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Keywords:

  • endothelial markers;
  • hemostatic factors;
  • racial/ethnic differences;
  • thrombogenicity

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References

Summary. Background: Hemostatic factors and endothelial markers may play some role in racial/ethnic differences in cardiovascular disease (CVD) rates. However, little information exists on hemostatic factors and endothelial markers across racial/ethnic groups. Objectives: To describe, in four American racial/ethnic groups (Caucasian, Black, Hispanic, and Chinese), mean levels of selected hemostatic factors and endothelial markers. Patients and methods: Multi-ethnic Study of Atherosclerosis baseline data were used (participant age: 45–84 years). Sex-specific analysis of covariance models, and t-tests for pairwise comparisons, were used to compare means of factors and markers. Adjustments were made for demographics and traditional CVD risk factors. Differences were significant at P < 0.05. Results: Blacks had the highest levels of factor VIII, D-Dimer, plasmin–antiplasmin (PAP), and von Willebrand factor, among the highest levels of fibrinogen and E-selectin (women only), but among the lowest levels of intercellular adhesion molecule 1 (ICAM-1), and, in men, the lowest levels of plasminogen activator inhibitor-1 (PAI-1). Whites and Hispanics tended to have intermediate levels of factors and markers, although they had the highest levels of ICAM-1, and Hispanics had the highest mean levels of fibrinogen and E-selectin (women only). Chinese participants had among the highest levels of PAI-1, but the lowest, or among the lowest, of all other factors and markers. No soluble thrombomodulin differences were observed. Conclusions: In this large cohort, hemostatic factor and endothelial marker mean levels varied by race/ethnicity, even after adjustment for traditional CVD risk factors.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References

Cardiovascular disease (CVD) rates vary greatly by country and race/ethnicity. In the USA, data have consistently shown that coronary heart disease (CHD) rates are highest among African Americans, followed by Caucasians, Hispanics, and Asians, respectively [1]. Racial/ethnic differences in CVD rates result from a myriad of factors, including possible differences in pathophysiology and genetics, and knowndifferences in exposure to traditional CVD risk factors, the sociocultural environment, economic status, diet, exercise, and access to healthcare. Although the major cardiac risk factors are similar across racial and ethnic groups, the relative weight attributed to each factor may differ [2].

Recent evidence has implicated hemostatic factors and endothelial markers in CVD [3–7], and these may play some role in racial/ethnic differences in CVD rates. However, little information exists on hemostatic factors and endothelial markers across various racial/ethnic groups. Most studies that have evaluated racial/ethnic-specific levels of hemostatic factors and endothelial markers have found differences [8–20], whereas other studies have reported mixed results [21–26].

The purpose of this study is to describe the distribution of selected hemostatic factor and endothelial marker concentrations in four racial/ethnic groups (Caucasian, Black, Hispanic, and Chinese). Describing normal plasma values of these factors and markers by race/ethnicity is important in order to establish whether there are differences between populations, as they may offer etiologic clues, and as they could possibly point to pharmacologic and lifestyle interventions that may improve levels of hemostatic factors and endothelial markers, thereby potentially reducing the risk of cardiovascular events.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References

The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective epidemiologic cohort initiated in July 2000 [27]. A specific objective of MESA is to assess race/ethnic, age and sex differences in subclinical and clinical CVD. Local institutional review committees approved the MESA protocol, and all subjects gave informed consent. In total, 6814 men and women between the ages of 45 and 84 years, all of whom were free of clinical CVD at baseline, were recruited in six US field centers. Of the original sample of 6814, 23 participants taking warfarin at baseline and 44 without blood samples were excluded.

Fibrinogen, factor (F) VIII, D-dimer and PAP were measured in the entire cohort at baseline, whereas plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (VWF), soluble thrombomodulin (STM) and E-selectin were measured in a random sample of 1000. Intercellular adhesion molecule 1 (ICAM-1) was measured in 2614 participants, including the random subset of 1000 and all participants enrolled before February 2003. The characteristics of the randomly selected subset do not differ from those of the entire MESA cohort.

The Laboratory for Clinical Biochemistry Research (University of Vermont, Burlington, VT, USA) measured fibrinogen with a BNTMII nephelometer (N Antiserum to Human Fibrinogen; Dade Behring Inc., Deerfield, IL, USA), FVIII coagulant activity using the Sta-R analyzer (STA-Deficient VIII; Diagnostica Stago, Parsippany, NJ, USA), D-dimer and VWF by immunoturbidometric methods on the Sta-R analyzer (Liatest D-DI; Liatest VWF; Diagnostica Stago, Parsippany, NJ, USA), PAP by a two-site enzyme-linked immunosorbent assay (ELISA) that utilizes two monoclonal antibodies [28], PAI-1 by a two-site ELISA [29], ICAM-1 by ELISA (Parameter Human sICAM-1 Immunoassay; R&D Systems, Minneapolis, MN, USA), STM by an enzyme immunoassay (Asserachrom Thrombomodulin; Diagnostica Stago, Asnières-sur-Seine, France), and E-selectin by a quantitative sandwich ELISA (Parameter Human sE-Selectin Immunoassay; R&D Systems, Minneapolis, MN, USA). Laboratory technicians were blinded to the race/ethnicity of the samples.

Only individuals identifying themselves, by self-report, as Spanish/Hispanic/Latino, African American or Black, Caucasian or White, or Asian of Chinese descent, were included in MESA. In this article, racial/ethnic groups are mutually exclusive, and are designated as Caucasian, Black, Hispanic, and Chinese. The 62 individuals who identified with multiple racial/ethnic groups were classified preferentially as Hispanic or Chinese, and then as Black. Caucasian participants were recruited from all study sites, whereas Blacks were recruited from Forysth County, NC, Chicago, New York, Baltimore, and Los Angeles, Hispanics from St Paul, New York, and Los Angeles, and Chinese from Chicago and Los Angeles.

Statistical analysis

All analyses were performed with sas (version 8.0; Cary, NC, USA: SAS Institute Inc.). Means and frequencies of unadjusted demographic characteristics, traditional CVD risk factors and hemostatic factor and endothelial marker levels were calculated by sex. Logarithmically transformed values were utilized to improve the normality of D-dimer, PAP, PAI-1, and STM. Arithmetic means of these log-transformed variables as well as geometric means are reported.

Owing to interactions between race/ethnicity and sex, sex-specific analysis of covariance models, and t-tests for pairwise comparisons, were used to compare means of hemostatic factors and endothelial markers. A first model was adjusted for demographic characteristics, including age, education (< high school, high school, some college, bachelor's degree, graduate or professional degree), individual income (quintiles of ‘household income/# supported’), and site. Our second model was aimed at determining whether racial/ethnic differences in hemostatic factors and endothelial markers were independent of traditional CVD risk factors. This model controlled for model 1 covariates, and additionally adjusted for major CVD risk factors, including current smoking (Y/N), current alcohol use (Y/N), body mass index (BMI) (continuous), leisure physical activity (MET min week−1; which is the sum of walking, conditioning, sports, and dance) (MET = work metabolic rate/resting metabolic rate; 1 MET = 3.5 mL kg−1 h−1), sedentariness score (MET min week−1; which is the sum of sitting or reclining, reading, knitting, sewing, etc.), diabetes status by ADA 2003 criteria (Y/N), hypertension status by JNC VI 1997 criteria (Y/N), statin use (Y/N), and current postmenopausal hormone use among women (Y/N). Lipids and C-reactive protein were not included in model 2, as they are biochemicals, and may be causally linked to the hemostatic factors and endothelial markers being assessed. Overall, differences between the base model (model 1) and the model adjusted for major CVD risk factors (model 2) were minimal. Results from the base model are discussed, and instances where adjustment for major CVD risk factors substantially impacted estimates are noted.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References

Men had higher crude levels of PAI-1, STM, and E-selectin, whereas women had higher crude levels of fibrinogen, factor VIII, D-dimer, and PAP (Table 1). No sex differences were found for ICAM-1 and VWF.

Table 1.   Distributions of demographic characteristics, major cardiovascular disease (CVD) risk factors, and hemostatic factor and endothelial marker levels, in men and women; the MESA study
VariableMenWomen
  1. *MET = work metabolic rate/resting metabolic rate; 1 MET = 3.5 mL kg−1 h−1. §Natural log. **Geometric mean. §§ Measured in 1000 participants. *§Measured in 2614 participants. HRT, hormone replacement therapy; PAP, plasmin–antiplasmin; PAI-1, plasminogen activator inhibitor-1; ICAM, intercellular adhesion molecule 1; VWF, von Willebrand factor; STM, soluble thrombomodulin.

Demographics
 n (%)3196 (47.1)3595 (52.9)
 Age, mean years (SD)62.1 (10.2)62.1 (10.3)
Race/ethnicity, n (%)
 Caucasian1253 (39.2)1359 (37.8)
 Black841 (26.3)1050 (29.2)
 Hispanic712 (22.2)773 (21.5)
 Chinese390 (12.2)413 (11.5)
Education, n (%)
 < High school515 (16.2)703 (19.6)
 High school489 (15.4)741 (20.7)
 Some college867 (27.2)1063 (29.6)
 Bachelor's degree606 (19.0)563 (15.7)
 Graduate or professional degree707 (22.2)513 (14.3)
Household income < $40 000 year−1, n (%)1308 (46.6)1984 (57.6)
Major CVD risk factors
 Smoked within past 30 days, n (%)467 (14.6)420 (11.7)
 Alcohol, current use, n (%)1995 (69.4)1741 (67.5)
 BMI, mean kg m−2 (SD)27.9 (4.5)28.7 (6.2)
 HRT, current use, n (%)1028 (31.7)
 Leisure physical activity, mean MET* min week−1 (SD)2633 (3242)2281 (2673)
 Sedentariness score, mean MET* min week−1 (SD)1620 (1068)1782 (1204)
 Diabetes, n (%)341 (10.7)335 (9.4)
 Hypertension, n (%)1367 (42.8)1676 (46.6)
 Statin use, n (%)468 (14.7)533 (14.8)
Hemostatic factor and endothelial marker levels (arithmetic mean and SD)
 Fibrinogen (mg dL−1)332 (70)360 (75)
 Factor VIII (%)157 (64)170 (68)
 Ln§ D-dimer−1.59 (0.95)−1.41 (0.89)
 D-dimer** (μg mL−1)0.200.24
 Ln§ PAP1.43 (0.39)1.55 (0.38)
 PAP** (nm)4.164.69
 Ln§ PAI-1§§2.97 (0.88)2.85 (0.93)
 PAI-1**§§ (ng mL−1)19.517.3
 ICAM-1*§ (ng mL−1)272 (79)275 (77)
 VWF§§ (%)138 (54)140 (58)
 Ln§ STM§§3.69 (0.46)3.38 (0.46)
 STM**§§ (ng mL−1)40.029.2
 E-selectin§§ (ng mL−1)58.4 (25.8)52.8 (24.7)

As shown in Table 2, fibrinogen levels varied across racial groups. Among men, Hispanics had the highest mean levels, followed by Blacks and Caucasians, and then Chinese, whereas among women, Blacks had the highest levels, followed by Hispanics, Caucasians, and Chinese, respectively. For example, in men, mean fibrinogen levels among Hispanics were 15 mg dL−1, or about one-quarter SD, greater than in Caucasians. In women, mean fibrinogen levels in Blacks were over one-half SD (41 mg dL−1) greater than in Caucasians, although this difference was attenuated somewhat with adjustment for traditional CVD risk factors. For both men and women, FVIII differed significantly across racial/ethnic groups, with mean levels being about one-quarter SD greater in Blacks than in other racial/ethnic groups. There were large differences among racial/ethnic groups for D-dimer, with Blacks having mean log D-dimer concentrations one-third SD greater, and Chinese having levels one-third SD lower, than Caucasians and Hispanics. Levels of PAP also varied across racial/ethnic groups, with Blacks having the highest values and Chinese the lowest. For example, the mean log PAP was about one-third SD greater in Black men, and one-half SD smaller in Chinese women, than in their Caucasian counterparts. The difference between Caucasian and Chinese women grew larger with additional adjustments. Among the races/ethnicities, differences in PAI-1 concentration, after base adjustments, were found only in men. Black men had a geometric mean PAI-1 concentration 6.2 ng mL−1, or nearly one-half log PAI-1 SD lower than in Caucasian men. After adjustment for CVD risk factors, racial/ethnic differences were also found in women. Following CVD risk factor adjustments, both Chinese men and women had PAI-1 concentrations notably higher than those in other races/ethnicities. These differences were, however, only significant in women, possibly because of the low number of Chinese men in the sample. Further analyses revealed that adjustment for BMI was responsible for the elevated PAI-1 concentrations among Chinese participants in model 2.

Table 2.   Mean hemostatic factor levels by race/ethnicity in men and women; the MESA study
FactorModelCaucasianBlackHispanicChineseP-value*
  1. WBHCLetters indicate significant differences between the races/ethnicities: W, Caucasian; B, Black; H, Hispanic; C, Chinese. *P-values for overall racial/ethnic difference in mean levels of hemostatic factors. §Geometric mean. Model 1: adjusted for age, education, individual income, and site. Model 2: adjusted for model 1 + smoking, current alcohol use, body mass index, leisure physical activity, sedentariness score, diabetes status, hypertension status, statin use, and current hormone replacement therapy use among women. PAP, plasmin–antiplasmin; PAI-1, plasminogen activator inhibitor-1; ICAM-1, intercellular adhesion molecule 1; VWF, von Willebrand factor; STM, soluble thrombomodulin.

Fibrinogen (mg dL−1) n = 2599n = 1864n = 1481n = 803 
 Men (n = 3184)Model 1329HC334HC344WBC317WBH< 0.0001
Model 2329H327H341WBC326H0.0009
 Women (n = 3560)Model 1343BH384WHC368WBC337BH< 0.0001
Model 2349BH369WC369WC349BH< 0.0001
Factor VIII (%)
 Men (n = 3182)Model 1153B172WHC150B153B< 0.0001
Model 2154BH169WHC147WB155B< 0.0001
 Women (n = 3560)Model 1162B185WHC166B159B< 0.0001
Model 2163B180WH164B164< 0.0001
D-dimer§ (μg mL−1)
 Men (n = 3185)Model 10.20BC0.23WHC0.20BC0.15WBH< 0.0001
Model 20.20BC0.22WHC0.20BC0.17WBH< 0.0005
 Women (n = 3561)Model 10.23BHC0.29WHC0.25WBC0.18WBH< 0.0001
Model 20.24BC0.27WHC0.23BC0.17WBH0.0002
PAP§ (nm)
 Men (n = 3120)Model 14.02B4.47WHC4.13B3.94B< 0.0001
Model 24.04BC4.43WHC4.13BC3.78WBH< 0.0001
 Women (n = 3485)Model 14.71BC4.98WHC4.62BC3.87WBH< 0.0001
Model 24.70BC5.04WHC4.72BC3.55WBH< 0.0001
       
PAI-1§ (ng mL−1) n = 458n = 210n = 229n = 99 
 Men (n = 418)Model 120.4B14.2WH20.1B18.40.0251
Model 220.7B13.4WHC20.7B27.5B0.0007
 Women (n = 552)Model 116.119.017.019.30.3275
Model 218.4C15.2C16.6C31.1WBH0.0407

As shown in Table 3, overall racial/ethnic differences were found in the concentrations of ICAM-1. Compared to Caucasians and Hispanics, mean ICAM-1 concentrations were about 0.40 SD lower in Blacks and three-fourths SD lower in Chinese. With additional adjustments, the difference between Caucasian and Chinese women became smaller. There was an overall difference in VWF levels for women but not for men. As compared to Caucasians, the mean VWF level was 0.40 SD higher in Black women. In model 2, Hispanic women had VWF concentrations one-third SD lower than those in Caucasian women. No associations between STM and race/ethnicity were found. E-selectin concentration varied by race/ethnicity in women but not in men. White women had mean levels lower than those in Black (0.40 SD), Hispanic (0.55 SD), and Chinese (0.16 SD) women. Adjustment for major CVD risk factors attenuated differences between Caucasians, Blacks, and Chinese, but increased differences between Hispanics and all other groups.

Table 3.   Mean endothelial marker levels by race/ethnicity in men and women; the MESA study
MarkerModelCaucasianBlackHispanicChineseP-value*
  1. WBHCLetters indicate significant differences between the races/ethnicities: W, Caucasian; B, Black; H, Hispanic; C, Chinese. *P-values for overall racial/ethnic difference in mean levels of endothelial markers. §Geometric mean. Model 1: Adjusted for age, education, individual income, and site. Model 2: Adjusted for model 1 + smoking, current alcohol use, body mass index (BMI), leisure physical activity, sedentariness score, diabetes status, hypertension status, statin use, and current hormone replacement therapy use among women. ICAM-1, intercellular adhesion molecule 1; VWF, von Willebrand factor; STM, soluble thrombomodulin.

ICAM-1 (ng mL−1) n = 1239n = 491n = 577n = 307 
 Men (n = 1145)Model 1285BC252WHC282BC233WBH< 0.0001
Model 2286BC247WH282BC235WH< 0.0001
 Women (n = 1469)Model 1288BC255WHC287BC229WBH< 0.0001
Model 2291BC254WH293BC253WH< 0.0001
VWF (%) n = 458n = 210n = 229n = 99 
 Men (n = 425)Model 1136B152W1401440.2033
Model 21361461381540.3468
 Women (n = 569)Model 1138B162WH130B143< 0.0001
Model 2142B162WH125B1350.0057
STM§ (ng mL−1)
 Men (n = 426)Model 141.838.542.036.60.2535
Model 242.438.339.936.20.2702
 Women (n = 568)Model 129.828.3H32.1B29.20.2348
Model 230.127.631.126.70.3720
E-selectin (ng mL−1)
 Men (n = 426)Model 157.061.8C56.950.8B0.2298
Model 257.362.756.454.20.4292
 Women (n = 570)Model 145.8BH55.3W59.1WC49.8H< 0.0001
Model 246.7H48.8H61.6WB50.50.0010

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References

In the MESA cohort, mean values of selected plasma hemostatic factors and endothelial markers varied by race/ethnicity, even after adjustment for major CVD risk factors. Specific variations and interactions by race/ethnicity and sex differed among the individual markers studied in this large, multiethnic population. Results of prior studies that examined racial/ethnic differences in the hemostatic factors and endothelial markers that were evaluated in this study are presented in Table 4.

Table 4.   Results of studies examining racial/ethnic differences in selected hemostatic factors and endothelial markers
Factor or markerAuthor, yearFinding
  1. PAP, plasmin–antiplasmin; PAI-1, plasminogen activator inhibitor-1; ICAM-1, intercellular adhesion molecule 1; VWF, von Willebrand factor; STM, soluble thrombomodulin.

FibrinogenPresent studyUS Hispanic ≥ US Black ≥ US Caucasian ≥ US Chinese
Meade, 1978 [21]UK black = UK white
Meade, 1986 [8]Gambian > European
Iso, 1989 [22]US white > Japanese in USA and Japan
Bao, 1992 [23]US black = US white
Folsom, 1992 [9]US black > US white
Tracy, 1992 [10]US black > US white
Green, 1994 [14]US black > US white
Cook, 2001 [17]UK white and UK South Asian immigrants > UK African immigrants
Matthews, 2005 [19]US black > US white, Hispanic, Chinese, Japanese
Factor VIIIPresent studyUS Black > US Chinese = US Hispanic = US Caucasian
Meade, 1978 [21]UK black > UK white
Meade, 1986 [8]Gambian > European
Iso, 1989 [22]US white = Japanese in USA and Japan
Folsom, 1992 [9]US black > US white
Tracy, 1992 [10]US black > US white
Green, 1994 [14]US black > US white
D-dimerPresent studyUS Black > US Hispanic = US Caucasian > US Chinese
Cushman, 2003 [20]US ‘non-white’ > US white
PAPPresent studyUS Black > US Caucasian = US Hispanic ≥ US Chinese
Sakkinen, 1999 [26]US white = Hawaii Japanese Americans
PAI-1Present studyUS Caucasian = US Hispanic = US Chinese ≥ US Black
Iso, 1993 [13]US white > Japanese in Japan
Festa, 2003 [18]US Hispanic > US white > US black
Matthews, 2005 [19]US Hispanic > US white, black, Chinese, Japanese
ICAM-1Present studyUS Hispanic = US Caucasian > US Black > US Chinese
Hwang, 1997 [24]US white > US black
Miller, 2003 [25]UK white and UK South Asian immigrants > UK African immigrants
VWFPresent studyUS Black > US Chinese = US Hispanic = US Caucasian
Iso, 1989 [22]US white = Japanese in USA and Japan
Folsom, 1992 [9]US black > US white
Green, 1994 [14]US black > US white
STMPresent studyUS Hispanic = US Caucasian = US Black = US Chinese
Salomaa, 1999 [16]US white > US black
E-selectinPresent studyUS Black = US Hispanic > US Caucasian = US Chinese
Hwang, 1997 [24]US black = US white
Miller, 2003 [25]UK white = African immigrants = South Asian immigrants

Of the factors we studied, fibrinogen has been most consistently associated with CVD events. In a recent meta-analysis, the hazard ratio for CHD per 1 g L−1 increase in usual fibrinogen level was 2.42 (95% CI: 2.24–2.60) [30]. In our analysis, racial/ethnic differences in fibrinogen levels varied somewhat by sex, with Hispanic men having higher and Chinese men having lower fibrinogen levels than Caucasian and Black men, and Black and Hispanic women having higher values than Caucasian and Chinese women. Most [8–10,12,14,15,19], but not all [17,21,23], previous studies have found higher fibrinogen levels in blacks than in whites, whereas another study found lower levels in Japanese than in whites [22]. D-dimer, which is a fibrin degradation product that reflects ongoing fibrin formation, is strongly and positively associated with CVD outcomes [31] and venous thrombosis [20]. In this study, Blacks had higher and Chinese lower D-dimer concentrations than Caucasians and Hispanics. The LITE Study has previously reported lower D-dimer concentrations among white participants than among ‘non-white’ participants, most of whom were black [20].

The associations of VWF with CVD have generally been positive [32], whereas associations of FVIII with CVD have been somewhat inconsistent, but suggestive of a positive association [3]. Given that FVIII circulates bound to VWF [4], it is not surprising that racial/ethnic patterns for FVIII and VWF were similar, with Blacks having levels greater than those in all other racial/ethnic groups, in both sexes. Our results are consistent with other studies that have found higher levels of FVIII [8–11,14,15,21] and VWF [9,11,14,15] among blacks as compared to whites, and no differences between levels of FVIII and VWF between individuals of Asian descent and whites [22].

PAP is a complex formed when plasmin is inactivated by antiplasmin. Relatively little is known about the epidemiology of PAP, although higher concentrations have been associated with CVD risk [26,33]. PAP concentrations were highest among Blacks and lowest among Chinese. A previous study [26] found no difference in mean PAP concentration between Japanese Americans and white Americans.

Differences in the concentration of PAI-1, which inhibits fibrinolysis by binding to tissue-type plasminogen activator, existed for men but not for women, with Black men having lower levels than all other racial groups. Previous studies evaluating PAI-1 levels by race/ethnicity have been somewhat inconsistent [13,18,19], but have tended to report higher levels among Hispanics. Prospective epidemiologic studies of PAI-1 have also been inconsistent, with associations generally being eliminated after multivariate adjustment [3].

The levels of ICAM-1, which is involved in leukocyte endothelial adherence and transmigration, were highest in Caucasians and Hispanics, followed by Blacks and Chinese, respectively. These results are consistent with the ARIC study and the Wandsworth Heart and Stroke Study, which reported lower ICAM-1 levels among blacks [24] and African immigrants [25] than among whites. ICAM-1 has been positively associated with CVD in most prospective epidemiologic studies [34].

Unlike a previous study, which found higher STM concentrations in whites than blacks [16], we found no significant differences in STM levels, although levels tended to be lower in Chinese than in other groups. STM is believed to indicate endothelial cell damage; however, its association with CVD is uncertain [16]. E-selectin is key to leukocyte rolling along the endothelium, and has been inconsistently associated with CVD [34]. We observed significant ethnic differences in women but not in men, with Hispanic women having the greatest levels, followed by Blacks and then Chinese and Caucasians. This is inconsistent with previous studies that reported no differences between blacks and whites [24,25].

In sum, differences in hemostatic factor and plasma endothelial marker levels seem to coincide with rank ordering of CVD risk across these racial/ethnic groups. Blacks generally had the most thrombogenic and dysfunctional endothelial profile, followed by Hispanics and Caucasians with similar levels, and then Chinese.

‘Racial/ethnic differences’ should be interpreted cautiously, especially in light of recent discussions questioning the interpretation of race/ethnicity classification in biomedical research [35,36]. True biological differences may exist among the groups. Alternatively, the variation that we found may arise from differential exposure to traditional CVD risk factors not controlled for in our analyses, the sociocultural environment, economic status, and/or dietary influences. However, racial/ethnic differences in hemostatic factors and endothelial makers were not well explained by traditional CVD risk factors, as differences before and after adjustment for these risk factors were small or non-existent.

Genetic differences might play some role. Genes have been identified that influence some biomarker levels, and racial/ethnic differences in gene frequencies do exist. For example, in a UK-based study, a common mutation of the β-fibrinogen promoter (G-455[RIGHTWARDS ARROW]A), which has been consistently associated with higher fibrinogen levels [37], was less common among immigrants of African origin than among whites or immigrants of South Asian origin. In that study, lower fibrinogen levels were also found among immigrants of African origin than among whites or South Asian immigrants [17]. It has also been speculated that drugs (i.e. angiotensin-converting enzyme inhibitors and statins) might exert differential effects on hemostatic factors and endothelial markers by race/ethnicity because of variations in gene frequencies [18]. Finally, venous thrombosis, which can be largely attributed to inherited hemostatic disorders, is relatively uncommon among Asians compared to other groups [38], and Asians have a lower incidence of the predisposing genetic disorders [39].

A limitation of our study was its cross-sectional design, hampering our ability to infer causality or true physiologic differences. Another limitation was that ICAM-1, PAI-1, VWF, STM and E-selectin were only measured in a subset of individuals; consequently, the study may have been underpowered to find weak but true associations in some instances. Conversely, given the large sample size of MESA, some of the observed associations, although statistically significant, may not be clinically relevant. Additionally, the MESA study sample may not be representative of the general population free of CVD. However, it seems unlikely that participation would have been related to hemostatic factor or endothelial marker levels, so the observed associations may not be biased.

To conclude, in this cross-sectional study, hemostatic factor and endothelial marker levels varied by race/ethnicity, even after adjustment for traditional CVD risk factors. Prospective research is needed to determine whether these ethnic-specific differences can account for ethnic-specific variations in rates of CVD. As additional research continues to clarify the relationships between hemostatic factors, endothelial markers, and CVD, opportunities may exist for the use of these novel risk factors in CVD risk screening and in the development of innovative interventions and therapeutic approaches.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References

The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa.nhlbi.org.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References

This research was supported by N01-HC-95159 through N01-HC-95166 from the National Heart, Lung, and Blood Institute.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
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