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Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:734-741

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:734-741.)
© 1996 American Heart Association, Inc.

Articles

`Silent' Cerebral Infarction Is Associated With Hypercoagulability, Endothelial Cell Damage, and High Lp(a) Levels in Elderly Japanese

Kazuomi Kario; Takefumi Matsuo; Hiroko Kobayashi; Reiko Asada; Miyako Matsuo

From the Department of Internal Medicine (K.K.), Awaji-Hokudan Public Clinic, Hokudan, and the Departments of Internal Medicine (K.K., T.M.) and Central Laboratory (H.K., R.A., M.M.), Hyogo Prefectural Awaji Hospital, Sumoto, Hyogo, Japan.

Correspondence to Dr Kazuomi Kario, Department of Cardiology, Jichi Medical School, 3311-1, Yakushiji, Minami-kawachi, Kawachi, Tochigi 329-04, Japan.


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Abstract "Silent" lacunar stroke, often found in the elderly, has been proposed as a predisposing condition for clinically overt stroke. However, the risk factors related to this condition have not been studied thoroughly. We conducted brain magnetic resonance imaging and measured the levels of fibrinogen, molecular markers of coagulation activation [prothrombin fragment 1+2 (F1+2)] and endothelial cell damage [von Willebrand factor (vWF) and thrombomodulin], and lipid profiles including lipoprotein (a) [Lp(a)] in 178 asymptomatic, high-risk, Japanese subjects aged 44 to 93 years. We also studied 32 symptomatic patients with lacunar stroke (symptomatic lacunar group). The prevalence of silent lacunar stroke increased with age up to 85 years but decreased with age in those 85 years old and older. Of the 160 elderly subjects (>=60 years) 84 (53%) had >=1 lacunar infarcts (silent lacunar group) and the remaining 76 were considered as the nonlacunar group. Fibrinogen and F1+2 levels in the silent lacunar group were significantly higher than those in the nonlacunar group (P<.01). Mean Lp(a) levels and the prevalence of subjects with an Lp(a) level >30 mg/dL were significantly higher in the symptomatic lacunar group than the nonlacunar group (P<.05), whereas these levels in the silent lacunar group were intermediate to those of the other two groups. When we further classified the silent lacunar group into three subgroups based on the number of lacunes (few lacunes, 1 or 2; moderate number of lacunes, 3 or 4; and numerous lacunes, >=5), levels of Lp(a), F1+2, vWF, and thrombomodulin were significantly higher and Lp(a) levels >30 mg/dL more common in the numerous-lacune than in the few-lacune subgroup. We conclude that silent lacunar stroke is often found in asymptomatic, high-risk, elderly Japanese patients and that silent multiple lacunar stroke is associated with hypercoagulability, endothelial cell damage, and high Lp(a) levels.


Key Words: elderly • hypercoagulability • endothelial cell damage • lipoprotein(a) • silent lacunar stroke


*    Introduction
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 up arrowAbstract
 *Introduction
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 down arrowResults
 down arrowDiscussion
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There are some racial differences in the demographics of cardiovascular diseases. In Japan stroke is more common while CAD is less common than in Western countries.1 However, in contrast with CAD, few important risk factors for stroke have been established, other than age, smoking, and high BP. Dyslipidemias that are important for the assessment of CAD risk show far less reliability in identifying those individuals who are at high risk for developing stroke. It has recently been reported that hypercoagulable states, which can be produced by decreased levels of various coagulation inhibitors (eg, antithrombin III, protein C, protein S, and heparin cofactor II), increased levels of fibrinogen or factor VII activity,2 3 4 5 6 7 8 and high Lp(a) levels,9 10 11 12 13 14 15 16 are involved in the development of ischemic stroke or acute transient ischemic attack.

Asymptomatic or "silent" cerebral infarction is sometimes detected incidentally by MRI or other imaging modalities in patients who demonstrate no localized neurological symptoms of stroke.17 18 19 Silent cerebral infarction, which is now classified as a type III cerebrovascular disorder by the National Institute of Neurological Disorders and Stroke, has been proposed as a predisposing condition for subsequent overt stroke.20

In Japan lacunar stroke is the most common subtype of ischemic stroke,21 and vascular dementia due to multiple lacunar infarctions constitutes a substantial proportion of all cases of dementia. In most cases of silent cerebral infarction, lacunar stroke (<1 cm2 in size) is present in the basal ganglia and deep white matter of the brain, and this condition is very common in elderly subjects, even in those who appear otherwise healthy.17 18 19 Identification of the risk factors closely associated with silent lacunar stroke might lead to the prevention of subsequent overt ischemic stroke through reduction of these risk factors. Previous reports have indicated that hypertension and advanced age are associated with silent lacunar stroke.17 18 19 However, the relationships between silent lacunar stroke and hypercoagulability, EC damage, and lipid profiles (including Lp[a]) have not been studied thoroughly. To help elucidate some of these relationships, we examined lacunar stroke in relation to MRI findings, coagulation activation, EC damage, and lipid profiles in asymptomatic high-risk elderly Japanese outpatients.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Patients
We studied 182 consecutive outpatients, aged 44 to 93 years, who had at least one cardiovascular risk factor: hypertension, dyslipidemia, elevated Hct (>.45), and current cigarette smoking. Hypertension was diagnosed when the office systolic BP was >=160 mm Hg and/or the office diastolic BP was >=95 mm Hg. Office BP was measured with an automated sphygmomanometer (BP103N-II, Nippon Colin Co, Ltd) while the patient was seated and after at least a 5-minute rest. None of the patients had received antihypertensive medication for at least 1 month before this study. Dyslipidemia was diagnosed when any one of the following fasting serum lipid levels was obtained: TC >220 mg/dL, TGs >150 mg/dL, or HDL cholesterol <35 mg/dL. The cutoff value for the definition of elevated Hct (>.45) was the 94th percentile for healthy, elderly participants in our health examination program for the aged.22 Excluded from this study were patients with renal failure and hepatic damage (serum creatinine >1.7 mg/dL, urea >35 mg/dL, and aspartate aminotransferase or alanine aminotransferase >40 IU/L) as well as obvious present and/or previous CAD, stroke, congestive heart failure, atrial fibrillation, or malignancy. Patients with signs of overt diabetes mellitus (fasting glucose >140 mg/dL and/or hemoglobin A1c >.064) were also excluded. All subjects were ambulatory and had a normal appetite. Results of physical examination and laboratory studies (blood and urine tests, chest x-ray films, and resting electrocardiography) were normal or consistent with World Health Organization hypertensive stage I or II. No cervical bruits were audible.

We also studied 32 elderly patients with symptomatic lacunar stroke that had been diagnosed on the basis of neurological signs and either brain computed tomography or MRI findings (symptomatic lacunar group). The interval between the ictus and examination ranged from 8 to 144 months in these patients. Smokers and nonsmokers were defined by their current smoking status. Body mass index was calculated as weight in kilograms divided by the square of height in meters squared.

MRI
Brain MRI was performed in all 182 asymptomatic patients with a superconducting magnet with a main field strength of 1.5 T (Toshiba MRT 200 FXII). The brain was imaged in the axial plane at an 8-mm slice thickness. T1-weighted images were obtained by using a short spin-echo pulse sequence with a repetition time of 500 msec and an echo time of 13 msec. T2-weighted images were obtained by using a long spin-echo pulse sequence with a repetition time of 4000 msec and echo times of 60 and 112 msec. The matrix was 256x224 pixels. The images were evaluated for the number and location of lacunes. A lacune was defined exclusively as a low-intensity signal area (<1 cm2 in size) on T1-weighted images that was also visible as a hyperintense lesion on T2-weighted images, as illustrated previously.17 The number of lacunes in each patient was counted. Lacunes, as defined by the aforementioned criteria, might include lesions other than true infarcts, such as état criblé, especially if they were small (<5 mm2 in size).17 All of the MRI images were interpreted in a blinded fashion. The data for 4 subjects who had infarcts >10 mm2 in size (2 with cerebellar and 2 with frontal lobe infarction) were excluded from the following analysis.

Sample Collection
The 160 subjects aged >=60 years were studied further by examining their blood chemistry profiles. Blood samples were obtained before noon after an overnight fast. Blood samples were drawn with minimal hemostasis from the antecubital vein of the seated subject. Specimens for the assay of coagulation parameters were collected by the two-syringe method into disposable, siliconized, evacuated glass tubes containing a 1/10 volume of 3.8% trisodium citrate. Specimens for glucose and lipid determinations were collected into NaF and plain tubes, respectively, and centrifuged at 3000g for 15 minutes at room temperature. After separation the serum samples were stored at 4°C if the analysis was not to be performed within a few days. The plasma samples for the coagulation assay were subsequently separated and stored in several plastic tubes at -80°C until laboratory determinations were performed. The first thawed sample was used for the F1+2 assay.

Assay Procedures
Plasma fibrinogen levels were determined with the one-stage Data-Fi clotting assay kit (Dade).23 Plasma levels of vWF, thrombomodulin, and F1+2 were determined with ELISA kits from Diagnostica Stago, Mitsubishi Gas Chemical Co, and Behringwerke AG, respectively.24 25 For the vWF assay the value for commercially available pooled plasma (CTS Standard Plasma, Behringwerke AG) was set at 100%.

Serum TC and TG levels were determined with commercial enzyme assay kits (Wako). Serum HDL cholesterol values were determined by an enzymatic procedure after precipitation with phosphotungstic acid (Wako). Lp(a) levels were assayed with an ELISA kit (Biopool). Serum glucose values were determined with a commercial glucose oxidase method kit (Kanto Chemicals). Serum albumin, pseudocholinesterase, creatinine, and uric acid were also measured by routine enzymatic assays. In our laboratory the coefficients of variation were 3.6% for F1+2, 3.8% for vWF, 4.7% for thrombomodulin, 3.6% for Lp(a), and 2.5% for fibrinogen.

Statistical Analysis
Data are shown as mean±SD. The distributions of TG, Lp(a), fibrinogen, F1+2, and thrombomodulin values were examined and logarithmically transformed to reduce the skewness and kurtosis of the distribution curve prior to statistical analysis. The geometric mean (±SD range) of each parameter was determined. One-way ANOVA was performed to detect differences among groups, and Fisher's protected least significant difference test was used to compare mean values between two groups. The {chi}2 test was used to compare the prevalence of each parameter or silent lacunar stroke among the groups. Spearman's correlation coefficient was calculated for each parameter. Differences with a value of P<.05 were considered significant.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 *Results
down arrowDiscussion
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Age and Silent Lacunar Stroke
Fig 1Down shows the prevalence of silent lacunar stroke in the various age groups of the 178 asymptomatic high-risk subjects (age 44 to 93 years). The prevalence of silent lacunar stroke increased with age up to 85 years but decreased with age in those 85 years old or older. Of the 160 elderly subjects (>=60 years of age) 84 (53%) had >=1 lacunar infarct. The highest number of lacunes found in any 1 patient was 12. A total of 312 lacunar lesions was found (mean, 1.95 per subject or 3.71 per subject with lacunes). The lesion location in 18 (6%) was the brain stem, in 207 (66%) the basal ganglia, and in 87 (28%) the deep white matter. No lacunes were found in the cerebral or cerebellar cortex.



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  		Figure 1. Prevalence of silent lacunar stroke detected by MRI in 182 asymptomatic, high-risk subjects distributed by age.

Characteristics of Elderly Study Subjects
Table 1Down shows the characteristics of the 160 high-risk elderly subjects and the 32 elderly patients with symptomatic lacunar stroke. We classified the 160 asymptomatic subjects into the silent lacunar group (84 subjects with >=1 lacune detected by MRI) and the remaining 76 subjects into the nonlacunar group. Subjects in the silent lacunar group were generally older than those in the nonlacunar group.


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  		Table 1. Characteristics of Elderly Study Subjects by Group

Of the 4 risk factors (hypertension, dyslipidemia, elevated Hct, and current cigarette smoker status) examined in the high-risk subjects, hypertension and elevated Hct were significantly more common in the silent lacunar group than in the nonlacunar group (Table 1Up, P<.05). The prevalence of lacunar stroke was 38% in those subjects with neither hypertension nor elevated Hct, 61% in those with 1 of these 2 risk factors, and 73% in those with 2 risk factors, and these differences were significant ({chi}2=10.1, P<.01). Other combinations of the 4 risk factors had no effect on the prevalence of silent lacunar stroke (data not shown). Those subjects with multiple risk factors (at least 3 of the 4 risk factors) tended to be more common in the silent lacunar or symptomatic group than in the nonlacunar group, although differences were not significant. The levels of Lp(a), F1+2, and markers of EC damage (vWF and thrombomodulin) were not significantly different in those with versus those without these 4 risk factors (data not shown).

We excluded from this study patients with a history of CAD, but we diagnosed 18 asymptomatic patients with CAD on the basis of abnormal Q waves on the electrocardiogram. There was no difference in prevalence of previous antihypertensive treatment between the nonlacunar (37%) and silent lacunar (32%) group.

Silent Lacunar Stroke and Cardiovascular Risk Factors
Table 2Down shows the various parameters in the nonlacunar, silent lacunar, and symptomatic groups. Serum creatinine level was higher in the silent and symptomatic lacunar groups than in the nonlacunar group. Mild renal failure (defined as a serum creatinine level of 1.3 to 1.7 mg/dL) was more common in the silent lacunar than in the nonlacunar group. The symptomatic lacunar group had the highest prevalence of mild renal failure (38%). For all 160 asymptomatic high-risk subjects, only the F1+2 level was significantly higher in the 12 subjects with mild renal failure than in the 148 subjects with a serum creatinine level <=1.2 mg/dL [geometric mean (±SD range): 1.65 (1.35 to 2.00) nmol/L versus 1.23 (1.16 to 1.29) nmol/L, P<.005], whereas there were no significant differences between these two groups for the other parameters (lipid profiles, fibrinogen, and markers of EC damage; data not shown). When these 12 subjects with mild renal failure were excluded from the 160 asymptomatic high-risk subjects, there was no significant difference in the F1+2 level between the nonlacunar and silent lacunar groups.


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  		Table 2. Cardiovascular Risk Factors in Elderly Study Subjects by Group

Lp(a) levels were significantly higher and levels >30 mg/dL significantly more common in the symptomatic lacunar group than in the nonlacunar group, whereas other lipid profile measures were not different among the three groups. Fibrinogen and F1+2 levels were significantly higher in the silent and symptomatic lacunar groups than in the nonlacunar group. The F1+2 level was significantly higher in the symptomatic lacunar group than in the silent lacunar group, and the vWF level was significantly higher in the symptomatic lacunar group than in the nonlacunar group.

Number of Lacunes and Cardiovascular Risk Factors
We further classified the subjects in the silent lacunar group into three subgroups based on the number of lacunes: those with few (1 or 2) lacunes, those with a moderate number (3 or 4) of lacunes, and those with numerous (>=5) lacunes (Table 3Down). The levels of Lp(a), F1+2, vWF, and thrombomodulin were significantly higher and an Lp(a) level >30 mg/dL more common in the numerous-lacune subgroup than the few-lacune subgroup.


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  		Table 3. Relationships Between Number of Lacunes and Cardiovascular Risk Factors in Elderly Study Subjects (by Subgroup) With Silent Lacunar Infarction

Next we divided the 160 asymptomatic high-risk patients into quintiles of each factor (Fig 2Down). In silent lacunar stroke, especially multiple lacunar stroke, the prevalence was significantly higher for Lp(a), fibrinogen, F1+2, thrombomodulin, and creatinine in the highest compared with the lowest two quintiles. However, the relationships between silent lacunar stroke and vWF levels were not significant.




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  		Figure 2. Relationships between silent lacunar stroke and Lp(a), markers of coagulation activation and EC damage, and renal failure in 160 high-risk, elderly subjects. Prevalence (%) of silent lacunar stroke is shown in each quintile (Q) for each factor. Hatched areas show levels for the few-lacune subgroup (1-2 lacunes per person) and solid areas those for the moderate-numerous lacune subgroups (>=3 lacunes per person). Probability value above each column was obtained by comparing the prevalence of silent lacunar stroke (>=1 lacunes per person) in each quintile with that in the 2 lowest quintiles (Q1-2), and the probability within each solid area was obtained by comparing the prevalence of the moderate-numerous lacune subgroups (>=3 lacunes per person) in each quintile with that in the 2 lowest quintiles (Q1-2).

Correlations Between Cardiovascular Risk Factors
The scatterplot of Lp(a) versus F1+2 levels in the 160 high-risk subjects is shown in Fig 3Down. There were no significant relationships between these two variables. Lp(a) level had a significant, positive correlation with the markers of EC damage (for vWF, r=.185, P<.02; for thrombomodulin, r=.171, P<.05).



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  		Figure 3. Scatterplot of F1+2 and Lp(a) levels in 160 high-risk, elderly subjects. {circ} indicate data points for subjects in the nonlacunar group; {bullet}, data points for those in the silent lacunar group. Dashed lines indicate cutoff levels for the highest quintile (Q5) for each parameter.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The present study, which included brain MRI, the most reliable method for detecting lacunes,26 revealed that hypercoagulability, EC damage, and high Lp(a) level were related to silent, multiple lacunar stroke in asymptomatic, high-risk, elderly subjects. The prevalence of silent lacunar stroke increased with increasing age (up to 85 years) in the 178 asymptomatic high-risk subjects aged 44 to 93 years but decreased with age in those >=85 years old (Fig 1Up). Very elderly subjects (those >=85 years) may be those who are resistant to cerebrovascular disease, even though they may have various cardiovascular risk factors. The prevalence of lacunes was 53% in the 160 subjects of the present study, and this value is very similar to that obtained ({approx}50%) in previous MRI studies of high-risk elderly Japanese subjects.17 18 19 There are few studies of silent lacunar stroke (detected by MRI) in healthy elderly subjects. One or more lacunes were detected by MRI in 14 of 34 (41%) normotensive, healthy, elderly subjects recruited from a rural Japanese community.19 Thus, silent lacunar stroke is very common in elderly individuals. The prevalence of lacunar stroke in our high-risk elderly subjects (53%) appears slightly higher than that reported for healthy elderly subjects (41%).

Hypertension, dyslipidemia, and cigarette smoking have been reported to be 3 major risk factors for CAD,27 whereas dyslipidemia may be less important in the pathogenesis of cerebrovascular disease. In addition to these risk factors, we have added elevated Hct to the selection criteria for classifying patients at high-risk, since a Japanese necropsy report has indicated that the incidence of cerebral infarction is higher in subjects with Hct >.45.28 We found that hypertension and an elevated Hct level were significantly more common in the silent lacunar and symptomatic lacunar groups than in the nonlacunar group, while there were no significant differences for dyslipidemia and cigarette smoking among these groups (Table 1Up). Concerning dyslipidemia, instead of the 240 mg/dL value that is widely used as the cutoff for high TC,29 we used 220 mg/dL as the cutoff for the high-risk subjects in this study. This difference in cutoff value did not affect interpretation of our results, and only 7 subjects had a TC value between 220 and 239 mg/dL but none of the other 3 risk factors. Although TC, HDL cholesterol, and TGs may have different effects on the atherogenesis and progression of cerebrovascular disease, there were no differences in the levels of any of these three lipids among the nonlacunar, silent lacunar, and symptomatic lacunar groups or among the few-lacune, moderate-lacune, and numerous-lacune subgroups in the silent lacunar group. Those with multiple risk factors (>=3) were more often found in the silent lacunar and symptomatic lacunar groups than in the nonlacunar group, although there were no significant differences.

To assess hypercoagulability we measured F1+2 plasma levels. Conversion of prothrombin to thrombin is the central event in blood coagulation. This reaction occurs continuously at an appropriate rate under physiological conditions in vivo. During this process the amino terminus of prothrombin is released as the inactive F1+2 by the action of factor Xa.24 Measurement of F1+2 in the bloodstream allows assessment of hypercoagulability as well as hypocoagulability, as may be seen in patients undergoing warfarin treatment.24 25 Thus, even low-grade hypercoagulability in the atherosclerotic process may be assessed precisely by measuring F1+2 levels. In the present study, F1+2 levels were significantly higher in the silent lacunar than the nonlacunar group and were even higher in the symptomatic lacunar group (Table 2Up). In the silent lacunar group the F1+2 level increased with the number of lacunes (Table 3Up). In the 160 asymptomatic high-risk subjects, silent lacunar stroke, especially multiple lacunar stroke, was more common in the upper two than in the lowest two quintiles (Fig 2CUp). Lacunar stroke is thought to be caused by lipohyalinosis or atherothrombotic occlusion of small, perforating arteries of the brain. Our results indicate that hypercoagulability is closely involved in lacunar stroke, even in its silent stage. Thus, warfarin treatment of individuals with silent lacunar stroke in the hypercoagulable state, which can be assessed by measuring F1+2 levels, may prevent the often subsequent overt ischemic stroke.

To assess EC damage we measured plasma levels of vWF and thrombomodulin. vWF is a glycoprotein that is stored in ECs and secreted into the circulation,30 whereas thrombomodulin, a membrane glycoprotein expressed on the surface of ECs, is an important cofactor in the thrombin-catalyzed activation of protein C. Soluble thrombomodulin is also present in human plasma, probably due to proteolysis.31 Although their release mechanisms from ECs are different, both vWF and thrombomodulin have been reported to show increases that parallel the degree of EC damage in vitro and in vivo.32 33 34 35 36 Thus, plasma levels of vWF and thrombomodulin are widely used as indicators of EC damage.33 34 35 36 Increased vWF levels have been reported in patients with cerebral infarction,35 and thrombomodulin levels have been reported to be slightly higher or unchanged in focal atherothrombotic disease such as CAD and ischemic stroke,36 whereas they are noticeably higher in systemic vasculopathy due to systemic lupus erythematosus or diabetes mellitus.34 In the present study, only vWF levels were significantly elevated in the symptomatic lacunar group compared with the nonlacunar group (Table 2Up). This increase might be due to decreased thrombomodulin levels in the ECs of the brain.37 However, these two molecular markers of EC damage both showed higher levels in the numerous-lacune subgroup than in the few-lacune subgroup (Table 3Up). Thus, this finding may indicate that EC damage is not essential to the initial lacune formation but might act as an accelerant for multiple lacunar formation.

Concerning the metabolic risk factors for large-artery disease, dyslipidemia, coagulation factors (fibrinogen and factor VII),38 and an EC-derived marker (tissue plasminogen activator)39 have been reported to be risk factors for CAD. On the other hand for stroke, all of these risk factors except fibrinogen5 38 and tissue plasminogen activator40 are controversial because no definitive results from a prospective study have been obtained. Lp(a) is a complex macromolecule that consists of LDL-like particles and apo(a), which has close structural homology to plasminogen.41 Elevated Lp(a) levels are associated with a higher risk for atherosclerosis, especially of the large arteries, and its manifestations, such as myocardial infarction, stroke, and restenosis after percutaneous transluminal coronary angioplasty, especially when levels exceed 30 mg/dL.14 15 In the present study there was no significant relationship between elevated Lp(a) and hypercoagulability (Fig 3Up), but there were positive correlations between Lp(a) level and markers of EC damage (vWF and thrombomodulin, P<.05) in the high-risk patients. These results suggest that atherosclerosis, especially of large arteries, is accelerated by elevated Lp(a) levels and may have some role in inducing EC damage, but the effect may not be significant activation of coagulation.

Concerning stroke subtype, some discrepancies have appeared in previous reports. Some reports have indicated that increased Lp(a) levels are found only in atherothrombotic stroke (mainly corresponding to the cortical artery occlusion type) but not in lacunar stroke (mainly corresponding to the perforating artery occlusion type).9 11 13 A recent MRI study on the diagnosis of lacunes revealed a positive association between high Lp(a) and the perforating artery occlusion type of cerebral infarction.12 In the present study mean Lp(a) level and the proportion of subjects with an Lp(a) level >30 mg/dL were significantly higher in the symptomatic lacunar group compared with the control group, and the silent lacunar group had intermediate levels (Table 2Up). Among the silent lacunar subgroups, the numerous-lacune subgroup showed significantly higher Lp(a) levels than did the few-lacune subgroup, and Lp(a) levels >30 mg/dL were more common in the moderate- or numerous-lacune subgroup than in the few-lacune subgroup (Table 3Up). Furthermore, silent lacunar stroke, especially multiple lacunar stroke, was more common in the highest than the lowest two quintiles (Fig 2AUp). Thus, Lp(a) is also probably closely associated with the pathogenesis of lacunar stroke, even during its silent stage.

In the present study we measured Lp(a) levels in the same manner (sample collection and assay method) as in the JMS Cohort Study. We are now participating in the JMS Cohort Study, which began in several rural Japanese communities in 1992. The JMS Cohort Study is a population-based study that was designed to explore the risk factors, including coagulation factors and Lp(a), for atherosclerosis in Japan.42 43 The results of the 1992 to 1993 JMS Cohort Study, conducted with 1235 men and 1762 women, reported the prevalence of Lp(a) >30 mg/dL to be 18.3% in men and 22.8% in women and in subjects 60 years or older, 20.0% in 550 men and 25.6% in 734 women.42 In the nonlacunar group in our study, because the percentage of male participants was 29 (Table 1Up), those in the control population with an Lp(a) level >30 mg/dL were calculated to represent 24%. This control value is not significantly different from that for our nonlacunar group. Thus, all of the cardiovascular risk factors that were examined in the present study (ie, hypertension, dyslipidemia, elevated Hct, and current smoker status) are probably independent of Lp(a) level. The prevalence of elevated Lp(a) values (>30 mg/dL) in both the present study and the JMS Cohort Study is higher than that reported for Western populations (5% to 20% of the healthy control population).44 45 46 However, the Lp(a) values found in either the present or the JMS Cohort Study cannot be simply compared with those reported for Western populations because sample storage conditions and assay procedures have essential effects on Lp(a),15 47 and these conditions would be different for each study.

Increases in plasma levels of fibrinogen have been reported to be a risk factor for cardiovascular disease.5 38 We also found that fibrinogen levels were significantly higher in the silent lacunar and symptomatic lacunar groups than in the nonlacunar group (Table 2Up). Serum creatinine levels were also significantly higher and mild renal failure (serum creatinine level, 1.3 to 1.7 mg/dL) more common in the silent lacunar and symptomatic lacunar groups than in the nonlacunar group (Table 2Up). Overt renal failure and albuminuria (including microalbuminuria) have been reported to be accompanied by hypercoagulability, increased levels of markers of EC damage, and elevated Lp(a) levels.25 48 49 50 51 Therefore, to obviate the effect of renal failure, we excluded from study those subjects with overt proteinuria or a serum creatinine level >1.7 mg/dL. In addition, the F1+2 level was significantly higher in the 12 subjects with mild renal failure than in the 148 subjects with lower serum creatinine levels, but there were no significant differences between these two groups in terms of lipid profiles, fibrinogen, and markers of EC damage. Thus, in elderly, asymptomatic, high-risk subjects, even mild renal failure is accompanied by hypercoagulability and appears to be a risk factor for lacunar stroke.

It remains unknown whether the presence or the number of lacunes is more important in the development of symptomatic lacunar stroke. In our study the numerous-lacune subgroup had significantly higher F1+2 levels, markers of EC damage (vWF and thrombomodulin), and Lp(a), which were as high as those in the symptomatic lacune group (Tables 2Up and 3Up). On the other hand, levels of these factors in the few-lacune group were as low as those in the nonlacunar group. Thus, on the basis of these cardiovascular risk factors, the number of lacunes seems to be more important than the presence of lacunes per se in high-risk elderly subjects.

In conclusion, the present study revealed that silent lacunar stroke is often found in the elderly and that silent multiple lacunar stroke is closely associated with hypercoagulability, EC damage, and high Lp(a) level. Thus, correction of these risk factors may help prevent the often subsequent overt ischemic stroke in elderly patients with silent multiple lacunar strokes.


*    Selected Abbreviations and Acronyms
 
BP = blood pressure
CAD = coronary artery disease
ELISA = enzyme-linked immunosorbent assay
F1+2 = prothrombin fragment 1+2
Hct = hematocrit
JMS = Jichi Medical School
MRI = magnetic resonance imaging
TC = total cholesterol
TG(s) = triglyceride(s)
vWF = von Willebrand factor


*    Acknowledgments
 
This study was supported by grants in aid (1992 to 1995) from the Foundation for the Development of the Community, Tochigi, Japan. We are indebted to Professor Kazuyuki Shimada (Department of Cardiology, JMS, Tochigi) for his thoughtful comments regarding this manuscript; to Drs Koji Eno (Department of Radiology, Hyogo Prefectural Awaji Hospital) and Masahiro Imiya (Department of Neurology, Awaji-Hokudan Public Clinic and Hyogo Prefectural Awaji Hospital) for their helpful advice regarding MRI findings; and to Dr Satoko Fuji (Department of Statistics and Central Laboratory, Hyogo Prefectural Awaji Hospital) for statistical analysis of the data.

Received July 26, 1995; accepted March 19, 1996.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

  1. Marmot MG, Smith GD. Why are the Japanese living longer? Br Med J. 1989;299:1547-1551.
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