Eur. J. Lipid Sci. Technol.

108 (2006) 383388 Roman Herziga Ivanka Vlachova a Jan Mares upkaa Bohdan Kr b Martin Gabrys Helena Vaverkovc an ka Daniel S Petr Schneiderkad vale Stanislav Bur ovsky a Petr Kan
a

DOI 10.1002/ejlt.200500285

383

Occurrence of dyslipidemia in spontaneous intracerebral hemorrhage*

Background: Dyslipidemia, mainly hypocholesterolemia is considered to be a risk factor (RF) for spontaneous intracerebral hemorrhage (SICH). The aim of our study was to assess its role in our SICH patients. Methods: In a hospital-based cross-section study, laboratory assessments of total cholesterol (TC), triglycerides (TG), high-density cholesterol (HDL-C) and low-density cholesterol (LDL-C) plasma levels were performed in 80 SICH patients without vascular malformation and in a control group (CG) of 80 age- and sex-matched patients with low back pain. All patients were treated at the Departments of Neurology and Neurosurgery, University Hospital, Olomouc, Czech Republic. Two-sample t-test and Mann-Whitney test were applied when assessing statistical significance. Results: The following mean lipid plasma levels were found in SICH patients versus CG subjects (in mmol/L): TC, 5.89 vs. 5.48 (p = 0.007); TG, 1.31 vs. 2.10 (p ,0.0001); HDL-C, 1.58 vs. 1.33 (p = 0.0001); LDL-C, 3.70 vs. 3.18 (p = 0.0004). Conclusions: TC and LDL-C plasma levels were higher in SICH patients in the Olomouc region of the Czech Republic. Keywords: Cerebrovascular diseases, spontaneous intracerebral hemorrhage, risk factors, dyslipidemia, cholesterol.

Stroke Center, Department of Neurology, University Medical Palacky School and University Hospital, Olomouc, Czech Republic b Stroke Center, Department of Neurosurgery, University Medical Palacky School and University Hospital, Olomouc, Czech Republic c Stroke Center, IIIrd Internal Department, University Medical Palacky School and University Hospital, Olomouc, Czech Republic d Department of Clinical Biochemistry, University Hospital, Olomouc, Czech Republic e Stroke Center, Department of Radiology, University Medical Palacky School and University Hospital, Olomouc, Czech Republic

1 Introduction
Several risk factors (RF) play a role in the etiopathogenesis of spontaneous intracerebral hemorrhage (SICH). Dyslipidemia (DLP) is considered to be one of these RF. However, contradictory results in this field can be encountered in the literature. For example, the role of hypocholesterolemia (hypoCH) has been discussed. It has been unambiguously accepted as a RF for hemorrhagic stroke (HS) by the majority of authors of both the large studies [112], cohort studies [1319] and meta-analyses and reviews [2025]. However, an opposite opinion can also be found again in all mentioned categories of large [2628] and cohort [2931] studies and reviews [32].

2 Subjects and methods

Eighty consecutive patients with spontaneous (non-traumatic) intracerebral hemorrhage (ICH), living in the Olomouc region, who were admitted to the Department of Neurology or Department of Neurosurgery, University
* The paper was presented in part as a poster at the 12th European Stroke Conference in Valencia, Spain, in May 2003 and at the 9th Congress of the European Federation of Neurological Societies in Athens, Greece, in September 2005, and as a lecture at the XXXIst Slovak-Czech Neurovascular Symposium in Bratislava, Slovakia, in October 2003.

Correspondence: Roman Herzig, Stroke Center, Department of Neurology, University Hospital, I. P. Pavlova 6, CZ-775 20 Olomouc, Czech Republic. Phone: 1420 588 443432, Fax: 1420 588 442528, e-mail: herzig.roman@seznam.cz

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Research Paper

The aim of our study was (1) to assess the role of DLP in our SICH patients and (2) to compare it to the findings in the general population (as represented by our control group subjects with low back pain). We reviewed the literature concerning the relationship between DLP and SICH.

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Eur. J. Lipid Sci. Technol. 108 (2006) 383388 This formula was not used in patients with triglyceridemia .5 mmol/L. Mean plasma lipid levels found in SICH patients and CG subjects were compared both in males and females. The following tests were applied for assessing the statistical significance of the differences between SICH patients and CG subjects: two-sample t-test and MannWhitney test for the age comparison, and Mann-Whitney test for the comparison of the mean plasma lipid levels. In ICH patients, the presence of some other major ICH RF, such as arterial hypertension known prior to stroke, anticoagulant therapy and other coagulopathies (Quick-INR .1.25 or aPTT .36 s), anti-platelet therapy, and thrombocytopenia (,1506109/L), was also observed. The whole study was conducted in accordance with the Helsinki Declaration of 1975 (as revised in 1983) and it was approved by the local ethics committee of our hospital.

Hospital, Olomouc, Czech Republic, between January 1, 1998 and December 31, 2000, were included in this hospital-based cross-section study. These patients represent all SICH patients from the Olomouc region admitted to our hospital during this interval. Patients with hemorrhage secondary to brain tumor or with hemorrhagic infarction as well as patients with underlying vascular malformation were excluded. The authors excluded also SICH patients referred from other hospitals, or those living outside the Olomouc region, in order to minimize referral bias. Stroke was defined according to the World Health Organization criteria as rapidly developed clinical signs of focal disturbance of the cerebral function, lasting more than 24 h or leading to death, with no other apparent cause than cerebrovascular disease [33]. The type of HS [ICH, subarachnoid hemorrhage (SAH), intraventricular hemorrhage] was diagnosed by computerized tomography (CT) performed at the time of admission. Various examination methods were used in some patients (mainly with ICH in other localizations than in the thalamus or basal ganglia) in the search for possible underlying vascular malformations. Out of the group of 80 patients, four patients underwent magnetic resonance imaging including magnetic resonance angiography (MRI/MRA), and six underwent digital subtraction angiography (DSA). In three other patients, both MRI/MRA and DSA were performed. An autopsy was performed in 32 patients (DSA was performed in three of these patients before they died). In total, at least one type of the above-mentioned examinations, or autopsy, was used in 42 (i.e. 52.5%) of the 80 patients, including all 23 patients presenting with ICH in other localizations than in the thalamus or basal ganglia. We also examined a control group (CG) of 80 (age- and sex-matched) patients with low back pain, treated at our (both inpatient and outpatient) department. Laboratory assessment of fasting total cholesterol (TC), triglycerides (TG), high-density cholesterol (HDL-C) and low-density cholesterol (LDL-C) plasma levels were performed both in SICH patients (samples taken within 24 h after admission) and in CG subjects. Examination was performed in all 80 consecutively admitted ICH patients (none of the admitted patients died before blood taking). This analysis was performed by the use of the commercial diagnostic kits CHOL, TG and HDL-C plus (all produced by Roche Diagnostics, Mannheim, Germany). The LDL-C value was counted using the following Friedewald formula: LDL-C = TC 2 HDL-C 2 TG/2.2

3 Results
The set of SICH patients consisted of 44 males (aged 36 87 years; mean 67.1 6 11.9 years), and 36 females (aged 5686 years; mean 71.1 6 8.3 years). The set of CG patients consisted of 44 males (aged 3681 years; mean 63.7 6 9.53 years), and 36 females (aged 5683 years; mean 68.7 6 7.66 years). According to the results of both the two-sample t-test and the Mann-Whitney test, the age differences between SICH patients and CG subjects in both sexes were not statistically significant (p = 0.145 and 0.097, respectively, in males; p = 0.209 and 0.215, respectively, in females). The characteristics of hemorrhage localization in the studied SICH patient group are shown in Tab. 1. A previous history of treated DLP was present in none of the SICH patients and in two of the CG subjects. In these two cases, only lipid plasma levels as present before the start of treatment (and not the actual ones) were taken into consideration. Tab. 2 demonstrates the comparison of the mean plasma levels of TC, TG, HDL-C and LDL-C in SICH patients and CG, both in males and females, including the statistical significance as assessed by Mann-Whitney test. The occurrence of arterial hypertension known prior to stroke, anti-coagulant therapy and other coagulopathies, anti-platelet therapy, and thrombocytopenia in ICH patients is presented in Tab. 3. www.ejlst.com

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Tab. 1. Hemorrhage localization within the group of 80 SICH patients without vascular malformation. Localization Number of patients 56 1 16 2 5 Co-existing localization SAH 2 1 0 0 0 IVH 19 1 4 0 1

Supratentorial: basal ganglia, thalamus Supratentorial: (basal ganglia, thalamus) 1 brain stem Supratentorial: other subcortical and cortical localizations Brain stem Cerebellar

SAH, subarachnoid hemorrhage; IVH, intraventricular hemorrhage.

Tab. 2. Comparison of the mean plasma levels of TC, TG, HDL-C and LDL-C in SICH patients and the CG in males and females (mmol/L). Lipid SICH patients TC TG HDL-C LDL-C 5.59 6 1.30 1.30 6 0.86 1.53 6 0.42 3.50 6 1.18 Males CG subjects 5.12 6 0.96 1.99 6 1.03 1.14 6 0.27 3.07 6 0.75 MannWhitney test SICH patients 6.25 6 1.11 1.32 6 0.84 1.65 6 0.41 4.01 6 1.02 Females CG subjects 5.95 6 1.76 2.24 6 2.42 1.57 6 0.35 3.24 6 0.97 MannWhitney test SICH patients 5.89 6 1.25 1.31 6 0.84 1.58 6 0.41 3.70 6 1.14 Total CG subjects 5.48 6 1.42 2.10 6 1.78 1.33 6 0.38 3.18 6 0.85 MannWhitney test

p = 0.033 p = 0.0002 p , 0.0001 p = 0.034

p = 0.081 p = 0.002 p = 0.463 p = 0.003

p = 0.007 p , 0.0001 p = 0.0001 p = 0.0004

Tab. 3. Occurrence of arterial hypertension known prior to stroke, anti-coagulant therapy and other coagulopathies, antiplatelet therapy, and thrombocytopenia in ICH patients. Sex Males Females Arterial hypertension 68.2% 63.9% Anti-coagulant therapy 6.8% 8.3% Other coagulopathies 22.7% 13.9% Anti-platelet therapy 11.4% 27.8% Thrombocytopenia 13.6% 11.1%

4 Discussion
HypoCH is considered to be one of the SICH RF [125], especially if diagnosed in the acute phase of stroke according to some authors [13, 18], although it can be influenced by stress. Cheng et al. reported a gradual decrease of not only TC but also of HDL-C plasma levels during the acute phase of ICH, reaching the lowest levels on the 14th day, while no obvious change of TG levels was detected in their patients [34]. Nevertheless, acute ICH appeared to have little effect on the serum lipid profile, as published by Woo at al. [35]. Jacobs et al. also consider TC levels at the time of stroke to be more representative of its usual levels, because poor nutrition or newly developed post-stroke liver or renal dysfunction may result in TC level lowering [36]. In the study performed by Neaton et al., a twofold increase in the risk of intracranial hemorrhage was found in males with cholesterolemia ,4.14 mmol/L when com-

pared to those with higher levels [7]. Similarly, in the study performed by Iribarren et al., a significantly higher risk (relative risk 2.7) of ICH in males older than 65 years with cholesterolemia ,4.62 mmol/L was recorded [10]. The role of hypoCH as a significant RF for the ICH incidence (relative risk 2.55) was confirmed also by Yano et al. [6]. Even the opinion that hypercholesterolemia (hyperCH) is associated with lower ICH risk can be encountered [25, 3739]. Gatchev et al. [40] reported hypoCH to be a RF for ICH in women, while in men the risk function of cholesterolemia was U-shaped, whereas in the study performed by Okumura et al. [41], hypoCH was an independent ICH predictor only in men. Iso et al. evaluated the association between fat intake and risk of ICH in women. Low intake of saturated fat was associated with an increased ICH risk in their study [42]. When assessing the role of hypoCH as a prognostic factor, Iso et al. found a threefold higher risk of 6-year mortality due to intracranial hemorrhage in males with cholesterolemia ,4.14 mmol/L [5], and Iriwww.ejlst.com

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Eur. J. Lipid Sci. Technol. 108 (2006) 383388 (including ICH) correspond to our findings. For example, in the study published by White et al., pravastatin administration did not significantly increase the risk of HS (its incidence was 0.2% in the placebo group versus 0.4% in the pravastatin group; p = 0.28) [47]. Also Collins et al. [48] found no apparent difference in the HS risk in patients treated with simvastatin (incidence 0.5% both in the statin and the placebo group; p = 0.8), and in the study performed by Woo et al. [39] hyperCH with statin therapy was associated with a lower risk of ICH (OR = 0.3; p = 0.0008) in multivariate analysis, when compared to controls. Several limitations of our study should be mentioned. Concerning the selection of patients with low back pain as CG subjects, we consider these patients to be quite a good representative sample of the general population, as spinal problems do not interfere with vascular RF. However, a bias in this study could be introduced by the use of hospital controls and a little lower (although not statistically significant) average age. Although the presence of other cardiovascular RF was not investigated in this study, the data collected are reliable enough when assessing the role of DLP (as at least one of the RF) in SICH. Comparison of the role of DLP in the SICH etiopathogenesis, as assessed by different types of epidemiological studies, represents another problem. The finding from large epidemiological studies that hypoCH increases the risk of HS means that the relative risk (and not the absolute risk) is inversely related to cholesterol levels. Nevertheless, the absolute risk of SICH is higher in patients with multiple RF and thus higher cholesterol levels, as in our study. Examination was performed in all of our 80 consecutively admitted ICH patients. Thus, the very limited number of patients having died before their transfer to the hospital did not cause any significant bias in this study.

barren et al. documented a significantly higher risk (relative risk 2.41) of mortality from ICH in males with cholesterolemia ,4.66 mmol/L [9]. However, according to other authors, no significant relationship between hypoCH and the risk of either ICH [26, 27, 30] or hemorrhagic stroke (ICH and SAH) in total [28, 32] exists. For example, hypoCH was not an independent RF for ICH in men in the study performed by Suh et al. [28]. Additionally, Shimamoto et al. found hypoCH to be a RF for ICH only in their first cohort of patients, followed from 1963-6 to 1973, but not in the latter one, followed from 1972-5 to 1983 [43]. HypoCH was not associated with the risk of ICH in the Framingham Study [44]. Completely different results were found in our study. The mean TC plasma level was significantly higher in SICH male patients than in the CG male subjects. Our findings are consistent with the results reported by Park et al. [29] and Zodpey et al. [31] who found a positive association between the TC levels and the ICH risk in their cohort studies. The mean TG plasma levels found in SICH patients were significantly lower when compared to CG subjects, regardless of their gender. The mean HDL-C plasma levels were significantly higher in SICH male patients when compared to CG male subjects in our study. However, Curb et al. found no relationship between HDL-C levels and HS risk in elderly men [45]. The explanation of the role of the higher HDL-C plasma levels, as observed in our male patients, in the SICH etiology is not known because HDL-C has, on the contrary, a protecting effect for the atherosclerotic changes of the vessels. Lower levels of LDL-C were observed in ICH patients by Peng et al. [17]. Nevertheless, the mean LDL-C plasma levels were significantly higher in our SICH patients than in the CG subjects, both in males and females. Thus, our results are similar to those reported by Zhou et al. who have also encountered higher levels of LDL-C in their ICH patients when compared to controls [46]. In the study performed by Xu et al., no significant differences in TG, HDL-C and LDL-C plasma levels were found between ICH patients and controls [30]. Based upon our findings, an important role of atherosclerosis (with not only TC increase [11] but also LDL-C increase belonging among its RF) in the ICH etiopathogenesis in our population should be considered. This surely corresponds to both the dietary problems (with high intake of saturated animal fat) and the DLP undertreatment in the Czech population. Results of some other papers that focused on the evaluation of the relationship between the modification of cholesterolemia by statin therapy and the risk of the particular types of stroke

5 Conclusions
The TC plasma levels in males and the LDL-C plasma levels in both sexes were higher in SICH patients in the Olomouc region, Czech Republic. Further identification of their role in the etiopathogenesis of this type of HS and their active modification, which is often manageable by mere regime adjustment, are needed to lower the incidence of not only ICH but also other cerebro- and cardiovascular diseases, because hyperCH and LDL-C increase are common RF for these disorders. Furthermore, the results of our study contradict the results of the majority of both large and cohort studies assessing the SICH RF, but confirm the findings of some other studies of both types, performed previously. Thus, we think that our results should be confirmed or refuted by epidemiological surveys of large populations in the future. www.ejlst.com

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Acknowledgments
We thank Dr. Jana Zapletalov, Department of Biometry, University Medical School, Olomouc, Czech RePalacky public, for testing the statistical significance of the results of this study. We are also indebted to Mr. Milan Sekanina for his technical support of our study. This work was supported by the IGA Ministry of Health CR grant number NF/7492-3/2003.
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