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(Circulation. 1997;96:3842-3848.)
© 1997 American Heart Association, Inc.
Articles |
Exaggerated Blood Pressure Responses During Mental Stress Are Associated With Enhanced Carotid Atherosclerosis in Middle-Aged Finnish Men
Findings From the Kuopio Ischemic Heart Disease Study
From the Human Population Laboratory (S.A.E.), Public Health Institute, Berkeley, Calif; Department of Epidemiology (G.A.K.), School of Public Health, University of Michigan (Ann Arbor); and Departments of Psychology and Psychiatry (T.W.K., S.B.M., J.R.J.), University of Pittsburgh, Pittsburgh, Pa; and Research Institute of Public Health and Department of Community Health and General Practice (R.S., J.T.S.), University of Kuopio, Kuopio, Finland.
Correspondence to Dr Thomas W. Kamarck, Departments of Psychology and Psychiatry, University of Pittsburgh, Suite 520, Bellefield Professional Building, 130 N Bellefield Ave, Pittsburgh, PA 15260. E-mail tkam+{at}pitt.edu
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Abstract |
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Background Exaggerated cardiovascular reactivity to mental stress is hypothesized to increase atherosclerotic risk. We examined this hypothesis using cross-sectional data from the Kuopio Ischemic Heart Disease study, a population-based epidemiological sample.
Methods and Results 901 Eastern Finnish men from four age cohorts (age, 42 to 60 years) were administered a standardized testing battery to assess cardiovascular reactivity to mental stress. Ultrasound measures of intima-medial thickness (IMT) and plaque height from the common carotid arteries were used as noninvasive markers of atherosclerosis. Diastolic blood pressure (DBP) responses to mental stress were significantly associated with mean IMT (b=.021, P=.006), maximum IMT (b=.026, P=.013), and mean plaque height (b=.017, P=.041). Significant associations were also shown between stress-related systolic blood pressure (SBP) reactivity and mean IMT (b=.0151, P=.042). When examined separately by age, associations with IMT were significant only in the youngest half of the sample (age, 46 and 52 years, n=433; for mean IMT, DBP b=.033, P=.0002, SBP b=.0266, P=.003; for maximum IMT, DBP b=.039, P=.002, SBP b=.032, P=.011). Results remained significant in the younger subjects after adjustment for smoking, lipid profiles, fasting glucose, and resting blood pressure (b=.024, P=.011); results also remained significant in a subgroup of unmedicated younger subjects without symptomatic cardiovascular disease (n=135; for SBP reactivity, b=.031, P=.036; for DBP, b=.037, P=.007).
Conclusions The tendency to show exaggerated pressor responses to mental stress is a significant independent correlate of atherosclerosis in this population sample of Finnish men. The effect does not appear to be accounted for by the confounding influence of other risk factors or preexisting clinical disease.
Key Words: atherosclerosis • cardiovascular diseases • carotid arteries • risk factors • stress
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Introduction |
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The tendency to show exaggerated cardiovascular responses to mental stress ("cardiovascular reactivity") is hypothesized to be a potential risk factor for the development of atherosclerosis and coronary heart disease.1–3 Nonhuman primate studies are consistent with this "reactivity hypothesis": cynomolgus macaques showing the most pronounced HR responses during a fear-eliciting stimulus have been found to exhibit more extensive atherosclerosis than their less reactive counterparts.4,5 Stress-related SNS activation has been linked with a number of atherogenic processes; for example, prolonged exposure to aversive stimuli enhances artery wall endothelial injury and dysfunction in experimental rat and monkey models, and these changes have been shown to be mediated by SNS responding.6–9 Exaggerated cardiovascular reactors are assumed to be more susceptible to this type of stress-related SNS activation and, thus, at greater risk for atherosclerotic disease.
Although most of the evidence supporting the association between cardiovascular reactivity and atherosclerosis is derived from animal models, recent evidence is emerging consistent with this hypothesis from studies of human volunteers as well.10–12 The recent development of standardized assessment strategies for the laboratory assessment of cardiovascular reactivity has enhanced the ability to assess this characteristic in a reliable manner.13 To date, there are no population-based studies with standardized assessments that examine the association between reactivity and atherosclerosis in humans. The purpose of the present study was to examine the link between exaggerated stress-related reactivity and atherosclerosis in an epidemiological sample and to explore some possible pathways that account for this proposed association.
Standard risk factors for symptomatic coronary heart disease, including smoking, hypertension, cholesterol and triglycerides, and diabetes, are also significantly associated with indices of carotid atherosclerosis.14–18 If exaggerated cardiovascular reactivity promotes atherosclerosis in humans, the extent to which this enhanced risk may be accounted for, in part, by these established risk factor concomitants remains to be explored. These factors are examined in this report.
Data presented here are from the KIHD, an ongoing epidemiological study of risk factors for atherosclerotic vascular disease and other outcomes in a population sample of Eastern Finnish men.19,20 Important features of this study, for the purpose of this report, include the assessment of noninvasive markers of the extent of carotid atherosclerosis (ultrasound measures of IMT), the use of an extensive testing battery for measuring cardiovascular reactivity, and the availability of multiple measures of cardiovascular risk in the sample. We examined the concurrent association between reactivity and disease in this group; we examined age differences in the extent of this association; we explored the role of preexisting disease in contributing to our findings; and we investigated the effects of established risk factors in accounting for these results.
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Methods |
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Subjects
The KIHD is a population-based epidemiological investigation of risk factors for ischemic heart disease, atherosclerotic vascular disease, and other outcomes in Eastern Finnish men. The subjects involved in the reactivity testing were drawn from four cohorts of men ages 42, 48, 54, and 60 years at time of initial testing who were born in the city and region of Kuopio, Finland. A total of 2682 men were enrolled and participated in baseline assessments between March 1984 and December 1989. A 4-year follow-up examination was conducted between 1991 and 1993 on the men (n=1229) who had undergone carotid ultrasound assessments at baseline. Of those, 52 had died, had severe illness, or had migrated away from the region, and 139 could not be contacted or refused to participate. Thus, a total of 1038 volunteers (88.2% of those eligible) participated in the 4-year follow-up testing. Due to subject availability and scheduling constraints, only 901of the 1038 men participated in the cardiovascular reactivity testing as part of this 4-year follow-up examination: 433 subjects in the youngest two age cohorts (age 46 and 52 at the time of follow-up testing) and 468 subjects in the oldest two cohorts (age 58 and 64 at the time of testing). It should be noted that the tested sample (n=901) was somewhat younger and better educated and showed somewhat less disease at the 4-year follow-up than the subjects (n=137) who were not available for reactivity testing (age difference t [1036], 3.34, P<.001; mean age of tested subjects, 51.14 years; mean age of untested subjects, 53.17 years; education difference [four category]
2=13.10, P<.01, 7% of
participants and 13% of nonparticipants had not completed elementary
school; prevalence of symptomatic coronary heart
disease,2 2=2.88, P<.10;
21% of participants and 28% of nonparticipants had a diagnosis of
coronary heart disease). Because these differences were
relatively small in absolute terms, we do not expect the sample
characteristics to affect the generalizability of the results.
Procedures
Examinations for the 4-year follow-up point were carried out
over 2 days, 1 week apart, and consisted of a variety of biochemical,
physiological, anthropometrical, and psychosocial
measures. All subjects gave their informed consent to the testing, and
the study protocol was reviewed and approved by the Institutional
Ethical Committee of the University of Kuopio.
Measures
Measurement of Carotid Atherosclerosis
The extent of carotid atherosclerosis was
assessed by high-resolution B-mode ultrasonography of the right and
left CCAs in a 1.0- to 1.5-cm section at the distal end of the CCA,
proximal to the carotid bulb. Images were focused on the posterior wall
of the right and left CCAs and recorded on videotape for later
analysis. Ultrasound examinations were conducted by one of four
trained sonographers and were performed with the subject in a supine
position after a 15-minute rest.
At the 4-year follow-up, images were obtained with a Biosound Phase 2 scanner equipped with a 10-MHz annular array probe.21 Wedge phantom studies of this system, calibrated against an RMI 414B tissue phantom, have demonstrated measurement precision of ±0.03 mm.21,22 Four-year follow-up scans were taken concurrently with the reactivity assessments and are used in all of the analyses described below; all carotid measures were statistically adjusted for sonographer (multiple sonographers were used for the 4-year assessments).
IMT measurements were made via computerized analysis of the
videotaped ultrasound images using Prosound software (University of
Southern California, Los Angeles, Calif). This software uses an
edge-detection algorithm, specifically designed for use with ultrasound
imaging,23,24 that allows automatic detection,
tracking, and recording of the intima/lumen and
media/adventitia interfaces. IMT, calculated as the mean distance
between these interfaces, was estimated at 
100 points in both the
right and left CCAs.
For the present study, three measures of IMT were used: (1) mean IMT, calculated as the mean of all IMT estimates from the right and left CCAs and considered an overall measure of the atherosclerotic process in the carotid arteries; (2) maximum IMT, the average of the points of maximum thickness from the right and left CCAs and indicative of the depth of intrusion of atherosclerotic thickening into the lumen in this part of the CCA; and (3) plaque height, the average of right and left CCA measurements of plaque height, calculated as the difference between maximum and minimum thickness, and an assessment of how steeply atherosclerotic lesions protruded into the lumen.
Growing evidence supports the use of carotid ultrasound measures as valid noninvasive markers of atherosclerosis. Ultrasound carotid assessments are associated with pathological and histological measures of atherosclerosis in autopsy samples,25 appear to reliably discriminate between patients with and without coronary artery stenosis by angiography,26,27 and have been shown to be prospectively associated with the risk for coronary events (eg, myocardial infarction, sudden cardiac death), even among initially asymptomatic individuals.15,28–30 Because carotid measures can be used to assess preclinical manifestations of vascular disease, they are well suited for investigation of possible antecedents of atherosclerosis in a population sample.
Assessment of Standard Risk Factors
Blood samples were drawn after fasting and abstinence from
smoking for 12 hours, abstinence from alcohol for 3 days, and
abstinence from analgesic medications for 7 days. Subjects rested
supine for 30 minutes, after which blood was drawn without the use of a
tourniquet by using Terumo Venoject VT-100 PZ vacuum tubes (Terumo
Corp). Lipoproteins were separated from unfrozen plasma within 3 days
of sampling. The HDL and LDL fractions were separated from fresh plasma
through the use of both ultracentrifugation and
precipitation. The cholesterol content of all lipoprotein
fractions and serum triglycerides was measured
enzymatically (CHOD-PAP method for lipoproteins and GPO-PAP method for
triglycerides; Boehringer-Mannheim Biochemica) on
the day after the last spin. Blood glucose was measured according to
the glucose dehydrogenase method after precipitation of the proteins
with trichloric acetic acid. Resting blood pressure assessments were
obtained by a trained observer using a random-zero muddler
sphygmomanometer (Hawksley) at minutes 5 and 10 during a seated rest
period; the two readings were averaged. Medical history and medication
use were recorded during a medical examination at the baseline and
follow-up assessments. Smoking status was measured by self-report.
Cardiovascular Reactivity Testing
A recently developed automated test battery for the assessment
of individual differences in cardiovascular reactivity
was used in this study. The version of the battery used here involved
four standardized computer-based tasks, each 9 minutes long, that
required a range of cognitive and psychomotor skills (memory task,
reaction time task, tracing task, and computerized version of the
Stroop Color Word Task20,31). Each task was
designed to simulate a state of mild mental stress or challenge and was
preceded by a 9-minute baseline (rest and recovery)
period.32 The difficulty level of each task was
adjusted after each trial to maintain a performance level of
60% success, ensuring a continuous and optimal level of challenge
for each subject. These tasks have been shown to elicit significant
acute changes in cardiovascular activity (changes from
baseline in HR, blood pressure, and other
cardiovascular functions), and this multiple-task
battery has been shown to yield stable estimates of individual
differences in reactivity in a variety of US
samples.13,33,34 Reliable measures of reactivity
were also obtained from this battery in a subsample from the KIHD study
retested 8 to 12 months after the initial
assessment.20 With instrumentation and
instructions, the entire reactivity assessment protocol lasted 2
hours for each participant.
In preparation for reactivity testing, each subject was instrumented
with a two-lead ECG across the chest, an automated blood pressure
device (Dinamap Vital Signs Monitor) on the dominant arm, impedance
cardiograph electrodes (Minnesota Impedance Cardiograph model
304B35) on the neck and thorax, and a
peripheral vascular pulse
transducer36 on the thumbnail of the nondominant
arm. Blood pressure measurements were taken every 90 seconds during the
baseline and task periods; ECG measures were ensemble-averaged across
each consecutive 30-second interval throughout the assessment period.
Additional impedance cardiography and pulse wave measurements were
collected but are not reported here. These additional measures were not
consistently associated with indices of
atherosclerosis in the sample; some, however, were
affected by the health status of the
participants.20 The scoring and measurement
systems associated with this task battery have been previously
described.37 Because of occasional arm movement
or equipment failure, there was some data loss on 5% of the sample
for the blood pressure and HR measurements, so we report the sample
size separately for each of the analyses described below.
Assessments for each cardiovascular
parameter (HR, SBP, and DBP) were averaged separately
across the 9-minute period for each rest period and each task. The four
resulting rest period values were averaged and subtracted from each
averaged task score to derive estimates of
cardiovascular reactivity. Each of these reactivity
scores was performance-adjusted by removing any linear
relationship between the response to each task and the level of
performance (average difficulty level for each trial) achieved
by the subject on the task. This correction was introduced to reduce
the small but significant association between task performance
and cardiovascular responsiveness (r=
.13) shown in
this sample. Resulting adjusted reactivity measures were standardized
within each task and averaged across tasks, yielding a single
performance-adjusted score for each subject for each
cardiovascular parameter.*
Data Analysis
Measures of carotid IMT were regressed on measures of HR and
blood pressure reactivity using a general linear models procedure (PROC
GLM38). Associations were explored separately in
subjects above and below the median age of the sample (55 years) at the
time of testing. Because of their previously observed effects on
cardiovascular
responsiveness,33,39 educational level and
remaining variations in age were used as covariates in all models. To
reduce the possible confounding effects of concurrent disease on
reactivity as a plausible causal explanation for the results, we
repeated our significant analyses in the subgroup of subjects
who were free of symptomatic cardiovascular
disease and cardioactive medication. Finally, in our initial model, we
entered established cardiovascular risk factors as
additional covariates to assess their contribution to the results.
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Results |
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Blood pressure reactivity to the testing battery was significantly and positively associated with ultrasound measures of carotid atherosclerosis in this sample, with the results being largest for the measure of DBP response. Reported results include the unstandardized partial regression coefficients describing the change in carotid wall or plaque thickness (in mm) for each average mm Hg change in blood pressure response after adjustment for age and education and associated P values for each parameter: DBP reactivity showed significant associations with all three measures of carotid morphology (n=859; for mean IMT, b=.021, P=.006; for maximum IMT, b=.026, P=.013; and for mean plaque height, b=.017, P=.041). Significant effects were shown for SBP reactivity on average IMT (n=867; mean IMT, b=.0151, P=.042), and SBP reactivity was marginally related to maximal IMT as well (maximum IMT b=.0187, P=.078, n=867). HR reactivity showed a marginally significant inverse association with mean IMT (b=-.014, P=.054, n=868) and maximum IMT (b=-.019, P=.071, n=868).
When results were examined separately by age group, we found that the
association between blood pressure reactivity and carotid
atherosclerosis was accounted for entirely by the
youngest half of the sample (age, 46 and 52 years; n=433). Again, all
models included covariates for the remaining variance in age and
education. In these younger age cohorts, both SBP and DBP reactivity
were significantly associated with mean and maximum IMT (for mean IMT,
DBP b=.033, P=.0002, n=420, SBP
b=.0266, P=.003, n=422; for maximum IMT, DBP
b=.039, P=.002, n=420, SBP b=.032,
P=.011, n=422) (see Table 1
). For the older half of the
sample (age, 58 and 64 years; n=469), these associations were not
significant (blood pressure b=.005 to .017,
P>.18 for SBP and DBP responses). There were no marginal or
significant associations involving HR reactivity in either the older or
the younger half of the sample. Fig 1
illustrates the association between DBP reactivity and mean carotid IMT
(carotid IMT scores adjusted for age and education)
across each of the five quintiles for DBP response separately in the
younger and older groups and across the entire sample. Although the
pattern of associations between blood pressure reactivity and IMT
appeared quite different in the younger and older groups, the
interactions between age and reactivity were not significant (for DBP
reactivity, P=.124 to .944).
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To reduce the possible confounding effects of preexisting disease on cardiovascular reactivity, we selected a subsample of healthy and unmedicated subjects by excluding the following groups: (1) all subjects with a reported history of symptomatic coronary disease, stroke, hypertension, or diabetes at baseline or the 4-year follow-up; (2) all subjects with resting blood pressure in the hypertensive range (SBP >140 or DBP >90) at the follow-up; and (3) all subjects who indicated that they were taking cardiac medications, including any antihypertensive medications or antiarrhythmic drugs, at either baseline or follow-up. After selection of a healthy and unmedicated subgroup, we reexamined the data from the youngest half of the sample (135 subjects met all of the criteria). Significant effects of reactivity were retained for the mean IMT measure among these healthy subjects (for SBP reactivity, b=.031, P=.036, n=132; for DBP reactivity, b=.037, P=.007, n=132). In this healthy subgroup, there were no significant effects of reactivity on maximum IMT and no significant effects of HR reactivity on any of the carotid measures.*
In the two younger age cohorts, we also examined the relationship
between measures of blood pressure reactivity and seven standard
measures of cardiovascular risk that have been
implicated in the development of carotid
atherosclerosis (smoking status; LDL and HDL
cholesterol, serum triglycerides, and fasting
serum glucose; and SBP and DBP at rest). Each of these risk factor
measures was collected at the 4-year follow up, along with the
reactivity assessments. As shown in Table 2, blood pressure reactivity measures
showed small but significant associations with each of the seven
measures of cardiovascular risk. Hierarchical
regression analyses (PROC GLM; Type III sums of
squares38) in the younger half of the sample were
used to regress each carotid thickness measure on reactivity after
these standard risk factors were controlled, along with age and
education. The adjusted effect associated with reactivity was somewhat
smaller in the model with these nine covariates compared with the
two-covariate model described above, suggesting that shared variance
with these other risk factors accounts for some portion of the
association between reactivity and carotid disease. The association
between DBP reactivity and mean IMT remained statistically significant,
however, after these risk adjustments (b=.024,
P=.011 in the model with risk factor covariates versus
b=.033, P=.0002 in the original model, as
described above). This suggests that an important part of the
reactivity-IMT association cannot be entirely accounted for by other
major predictors of atherosclerosis. Table 3 presents the standardized
regression coefficients associated with each of the risk factors
covariates, for the purpose of comparing the relative magnitude of
effect associated with each. As can be seen, DBP reactivity, smoking,
and LDL cholesterol are roughly equivalent in terms of
their independent associations with mean IMT in this sample. The
association between DBP reactivity and maximal IMT was only marginally
significant in these analyses, and none of the SBP and HR
reactivity effects were significant after the introduction of the
additional covariates.
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Discussion |
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We have shown that blood pressure reactivity to mental stress is positively associated with ultrasound measures of carotid artery wall thickness, a marker of atherosclerosis, in a sample of middle-aged Finnish men. Our data suggest an additional 0.02 to 0.03 mm of carotid artery thickness for every mm Hg of stress-related blood pressure responsiveness, with reactivity carrying a level of risk of the same order of magnitude as that associated with smoking or elevated LDL cholesterol in this sample. These associations are significant in the group as a whole, but there is no significant relationship between reactivity and disease in the subjects over age 55 in the sample. Although cross-sectional, these findings may not be entirely accounted for by any effects of preexisting disease on cardiovascular dynamics: In subjects under 55, significant effects remain among those who were completely unmedicated and asymptomatic at the time of testing. In addition, the results cannot be explained in terms of established risk factors for cardiovascular disease because some of the effects remain significant after adjustment for traditional indices of disease risk.
This is the first study to examine the association between standardized measures of cardiovascular reactivity and quantitative assessment of carotid atherosclerosis in a population sample. We used an extensive testing protocol for assessing individual differences in cardiovascular reactivity in this study, a procedure that has been shown to produce reproducible results in this as well as previous samples. The use of noninvasive measures of carotid atherosclerosis allowed us to assess the extent of disease in symptomatic as well as asymptomatic subjects. These carotid measures have been previously validated as markers of atherosclerosis25–27 and as predictors of future cardiovascular events. Indeed, in a previous report from the KIHD sample, each incremental 0.1 mm of carotid IMT was prospectively associated with an 11% increased risk for acute myocardial infarction across a 3-year follow-up period,15 a finding that lends plausible clinical significance to the current results.
The reactivity-atherosclerosis association shown in this sample was quite strong for subjects younger than age 55, but it was attenuated in the older two age cohorts in the sample. There are at least four possible explanations for these apparent age-related differences in the significance of reactivity-disease associations. First, given the high burden of cardiovascular disease in this population, characteristics that reduce susceptibility to disease risk may be more prevalent among older Finnish men compared with their younger counterparts ("survivor" effects40). Second, the influence of aging (eg, reductions in ß-adrenergic activity) may reduce the relative importance of reactivity on the pathogenesis of cardiovascular disease over time.40 Third, there may be differences in the meaning or determinants of reactivity measurements with age. For example, although reactivity measures may reflect sympathetic nervous system activation in the young, alterations in vascular distensibility41 may play an increasing role as determinants of reactivity in the elderly. It should be noted that changes in the predictive value of risk factors at this age transition have been previously observed.42,43 Indeed, results in this current sample suggest an age-related attenuation in the predictive value of cholesterol as well as reactivity, with LDL cholesterol concentrations here being significantly associated with mean IMT only in the subjects under age 55 (in age-adjusted models, b=.026, P=.002 for the youngest half of the sample) and no significant effects of LDL cholesterol shown among older men (b=.009, P=.427 for the older half of the sample). Fourth, these age-related differences may be attributable to chance (consistent with this interpretation, the agexreactivity interaction effect was not significant in this study). Further investigation is necessary to determine the processes by which age may modify the association between cardiovascular reactivity and atherosclerosis.
Our data suggest that excessive blood pressure reactivity is associated with a number of established coronary risk factors, including high concentrations of serum triglycerides and LDL cholesterol, low HDL cholesterol, and high blood glucose. These correlated risk factors, however, do not appear to entirely account for the association between reactivity and atherosclerosis. A number of possible pathways by which excessive sympathoadrenal activation may uniquely contribute to the pathogenesis of coronary heart disease have been described previously.1 For example, frequent and prolonged periods of hyperdynamic cardiovascular activity may promote mechanical injury to the endothelial lining of the coronary arteries,9 a process that may foster coronary vasospasm44 and the development of atherosclerotic plaque.45 Alternatively, the neuroendocrine correlates of exaggerated reactivity (most notably, epinephrine, norepinephrine, and cortisol response) may contribute over time to lipid mobilization46,47 or platelet aggregation,48 each of which may exacerbate vascular injury or plaque development.49
The strongest form of the "reactivity hypothesis" implies that stressor exposure, as well as stress responsiveness, may contribute to SNS-mediated disease risk: To the extent that reactivity may play a causal role in the development of atherosclerosis, we might expect the association between reactivity and carotid disease to be strongest among those exposed to the most frequent or intense pressor episodes during daily life. Future research should be designed to evaluate this "diathesis-stress" model of disease pathogenesis12,50 in human populations.
A number of limitations to this study should be acknowledged. First, the rates of cardiovascular events among Finnish men, the population used for this study, are among the highest in the world,51 raising questions about the generalizability of these findings to lower-risk populations. The associations shown here were maintained, however, within an unmedicated healthy subgroup with no obvious signs or symptoms of coronary disease. Second, the KIHD sample is entirely male and an ethnically homogeneous group; racial and gender differences in the prevalence of hypertensive and coronary heart disease52,53 suggest that caution should be exercised in extending these results to more heterogeneous samples. Third, the limitations of the cross-sectional design used in the present report should also be acknowledged. Although measures were taken to enhance the interpretation of the results in the present report (subgroup analyses to reduce the influence of clinical disease or medication use, covariate adjustment for age to reduce the confounding influence of this factor), causal effects of reactivity on carotid disease cannot be inferred from this report. Prospective analyses adjusting for initial disease severity are required to establish the temporal precedence of reactivity differences as a risk factor or causal agent in the development of atherosclerosis.
It will also be critical to establish the independent predictive power of reactivity as a predictor of clinical end points in population samples. Data linking reactivity differences with clinical coronary disease end points have been reported,54,55 although there have also been conflicting findings.56 Continued follow-up data collection from the KIHD sample in the years ahead will permit us to draw more definitive conclusions about the potential role of exaggerated blood pressure reactivity to mental stress in contributing to atherosclerotic disease and the clinical implications of this association.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grant HL-44199 from the National Heart, Lung, and Blood Institute and by grants from the Academy of Finland and the Finnish Ministry of Education.
Received May 29, 1997; revision received August 25, 1997; accepted August 27, 1997.
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