Plasma Fibrinogen, Ambulatory Blood Pressure, and Silent Cerebrovascular Lesions
The Ohasama Study
Objective— Twenty-four–hour ambulatory blood pressure (24-hour ABP) values are considered a powerful predictor of stroke. Silent cerebrovascular lesions are associated with an increased risk of stroke. Because fibrinogen is a major determinant of plasma viscosity, an elevated fibrinogen level might also be associated with stroke risk. We evaluated the association of 24-hour ABP and plasma fibrinogen levels with the risk of silent cerebrovascular lesions (white matter hyperintensity and lacunar infarct) detected by MRI.
Methods and Results— The study cohort comprised 958 individuals from the general population of Ohasama, a rural Japanese community. Multiple logistic regression analysis adjusted for age, sex, smoking and drinking status, use of antihypertensive medication, body mass index, 24-hour ABP, and a history of hypercholesterolemia, diabetes mellitus, and atrial fibrillation demonstrated that each 1-SD increase in fibrinogen level was associated with a significantly increased risk of silent cerebrovascular lesions (odds ratio, 1.26; P=0.001). The 24-hour ABP was also significantly and independently associated with the risk of silent cerebrovascular lesions. Even when 24-hour ABP values were within normal range (<135/80 mm Hg), elevated fibrinogen levels were associated with an increased risk of silent cerebrovascular lesions. Fibrinogen and 24-hour BP had additive effects on silent cerebrovascular lesions.
Conclusion— The 24-hour ABP and plasma fibrinogen levels were closely and independently associated with the risk of silent cerebrovascular lesions including white matter hyperintensity and lacunar infarct.
- ambulatory blood pressure
- lacunar infarct
- plasma fibrinogen
- silent cerebrovascular lesions
- white matter hyperintensity
Silent cerebrovascular lesions as white matter hyperintensity (WMH) and lacunar infarcts are frequently observed on MRI scans of elderly individuals. Silent cerebrovascular lesions constitute an independent predictor of the risk of symptomatic stroke,1,2 and are associated with cognitive impairment or dementia.3
Fibrinogen is involved in primary hemostasis, platelet aggregation, and leukocyte–endothelial cell interaction, and it is the major determinant of whole blood and plasma viscosity.4,5 Elevated fibrinogen levels induce a state of hypercoagulability,6,7 and may reflect the progression of atherosclerosis.
Growing evidence indicates that fibrinogen is a risk factor for coronary heart disease.8–10 A large meta-analysis11 has shown close associations between elevated plasma fibrinogen levels and the risk of coronary heart disease and stroke mortality. However, findings regarding the incidence of stroke,12–14 as well as the relationship between fibrinogen and silent cerebrovascular lesions15–18 are inconsistent. The latter studies included patients with a history of cerebrovascular diseases,16 or a comparatively small study cohort.15–17 One study has found that fibrinogen predicts coronary heart disease in Asian countries including Japan,19 but the association between silent cerebrovascular lesions and fibrinogen in the Asian general population has not been described.
Hypertension is a major risk factor for silent cerebrovascular lesions,18,20 and ambulatory blood pressure (ABP) is more closely correlated with target organ damage than casual blood pressure (CBP).21,22
We conducted a cross-sectional study to determine the association between plasma fibrinogen and silent cerebrovascular lesions in a general population. We also evaluated the association between silent cerebrovascular lesions and the risk conferred by combined fibrinogen and ABP levels.
This investigation was a part of the Ohasama study. The socioeconomic and demographic characteristics of this region and full details of the project have been described elsewhere.23 The study protocol was approved by the Institutional Review Board of Tohoku University School of Medicine, Sendai, Japan, and by the Department of Health of the Ohasama Town Government.
The population of Ohasama in 1998 was 7202. Of those, 3077 were 55 years or older. Individuals (n=492) who were not at home during the normal working hours of the study nurses, and those hospitalized, mentally ill, or bedridden (n=185), were not eligible for inclusion. Of the remaining 2400 eligible individuals, 1174 subjects (49%) gave informed consent and participated in the MRI examination. We excluded 173 subjects whose BP and fibrinogen levels were not adequately measured. We also exclude 43 subjects with history of previous stroke or transient ischemic attack. Therefore, a total of 958 individuals (40%; mean age 66.0±5.7 years; 32% men) were included in the present analysis.
We obtained MR images using a superconducting magnet with a main 0.5 T. The brain was imaged in the axial plane in 10-mm-thick slices and we collected T1- and T2-weighted images. A lacunar infarct was defined as an area of low signal intensity measuring ≤15 mm and ≥3 mm on T1-weighted images and that was visible as a hyperintense lesion on T2-weighted images. Hyperintense punctate lesions evident only on the T2-weighted images were not counted as lacunar infarcts. We defined WMH as hyperintensities on only T2-weighted images, and graded it according to Fazekas24 as follows: absent (grade 0), punctate (grade 1), early confluent (grade 2), and confluent (grade 3). Small caps (<5×10 mm) on the horns of the lateral ventricles and pencil-thin lining around the ventricles were considered normal. Larger caps (≥5×10 mm) were considered as grade 2. A neurosurgeon and 4 technical experts directed by the neurosurgeon independently evaluated the MRI findings in a blinded manner. In the case of disagreement, a consensus reading was held. Both intra-reader and inter-reader studies (n=111) showed good agreement. Kappa statistics were between 0.68 and 0.86 for lacunar infarct, and between 0.72 and 0.86 for WMH. We defined silent cerebrovascular lesions as: (1) WMH of grade 1 or more; (2) presence of lacunar infarcts; or (3) any combination of these findings.
ABP was monitored using a fully automatic ABPM630 device (Nippon Colin, Komaki, Japan)25 preset to measure BP every 30 minutes. Mean 24-hour, daytime, and nighttime values for ABP were calculated for each participant. Daytime and nighttime values were estimated from the subjects’ diaries.
CBP was measured twice consecutively in the sitting position, after a minimum 2-minute interval of rest, by a doctor using a mercury sphygmomanometer or an automatic device (HEM907; Omron Healthcare Co. Ltd, Kyoto, Japan) at the time of MRI examination. The average of the 2 readings was defined as the CBP.
Physical and Biochemical Examination
Fibrinogen (mg/dL) was measured by the Clauss method. Hypercholesterolemia was defined as total cholesterol ≥220 mg/dL, use of medication for hypercholesterolemia, and/or a history of hypercholesterolemia. Diabetes mellitus was defined as a nonfasting glucose level of ≥200 mg/dL, HbA1c level of ≥6.5%, use of medication for diabetes, and/or a history of diabetes mellitus.
To analyze the relationship between silent cerebrovascular lesions and patient characteristics, we used the χ2 test for categorical data and the Student t test for continuous data. We examined the associations between fibrinogen and silent cerebrovascular lesions using logistic regression analysis. Quartiles were initially analyzed, where the lowest quartile was treated as the reference category. We then entered fibrinogen as a linear term (per SD) into the model. We adjusted for age (continuous variable), sex (men, women), cardiovascular risk factors including smoking status (ever, never), drinking status (ever, never), use of antihypertensive medication (treated, untreated), body mass index (≥25 kg/m2, <25 kg/m2), 24-hour ABP (continuous variable), and a history of hypercholesterolemia, diabetes mellitus, and atrial fibrillation (present, absent). We also examined the combination of fibrinogen and 24-hour ABP levels using logistic regression analysis. All statistical analyses were conducted using SAS software, version 9.1 (SAS Institute Inc, Cary, NC). Values are expressed as means±SD. P<0.05 was considered statistically significant.
Fibrinogen and Silent Cerebrovascular Lesions
Individuals with silent cerebrovascular lesions were significantly older, had higher frequencies of use of antihypertensive medication, cardiovascular disease, lower body mass index, and higher 24-hour, daytime, nighttime ABP (both systolic and diastolic BP), and fibrinogen levels (Table 1). In individuals with silent cerebrovascular lesions, serum creatinine levels were significantly higher. Other biochemical factors were not associated with silent cerebrovascular lesions.
Figure 1 shows the adjusted odds ratios (ORs) and 95% CIs for silent cerebrovascular lesions among the quartiles of fibrinogen. The highest quartiles of fibrinogen were associated with a significant increase in the risk for silent cerebrovascular lesions (OR, 1.99; 95% CI, 1.34 to 2.97; P=0.0007). The associations were also similar for WMH and lacunar infarct, respectively (Figure 2a, 2b). The highest quartiles of fibrinogen were associated with a significant increase in the risk for WMH (OR, 1.78; 95% CI, 1.20 to 2.65; P=0.004) and lacunar infarct (OR, 1.70; 95% CI, 1.09 to 2.65; P=0.02).
The logistic regression analysis showed that more advanced age, use of antihypertensive medication, lower body mass index, higher 24-hour ABP, and fibrinogen levels were significantly associated with silent cerebrovascular lesions (Table 2). Each 1-SD (62.0 mg/dL) increase in fibrinogen was significantly associated with a risk for silent cerebrovascular lesions (OR, 1.26; 95% CI, 1.09 to 1.46; P=0.001). When daytime or nighttime ABP or CBP was adapted to this model instead of 24-hour ABP, the trends were similar, although CBP was not significantly associated with silent cerebrovascular lesions (data not shown). When 24-hour ABP and CBP were adapted to the same model, the trends were similar, although only CBP was not significantly associated with silent cerebrovascular lesions (data not shown). The associations were also similar for WMH and lacunar infarct, respectively (data not shown).
Other biochemical factors were not significantly associated with silent cerebrovascular lesions in the multivariate analysis (P>0.08).
We also performed stratified analysis. Sex (men/women), age (<65 /≥65 years), and use of antihypertensive medication (treated/untreated) did not significantly interact the association between fibrinogen and silent cerebrovascular lesions (all P for interaction >0.2).
Association of 24-Hour ABP and Plasma Fibrinogen Levels With the Risk of Silent Cerebrovascular Lesions
Higher fibrinogen (≥328 mg/dL) and higher 24-hour ABP (≥135/80 mm Hg28) levels were independently associated with an increase risk for silent cerebrovascular lesions (Figure 3). Even when 24-hour ABP values were within normal range (<135/80 mm Hg), elevated fibrinogen levels were associated with an increased risk of silent cerebrovascular lesions. There were no significant interactions between 24-hour ABP and fibrinogen on the risk of silent cerebrovascular lesions (P>0.8). Fibrinogen and 24-ABP had additive effects on silent cerebrovascular lesions.
The present cross-sectional study found that 24-hour ABP and fibrinogen levels were significantly and independently associated with prevalence of silent cerebrovascular lesions, including WMH and lacunar infarct, in a comparatively large general population.
The findings of previous studies15–18 that investigated the association between fibrinogen and silent cerebrovascular lesions are inconsistent. For example, Schmidt et al15 found that higher fibrinogen levels are associated with WMH and lacunes in a multivariate analysis of 349 individuals. Meanwhile, in a population-based study of 3301 elderly individuals, Longstreth et al18 found that fibrinogen levels were not independently related to white matter grade in fully adjusted multivariate models. In this study, associations between fibrinogen and silent cerebrovascular lesions remained statistically significant even after adjustment for various confounding variables in the general population.
Recently, Sato et al demonstrated in a prospective study of Japanese subjects with no history of stroke and/or coronary heart disease that high plasma fibrinogen concentration was a predictor for risk of intraparenchymal hemorrhage but not of cerebral infarction.14 However, the clear mechanism responsible to the difference between cerebral hemorrhage and cerebral infarction was not described. The present study found that fibrinogen levels were associated with silent cerebrovascular lesions. Because silent cerebrovascular lesions constitute an independent predictor of the risk of cerebral infarction,1 it is possible that fibrinogen would be a risk of cerebral infarction. We are following-up the present subjects to clarify this question.
The exact mechanism by which elevated fibrinogen might contribute to WMH and lacunar infarct remains unknown. However, these lesions are considered to reflect ischemic small vessel disease. Fibrinogen triggers a variety of atherogenic processes such as endothelial injures.10 Thus, fibrinogen might promote atherogenesis not only in large vessels but also in small vessels. Elevated fibrinogen levels induce a state of hypercoagulability,6,7 and might reflect the progression of atherosclerosis. Such hemorheological impairments caused by increased levels of fibrinogen would aggravate cerebral hypoperfusion.
Hyperfibrinogenemia can be alleviated using drugs and by making lifestyle modifications, such as stopping smoking and starting to exercise.29 Fibrinogen levels are inversely associated with dietary consumption of seafood.30 Miura et al reported that higher intake of iron, sugar, and caffeine, in addition to obesity, account largely for higher fibrinogen levels.31 Several drugs reduce fibrinogen levels, including bezafibrate and ticlopidine.4,5,32 However, no reliable evidence yet supports the routine use of fibrinogen-lowering agents to reduce the risk of cerebrovascular diseases. Further study is needed to clarify this issue.
The present study indicated that ABP values are more closely associated with silent cerebrovascular lesions than with 2 measurements of CBP at one visit. This finding is consistent with those of a previous study.22 Furthermore, the present study discovered that 24-hour ABP and plasma fibrinogen levels are closely and independently associated with a risk of silent cerebrovascular lesions. Even when 24-hour ABP values were within normal range, elevated fibrinogen levels were associated with an increased risk of silent cerebrovascular lesions. These findings suggest that both factors are strong risk factors for silent cerebrovascular lesions.
Possibility of selection bias needs to be considered to generalize the present findings, because there were differences in age between the study subjects and those excluded (958 study subjects, 66.0±5.7 years; 216 excluded subjects, 69.2±7.0 years; P<0.0001). In addition, marked differences exist in the epidemiologies of cerebrovascular disease between Japan and US or European countries. Further research in other ethnic and cultural populations is needed to confirm the generalizability of our findings.
In conclusion, the present study demonstrated that 24-hour ABP and plasma fibrinogen levels are closely and independently associated with the risk of silent cerebrovascular lesions, suggesting that fibrinogen is an independent risk factor or predictor of silent cerebrovascular lesions.
Sources of Funding
This work was supported by grants for Scientific Research (15790293, 17790382, 18390192, and 18590587) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan; grant-in-aid for Japan Society for the Promotion of Science (JSPS) fellows (16.54041, 18.54042); Health Science research grants and Medical Technology Evaluation research grants from the Ministry of Health, Labor, and Welfare, Japan; Japan Atherosclerosis Prevention Fund; Uehara Memorial Foundation; and Takeda Medical Research Foundation.
Original received December 4, 2006; final version accepted December 21, 2006.
Vermeer SE, Hollander M, van Dijk EJ, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke. 2003; 34: 1126–1129.
Kobayashi S, Okada K, Koide H, Bokura H, Yamaguchi S. Subcortical silent brain infarction as a risk factor for clinical stroke. Stroke. 1997; 28: 1932–1939.
Kannel WB. Influence of fibrinogen on cardiovascular disease. Drugs. 1997; 54 (Suppl 3): 32–40.
Fisher M, Meiselman HJ. Hemorheological factors in cerebral ischemia. Stroke. 1991; 22: 1164–1169.
Iwamoto T, Kubo H, Takasaki M. Platelet activation in the cerebral circulation in different subtypes of ischemic stroke and Binswanger’s disease. Stroke. 1995; 26: 52–56.
Di Minno G, Mancini M. Measuring plasma fibrinogen to predict stroke and myocardial infarction. Arteriosclerosis. 1990; 10: 1–7.
Moons KG, Bots ML, Salonen JT, Elwood PC, Freire de Concalves A, Nikitin Y, Sivenius J, Inzitari D, Benetou V, Tuomilehto J, Koudstaal PJ, Grobbee DE. Prediction of stroke in the general population in Europe (EUROSTROKE): Is there a role for fibrinogen and electrocardiography? J Epidemiol Community Health. 2002; 56 (Suppl 1): i30–i36.
Kofoed SC, Wittrup HH, Sillesen H, Nordestgaard BG. Fibrinogen predicts ischaemic stroke and advanced atherosclerosis but not echolucent, rupture-prone carotid plaques: The Copenhagen City Heart Study. Eur Heart J. 2003; 24: 567–576.
Sato S, Iso H, Noda H, Kitamura A, Imano H, Kiyama M, Ohira T, Okada T, Yao M, Tanigawa T, Yamagishi K, Nakamura M, Naito Y, Shimamoto T. Plasma fibrinogen concentrations and risk of stroke and its subtypes among Japanese men and women. Stroke. 2006; 37: 2488–2492.
Breteler MM, van Swieten JC, Bots ML, Grobbee DE, Claus JJ, van den Hout JH, van Harskamp F, Tanghe HL, de Jong PT, van Gijn J, Hofman A. Cerebral white matter lesions, vascular risk factors, and cognitive function in a population-based study: The Rotterdam study. Neurology. 1994; 44: 1246–1252.
Longstreth WT Jr., Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA, Enright PL, O’Leary D, Fried L, for the Cardiovascular Health Study Collaborative Research Group. Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people: The Cardiovascular Health Study Stroke. 1996; 27: 1274–1282.
Sato S, Nakamura M, Iida M, Naito Y, Kitamura A, Okamura T, Nakagawa Y, Imano H, Kiyama M, Iso H, Shimamoto T, Komachi Y. Plasma fibrinogen and coronary heart disease in urban Japanese. Am J Epidemiol. 2000; 152: 420–423.
Lee SC, Park SJ, Ki HK, Gwon HC, Chung CS, Byun HS, Shin KJ, Shin MH, Lee WR. Prevalence and risk factors of silent cerebral infarction in apparently normal adults. Hypertension. 2000; 36: 73–77.
Sokolow M, Werdegar D, Kain HK, Hinman AT. Relationship between level of blood pressure measured casually and by portable recorders and severity of complications in essential hypertension. Circulation. 1966; 34: 279–298.
Shimada K, Kawamoto A, Matsubayashi K, Ozawa T. Silent cerebrovascular disease in the elderly. Correlation with ambulatory pressure. Hypertension. 1990; 16: 692–699.
Imai Y, Nagai K, Sakuma M, Sakuma H, Nakatsuka H, Satoh H, Minami N, Munakata M, Hashimoto J, Yamagishi T, Watanabe N, Yabe T, Nishiyama A, Abe K. Ambulatory blood pressure of adults in Ohasama, Japan. Hypertension. 1993; 22: 900–912.
Fazekas F, Kleinert R, Offenbacher H, Schmidt R, Kleinert G, Payer F, Rander H, Lechner H. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology. 1993; 43: 1683–1689.
Imai Y, Abe K, Sasaki S, Minami N, Munakata M, Sekino H, Nihei M, Yoshinaga K. Determination of clinical accuracy and nocturnal blood pressure pattern by new portable device for monitoring indirect ambulatory blood pressure. Am J Hypertens. 1990; 3: 293–301.
Association for the Advancement of Medical Instrumentation. Am national standards for electronic or automated sphygmomanometers. Washington, DC. AAMI Analysis and Review. 1987.
Guidelines Subcommittee of the Japanese Society of Hypertension. Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2004). Hypertens Res. 2006; 29 (Suppl): S1–S105.
Wannamethee SG, Lowe GDO, Whincup PH, Rumley A, Walker M, Lennon L. Physical activity and hemostatic and inflammatory variables in elderly men. Circulation. 2002; 105: 1785–1790.
Sato S, Iso H, Naito Y, Kiyama M, Kitamura A, Iida M, Shimamoto T, Komachi Y. Plasma fibrinogen and its correlates in urban Japanese men. Int J Epidemiol. 1996; 25: 521–527.
Miura K, Nakagawa H, Ueshima H, Okayama A, Saitoh S, Curb JD, Rodriguez BL, Sakata K, Okuda N, Yoshita K, Stamler J; for the INTERMAP and INTERLIPID Research Groups. Dietary factors related to higher plasma fibrinogen levels of Japanese-americans in Hawaii compared with Japanese in Japan. Arterioscler Thromb Vasc Biol. 2006; 26: 1674–1679.
Tanne D, Benderly M, Goldbourt U, Boyko V, Brunner D, Graff E, Reicher-Reiss H, Shotan A, Mandelzweig L, Behar S; the Bezafibrate Infarction Prevention Study Group. A prospective study of plasma fibrinogen levels and the risk of stroke among participants in the Bezafibrate Infarction Prevention Study. Am J Med. 2001; 111: 457–463.