Affective impairment in chronic low blood pressure

Journal of Psychosomatic Research 93 (2017) 33–40

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Journal of Psychosomatic Research

Affective impairment in chronic low blood pressure☆ Stefan Duschek a,⁎, Alexandra Hoffmann a, Gustavo A. Reyes del Paso b a b

UMIT - University of Health Sciences Medical Informatics and Technology, Institute of Psychology, Austria University of Jaén, Department of Psychology, Spain

a r t i c l e

i n f o

Article history: Received 5 August 2016 Received in revised form 21 November 2016 Accepted 10 December 2016 Available online xxxx Keywords: Hypotension Blood pressure Mood Depression Autonomic control

a b s t r a c t Objective: Physical complaints such as faintness, dizziness, cold limbs and headaches have been well-established in chronic low blood pressure (hypotension). This study investigated the occurrence of adverse emotional states and the symptoms of depression in this condition. As autonomic dysregulation, particularly diminished sympathetic tone, is believed to be involved in the etiology of hypotension, the impact of different facets of autonomic cardiovascular control on mood and depressive symptoms was also explored. Methods: Forty individuals with chronic hypotension and forty normotensive control persons were presented with the Mood Scale and Beck Depression Inventory. Stroke volume, cardiac output, pre-ejection period, Heather index and aortic peak blood flow velocity were recorded under resting conditions as indices of beta-adrenergic inotropic drive. Respiratory sinus arrhythmia and baroreflex sensitivity were additionally obtained. Results: Hypotensive individuals scored markedly higher on both questionnaire scales than controls, indicating an adversely affected emotional state and more severe depressive symptoms. In the entire sample, cardiac output, Heather index, and aortic peak blood flow velocity correlated negatively with the questionnaire scores; according to regression analysis, the Heather index explained the largest proportion of test score variance. Conclusion: Although hypotension does not constitute a serious medical condition, the findings of an adverse affective state and increased burden with depressive symptoms corroborate the view that it can have a considerable impact on wellbeing and quality of life. The correlations of the beta-adrenergic indices with the questionnaire scales indicate that cardiac sympathetic regulation plays a key role in the psychophysiological mediation of hypotension-related mood impairment. © 2016 Elsevier Inc. All rights reserved.

1. Introduction Chronic hypotension is referred to as a persistent state of inappropriately low blood pressure independent of the occurrence of other pathological conditions [1]. The chronic form is distinguished from orthostatic hypotension (that is, circulatory problems when assuming an upright position) and symptomatic hypotension, which occurs, for example, due to blood loss or medication [2]. According to WHO [3] criteria, hypotension is diagnosed when systolic blood pressure falls below 100 mmHg in women and 110 mmHg in men. Chronically low blood pressure is relatively widespread; in the general population its prevalence has been estimated at 2–3% with younger women being especially affected [4,5]. It is generally the case that in research, as well as in clinical practice, relatively little importance is ascribed to chronic hypotension [5]. In ☆ Place of study: Institute of Psychology, UMIT - University of Health Sciences Medical Informatics and Technology. ⁎ Corresponding author at: UMIT - University for Health Sciences, Medical Informatics and Technology, Institute of Psychology, Eduard Wallnöfer-Zentrum 1, 6060 Hall in Tirol, Austria. E-mail address: [email protected] (S. Duschek).

http://dx.doi.org/10.1016/j.jpsychores.2016.12.008 0022-3999/© 2016 Elsevier Inc. All rights reserved.

contrast to elevated blood pressure, which constitutes a major risk factor for cardiovascular diseases, chronic hypotension is not regarded as a dangerous medical condition. However, low blood pressure is associated with increased risk in pregnancy [6,7]; and longitudinal studies have revealed associations of hypotension with brain atrophy and cognitive decline in the elderly [8,9]. Typical complaints reported by affected individuals include dizziness, cold limbs, fatigue, reduced drive and concentration difficulties [5]. Various studies comparing hypotensive individuals with those with blood pressure in the normotensive range confirmed the increased prevalence of the physical symptoms [10,11]. Furthermore, population-based studies of cases spanning the whole blood pressure spectrum revealed inverse relationships between blood pressure and symptoms like faintness, dizziness and poor appetite [12,13]. In the field of psychological symptoms ascribed to chronic hypotension, various studies have confirmed the presence of deficits in attention and memory [14,15]. In contrast, abnormalities in affect-related features have received less attention thus far. In a study on quality of life, conducted in 50 years old men drawn from the general population, an inverse association between systolic and diastolic blood pressure and mental wellbeing was observed [16]. In another study, blood pressure-

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dependent symptoms of depression were investigated in a male sample aged between 60 and 89 years [17]. Men with diastolic values below 75 mmHg scored higher on the Beck Depression Inventory [18] than those with elevated (diastolic values above 85 mmHg) or normal blood pressure (intermediate range). Categorically diagnosed depression was also more frequent in hypotensive men. By definition, the generalizability of these findings is limited by the sample composition, which is particularly relevant given that young women constitute the population primarily affected by chronic hypotension [5,19]. In addition to quantification of affective state and depressive symptoms in chronic hypotension, the present study aimed to investigate possible psychophysiological mechanisms of action mediating the expected mood impairment. Autonomic nervous system dysregulation is believed to be involved in the etiology of chronic hypotension, where reduced sympathetic activity may play a key role [5,20]. This is supported by evidence of diminished electrodermal activity (EDA), in terms of reduced tonic EDA level, faster EDA habituation to sensorial stimuli and a lower rate of spontaneous EDA fluctuations, in hypotensive vs. normotensive individuals [21,22]. Regarding cardiovascular sympathetic control, reduced stroke volume (SV) and cardiac output (CO), as well as a longer pre-ejection period (PEP), were reported in hypotension at rest, under stress conditions and during sleep [23–25]. Considering that SV and CO are positively, and PEP is inversely, related to cardiac contractility, and that the ventricles are innervated by the beta-adrenergic system, the findings suggest diminished cardiac sympathetic drive in hypotension. As sympathetic hypoactivity has been related to adverse mood states and depression [26–28], it may be considered as a factor relevant to the association between hypotension and mood impairment. In this study, baroreflex sensitivity (BRS) and respiratory sinus arrhythmia (RSA) were investigated as further autonomic parameters potentially linking hypotension to an adverse affective state and depressive symptoms. The baroreflex consists of a negative feedback loop, in which activity changes in arterial baroreceptors, due to blood pressure fluctuations, precipitate compensatory changes in heart rate and myocardial contractility [29]. Baroreflex-related mechanisms have been suggested to contribute to the manifestation of chronic hypotension; and there is strong evidence that the baroreflex is also involved in behavioral regulation [30–33]. Regarding affective states, an association between high trait anxiety and reduced baroreflex control of heart rate was reported in a healthy sample [34]. High levels of state anxiety were related to lower baroreflex control of heart rate in elderly depressed patients [35]. Furthermore, in healthy subjects, proneness to worry was accompanied by reduced BRS [36]. In patients with coronary artery disease, higher burden with symptoms of depression was associated with lower BRS [37]. Various studies compared patients with depressive disorders and healthy controls in terms of baroreflex function. Lower BRS was observed in otherwise healthy patients with recurrent depression and no risk factors for cardiovascular disease [38]. Another study reported that initially reduced BRS in major depression was further decreased during antidepressant treatment [39]. A detailed analysis showed that lower BRS in depression was associated with increased gain of the afferent component of the reflex, without adjustment of its efferent component, and a higher number of reflex operations [40]. RSA, i.e. the variation in heart rate that occurs during a breathing cycle, constitutes the most well-established index of parasympathetic cardiac tone [29]. Increased parasympathetic cardiac tone has been proposed as an additional etiological factor underlying chronic hypotension, although empirical research has yielded mixed results [24,25]. Nonetheless, considering that various studies pointed toward the relevance of interindividual differences in RSA to affect regulation [41,42], and given the well-established reduction in heart rate variability in depressive disorders [39,40,43,44], this parameter was also included in our analysis.

In the study, the main hypothesis, of an adversely affected emotional state and increased burden with depressive symptoms in chronic hypotension, was tested. While previous research on this topic was conducted in older men [16,17], a sample of younger, healthy individuals, with a high proportion of female subjects, was presently included. In contrast to the previous studies [16,17], hypotensive individuals were selected according to WHO criteria [3]. For the first time, the role of autonomic cardiovascular autonomic control in mediating hypotension-related mood impairment was investigated. For this purpose, cardiac sympathetic control was assessed using impedance cardiography. Obtained parameters comprised SV, CO, PEP, the Heather index (HI) and aortic peak blood flow velocity (velocity index, VI), all of which are linked to contractility and beta-adrenergic inotropic influences [29,45]. In addition, BRS was extrapolated from continuous blood pressure measurements using time domain analysis [46]. RSA was computed by means of spectral analysis of ECG recordings [29]. While lower cardiac sympathetic drive was expected to be associated with stronger adverse affect and higher burden with depressive symptoms, the current state of research was not conducive to forming directed hypotheses regarding the impact of BRS and RSA. On account of evidence of lower body weight in hypotensive vs. normotensive individuals [5,30], and considering possible associations of body weight with affective state and depression, body mass index (BMI) served as a control variable in all analyses. 2. Method 2.1. Participants The study sample included 40 participants with hypotension according to WHO [3] criteria and 40 normotensive control persons (35 women and 5 men in each group). Health status was assessed by means of an anamnestic interview and a questionnaire covering diseases of the cardiovascular, respiratory, gastro-intestinal and uro-genital systems, as well as the thyroid and the liver, in addition to metabolic diseases and psychiatric disorders. Persons suffering from a relevant physical disease or mental disorder were excluded from participation. In addition, none of the participants used any kind of medication affecting the cardiovascular or central/peripheral nervous system. In total, 67 of the participants were university students (34 in the hypotensive sample, 33 in the control group). The remaining subjects were drawn from the workforce. Table 1 provides information about blood pressure and heart rate, as recorded at the beginning of the study session, in addition to age and BMI data. 2.2. Assessment of affective state and depression The “Befindlichkeits-Skala” [Mood Scale] [47] was applied for quantification of current affective state. This 28-item self-rating scale, which is widely used in German-speaking countries, includes positive and negative adjectives, which are related to general aspects of well-being (e.g. cheerful, relaxed), as well as to more specific emotions (e.g. depressed, insecure). Higher values on the scale represent a more adversely Table 1 Means (M) and standard deviations (SD) of systolic blood pressure, diastolic blood pressure, heart rate, age and body mass index in both samples; t and p values of the group comparison (df = 78 for all parameters except body mass index, where Welch's unequal variances t-test with df = 68.14 was applied). Hypotension Control group

Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (beats/min) Age (years) Body mass index (kg/m2)

M

SD

M

95.41 64.59

6.69 6.30

119.57 4.17 77.21 5.48

71.70 24.70 20.15

9.54 4.90 1.85

81.00 24.00 21.89

t

p

SD −19.03 b0.01 −9.57 b0.01

12.00 −3.20 4.26 0.68 2.77 −3.30

b 0.01 0.50 b 0.01

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affected emotional state. In addition, the German version of the Beck Depression Inventory [48] was used, which represents an internationally established instrument to assess the severity of depressive symptoms. Higher scores indicate increased burden with depression. 2.3. Hemodynamic recordings The ECG was obtained at a sampling rate of 1000 Hz from two electrodes placed at the right mid-clavicle and lowest left rib using a Biopac system (MP 150, Biopac Systems Inc., Goleta, CA). The back of the left hand served as a ground. For impedance cardiography, a CardioScreen 1000 (Medis Inc., Ilmenau, Germany) device was used. The impedance signal was recorded using four spot electrodes positioned at the lateral neck and the lateral chest (left side), with alternating current of 1.5 mA and 85 kHz. Blood pressure was measured continuously by means of a Finometer Model-2 (Finapres Medical Systems, Amsterdam, Netherlands). The cuff of the device was applied to the left index finger and that hand was positioned at the level of the heart. Blood pressure wave forms were recorded using the Biopac system (sampling rate 1000 Hz).

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The ECG data were visually screened, and artifacts were corrected by linear interpolation prior to computation of RR intervals. RSA was computed by means of Fast-Fourier transformation using Kubios HRV software [50]. It was indexed by spectral power density in the frequency range between 0.15 and 0.40 Hz. For quantification of BRS, the software developed by Reyes del Paso [51] was used. The program locates sequences of three to six consecutive heart cycles (reflex sequences) in which systolic blood pressure increases are accompanied by increases in heart cycle duration, and those in which blood pressure decreases are accompanied by decreases in heart cycle duration; 1 mmHg and 2 ms were applied as minimal criteria for changes in blood pressure and heart cycle duration, respectively. The interval between systolic points (intersystolic interval) was taken as an index of heart cycle duration [46]. When one of these reflex sequences was detected, the regression line was computed across all heart cycles of the given sequence. BRS was expressed as the change in heart cycle duration (ms) per mmHg blood pressure change, measured by the slope of the regression line. The reliability and validity of this method have been well-established [32,51]. 2.6. Statistical analysis

2.4. Procedure The study was part of a larger project investigating psychophysiological aspects of chronic hypotension [49]. Assignment of subjects to the two study groups was carried out on the basis of blood pressure readings taken in a screening session, which was conducted at least 1 week prior to the actual study session and again at the beginning of the study session. For this purpose, after a rest period of 10 min, three sphygmomanometric blood pressure measurements were taken in a sitting position using an automatic inflation blood pressure monitor (Omron M400; Omron Healthcare, Lake Forest, IL). Blood pressure readings were separated by 5-min rest intervals. The mean value of the three measurements was used for group assignment. Females with a mean systolic blood pressure of b 100 mmHg, and males with a mean value below 110 mmHg, were assigned to the hypotensive group. Subjects with systolic blood pressure between 115 and 140 mmHg were included in the control group. The criteria had to be fulfilled at both the screening and study sessions. Hemodynamic recordings were accomplished during a 7 min resting phase, during which participants were asked to sit still, refrain from speaking and relax with their eyes open. Participants were requested not to drink alcohol or caffeine-containing beverages for 3 h prior to the screening and study sessions. The study was approved by the Board for Ethical Questions in Science of the University of Innsbruck/Austria and all participants provided written informed consent. 2.5. Aggregation of psychophysiological data The data revealed by impedance cardiography was processed using Cardio-Vascular-Lab software (Medis Inc.). SV was obtained by applying the Kubicek equation [29], and CO was computed by multiplying SV by heart rate. PEP was defined as the period between the onset of ventricular depolarization (Q-point in ECG) and the onset of left ventricular ejection (B-point in impedance signal). VI and HI constitute flowbased indices of (sympathetically mediated) myocardial contractility. In the case of stronger myocardial contraction, blood flow velocity during ventricular ejection is higher and maximum velocity is reached earlier. VI represents peak aortic blood flow velocity during ventricular ejection and is calculated as the maximal value of the first derivative of the impedance signal (dZ/dtmax). In the computation of HI, VI is adjusted by the interval to maximal blood flow velocity. It is expressed as the ratio of dZ/dtmax (VI) to the time interval between the onset of ventricular depolarization and maximal ejection velocity (HI = dZ/dtmax / (Q − dZ/dtmax interval)) [29,45].

Questionnaire scores were compared between study groups by means of MANOVA. As expected, BMI was lower in the hypotensive vs. control group, and therefore was applied as a covariate. To quantify the relationships of the hemodynamic parameters with affective state and depression, Pearson correlations were computed among heart rate, systolic and diastolic blood pressure, SV, CO, PEP, HI, VI, BRS, RSA and the questionnaire scores. BMI was partialed out in the computation of the correlation coefficients. Correlation analysis was performed in the total sample, as well as separately in the hypotension and control groups. Correlation coefficients were compared between study groups using Fisher's r-to-z transformation. In addition, regression analyses were accomplished with the questionnaires scores used as dependent variables. The “enter” method was used for inclusion of predictors. As collinearity occurred due to strong correlations between the sympathetic indices, only systolic blood pressure, HI, RSA, BRS and BMI were applied as predictors. HI was chosen as a sympathetic index, because according to correlation analysis it showed the closest association with the dependent variables among all of the indices revealed by impedance cardiography (c.f. Results section). Regression analyses were performed in the total sample, as well as separately in the hypotension and control groups. 3. Results As depicted in Fig. 1, the hypotensive group exhibited higher scores on the Mood Scale and the Beck Depression Inventory than the control group, indicating more adversely affected mood and higher burden with depressive symptoms. The MANOVA revealed a significant multivariate effect (F [2,76] = 4.94, p b 0.01, η2p = 0.12). In univariate analyses, the group difference was significant for both assessment instruments (Mood Scale: F [1,77] = 9.07, p b 0.01, η2p = 0.11; Beck Depression Inventory: F [1,77] = 7.88, p b 0.01, η2p = 0.093). Table 2 presents the correlations between heart rate, systolic and diastolic blood pressure, SV, CO, PEP, HI, VI, BRS, RSA and the questionnaire scales, with BMI partialed out.1 In the total sample, systolic blood pressure, heart rate, CO, HI and VI correlated negatively with the Mood Scale. The same pattern of correlations was observed for the Beck Depression Inventory; however, here a negative correlation with diastolic blood pressure also arose (c.f. Fig. 2 for scatter plots for the associations of HI and VI with the questionnaire scales). In the hypotensive group, HI and VI correlated negatively with the Mood Scale, and 1 Results of the comparison of the cardiovascular parameters between the hypotensive and normotensive groups are reported elsewhere [49].

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scores. HI was also predictive of the Mood Scale score in the model conducted in the hypotensive group. According to current guidelines, the obtained values of tolerance and VIF are outside the critical range [52]. 4. Discussion

Fig. 1. Mean scores on the Mood Scale and Beck Depression Inventory in both study groups (p b 0.01 for both scores; bars denote standard errors of the mean).

VI correlated negatively with the Beck Depression Inventory. In the control group, negative correlations arose between diastolic blood pressure and both questionnaire scales. The group comparison revealed stronger negative correlations between diastolic blood pressure and both questionnaire scales in the control vs. hypotensive group (Mood Scale: z = 2.40, p b 0.01; Beck Depression Inventory: z = 2.39, p b 0.01). Stronger negative correlations in hypotensive vs. control subjects were observed between HI and the Mood Scale (HI: z = −2.14, p = 0.016), VI and the Mood Scale (z = −2.89, p b 0.01) and VI and the Beck Depression Inventory (z = −2.30, p = 0.011). The results of the regression analyses for the prediction of the Mood Scale and Beck Depression Inventory scores from the cardiovascular parameters are summarized in Tables 3 and 4. The models computed in the total sample revealed significant effects of HI on both questionnaire

This study investigated affective state and symptoms of depression in young people with chronic hypotension. Hypotensive individuals scored markedly higher on the Mood Scale and Beck Depression Inventory than a control group with blood pressure within the normotensive range. The finding pertaining to the Mood Scale indicates an adversely affected affective state in hypotension, in terms of reduced current subjective wellbeing and increased negative emotionality. The elevated Beck Depression Inventory score supports the notion of increased burden with symptoms of depression. Some somatic symptoms covered by the questionnaire, e.g. fatigue or lack of appetite, resemble typical bodily complaints of hypotension. However, as most of the items refer to mood-related symptoms, the findings suggest that the affective dimension of depression is also more pronounced in hypotension. According to commonly applied cut-off criteria, the mean Beck Depression Inventory score in the hypotensive sample was below the clinically relevant range [48]. In this regard, one should bear in mind that individuals suffering from psychiatric disorders, including depression, were explicitly excluded from participating in the study. This finding therefore reflects symptom severity in the subclinical range in hypotension, which nevertheless far exceeded burden due to depressive symptoms in healthy normotensive individuals. The finding of affective impairment complements earlier studies, which established subjective physical symptoms and cognitive deficits in chronic hypotension [10–13,16]. Despite this evidence, we believe that it would certainly be misleading to classify chronic hypotension as a serious medical condition. Nonetheless, the observations substantiate the view that the associated complaints can indeed have a considerable impact on wellbeing and quality of life [5,16]. More attention should therefore be given to this topic within basic and clinical research, as well as in clinical practice [5]. Connections between blood pressure and various aspects of affect and wellbeing have previously been studied in individuals with blood pressure in the normotensive and hypertensive ranges. In a survey study conducted in an adolescent sample, elevated blood pressure was associated with increased wellbeing and lower distress levels [53]. In adults from among the general population, blood pressure was positively related to positive emotionality and inversely related to negative emotionality [54]. Negative correlations between blood pressure and trait worry, and the intensity of adverse affect during stress exposure, were also reported previously [36,55,56]. Individuals with elevated blood pressure and those with a parental history of hypertension showed lower emotional ratings on affective pictures [57,58]. Furthermore, high blood pressure was associated with lower expression of negative affect [59] and reduced accuracy in identifying facially expressed

Table 2 Partial correlations between cardiovascular parameters and scores on the Mood Scale and Beck Depression Inventory, with BMI held constant (HR = heart rate, SBP = systolic blood pressure, DBP = diastolic blood pressure, SV = stroke volume, PEP = pre-ejection period, HI = Heather index, VI = velocity index, BRS = baroreflex sensitivity, RSA = respiratory sinus arrhythmia, *p b 0.05, **p b 0.01). SBP

DBP

HR

SV

CO

PEP

HI

VI

BRS

RSA

Total sample Mood Scale Beck Depression Inventory

−0.26* −0.22*

−0.18 −0.25*

−0.22* −0.20*

−0.05 −0.01

−0.25* −0.22*

0.16 0.16

−0.30** −0.24*

−0.30** −0.21*

0.13 0.11

0.16 0.10

Hypotension Mood Scale Beck Depression Inventory

0.17 0.18

0.19 0.21

0.25 0.06

−0.17 −0.07

−0.03 −0.12

−0.11 −0.08

−0.42** −0.22

−0.47** −0.31*

0.03 0.15

−0.05 0.11

Control group Mood Scale Beck Depression Inventory

−0.13 −0.14

−0.35* −0.33*

−0.12 −0.26

−0.13 −0.13

−0.18 −0.01

0.24 0.26

0.05 −0.04

0.16 0.21

0.19 −0.03

0.23 0.07

S. Duschek et al. / Journal of Psychosomatic Research 93 (2017) 33–40

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Fig. 2. Scatter plots for the associations of Velocity Index and Heather Index with the Mood Scale and Beck Depression Inventory.

emotions [60]. Numerous studies have indicated that sensitivity to experimental pain stimulation, and the prevalence of clinical pain, are also negatively associated with blood pressure [61–63]. Although overgeneralization should be avoided, research currently suggests a general tendency toward inverse relationships between blood pressure and a variety of distress-related variables, across the entire blood pressure spectrum. The association of elevated blood pressure with enhanced positive and reduced negative affect is discussed in the framework of the theory of learned hypertension [64]. This theory is based on the observation of a generalized central-nervous inhibitory effect due to baroreceptor stimulation [31,65]. In addition to dampening pain perception, this effect encompasses attenuation of negative affect and behavioral

reactions to aversive stimuli (c.f. [66,67]). According to the theory, baroreceptor-mediated relief of negative affective states contributes to hypertension development through an operant conditioning mechanism. The experience of reductions of unpleasant emotional states may negatively reinforce phasic blood pressure increases. Repeated use of this learned coping mechanism is believed to lead to stabilization of tonic blood pressure at higher levels [31,64]. Various physiological parameters were assessed in the study to obtain insight into mediation of the connection between low blood pressure and mood impairment by features of autonomic cardiovascular control. In the total sample, negative correlations of blood pressure, heart rate, CO, HI and VI with scores on the Mood Scale and the Beck Depression Inventory were observed. In regression analysis, HI explained

Table 3 Regression analyses for the prediction of the Mood Scale score from cardiovascular parameters and BMI (SBP = systolic blood pressure, HI = Heather index, BRS = baroreflex sensitivity, RSA = respiratory sinus arrhythmia, BMI = body mass index).

Table 4 Regression analyses for the prediction of the Beck Depression Inventory score from cardiovascular parameters and BMI (SBP = systolic blood pressure, HI = Heather index, BRS = baroreflex sensitivity, RSA = respiratory sinus arrhythmia, BMI = body mass index).

Total sample SBP HI BRS RSA BMI Hypotension SBP HI BRS RSA BMI Control group SBP HI BRS RSA BMI

R

F [5]

0.40

2.80

0.50

0.45

β

t

p

Tolerance

VIF

−0.19 −0.31 −0.02 0.19 −0.05

−1.64 −2.78 −0.12 1.10 −0.39

0.11 b0.01 0.90 0.27 0.70

0.82 0.90 0.37 0.37 0.77

1.22 1.11 2.71 2.67 1.30

0.09 −0.49 0.43 −0.29 −0.26

0.52 −2.67 1.75 −1.26 −1.59

0.61 0.01 0.09 0.22 0.12

0.75 0.65 0.36 0.41 0.81

1.34 1.53 2.82 2.44 1.24

−0.13 −0.05 −0.28 0.55 0.14

−0.87 −0.30 −0.99 2.03 0.77

0.39 0.77 0.33 0.06 0.44

0.99 0.75 0.30 0.30 0.73

1.01 1.34 3.35 3.38 1.36

2.32

1.69

Total sample SBP HI BRS RSA BMI Hypotension SBP HI BRS RSA BMI Control group SBP HI BRS RSA BMI

R

F [5]

0.36

2.25

0.34

0.28

β

t

p

Tolerance

VIF

−0.24 −0.24 0.04 0.08 −0.07

−1.97 −2.09 0.20 0.44 −0.60

0.052 0.04 0.84 0.66 0.55

0.82 0.90 0.37 0.37 0.77

1.22 1.11 2.71 2.67 1.30

0.08 −0.29 0.337 −0.09 −0.16

0.42 −1.47 1.25 −0.37 −0.91

0.68 0.15 0.22 0.72 0.37

0.75 0.65 0.36 0.41 0.81

1.34 1.53 2.82 2.44 1.24

−0.15 −0.16 −0.34 0.37 −0.02

−0.88 −0.85 −1.11 1.20 −0.11

0.38 0.40 0.28 0.24 0.92

0.99 0.75 0.30 0.30 0.73

1.01 1.34 3.35 3.38 1.36

0.91

0.56

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the largest proportion of variance in the scores on both scales. The expressions of HI and VI are closely related to beta-adrenergic outflow to the myocardium [29,45]. Therefore, the correlations of these parameters can be interpreted as reflecting an inverse relationship of cardiac sympathetic drive with affective state and depressive symptoms. CO is given by the product of heart rate and SV. As SV was unrelated to the questionnaire scales, the association between CO and the scales may primarily be ascribed to the impact of heart rate. Heart rate varies subject to the activity of both branches of the autonomic nervous system [29]; as such, its associations with the scales cannot be unambiguously attributed to sympathetic or parasympathetic effects. However, because RSA was also unrelated to the scales, a relevant influence of cardiac vagal tone on mood and depressive symptoms seems unlikely. As initially stated, there is substantial evidence of reduced general sympathetic tone, as well as diminished cardiac beta-adrenergic drive, in chronic hypotension [21–25]. In addition, various studies showed blunted sympathetic reactivity during mental stress in this condition [16,20,30]. Taking this into account, as well as the presently observed correlations of sympathetic indices with the questionnaire scores, it may be hypothesized that sympathetic hypoactivity constitutes a factor relevant to the genesis of the mood impairment seen in chronic hypotension. Although earlier research suggested connections between RSA, BRS and emotional regulation [34,36,39,41,42], the present data does not support the assumption of a relevant role of vagal or baroreflex-related mechanisms in mediating the affective symptoms related to hypotension. Associations between general sympathetic tone and negative affective states have been previously reported. In children, low resting EDA was related to increased anxiety and depressiveness, as well as poor self-esteem [27]. In adults, decreased beta-receptor function was associated with higher levels of anxiety, depressiveness and anger [26,27]. Furthermore, there is ample evidence suggesting diminished sympathetic tone in clinical depression, indicated by lower baseline EDA [28, 68,69]. Sympathetic underarousal results in a deficient energetic state and limited adaptive resources of the organism; such a state, by extension, implies a higher cost per unit of effort in an individual's adjustment to daily requirements [70]. Referring to the cognitive theory of depression, it has been claimed that internal and stable attribution of a lack of energy and increased cost of everyday efforts promotes the occurrence of depressive symptoms [70]. Furthermore, some authors interpreted the connection between low sympathetic arousal and depression within the framework of central nervous and behavioral inhibition [27,71]. According to Gray's motivational theory [72], sympathetic underarousal may represent a predisposition toward low behavioral activation due to reduced sensitivity to reward and enhanced sensitivity to punishment [27]. Diminished myocardial contractility due to low sympathetic outflow is likely to account for impaired cerebral blood perfusion in hypotension, which has been documented both in terms of tonic hypoperfusion and blunted blood flow adjustment to situational challenges [73,74]. Cerebral hemodynamic deficits have been primarily regarded in the context of hypotension-related cognitive deficits [5,73]. However, it may be hypothesized that impaired blood flow regulation also interferes with optimal affective regulation, resulting in adverse mood states [75, 76]. Physical complaints, such as low skin temperatures and the experience of cold limbs, may be another consequence of low contractility and CO possibly affecting mental wellbeing. Comparison of the pattern of correlations between the two study groups revealed that the association of diastolic blood pressure with mood and depressive symptoms was stronger in normotensive vs. hypotensive individuals. Although this might suggest a stronger impact of individual blood pressure differences on affective variables in the normotensive vs. hypotensive blood pressure range, the significance of the finding is clearly limited by it being restricted to the diastolic values. On the other hand, the relationships between HI and VI and the psychological variables were closer in hypotensive vs. normotensive individuals.

Consistent with this, in regression analysis HI predicted the Mood scale score in the hypotensive group, but not in the control group. The finding might be indicative of a particular vulnerability of hypotensive individuals to the affective effects of low cardiac sympathetic arousal. While in the normotensive situation, affective state may be virtually independent of cardiac sympathetic tone, in hypotension low levels of beta-adrenergic drive seem to be accompanied by substantial mood impairment. By definition, the quasi-experimental design of the study limits causal interpretation of the results. In addition to the postulated contribution of low blood pressure and cardiovascular adrenergic tone to negative affect and symptoms of depression, influences of psychological factors on the cardiovascular system are plausible. Specifically, adverse mood state, or the motivational and behavioral symptoms of depression, may contribute to diminished sympathetic tone. It has been hypothesized, for example, that anhedonic depressive symptoms may influence the autonomic state by reducing cardiac sympathetic drive [77]. By definition, third variable effects must also be considered in the observed interactions, for instance due to habitual physical activity and other behavioral factors, which affect both mood state and autonomic regulation [78,79]. Experimental approaches would certainly be helpful in establishing causal relationships. It may be informative, for example, to study the affective and behavioral effects of systematic manipulations of cardiovascular features using biofeedback or pharmacological methods. Further restrictions pertain to sample selection and description. In the first instance, this concerns the lack of any assessment of physical complaints of hypotension in the study. In addition to subjective symptom assessment, orthostatic testing or autonomic assessments during mental challenge would have been informative. Moreover, the exclusion of individuals suffering from relevant diseases was only based on an anamnestic questionnaire and interview. Higher diagnostic precision could have been achieved by physical examination and a structured interview for mental disorders [80]. Regarding the cardiovascular assessments, an influence of the particular laboratory environment cannot be ruled out, which might have contributed to cardiovascular activation in the normotensive sample. Comprehensive clinical assessment in future studies might allow the establishment of further pathways underlying the interactions between low blood pressure, autonomic dysregulation and physical and mental complaints. Moreover, it would also be worthwhile to assess behavioral abnormalities, such as low rates of physical activity or reduced liquid intake, which have been implicated in the origin of hypotension and may potentially contribute to mood impairment [5]. Furthermore, this line of research could be extended to higher age groups, as well as to individuals suffering from psychiatric conditions. As mentioned in the Introduction, evidence is available regarding aberrant baroreflex and heart rate variability in depression [38–40,43,44]. However, research on possible mediation of affective symptoms by mechanisms of sympathetic cardiovascular control remains scant [81]. Autonomic cardiovascular dysregulation has also been implicated, for example, in symptoms of chronic pain and anxiety disorders [82,83]. In summation, the study revealed evidence of adversely affected mood and increased burden with symptoms of depression in young individuals with chronic hypotension. Regarding the psychophysiological factors mediating these impairments, reduced cardiac sympathetic drive may play a crucial role. Finally, the issue of treatment of hypotension should be discussed. Clinical trials conducted in mixed samples of individuals with chronic and orthostatic hypotension showed that the application of adrenergic substances leads to a reduction in subjectively reported bodily symptoms in addition to blood pressure elevation [84, 85]. In chronic hypotension, acute adrenergic treatment was also followed by enhancements in cerebral blood flow and cognitive performance, and reduction in pain sensitivity [86,87]. It may be of interest to also assess the possible effects of sympathomimetic drugs on affective symptoms of hypotension. However, there is no consensus regarding

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