Published online before print April 13, 2009, doi: 10.1161/CIRCULATIONAHA.108.795666
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(Circulation. 2009;119:2136-2145.)
© 2009 American Heart Association, Inc.
Epidemiology |
Low-Density Lipoprotein Cholesterol Concentrations and Death Due to Intraparenchymal Hemorrhage
The Ibaraki Prefectural Health Study
From Public Health (H.N., H.I.), Department of Social and Environmental Medicine, Osaka University, Graduate School of Medicine, Osaka, Japan; Harvard Center for Population and Development Studies (H.N.), Harvard School of Public Health, Cambridge, Mass; Department of Health and Social Services (F.I., M.D., Y.I.), Ibaraki Prefectural Office, Ibaraki, Japan; Department of Public Health (T.S.), Dokkyo Medical University School of Medicine, Tochigi, Japan; and Ibaraki Prefectural Health Plaza (T.S., E.O., H.O.), Ibaraki Health Service Association, Ibaraki, Japan. Dr Izumi is currently with the Office for Health Hazards Caused by Asbestos, Ministry of Environment, Tokyo, Japan.
Reprint requests to Professor Hiroyasu Iso, MD, Public Health, Department of Social and Environmental Medicine, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Shuita-shi, Osaka 565-0871 Japan. E-mail iso{at}pbhel.med.osaka-u.ac.jp
Received May 31, 2008; accepted February 5, 2009.
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Abstract |
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Background— Few studies have examined the association between low levels of low-density lipoprotein (LDL) cholesterol and risk of intraparenchymal hemorrhage.
Methods and Results— A total of 30 802 men and 60 417 women, 40 to 79 years of age with no history of stroke or coronary heart disease, completed a baseline risk factor survey in 1993 under the auspices of the Ibaraki Prefectural Health Study. Systematic mortality surveillance was performed through 2003, and 264 intraparenchymal hemorrhage deaths were identified. LDL cholesterol levels were calculated with the Friedewald formula. Persons with LDL cholesterol 
140 mg/dL had half the sex- and age-adjusted risk of death due to intraparenchymal hemorrhage of those with LDL cholesterol <80 mg/dL. After adjustment for cardiovascular risk factors, the multivariable hazard ratio compared with persons with LDL cholesterol <80 mg/dL was 0.65 (95% CI 0.44 to 0.96) for those with LDL cholesterol 80 to 99 mg/dL, 0.48 (0.32 to 0.71) for 100 to 119 mg/dL, 0.50 (0.33 to 0.75) for 120 to 139 mg/dL, and 0.45 (0.30 to 0.69) for 140 mg/dL. These inverse associations were not altered substantially after the exclusion of persons with hypertriglyceridemia, after analysis with a Cox proportional hazard model with time-dependent covariates, or in sensitivity analysis for the potential effect of competing risks.
Conclusions— Low LDL cholesterol levels are associated with elevated risk of death due to intraparenchymal hemorrhage.
Key Words: cholesterol • arteriosclerosis • intraparenchymal hemorrhage • follow-up studies
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Introduction |
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Intraparenchymal hemorrhage, which has a low survival rate and a high risk of disability,1 has unique pathological and epidemiological characteristics that distinguish it from coronary heart disease.2 This type of stroke is caused primarily by hypertension and possibly by low concentrations of low-density lipoprotein (LDL) cholesterol.3,4
Editorial p 2131
Clinical Perspective p 2145
An association between low total cholesterol levels and increased risk of intraparenchymal hemorrhage was reported among Japanese men and women5–9 and among Japanese American,10–12 American,13–15 Finnish,16 and Swedish men,17 whereas a U-shaped association was found for Japanese men and women,18–20 and no association was found for Swedish women17 or Korean men.21 Recent prospective studies have shown an inverse association primarily among hypertensive persons or usual drinkers or with high levels of 
-glutamyl transferase22,23; however, no study has examined the association between LDL cholesterol and risk of intraparenchymal hemorrhage. For this reason, we looked for an association between LDL cholesterol levels and risk of death due to intraparenchymal hemorrhage in a large Japanese population–based cohort study.
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Methods |
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Study Cohort and Population
The Ibaraki prefectural government initiated a community-based cohort study, known as the Ibaraki Prefectural Health Study, in 1993 to obtain information on health status for the purpose of health education and policy making.24 Participants in the cohort were 98 196 individuals (33 414 men and 64 782 women) 40 to 79 years of age living in Ibaraki Prefecture who underwent an annual health checkup in 1993, which included an examination of blood lipids for 96 610 individuals (32 984 men and 63 626 women).
We excluded 5391 persons (2182 men and 3209 women) from the analysis because of a history of stroke or coronary heart disease at the time of baseline inquiry. Thus, a total of 91 219 individuals (30 802 men and 60 417 women) were enrolled in the present study.
Informed consent was obtained from community representatives to conduct an epidemiological study based on guidelines of the Council for International Organizations of Medical Science.25 The Ethics Committee of Ibaraki Prefecture approved this study.
Measurement of Risk Factors
Serum total cholesterol and triglycerides were measured by enzymatic methods with an RX-30 device (Nihon Denshi, Tokyo, Japan), and high-density lipoprotein (HDL) cholesterol levels were measured by phosphotungstic acid magnesium methods with an MTP-32 (Corona Electric, Ibaraki, Japan). These measurements were performed on the premises of the Ibaraki Health Service Association and were standardized by the Osaka Medical Center for Health Science and Promotion under the aegis of the US National Cholesterol Reference Method Laboratory Network. The laboratory of the Osaka Medical Center for Health Science and Promotion has been standardized since 1975 by the CDC-NHLBI Lipid Standardized Program provided by the Centers for Disease Control and Prevention (Atlanta, Ga) and has met all criteria for both precision and accuracy of lipid measurements.26 LDL cholesterol was calculated with the Friedewald formula as follows: LDL cholesterol (mg/dL)=total cholesterol (mg/dL)–HDL cholesterol (mg/dL)–0.2xtriglycerides (mg/dL).27 A previous study showed no bias related to LDL cholesterol levels among persons with triglycerides <802 mg/dL (<8.8 mmol/L).28 We also calculated non-HDL cholesterol as follows: Non-HDL cholesterol (mg/dL)=total cholesterol (mg/dL)–HDL cholesterol (mg/dL).
Mild hypertension was defined as systolic blood pressure 140 to 159 mm Hg or diastolic blood pressure 90 to 99 mm Hg; the corresponding values for moderate hypertension were 160 to 179 mm Hg or 100 to 109 mm Hg, and for severe hypertension, they were 180 or 110 mm Hg. Diabetes mellitus was defined as a fasting plasma glucose level 126 mg/dL (7.0 mmol/L) or 200 mg/dL (11.1 mmol/L) during nonfasting or as use of medication for diabetes, and impaired glucose tolerance was defined as a fasting plasma glucose level 110 to 125 mg/dL (6.1 to 6.9 mmol/L) or a nonfasting level of 140 to 199 mg/dL (7.8 to 11.0 mmol/L) and no use of medication for diabetes. Kidney dysfunction was defined as serum creatinine levels 1.2 mg/dL (110 µmol/L) for men or 1.0 mg/dL (90 µmol/L) for women and/or as a history of kidney disease. Height in stocking feet and weight in light clothing were measured, and body mass index was calculated as weight (kg)/height (m)2. An interview was conducted to ascertain smoking status, number of cigarettes smoked per day, usual weekly intake of alcohol in go units (a Japanese traditional unit converted to grams of ethanol per day by 23 g of ethanol per go unit), and histories of stroke and heart disease. Current drinkers were defined as occasional and habitual drinkers.
Follow-Up Surveillance
To ascertain deaths in the cohort, the investigators conducted a systematic review of death certificates, which in Japan are forwarded to the local public health center in each community. It is believed that all deaths that occurred in the cohort were ascertained, except for subjects who died after they had moved from their original community, in which case the subject was treated as a censored case. Data on death rates are centralized at the Ministry of Health and Welfare, where the underlying causes of death are coded for the National Vital Statistics according to the International Classification of Diseases, 9th (1993–1994) and 10th (1995–2004) revisions. Cause-specific mortality was determined by total deaths due to intraparenchymal hemorrhage (International Classification of Diseases, 10th revision, code I61), hemorrhagic stroke (I60 to I61), subarachnoid hemorrhage (I60), ischemic stroke (I63), and coronary heart disease (I20 to I25).
To confirm the validity of the death certificate diagnoses for stroke and its subtypes in the Ibaraki Prefectural Health Study, a validation study was conducted in community-based samples (6004 persons 40 to 79 years of age) from Ibaraki prefecture, where a community-based stroke registry was conducted,29 between 1993 and 1997. In this stroke registry, the information for stroke cases (eg, episodes of symptom onset and imaging data of CT/MRI) was collected, and a final diagnosis was made by a panel of 3 or 4 physicians. We used 25 fatal cases (deaths within 28 days of symptom onset) in this stroke registry as the "gold standard" of stroke death and compared these with 94 stroke cases based on death certificate diagnoses. The sensitivity and specificity of death certificate diagnoses, respectively, were 80% and 100% for intraparenchymal hemorrhage, 71% and 100% for subarachnoid hemorrhage, 63% and 99% for ischemic stroke, and 76% and 99% for total stroke.
The follow-up inquiry for the present study was conducted until the end of 2003, and the median length of follow-up was 10.3 years. Only 3.2% of the subjects had moved out of the communities and were treated as censored. Whereas 0.3% of the subjects had died of intraparenchymal hemorrhage, 7.5% had died of other causes and were treated as censored.
Statistical Analysis
Statistical analysis was based on death rates from intraparenchymal hemorrhage divided by clinical categories of LDL cholesterol (<80, 80 to 99, 100 to 119, 120 to 139, and 140 mg/dL [<2.06, 2.06 to 2.57, 2.58 to 3.09, 3.10 to 3.61, and 3.62 mmol/L]) and other lipid profiles, that is, total cholesterol, HDL cholesterol, and triglycerides. Person-years of follow-up were calculated from the date of the baseline survey in 1993 to the date of death due to intraparenchymal hemorrhage or other causes, exit from the community, or the end of 2003, whichever occurred first.
Sex- and age-adjusted means and proportions of selected cardiovascular risk factors at baseline survey were presented among the categories of LDL cholesterols. Differences from the lowest category of LDL cholesterol in sex- and age-adjusted mean values and proportions of baseline characteristics were examined by ANCOVA and Mantel-Haenszel 
2 tests. Multivariable hazard ratios (HRs) and 95% CIs were calculated after adjustment for sex, age, and potential confounding factors by use of the Cox proportional hazards model. These potential confounding factors included body mass index (sex-specific quintiles), blood pressure categories (normal, mild hypertension, moderate hypertension, or severe hypertension), antihypertensive medication use (yes or no), lipid medication use (yes or no), diabetes status (normal, impaired glucose tolerance, or diabetes mellitus), -glutamyl transferase (sex-specific quintiles), kidney dysfunction (yes or no), smoking status (never, ex-smoker, and current smokers of 1 to 19 or 20 cigarettes/d), alcohol intake category (never or ex-drinkers, occasional drinkers, and habitual drinkers of <69 and 69 g of alcohol per day).
We tested the assumption of proportional hazards according to lipid profiles and found no violation for proportionality. Tests for effect modification by sex or other variables were conducted with an interaction term generated by multiplying the variables of lipids by sex or other variables. Because the Friedewald formula introduces biased data for LDL cholesterol,28 we additionally conducted our analysis after the exclusion of persons with hypertriglyceridemia (triglycerides 300 mg/dL) at baseline survey (2025 men and 2360 women).
We further analyzed the data with the time-dependent covariate Cox proportional hazard model using the additional data of lipid profiles and confounding factors for 80 578 persons (88.3% of the participants) who had undergone examination of blood lipids more than twice. The median duration between the date of the latest examination and the date of the end of follow-up was 0.7 years. We used blood pressure categories, antihypertensive medication use, diabetes mellitus, lipid medication use, body mass index, -glutamyl transferase, smoking status, alcohol consumption, and kidney dysfunction as time-dependent covariates.
Because the presence of competing risks may lead to biased results, we also conducted sensitivity analysis in several models. We used a stratified Cox proportional hazard model with interaction terms of competing risks,30 a proportional hazards model for the subdistribution of competing risks,31 and 2 types of "worst-case" scenarios: (1) All subjects censored because of disease other than intraparenchymal hemorrhage or because they moved out of the communities were assumed to have died of intraparenchymal hemorrhage instead, and (2) all subjects censored because of disease other than intraparenchymal hemorrhage or who moved out of the communities were assumed to have survived as long as the longest survival time observed in the present study.
All statistical tests were 2-sided, and P<0.05 was regarded as statistically significant. All statistical analyses except for the proportional hazard model for the subdistribution of competing risks were conducted with SAS, version 9.13 (SAS Institute, Inc, Cary, NC). R version 2.6.1 (R Foundation for Statistical Computing, Vienna, Austria) was used for calculations pertaining to the proportional hazard model for the subdistribution of competing risks.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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A total of 91 219 persons (30 802 men and 60 417 women) were followed up for a median of 10.3 years, during which time 264 subjects (125 men and 139 women) died of intraparenchymal hemorrhage. The crude death rate was 29 per 100 000 person-years for intraparenchymal hemorrhage and 795 per 100 000 person-years for all-cause death.
Table 1 shows selected cardiovascular risk factors by LDL cholesterol concentration category. Compared with persons who had the lowest levels of LDL cholesterol (<80 mg/dL [<2.06 mmol/L]), those who had the highest levels (140 mg/dL [3.62 mmol/L]) were older, more likely to be female and to use medication for a lipid abnormality, and less likely to smoke or drink heavily. They also tended to have kidney dysfunction; higher means of systolic and diastolic blood pressure, body mass index, and total and non-HDL cholesterol levels; and lower means of -glutamyl transferase, HDL cholesterol, and triglycerides.
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Sex- and age-adjusted death due to intraparenchymal hemorrhage was half as low for the highest category of LDL cholesterol as for the lowest category, whereas there was a weak inverse association with total cholesterol and no association with HDL cholesterol or triglycerides (Table 2). Adjustment for known cardiovascular risk factors did not alter these associations materially. The multivariable HR (95% CI) for the highest versus lowest lipid levels was 0.45 (0.30 to 0.69; P<0.001) for LDL cholesterol, 0.55 (0.33 to 0.91; P=0.02) for total cholesterol, 0.98 (0.62 to 1.53; P=0.91) for HDL cholesterol, 0.42 (0.26 to 0.68; P<0.001) for non-HDL cholesterol, and 1.13 (0.63 to 2.02; P=0.69) for triglycerides.
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These inverse associations were not altered substantially after we excluded persons with hypertriglyceridemia or when we analyzed with the time-dependent covariate Cox proportional hazard model. The HR (95% CI) for highest versus lowest LDL cholesterol was 0.48 (0.31 to 0.74; P=0.001) after the exclusion of persons with hypertriglyceridemia and 0.53 (0.34 to 0.81; P=0.003) when we used the time-dependent covariate Cox proportional hazard model.
To identify the confounding effect of lipid-lowering medication use, we also calculated the HR of death due to intraparenchymal hemorrhage. The HR for users versus nonusers of lipid-lowering medication was 0.39 (0.12 to 1.21; P=0.10) after sex and age adjustment, 0.41 (0.13 to 1.28; P=0.13) after multivariable adjustment, and 0.48 (0.25 to 0.92; P=0.03) in the time-dependent covariate Cox proportional hazard model. We also excluded persons with lipid medication use (n=2273) at baseline inquiry and confirmed that there were no differences in the association between LDL cholesterol and death due to intraparenchymal hemorrhage before and after such exclusion; the multivariable HR for highest versus lowest categories of LDL cholesterol was 0.45 (0.30 to 0.69; P<0.001) after this exclusion.
To examine the effect of extremely low levels of LDL cholesterol on death due to intraparenchymal hemorrhage, we subgrouped persons with LDL <80 mg/dL into those with <60 mg/dL, 60 to 69 mg/dL, and 70 to 79 mg/dL (Table 3). Compared with persons with <60 mg/dL of LDL cholesterol (number of events=17), the multivariable HR of death due to intraparenchymal hemorrhage was 0.52 (0.24 to 1.12; P=0.09) for those with LDL cholesterol 60 to 69 mg/dL (number of events=11); 0.49 (0.25 to 0.94; P=0.03) for 70 to 79 mg/dL (number of events=18); 0.40 (0.23 to 0.69; P=0.001) for 80 to 99 mg/dL; 0.29 (0.17 to 0.51; P<0.001) for 100 to 119 mg/dL; 0.30 (0.17 to 0.53; P<0.001) for 120 to 139 mg/dL; and 0.28 (0.16 to 0.49; P<0.001) for 140 mg/dL.
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To examine the effect of competing risks, we also conducted sensitivity analysis (Table 4). The HR did not change substantially among each model of sensitivity analysis except in worst-case scenario 1. Although the association in worst-case scenario 1 became weaker, the effect of low LDL cholesterol for increased risk of death due to intraparenchymal hemorrhage remained statistically significant.
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The inverse association between LDL cholesterol and cardiovascular disease mortality was confined to intraparenchymal hemorrhage (Table 5). LDL cholesterol levels were positively associated with death due to coronary heart disease, and the multivariate hazard ratio was 1.50 (1.07 to 2.10; P=0.02) for the highest versus lowest LDL cholesterol level. When death due to intraparenchymal hemorrhage and coronary heart disease was combined, we found a U-shaped relationship between LDL cholesterol and mortality risk, with a nadir at LDL cholesterol levels of 120 to 139 mg/dL (3.10 to 3.61 mmol/L). There was no significant association of LDL cholesterol with death due to subarachnoid hemorrhage or ischemic stroke.
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The inverse associations between LDL cholesterol and intraparenchymal hemorrhage were examined, stratified by sex, hypertension, fasting, smoking, and drinking status (Table 6). The associations did not vary by sex, hypertension, fasting, or smoking status. We observed an inverse association among current drinkers versus nondrinkers, although statistically significant associations were observed even among nondrinkers.
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Discussion |
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In the large population-based prospective study of Japanese reported here, we observed a significant association between low LDL cholesterol levels and increased risk of death due to intraparenchymal hemorrhage. These associations were not altered substantially after adjustment for known risk factors, the use of time-dependent covariates, the exclusion of persons with hypertriglyceridemia, or by stratification by sex, hypertension, fasting, smoking, and drinking status.
To examine the potential effect of competing risks, we conducted sensitivity analysis. We found a statistically significant association between low LDL cholesterol and increased risk of death due to intraparenchymal hemorrhage among all models of the sensitivity analysis, which suggests that the effect of competing risks may be small.
Arteriolosclerosis is characterized by angionecrosis of smooth muscles cells and an increase in basement membrane–like substance in the outer layer of smooth muscle cells of intracerebral arteries in the basal ganglia, thalamus, and brain stem.2,3 A hypercholesterolemic diet reduces angionecrosis and prevents occurrence of hemorrhagic stroke among spontaneously hypertensive rats,4 and higher intake of saturated fat, which leads to higher LDL cholesterol concentrations, was shown to be associated with reduced risk of intraparenchymal hemorrhage for both Japanese and Americans.32 Furthermore, low LDL cholesterol concentrations were associated with multifocal signal loss lesion detected on T2*-weighted gradient-echo (GE) MRI,33 which was a predictor of intraparenchymal hemorrhage.34 Moreover, a recent randomized clinical trial for LDL cholesterol lowering with high-dose atorvastatin after stroke or transient ischemic attack demonstrated a reduction of risk for overall fatal stroke but an increase in risk of hemorrhagic stroke.35 The mean LDL cholesterol level among patients receiving atorvastatin during the trial was 73 mg/dL.35 Although it is difficult to confirm the causality between low LDL cholesterol and increased risk of intraparenchymal hemorrhage through the present observational study only, the consistency of epidemiological and experimental evidence stated above also supports a causal relationship.
Many previous population-based cohort studies,5–20 but not all,17,21 revealed a similar association between low total cholesterol, but not LDL cholesterol, and increased risk of intraparenchymal hemorrhage. In the present study, the association with total cholesterol was weaker than that with LDL cholesterol, probably due to surrogate dilution bias.36 We also observed an association between high LDL cholesterol and increased risk of death due to coronary heart disease, consistent with the large body of evidence from previous cohort studies.22,36
There was a U-shaped relationship between LDL cholesterol and combined death due to intraparenchymal hemorrhage and coronary heart disease, with a nadir at LDL cholesterol levels of 120 to 139 mg/dL (3.10 to 3.61 mmol/L), because these 2 outcomes have an opposite direction in the association with LDL cholesterol. On the other hand, we observed inverse associations of LDL cholesterol with death due to total cardiovascular disease and all-cause mortality, because the Japanese population had high rates of death due to total stroke, with a high proportion of intraparenchymal hemorrhage, and low rates of death due to coronary heart disease compared with Americans. A previous study of Americans showed a U-shaped relationship between LDL cholesterol and all-cause mortality, with a nadir at LDL cholesterol levels of 160 to 189 mg/dL (4.14 to 4.90 mmol/L) for men and 130 to 159 mg/dL (3.36 to 4.12 mmol/L) for women.37 Because the present study population had a lower mean level of LDL cholesterol (119 mg/dL [3.09 mmol/L]) and lower mortality rate due to coronary heart disease (60 per 100 000 person-years), it was difficult to identify the effect of high LDL cholesterol on increased risk of all-cause mortality.
We found no significant association of low LDL cholesterol with death due to subarachnoid hemorrhage, probably because the pathological mechanism in subarachnoid hemorrhage differs from that in intraparenchymal hemorrhage.3 On the other hand, we observed a significant association with death due to hemorrhagic stroke, more specifically intraparenchymal hemorrhage.
A limitation of the present study is that we estimated LDL cholesterol levels using the Friedewald formula, which cannot be used for specific metabolic conditions such as hypertriglyceridemia and which was constructed based on fasting subjects.28 However, there was no change in the association between LDL cholesterol and intraparenchymal hemorrhage after the exclusion of persons with hypertriglyceridemia at the baseline survey and after stratification by fasting status. Second, we used mortality data based on death certificate diagnoses; however, validation studies have shown that death certificate diagnosis with regard to stroke and its subtypes is valid because of the high use of CT scans and MRIs in general hospitals in Japan.29 Third, we had no incidence data; thus, it remains unclear whether LDL cholesterol may be associated with increased risk of nonfatal intraparenchymal hemorrhage. Fourth, because drinking status was ascertained by interview survey, nondrinkers could be contaminated with drinkers; however, only 5.2% of nondrinkers designated themselves as current drinkers 5 years after the baseline survey (3.8% as occasional drinkers and only 0.02% as heavy drinkers). Thus, the potential effect of misclassification is unlikely to be large. Fifth, we could not obtain data on hepatic cirrhosis and its indicators (eg, international normalized ratio of prothrombin time) in the baseline inquiry; however, the prevalence of hepatic cirrhosis was only 0.03% (1 of 2917 persons) in community-based samples from Ibaraki prefecture,29 which suggests that the effect of residual confounding by the existence of hepatic cirrhosis would be small. Moreover, although it was difficult to examine the effect of extremely low levels of LDL cholesterol on death due to intraparenchymal hemorrhage because of the small sample size, we observed a consistent inverse association between LDL cholesterol and death due to intraparenchymal hemorrhage among persons with LDL <100 mg/dL, which includes the target LDL cholesterol level for prevention of coronary heart disease.38 Finally, extrapolation of the results to the general population must be done carefully. The study subjects were selected from the general population, but the participation rate was only 36.4%. However, the standard mortality ratio did not differ from that in the total Japanese population,24 which suggests that the potential selection bias is small.
The strength of the present study is that we had standardized lipid measurement values in a single laboratory, which in turn was standardized by the CDC-NHLBI Lipid Standardized Program.26 This justifies our assumption that misclassification bias due to lipid measurement errors has been reduced appropriately and that the resultant accuracy of lipid measurement has led to comparable results with previous well-standardized studies.
In conclusion, the present study provides epidemiological evidence that low LDL cholesterol levels are associated with increased risk of death due to intraparenchymal hemorrhage. Low LDL cholesterol may be an independent risk factor for intraparenchymal hemorrhage.
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Acknowledgments |
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We thank Dr Ai Ikeda, Harvard School of Public Health, for her assistance for statistical analysis.
Sources of Funding
This study was supported by a grant for health and medical services for the aged and health promotion of the Ministry of Health and Welfare, Japan in 1998 and 1999. Hiroyuki Noda was also supported by the postdoctoral fellowship program of the Uehara Memorial Foundation in 2007 (Tokyo, Japan).
Disclosures
None.
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CLINICAL PERSPECTIVE
Previous studies have suggested that low total cholesterol levels are associated with an increased risk of intraparenchymal hemorrhage. The present study extends the evidence of an association between low total cholesterol levels and hemorrhage risk. We showed an association between low low-density lipoprotein cholesterol (<80 mg/dL [<2.06 mmol/L]) and increased risk of death due to intraparenchymal hemorrhage in the general population. The basic pathology of intraparenchymal hemorrhage is arteriolosclerosis, characterized by angionecrosis (destruction) of smooth muscle cells in intracerebral small arteries, as opposed to atherosclerosis (plaque formation) in medium to large arteries. Low-density lipoprotein cholesterol may have an opposite effect on development of intraparenchymal hemorrhage than on coronary heart disease. The present finding suggests that low low-density lipoprotein cholesterol may be an independent risk factor for intraparenchymal hemorrhage.
Circulation 2009 119: 2125-2126.
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  H. Noda and H. Iso Letter by Noda and Iso Regarding Article, "Low-Density Lipoprotein Cholesterol Concentrations and Death Due to Intraparenchymal Hemorrhage: The Ibaraki Prefectural Health Study" Circulation, December 1, 2009; 120(22): e280 - e280. [Full Text] [PDF]
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L. B. Goldstein Response to Letter Regarding Article, "Low-Density Lipoprotein Cholesterol Concentrations and Death Due to Intraparenchymal Hemorrhage: The Ibaraki Prefectural Health Study" Circulation, December 1, 2009; 120(22): e281 - e281. [Full Text] [PDF]
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L. B. Goldstein The Complex Relationship Between Cholesterol and Brain Hemorrhage Circulation, April 28, 2009; 119(16): 2131 - 2133. [Full Text] [PDF]
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