. After resting for 5 minutes, the pulse wave was simultaneously detected in the upper arms and ankles. Time difference between the upper arm and ankle waveforms was measured automatically.

Statistical analysis

Statistical analyses were performed using Windows SPSS package (version 20.0, Chicago, IL, USA). Continuous variables were reported as mean±SD and categorical variables as frequency and percentage. Chi-square test, Fisher exact test, and independent t test were used for comparisons. To determine the association between CMBs burden and AA, patients with CMBs were categorized into three groups according to number of CMBs (none, 1-2, and ≥3) [26]. Multivariable analysis was performed using the factors with a P value <0.1 in the univariable analysis. Independent factors of presence of AAs were determined with binary logistic regression analysis. For the existence of CAP and SAP, multinomial logistic regression analysis was used with CAPs and SAPs as dependent variables. Because the variance inflation factor was higher than six among SVDs, each SVD and total SVD score were separately analyzed in multivariable analyses. Statistical significance was set at P<0.05. Odds ratios (OR) and 95% confidence interval (CI) were also calculated.

Study patients

Among the 1,888 patients who were prospectively registered in the stroke data base, patients with transient ischemic attack (n=177), stroke due to other rare causes (n=45), and incomplete stroke evaluation (n=18) were excluded. Patients without evaluation by TEE (n=759), brain MRI (n=81), gradient recalled echo images (n=35), lack of vascular imaging studies (n=32), or poor image quality (n=4) were also excluded. Finally, a total of 737 patients were included (Supplemental Figure 3). Patients who underwent TEE were younger (P=0.001), more likely to be smokers (P=0.021), and less frequently had a history of stroke (P= 0.010) than those without TEE, although the other variables were similar between the groups (Supplementary Table 1).

Aortic atheroma and cerebral small vessel diseases

AA was found by TEE in 360 (48.8%) patients, including 11.6% with CAP and 37.2% with SAP. Patients with AA were older and included a higher proportion of males compared to those without AA. Most risk factors, including hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, and metabolic syndrome were more common in patients with AA. In the TOAST classification, large artery atherosclerosis was similar between patients with AA and those without. Undetermined two or more causes identified were twice as common in patients with AA (27.2%) as those without (14.9%). The undetermined two or more causes identified subtypes were consisted of 59/98 (59.3%) with large artery atherosclerosis plus lacunar infarction, 19/98 (19.4%) with large artery atherosclerosis plus cardioembolism, 17/98 (17.3%) with lacunar infarction plus cardioembolism, and 3/98 (3.0%) with large artery atherosclerosis plus lacunar infarction plus cardioembolism. Undetermined two or more causes identified subtype was more common in patients with CAP (57.0%) than those with SAP (17.9%) (Table 1). When we reclassified TOAST classification, patients with CAP more frequently had large artery atherosclerosis or lacunar infarction than those with SAP and without AA (P=0.001) (Supplementary Table 2).

Table 1.

Demographic characteristics of patients with aortic atheroma (AA)

One or more types of SVDs were found in 269 (36.4%) patients, including 161 (21.8%) CMBs, 218 (29.6%) high-grade WMHs, 152 (20.6%) high-grade PVSs, and 230 (31.2%) ALIs. Among the patients with CMB, 153 (95.0%) had non-lobar CMBs, and 8 (5.0%) had strictly lobar CMBs, including 7 (4.3%) with probable CAA and 1 (0.7%) with possible CAA. Total SVD score=0 was found in 63.2% patients, 1 in 3.1%, 2 in 11.7%, 3 in 11.1%, and 4 in 10.9%. A total SVD score of 1 was found in 23 (3.1%) patients, who most commonly had only CMB (52.1%). In patients with a total SVD score of 2, the most common combination was high-grade WMH plus ALI in 86 patients (76.7%). For patients with a total SVD score of 3, CMB plus high-grade PVS plus ALI was most common and was found in 82 (40.2%) patients. Total SVD score was higher in patients with AA compared to those without and CAP compared to SAP (Table 2).

Table 2.

Univariable analysis for association between aortic atheroma (AA) and cerebral small vessel diseases (SVDs)

All subtypes of SVDs were common in patients with AA and CAP (Table 2). Regarding the location of CMBs, strictly lobar and non-lobar CMBs were more common in patients with AA than in those without (P<0.001). Patients with CAP had high-grade WMHs in both periventricular and deep white matter regions. Number of CMBs, degree of WMHs, and degree of PVSs were highest in patients with CAP, followed by those with SAP, compared to those without AA (P for trend <0.001). Moreover, CAP was more common as burden of total SVD score increased (P for trend <0.001) (Figure 2).

Figure 2.

Association between aortic atheroma and burden of cerebral small vessel diseases. Number of CMBs (A), degree of high-grade WMH (B), degree of PVS (C), and total SVD score (D) were highest in patients with CAP, followed by those with SAP, compared to patients without AA (P for trend <0.001). AA, aortic atheroma; CMB, cerebral microbleed; SAP, simple aortic plaque; CAP, complex aortic plaque; WMH, white matter hyperintensity; PVS, perivascular space; SVD, small vessel disease.

Multivariable analysis of presence of AA

Binary logistic regression analysis revealed that patients with AA were 4.68-fold (95% CI 3.01-7.28) more likely to have CMBs compared to those without. High-grade WMHs (OR 3.13, 95% CI 2.15-4.57), high-grade PVSs (OR 3.13, 95% CI 2.15-4.57), and presence of ALIs (OR 4.24, 95% CI 2.90-6.20) were also more common in patients with AA. Both periventricular and deep WMHs were common in patients with AA. Total SVD score ≥2 was independently associated with presence of AA (Table 3).

Table 3.

Multivariable analysis for association between aortic atheroma (AA) and cerebral small vessel diseases (SVDs)

In multinomial logistic regression analysis, patients with CAP (OR 8.72, 95% CI 4.71-16.14) or SAP (OR 3.94, 95% CI 2.48-6.25) more frequently had cerebral SVD. They also more commonly had all subtypes of SVDs. Regarding the location of CMBs, patients with CAP or SAP were more likely to have both non-lobar and strictly lobar CMBs. In particular, patients with CAP were more likely to have strictly lobar CMBs. Total SVD score ≥2 was independently related with presence of CAP or SAP, and each 1-point increase in total SVD score increased the odds of presence of CAP (OR 1.94, 95% CI 1.44-1.85) and SAP (OR 1.54 95% CI 1.35-1.75) (Table 3).

Sensitivity analysis of patients who underwent baPWV was conducted. Among total 737 patients, 143 patients who did not performe baPWV were excluded. Then, 174 patients who have potential cardiac sources of embolism were excluded because arrhythmia can prevent accurate measurement of baPWV and steno-occlusive lesions that can be indistinguishable from cardiac embolism [28]. Finally, 420 patients were included in subgroup analysis for relationship between AA and arterial stiffness. Regarding arterial stiffness, increased pulse wave velocity was associated with presence of AA and higher burden of AA (CAP) but not SAP (Supplementary Table 3).

When applying reclassification of the TOAST classification, index acute lacunar infarction was not related with presence of AA but there were trend of their association (OR 1.67, 95% CI 0.93-2.99). Whereas the index lacunar infarction was independently associated with CAP (OR 3.27, 95% CI 1.51-7.08) but not with SAP (OR 1.19, 95% CI 0.61-2.30) (Supplementary Table 4).