Alcohol consumption and plasminogen activator inhibitor type 1: The national heart, lung, and blood Institute family heart study

Alcohol consumption6and plasminogen activator inhibitor type 1:‘The National Heart, lung, and Blood Institute Family Heart Study Luc Djouss6, Ml&a James S. Pankow, PhD,b Donna K. Amett, PhD,= Yuqing Zhang, DSc,a Yuling Hong, MD, PhD,d Michael A. Province, PhD,d and R. Curtis Ellison, MDa Boston, Muss; Chapel HilJ NC; Mitaneupolfs, Mitan; and St Louis, MO

Background for thrombotic nary

PI asminogen

activator

cardiovascular

heart

disease

and

events. ischemic

stroke.

Methods

and Results

among

participants

1862

adjusting had

higher

high-density

neverdrinkers. 14.9,

lipoprotein

215

g/d

of alcohol,

and

16.40

g/d,

PAI-

levels

Conch!sions whereas

the findings

These

res$ts

suggest

Lung,

lifestyle

men

and

were

show increased

18.43, that PAI-

geometric

With

alcohol with

cigarettes,

consumption greater

Studies have reported positive associations between plasminogen activator inhibitor type 1 (PA&l) and cardiovascular diseases.‘-7 PAI- plays a key role in fibrinolytic activity: PAI- is a rapid inhibitor of tissue plasminogen activator, which converts plasminogen to plasmin, leading to degradation of fibrin on the vascular wall. Experimental and observational studies have shown that alcohol consumption is associated with increased PAI- levels,~l* which suggests that alcohol consumption would decrease fibrlnolysis. However, prior studies have not assessedthe dose-response relation of alcohol to PAI-1. Because protective effects of alcohol on coronary heart disease (CID) and stroke have been substantial with light to moderate alcohol consumption, it is conceivable that the relation of alcohol to PAI- may

From the ‘Gxtion of Preventive Medicine and Epidemiology, Evans Deportment of Medicine, Boston University School of Medicine; the Qeportment of Epidemiology, University of North Carolina; the Qivision of Epidemiology, University of Min. nesota; and the Qvision of Biostotirtics, Washington University School of Medicine. Supported by contracts NO I-HC.25 104, NO I-HC-25 105, NO I -HC-25 106, NO I-HC-25 107, NO I -HC-25 108, and NO I -HC-25 IO9 from the Notional Heart, Lung, and Blood Institute, Bethesda, Md. Submitted May 17, 1999; accepted September 4, 1999. Reprints not available from authors. Copyright 0 2000 by Mosby, Inc. 0002-8703/2000/$12.00 + 0 4/l/102912 doi: IO. 1067/mhj.2000. IO29 12

and

Study.

16.20,

intake.

alcohol

24.02, g/d

(Am

2000;

category

were

29.46

ng/mL, with

PAIleaner,

compared

10.77, into

model,

were

fiber

divided

is not associated HeartJ

and

a regression

1.5 to 4.9,

women and

fitted

coro-

on PAI-1.

to 1.4,

the top category

17.27,

of alcohol

less dietary

of 0.1

among

is important against

consumptidn

We intake

consumed

drinkers

levels

except

up to 14.9 alcohol

of alcohol

Heart

which protect

doses

levels

and

current

PAI-

categories

15.19,

activity, may

in the highest

mean

similar

15.77,

Family

Individuals

in fibrinolytic consumption of moderate

different

Institute

exdrinkers,

adjusted

the effects

between

more

role

alcohol

about

Blood

smoked

of never-drinkers, respectively.

moderate

is known

factors.

levels,

) pI a y s a key

that

the association

Heart, and

1 (PAI-

little

assessed

multivariate

ng/mL,

among

suggested

cholesterol

categories

1 1.2 1, 1 1.28, 230

and

We

metabolic,

For drinking

type

been

However,

of the National

for anthropometric,

inhibitor

It has

with

5.0

9.41, 15.0

to 9.99,

to 29.9

and

respectively. increased

PAI-1,

139:704-9.)

differ according to the amount of alcohol consumed. We used data collected in the National Heart, Lung, and Blood Institute (NI-ILEQ Family Heart Study to evaluate the relation between different levels of alcohol consumption and PAI- among women and men.

Methods Study

population

The NHLBI FamilyHeart Study is a multicenter, populationbased study designed to identify and evaluate genetic and nongenetic determinants of CHD, preclinical atherosclerosis, and cardiovascular risk factors. A detailed description of the methods and design has been published. I3 The individuals described in the current report represent members from families that had been chosen at random from previously established population-based cohort studies (referred to as “parent studies”): The Framingham Heart Study in Framingham, Mass; the Atherosclerosis Research in Communities (ARK) Study cohorts in Forsyth County, NC, and Minneapolis, Minn; and the Utah Health Family Tree Study in Salt Lake City, Utah. From 1993 to 1995, groups of individuals participating in each of the parent studies were selected at random and invited to furnish an updated family health history that contained information on their parents, children, and siblings. Of 4679 individuals contacted, responses were obtained from 3 150 (67%); their other family members were then contacted, and selfreported health data were obtained from a total of 22,908 individuals (86% of those contacted).

American Heart Journal Volume 139, Number 4

From the families responding to the health questionnaire, 588 were chosen at random, and all members of these families were invited to come to 1 of the 4 study clinics for an approximately Qhour clinical evaluation. The evaluation included a detailed medical and lifestyle history, obtained through interview. All interviewers were trained centrally and required periodic certification; standardization of interviews was facilitated by periodic review of taped interviews and by frequent circulation of the distributions of responses obtained by different interviewers and different centers, with prompt corrective actions taken when nonstandardized interviewing techniques were detected. The study protocol was reviewed and approved by the institutional review board at each of the participating institutions. Blood collection and assays All participants were asked to fast for 12 hours before arrival at the study center. Blood samples for PAL-1 antigen were drawn between 7 and 11:30 AM from the antecubital vein of seated participants; sodium citrate Vacutainers were used (citrate/blood ratio of 1:9). For lipids, glucose, and insulin, Vacutainers without additives were used. Blood samples were spun at 2OOOg for 10 minutes at 4X, and sera and plasma were stored at -70°C. PAl-1 antigen was measured by enzyme-linked immunosorbent assay,t4 with reagents from Diagnostica Stago Asserachrom PAL-1 kit No. 00577 (Diagnostica Stago, American Bioproducts, Parsippany, NJ). Serum insulin was measured by radioimmunoassay method (Diagnostic Products Corp, Los Angeles, Calif). All samples were processed at the collaborative study’s clinical laboratory at the Fairview-University Medical Center in Minneapolis, Minn. Other variables Alcohol consumption data were collected during the clinic interviews by asking whether the person “ever consumed alcoholic beverages” or “presently drinks alcoholic beverages at all,” and, if so, participants were asked specifically about the number of drinks per week of each type of beverage. For the purposes of the study, a “drink” was defined as a 360-mL bottle or can of beer containing 12.6 g of alcohol, a 12OmL glass of wine containing 13.2 g of alcohol, or a 37.5-n& shot of 8@proof spirits containing 15 g of alcohol. Total alcohol was computed as the sum of the 3 beverage-specific alcohol contents. Because alcohol is Lighter than water, we used 1 mL of alcohol as the equivalent of 0.886 g to convert alcohol in grams. The reported alcohol data were highly correlated with serum gamma-glutamyltranspeptidase measured on a subsample (r=O.51,Pc.O001 amongdrinkers). Dietary information was collected by means of a sta&administered semiquantitative food frequency questionnaire.ts~t6 From the food frequency questionnaire, intake of specific nutrients was computed by multiplying the frequency of consumption of an item by its nutrient content. Nutrient content was derived from a database program based on US Deparmrent of Agricukure sources. Information on cigarette smoking was obtained by interview during the clinic visit. Oral contraceptive use or hormone replacement therapy was assessed with the use of a reproductive history questionnaire and medication inventory. Frequency and duration of strenu-

Dioussb

et al

ous, moderate, and light physical activity during the previous year were estimated from a physical exercise questionnaire. Participants wore scrub suits during the collection of anthropo metric data. A balance scale was used to measure body weight, and height was measured with a wall-mounted vertical ruler. Cardiovascular disease was assessed from the medical history and a 1Zlead electrocardiogram. Prevalent CHD was defined as a self-reported history of myocanlial infamtion, percutaneous transluminal coronary angioplasty or coronary artery bypass grafting, or the presence of Q waves (Minnesota codes 1. l1.2) on the resting 12-lead electrocardiogram. Statistical analysis Exclusion criteria were as follows: Of the 2310 participants from the random sample who had a clinic examination at one of the participating centers, 448 were excluded from the analysis for the following reasons: (1) 142 participants because fasting time was cl2 hours; (2) 117 participants with CHD (because PAL-1 is an acute-phase protein and may be elevated in individuals with prevalent CHD,” the geometric mean of PAL-1 was 20.50 ng/mL among individuals with CHD compared with 13.60 ng/mL among those without CHD); (3) 107 with probable errors on food frequency questionnaires [(i) answers on the food frequency questionnaire judged by the interviewer as unreliable, (ii) 218 items left blank on the dietary questionnaires, or (ii) energy intake outside a priori ranges (acceptance range: 3347.2 to 17,572.8 kJ for men’s and 2510.4 to 14,644 kJ for woment6)]; (4) 80 with missing alcohol data; and (5) 2 missing an electrocardiogram. Because PAL-1 distribution was positively skewed (coeffrcient of skeweness 2.7 for women and 2.4 for men), we used the natural logarithm to transform PAL-1 to ln(PAI-1). Because women consumed less alcohol than men, we conducted sex-specific analyses. We created the following categories of alcohol consumption: never-drinkers, exdrinkers, and current intake of 0.1 to 1.4, 1.5 to 4.9, 5.0 to 14.9, and 215 g/d for women and never-drinkers, exdrinkers, and current intake of 0.1 to 1.4, 1.5 to 4.9, 5.0 to 14.9, 15 to 29.9, and 2 30 g/d for men. We used analysis of covariance to assess the association between alcohol intake and PAL-l. The crude model included PAL-1 as the dependent variable and dummy variables for alcohol consumption, with neverdrinkers used as the referent category. The adjusted model accounted for potential confounders: age, age2, body mass index, waist-to-hip ratio, triglycerides, smoking, dietary fiber, high-density lipoprotein (HDL) cholesterol, homeostasis insulin resistance index [(insulin x gh1cose)/22.5],~* physical activity, and estrogen usage for women. We used a bootstrap method in multivariate regression to correct the variance for the correlation among family members. The bootstrap, which randomly selects 1 individual per family for modeling, was run over 300 replications. The a level was set at 0.05 for statistical significance. All analyses were performed with the use of SAS software.‘9

Results Of the 1862 individuals included in the analysis, 1031 were women and 831 were men. The mean age was 52.3 years (range 25 to 91) for women and 50.6 years

705

Amerlcon

706

Djousse

et 01

~~i’&l&‘C~‘batiline . .,

chb~ctetistics

of women

in the NHCBI

Family

Heart

Study

by level

of alcohol

Drinking Never-drinkers (n = 308)

Characteristic Alcohol (g/d) Age at examination (y) Body moss index (kg/m21 Waist-to-hip ratio Dietary fiber (g/d) HDL cholesterol (mmol/L) Triglycerides (mmol/L) Homeostasis insulin resistance Smoking Never-smokers Former smokers Current smokers (cigarettes/d) 115 >15 Physical activity (min/d) 0 1 to15 16to30 31 to60 >60

55.9 27.9 0.88 18.3 1.4 1.6 2.8

index’

Values are mmm i SD or percentoger. ‘Homeostasis insulin resistance index - [Fasting insulin (pU/ml]

TabI&

‘II. Baseline

characteristics

among

consumption

categories Exdrinkers (n = 217)

+ 13.4 f 5.8 f 0.09 ztz 7.7 IL 0.4 + 0.9 + 3.2

51.B+ 27.3 + 0.88 + 17.4 + 1.4 f 1.6f0.9 2.7 f

~1.4 g/d (n = 221) 1 .o 49.7 27.4 0.87 17.8 1.5 1.5 2.3

13.6 5.8 0.09 8.2 0.4 3.5

men in the FjHLBl

64.1 23.0

60.0 29.0

0.6 1 .o

6.9 6.0

7.0 4.0

11.4 41.6 22.4 20.1 4.5

9.7 42.6 20.8 17.6 9.3

9.5 34.4 22.2 22.2 11.8

Family

Heart

Study

by level of alcohol

consumption

l

Homeostasis

Exdrinkers (n = 184)

11.4 g/d (n = 109) 1 .o f 0.0

52.4 27.9 0.95 20.3

index’

I? 13.4 f 4.6 f 0.06 f 9.2 1.1 f0.2 1 .B + 1 .O 3.3 f 4.2

insulin resistance index - [Fasting insulin (~U/ml]

0.0 13.6 6.3 0.08 8.2 0.4 0.8 2.7

X Fasting glucose (ppol/L]]/22.5.

Neverdrinkers (n = 180)

Alcohol (g/d) Age at examination (y) Body mass index (kg/m21 Waist-to-hip ratio Dietary fiber (g/d) HDL cholesterol (mg/dL) Triglycerides (mmol/L) Homeostasis insulin resistance Percentage Smoking Never-smokers Former smokers Current smokers (cigarettes/d) 115 >15 Physical activity (min/d) 0 1 to15 16to30 31 to60 >60

f IL rk f + + f f

95.1 3.2

Drinking Characteristic

Heart Journal April 2000

51.4f 28.0 0.96 18.3 1.1 1.7f 3.1

94.4 4.4

0.0

13.9 f 5.2 f 0.07 f 8.2 i:o.2 1.3 & 2.3

49.4 39.8

52.6 28.6 0.97 18.0 1.1 l.Bf 3.5

f 13.2 f 4.8 f 0.06 +I 8.0 f0.3 1.2 f 4.8

54.1 33.0

1.5 to 4.9 g/d (n = 62) 3.1 f 1.0 51.8 f 12.7 27.1 f 3.8 0.96kO.12 18.4 f 8.6 1.1 f0.2 1.5 + 0.8 4.6 f 16.3

58.1 37.1

1.2

2.5 8.5

10.1

3.2 1.6

10.6 31.7 24.0 17.7 16.0

14.4 25.4 22.9 22.4 14.9

9.2 29.4 26.6 18.3 16.5

9.8 32.8 8.2 29.5 19.7

x Fasting glucose (mmol/L]]/22.5.

2.8

categories

American Heart Journcl Volume 139.Number4

1.5 to 4.9 (n=lOO)

g/d

Dioussk

5.0to

14.9

(n = 123)

g/d

215 g/d (n -62)

3.1 f 1.1 49.2 f 13.9 25.9f5.8 0.87kO.08 16.4 f 6.3 1.5 k 0.4 1.4 f 1.2 2.1 f 1.7

9.3 + 2.8 50.3 f 14.2 26.1 f 5.2 0.87f0.07 17.7f 7.0 1.6f0.4 1.3kO.8 1.9f 1.5

27.2 + 12.8 54.6f 11.7 25.5 55.5 0.89f0.11 15.2 + 7.6 1.8 f 0.6 1.4 f 0.7 1.9f 1.4

55.0 34.0

37.4 44.7

25.8 38.7

10.0 1.0

12.2 5.7

16.1 19.4

14.0

6.5 35.0 23.6 30.9 4.1

16.1 33.9 24.2 16.1 9.7

38.0 20.0 21.0 7.0

et01

(range 25 to 91) for men. The range of alcohol intake was 0 to 69 g/d for women and 0 to 97 g/d for men. Geometric mean PAI- level was 10.65 and 18.36 ng/mL for women and men, respectively. Tables I and II show the sex-specific baseline characteristics according to categories of alcohol consumption. Participants with higher alcohol consumption tended to be younger and leaner and tended to consume less dietary fiber, smoke more cigarettes, and have higher HDL cholesterol than never-drinkers. The homeostasis insulin resistance index was suggestive of a decrease across categories of alcohol intake among women but did not show a clear pattern among men. There was no clear pattern in physical activity levels across drinking categories in either sex. From the neverdrinkers through the highest category of alcohol consumption, geometric means of PA&l were 10.77, 9.41, 9.99, 11.21, 11.28, and 16.40 ng/mL, respectively, among women and 18.43, 15.77, 15.19, 16.20, 17.27, 24.02, and 29.46 ng/mL, respectively, among men; these values were adjusted for age, agea, body fatness, homeostasis insulin resistance index, triglycerides, HDL cholesterol, dietary fiber, smoking, exercise, and estrogen (for women). As shown in Table III, compared with never-drinkers, the corresponding multivariate regression coefficients for ln (PA&l) were either negative or close to zero for alcohol consumption S14.9 g/d but positive for consumption of 215 g/d.

Discussion

5 to

14.9 g/d 118)

15 to 29.9 g/d (n = 100)

9.6f2.7 47.8 f 14.5 27.1 f3.5 0.95 kO.06 17.2 f 9.5 1.2 f 0.3 1.7f 1.2 2.4f 1.8

21.9k4.0 47.3 f 15.2 26.7f 3.7 0.93 + 0.06 16.6 + 8.7 1.3kO.3 1.5 + 1.0 2.9f5.4

44.1 39.0

39.0 38.0

20.5 44.9

7.6 9.3

11.0 12.0

10.3 24.4

10.2 16.9 23.7 30.5 18.6

6.0 21.0 19.0 29.0 25.0

10.3 23.1 21.8 21.8 23.1

(n-

230 g/d (n = 78) 47.8 49.1 27.7 0.98 15.2 1.3 2.0 3.8

f 16.7 f 13.5 f 4.2 f0.08 zk 7.4 f 0.4 + 1.8 f5.6

Normal hemostasis is maintained through a balance between coagulation and the fibrinolytic system. It has been shown that alcohol increases surface-localized fibrinolytic activity in cultured endothelial cells.20 However, Tran-Thang et a12i reported significantly elevated PAI- (which would decrease fibtinolysis) among patients with Liver deficiency caused by long-term alcohol consumption. In a randomized controlled trial, Hendriks et als reported a 283% increase of postprandial PAIafter consumption of 40 g of alcohol with dinner. Other investigators also have found a positive association between alcohol consumption and PAI-l.p12 In the current study, we found that alcohol consumption up to 14.9 g/d (approximately 1 drink per day) was not associated with an increased PAI- level among women or men. Although we had relatively small numbers of individuals consuming 15 g/d or more of alcohol, our findings of increased PAI-1 levels among such individuals are consistent with previous reports.9Ti2 These findings were not altered after adjustment for metabolic, lifestyle, and anthropometric parameters. Our findings of no increased PAI-1 with light to moderate alcohol intake are consistent with results of previous studies that have shown an inverse relation between moderate alcohol consumption and

707

American

708

Diouss6

T~b;b~lll.

April 2000

Regression

coefficients

(95%

confidence

it?tetervals) of In(PAI-1)

and

alcohol

consumption

in the NHLBI

Regression Alcohol categories

intake (g/d)

Women Neverdrinkers Exdrinkers S1.4 1.5 to 4.9 5.0

Heart journal

et 01

to 1 h.9

n

model

’

1

1 -0.23 -0.22

(-0.44, (-0.43,

-0.18

(-0.48,0.12)

-0.30 0.08

(-0.54, (-0.18,

-0.06) 0.33)

(-0.28,

0.15)

100 123

Study

Multivariate model

and

217 221

Heart

coefficient

308

62

215

Age age%djusted

Family

-0.12

-0.02) -0.01)

(-0.28,0.05) (-0.21,0.13)

-0.04 -0.00 0.05

(-0.22,

0.54

(0.28,

0.22)

(-0.15,

0.25) 0.79)

Men

.

Never-drinkers Exdrinkers

180 184

11.4

109 62

1.5 lo 4.9 to 14.9

5.0

15.0 530

to 29.9

118 100 78

1

1 -0.06 -0.06 -0.2 -0.18 -0.01

-0.14

(-0.27,0.16)

(-0.26,

(-0.26,0.25)

-0.05 0.28

(-0.23, 0.12) (0.06,0.51)

(0.16,0.63)

0.48

1 (-0.47,0.05) (-0.40,0.04)

0.40

‘Regression coefficients adiusfed for oge, age2, body mass index, waisuc-hip ratio, homeosbsis insulin resistance index, Wxylglycerol, activity, smoking, and estrogen (for women). (In)PAI-1 is the natural logarithmic honskrmed PAI-I.

myocardial infarction,22-24 carotid atherosclerosis,25 and ischemic stroke.26 The findings of this study are not likely to be the result of recall biases; study participants were not aware of their PAI-1 levels (which could lead to differential reporting of drinking habits). In addition, standardized questionnaires were used to minimize interinterviewer variability. The large sample size of this study and the random selection of participants are strengths of this report. Given the cross-sectional nature of the data, the issue of residual confounding and the inability to determine whether the change observed in PAI-1 preceded or was a consequence of alcohol intake is a major limitation of this study. In summary, this study shows that alcohol consump tion up to 14.9 g/d is not associated with an increase of plasma PAI-1 concentration among women or men. Our data support previous findings of increased PAI-1 with greater alcohol consumption. Previous reports have demonstrated that light to moderate alcohol consumption is inversely associated with coronary heart disease and ischemic stroke through its effects on HDL choles terol, coagulation factors, and other mechanisms. The current study suggests that as long as the intake does not exceed 1 drink per day, an increase in PAI- from alcohol consumption should not be a concern. This study is presented on behalf of the Investigators of the NHLBI Family Heart Study. Participating Institutions and Principal Staff of the study are as follows: Forsyth County/University of North Carolina/Wake Forest University: Gerard0 Heis!,

(-0.33,0.05) (-0.38, -0.03)

-0.20 -0.03

0.19)

(0.24,

0.73)

HDL cholesterol. dietary fiber, physical

Stephen Rich, Greg Evans, James Pankow, H.A. Tyroler, Jeannette T Bensen, Catherine Paton, Delilah Posey, and Amy Haire; University of Minnesota Field Center: Donna K. Amett, Aaron R. Folsom, Larry Atwood, James Peacock, Greg Feitl; Boston University/Framingbam Field Center: R. Curtis Ellison, Richard H. Myers, Yuqing Zbang, Andrew G. Bostom, Luc Djoussg, Jemma B. Wilk, and Greta Lee Splansky; University of Utah Field Center: Steven C. Hunt, Roger R. Williams (deceased), Paul N. Hopkins, Jan Skuppin, and Hila y Coon; Coordinating Center, Washington University, St Louis: Michael A. Province, D.C. Rao, Ingrid B. Borecki, Yuling Hong, May Feitosa, Jeanne Casbman, and Avril Adelman; Central Biocbemisty Laborato y, University of Minnesota: John H. Eckfeldt, Greg RJjnders, Catberine Leiendecker-Foster, and Michael Y. Tsai; Central Molecular Laborato y, University of Utah: Mark F. Leppert, Jean-Marc Lalouel, Tena Varvil, Lisa Baird; National Heart, Lung, and Blood Institute, Project Office: Pbylliss Sbolinsky, Millicent Higgins (retired), Jacob Keller (retired), Sarah Knox, and Lorraine Silsbee.

References 1. Homsten

A, Wolldius

inhibitor Lancet

in plasma:

A, et 01. Plasminogen

for recurrent

myocordiol

activator infarction.

1987;2:3-9.

2. Cortelloro turnover

G, Szamosi risk factor

M, Cofrancesco

E, Boschetti

and high PAL1 activity

atherosclerotic 1993;13:1412-7.

potienb:

C, et 01. Increased

as predictors

o case-control

study.

fibrin

of ischemic

events

Arterioscler

Thromb

in

Amercon Heart Journcl Volume 139. Number 4

Djoussd

3. Held C, Hiemdahl cardiovascular treated

P, Rehnqvist

prognosis

with verapamil

in the blood

variables

with stable angina

or metoprolol:

nosis study in Stockholm. 4. Poramo JA, Colucci

N, et al. Fibrinolytic

in patients Circulation

results from the Angino

15. Stein AD, Shea S, Bosch semiquantitative

Prog-

with coronary

artery

activator

disease.

inhibitor

16. Rimm EB, Giovonnucci

BMJ 1985;

validity

29 1:573-4. 5. Nilsson

TK, Johnson

of myocordial 6. Olofsson

infarction.

80,

Dahlen

of plosminogen in plasma disease.

Thromb G, Nilsson

activator

of patients

inhibitor

fibrinolytic

Res 1987;48:62 TK. Evidence

l-30. levels

and tissue plasminogen

with angiographicclly

verified

activator

coronary

artery

C, Jager

inhibitor

1988;66(suppl 8. Hendriks

R, Huber

in patients

pectoris.

Klin Wochenschrift

U, et al. Effect of moderate

meal on fibrinolytic

factors.

dose

20. Aikens

BMJ 1994;

coagulation

and fibrinolytic

Fibrinolysis

1998;9:39-45.

factors: a controlled

T, Kojima Y, Tokahoshi

hypertension inhibitor-l

and obesity level in plasma.

18, et al. The effects of alcohol

fibrinolysis

due to high plasminogen 1993;43:22

in

activator

Hoemost

Japanese

and Caucasian

men and women.

JP, Nicaud

factors and alcohol consumption in France and Northern Atherosclerosis 1995; 1 15:225-32. 13. Higgins

M, Province

objectives

and design.

M, Heiss G, et al. NHLBI Am J Epidemiol

1996;143:

Blood

antibody-based

1988;71:220-5.

enzyme-linked

risk

NC:

endothelial

surface-

cells. Alcohol

or infectious

consumption

G, et al. Plasminogen

inhibitors

Et, Willett

octivo-

in liver deficiencies

hepatitis. Thromb

WC, et al. Prospective

and risk of coronary

disease

caused

Haemost

1989;

study of

in men. Lancet

MJ, Colditz alcohol

GA, Willett

WC,

consumption

N Engl J Mad

24. Rimm EB. Alcohol consumption habits may be more important

et al. A prospective

and the risk of coronary 1988;3

and coronary than just good

study disease

19;267-73. heart disease: good wine. Am J Epidemiol

1996: 143: 10960. Study:

25.

Kiechl S, Willeit atherosclerosis:

12 19-28.

immunosorbent

edition, vol 2. Cary,

26.

J, Prolong

by chronic alcoholism 62:65 1-3.

of moderate

14. de Clerck PJ, Alessi MC, Verstreken M, et al. Measurement of plasminogen activator inhibitor 1 in biologic Huids with Q murine monoclonal

in man. Diabetologia

1991;338:464-Et.

Ireland.

Family Heart

1 and

HE, et al. Ethanol increases

activator

23. Stampfer

Thromb

V, et al. Cardiovascular

inhibitor

1: 147 l-8.

C, Fassel-Felley

and stroke in women.

P, Combou

6,4th

in cultured

tars and plasminogen

alcohol

1993;70:475-80.

12. Marques-Vidal

activator

Am J

1993;70:138-43.

p. 1071-l

activity

22. Rimm EB, Giovannucci

l-8.

1 1. lso H, Folsom AR, Koike KA, et al. Antigens of tissue plasminogen activator and plosminogen activator inhibitor-l : correlates in nonsmoking

Hoemost

RL, Greneti

fibrinolytic

2 1. Tran-Thang

trial. Blood Coagul

M, et al. Impaired

Jpn J Physiol

on

food

male health professionals.

Version

Inc; 1989.

Clin Exp Res 1997;2 V, Puddey

and

semiquantitative

and insulin concentrations

ML, Benza

localized

308: 1003-6. 9. Dimmitt SE, Rockic

10. Urano

glucose

1985;28:412-9. 19. SAS/STAT User’s Guide. SAS Institute,

J, Wierik

with evening

Am J

MJ, et al. Reproducibility

Plaspinogen

Thromb

dietary

children.

18. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting

X11):59-61.

HF. Veenstra

of alcohol

with ongino

acti-

I, Alessi MC.

atherothrombosis.

plasma

K, et al. Levels of plosminogen

among 1 14-26.

of the Willett

and 24-hour

of preschool

self-administered

questionnaire 1992;135:1

17. Juhan-Vogue

for increased

questionnaire

Et, Stampfer

of an expanded

frequency Epidemiol

system in survivors

Eur Heart J 1989;10:77-82.

7. Korninger vator

0. The extrinsic

CE, et al. Consistency

food frequency

recalls in estimating nutrient intakes Epidemiol 1992; 135:667-77.

1997;95:2380-6.

M, Collen D, et al. Plosminogen

of patients

and

pectoris

et al 709

ossoy.

Bruneck 26. Sacco

J, Rungger

G, et al. Alcohol

what is the relation?

Study. Stroke

28 1:53-60.

alcohol

and

results from the

1998;29:900-7.

RL, Elkind M, BodenAlbala

moderate

consumption

Prospective

consumption

N, et al. The protective on ischemic

stroke. JAMA

effect of 1999;