Abstract
Aims: Atherogenic dyslipidemia (AD) is regarded as a residual risk of cardiovascular diseases characterized by low high-density lipoprotein cholesterol (HDL-C) and high triglyceride (TG) levels and related to the intracranial stenosis of atheromatous thrombotic brain infarction (ATBI). Further, atherosclerosis is possibly related to another stroke subtype, including cryptogenic stroke (CS). In particular, an aortic complicated lesion (ACL) is a notable embolic source of CS, since recurrence of aortogenic brain embolism is not rare. This study aimed to clarify the underlying association between AD and CS.
Methods: CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for ESUS/CS) had extensive data from CS patients who underwent transesophageal echocardiography (TEE). AD was defined as HDL-C ≤ 40 mg/dl and TG ≥ 150 mg/dl. Based on these criteria, patients were divided into an AD group and a non-AD group to compare the clinical features.
Results: Of 664 CS patients (446 men, 68.7±12.8 years), 68 (10.2%) met the criteria of AD (AD group), and 596 (89.8%) were in the non-AD group. On multiple logistic regression analysis, body mass index (unit OR 1.11, 95%CI 1.04-1.19, p=0.002), diabetes mellitus (OR 2.23, 95%CI 1.28-3.87, p=0.004), ACL in the arch (OR 1.89, 95%CI 1.09-3.31, p=0.025), and deterioration during hospitalization (OR 3.96, 95%CI 1.32-10.68, p=0.009) were independently associated with AD.
Conclusion: AD was not rare in the present CS population. Moreover, AD was crucially related to ACL in CS. Therefore, intensive and pleiotropic lipid-modifying therapy would be efficacious for further treatment of aortogenic brain embolism.
Introduction
Dyslipidemia is a frequent risk factor for stroke, as represented by atherothrombotic brain infarction (ATBI)1, 2). Above all, statin therapy to decrease low-density lipoprotein cholesterol (LDL-C) is important in the primary and secondary prevention of stroke, with risk reduction of approximately 20%3, 4). However, recurrences of cardiovascular disease (CVD), including stroke, on statin therapy cannot be ignored4, 5). One of the explainable residual cardiovascular risk factors is atherogenic dyslipidemia (AD), a specific type of dyslipidemia characterized by low levels of high-density lipoprotein cholesterol (HDL-C) and high triglyceride (TG) levels5-7). Previous reports showed that AD induced coronary artery disease and microvascular complications such as maculopathy, retinopathy, and neuropathy8-11). In addition, recent studies demonstrated that AD also gave rise to strokes and transient ischemic attacks and was associated with intracranial stenosis in ATBI5, 12, 13). Therefore, AD was also regarded as a crucial risk factor for stroke.
Whereas cryptogenic stroke (CS) has heterogeneous pathophysiologies, one of the potential embolic origins is atherosclerosis represented by nonstenotic carotid plaques and aortic complicated lesions (ACLs)14). In CS patients, nonstenotic carotid plaques were seen in 20-60% on carotid duplex ultrasonography and CT angiography14, 15). Meanwhile, ACLs were observed in 10-40% on transesophageal echocardiography (TEE) and 60% on autopsy studies16-18). Importantly, regarding treatment of ACL, recurrences of aortogenic brain embolism are not rare even on antithrombotic and statin therapies19). Although retrospective studies suggested the effectiveness of anticoagulation with warfarin, no randomized, clinical trials have shown the superiority or inferiority of anticoagulants to antiplatelets16, 19, 20). In contrast, some investigations suggested that lipid-lowering therapy could stabilize and even slightly diminish aortic plaques21). As a whole, optimal secondary prophylaxis for aortogenic stroke is still unsettled.
Aim
To date, the relationship between AD and atherosclerosis including ACLs in CS has hardly been explored. The aim of this study was to elucidate the prevalence of AD in CS patients and the underlying pathophysiology and embolic sources, especially ACLs, of AD-related CS using data from a multicenter registry with a comprehensive database of CS patients who underwent TEE.
Methods
Study Population
As formerly reported17), the Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke (CHALLENGE ESUS/CS) registry was a multicenter, retrospective study enrolling consecutive patients with CS who underwent TEE in eight Japanese institutes between April 2014 and December 2016. The inclusion criteria for the registry were: 1) within 7 days of stroke onset; 2) non-lacunar stroke on neuroradiological imaging; 3) absence of arterial stenosis ≥ 50% or occlusion in a corresponding large artery; 4) absence of major emboligenic cardiac diseases; and 5) absence of other determined stroke etiologies. Aside from the medical history, diagnostic modalities including CT/MRI, carotid duplex ultrasonography, 12-lead electrocardiography, blood examinations, and chest X-ray were performed at the time of admission for the diagnosis of CS and registration for the study. Institutional review boards in all eight hospitals approved the protocol. Clinical information was obtained from medical records, and the need to obtain written, informed consent from each patient was therefore waived in this retrospective study. The present study was registered at http://www.umin.ac.jp/ctr/ (UMIN000032957).
TEE Study and MRI Sequence
TEE was performed as explained in our previous work17). Subjects were awake, and no premedication was used except for lidocaine spray. Under multiplane probe manipulation, right-to-left shunt (RLS) was assessed by injecting agitated saline and the Valsalva maneuver, counting the numbers of microbubbles with and without contrast agents. An aortic complicated lesion (ACL) was defined as measured plaque thickness ≥ 4 mm or mobile plaques seen swinging on their pedicles, or ulcerative plaques with width and maximum depth of at least 2 mm each. Examinations were performed by two or three experienced sonographers in each institution.
MRI scans were performed at each institution using 1.5- or 3-Tesla scanners during hospitalization. Sequences included axial diffusion-weighted imaging (DWI), fluid-attenuated inversion recovery imaging (FLAIR), magnetic resonance angiography (MRA), and the GRE-T2* sequence. DWI (repetition time (TR) / echo time (TE)=3000-8000/60-91 ms) was used to estimate the size and distribution of index stroke lesions. FLAIR (TR/TE=9000-12000/94-120 ms) was used to assess the degree of deep and subcortical white matter hyperintensity (DSWMH) and periventricular hyperintensity (PVH) using the Fazekas grade (0-3). MRA (TR/TE=19-37/2.8-7.5 ms) was used to detect intracranial stenosis ＞50%, principally not relevant to the infarction area. GRE-T2* (TR/TE=410-740/12-20 ms) was used to identify cerebral microbleeds (CMBs), defined as rounded areas of signal loss with diameter ＜10 mm. The size and distribution of stroke lesions, the degree of DSWMH and PVH, the presence of intracranial stenosis, and the existence of CMBs were all evaluated by several experienced neurologists in each institution.
Data Collection and Analyses
Collection of baseline clinical information including cardiovascular risk factors, laboratory and radiological data on admission, echocardiographic findings, and clinical courses on admission was conducted through hospital chart or database reviews during the study period from May 2017 to July 2019. The definitions of cardiovascular risk factors were as stated in our previous work22). For the definition of AD, the TG and HDL-C levels within 48 hours from admission or onset for patients in case of stroke during hospitalization were used. Patients without comprehensive data on lipid status (LDL-C, HDL-C, TG) were excluded from the present study. Based on previous analyses, AD was defined as having both TG levels ≥ 150 mg/dl and HDL-C levels ≤ 40 mg/dl, regardless of subjects’ sex5, 7, 12). Baseline characteristics, radiological and laboratory data, echocardiographic findings including potential embolic diseases, and clinical courses were compared according to the presence of AD (AD group, non-AD group). For the purpose of more detailed analyses, several patients’ background characteristics were compared among four groups: the AD group; the HDL group, with only low HDL-C (≤ 40 mg/dl); the TG group, with only high TG (≥ 150 mg/dl); and the normal group, with neither low HDL-C nor high TG.
In addition, to explore the association of AD with embolic sources and etiologies, clinical features with or without ACLs and frequency of AD by CS subtype were compared, respectively. CS subtypes were classified as CS with RLS, covert AF, ACL, multiple etiologies, and truly undetermined CS. Multiple etiologies was determined as CS having more than two of these three etiologies, and truly undetermined CS was determined as having no major embolic sources and etiologies after the investigations during hospitalization.
Moreover, a sub-group analysis with or without prior statin use before admission was also performed to estimate the effect of statins on AD and ACLs.
Statistical Analysis
Numerical values are reported as means±standard deviation or medians with interquartile range (IQR). Data were analyzed using the Wilcoxon or Kruskal-Wallis test for continuous variables and the chi-squared test for categorical variables. All variables with values of p＜0.05 on univariate analyses were entered into multiple logistic regression analyses to identify independent variables for AD. A two-sided probability value of p＜0.05 was considered significant. All data were analyzed using SPSS for Macintosh version 29.0 software (SPSS, Chicago, IL).
Results
A total of 677 patients with CS were included in the CHALLENGE ESUS/CS registry. Of these, 664 patients (447 males) with comprehensive data on lipid status were enrolled in the present study. Their mean age was 68.6±12.8 years. The median baseline National Institutes of Health Stroke Scale (NIHSS) score was 2. Overall, 113 (17.0%) were treated with statins before the index stroke, and the mean LDL-C of all participants was 112.4±34.0 mg/dl. Of these patients, 176 (26.5%) had low HDL-C (≤ 40 mg/dl), 185 (27.9%) had high TG (≥ 150 mg/dl), and 68 (10.2%) fulfilled the diagnostic criteria of AD (Fig.1).
AD and Baseline Characteristics Including Potential Embolic Sources
The baseline characteristics of the two groups according to AD status are shown in Table 1. The AD group had more male patients (83.8% vs. 65.4%, p=0.002), higher body mass index (BMI, 25.1±4.0 vs. 23.0±3.8 kg/m2, p＜0.001), and more diabetes mellitus (50.0% vs. 23.0%, p＜0.001). On TEE, ACLs in the aortic arch were more frequent in the AD group (55.9% vs. 35.5%, p=0.001). As secondary prevention, the rate of antiplatelet therapy was higher (83.3% vs. 67.4%, p=0.008), and that of anticoagulant therapy was lower (21.2% vs. 35.5%, p=0.020) in the AD group. In addition, deterioration during hospitalization was more common (8.8% vs. 3.4%, p=0.028) in the AD group.
Table 1.Baseline characteristics, MRI and TEE findings, and clinical courses of patients by the presence of AD
|
AD group
n= 68
10.2%
|
Non-AD group
n= 596
89.8%
|
p value
|
| Age, y |
68.6±11.1 |
68.7±13.0 |
0.582 |
| Male |
57 (83.8) |
390 (65.4) |
0.002 |
| BMI, kg/m2
|
25.1±4.0 |
23.0±3.8 |
＜0.001 |
| Premorbid mRS score 0-2 |
62 (91.2) |
566 (95.0) |
0.191 |
| Hypertension |
54 (79.4) |
421 (70.6) |
0.129 |
| Diabetes mellitus |
34 (50.0) |
137 (23.0) |
＜0.001 |
| CKD |
29 (42.7) |
213 (35.7) |
0.262 |
| Ischemic heart disease |
8 (11.8) |
58 (9.7) |
0.596 |
| Heart failure |
2 (2.9) |
17 (2.9) |
0.967 |
| Previous stroke |
8 (11.8) |
114 (19.1) |
0.138 |
| Malignancy |
11 (16.2) |
84 (14.1) |
0.642 |
| Smoking |
21 (30.9) |
157 (26.3) |
0.423 |
| Prior antiplatelet agents |
17 (25.0) |
147 (24.7) |
0.952 |
| Prior anticoagulants |
0 (0.0) |
17 (2.9) |
0.158 |
| Prior statins |
17 (25.0) |
97 (16.1) |
0.065 |
| NIHSS score on admission |
2.5 (1-6) |
2 (1-5) |
0.455 |
| DWI lesion size ＞3 cm |
39 (57.4) |
329 (55.7) |
0.791 |
| Cortical infarction |
53 (77.9) |
475 (80.4) |
0.634 |
| Infarctions in multiple vascular territories |
24 (35.3) |
148 (25.0) |
0.068 |
| DSWMH |
26 (38.2) |
196 (33.2) |
0.418 |
| PVH |
22 (32.4) |
224 (37.9) |
0.370 |
| CMBs |
17 (25.4) |
187 (32.2) |
0.256 |
| Intracranial artery stenosis |
11 (16.2) |
61 (10.3) |
0.143 |
| Contralateral carotid artery stenosis |
4 (5.9) |
28 (4.7) |
0.668 |
| Right-to-left shunt |
34 (50.0) |
273 (47.6) |
0.703 |
| ACL in the aortic arch |
38 (55.9) |
211 (35.5) |
0.001 |
| Covert atrial fibrillation |
3 (4.4) |
60 (10.1) |
0.132 |
| Calcification of aortic valve |
18 (26.5) |
134 (22.6) |
0.472 |
| Calcification of mitral valve |
5 (7.8) |
64 (11.6) |
0.364 |
| WBC |
7575±3456 |
7250±2600 |
0.600 |
| CRP |
0.50±1.33 |
0.66±2.26 |
0.085 |
| D-dimer |
2.50±5.20 |
3.06±17.30 |
0.253 |
| LDL-C |
108.1±30.2 |
112.9±34.4 |
0.350 |
| Antiplatelet therapy on discharge |
55 (83.3) |
397 (67.4) |
0.008 |
| Anticoagulant therapy on discharge |
14 (21.2) |
209 (35.5) |
0.020 |
| Statin on discharge |
43 (63.2) |
352 (59.1) |
0.506 |
| mRS score 0-2 on discharge |
55 (80.9) |
466 (78.2) |
0.609 |
| Death on discharge |
0 (0) |
2 (0.3) |
0.632 |
| Deterioration during hospitalization |
6 (8.8) |
20 (3.4) |
0.028 |
| Recurrence of stroke |
5 (7.4) |
19 (3.2) |
0.081 |
| Any hemorrhagic stroke |
4 (5.9) |
65 (10.9) |
0.198 |
MRI=magnetic resonance imaging, TEE=transesophageal echocardiography, AD=atherosclerotic dyslipidemia, BMI=body mass index, mRS=modified Rankin Scale, CKD=chronic kidney disease, NIHSS=National Institutes of Health Stroke Scale, DWI=diffusion-weighted imaging, DSWMH=deep and subcortical white matter hyperintensity, PVH=periventricular hyperintensity, CMBs=cerebral microbleeds, ACL=aortic complicated lesion, WBC=white blood cell, CRP=C-reactive protein, LDL-C=low-density lipoprotein cholesterol.
a.CKD was defined as estimated glomerular filtration rate ＜60 ml/min/1.73 m2.
b.Deterioration during hospitalization was assessed as neurological worsening ≥ NIHSS 2 points.
On multiple logistic regression analysis, BMI (unit OR 1.11, 95% confidence interval (CI), 1.04-1.19, p=0.002), diabetes mellitus (OR 2.23; 95% CI, 1.28-3.87; p=0.004), ACLs in the aortic arch (OR 1.89; 95% CI, 1.09-3.31; p=0.025), and deterioration during hospitalization (OR 3.96; 95% CI, 1.32-10.68; p=0.009) were significantly associated with AD (Table 2).
Table 2.Multiple logistic regression analysis for factors associated with AD
|
OR |
95% CI |
p value
|
| Male |
1.90 |
0.97-4.04 |
0.074 |
| BMI (per unit) |
1.11 |
1.04-1.19 |
0.002 |
| Diabetes mellitus |
2.23 |
1.28-3.87 |
0.004 |
| ACL in the aortic arch |
1.89 |
1.09-3.31 |
0.025 |
| Antiplatelet therapy on discharge |
0.92 |
0.24-3.21 |
0.895 |
| Anticoagulant therapy on discharge |
0.53 |
0.14-1.65 |
0.309 |
| Deterioration during hospitalization |
3.96 |
1.32-10.68 |
0.009 |
OR=odds ratio, CI=confidence interval, BMI=body mass index, ACL=aortic complicated lesion.
a. Deterioration during hospitalization was assessed as neurological worsening ≥ NIHSS 2 points.
For more detailed analysis, the non-AD group was divided into the HDL-C, TG, and normal groups; 108 (16.3%) patients had low HDL-C only, 116 (17.5%) had high TG only, and 372 (56.0%) had neither (Fig.1). Regarding significant associated factors on multiple logistic regression analysis, further analysis was performed with the four cohorts (AD, HDL-C, TG, and normal groups). BMI (25.1±4.0 vs. 23.3±3.9, 24.0±3.6, 22.6±3.8 kg/m2, p＜0.001), diabetes mellitus (50.0% vs. 29.6% vs. 25.9% vs. 20.2%, p＜0.001), ACLs in the aortic arch (55.9% vs. 38.0% vs. 39.1% vs. 33.7%, p=0.007), and deterioration during hospitalization (8.8% vs. 3.7% vs. 0% vs. 4.3%, p=0.026) were still significantly associated with AD (Fig.2).
Patients’ Clinical Characteristics with or without ACLs and Frequency of AD by Final Diagnosis of CS Subtype
For the purpose of verifying the relationship between AD and ACL, the baseline characteristics of the two groups according to the presence of ACL are shown in Supplemental Table 1. On multiple logistic regression analysis, age (unit OR 1.06, 95% CI, 1.04-1.08, p＜0.001), male sex (OR 3.11; 95% CI, 1.96-5.03; p＜0.001), AD (OR 2.13; 95% CI, 1.04-4.00; p=0.017), aortic valve calcification (OR 1.87; 95% CI, 1.18-2.96; p=0.007), and statin use on discharge (OR 1.86; 95% CI, 1.21-2.86; p=0.004) were independently associated, and RLS (OR 0.53; 95% CI, 0.36-0.79; p=0.002) and covert AF (OR 0.33; 95% CI, 0.13-0.73; p=0.013) were inversely associated with ACLs (Table 3).
Supplemental Table 1.Baseline characteristics, MRI and TEE findings, and clinical courses of patients by the presence of ACL
|
With ACL
n= 249
37.6%
|
Without ACL
n= 413
62.4%
|
p value
|
| Age, y |
73.3±9.3 |
65.9±13.7 |
＜0.001 |
| Male |
196 (78.7) |
249 (60.3) |
＜0.001 |
| BMI, kg/m2
|
23.2±3.6 |
23.3±4.0 |
0.541 |
| Premorbid mRS score 0-2 |
232 (93.2) |
394 (95.4) |
0.221 |
| Hypertension |
205 (82.3) |
270 (65.4) |
＜0.001 |
| Diabetes mellitus |
78 (31.3) |
93 (22.5) |
0.012 |
| CKD |
116 (46.6) |
125 (30.3) |
＜0.001 |
| Ischemic heart disease |
38 (15.3) |
28 (6.8) |
＜0.001 |
| Heart failure |
9 (3.6) |
10 (2.4) |
0.472 |
| Previous stroke |
62 (24.9) |
60 (14.5) |
0.001 |
| Malignancy |
47 (18.9) |
48 (11.6) |
0.010 |
| Smoking |
74 (29.7) |
102 (24.7) |
0.156 |
| Prior antiplatelet agents |
85 (34.1) |
78 (18.9) |
＜0.001 |
| Prior anticoagulants |
6 (2.4) |
11 (2.7) |
0.842 |
| Prior statins |
48 (17.1) |
65 (15.7) |
0.243 |
| Atherogenic dyslipidemia |
38 (15.3) |
30 (7.3) |
0.001 |
| NIHSS score on admission |
2 (1-5) |
2 (1-5) |
0.369 |
| DWI lesion size ＞3 cm |
140 (56.9) |
228 (55.5) |
0.720 |
| Cortical infarction |
202 (82.1) |
324 (78.8) |
0.308 |
| Infarctions in multiple vascular territories |
76 (30.9) |
96 (23.4) |
0.033 |
| DSWMH |
104 (42.3) |
118 (28.7) |
＜0.001 |
| PVH |
110 (44.7) |
136 (33.1) |
0.003 |
| CMBs |
137 (57.1) |
305 (75.1) |
＜0.001 |
| Intracranial artery stenosis |
44 (17.8) |
28 (6.8) |
＜0.001 |
| Contralateral carotid artery stenosis |
17 (6.8) |
15 (3.6) |
0.063 |
| Right-to-left shunt |
92 (38.2) |
213 (53.4) |
＜0.001 |
| Covert atrial fibrillation |
15 (6.0) |
48 (11.6) |
0.017 |
| Calcification of aortic valve |
86 (34.7) |
66 (16.1) |
＜0.001 |
| Calcification of mitral valve |
26 (11.2) |
43 (11.3) |
0.985 |
| WBC |
7545.8±2744.8 |
7250.3±2678.3 |
0.560 |
| CRP |
0.67±1.95 |
0.63±2.33 |
0.001 |
| D-dimer |
2.33±3.38 |
3.42±20.72 |
＜0.001 |
| LDL-C |
111.3±38.3 |
113.0±31.2 |
0.193 |
| Antiplatelet therapy on discharge |
199 (80.6) |
252 (62.1) |
＜0.001 |
| Anticoagulant therapy on discharge |
63 (25.5) |
159 (39.2) |
＜0.001 |
| Statin on discharge |
177 (71.1) |
217 (52.5) |
＜0.001 |
| mRS score 0-2 on discharge |
197 (79.1) |
322 (78.0) |
0.730 |
| Death on discharge |
0 (0) |
2 (0.5) |
0.271 |
| Deterioration during hospitalization |
10 (4.0) |
16 (3.9) |
0.927 |
| Recurrence of stroke |
7 (2.8) |
17 (4.1) |
0.384 |
| Any hemorrhagic stroke |
23 (9.2) |
46 (11.1) |
0.438 |
MRI=magnetic resonance imaging, TEE=transesophageal echocardiography, ACL=aortic complicated lesion, BMI=body mass index, mRS=modified Rankin Scale, CKD=chronic kidney disease, NIHSS=National Institutes of Health Stroke Scale, DWI=diffusion-weighted imaging, DSWMH=deep and subcortical white matter hyperintensity, PVH=periventricular hyperintensity, CMBs=cerebral microbleeds, WBC=white blood cell, CRP=C-reactive protein, LDL-C=low-density lipoprotein cholesterol.
a.CKD was defined as estimated glomerular filtration rate ＜60 ml/min/1.73 m2.
b.Deterioration during hospitalization was assessed as neurological worsening ≥ NIHSS 2 points.
Table 3.Multiple logistic regression analysis for factors associated with ACL
|
OR |
95% CI |
p value
|
| Age (per unit) |
1.06 |
1/04-1.08 |
＜0.001 |
| Male |
3.11 |
1.96-5.03 |
＜0.001 |
| Hypertension |
1.17 |
0.71-1.92 |
0.545 |
| Diabetes mellitus |
0.81 |
0.51-1.26 |
0.351 |
| CKD |
1.16 |
0.76-1.78 |
0.492 |
| Ischemic heart disease |
1.30 |
0.65-2.63 |
0.462 |
| Previous stroke |
1.43 |
0.80-2.54 |
0.225 |
| Malignancy |
1.52 |
0.87-2.67 |
0.139 |
| Prior antiplatelet agents |
0.92 |
0.52-1.62 |
0.773 |
| Atherogenic dyslipidemia |
2.13 |
1.14-4.00 |
0.017 |
| Infarctions in multiple vascular territories |
1.18 |
0.75-1.83 |
0.477 |
| DSWMH |
1.52 |
0.92-2.51 |
0.098 |
| PVH |
0.63 |
0.37-1.05 |
0.078 |
| CMBs |
1.54 |
0.98-2.41 |
0.059 |
| Intracranial artery stenosis |
1.84 |
0.98-3.51 |
0.060 |
| Right-to-left shunt |
0.53 |
0.36-0.79 |
0.002 |
| Covert atrial fibrillation |
0.33 |
0.13-0.77 |
0.013 |
| Calcification of aortic valve |
1.87 |
1.18-2.96 |
0.007 |
| CRP (per unit) |
0.98 |
0.86-1.12 |
0.742 |
| D-dimer (per unit) |
1.00 |
0.96-1.01 |
0.774 |
| Antiplatelet therapy on discharge |
2.58 |
0.99-7.00 |
0.052 |
| Anticoagulant therapy on discharge |
1.34 |
0.54-3.50 |
0.531 |
| Statin on discharge |
1.86 |
1.21-2.86 |
0.004 |
OR=odds ratio, CI=confidence interval, ACL=aortic complicated lesion, CKD=chronic kidney disease, AD=atherosclerotic dyslipidemia, DSWMH=deep and subcortical white matter hyperintensity, PVH=periventricular hyperintensity, CMBs=cerebral microbleeds, CRP=C-reactive protein.
a. CKD was defined as estimated glomerular filtration rate ＜60 ml/min/1.73 m2.
Moreover, the prevalence of AD by definite etiologic diagnosis of CS was also analyzed (Fig.3). In CS with multiple etiologies, 88.5%, 25.4%, and 86.9% of patients had RLS, covert AF, and ACLs, respectively. AD was more frequent in CS with ACLs and CS with multiple etiologies than with other CS subtypes (CS with RLS, 8.5% vs CS with covert AF, 0% vs CS with ACL, 14.7% vs CS with multiple etiologies, 14.8% vs truly undetermined CS, 7.1%).
Factors Related to AD and ACL with or without Prior Statin Use
Sub-group analysis with or without prior statin use before hospitalization was also performed to assess the effect of statin use on AD and ACLs. First, the baseline characteristics of prior statin users and non-users according to the presence of AD are shown in Supplemental Tables 2 and 3, respectively. On multiple logistic regression analysis, diabetes mellitus (OR 7.63, 95% CI, 1.73-43.08, p=0.007) and ACLs in the arch (OR 8.70; 95% CI, 1.77-59.37; p=0.007) were independently associated, and premorbid mRS score 0-2 (OR 0.05; 95% CI, 0.003-0.45; p=0.007) and NIHSS score on admission (unit OR 0.78; 95% CI, 0.57-0.99; p=0.035) were inversely associated with AD in prior statin users before admission (Table 4). Meanwhile, male (OR 2.40; 95% CI, 1.07-6.14; p=0.033), BMI (unit OR 1.09; 95% CI, 1.01-1.18; p=0.024), diabetes mellitus (OR 2.02, 95% CI, 1.04-3.86, p=0.037), and infarctions in multiple vascular territories (OR 2.23; 95% CI, 1.14-4.30; p=0.020) were independently associated, and previous stroke (OR 0.14; 95% CI, 0.02-0.49; p＜0.001) was inversely associated with AD in prior statin non-users before admission on multiple regression analysis (Supplemental Table 4).
Supplemental Table 2.Baseline characteristics, MRI and TEE findings, and clinical courses of patients by the presence of AD in prior stain users before admission
|
AD group
n= 17
15.0%
|
Non-AD group
n= 96
85.0%
|
p value
|
| Age, y |
72.0±11.4 |
72.2±10.0 |
0.923 |
| Male |
13 (76.5) |
55 (57.3) |
0.137 |
| BMI, kg/m2
|
22.9±3.8 |
25.8±5.0 |
0.014 |
| Premorbid mRS score 0-2 |
12 (70.6) |
90 (93.8) |
0.003 |
| Hypertension |
16 (94.1) |
77 (80.2) |
0.166 |
| Diabetes mellitus |
11 (64.7) |
30 (31.3) |
0.008 |
| CKD |
8 (47.1) |
40 (41.7) |
0.679 |
| Ischemic heart disease |
4 (23.5) |
25 (26.0) |
0.827 |
| Heart failure |
1 (5.9) |
6 (6.3) |
0.954 |
| Previous stroke |
5 (29.4) |
29 (30.2) |
0.947 |
| Malignancy |
4 (23.5) |
15 (15.6) |
0.422 |
| Smoking |
9 (52.9) |
47 (49.0) |
0.512 |
| Prior antiplatelet agents |
9 (52.9) |
49 (51.0) |
0.885 |
| Prior anticoagulants |
0 (0.0) |
5 (5.2) |
0.336 |
| NIHSS score on admission |
1 (0-4.5) |
3 (1-6) |
0.033 |
| DWI lesion size ＞3 cm |
7 (41.2) |
53 (55.8) |
0.266 |
| Cortical infarction |
12 (70.6) |
82 (86.3) |
0.104 |
| Infarctions in multiple vascular territories |
4 (23.5) |
31 (32.6) |
0.456 |
| DSWMH |
8 (47.1) |
43 (45.3) |
0.891 |
| PVH |
8 (47.1) |
49 (51.6) |
0.731 |
| CMBs |
12 (70.6) |
51 (56.7) |
0.285 |
| Intracranial artery stenosis |
6 (35.3) |
11 (11.5) |
0.011 |
| Contralateral carotid artery stenosis |
2 (11.8) |
6 (6.3) |
0.414 |
| Right-to-left shunt |
10 (58.8) |
40 (44.0) |
0.259 |
| ACL in the aortic arch |
12 (70.5) |
36 (37.5) |
0.011 |
| Covert atrial fibrillation |
0 (0) |
14 (14.6) |
0.093 |
| Calcification of aortic valve |
5 (29.4) |
31 (32.3) |
0.814 |
| Calcification of mitral valve |
1 (5.9) |
13 (14.4) |
0.337 |
| WBC |
6591.8±2082.6 |
7142.7±2057.9 |
0.362 |
| CRP |
0.79±2.29 |
0.69±1.84 |
0.245 |
| D-dimer |
3.49±7.62 |
1.87±2.85 |
0.791 |
| LDL-C |
99.9±33.6 |
112.9±34.4 |
0.715 |
| Antiplatelet therapy on discharge |
14 (87.5) |
66 (70.2) |
0.151 |
| Anticoagulant therapy on discharge |
2 (12.5) |
38 (40.4) |
0.032 |
| Statin on discharge |
17 (100.0) |
89 (92.7) |
0.250 |
| mRS score 0-2 on discharge |
12 (70.6) |
63 (65.6) |
0.690 |
| Death on discharge |
0 (0) |
0 (0) |
- |
| Deterioration during hospitalization |
2 (11.8) |
3 (3.1) |
0.110 |
| Recurrence of stroke |
2 (11.8) |
4 (4.2) |
0.198 |
| Any hemorrhagic stroke |
1 (5.9) |
18 (18.8) |
0.191 |
MRI=magnetic resonance imaging, TEE=transesophageal echocardiography, AD=atherosclerotic dyslipidemia, BMI=body mass index, mRS=modified Rankin Scale, CKD=chronic kidney disease, NIHSS=National Institutes of Health Stroke Scale, DWI=diffusion-weighted imaging, DSWMH=deep and subcortical white matter hyperintensity, PVH=periventricular hyperintensity, CMBs=cerebral microbleeds, ACL=aortic complicated lesion, WBC=white blood cell, CRP=C-reactive protein, LDL-C=low-density lipoprotein cholesterol.
a.CKD was defined as estimated glomerular filtration rate ＜60 ml/min/1.73 m2.
b.Deterioration during hospitalization was assessed as neurological worsening ≥ NIHSS 2 points.
Supplemental Table 3.Baseline characteristics, MRI and TEE findings, and clinical courses of patients by the presence of AD in prior stain non-users before admission
|
AD group
n= 51
9.3%
|
Non-AD group
n= 500
90.7%
|
p value
|
| Age, y |
67.4±11.3 |
68.0±13.2 |
0.397 |
| Male |
44 (86.3) |
335 (67.0) |
0.005 |
| BMI, kg/m2
|
24.8±3.7 |
23.0±3.8 |
＜0.001 |
| Premorbid mRS score 0-2 |
50 (98.0) |
476 (95.2) |
0.353 |
| Hypertension |
38 (74.5) |
344 (68.8) |
0.400 |
| Diabetes mellitus |
23 (45.1) |
107 (21.4) |
＜0.001 |
| CKD |
21 (41.2) |
173 (34.6) |
0.349 |
| Ischemic heart disease |
4 (7.8) |
33 (6.6) |
0.735 |
| Heart failure |
1 (2.0) |
11 (2.2) |
0.911 |
| Previous stroke |
3 (5.9) |
85 (17.0) |
0.039 |
| Malignancy |
7 (13.7) |
69 (13.8) |
0.988 |
| Smoking |
18 (35.3) |
133 (26.6) |
0.185 |
| Prior antiplatelet agents |
8 (15.7) |
98 (19.6) |
0.499 |
| Prior anticoagulants |
0 (0.0) |
12 (2.4) |
0.263 |
| NIHSS score on admission |
3 (2-7) |
2 (1-4.75) |
0.059 |
| DWI lesion size ＞3 cm |
32 (62.8) |
276 (55.7) |
0.330 |
| Cortical infarction |
41 (80.4) |
393 (79.2) |
0.846 |
| Infarctions in multiple vascular territories |
20 (39.2) |
117 (23.6) |
0.014 |
| DSWMH |
18 (35.3) |
153 (30.9) |
0.514 |
| PVH |
14 (27.5) |
175 (35.3) |
0.263 |
| CMBs |
38 (76.0) |
343 (69.9) |
0.365 |
| Intracranial artery stenosis |
5 (9.8) |
50 (10.1) |
0.947 |
| Contralateral carotid artery stenosis |
2 (3.9) |
22 (4.4) |
0.873 |
| Right-to-left shunt |
24 (47.1) |
233 (48.2) |
0.872 |
| ACL in the aortic arch |
26 (51.0) |
175 (35.1) |
0.025 |
| Covert atrial fibrillation |
3 (5.9) |
46 (9.2) |
0.428 |
| Calcification of aortic valve |
13 (25.5) |
103 (20.7) |
0.428 |
| Calcification of mitral valve |
4 (8.5) |
51 (11.0) |
0.595 |
| WBC |
7903.3±3765.8 |
7270.7±2692.4 |
0.251 |
| CRP |
0.41±0.81 |
0.66±2.34 |
0.168 |
| D-dimer |
2.18±4.15 |
3.29±18.84 |
0.239 |
| LDL-C |
110.8±28.8 |
116.6±34.2 |
0.387 |
| Antiplatelet therapy on discharge |
41 (82.0) |
331 (66.9) |
0.029 |
| Anticoagulant therapy on discharge |
12 (24.0) |
171 (34.6) |
0.132 |
| Statin on discharge |
26 (51.0) |
263 (52.6) |
0.825 |
| mRS score 0-2 on discharge |
43 (84.3) |
403 (80.6) |
0.520 |
| Death on discharge |
0 (0) |
2 (0.4) |
0.651 |
| Deterioration during hospitalization |
4 (7.8) |
17 (3.4) |
0.114 |
| Recurrence of stroke |
3 (5.9) |
15 (3.0) |
0.270 |
| Any hemorrhagic stroke |
3 (5.9) |
47 (9.4) |
0.405 |
MRI=magnetic resonance imaging, TEE=transesophageal echocardiography, AD=atherosclerotic dyslipidemia, BMI=body mass index, mRS=modified Rankin Scale, CKD=chronic kidney disease, NIHSS=National Institutes of Health Stroke Scale, DWI=diffusion-weighted imaging, DSWMH=deep and subcortical white matter hyperintensity, PVH=periventricular hyperintensity, CMBs=cerebral microbleeds, ACL=aortic complicated lesion, WBC=white blood cell, CRP=C-reactive protein, LDL-C=low-density lipoprotein cholesterol.
a.CKD was defined as estimated glomerular filtration rate ＜60 ml/min/1.73 m2.
b.Deterioration during hospitalization was assessed as neurological worsening ≥ NIHSS 2 points.
Table 4.Multiple logistic regression analysis for factors associated with AD in prior statin users before admission
|
OR |
95% CI |
p value
|
| BMI (per unit) |
1.17 |
0.99-1.41 |
0.059 |
| Premorbid mRS score 0-2 |
0.05 |
0.003-0.45 |
0.007 |
| Diabetes mellitus |
7.63 |
1.73-43.08 |
0.007 |
| NIHSS score on admission (per unit) |
0.78 |
0.57-0.99 |
0.035 |
| ACL in the aortic arch |
8.70 |
1.77-59.37 |
0.007 |
| Intracranial stenosis |
2.35 |
0.47-11.79 |
0.295 |
| Anticoagulant therapy on discharge |
0.51 |
0.06-2.95 |
0.463 |
OR=odds ratio, CI=confidence interval, BMI=body mass index, mRS=modified Rankin Scale, NIHSS=National Institutes of Health Stroke Scale, ACL=aortic complicated lesion.
Supplemental Table 4.Multiple logistic regression analysis for factors associated with AD in prior statin non-users before admission
|
OR |
95% CI |
p value
|
| Male |
2.40 |
1.07-6.14 |
0.033 |
| BMI (per unit) |
1.09 |
1.01-1.18 |
0.024 |
| Diabetes mellitus |
2.02 |
1.04-3.86 |
0.037 |
| Previous stroke |
0.14 |
0.02-0.49 |
＜0.001 |
| Infarctions in multiple vascular territories |
2.23 |
1.14-4.30 |
0.020 |
| ACL in the aortic arch |
1.51 |
0.79-2.86 |
0.212 |
| Antiplatelet therapy on discharge |
1.49 |
0.70-3.45 |
0.312 |
OR=odds ratio, CI=confidence interval, BMI=body mass index, ACL=aortic complicated lesion.
Furthermore, the clinical features of prior statin users and non-users according to the presence of ACL were also analyzed and exhibited in Supplemental Tables 5 and 6, respectively. On multiple logistic regression analysis, aortic valve calcification (OR 3.45, 95% CI, 1.30-9.77, p=0.013) was significantly associated with ACL in prior statin users before admission (Supplement Table 7). Meanwhile, age (unit OR 1.07; 95% CI, 1.05-1.10; p＜0.001), male (OR 2.17; 95% CI, 1.33-3.60; p=0.002), malignancy (OR 1.84, 95% CI, 1.00-3.40, p=0.049), CMBs (OR 1.78; 95% CI, 1.10-2.91; p=0.020), and statin on discharge (OR 2.21, 95% CI, 1.42-3.48, p＜0.001) were independently associated with ACL in prior statin non-users before admission on multiple logistic regression analysis (Supplement Table 8).
Supplemental Table 5.Baseline characteristics, MRI and TEE findings, and clinical courses of patients by the presence of ACL in prior stain users before admission
|
With ACL
n= 48
42.5%
|
Without ACL
n= 65
57.5%
|
p value
|
| Age, y |
73.0±9.9 |
71.3±12.1 |
0.573 |
| Male |
37 (77.1) |
31 (47.7) |
0.002 |
| BMI, kg/m2
|
23.1±3.4 |
23.6±4.6 |
0.935 |
| Premorbid mRS score 0-2 |
43 (89.6) |
59 (90.1) |
0.834 |
| Hypertension |
44 (91.7) |
49 (75.4) |
0.025 |
| Diabetes mellitus |
14 (29.2) |
27 (41.5) |
0.176 |
| CKD |
27 (56.3) |
21 (32.3) |
0.011 |
| Ischemic heart disease |
13 (27.1) |
16 (24.6) |
0.767 |
| Heart failure |
4 (8.3) |
3 (4.6) |
0.418 |
| Previous stroke |
21 (43.8) |
13 (20.0) |
0.007 |
| Malignancy |
10 (20.8) |
9 (13.9) |
0.326 |
| Smoking |
13 (27.1) |
14 (21.5) |
0.495 |
| Prior antiplatelet agents |
31 (64.6) |
27 (41.5) |
0.015 |
| Prior anticoagulants |
1 (2.1) |
4 (6.2) |
0.298 |
| Atherogenic dyslipidemia |
12 (25.0) |
5 (7.7) |
0.011 |
| NIHSS score on admission |
3 (1-6) |
2 (1-5) |
0.498 |
| DWI lesion size ＞3 cm |
24 (51.1) |
36 (55.4) |
0.651 |
| Cortical infarction |
41 (87.2) |
53 (81.5) |
0.418 |
| Infarctions in multiple vascular territories |
16 (34.0) |
19 (29.2) |
0.588 |
| DSWMH |
22 (46.8) |
29 (44.6) |
0.818 |
| PVH |
23 (48.9) |
34 (52.3) |
0.725 |
| CMBs |
25 (56.8) |
38 (60.3) |
0.717 |
| Intracranial artery stenosis |
12 (25.0) |
5 (7.7) |
0.011 |
| Contralateral carotid artery stenosis |
4 (8.3) |
4 (6.2) |
0.655 |
| Right-to-left shunt |
20 (43.5) |
30 (48.4) |
0.613 |
| Covert atrial fibrillation |
3 (6.3) |
11 (16.9) |
0.089 |
| Calcification of aortic valve |
21 (43.8) |
15 (23.1) |
0.020 |
| Calcification of mitral valve |
3 (6.7) |
11 (17.7) |
0.094 |
| WBC |
7131.7±2132.6 |
7006.8±2023.0 |
0.710 |
| CRP |
0.70±1.45 |
0.71±2.18 |
0.030 |
| D-dimer |
2.40±3.74 |
1.90±4.09 |
0.053 |
| LDL-C |
87.8±27.5 |
99.3±29.3 |
0.018 |
| Antiplatelet therapy on discharge |
39 (83.0) |
41 (65.1) |
0.037 |
| Anticoagulant therapy on discharge |
15 (31.9) |
25 (39.7) |
0.402 |
| Statin on discharge |
45 (93.8) |
61 (93.9) |
0.983 |
| mRS score 0-2 on discharge |
32 (66.7) |
43 (66.2) |
0.955 |
| Death on discharge |
0 (0) |
0 (0) |
- |
| Deterioration during hospitalization |
2 (4.2) |
3 (4.6) |
0.909 |
| Recurrence of stroke |
1 (2.1) |
5 (7.7)5 |
0.189 |
| Any hemorrhagic stroke |
7 (14.6) |
12 (18.5) |
0.586 |
MRI=magnetic resonance imaging, TEE=transesophageal echocardiography, ACL=aortic complicated lesion, BMI=body mass index, mRS=modified Rankin Scale, CKD=chronic kidney disease, NIHSS=National Institutes of Health Stroke Scale, DWI=diffusion-weighted imaging, DSWMH=deep and subcortical white matter hyperintensity, PVH=periventricular hyperintensity, CMBs=cerebral microbleeds, WBC=white blood cell, CRP=C-reactive protein, LDL-C=low-density lipoprotein cholesterol.
a.CKD was defined as estimated glomerular filtration rate ＜60 ml/min/1.73 m2.
b.Deterioration during hospitalization was assessed as neurological worsening ≥ NIHSS 2 points.
Supplemental Table 6.Baseline characteristics, MRI and TEE findings, and clinical courses of patients by the presence of ACL in prior stain non-users before admission
|
With ACL
n= 201
36.6%
|
Without ACL
n= 348
63.4%
|
p value
|
| Age, y |
73.4±9.2 |
64.9±13.8 |
＜0.001 |
| Male |
159 (79.1) |
218 (62.6) |
＜0.001 |
| BMI, kg/m2
|
23.2±3.7 |
23.2±3.9 |
0.455 |
| Premorbid mRS score 0-2 |
189 (94.0) |
335 (96.3) |
0.226 |
| Hypertension |
161 (80.1) |
221 (63.5) |
＜0.001 |
| Diabetes mellitus |
64 (31.8) |
66 (19.0) |
＜0.001 |
| CKD |
89 (44.3) |
104 (29.9) |
＜0.001 |
| Ischemic heart disease |
25 (12.4) |
12 (3.5) |
＜0.001 |
| Heart failure |
5 (2.5) |
7 (2.0) |
0.713 |
| Previous stroke |
41 (20.4) |
47 (13.5) |
0.034 |
| Malignancy |
37 (18.4) |
39 (11.2) |
0.019 |
| Smoking |
61 (30.4) |
88 (25.3) |
0.199 |
| Prior antiplatelet agents |
54 (26.9) |
51 (14.7) |
＜0.001 |
| Prior anticoagulants |
5 (2.5) |
7 (2.0) |
0.713 |
| Atherogenic dyslipidemia |
26 (12.9) |
25 (7.2) |
0.025 |
| NIHSS score on admission |
2 (1-5) |
2 (1-5) |
0.526 |
| DWI lesion size ＞3 cm |
116 (58.3) |
192 (55.5) |
0.330 |
| Cortical infarction |
161 (80.9) |
271 (78.3) |
0.474 |
| Infarctions in multiple vascular territories |
60 (30.2) |
77 (22.3) |
0.041 |
| DSWMH |
82 (41.2) |
89 (25.7) |
＜0.001 |
| PVH |
87 (43.7) |
102 (29.5) |
＜0.001 |
| CMBs |
84 (42.9) |
76 (22.2) |
＜0.001 |
| Intracranial artery stenosis |
32 (16.1) |
23 (6.7) |
＜0.001 |
| Contralateral carotid artery stenosis |
13 (6.5) |
11 (3.2) |
0.068 |
| Right-to-left shunt |
72 (36.9) |
183 (54.3) |
＜0.001 |
| Covert atrial fibrillation |
12 (6.0) |
37 (10.6) |
0.065 |
| Calcification of aortic valve |
65 (32.5) |
51 (14.7) |
＜0.001 |
| Calcification of mitral valve |
23 (12.3) |
32 (10.0) |
0.422 |
| WBC |
7396.9±2873.9 |
7295.8±2783.7 |
0.587 |
| CRP |
0.66±2.05 |
0.62±2.35 |
0.010 |
| D-dimer |
2.31±3.30 |
3.70±22.49 |
＜0.001 |
| LDL-C |
117.0±38.4 |
115.6±30.9 |
0.959 |
| Antiplatelet therapy on discharge |
26 (12.9) |
25 (7.2) |
0.025 |
| Anticoagulant therapy on discharge |
160 (80.0) |
211 (61.5) |
＜0.001 |
| Statin on discharge |
48 (24.0) |
134 (39.1) |
＜0.001 |
| mRS score 0-2 on discharge |
165 (82.1) |
279 (80.2) |
0.582 |
| Death on discharge |
0 (0) |
2 (0.6) |
0.282 |
| Deterioration during hospitalization |
8 (4.0) |
13 (3.7) |
0.886 |
| Recurrence of stroke |
6 (3.0) |
12 (3.5) |
0.769 |
| Any hemorrhagic stroke |
16 (8.0) |
34 (9.8) |
0.478 |
MRI=magnetic resonance imaging, TEE=transesophageal echocardiography, ACL=aortic complicated lesion, BMI=body mass index, mRS=modified Rankin Scale, CKD=chronic kidney disease, NIHSS=National Institutes of Health Stroke Scale, DWI=diffusion-weighted imaging, DSWMH=deep and subcortical white matter hyperintensity, PVH=periventricular hyperintensity, CMBs=cerebral microbleeds, WBC=white blood cell, CRP=C-reactive protein, LDL-C=low-density lipoprotein cholesterol.
a.CKD was defined as estimated glomerular filtration rate ＜60 ml/min/1.73 m2.
b.Deterioration during hospitalization was assessed as neurological worsening ≥ NIHSS 2 points.
Supplemental Table 7.Multiple logistic regression analysis for factors associated with ACL in prior statin users before admission
|
OR |
95% CI |
p value
|
| Male |
2.44 |
0.87-7.22 |
0.090 |
| Hypertension |
1.97 |
0.51-8.94 |
0.331 |
| CKD |
1.72 |
0.65-4.66 |
0.274 |
| Previous stroke |
2.46 |
0.77-8.37 |
0.130 |
| Prior antiplatelet agents |
1.32 |
0.45-3.82 |
0.607 |
| Atherogenic dyslipidemia |
3.26 |
0.78-14.88 |
0.105 |
| Intracranial artery stenosis |
3.71 |
0.86-19.41 |
0.080 |
| Aortic valve calcification |
3.45 |
1.30-9.77 |
0.013 |
| CRP (per unit) |
0.93 |
0.71-1.18 |
0.526 |
| LDL-Chol (per unit) |
1.00 |
0.98-1.02 |
0.770 |
| Anticoagulant therapy on discharge |
1.99 |
0.66-6.48 |
0.222 |
OR=odds ratio, CI=confidence interval, ACL=aortic complicated lesion, CKD=chronic kidney disease, CRP=C-reactive protein, LDL-C=low- density lipoprotein cholesterol.
a. CKD was defined as estimated glomerular filtration rate ＜60 ml/min/1.73 m2.
Supplemental Table 8.Multiple logistic regression analysis for factors associated with ACL in prior statin non-users before admission
|
OR |
95% CI |
p value
|
| Age (per unit) |
1.07 |
1.05-1.10 |
＜0.001 |
| Male |
2.17 |
1.33-3.60 |
0.002 |
| Hypertension |
0.97 |
0.58-1.65 |
0.924 |
| Diabetes mellitus |
1.01 |
0.62-1.64 |
0.972 |
| CKD |
1.06 |
0.67-1.67 |
0.808 |
| Ischemic heart disease |
2.31 |
1.00-5.66 |
0.051 |
| Previous stroke |
1.21 |
0.65-2.25 |
0.552 |
| Malignancy |
1.84 |
1.00-3.40 |
0.049 |
| Prior antiplatelet agents |
0.89 |
0.48-1.64 |
0.704 |
| Atherogenic dyslipidemia |
1.99 |
1.00-4.01 |
0.051 |
| Infarctions in multiple vascular territories |
1.21 |
0.74-1.97 |
0.440 |
| DSWMH |
1.31 |
0.77-2.22 |
0.316 |
| PVH |
0.81 |
0.46-1.40 |
0.447 |
| CMBs |
1.78 |
1.10-2.91 |
0.020 |
| Intracranial artery stenosis |
1.64 |
0.82-3.34 |
0.165 |
| CRP (per unit) |
1.05 |
0.92-1.17 |
0.437 |
| D-dimer (per unit) |
0.99 |
0.95-1.01 |
0.377 |
| Antiplatelet therapy on discharge |
2.13 |
0.69-6.79 |
0.189 |
| Anticoagulant therapy on discharge |
0.92 |
0.31-2.74 |
0.872 |
| Statin on discharge |
2.21 |
1.42-3.48 |
＜0.001 |
OR=odds ratio, CI=confidence interval, ACL=aortic complicated lesion, CKD=chronic kidney disease, DSWMH=deep and subcortical white matter hyperintensity, PVH=periventricular hyperintensity, CMBs=cerebral microbleeds, CRP=C-reactive protein, LDL-C=low-density lipoprotein cholesterol.
a.CKD was defined as estimated glomerular filtration rate ＜60 ml/min/1.73 m2.
Discussion
In the present study using data from the CHALLENGE ESUS/CS registry, 26.5% of CS patients had low HDL-C (≤ 40 mg/dl), 27.9% had high TG (≥ 150 mg/dl), and 10.2% of CS patients fulfilled the AD criteria. It was found that BMI, diabetes mellitus, ACLs in the aortic arch, and deterioration during hospitalization were independently associated with the presence of AD. In addition, AD was a significant factor associated with ACL, which was also seen in prior statin users before the index stroke.
Previous reports showed that 5.8% of French TIA patients and 12.2% of the Japanese stroke population met the criteria for AD12, 13). In addition, two international, prospective, randomized studies showed that the frequencies of AD in statin-treated patients for 3 months after stroke and after TIA were 10.1% and 8.9%, respectively5). Since Asian people tended to have lower HDL-C and higher TG levels, the prevalence of AD in CS patients in the present study seemed to be in good agreement with the results of prior studies.
Previous studies reported that AD was related to BMI, obesity, diabetes mellitus, metabolic syndrome, and other established coronary risk factors6, 7, 23). Namely, AD overlapped partly with lifestyle diseases and metabolic disorders. In the present study as well, BMI and diabetes mellitus were independently associated with AD.
In addition, AD definitely causes CVD, including strokes and even microvascular complications, as described above7-13). Previous studies showed that patients with increased TG levels develop CVD and atherosclerotic progression; increased TG levels are a marker of elevated levels of remnants rich in cholesterol, which enter into the intima and lead to low-grade inflammation and foam cell formation24). Meanwhile, HDL-C alone has some protective effect against atherosclerosis due to its antioxidant, anti-inflammatory, antithrombotic, and vasoprotective activities25). Although high TG and low HDL-C levels as risk factors for CVD have often been discussed separately, the coexistence of high TG and low HDL-C levels in AD could accelerate CVD and atherosclerosis more than either alone. As an illustration, in the Prospective Cardiovascular Münster (PROCAM) study, one in seven subjects with the combination of TG ＞200 mg/dl and HDL-C ＜35 mg/dl experienced a myocardial infarction over the 12-year follow-up period8), and this increased risk was substantially higher than with isolated high TG levels or low HDL-C levels. Moreover, AD induced maculopathy, retinopathy, and neuropathy through a mechanism involving inflammation, oxidative stress, and insulin resistance9-11). Though the participants in the present study with AD had no significant history of CVD and stroke, they were limited to a population with CS. Since CS patients have established risk factors, including CVD and diabetes mellitus, less frequently than cardiac embolism, ATBI, and lacunar infarctions14, 26), the prevalence of CVDs could be lower in the present study.
Regarding stroke classifications, previous studies showed that AD was particularly linked to ATBI and less likely associated with cardiogenic embolism13). Moreover, AD was also more robustly related to intracranial stenosis than to extracranial stenosis and aortic plaques12, 13). However, in the present study, ACLs in the aortic arch were rather significantly associated with AD in CS. Furthermore, AD itself was an independent factor associated with ACL, and the prevalence of AD was higher in CS patients with ACLs and with multiple etiologies, with a higher frequency of ACLs than other CS subtypes. Namely, this multicenter registry of CS patients who underwent TEE is the first to demonstrate the relationship between AD and ACLs. In the previous study, most patients had at least one known stroke etiology with atherosclerosis, small vessel disease, cardiac pathology, other definite causes, and dissection (ASCOD) grading systems, and their rate of TEE was only 30%13). In contrast, the present data were limited to patients diagnosed as having CS on examination at admission, and all of them underwent TEE. Therefore, the relatively lower rate of TEE in other studies than in the present study could cause the underestimation of the presence of ACLs in CS patients with AD.
Though intracranial arteries have anatomically thinner media and less abundant adventitia and elastic fibers than extracranial arteries and the aorta, previous studies showed that these histological features were linked to the permeability of lipid molecules, rendering the arteries more susceptible to oxidative stress in AD patients27, 28). Nevertheless, a recent study with nonobstructive general angioscopy (NOGA) demonstrated that the aortic plaques in cardiovascular patients frequently ruptured and excreted cholesterol crystals, which increased aortic inflammation29, 30). Therefore, lipid molecules in AD could affect even the aorta in a different pathophysiological way. In AD-related CS patients, the aorta could be an essential field of interactions among lipid molecules, inflammation, and embolism.
Another notable finding of the present study was that AD was associated with deterioration during hospitalization. Even though previous studies showed that diabetes mellitus and high BMI had an impact on early neurological deterioration (END)31, 32), AD was also independently associated with END on multivariate analysis in the present study. In a prior report, TIA patients with AD had a higher risk of early recurrent stroke despite appropriate interventions12). In addition, other studies reported that stroke patients with AD had more major adverse cardiovascular events5, 13). These vascular events of AD patients were partly explained by the deleterious impact of symptomatic intracranial stenosis and systemic vascular comorbidities. Though the present data regarding CS were limited to short-term hospitalization, and there was no difference in recurrence with or without AD, the increased rate of deterioration implied that other mechanisms such as inflammation and oxidative modification might play a crucial role in AD-associated vascular events.
As for the treatment of AD, statins reduce not only LDL-C, but also TG levels, and increase HDL-C levels modestly33). Furthermore, statins have pleiotropic effects, such as anti-inflammatory effects, endothelial protection, and plaque stabilization21, 34). Nevertheless, stroke patients in whom AD was treated with statins for more than 3 months still developed more recurrences, as described above5). In addition, the sub-analysis regarding prior statin users before admission in the present study showed a significant association between AD and ACLs, a substantial embolic source in CS patients. Although the present multiple logistic regression analysis concerning ACL statistically limited to the relative associations between AD and ACL regardless of prior statin use, previous study revealed that unignorable proportion of patients with severe aortic plaque under statin therapy still developed recurrence of embolic events35). For these high-risk atherosclerotic patients with ACL, more active and multifaceted antilipidemic treatment would be a potential supplemental prevention.
Previous reports suggested the additional use of fibrates, niacin, and omega-3 fatty acids with statins for AD patients at high risk for CVD36-38). Each medication not only decreases TG levels and raises HDL-C levels, but has some pleiotropic effects. As examples, fibrates reduce insulin resistance and inflammation39), niacin, vitamin B3, has several anti-atherothrombotic effects such as endothelial protection, anti-inflammation, plaque stabilization, coagulation and platelet aggregation inhibition, and fibrinolytic activation40), and omega-3 fatty acids derived from marine sources lower blood pressure and platelet aggregation, and improve fibrinolysis, endothelial function, and arterial compliance41, 42). These lipid modification therapies combined with statins would be beneficial for AD-related CS patients, especially with ACLs.
There were some limitations to the interpretation of the results of the present study. First, this study was retrospective, which might have affected the accuracy of the CS and AD diagnoses, since they depended on each institution in this multicenter, stroke registry. Notably, laboratory testing was performed within 48 hours from admission or onset for patients in case of stroke during hospitalization in each institute, and the timing from admission and system of measurement were not standardized. Therefore, effects of the stroke itself, diet, or infusion therapy after admission could not be ruled out. Second, though TEE was used to assess ACLs in the present study, this modality itself had some limitations, such as selection bias of patients due to its slight invasiveness and blind spots due to air in the trachea. Third, since the follow-up period in the present registry was limited to the acute stage of admission, the long-term prognosis of the CS population was not adequately assessed. Finally, the sub-analysis of prior statin use could have been statistically underpowered owing to the peculiarity and limited number of subjects, and the unavailability of the intensity and duration of statin treatment was also a limitation of this multicenter registry.
Conclusions
The prevalence of AD in CS patients enrolled in the CHALLENGE ESUS/CS registry was 10.2%. CS patients with the underlying pathologic condition of AD are more likely to have higher BMI, diabetes mellitus, ACLs in the aortic arch, and neurological deterioration during hospitalization.
Although intracranial stenosis has been shown to be associated with AD in ATBI, AD is also crucially related to ACLs in CS. More intensive and pleiotropic lipid-modifying therapy would be efficacious for further treatment of aortogenic brain embolism.
Conflicts of Interest
YU received lecture fees from OHARA Pharmaceutical Co., Ltd. and Daiichi Sankyo Co., Ltd. HT received lecture fees from Pfizer Japan Inc. and Daiichi Sankyo Co., Ltd. MK received honoraria from Daiichi-Sankyo Co., Ltd. and research support from Nippon Boehringer Ingelheim. YK received lecture fees from Daiichi Sankyo Co., Ltd., Medtronic CO. Ltd., Bayer Healthcare CO. Ltd. MI received lecture fees from Daiichi Sankyo Co., Ltd., Eisai Co. Ltd., and Bayer Pharmaceutical Co and a research grant from Shimadzu Corporation, Otsuka Pharmaceutical, and Panasonic Corporation. KH received lecture fees from Amgen Astellas BioPharma K.K., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Otsuka Pharmaceutical Co., Ltd. YH received lecture fees from Bayer Pharmaceutical Co. and Nippon Boehringer Ingelheim, Co., Ltd. NH was an advisory member of Dai-Nippon Sumitomo Pharma Co., Ltd., Hisamitsu Pharmaceutical Co., Inc., and Biogen Idec Japan Ltd., received lecture fees from Dai-Nippon Sumitomo Pharma Co., Ltd., Otsuka Pharmaceutical, Co., Ltd., Takeda Pharmaceutical Co., Ltd., Kyowa Hakko-Kirin Co., Ltd., FP Pharmaceutical Corporation, Eisai Co., Ltd., Novartis Pharma K.K., and AbbVie, and received departmental endowments by commercial entities from Kyowa Hakko-Kirin Co., Ltd., Nippon Boehringer Ingelheim, Co., Ltd., AbbVie GK, FP Pharmaceutical Corporation, Otsuka Pharmaceutical, Co., Ltd., Dai-Nippon Sumitomo Pharma Co., Ltd., Eisai Co., Ltd., Nihon Medi-physics Co., Ltd., Asahi Kasei Medical Co., Ltd., Ono Pharmaceutical Co., Ltd., MiZ Co., Ltd., AbbVie GK, OHARA Pharmaceutical Co., Ltd., Nihon Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Boston Scientific Corporation, and Medtronic Inc. HT received lecture fees from Takeda Pharmaceutical CO., Ltd., Eisai CO., Ltd. NH received Stock holdings from PARKINSON Laboratories Co., Ltd, Stock option from NYSNOBIO GT NEUROLOGY, LLC, honoraria from Sumitomo Pharma Co., Ltd., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., FP Corp., Eisai Co., Ltd., Nihon Medi-physics Co., Ltd., Novartis Pharma K.K., Biogen Idec Japan Ltd., AbbVie GK, Teijin Pharma Limited, Alexion Pharmaceuticals, Inc., Daiichi Sankyo Co., Ltd. and Teijin Pharma Limited, grants from Asahi Kasei Medical Co. Ltd., SNBL, Ltd, and funds for contract research from CellSource Co., Ltd., MJFF and MDS, scholarship grants from FP Corp. and Eisai Co., Ltd., and donations to the department, endowed research departments and joint collaborative research departments from Sumitomo Pharma Co., Ltd., Otsuka Pharmaceutical, Co., Ltd., Takeda Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., SUNWELS Co., Ltd., Eisai Co., Ltd., Nihon Medi-physics Co., Ltd., Abbott Japan LLC , AbbVie GK, Medtronic, Inc., Boston Scientific Japan K.K., Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., ZEBRA CO., LTD., KOWA Co., LTD, PARKINSON Laboratories Co., Ltd and OHARA Pharmaceutical Co., Ltd. Outside the submitted work. TU received lecture fees from Daiichi Sankyo Co., Ltd., Boehringer Ingelheim, Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical CO., Ltd.and research funds from Otsuka Pharmaceutical Co., Ltd. and AbbVie GK.
Funding
This work did not receive any grants from funding agencies in the public, commercial, or not-for-profit sectors.
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