© 1996 American Heart Association, Inc.
Articles |
Association of Chronic Stress With Plasminogen Activator Inhibitor–1 in Healthy Middle-aged Men
From the Departments of Psychology (K.R., L.K.-J.) and Clinical Chemistry (A.H.), University of Helsinki, and the Wihuri Research Institute (R.L.), Helsinki, Finland.
Correspondence to Dr K. Räikkönen, Department of Psychology, University of Helsinki, PO Box 4, SF-00014 Helsinki, Finland.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Abstract The effect of chronic stress on tissue-type plasminogen activator (TPA) and plasminogen activator inhibitor–1 (PAI-1) antigens was studied in 69 healthy middle-aged men. Chronic stress, defined as feelings of fatigue, lack of energy, increased irritability, and demoralization, was positively associated with plasma concentrations of PAI-1 antigen but was unrelated to TPA. The association remained unaltered after controlling for age, smoking, alcohol consumption, and physical activity but became nonsignificant after further controlling for abdominal obesity, BMI, and serum insulin and triglyceride levels. This attenuated association implies that the relationship between vital exhaustion and PAI-1 may be secondary to the effects of the metabolic variables. Thus, the present study shows that long-term stress affects the fibrinolytic system and suggests that obesity and insulin and triglyceride concentrations, which are closely correlated with the fibrinolytic parameters, may mediate the association. These findings are consistent with the hypothesis that chronic stress causes increased synthesis of PAI-1, thus promoting the risk for atherothrombotic disease by decreasing the likelihood of spontaneous fibrinolysis and increasing the likelihood of fibrin deposition.
Key Words: stress • fibrinolysis • PAI-1 • vital exhaustion • psychosocial
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Blood coagulation and fibrinolysis are processes intimately involved in acute thrombus formation and may also promote the long-term inflammatory atherosclerotic process of arteries1 2 3 that underlies thrombosis. Furthermore, several conventional factors that promote atherosclerosis, such as dyslipoproteinemia, hyperinsulinemia, and central obesity, interact with the measures of blood coagulation and fibrinolysis.2 3 4
Evidence from various sources shows that mental stress and catecholamines also interact with hemostatic functions. Acute stress has been shown to enhance not only blood coagulation but also fibrinolysis by increasing fibrinogen, von Willebrand factor antigen; coagulation factors VII, VIIc, and VIII5 ; and TPA activity5 and antigen5 6 and by decreasing free and total PAI-1.7 Administration of epinephrine causes similar changes in blood coagulation and fibrinolytic activity, which lends further support to the functional role of acute stress in hemostasis. These changes are also likely to associate with the platelet-activating effect of epinephrine and norepinephrine at physiologically meaningful concentrations.8 9 Epinephrine triggers vessel occlusion in animal models of acute arterial thrombosis.10
Evidence also exists that long-term mental stress affects blood coagulation, but in a different way than acute stress, although the number of studies is limited and their results are contradictory. Thus, fibrinogen11 12 and blood coagulation factors V, VIII, and IX11 have been shown to decrease in response to long-term mental stress. Yet another study found an increase in fibrinogen and no changes in coagulation factors II, VII, VIII, and X, antithrombin III, or platelet aggregation,13 and Rosengren et al14 found no changes in fibrinogen during long-term stress. The present study was conducted to assess the effects of long-term mental stress on the fibrinolytic system, an issue that has not received attention. We examined whether chronic perceived stress, defined in terms of VE,15 ie, feelings of fatigue, lack of energy, increased irritability and demoralization, and depression, is related to plasma TPA and PAI-1 antigen levels in healthy middle-aged men. We took into account that age, factors of lifestyle, abdominal obesity, BMI, and insulin and TG levels might confound the associations.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Subjects
The subjects were 101 middle-aged men in managerial-level positions who responded to a letter sent to large companies, trade unions, and sporting societies inviting men in this age group to participate in the study. All potential participants read a lay version of the research plan describing the methods and purpose of the study. The study protocol was approved by the local ethics committee.
Of the 101 men, 32 were excluded from the present study. Twenty-five had either borderline (140/90 to 160/95 mm Hg) or definite (>160/95 mm Hg) hypertension16 based on medical history and/or blood pressures measured during a physical examination. One subject had diabetes, 4 suffered from coronary heart disease, and 2 were excluded because of incomplete psychological data. Thus, this study included 69 healthy 30- to 55-year-old men (44.4±5.2 years, mean±SD). The subjects took no medication and had no history or evidence of liver, kidney, gastrointestinal, endocrine, inflammatory, or atherothrombotic diseases or acute infections as determined by clinical examinations and laboratory analyses including blood cell counts, serum chemistry profiles, urinalyses, and electrocardiograms.
Procedures
Subjects were evaluated starting at 7:30
AM after a
12-hour overnight fast. During the blood sample collection the subjects
were either lying down or semi-reclining.
TPA and PAI-1
Blood samples for the determination of TPA and PAI-1 antigens
were collected in sodium citrate (0.11 mol/L) at 4°C and
centrifuged immediately.17 Plasma was stored at
-70°C. TPA (normal range, 3 to 10 ng/mL) and PAI-1 (normal
range, 4 to 43 ng/mL) antigen concentrations were determined by using
enzyme-linked immunosorbent assays (TintElize tPA and TintElize
PAI-1, Biopool). Before the determinations the samples were rapidly
thawed at 37°C.
TG and Insulin Levels, Abdominal
Obesity, and BMI
TG levels were measured by using the GPO-PAP method
(Boehringer-Mannheim GMbH).18 19 Insulin was
measured during an oral glucose tolerance test. An indwelling cannula
was inserted into an antecubital vein, and 30 minutes later a standard
75-g glucose load was given. Blood was sampled in the fasting state and
1 and 2 hours after the administration of glucose. Insulin was
analyzed by using a commercial radioimmunoassay kit
(Pharmacia). Abdominal obesity was measured after the oral glucose
tolerance test and defined as WHR; waist circumference was measured as
the smallest girth between the rib cage and the iliac crest and hip
circumference as the largest girth between the waist and thigh. BMI was
defined as the ratio of weight in kilograms divided by height in meters
squared.
Smoking, Alcohol Consumption, and Physical
Activity
Smoking was assessed as the current reported smoking status
and
alcohol consumption as the reported amount of alcoholic beverages
consumed per week converted into grams of absolute alcohol. Weekly
physical activity was measured with a four-point scale ranging from
no regular physical activity to strenuous physical activity.
Measures of Stress
In the afternoon following the
blood sample collection, the
subjects completed two tests of chronic perceived stress: form B of the
Maastricht Questionnaire for VE15 and a shortened version
of the Depressive Behavior Survey Schedule for
depression.20 21 The Maastricht Questionnaire
measures
feelings of fatigue ("I often feel tired"), lack of energy
("I
feel I haven't been accomplishing much lately"), irritability
("Little things have irritated me more lately than they used
to"), and demoralization ("I feel I want to give up
trying").15 The Depressive Behavior Survey Schedule
focuses on dysphoria ("I am sad"), anergia ("I have trouble
in
concentrating"), anhedonia ("I don't seem to enjoy
anything"), and insomnia ("I don't sleep through the
night").20
Statistical Analyses
To examine the association between VE,
depression, and
fibrinolytic parameters, Pearson correlation coefficients
and multiple linear regression analyses were computed. After
dividing the subjects into tertiles according to their scores on VE and
depression, mean differences in the fibrinolytic variables were
examined by using univariate ANOVA. Whenever a significant
F ratio was found, the mean differences between tertiles were further
examined by t tests. Partial correlations and/or multiple
linear regression analyses were employed to adjust for the
possible confounding effects of age, lifestyle, and
metabolic factors when VE, depression, and the fibrinolytic
parameters were continuous measures. ANCOVAs were employed
to adjust for confounding effects when the differences in means of
fibrinolytic measures between the tertiles of VE and depression were
analyzed. TPA, PAI-1, and insulin values were log10
transformed to normalize their distributions in correlations and
regression analyses. All statistical tests were
two-tailed.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Mean values of the fibrinolytic and metabolic variables are shown in Table 1
. The average reported
alcohol consumption rate was 172±126 g/wk, and of the 69 men 35%
(n=24) reported smoking, 35% (n=24) reported physical exercise
three
times or more per week, and 19% (n=13) were physically inactive.
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TPA and PAI-1 levels were significantly correlated
(r=.50, P<.001). Fibrinolytic variables were
unrelated to age, alcohol consumption, and smoking but were
significantly related to low physical activity level, fasting and
summed (the sum of the measured values at 0, 60, and 120 minutes during
the oral glucose tolerance test) insulin, TGs, WHR, and BMI (Table
2). VE and depression were significantly correlated with
each other (r=.76, P<.001).20 Age,
lifestyle factors, and metabolic variables were
unrelated to VE and depression with the exception of the relationship
of summed insulin to VE (Table 2).20
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Association of VE and Depression With Fibrinolytic
Parameters
VE correlated significantly with PAI-1
(r=.27,
P=.03) but was unrelated to TPA. Depression was not
significantly associated with either PAI-1 or TPA. When VE and
depression were entered simultaneously in the regression
equation, only VE was significantly associated with the PAI-1 antigen
level; this model explained as much as 11.5% (F[2, 64]=4.2,
P=.019) of the variance of PAI-1 (Table 3).
VE and depression did not contribute significantly to the variation of
TPA. The association between VE and PAI-1 remained significant when
partial correlations were used, after the adjustment for age, smoking,
alcohol consumption, and physical activity (r=.24,
P=.045). The addition of age and lifestyle factors as
covariates into multiple regression equations did not alter this
association (Table 3). However, after additionally controlling
for
obesity (WHR or BMI), insulin (fasting or summed), and TGs by means of
partial correlations, the association between VE and PAI-1 became
nonsignificant (r=.16 to .18, P=.14 to .19).
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Mean differences in the fibrinolytic variables between the tertiles
of VE and depression are presented in Table 4.
VE had a significant effect on PAI-1 (F[2, 68]=3.2,
P=.023), with subjects in the higher tertile having
significantly higher PAI-1 levels (t=2.8,
P=.007;
Bonferroni significance level, P<.05) than those in the
lower tertile. After controlling for age, smoking, alcohol consumption,
and physical activity, the differences in tertiles became marginally
significant (F[2, 60]=2.8, P=.068). However,
the
difference between subjects in the higher and lower tertiles remained
unaltered (t=2.6, P=.009; Bonferroni
significance
level, P<.05). When obesity (WHR or BMI), insulin (fasting
or summed), and TGs were added as covariates the mean differences in
tertiles became nonsignificant. Other mean differences in the
fibrinolytic variables between tertiles of VE and depression were
also nonsignificant.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The foregoing analyses show, first, that VE is associated with the fibrinolytic system at the level of circulating PAI-1 antigen, and second, that this association may be secondary to the effects of obesity and insulin and TG concentrations. VE was not related to TPA antigen, while depression was unrelated to both measured variables.
Altered fibrinolytic activity following acute experimentally induced mental stress has been demonstrated.5 6 7 The present finding that psychological states reflecting chronic perceived stress are associated with the fibrinolytic mechanisms thus adds to the evidence on the role of psychological stress in fibrinolysis. The differentiating associations of acute stress with upregulation of TPA versus chronic stress with increased PAI-1 may well coincide with the altered adrenergic receptor regulation during persistent stimulation, a matter that warrants further investigation.8 22
With regard to the possible pathophysiological relevance of the present finding, there is evidence that VE is related to both angina pectoris and an increased risk for future fatal and nonfatal myocardial infarction.23 24 VE may exert its pathophysiological influence on coronary heart disease through lipid metabolism.25 The present finding suggests that deficient fibrinolysis, as measured by elevated levels of circulating PAI-1 antigen, may also be involved in this interaction. There is evidence that deficient fibrinolysis, mainly due to an increased amount of active PAI-1, may be involved in arterial thrombosis.4 Several studies have in fact observed high PAI-1 levels in patients with atherothrombotic coronary artery disease.26 27 28 29 In experimental studies the pathogenic role of increased PAI-1 in the progression of atherosclerosis and the development of thrombosis is illustrated by fibrin deposition in vivo.30
The fact that the present study involved a selected group of healthy middle-aged male volunteers employed at a managerial level should be considered in evaluating the external validity of the findings. However, the subjects expressed varying degrees of stress, depression, and TPA and PAI-1 levels; all these variables showed normal or expected distributions. Thus, there is no reason to assume that the associations found reflect any selection bias.
Furthermore, the results indicate that the association between VE and circulating PAI-1 was not explained by age, smoking, alcohol consumption, or physical activity. However, when the variations in insulin, TGs, WHR, and BMI were taken into account, the association became nonsignificant. Thus, the present results show that the association between VE and PAI-1 may be confounded by the effects of obesity (measured as either BMI or WHR) and insulin and TG concentrations. That obesity, hyperinsulinemia, dyslipidemia, and deficient fibrinolysis are frequently comorbid conditions2 3 4 may underlie this attenuation of the association. Thus, the findings that VE is correlated with elevated serum cholesterol,25 increased levels of insulin and C-peptide and increased insulin/glucose ratio,20 and in lean men with increased WHR31 may reflect the close internal relationship between the metabolic and fibrinolytic parameters.
The physiological mechanisms underlying these associations remain to be uncovered, but stress-induced neuroendocrine responses, sympathetic activity, or both may be involved.32 Catecholamines, growth hormone, and cortisol, which are secreted excessively during physical and emotional stress,33 may all be involved in the process toward obesity, hyperinsulinemia, dyslipidemia, and altered fibrinolysis.8 9 34 35 36 Recent results from our laboratory suggest, indeed, that several abnormalities of insulin and lipoprotein metabolism are associated with an altered function of the pituitary-adrenal axis.37 38 Unexpectedly, in the current subjects, abdominal obesity, hyperinsulinemia, TGs, and HDL cholesterol appear to be associated with a subtle hypocortisolism.38 There is evidence that hypocortisolism may also be associated with elevated PAI-1 antigen and activity.39 Efforts to unravel the relations between stress, hormonal, metabolic, and fibrinolytic variables are in progress.
In conclusion, our results support the notion that mental stressors are associated with the fibrinolytic system, and metabolic variables may interfere in the association. The cross-sectional nature of this study does not, however, allow causal interpretations. The feasibility of applying a causal model to VE, metabolic parameters, and PAI-1 warrants longitudinal analysis.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was partially supported by a grant from the Signe and Ane Gyllenberg foundation (Dr Hautanen). The skillful technical assistance of Tuula Järvenpää in performing the fibrinolytic assays and the expertise of the personnel in the hormone laboratory at the Department of Clinical Chemistry are gratefully acknowledged.
Received October 12, 1995; accepted November 7, 1995.
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