Early atherosclerosis and cardiac autonomic responses to mental stress: a population-based study of the moderating influence of impaired endothelial function.
ABSTRACT Acute mental stress may contribute to the cardiovascular disease progression via autonomic nervous system controlled negative effects on the endothelium. The joint effects of stress-induced sympathetic or parasympathetic activity and endothelial function on atherosclerosis development have not been investigated. The present study aims to examine the interactive effect of acute mental stress-induced cardiac reactivity/recovery and endothelial function on the prevalence of carotid atherosclerosis.
Participants were 81 healthy young adults aged 24-39 years. Preclinical atherosclerosis was assessed by carotid intima-media thickness (IMT) and endothelial function was measured as flow-mediated dilatation (FMD) using ultrasound techniques. We also measured heart rate, respiratory sinus arrhythmia (RSA), and pre-ejection period (PEP) in response to the mental arithmetic and speech tasks.
We found a significant interaction of FMD and cardiac RSA recovery for IMT (p = 0.037), and a significant interaction of FMD and PEP recovery for IMT (p = 0.006). Among participants with low FMD, slower PEP recovery was related to higher IMT. Among individuals with high FMD, slow RSA recovery predicted higher IMT. No significant interactions of FMD and cardiac reactivity for IMT were found.
Cardiac recovery plays a role in atherosclerosis development in persons with high and low FMD. The role of sympathetically mediated cardiac activity seems to be more important in those with impaired FMD, and parasympathetically mediated in those with relatively high FMD. The development of endothelial dysfunction may be one possible mechanism linking slow cardiac recovery and atherosclerosis via autonomic nervous system mediated effect.
- SourceAvailable from: Mario Clerici[show abstract] [hide abstract]
ABSTRACT: Psychological stress represents a risk factor for hypertension, but mechanisms are not known in detail. In this investigation we tested the hypothesis that real-life stress conditions produce changes in autonomic cardiac and vascular regulation that might differ in magnitude. University students, a well-established model of mild real-life stress, were examined shortly before a university examination, and a second time 3 months afterward, during holiday. Autonomic cardiovascular regulation was assessed by a noninvasive approach, based on autoregressive analysis of RR interval variability (V) and of systolic arterial pressure (SAP) V. The overall level of stress in the two sessions was gauged from the elevated salivary cortisol (5.6+/-0.5 versus 2.4+/-0.2 ng/mL, P<0.05) and altered cytokine profile (P<0.05). During the stress day, the RR interval was reduced and arterial pressure increased significantly; simultaneously, the normalized low frequency component of RRV (a marker of sympathetic modulation of the sinoatrial node) was increased and the index alpha (a measure of baroreflex gain) reduced. Concomitantly, the autonomic response to the sympathetic excitation produced by standing was altered: cardiac response was impaired and vascular responsiveness increased. Markers of autonomic regulation of the sinoatrial node correlated significantly with cortisol levels, both at rest and also considering standing induced changes, suggesting a gradual range of effects. The data support the concept that mild real-life stress increases arterial pressure and impairs cardiovascular homeostasis. These changes, assessable with spectral analysis of cardiovascular variability, might contribute, in susceptible individuals, to the link between psychological stress and increased cardiovascular risk of hypertension.Hypertension 01/2002; 39(1):184-8. · 6.87 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Recent studies provide clear and convincing evidence that psychosocial factors contribute significantly to the pathogenesis and expression of coronary artery disease (CAD). This evidence is composed largely of data relating CAD risk to 5 specific psychosocial domains: (1) depression, (2) anxiety, (3) personality factors and character traits, (4) social isolation, and (5) chronic life stress. Pathophysiological mechanisms underlying the relationship between these entities and CAD can be divided into behavioral mechanisms, whereby psychosocial conditions contribute to a higher frequency of adverse health behaviors, such as poor diet and smoking, and direct pathophysiological mechanisms, such as neuroendocrine and platelet activation. An extensive body of evidence from animal models (especially the cynomolgus monkey, Macaca fascicularis) reveals that chronic psychosocial stress can lead, probably via a mechanism involving excessive sympathetic nervous system activation, to exacerbation of coronary artery atherosclerosis as well as to transient endothelial dysfunction and even necrosis. Evidence from monkeys also indicates that psychosocial stress reliably induces ovarian dysfunction, hypercortisolemia, and excessive adrenergic activation in premenopausal females, leading to accelerated atherosclerosis. Also reviewed are data relating CAD to acute stress and individual differences in sympathetic nervous system responsivity. New technologies and research from animal models demonstrate that acute stress triggers myocardial ischemia, promotes arrhythmogenesis, stimulates platelet function, and increases blood viscosity through hemoconcentration. In the presence of underlying atherosclerosis (eg, in CAD patients), acute stress also causes coronary vasoconstriction. Recent data indicate that the foregoing effects result, at least in part, from the endothelial dysfunction and injury induced by acute stress. Hyperresponsivity of the sympathetic nervous system, manifested by exaggerated heart rate and blood pressure responses to psychological stimuli, is an intrinsic characteristic among some individuals. Current data link sympathetic nervous system hyperresponsivity to accelerated development of carotid atherosclerosis in human subjects and to exacerbated coronary and carotid atherosclerosis in monkeys. Thus far, intervention trials designed to reduce psychosocial stress have been limited in size and number. Specific suggestions to improve the assessment of behavioral interventions include more complete delineation of the physiological mechanisms by which such interventions might work; increased use of new, more convenient "alternative" end points for behavioral intervention trials; development of specifically targeted behavioral interventions (based on profiling of patient factors); and evaluation of previously developed models of predicting behavioral change. The importance of maximizing the efficacy of behavioral interventions is underscored by the recognition that psychosocial stresses tend to cluster together. When they do so, the resultant risk for cardiac events is often substantially elevated, equaling that associated with previously established risk factors for CAD, such as hypertension and hypercholesterolemia.Circulation 05/1999; 99(16):2192-217. · 15.20 Impact Factor
Chumaeva et al. BMC Cardiovascular Disorders 2010, 10:16
Early atherosclerosis and cardiac autonomic
responses to mental stress: a population-based
study of the moderating influence of impaired
© 2010 Chumaeva et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Com-
mons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduc-
tion in any medium, provided the original work is properly cited.
Nadja Chumaeva†1,2, Mirka Hintsanen†1, Taina Hintsa1, Niklas Ravaja†3, Markus Juonala†4, Olli T Raitakari4,5 and
Background: Acute mental stress may contribute to the cardiovascular disease progression via autonomic nervous
system controlled negative effects on the endothelium. The joint effects of stress-induced sympathetic or
parasympathetic activity and endothelial function on atherosclerosis development have not been investigated. The
present study aims to examine the interactive effect of acute mental stress-induced cardiac reactivity/recovery and
endothelial function on the prevalence of carotid atherosclerosis.
Methods: Participants were 81 healthy young adults aged 24-39 years. Preclinical atherosclerosis was assessed by
carotid intima-media thickness (IMT) and endothelial function was measured as flow-mediated dilatation (FMD) using
ultrasound techniques. We also measured heart rate, respiratory sinus arrhythmia (RSA), and pre-ejection period (PEP)
in response to the mental arithmetic and speech tasks.
Results: We found a significant interaction of FMD and cardiac RSA recovery for IMT (p = 0.037), and a significant
interaction of FMD and PEP recovery for IMT (p = 0.006). Among participants with low FMD, slower PEP recovery was
related to higher IMT. Among individuals with high FMD, slow RSA recovery predicted higher IMT. No significant
interactions of FMD and cardiac reactivity for IMT were found.
Conclusions: Cardiac recovery plays a role in atherosclerosis development in persons with high and low FMD. The role
of sympathetically mediated cardiac activity seems to be more important in those with impaired FMD, and
parasympathetically mediated in those with relatively high FMD. The development of endothelial dysfunction may be
one possible mechanism linking slow cardiac recovery and atherosclerosis via autonomic nervous system mediated
Mental stress has been shown to be a risk factor for ath-
erosclerosis . Acute mental stress may induce myocar-
dial infarction  or sudden cardiac death . It has been
found to impair the parameters of endothelial health,
reducing flow-mediated dilatation (FMD) [4,5]. Brachial
FMD is an adequate non-invasive measure of endothelial
function  and reduced brachial FMD reflects endothe-
lial dysfunction [6,7]. Endothelial dysfunction is a marker
of cardiovascular risk [6,7] and may be considered as an
indicator of atherosclerotic events in later stages in life
. Brachial FMD as well as carotid intima-media thick-
ness (IMT) are important non-invasive markers of sub-
clinical atherosclerosis [7,9]. Increased carotid IMT
correlates with coronary atherosclerosis  and
increased IMTs have been found among individuals with
impaired brachial FMD .
Mechanisms through which mental stress induces
harmful changes in vascular system functioning and
influences atherosclerosis development are not fully clear.
* Correspondence: firstname.lastname@example.org
1 Institute of Behavioural Sciences, University of Helsinki, P.O. Box 9, FIN-00014
† Contributed equally
Full list of author information is available at the end of the article
Chumaeva et al. BMC Cardiovascular Disorders 2010, 10:16
Page 2 of 8
A novel hypothesis has considered atherosclerosis as a
neurogenic phenomenon manifested by the autonomic
nervous system (ANS) dysfunction . It has been sug-
gested that chronic stress may promote atherogenesis
through the mechanism of autonomic neuropathy-
caused sympathetic hyperactivity .
Sympathetic hyperactivity impairs the ANS control of
the cardiovascular system . It has been considered
that suppressed ANS regulation may be related to athero-
sclerotic processes through the negative ANS-mediated
effect on the endothelium . Using a nonhuman pri-
mate model of atherogenesis, it has been found that psy-
chosocial stress can alter the autonomic balance towards
a state of sympathetic arousal leading to the development
of coronary heart disease (CHD), perhaps through
impairing endothelial function  and intensification of
endothelium-mediated atherogenic processes .
The reactivity hypothesis suggests that elevated cardio-
vascular reactivity evoked by the psychological stress fac-
tors is a risk for the development of hypertension,
atherosclerosis, and CHD . In addition, the disability
of the cardiovascular system to recover from psychologi-
cal stress has been mentioned in several studies as a risk
factor for the development of cardiovascular disorders
It has been shown that acute mental stress induces
changes in heart rate (HR) . Many studies of cardiac
reactivity have used pre-ejection period (PEP) as an ade-
quate noninvasive indicator of cardiac sympathetic regu-
lation [21,22] and respiratory sinus arrhythmia (RSA) as
an index of parasympathetic control of HR .
Psychological risk factors are highly associated with the
measures of cardiovascular ANS reactivity  and, on
the other hand, may accelerate endothelium-mediated
atherogenesis [15,16]. In addition, associations between
acute mental stress and IMT have recently been shown
, and increased carotid IMT levels have been found
among healthy young adults who have impaired brachial
FMD . It can be suggested that acute mental stress
may contribute to the cardiovascular disease progression
via ANS-controlled negative effects on the endothelium,
predisposing some individuals to an autonomic imbal-
ance that may be harmful to endothelial function and,
therefore, may represent a negative prognostic factor for
atherosclerosis. There is little knowledge on this hypoth-
esis so far.
The joint effects of acute mental stress-induced sympa-
thetic or parasympathetic activity and endothelial func-
tion on atherosclerosis development have not been
studied. The aim of this study was to examine the interac-
tive effect of acute stress-induced cardiac reactivity/
recovery and endothelial function, measured in terms of
FMD, on the prevalence of preclinical atherosclerosis
assessed by IMT in young healthy adults.
The participants were 100 healthy men and women aged
24-39 years (in 2001), who were participating in the pro-
spective multicenter epidemiological Cardiovascular Risk
in Young Finns (CRYF) study . Since 1980, the CRYF
study has been monitoring the development of risk fac-
tors for coronary heart disease at intervals of 3 or 5 years.
The CRYF study originally included a total of 3596
healthy Finnish children, adolescents, and young adults at
baseline in 1980. The design of the study and the sample
have recently been described . Of the original CRYF
sample, 2109 participants were examined in 2001 and
cardiovascular risk factor and ultrasound measurements
were performed on them. The stress testing (public
speaking task and mental arithmetic task) was adminis-
tered for 95 healthy young adults two years before the
ultrasound measurements (in 1999).
The present sample (originally a total of 100 subjects)
was randomly selected from the subjects who partici-
pated in the psychological study in 1997. The participants
were invited to the stress testing from the urban and rural
districts of Finland within a 100 km radius from Helsinki
(n = 382). Ninety-five subjects entered in the psychophys-
iological testing in 1999. In the present study, complete
data on psychophysiological reactivity/recovery testing
and ultrasound measurements were obtained from 81
participants. They comprised the final sample of this
The study followed the guiding principles of the Hel-
sinki Declaration and was approved by the Ethical Com-
mittee of the University of Helsinki and by the Joint
Ethical Committee of the University of Turku and Turku
University Hospital. All subjects gave their written,
informed consent in 1999 and in 2001.
We measured heart rate (HR), respiratory sinus arrhyth-
mia (RSA; indicator of the parasympathetic control of
HR), and pre-ejection period (PEP; indicator of the sym-
pathetic control of HR).
Electrocardiogram (ECG) and the first derivative of the
pulsatile impedance signal (dZ/dt) were measured con-
tinuously during the experiment with Minnesota Imped-
ance Cardiograph Model
Minneapolis, MN), using the standard tetrapolar band
electrode configuration . The ECG and dZ/dt signals
were sampled continuously at 500 Hz via a 12-bit 8-chan-
nel A/D converter, and stored on the hard disk of a PC for
later analysis. On-line data reduction was performed with
custom-programmed Labview data acquisition software
(National Instruments Co., Austin, TX).
304B (Surcom Inc.,
Chumaeva et al. BMC Cardiovascular Disorders 2010, 10:16
Page 3 of 8
Ultrasound studies of the carotid and brachial arteries
were performed using Sequoia 512 ultrasound main-
frames (Acuson, Mountain View, CA, USA) with 13.0
MHz linear array transducer, as previously described
[11,27]. To assess intra-individual reproducibility of ultra-
sound measurements, 57 subjects were re-examined 3
months after the initial visit (2.5% random sample) .
Carotid intima-media thickness, IMT
Carotid IMT was measured on the posterior (far) wall of
the left carotid artery. At least four measurements were
taken approximately 10 mm proximal to the bifurcation
to derive mean carotid IMT. The between-visit coeffi-
cient of variation of IMT measurements was 6.4% .
Brachial flow-mediated dilatation, FMD
To assess brachial FMD, the left brachial artery diameter
was measured both at rest and during reactive hypere-
mia. Increased flow was induced by inflation of a pneu-
matic tourniquet placed around the forearm to a pressure
of 250 mmHg for 4.5 min, followed by a release .
Arterial diameter was measured at end-diastole at a fixed
distance from an anatomic marker at rest and 40, 60 and
80 s after cuff release. The vessel diameter in scans after
reactive hyperemia was expressed as the percentage rela-
tive to resting scan. The average of three measurements
at each time point was used to derive the maximum FMD
(the greatest value between 40 to 80 s). The between-visit
coefficient of variation for brachial diameter was 3.2%
and for FMD 26.0% .
Before the experiment, the subjects were informed about
the general nature of the study, and gave their written
informed consent. Each participant was studied using a
standardized computer-controlled experimental session.
The experiment lasted for about 180 min, and the experi-
mental procedure started at the same time of the day
(9:00 am) for all participants. The subjects were
instructed to abstain from caffeine and cigarettes con-
sumption for 12 hr before the experimental procedure.
The experiment was conducted in a sound-attenuated
room equipped with a computer for stimulus presenta-
tion, and with a video system for monitoring and commu-
nication. The experiment consisted of five tasks: (1)
emotion-evoking picture viewing, (2) acoustic startle
stimuli, (3) a mental arithmetic task, (4) a reaction-time
task, and (5) a public-speaking task with three different
scenarios. The participants were alone in the room dur-
ing the tasks, with the exception of the public speaking
task. Two experimenters were present as an audience
during the public speaking task. The experiment started
and ended with a resting period of 10 min. Each of the
experimental tasks was followed by an 8 min resting
period. The mental arithmetic task and the speech task
were used in the current study. The tasks have been
described previously in more detail . The other tasks
were omitted because they evoked very different reactiv-
ity profiles compared to the two selected tasks. In the
present study, both the mental arithmetic and public
speaking tasks evoked an increase in HR and a decrease
in RSA and PEP, which is in line with many previous stud-
ies [20,29]. The public speaking and mental arithmetic
tasks have been shown to evoke stable and relatively high
cardiac autonomic responses [29,30].
The interbeat intervals (IBIs), in ms, were determined
from the ECG signal and deviant IBI values were identi-
fied using a 20% change from the previous IBI as a crite-
rion. They were corrected according to the guidelines of
. The beat-to-beat IBI data were transformed to equi-
distant IBI time series with 200 ms intervals using the
weighted-average interpolation method of . The spec-
tral analyses were conducted on 60-second segments of
the heart period series. The mean and trend were
removed from each IBI segment to exclude long-term
changes in the time series. The impedance data were
ensemble averaged within 60-s blocks. The Q-waves and
the B-points were determined by a careful visual exami-
nation with the aid of a self-programmed computer pro-
gram similar to that described by .
RSA was computed separately for each 60-s data seg-
ment. The logarithm of the variance (ms2) within the fre-
quency band associated with respiration (i.e., 0.12-0.40
Hz) was summed to index RSA. PEP, in ms, was calcu-
lated as the interval between the Q wave of the ECG and
the B-point of the dZ/dt waveform. HR, in bpm, was
computed for 60-s intervals from the mean IBI.
Mean HR, RSA, and PEP values were calculated for
each participant across each minute during the tasks. For
the resting periods, data were averaged across minutes 6,
7, and 8 during the 10-min initial baseline and last rest
baseline. Task HR, RSA, and PEP data were averaged
across the 6 min of the mental arithmetic task and across
the 3 min of the speech task. The mean of three speeches
was calculated and speech delivery period was used in the
present study. Reactivity scores were calculated by sub-
tracting the initial mean baseline value from average task
value (for each task separately). Averaged value for the
reactivity score across the two tasks was calculated
finally. Recovery scores were computed by subtracting
the initial mean baseline value from the average value
during the resting periods after the mental arithmetic and
The interaction between cardiac autonomic measures
and FMD in predicting carotid IMT was tested by linear
Chumaeva et al. BMC Cardiovascular Disorders 2010, 10:16
Page 4 of 8
regression analyses using SPSS Version 16.0. All regres-
sion models involving interactions between FMD and
cardiac reactivity/recovery were conducted separately for
reactivity and recovery terms, and separately for HR,
RSA, and PEP. Main effects of age, sex, brachial baseline
diameter, FMD, and the reactivity/recovery measure in
question were included in the regression models.
Table 1 shows the characteristics of the study variables.
Associations between the study parameters
Linear regression analyses showed that baseline HR,
baseline RSA, and baseline PEP were unrelated to IMT
(N = 75, p = 0.893; N = 76, p = 0.363; N = 75, p = 0.324,
respectively) and FMD (N = 69, p = 0.114; N = 70, p =
0.969; N = 69, p = 0.177, respectively). In addition, FMD
was not related to IMT (N = 74, p = 0.207). HR, RSA, and
PEP reactivity scores were not associated with FMD (N =
66, p = 0.805; N = 67, p = 0.615; N = 65, p = 0.152, respec-
tively). Likewise, HR, RSA, and PEP recovery scores were
unrelated to FMD levels (N = 65, p = 0.982; N = 66, p =
0.709; N = 65, p = 0.175, respectively).
Interactions between the cardiac measures and FMD in
Table 2 shows the results of linear regression analyses
examining the interactions of cardiac reactivity and
recovery with FMD for IMT. No significant interaction
effect of FMD and cardiac reactivity on IMT was found
A significant RSA recovery × FMD interaction (p =
0.037, N = 61) in predicting IMT was found. Further lin-
ear regression analyses conducted separately for high (N
= 31) and low (N = 30) FMD individuals (median split)
showed that, among participants with higher FMD, better
RSA recovery predicted lower IMT (β = 0.411, p = 0.022,
N = 31). No associations were found in low FMD partici-
pants (β = -0.265, p = 0.157, N = 30).
The PEP recovery × FMD interaction in predicting
IMT was also significant (p = 0.006; N = 61) (Table 2).
Linear regression analyses performed separately in high
(N= 31) and low (N = 30) FMD groups (median split)
showed that, among low FMD individuals, better PEP
recovery predicted lower IMT (β = 0.517, p = 0.003, N =
30). This association was non-significant in high FMD
subjects (β = 0.075, p = 0.690, N = 31). The HR recovery ×
Table 1: Characteristics of study participants
Variable Min MaxMean(SD)N
Age in 2001, years 24.0039.00 30.89 4.9281
dilatation, FMD, %
-0.26 23.436.785.00 74
0.43 0.960.590.09 81
Baseline HR, bpm 46.3094.4871.639.30 75
Baseline RSA, log
Baseline PEP, ms74.00 128.6796.9411.17 75
score, log ms2
-0.880.34-0.11 0.24 73
-44.335.30 -14.8010.65 70
HR recovery score,
score, log ms2
HR = heart rate (bpm); RSA = respiratory sinus arrhythmia (log ms2); PEP = pre-ejection period (ms).
Chumaeva et al. BMC Cardiovascular Disorders 2010, 10:16
Page 5 of 8
FMD interaction for IMT was non-significant (p = 0.886;
N = 61) (Table 2).
The results of the current study showed no significant
interactive effect of FMD and cardiac reactivity on IMT.
Previously, recovery responses have been reported to be
better predictors of cardiovascular risk than stress-
induced reactivity responses [18,19,34]. In line with this,
significant RSA recovery × FMD interactions in predict-
ing IMT, and a PEP recovery × FMD interaction for IMT,
were found in our study. Better RSA recovery responses
(mediated by parasympathetic activity) after acute mental
stress were shown to be related to lower IMT among par-
ticipants with higher FMD. These results are in agree-
ment with our previous findings demonstrating that
better cardiac recovery after acute mental stress is associ-
ated with less preclinical atherosclerosis among healthy
men and women . Other studies have also found that
impaired parasympathetic control is related to an
increased risk for early atherosclerosis development in
healthy individuals . In addition, slower PEP recovery
(mediated by sympathetic activity) after acute mental
stress was shown in our study to be related to higher IMT
among subjects with lower FMD. These results are in line
with the findings that acute mental stress may induce vas-
cular changes both among healthy individuals and among
patients with vascular disease . In addition, several
studies have reported negative relations between vascular
reactions in response to acute mental stress and endothe-
lial function [37,38].
It has been hypothesized that chronic stress can speed
up atherogenesis through the mechanism of autonomic
imbalance , and acute mental stress is associated with
sympathetic activation . In the current study, the rela-
tionship of slower PEP recovery to acute stress in combi-
nation with reduced FMD with higher IMT suggests that
slow sympathetic recovery increases the risk of athero-
sclerosis development among individuals with impaired
endothelial function, but not among subjects with normal
endothelial function. It is in agreement with the
response-to-injury model of atherosclerosis suggesting
that impaired endothelial function is a first step of ath-
erosclerosis development . Our results are also in line
with the findings that abnormalities in ANS regulation of
the cardiovascular system [41,42], as well as enhanced
endothelium-mediated atherogenic processes [43,44], are
typical for patients with cardiovascular and metabolic
However, the mechanisms underlying the relationships
between the ANS and endothelial systems and their joint
influence on atherosclerosis progression are not fully
clear. One of the recent hypotheses has considered ath-
erosclerosis as a vascular symptom of ANS dysregulation
induced by age, smoking, hypertension, dyslipidemia, and
diabetes . This hypothesis explains the atherogenic
processes as a result of a global ANS imbalance towards
to a state of enhanced sympathetic activity . In addi-
tion, local atherosclerotic tissue alterations, such as
endothelial dysfunction, have been suggested to result
from neurogenic adventitial stress mediated by ANS dys-
regulation . The delayed cardiovascular recovery may
Table 2: Linear regression examining the interactive effects of physiological reactivity/recovery and flow-mediated
dilatation on IMT (N = 61)
R2 change*** p-value
HR reactivity × FMD*0.380.310.002 0.704
RSA reactivity × FMD*0.330.25 0.0200.214
PEP reactivity × FMD* 0.460.40 0.0100.321
HR recovery × FMD*0.300.23 0.0000.886
RSA recovery × FMD*0.38 0.260.056
PEP recovery × FMD*0.430.36 0.087
*Each interaction is examined in a separate analysis including the main effects of sex, age, brachial baseline diameter, FMD, and the reactivity/
recovery measure in question, but the main effects are not presented in the Table.
**Calculated for the whole model.
***Refers to the interaction term.
HR = heart rate (bpm); RSA = respiratory sinus arrhythmia (log ms2); PEP = pre-ejection period (ms); FMD = flow-mediated dilatation (%).
Chumaeva et al. BMC Cardiovascular Disorders 2010, 10:16
Page 6 of 8
be considered as a result of a continual influence of acute
mental stressors on the cardiovascular system .
Our results showed that RSA recovery following acute
mental stress was related to atherosclerosis development
in young adults with a high level of FMD, whereas, for
PEP recovery the association with atherosclerosis devel-
opment emerged in participants with low FMD. The rea-
son for this discrepancy is not readily apparent. Our
results showing delayed RSA and PEP recovery may
reflect the autonomic imbalance. We can suggest that
ANS dysregulation is a very essential independent reason
for cardiovascular health problems, and it may increase a
risk of cardiovascular diseases independently on
endothelium functioning. In line with this suggestion,
ANS imbalance has been shown to be associated with
ineffective cardiovascular functioning or with a risk of
atherosclerosis even if the endothelium works properly,
i.e., among healthy individuals . On the other hand,
we can suggest, that harmful influence of ANS dysregula-
tion may be accelerated in impaired endothelium
(reflected by low FMD in the present study). Our results
reflect both these situations. In our study, slow RSA
recovery was shown to be related to an increased IMT in
normal endothelium, whereas slow PEP recovery was
related to higher IMTs in impaired endothelium. These
results are in line with the findings, that elevated sympa-
thetic activity [41,46] and impaired parasympathetic con-
trol  have been shown to exert a harmful effect on
cardiovascular functioning  or to be related with ath-
erosclerotic processes  in both healthy individuals
and in individuals with cardiovascular disease states. Car-
diac recovery seems to play an important role in athero-
sclerosis development in persons with high and low
FMD; however, we can suggest different impact of sym-
pathetic and parasympathetic nervous system in athero-
sclerosis risk in individuals with normal or impaired
endothelium. Thus, the role of sympathetically mediated
cardiac activity seems to be more important in those with
impaired FMD, and parasympathetically mediated in
those with relatively high FMD.
One possible mechanism linking ANS-mediated poor
cardiac recovery and atherosclerosis may be the develop-
ment of endothelial dysfunction. Accordingly, the associ-
ation of endothelial dysfunction and slow HR recovery
has recently been shown ; and endothelial dysfunc-
tion has been found to be associated with increased
carotid IMT . However, in a recent study, the contri-
bution of the sympathetic nervous system to the impair-
ment of endothelial function after acute mental stress has
been questioned, and an endothelin-A receptor mecha-
nism has been suggested to play a role in the endothelial
dysfunction-mediated relationship of mental stress with
atherosclerosis development .
There are some limitations in the present study. First, we
did not measure blood pressure responses; thus, we can-
not generalize our results to vascular reactivity and can-
not make conclusions regarding the reactivity hypothesis
that mainly concentrates on vascular reactivity.
Second, we did not measure respiration; thus, we can-
not be sure that respiration fell within the frequency band
used to compute RSA estimates. However, uncorrected
RSA has recently been shown to be viable in indexing
within-subject changes in the parasympathetic control of
HR in the majority of stress studies . It has been sug-
gested that during the stable experimental conditions
with constant respiratory parameters, the absence of
respiratory assessment may not preclude group contrasts
in well-specified populations with known patterns of res-
piration and large-amplitude RSA .
Third, the present analysis was conducted in partici-
pants aged 24 to 39 years. Our results cannot be general-
ized to older individuals
atherosclerosis. Finally, the ultrasound and cardiac auto-
nomic measurements were conducted only once, thereby
precluding conclusions concerning the progression of
In addition, the absence of blood pressure measure-
ment is a relevant limitation of the study. Therefore, we
cannot exclude the possibility of confounding.
with more manifest
Our results suggest that alterations in ANS functioning,
characterized by a decreased parasympathetic control in
combination with normal endothelial function or
increased sympathetic activity in combination with
impaired endothelial function, are associated to
increased risk of atherosclerosis progression in young
healthy individuals. Cardiac recovery seems to play an
important role in atherosclerosis development in individ-
uals with high and low FMD but the role of sympatheti-
cally mediated cardiac activity seems to be more
important in those with impaired FMD, and parasympa-
thetically mediated in those with relatively high FMD.
The present study is the first to demonstrate that the
development of endothelial dysfunction may be one pos-
sible mechanism linking slow cardiac recovery and ath-
erosclerosis via ANS pathways. Our results suggest that
psychophysiological risk factors may be associated with
the development of atherosclerosis via interactions
between the endothelial function and ANS regulation.
Chumaeva et al. BMC Cardiovascular Disorders 2010, 10:16
Page 7 of 8
The authors declare that they have no competing interests.
LK-J and OTR were responsible for planning the study. NC was responsible for
the data analysis and statistics. MH helped with data analysis and statistics. NC
and NR have made substantial contributions to conception and design and LK-
J, OTR, NR and MJ have made contribution to collecting and acquisition of
data. OTR, LK-J and TH participated in the study design and coordination. All
authors contributed in interpretation of data. All authors have been involved in
drafting the manuscript and revising it. NC and MH had the main responsibility
of the manuscript writing. All authors have read and given final approval of the
version to be published.
This study was supported by the Academy of Finland (Academy project num-
bers: 111056, 124399), Yrjö Jansson's Foundation (MH), Signe and Ane Gyllen-
berg's Foundation (LK-J and MH), Niilo Helander Foundation (MH), and The
Finnish Cultural Foundation (TH).
1Institute of Behavioural Sciences, University of Helsinki, P.O. Box 9, FIN-00014
Helsinki, Finland, 2Division of Medical Problems of Cell Biology, Institute of Cell
Biophysics, Institutional Street 3, Pushchino, Moscow region, 142290 Russia,
3Center for Knowledge and Innovation Research, Helsinki School of Economics,
P.O. Box 1210, 00101 Helsinki, Finland, 4Research Centre of Applied and
Preventive Cardiovascular Medicine, University of Turku, Kiinanmyllynkatu 10,
20520 Turku, Finland and 5Department of Clinical Physiology, University of
Turku and Turku University Hospital, P.O. Box 52, 20521 Turku, Finland
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Received: 3 September 2009 Accepted: 29 March 2010
Published: 29 March 2010
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Chumaeva et al. BMC Cardiovascular Disorders 2010, 10:16
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Cite this article as: Chumaeva et al., Early atherosclerosis and cardiac auto-
nomic responses to mental stress: a population-based study of the moderat-
ing influence of impaired endothelial function BMC Cardiovascular Disorders