Despite medical advances that have improved coronary artery disease (CAD) outcomes over the past fifty years, CAD remains the most common cause of premature mortality, accounting for almost one third of all deaths worldwide (Piepoli et al., 2016; Al-Mallah et al., 2018). CAD typically includes diagnoses of angina pectoris, and may lead to acute coronary syndrome (ACS) (De Lemos and Omland, 2017). Acute stress can act as a trigger for ACS, such as myocardial infarction and unstable angina pectoris (Amsterdam et al., 2014). Meanwhile, prolonged or chronic stress is considered an important risk factor for the development and progression of cardiovascular diseases (Holmes et al., 2006).

The traditional reactivity hypothesis states that higher cardiovascular response to emotional stressors contributes to the etiology of cardiovascular pathology (Steptoe and Kivimäki, 2012). However, a growing body of evidence posits that maladaptive regulation of the autonomic nervous system (ANS) can be expressed not only by exaggerated but also by blunted cardiovascular response to stress, both of which may signal physiological dysregulations (Lovallo, 2011). Prolonged psychological stress may disrupt biological regulatory systems, such as ANS, and so may lead to maladaptive blunted cardiovascular response (Hughes et al., 2018). Low cardiovascular responses to stress have been found to be associated with indices of poor health, such as physical disability (Phillips et al., 2011) and obesity (Phillips et al., 2012). Blunted cardiovascular response have also been associated with characteristics of psychological distress in cardiac patients, including Type D (Distressed) personality (Denollet, 2005) as well as anxiety and depressive symptoms (Howard et al., 2011; Kupper et al., 2013; Gecaite et al., 2019). Even though there are no clear cut-off points for determining whether the cardiovascular response is exaggerated or diminished (often referred to as “blunted”) (Turner, 1994), a burgeoning scientific literature suggests that blunted stress reactions are themselves associated with adverse health outcomes (Phillips et al., 2013).

Fatigue, defined as the multidimensional subjective experience of persistent and extreme tiredness, mental and physical exhaustion (Smets et al., 1995; Ream and Richardson, 1996; Aaronson et al., 1999), is one of the most frequent and distressing symptoms reported by patients with CAD after ACS (Burkauskas et al., 2017; Johnston and Eckhardt, 2018). In patients with CAD, the prevalence of moderate to severe fatigue has been reported to be as high as 39% during cardiac rehabilitation (CR), remaining up to 28% after 1 year (van Geffen et al., 2015). Meanwhile, mental fatigue is considered a risk factor for the development of heart diseases (Guan et al., 2017), while unusual fatigue is a strong predictor of longer prehospital delay (Zègre-Hemsey et al., 2018), poor health-related outcomes, and increased mortality (Irvine et al., 1999). Considering fatigue within the context of emotional stress, it may not only be a distressing symptom itself but also may play an important role in determining the effort and motivation to perform a task (Wright, 2014), and so in turn may shape variations of cardiovascular response to stress (Wright, 2009).

To date, there have been several studies suggesting positive associations between higher fatigue and higher perceived stress in patients with CAD after ACS (Cameron et al., 2005; Fredriksson-Larsson et al., 2015). However, to our knowledge, no study has examined links between psychophysiological stress parameters, such as cardiovascular response to stress, and fatigue in patients with heart related conditions (Johnston and Eckhardt, 2018), even though the psychophysiological research underlying the interplay between ANS and fatigue in this population is often proposed (Matura et al., 2018). Only several earlier studies in different populations reported that heart rate (HR) reactivity to mental stressor was lower in patients with chronic fatigue syndrome (CFS) than in healthy controls (Soetekouw et al., 1999). Meanwhile, significant inverse associations between the systolic blood pressure (SBP) and diastolic BP (DBP) response during mental stress and fatigue severity were detected in young women (Nolte et al., 2008). Nevertheless, conflicting results (Wright et al., 2008) and non-significant associations (Nelesen et al., 2008) have also been documented.

Considering the limited and inconsistent research regarding fatigue and its effects on cardiovascular response during mental stress, the current study aimed to investigate the relationship between cardiovascular response to mental stress and subjective fatigue in patients with CAD after ACS. Taking into account the results from previous studies (Soetekouw et al., 1999; Nolte et al., 2008), it was hypothesized that higher subjective fatigue would be associated with diminished cardiovascular response (ΔSBP; ΔDBP; ΔHR) to mental stress, even after possible confounders were considered.

Based on the criteria outlined above, 17 univariate outliers were identified, which were removed from the analysis. Thus, the remaining analysis was completed with 142 study patients. In terms of internal consistency, all study questionnaires and subscales showed adequate Cronbach α-coefficients (Tavakol and Dennick, 2011) as depicted in Table 1, and were used in the remaining analysis.

The present study investigated whether subjectively experienced fatigue is associated with cardiovascular function before, during and after mental stress in CAD patients who have experienced ACS. It was hypothesized that higher subjective fatigue would be linked with diminished cardiovascular function during mental stress. In the present study, effects were observed for cardiovascular function during anticipatory stress, while participants were preparing an oral presentation as part of the TSST. Associations were found for global fatigue, mental fatigue, and total fatigue. All measures of fatigue were associated with diminished cardiovascular function during anticipatory stress. These effects remained significant even after controlling for gender, age, education, heart failure severity, history of smoking, use of nitrates, anxiety/depressive symptoms, and presence of Type D personality, as well as perceived efforts and difficulty of the task. While the observed effects for fatigue arose for anticipatory stress, fatigue was not predictive of cardiovascular function during active stress phases of the TSST.

The current study is the first to explore links between fatigue and cardiovascular responses to stress in patients with CAD. It extends prior research investigating similar associations in other populations. For example, Nolte et al. (2008) investigated associations between cardiovascular stress reactivity and naturally occurring fatigue in undergraduate women, and found that blood pressure during stress was inversely associated with fatigue. Their study drew attention to the potential role of subjective task difficulty and effort in such effects (Nolte et al., 2008; Wright et al., 2008; Wright, 2009). Taking this into consideration, in the present study, all observed associations for fatigue and cardiovascular function during anticipatory stress remained significant even while controlling for subjective difficulty and efforts, as well as for other sociodemographic and clinical parameters.

Similar to the current study results, Soetekouw et al. (1999) reported that persons with CFS exhibited suppressed HR during mental arithmetic stress compared to controls, indicating maladaptive cardiac sympathetic reactivity to mental stress. While the methodology and study population differed, the present study yielded broadly similar findings. Together, both studies further implicate diminished cardiovascular stress reactivity as an indicator of maladaptive autonomic response that characterize poor states of health (Lovallo, 2011; Hughes et al., 2018).

Despite the consistent findings with previous research (Soetekouw et al., 1999; Nolte et al., 2008), the findings of the present study contrast with other published results. For instance, Wright et al. (2008) found an association between high fatigue and higher cardiovascular reactivity to an emotional stressor in female college students. Another study by Nelesen et al. (2008) reported no effect of fatigue with regards to cardiovascular reactivity during a mental stress challenge. These different results likely arise due to their methodological and population differences, chiefly the age and disease status of the participants, but also differences in the measurement of fatigue.

The current study revealed that an apparently blunted cardiovascular response to anticipatory stress is associated with subjectively experienced fatigue in CAD patients who have experienced ACS. Phillips et al. (2013) have summarized several reasons why diminished cardiovascular stress responsivity can arise, including lower task effort, reduced stress perception, disproportionate feelings of task difficulty, reduced physiological capacity to respond, and motivational dysregulation within brain activity. In this study, even while controlling for subjective efforts and assumed difficulty of the task, associations between lower cardiovascular stress reactivity and fatigue remained, suggesting—perhaps—that the effects were related more to central dysfunction than to perceptual factors. However, it was beyond the scope of this study to investigate the reduced physiological capacity to respond to stressful stimuli or motivational dysregulation.

Neither blunted nor exaggerated stress reactions can be considered adaptive (Phillips et al., 2013). In this study it was found that in CAD patients who were more fatigued, cardiovascular reactivity was more diminished during anticipatory stress. Anticipation ordinarily helps the body to prepare for oncoming stress. When an individual is suffering with fatigue, it may lead to poor bodily preparation for the upcoming stressor, thereby compounding the maladaptive effects of fatigue. It is well established that individuals with CFS show significant changes in the function of sympathetic as well as parasympathetic nervous systems (Soetekouw et al., 1999). The sympathetic nervous system predominance in persons with chronic fatigue highlights the way in which fatigued individuals are constantly under stress (Luyten et al., 2011), which leads to sympathetic over-activity (Martínez-Martínez et al., 2014). It has been argued that constant sympathetic over-activity could be partly responsible for lost functional capacity to confront life stressors (Siegrist et al., 1989). If that is the case, the current finding of blunted anticipatory cardiovascular stress response and its independent association with fatigue in patients with CAD after ACS may reflect maladaptive cardiac functioning.

Despite the consistent findings, several limitations should be noted. First, this study was completed in a single unit of a CR clinic. Therefore, generalizability to other cohorts should not be assumed until corroborated. Secondly, the current research followed a cross-sectional study design, thus a possible causational relationship between cardiovascular stress reactivity and subjective fatigue could not be drawn and further longitudinal studies are required. Thirdly, there was no inclusion of a healthy control group, which could have allowed for comparison of the cardiovascular stress response between those with CAD after ACS, and healthy individuals otherwise.

Nevertheless, the major strength of this study is the opportunity to isolate effects of fatigue in patients with CAD, for whom subtle variations in cardiovascular function during stress is likely of greater clinical significance than in health populations. Given the preponderance of past research on healthy populations, especially college students, the present findings also serve to complement the existing literature in cardiovascular reactivity and related factors. This research also examined variety of sociodemographic and clinical characteristics, which helped to isolate possible confounders for existing associations between cardiovascular reactivity during mental stress and fatigue in study patients. Given the severe illness of the study participants, the sample size was somewhat restricted in scope, but nonetheless large enough to demonstrate important effects.

Future replications will be of high importance in larger and more diverse samples. Such research should concentrate on not only cardiovascular reactivity, but also on neuroendocrinological stress responses (i.e., cortisol responses), as such responses are intricately intertwined with physical fatigue. Fatigue is a problematic symptom commonly experienced by patients with CAD. As such, the current findings draw attention to the way diminished stress responses in fatigued patient can serve as possible indicators of adverse health that may bolster clinical understanding, as well as diagnostic evaluation and treatment.

In the current study it was found that global, mental and overall fatigue were linked to cardiovascular reactivity during anticipatory stress in patients with severe cardiovascular pathology. The effects remained significant after comprehensively controlling for potential confounds, both medical, psychological, and perceptual. This is the first study to investigate psychophysiological stress response and its relationship with fatigue in an acutely ill cardiac population.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

This study involving human participants were reviewed and approved by the Kaunas Regional Ethics Committee for Biomedical Research in Lithuania. The participants provided their written informed consent to participate in this study.

JG-S: conceptualization, methodology, formal analysis, writing—original draft, review, and editing, and investigation. BH and LH: writing—review and editing. JBr and NM: conceptualization and supervision. AB, JBu, JN, NK, and NM: revision and supervision. All authors provided critical revision to its further development, read and approved the final manuscript.

JG-S served as a consultant at FACITtrans. In the past several years JBu has been serving as a consultant to Cogstate, Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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