Published online before print March 12, 2009, doi: 10.1161/STROKEAHA.108.539643
(Stroke. 2009;40:1627.)
© 2009 American Heart Association, Inc.
Original Contributions |
Low Level of Low-Density Lipoprotein Cholesterol Increases Hemorrhagic Transformation in Large Artery Atherothrombosis but Not in Cardioembolism
From Department of Neurology (B.J.K., S.-H.L., W.-S.R., B.S.K., C.K.K., B.-W.Y.), Seoul National University Hospital, Seoul, Republic of Korea; Clinical Research Center for Stroke (B.J.K., S.-H.L., W.-S.R., C.K.K., B.-W.Y.), Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
Correspondence to Seung-Hoon Lee, MD, PhD, Department of Neurology, Seoul National University Hospital, 28 Yongon-dong, Jongno-gu, Seoul, 110-744, Republic of Korea. E-mail sb0516{at}snu.ac.kr
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Abstract |
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Background and Purpose— Low cholesterol level is known to be associated with increased cerebral hemorrhage. However, the associations of hemorrhagic transformation (HTf) after acute ischemic stroke and the low levels of total cholesterol (TC) or low-density lipoprotein cholesterol (LDLC) are largely undiscovered.
Methods— Of the 1034 patients with acute ischemic stroke who were consecutively admitted to our hospital, 377 patients with stroke attributable to large artery atherothrombosis (LAA; n=210) or cardioembolism (n=167) were selected for this study. Demographic and clinical information was collected and HTf was evaluated through follow-up T2*-weighted gradient-echo MRI performed usually within 1 week after stroke. Measurement of lipid parameters included TC, LDLC, high-density lipoprotein cholesterol, and triglyceride.
Results— Of the 377 patients, HTf was noted in 74 patients (19.6%). When patients were divided into 4 groups according to their TC and LDLC levels, the incidence of HTf was significantly elevated in the lowest quartile of each TC (P<0.01) and LDLC (P<0.01) level in LAA subgroup, but not in cardioembolism. After adjusting covariates, a low level of LDLC (OR, 0.46 per 1 mmol/L-increase; 95% CI, 0.22–0.98) was independently associated with HTf in LAA, but not in cardioembolism. There was no significant association between low levels of TC (OR, 0.63 per 1 mmol/L-increase; 95% CI, 0.35–1.15) and HTf in LAA.
Conclusions— Low levels of LDLC, and possibly TC, are associated with greater risk of hemorrhagic transformation after acute ischemic stroke attributable to LAA.
Key Words: cholesterol • hemorrhagic • ischemic stroke • transformation • low-density lipoprotein cholesterol • neurovascular unit
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Introduction |
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Hemorrhagic transformation (HTf) frequently complicates ischemic stroke with or without thrombolytic treatment.1,2 HTf after acute ischemic stroke is known to associate with poor outcome3 and delays the initiation of proper anticoagulation treatment for stroke with cardioembolism (CE). HTf occurs after extravasation of blood over damaged cerebral vascular endothelium in acute ischemic stroke,4 and the following factors are known to be associated with HTf: systolic blood pressure,5 blood glucose level,6 thrombolysis,7 old age,8 and albuminuria.9 Low total cholesterol (TC) level is known to increase the incidence of cerebral hemorhage,10 suspiciously through unstable integrity of endothelial cells in cerebral small vessels.11 Recently, the ongoing dispute over the association of low cholesterol level and hemorrhagic stroke was flamed after a report of increased cerebral hemorrhage after intensive lipid-lowering therapy,12 but the association of hemorrhagic transformation and the level of low TC or low-density lipoprotein cholesterol (LDLC), which is a major target of the lipid-lowering therapy, is yet undiscovered. We hypothesized that a low level of cholesterol may be associated with HTf attributable to stroke only in patients with significant proximal large artery stenosis, which is indicative of a vulnerable neurovascular unit caused by long-standing sublethal ischemia, but not in stroke patients with CE, because it was not related to the narrowing of upstream arteries. In this context, we sought to investigate the effect of low TC and low LDLC level on the HTf after acute ischemic stroke.
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Subjects and Methods |
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A total of 1034 acute ischemic stroke patients who had been admitted to Seoul National University Hospital within 7 days after ictus between October 2002 and March 2006 were consecutively enrolled in this study, as previously described.13 Among the patients, subjects with the following conditions were excluded from this study: transient ischemic attacks (n=110; HTf=2), strokes attributable to small vessel disease (n=289; HTf=0), strokes of undetermined etiology (n=184; HTF=34), or strokes of other determined etiology (n=15; HTf=2), according to the classification of Trial of Org 10172 in Acute Stroke Treatment.14 Patients without complete workups for various reasons (n=59; 8 without initial MRI, 32 without follow-up MRI, 11 without cardiac workups, and 8 without cholesterol test) were further excluded. Therefore, our study population consisted of a total of 377 patients with strokes attributable to large artery atherothrombosis (LAA; n=217) and CE (n=160).
Baseline demographic and clinical information collected at admission included age at onset, gender, hypertension (previous use of antihypertensive medication, systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg at discharge), diabetes (previous use of antidiabetic medication, fasting blood glucose >7.0 mmol/L, or postprandial blood glucose after 2 hours >11.1 mmol/L at discharge), hyperlipidemia (previous use of lipid-lowering medication, TC >6.0 mmol/L, or LDLC >4.14 mmol/L at admission), smoking (current smoker or experience of regular smoking habit), history of stroke, previous use of antiplatelet or anticoagulant medications, systolic blood pressure and diastolic blood pressure levels at admission, blood glucose level, levels of TC, high-density lipoprotein cholesterol and triglycerides, prolonged prothrombin time or activated partial thromboplastin time, National Institute of Health Stroke Scale (NIHSS) score at admission, and thrombolytic treatment during acute stage. LDLC was calculated using the following equation: LDLC=TC–high-density lipoprotein cholesterol–0.2xtriglycerides.15
All participants underwent initial brain MRI before the initiation of thrombolytic or antithrombotic therapy (within 24 hours after admission) and follow-up brain T2*-weighted gradient echo MRI usually within 1 week after stroke (follow-up days; mean±SD, 6.71±1.43). The MRI studies were performed using 1.5-Tesla superconducting magnet (GE Medical System). The standardized MRI protocol consisted of axial T2-weighted spin echo (repetition time/echo time, 2500 to 4500/80 to 112 ms; flip angle, 20°; slice thickness 5 mm; gap width, 2 mm), axial gradient echo sequences (repetition time/echo time, 200 to 500/15 ms; flip angle, 20°; slice thickness, 5 mm; gap width, 2 mm) and diffusion-weighted imaging (repetition time/echo time, 4000/73 ms; flip angle, 90°; slice thickness, 5 mm; gap width, 2 mm). HTf was identified when follow-up gradient echo images showed a low-signal area consistent with blood within the acute ischemic lesion. Leukoariosis was judged as being absent, or present as a punctuate, early confluent or confluent abnormality as seen on T2-weighted MR images, according to the previously proposed method.16 Early confluent or confluent lesions were designated as advanced leukoariosis in this study. Microbleeds were defined as focal homogenous areas with a diameter of 2 to 5 mm, as previously described.17 Signal loss lesions secondary to globus pallidus calcification or thrombus in the cerebral artery were excluded. Old stroke lesions and the ischemic lesions involving cerebral cortex were also evaluated.
Differences between groups were examined by Pearson 
2 test, Student t test, or Fisher exact test. We also divided each TC level and LDLC level into 4 quartiles, and the differences of demographic and clinical characteristics in each quartile were examined by 2 test and ANOVA test. Multivariate logistic regression analysis was used to examine the association between HTf and the levels of TC and LDLC. Multivariate logistic regression analysis, using HTf as the dependent variable, was performed to adjust for risk factors of HTf, including age, gender, hypertension, diabetes, serum glucose level, admission systolic blood pressure, admission NIHSS, and thrombolytic treatment. Significance was established at the P<0.05 level. All relevant values were presented as the mean±SD. All the statistical analyses were performed using SPSS 12.0 (SPSS Inc).
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Results |
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Of the 377 included patients, male gender was 232 (62.1%) and the mean age was 66.2±1.7. There were 232 patients with hypertension (61.5%), 118 patients with diabetes (26.5%), 64 patients with hyperlipidemia (17.0%), and 78 patients with history of stroke (20.7%). Among them, thrombolytic treatment was given to 39 patients during acute stage (10.3%), and the mean NIHSS score was 6.43±6.47. The range and mean±SD of TC and LDLC were as follows: 2.15 to 8.95 mmol/L and 4.62±1.00 mmol/L, respectively, for TC, and 0.38 to 6.97 mmol/L and 2.90±0.88 mmol/L for LDLC.
HTf after ischemic stroke was found in 74 patients (19.6%) on follow-up brain gradient echo images. Comparison of the clinical, laboratory, and radiological variables in patients with or without HTf is shown in Table 1. HTf was more prevalent in CE subgroup (32.5%) than in LAA subgroup (10.1%), as previously reported.18 In LAA patients, patients with HTf were more likely to be male (P=0.03) and to have lower levels of LDLC (P=0.02). In the CE subgroup, there were significant associations between HTf and NIHSS score at admission (P<0.01) or thrombolytic treatment (P<0.01), but not with TC or LDLC levels. The level of triglyceride and high-density lipoprotein cholesterol showed no association with the incidence of HTf in any subgroup.
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The clinical characteristics of patients according to the levels of TC and LDLC are presented in Tables 2 and 3
, respectively. There was no difference in the demographic, clinical, and radiological variables among the quartiles stratified by TC and LDLC level. The LDLC levels of 26 patients were not reported because they were not measured at the time of admission. The incidence of HTf was higher in the lowest quartile (Q1) of TC (OR, 0.26; 95% CI, 0.10–0.67; P<0.01) and LDLC (OR, 0.21; 95% CI, 0.08–0.54; P<0.01) than in the rest of the LAA subgroup but not in the CE subgroup (Figure and Table 4).
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Table 4 shows the results of the multiple logistic regression analysis and the OR for the level of TC and LDLC. A significant association between HTf and TC, comparing the combined higher 3 TC quartiles with the lowest TC quartile, was detected in the LAA group (OR, 0.27; 95% CI, 0.09–0.81), but the association between HTf and the TC level per 1-mmol/L increase (treating TC as a continuous variable) did not achieve statistical significance (OR, 0.63; 95% CI, 0.35–1.15; P=0.13). Lower LDLC level was related to an increased HTf after ischemic stroke, with the risk of HTf increasing by 54.0% for each 1-mmol/L decrease in the LDL level, after adjusting for other risk factors (OR, 0.46 per 1-mmol/L increase; 95% CI, 0.22–0.98) in LAA. In addition, the associations between HTf and adjusted variables of clinical importance, including diabetes, NIHSS, and thrombolytic treatment, are shown in the supplemental Table I, available online at http://stroke.ahajournals.org.
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Discussion |
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Our results suggest that low levels of LDLC, and possibly TC, are associated with a high incidence of HTf after acute ischemic stroke in LAA but not in CE. The association between HTf and the level of LDLC in stroke attributable to LAA was established in both the lowest quartile model and the 1-mmol/L increase model. The association between HTf and the level of TC, however, was only evident in the lowest quartile model.
There has been a long-standing dispute over the increased risk of cerebral hemorrhage at lower levels of cholesterol. Various reports10,19,20 stated that low cholesterol level was associated with cerebral hemorrhage, but others21,22 reported against the positive association of low cholesterol level and hemorrhagic stroke. Whereas the initial lipid-lowering therapy trial23 reported the absence of significant association, recent intensive lipid-lowering treatment trial12 showed a 68% increase of hemorrhagic stroke by treating with 80-mg atorvastatin.
The underlying biological explanation over the mechanism of increased cerebral hemorrhages at low levels of TC or LDLC is not yet established. There has been reports that adequate cholesterol may be important for maintaining the integrity of cerebral small vessels,11,24 and that experimental injection of immunoliposome may ameliorate the endothelial damage after thrombolysis.25 Additionally, cerebral microbleeds, which may reflect the blood extravasation around cerebral small vessels,26 were known to be prevalent in ischemic stroke patients with low TC levels.27 Finally, the low TC or LDLC levels without lipid-lowering therapy may reflect poor general medical condition, which is indicative of increased HTf after ischemic stroke.28 From these considerations, low levels of TC and LDLC may increase the incidence of cerebral hemorrhage by way of disturbed cerebral small vessel integrity.
These findings lead to the question of under what circumstances does HTf occur. Blood-brain barrier consists of endothelial cells of cerebral microvessels and the basement membrane and protects the brain against noxious chemicals, variations in blood composition, and breakdown of the concentration gradient.29 HTf is linked to the processes that alter the integrity of the neurovascular unit, which consists of BBB, astrocytes, and adjacent neurons,4 and that causes the extravasation of blood over ischemic vascular endothelial cells. After ischemic insult, the permeability of BBB increases significantly,30 resulting in the extravasation of plasma components and edema formation.31 Moreover, not only the vascular endothelial cells but also the astroglial cells are known to protect against the increasing permeability after hypoxic insult.32 Therefore, after long-standing subclinical hypoxic injury to the brain, it is possible that the cumulative damage on endothelial cells, astroglia, and neurons, ie, the neurovascular unit, may evoke HTf after acute ischemic stroke.
One of the most important points distinguishing LAA from CE is the stenosis of proximal cerebral large arteries. The stenosed proximal arteries may damage cerebral neurovascular units of relevant territory in various ways. The narrow proximal larger arteries are known to associate with low perfusion state in the brain,33 and microemboli are reported to increase in stenosis of proximal arteries.34 In contrast, CE, by definition, implies heart-originating embolism without meaningful cerebral arterial stenosis,14 and may have relatively intact neurovascular unit without long-standing subclinical injuries. In other words, HTf may tend to occur in the cerebral vessels of LAA patients who have been exposed to various injuries associated with proximal arterial stenosis in the hemorrhage-prone condition of low TC or low LDLC. However, in the cerebral vessels of CE, which contain relatively intact neurovascular unit than those of LAA, low levels of TC or LDLC may have limited influence on the occurrence of HTf.
Our results should be interpreted with caution in consideration of a few points. Our study was conducted in a retrospective manner, and some of our patients had total cholesterol levels without LDL cholesterol levels. But 26 patients without LDL cholesterol levels were <1% of the total population, so that the quality of data are acceptable. Second, the long-term outcome of HTf, which is a major poor prognostic factor in acute ischemic stroke,3 was not evaluated in this study. We also did not distinguish between symptomatic and asymptomatic HTf. Third, the cholesterol level may change in the acute stages of stroke.35 However, a previous study suggested that the acute change in cholesterol after stroke would be insignificant,36 and the time interval between stroke ictus and admission was <2 days (mean±SD, 1.33±1.68). Based on these results, the change in cholesterol as an acute phase reactant was considered to have a minimal influence on our results. Fourth, an analysis of the influence of statin treatment on HTf could not be performed because of the lack of information on prestroke statin use in our patients. However, statins were only recently introduced to the Korean pharmaceutical market,37 and we therefore believe that the number of patients receiving prestroke statin treatment was minimal during our study period (October 2002 to March 2006). Fifth, these findings should be interpreted cautiously because they ultimately rest on only 22 HTf occurrences in LAA cases (11 in the lowest quartile of LDLC, compared to 3 to 5 in each of the remaining LDLC quartiles). Finally, we did not evaluate the subclinical damage of the neurovascular unit by LAA, because a direct investigation was yet unavailable.
This study suggests that low levels of LDLC, and possibly TC, may be associated with increased risk of HTf in LAA but not in CE. From this result, we were able to show the differential subclinical injuries on cerebral vasculature in LAA and CE, which should be considered in clinical stroke research in the future. The positive association between HTf and low levels of cholesterol in strokes attributable to LAA may be considered in the management of acute stroke patients.
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Acknowledgments |
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Sources of Funding
This study was supported by a grant from the Korean Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A080503).
Disclosures
None.
Received October 7, 2008; revision received November 8, 2008; accepted December 3, 2008.
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