Interactive effect of long-term mental stress and cardiac stress reactivity on carotid intima-media thickness: The Cardiovascular Risk in Young Finns study

Abstract

The present study examined the interaction between vital exhaustion and cardiac reactivity and recovery on preclinical atherosclerosis assessed by carotid intima-media thickness (IMT) in young men and women. We measured heart rate (HR), respiratory sinus arrhythmia (RSA), and pre-ejection period (PEP) in response to mental arithmetic and speech tasks. Vital exhaustion and carotid IMT were also measured. Significant associations were observed for men aged 28–37 years, but not for men aged 22–25 years, nor for women in these age groups. It was shown that, among highly exhausted men in the older age group, lower HR reactivity was related to greater IMT. Our results also imply that, among non-exhausted men in this age group, slow HR and RSA recovery after acute stress predicted higher IMT. These results suggest that long-term stress as assessed by vital exhaustion is a risk only if it has resulted in ineffective cardiac stress reactivity. Autonomic imbalance resulting from chronic stress may be the common mechanism linking vital exhaustion and cardiac responsiveness to an increased risk of atherosclerosis.

• Atherosclerosis
• cardiac reactivity
• chronic stress
• intima-media thickness
• parasympathetic tone
• ultrasound

Introduction

Coronary artery disease (CAD), which progresses gradually and leads to coronary heart disease (CHD), is still the leading cause of illness and death in Western industrialized countries. Mortality has decreased during the last decades although morbidity has not. However, overall mortality remains high, because CHD mortality has increased in the Eastern countries (Levi et al. 2002).

The pathological process responsible for CAD is atherosclerosis. Atherosclerosis develops slowly and gradually, and various genetic (Wood 2001; Seo et al. 2004), environmental, and life style risk factors may contribute to its progression (Wood 2001). Stress is one of the fundamental factors in the pathogenesis of atherosclerosis. Both acute (e.g. task-induced cardiac stress reactivity; Heponiemi et al. 2007) and chronic stress (e.g. long-term work stress; Hintsanen et al. 2005) have been shown to be associated with atherosclerosis.

The reactivity hypothesis proposes that elevated cardiovascular reactivity to stress is a risk factor for CAD (Matthews et al. 1986). Nevertheless, it has also been suggested that cardiac reactivity may be adaptive, reflecting behavioral plasticity, mobilisation of energy resources and successful coping in stressful situations (Dienstbier 1989; Tomaka et al. 1993). In line with this suggestion, we have found in the Cardiovascular Risk in Young Finns (CRYF) sample, that both parasympathetically and sympathetically mediated cardiac stress reactivity is related to a lower level of atherosclerosis in young adults (Heponiemi et al. 2007).

In addition to reactivity, a delayed cardiovascular recovery after stressful events might be an important risk factor for the development of cardiovascular disease (Schwartz et al. 2003). It has even been proposed that the rate of recovery may be a more important predictive factor of cardiovascular risk than stress reactivity (Palatini and Julius 1997; Brosschot and Thayer 2003; Pitsavos et al. 2004). A delayed recovery of heart rate (HR), in particular, has been associated with disease risk (Lipinski et al. 2004; Pitsavos et al. 2004). It has been found that a slow HR recovery after exercise reflects impaired parasympathetic activity (Pierpont and Voth 2004) that, in turn, predicts cardiovascular as well as total mortality (Cole et al. 2000). A prolonged high HR may contribute directly to the arterial wall abnormality (Brosschot and Thayer 2003), and be a risk factor for hypertension (Palatini and Julius 1997). Furthermore, it has been shown that a delayed HR recovery after exercise predicts coronary events (Pitsavos et al. 2004) and endothelial dysfunction (Huang et al. 2004) that, in turn, predicts progression of atherosclerotic disease (Schächinger et al. 2000). In line with these findings, results derived from the CRYF study showed that better cardiac recovery after a cognitive challenge is associated with a lower level of atherosclerosis (Heponiemi et al. 2007).

Acute stress reactivity demonstrates an individual's physiological response in stressful situations, but it might not reflect the general level of stress the individual experiences in daily life. Instead, general stress level is reflected by long-term psychological stress experience. It is controversial whether acute stress reactivity and experience of long-term psychological stress correlate at all, and if they do, which of these is more detrimental to health (Matthews et al. 1997). It has been suggested that chronic stress may impair an individual's capability to cope with acute stress (Matthews et al. 1997). To our knowledge, the interaction between acute stress reactivity and recovery, and long-term mental stress has not been examined in relation to atherosclerosis before. The current study was conducted to examine this issue.

Vital exhaustion is generally determined as a psychological state which can be described by unusual tiredness, a loss of physical and mental energy, feelings of demoralization, and heightened irritability (Appels and Mulder 1988; Ingles et al. 1999). Vital exhaustion has been viewed as an indicator of long-term mental stress (Ingles et al. 1999), and hypothalamic-pituitary-adrenocortical axis hypoactivity, that is, a decreased capacity to cope with stress (Keltikangas-Järvinen et al. 1996; Nicolson and van Diest 2000). Our previous finding on the association between vital exhaustion and cardiac stress reactivity (Keltikangas-Järvinen and Heponiemi 2004), suggests that vital exhaustion may serve as background stress and heighten a person's cardiac response to acute stress.

Vital exhaustion has also been suggested to be an independent risk factor for cardiovascular disease. It has been found to be associated with myocardial infarction (Appels and Mulder 1988) and stroke (Ingles et al. 1999), and has been considered to be a risk factor for ischemic heart disease (Prescott et al. 2003). The underlying mechanisms responsible for the elevated cardiac disease risk are not well-known, however. Exhaustion has been found to be related to reduced fibrinolytic capacity (Räikkönen et al. 1996) and to be a relevant parameter for atherosclerosis (Kop et al. 1994).

Carotid artery intima-media thickness (IMT) is a marker of subclinical atherosclerosis and increased IMT has been shown to predict future cardiovascular disease (O'Leary and Polak 2002). Ultrasound measurement of the common carotid artery IMT is widely used as a marker for atherosclerotic disease (Roman et al. 2006) and it may be utilized in testing the cardiovascular risk associated with cardiac reactivity and recovery (Heponiemi et al. 2007).

The aim of the present study was to explore the interaction between vital exhaustion and cardiac reactivity and recovery with atherosclerosis assessed by IMT. More specifically, we tested the following study questions: (a) Are feelings of vital exhaustion in combination with elevated cardiac reactivity associated with a higher prevalence of carotid atherosclerosis and (b) are exhausted participants who recover slowly from stress at an increased risk of atherosclerosis?

In many studies of vital exhaustion, a different effect of vital exhaustion between men and women has been found (Appels 2001; Keltikangas-Järvinen and Heponiemi 2004). Moreover, women develop atherosclerosis later in life than men, probably because of a protective role of female sex hormones (estrogen) (Manson 2002). In line with this findings it has recently been shown in 2265 subjects aged 24–39 years who took part in the CRYF study that men demonstrated a significantly increased risk of development of structural atherosclerosis (significantly greater carotid IMT) compared to women (Juonala et al. 2008).

IMT has also been found to increase significantly with age: by 6.3 ± 0.6 μm/year in men aged 24–39 years (Juonala et al. 2008). Thus the risk of atherosclerosis development is increased with age even in this young population. It is known that atherosclerosis is a dynamic and progressive disease, and, although the first clinical manifestations of the disease usually occur at older ages, atherosclerotic changes in the coronary arteries begin to form early in life, often during childhood (Stary 1989). Therefore, it is important to identify the first stages of atherosclerosis. Overall, we may hypothesize that effects on atherosclerosis are most pronounced in men and they increase with increasing age.

Materials and methods

Sample

The participants were 69 healthy men and women aged 22–37 years (in 1999), who were randomly selected from the participants in the ongoing prospective epidemiological CRYF study (Åkerblom et al. 1991). Since 1980, the CRYF study has been monitoring the development of risk factors for CHD in the population based sample of, originally, 3596 healthy Finnish children, adolescents, and young adults. The design of the study and the sample have been described previously (Åkerblom et al. 1991). Of the original CRYF sample, 2265 participants were examined in 2001 by measuring carotid IMT. The acute stress test (a speech task and mental arithmetic task) was administered two years before the ultrasound testing (in 1999).

The present sample (originally a total of 100 subjects) was randomly chosen from the subjects who participated in the psychological follow-up in 1997, and who lived in the urban and rural districts within a 100 km radius of Helsinki (n = 382). Ninety-five participants entered the psychophysiological experiment in 1999. Valid vital exhaustion questionnaires were obtained from 79 participants. Complete data on vital exhaustion in 1999 and IMT was obtained from 69 participants who took part in the psychophysiological measurements in 1999. They comprised the final sample of the present study. In the interaction analyses presented here, the number of participants varied from 56 to 63 for the whole group of participants. The study was approved by the local ethics committees and was in accordance with the Helsinki Declaration. All subjects gave their written, informed consent (Figure 1).

Figure 1 Forming the final sample from the Cardiovascular Risk in Young Finns study. CHD, coronary heart disease; IMT, carotid intima-media thickness; VE, vital exhaustion.

Cardiac measures

Cardiac autonomic measures used were HR, respiratory sinus arrhythmia (RSA; index of the parasympathetic control of HR), and pre-ejection period (PEP; index of sympathetic control of HR).

Electrocardiogram (ECG) and the first derivative of the pulsatile impedance signal (dZ/dt) were measured continuously during the experiment with a Minnesota Impedance Cardiograph Model 304B (Surcom Inc., Minneapolis, MN, USA). A tetrapolar aluminum/mylar tape electrode configuration was used, with four electrodes completely encircling the body, following guidelines set by Sherwood et al. (1990). ECG and dZ/dt signals were sampled continuously at a rate of 500 Hz, digitized with a 12-bit 8-channel 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, USA).

Carotid artery protocol

Ultrasound studies were performed using Sequoia 512 ultrasound mainframes (Acuson, CA, USA) with 13.0 MHz linear array transducers. The left carotid artery was scanned by ultrasound technicians following a standardized protocol (Raitakari et al. 2003). In brief, a magnified image was recorded from the angle showing the greatest distance between the lumen–intima interface and the media–adventitia interface. A moving scan with duration of 5 s, which included the beginning of the carotid bifurcation and the common carotid artery, was recorded and stored in digital format on optical discs for subsequent off-line analysis. The digitally stored scans were manually analyzed by a single reader blinded to the participants' details. The analyses were performed using ultrasonic calipers. From the 5 s clip image, the best quality end-diastolic frame was selected (coincident with the R-wave on a continuously recorded ECG). From this image, at least four measurements of the common carotid far wall were taken approximately 10 mm proximal to the bifurcation to derive mean carotid IMT. To reduce observer bias, the sonographers were instructed to scan the common carotid in the angle showing the greatest IMT. We have reported 6.4% between-visit coefficient and 5.2% between observer coefficient of variation for the IMT measurements (Raitakari et al. 2003).

Vital exhaustion

Vital exhaustion was assessed with the Maastricht Questionnaire, a 21-item checklist of signs and symptoms of exhaustion (Appels et al. 1987). Cronbach's alpha was 0.91, indicating good reliability. Instead of the original true–false response format, each of the items was rated on a five-point scale, ranging from 1 (not true for me at all) to 5 (true for me). The mean score of all items was used to index the level of vital exhaustion. The questionnaire was sent to the participants before the psychophysiological experiment included here (carried out in 1999) to be completed at home and returned at their laboratory visit or shortly after it by mail.

Experimental procedure

Each participant underwent a standardized computer-controlled experimental session of about 180 min. The procedure started at the same time of day (9:00 am) for all participants. The subjects were instructed to abstain from consumption of caffeine and cigarettes for 12 h before the experiment. The experiment was carried out in a room equipped with a computer with a large screen for stimulus presentation, and with a video camera to monitor the participant. Participants were seated in an upholstered chair during all procedures. An initial 10-min rest period preceded a series of five tasks, each of which was followed by a rest period. The tasks were an emotion-evoking picture viewing, an acoustic startle stimulus, a mental arithmetic task, a reaction time task, and a speech task. The last rest after all tasks lasted 10 min. The mental arithmetic task and speech task were included in the present study. The other tasks were omitted because the reactivity profiles related to them are different from those of the two chosen tasks that produce a strong increase in HR and a decrease in RSA and PEP (Matthews et al. 1986; Cacioppo et al. 1994b; Al'Absi et al. 1997). A clear advantage of the public speaking task is that it occurs frequently in daily life and is therefore a natural stressor. Mental arithmetic is, in turn, an active-coping task that requires sensory rejection and imposes substantial demands on working memory. The public speaking and mental arithmetic stressors produce responses that are of comparable magnitude, stable, uniform, and resemble daily life responses (Bongard 1995; Al'Absi et al. 1997).

Mental arithmetic

For the mental arithmetic task, the participants were asked to perform continuously six 1-min serial subtraction problems. The minuend was 297, 688, 955, 593, 1200, and 1741 for minutes 1, 2, 3, 4, 5, and 6, respectively. The subtrahend in minute 1 was 3. To maintain maximal task involvement and moderate task difficulty (i.e. approximately 10 correct answers/min), the subtrahend specified for each subsequent minute was contingent on the participant's performance during the preceding minute. The minuend and the subtrahends were presented on the computer screen, and participants gave their answers using the keyboard. The participant was told that the three best participants would be awarded a prize of $40, which made mental arithmetic mainly an appetitive task requiring sensory rejection (Turner 1994).

Speech task

The speech task involved three scenarios in which the participant was asked to construct and deliver a 3-min public speech after a 3-min silent preparation period. Two experimenters (one male and one female) were sitting in the room during the task as an audience and the speech was videotaped. The participants were told that the speech would be evaluated later and that the best-rated speeches would be awarded a prize of $40. Three scenarios were presented in a counterbalanced order: (a) a presentation based on a Reader's Digest article about the need for sleep (high in informational content but lacking emotional content); (b) the participant's own reasoned opinion about homosexuals' rights to marry and adopt children (at that time a much discussed topic in the media); and (c) a speech in which the participants were to defend themselves in a hypothetical scenario in which they were wrongly accused of shoplifting. The public speech task is known to have a great deal of social relevance and ecological validity. Similar scenarios have previously been used by Al'Absi et al. (1997), among others.

Data treatment

Cardiac interbeat intervals (IBIs), in ms, were determined from the ECG signal. Deviant IBI values were identified using a 20% change from the previous IBI as a criterion. If needed, values were corrected following the guidelines of Porges and Byrne (1992). The beat-to-beat IBI data were transformed to equidistant IBI time series with 200 ms intervals using the weighted-average interpolation method of Cheung and Porges (1977). To conduct a time series analysis, IBI series were divided into separate 60-s blocks. 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 examination with the aid of a self-programmed computer program similar to that described by Kelsey and Guethlein (1990).

RSA has been found to be an accurate non-invasive indicator of parasympathetic regulation of HR when respiration falls within the usual respiratory frequencies (Porges and Bohrer 1990). It is widely measured by quantifying the amplitude of rhythmic fluctuations in HR that are associated with breathing frequencies. RSA was computed separately for each 60-s data segment. The total variance (in ms²) within the respiratory range (0.12–0.40 Hz) was summed to index RSA (Berntson et al. 1997). RSA was logarithm-transformed to reduce positive skewness.

PEP, as derived from systolic time intervals, provides a reliable noninvasive marker of cardiac sympathetic activity, so long as variations in preload and afterload are small (Cacioppo et al. 1994a,b). PEP, in ms, was calculated as the interval between the Q-wave of the ECG and the B-point of the dZ/dt waveform. In addition, HR, in bpm, was computed for each participant in 60-s intervals from the mean IBI.

One-minute means for baseline HR, RSA, and PEP were averaged across minutes 6, 7, and 8 during the 10-min initial baseline and last rest; and across minutes 4, 5, and 6 during 8-min rest after the mental arithmetic task. 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. We used the mean of speech preparation and speech delivery periods. The mean of three speeches was calculated. Reactivity scores were computed by subtracting the initial mean baseline value from the average task value (for each task separately). Finally, the averaged value for the reactivity score across the two tasks was calculated. Recovery scores were computed by subtracting the initial mean baseline value from the average value during the resting periods after the mental arithmetic and speech tasks.

Statistical analysis

The interaction between cardiac autonomic measures and vital exhaustion in predicting carotid IMT was studied by linear regression analyses using SPSS Version 13.0. All regression models for interactions between vital exhaustion and reactivity/recovery on IMT were conducted separately for reactivity terms and recovery terms and separately for HR, RSA, and PEP. In the first analysis, the carotid IMT was regressed on vital exhaustion and HR reactivity, and interaction of vital exhaustion and HR reactivity. Vital exhaustion, RSA reactivity, and interaction of vital exhaustion and RSA reactivity were examined in another analysis. Similarly, vital exhaustion, PEP reactivity, and interaction of vital exhaustion and PEP reactivity were examined in still another analysis. Similar regression models were used for cardiac recovery. Vital exhaustion and physiological measures included in interaction models were centralized to avoid multicollinearity (Aiken and West 1991).

First, the data were analyzed for all participants together. Then, the participants were divided into four groups – younger women (22–25 years); older women (28–37 years); younger men (22–25 years); older men (28–37 years). This method was chosen because it is known that women develop heart disease several years later than men (Rossouw 2002), and because the atherosclerosis development is more advanced in older populations the associations to atherosclerosis become clearer in older subjects even within a young population (Juonala et al. 2008). It is therefore likely that the two sex and age groups present different associations between the physiological stress responses and measures of IMT, especially in highly exhausted participants.

Regression analyses were conducted separately for these four groups using the linear regression models described above. Of the four investigated groups, significant relationships were observed only for the group of men aged 28–37 years. Only the results for this group are presented in more detail. In the interaction analyses, the number of participants varied from 19 to 23 in this group.

Results

Tables I and II show the mean values for the study characteristics in women in the two age groups: 22–25 and 28–37 years (Table I), and in men in the two age groups: 22–25 and 28–37 years (Table II).

Table I.  Study characteristics for women.

	Age group
	22–25 years			28–37 years
Variable	Mean	(SD)	N	Mean	(SD)	N
Age in 1999 (years)	23.50	1.55	16	31.41	3.50	22
Initial baseline HR (bpm)	74.84	9.28	14	72.11	8.06	20
Initial baseline RSA (log ms^2)	2.82	0.30	15	2.82	0.23	20
Initial baseline PEP (ms)	94.53	12.63	15	95.06	7.62	22
HR reactivity (bpm)	88.79	14.45	14	93.62	13.31	20
RSA reactivity (log ms^2)	2.76	0.24	15	2.65	0.22	20
PEP reactivity (ms)	83.55	11.16	15	77.12	12.51	18
HR recovery (bpm)	70.77	10.25	14	69.89	10.19	20
RSA recovery (log ms^2)	2.86	0.24	15	2.82	0.21	20
PEP recovery (ms)	95.28	13.62	15	96.55	7.90	20
Carotid IMT (mm)	0.57	0.08	16	0.60	0.07	22
Vital exhaustion	2.34	0.54	16	2.13	0.53	22

Note: HR, heart rate; RSA, respiratory sinus arrhythmia; PEP, pre-ejection period; IMT, intima-media thickness.

Table II.  Study characteristics for men.

	Age group
	22–25 years			28–37 years
Variable	Mean	(SD)	N	Mean	(SD)	N
Age in 1999 (years)	24.57	1.13	7	32.62	3.54	24
Initial baseline HR (bpm)	64.22	13.76	7	70.45	7.97	24
Initial baseline RSA (log ms^2)	3.06	0.16	7	2.81	0.19	24
Initial baseline PEP (ms)	94.29	6.70	7	99.54	13.63	21
HR reactivity (bpm)	82.86	25.73	7	83.90	12.07	23
RSA reactivity (log ms^2)	2.84	0.30	7	2.71	0.22	23
PEP reactivity (ms)	81.49	17.39	7	79.78	19.51	20
HR recovery (bpm)	66.12	17.40	7	68.87	9.09	23
RSA recovery (log ms^2)	2.99	0.12	7	2.85	0.25	23
PEP recovery (ms)	98.14	10.96	7	99.17	13.77	22
Carotid IMT (mm)	0.50	0.05	7	0.61	0.08	24
Vital exhaustion	1.90	0.50	7	1.95	0.63	24

Note: HR, heart rate; RSA, respiratory sinus arrhythmia; PEP, pre-ejection period; IMT, intima-media thickness.

Association of vital exhaustion and IMT

Linear regression analyses showed that vital exhaustion was not related to IMT among all participants (N = 69, p = 0.76) nor in any age of sex group (p≧0.37).

Cardiac reactivity × vital exhaustion in predicting IMT

No significant interaction effect of vital exhaustion and cardiac reactivity on IMT was found for women aged 22–25 years and 28–37 years (Table III) and for the group of younger men aged 22–25 years (Table IV).

Table III.  Regression analyses examining interactions of cardiac reactivity and vital exhaustion on IMT and interactions of cardiac recovery and vital exhaustion on IMT for women aged 22–25 and 28–37 years.

	22–25 years				28–37 years
	R^2	R^2 change	p-value	N	R^2	R^2 change	p-value	N
Reactivity
HR reactivity	0.38			12	0.10			16
HR reactivity × VE*		0.10	0.298			0.01	0.781
RSA reactivity	0.40			13	0.05			16
RSA reactivity × VE*		0.12	0.203			0.01	0.778
PEP reactivity	0.39			13	0.17			17
PEP reactivity × VE*		0.07	0.326			0.02	0.584
Recovery
HR recovery	0.21			10	0.21			15
HR recovery × VE*		0.04	0.621			0.16	0.161
RSA recovery	0.27			12	0.07			15
RSA recovery × VE*		0.00	0.978			0.02	0.629
PEP recovery	0.42			12	0.02			15
PEP recovery × VE*		0.05	0.407			0.00	0.950

Note: HR, heart rate (bpm); RSA, respiratory sinus arrhythmia (log ms²); PEP, pre-ejection period (ms); VE, vital exhaustion

* Main effects of VE were included in each analysis but they are not reported in the table.

Table IV.  Regression analyses examining interactions of cardiac reactivity and vital exhaustion on IMT and interactions of cardiac recovery and vital exhaustion on IMT for men aged 22–25 and 28–37 years.

	22–25 years				28–37 years
	R^2	R^2 change	p-value	N	R^2	R^2 change	p-value	N
Reactivity
HR reactivity	0.74			7	0.43			23
HR reactivity × VE^†		0.07	0.452			0.42	0.001*
RSA reactivity	0.74			7	0.14			23
RSA reactivity × VE^†		0.02	0.671			0.14	0.095
PEP reactivity	0.75			7	0.23			20
PEP reactivity × VE^†		0.05	0.580			0.14	0.109
Recovery
HR recovery	0.68			7	0.32			23
HR recovery × VE^†		0.11	0.381			0.26	0.014*
RSA recovery	0.82			7	0.41			23
RSA recovery × VE^†		0.00	0.794			0.39	0.002*
PEP recovery	0.56			7	0.35			19
PEP recovery × VE^†		0.00	0.911			0.03	0.399

Note: HR, heart rate (bpm); RSA, respiratory sinus arrhythmia (log ms²); PEP, pre-ejection period (ms); VE, vital exhaustion

* Significance level set at p < 0.017

^† Main effects of VE were included in each analysis but they are not reported in the table.

Table IV presents the results of linear regression analyses for interactions of cardiac reactivity with vital exhaustion on IMT in men in the older age group. A significant HR reactivity × vital exhaustion interaction effect (p = 0.001) in predicting IMT was found. Further linear regression analyses conducted separately for older men with high level of exhaustion and low level of exhaustion (divided at the median, N = 23) showed that among older men with a high level of vital exhaustion, greater HR reactivity predicted lower IMT (β = − 0.74, p = 0.006, N = 12). This association was non-significant in older men with a low level of exhaustion (β = 0.52, p = 0.098, N = 11). RSA reactivity × vital exhaustion interaction and PEP reactivity × vital exhaustion interaction effects on IMT were non-significant (p = 0.095; p = 0.11, respectively) (Table IV).

Cardiac recovery × vital exhaustion in predicting IMT

No significant interaction effect of vital exhaustion and cardiac recovery on IMT was observed for women aged 22–25 years and 28–37 years (Table III) and for men aged 22–25 years (Table IV).

Table IV presents interactions of cardiac recovery with vital exhaustion on IMT in men in the older age group. The HR recovery × vital exhaustion interaction effect was significant (p = 0.014) in predicting IMT. Further linear regression analyses conducted separately for older men with high level of exhaustion and low level of exhaustion (divided at the median, N = 23) showed that better HR recovery predicted lower IMT levels among men low in vital exhaustion (β = 0.77, p = 0.005, N = 11). HR recovery did not predict IMT in older men with high level of exhaustion (β = − 0.42, p = 0.168, N = 12). An RSA recovery × vital exhaustion interaction effect was significant in predicting IMT levels for men in the older age group (p = 0.002). Separate linear regression analyses for participants with high and low levels of exhaustion showed that among older men with low level of exhaustion, better RSA recovery (high RSA level) predicted lower IMT (β = − 0.75, p = 0.008, N = 11). RSA recovery in older men with high level of vital exhaustion did not predict IMT (β = 0.51, p = 0.087, N = 12). A PEP recovery × vital exhaustion interaction effect on IMT was non-significant in older men (p = 0.40).

To take into account the multiple statistical tests, the alpha level (p = 0.05) was corrected by dividing it by the number of physiological parameters used in our analyses (three). This resulted in a new p-value of 0.017. The above mentioned significant interactions remained significant after this correction (see Table IV).

Discussion

An association between vital exhaustion and greater parasympathetic reactivity in response to experimental challenge has been previously reported in 76 randomly selected healthy young men and women participating in the CRYF study (Keltikangas-Järvinen and Heponiemi 2004). In the current study, we found that vital exhaustion was not related to carotid IMT, but interacted with task-induced stress reactivity: HR reactivity to laboratory stressors seemed to be associated with a lower level of atherosclerosis in men with a high level of vital exhaustion. More specifically, among older men with a high level of vital exhaustion, elevated HR reactivity was associated with low IMT values, whereas low HR reactivity was related to high IMT. Thus, long-term stress is suggested to be pathogenic only in combination with low cardiac reactivity, i.e. when chronic mental stress is considered to have suppressed the autonomic nervous system (ANS) responses to acute stressors. This mental and physiological fatigue may indicate a risk of atherosclerosis.

Our results support the previous propositions (Dienstbier 1989; Tomaka et al. 1993) that increased cardiac reactivity should not necessarily be considered harmful. Elevated cardiac reactivity responses to mental stress may result from a normal reaction of the ANS and indicate adaptive and effective coping with stressful events (Dienstbier 1989). Accordingly, previous studies have reported an inverse association between HR reactivity and carotid IMT (Barnett et al. 1997; Heponiemi et al. 2007).

Vital exhaustion has been previously found to be related to withdrawal of parasympathetic tone, that is, to low RSA magnitudes during stress (Keltikangas-Järvinen and Heponiemi 2004). Furthermore, vitally exhausted individuals have been shown to have low HR variability (Watanabe et al. 2002), resulting in greater variability in blood pressure, which, in turn, could promote atherosclerosis development (Sloan et al. 1999). Autonomic dysfunction seems to be the common mechanism linking vital exhaustion and cardiac responses to an increased risk of atherosclerosis.

In the current study, among men with a low level of vital exhaustion, slower HR recovery predicted greater IMT. In addition, our results imply that slower RSA recovery (low RSA level) after acute stress is related to more advanced atherosclerosis development among older men in the low level of vital exhaustion group.

No significant associations for HR and RSA recovery with IMT were found in the group of older men with a high level of vital exhaustion. It is possible that the ability to recover after acute stress may have deteriorated in the whole group of vitally exhausted older men so that variance in recovery was less. Therefore, possible differences related to recovery may be difficult to find in this group.

A slow HR recovery is clinically important because it has been shown to be a risk factor for coronary disease and coronary disease events (Lipinski et al. 2004; Pitsavos et al. 2004), and it also predicts total mortality (Cole et al. 2000). The underlying mechanisms linking HR recovery and cardiovascular morbidity are unclear. One possible mechanism is endothelial dysfunction as this is associated with slow HR recovery (Huang et al. 2004). Association of endothelial dysfunction with increased carotid IMT (Juonala et al. 2004), implies that slow HR recovery might be linked to carotid atherosclerosis. Endothelial dysfunction may contribute to inflammatory processes in the walls of arteries and thus speed up atherosclerosis development (Järvisalo et al. 2006). In addition, known links between HR recovery and both blood glucose level (Carnethon et al. 2003) and insulin resistance (Lind and Andrén 2002), and possible links between these metabolic factors and carotid atherosclerosis (Folsom et al. 1994), offer another potential explanation for the found association between slow HR recovery and carotid atherosclerosis.

Responses mediated by autonomic nervous system function, especially, parasympathetic reactivation, are an important determinant of HR recovery (Ferrari 1993; Pierpont and Voth 2004). Recent exercise stress research has reported that impaired parasympathetic activity indicated by slow HR recovery is related to risk for early atherosclerosis in healthy middle-aged men (Jae et al. 2008). Furthermore, patients with reduced HR recovery have a greater number of established atherosclerotic changes in coronary arteries compared to patients without reduced HR recovery to exercise testing (Lipinski et al. 2004). These findings suggest that atherosclerosis occurs in concert with low parasympathetic control.

In the current study, predictive interaction of long-term stress and acute stress reactivity and recovery to preclinical atherosclerosis was only observed in men. These results are in line with previous research reporting a gender gap in CHD development, CHD mortality, and behavioral and psychosocial coronary risk factors favoring women (Weidner 2000). Furthermore, it has been previously shown in the CRYF study that work stress was associated with IMT only in men (Hintsanen et al. 2005). Based on considerable evidence, it has been proposed that, as compared to women, stress coping strategies in men might be less effective behaviorally, physiologically and emotionally, therefore leading to elevated risk of heart diseases (Courtenay 2000; Weidner 2000).

Methodological considerations

There are some limitations in the current study. First, we did not measure blood pressure responses, thus our results cannot be generalized to vascular reactivity and we cannot draw inferences regarding the reactivity hypothesis, which mainly focuses on vascular reactivity. Second, we did not measure respiration; thus, we cannot be sure that respiration fell within the frequency band used to compute RSA estimates. However, uncorrected RSA has been shown to be valid in indexing within-subject changes in parasympathetic control of HR in the majority of stress studies (Houtveen et al. 2002). It has been suggested that under experimental conditions, when respiratory parameters do not change essentially, the absence of respiratory assessments may not preclude group contrasts in well-specified populations with known patterns of respiration and large-amplitude RSA (Berntson et al. 1997). Additionally, some studies have shown that RSA that has not been controlled for respiration, is related to invasively estimated parasympathetic cardiac activity (Akselrod et al. 1981).

The present analysis was conducted in participants aged 22–37 years. The results cannot be directly generalized to older individuals with more pronounced atherosclerosis. Because of our small sample size the results should be considered as preliminary, and need replication in a larger sample.

Our design was longitudinal as we measured VE and physiological measures two years before IMT. However, as vital exhaustion, IMT and physiological cardiac reactivity/recovery were measured only once, the design of the present study does not enable us to make inferences regarding the progression of carotid atherosclerosis, or to establish firm cause and effect relations.

Conclusions

Our results imply that vitally exhausted men aged 28–37 years are not at increased risk of carotid atherosclerosis if they retain an ability to produce high cardiac reactivity in an acute challenging situation. A combined effect of vital exhaustion and low cardiac reactivity during experience of an acute psychological stressor was, instead, related to an increased risk of atherosclerosis as determined by greater IMT. It is possible that for the group of men with suppressed cardiac reactivity, chronic mental stress might have caused changes in the functioning of the ANS that have increased their risk for atherosclerosis. Autonomic imbalance may be the common mechanism linking vital exhaustion and cardiac responses to an increased risk of atherosclerosis.

Acknowledgements

This study was supported by the Academy of Finland (Academy project nos: 111056, 209514, 124399, project no. 123621 for L.P.-R.), Research Funds of the University of Helsinki (project no. 2106012 for L.P.-R.), Yrjö Jansson's Foundation (L.K.-J. and M.H.), Signe and Ane Gyllenberg's Foundation (L.K.-J. and M.H.) and Niilo Helander Foundation (M.H.).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.