Orienting-Defense Responses and Psychophysiological Reactivity in ...

Clinical and Experimental Hypertension, 29:175–188, 2007 Copyright © Informa Healthcare ISSN: 1064-1963 print / 1525-6006 online DOI: 10.1080/10641960701361577

1525-6006 1064-1963 LCEH Clinical and Experimental Hypertension Hypertension, Vol. 29, No. 3, Mar 2007: pp. 0–0

Orienting-Defense Responses and Psychophysiological Reactivity in Isolated Clinic versus Sustained Hypertension Isolated M.P. García-Vera Clinic vs. et Sustained al. Hypertension

MARÍA PAZ GARCÍA-VERA, JESÚS SANZ, AND FRANCISCO J. LABRADOR Departamento de Personalidad, Evaluación y Psicología Clínica, Universidad Complutense de Madrid, Madrid, Spain This study sought to determine whether patients with white-coat or isolated clinic hypertension (ICH) show, in comparison to patients with sustained hypertension (SH), a defense response pattern to novel stimuli and an enhanced psychophysiological reactivity to stress. Forty-three patients with essential hypertension were divided into two groups after 16 days of self-monitoring blood pressure (BP): ICH (24 men; selfmeasured BP < 135/85 mmHg) and SH (19 men; self-measured BP ≥ 135/85 mmHg). Defense responses were measured as the cardiac changes to phasic non-aversive auditory stimuli. Psychophysiological reactivity (heart and breath rate, blood volume pulse, electromyography, and skin conductance) was measured during mental arithmetic and video game tasks. The standard deviation of self-measured BPs and the difference between mean BPs at work and at home were used as indicators of cardiovascular reactivity to daily stress. No significant differences were seen in defense responses or psychophysiological reactivity to laboratory or naturally occurring stressors. These results do not support the hypothesis that ICH can be explained in terms of a generalized hyperreactivity to novel or stressful stimuli. Keywords orienting-defense response, psychophysiological reactivity, essential hypertension, isolated clinic hypertension, white coat hypertension

Introduction Although research on the phenomenon known as “white coat” or “isolated clinic” hypertension (ICH)—patients with persistently elevated blood pressure (BP) when measured in the clinic environment but normal BP when measured outside the clinic—has a long history (1), its origins and clinical significance are still a matter of debate (2,3). Regarding factors and mechanisms underlying ICH, it has been suggested that this condition originates as part of a defense response (4,5). This refers to a complex group of Submitted October 22, 2006; revised December 8, 2006; accepted December 13, 2006. Address correspondence to Dr. María Paz García-Vera, Departamento de Personalidad, Evaluación y Psicología Clínica, Facultad de Psicología, Universidad Complutense de Madrid, Campus de Somosaguas, 28223 Madrid, Spain; E-mail: [email protected]

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reactions that usually responds to threatening or intense stimuli and includes a hemodynamic pattern characterized by an increase of BP, heart rate (HR), and cardiac output. In addition, the defense response habituates very slowly, or not at all. These characteristics of the defense response very closely resemble those of ICH. In this condition, it is supposed that the clinic-nonclinic BP difference would reflect in part the increase of BP that occurs to the potentially threatening figure of the physician carrying out the BP measurement at the clinic; by definition, this response would not habituate in ICH. On the contrary, the normal response to BP measurement may be understood as related to the orienting response—a group of reactions that usually occurs to novel stimuli, is characterized by an elevation of BP but decrease of HR, and habituates rapidly with repeated exposure to stimuli. The main aim of the present study was to examine whether patients with ICH and patients with sustained hypertension (SH) differ on the pattern of orienting and defense cardiac responses to novel and non-threatening stimuli. It is hypothesized that patients with ICH will show more defense responses (HR accelerations) than patients with SH, whereas these last patients will show more orienting responses (HR decelerations). To this end, data from a larger study investigating the nonpharmacological treatment of essential hypertension with a sample of 43 male patients were analyzed (6,7). That sample was divided into two groups, ICH and SH, according to their clinic and self-measured BPs. The present study then compared their defense and orienting responses to a set of innocuous phasic auditory stimuli that had allowed to differentiate in previous studies (8–10) between patients with various psychophysiological disorders and healthy controls, depending on their orienting-defense response patterns. Another aim of the present study was to test other hypothesis suggested in the literature to account for ICH. It has been hypothesized that patients with ICH might have an exaggerated BP rise during exposure to other stressful situations in addition to the stress of a clinic visit; that is, ICH might be a manifestation of an enhanced cardiovascular reactivity to stress (4,5). To examine this hypothesis, isolated clinic and sustained hypertensive patients were exposed to a set of standardized mental stressors and their physiological responses were compared. In addition, to get an estimation of cardiovascular reactivity to stress in daily life, BP variability as reflected by the standard deviation of self-measured BP values and the differences between mean BPs at work and at home were compared.

Method Participants Over a three-year period, 43 male patients diagnosed as having essential hypertension by their family physicians volunteered to participate in a study on behavioral treatment of essential hypertension, after having been referred by their doctors for an exhaustive evaluation of their BP. Subjects were referred if their BP was not well-controlled (i.e., diastolic BP [DBP] ≥ 90 mmHg or systolic BP [SBP] ≥ 140 mmHg) despite previous pharmacological treatments or despite having one or two medications. All subjects were recruited from two health centers near Madrid. Potential patients were considered for this study if the following criteria were met: • the diagnosis was confirmed by readings of either DBP above 90 mmHg or SBP above 140 during three consecutive casual BP measurement sessions occurring over a 2- or 3-month period in the clinic;

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• the patient’s physician agreed not to change patient’s dose of medication or patient’s usual diet throughout the duration of the investigation; and • they did not suffer severe psychiatric disturbances. Based upon the average self-measured BPs, the patients were divided into two groups: an ICH group (self-measured BPs < 135/85 mmHg and clinic BPs ≥ 140/90 mmHg) and a SH group (self-measured BPs ≥ 135/85 mmHg and clinic BPs ≥ 140/90 mmHg). These blood pressure thresholds correspond to the current consensus for the upper limit of normal clinic and self-measured BP. Thus, the European Society of Hypertension—European Society of Cardiology (11), the World Health Organization—International Society of Hypertension (12), and the US Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (13) have defined hypertension as a clinic BP level above 140/90 mmHg and proposed 135/85 mmHg as the values for self-measured BP to correspond to 140/90 mmHg measured in the office or clinic. A breakdown of demographic and clinical characteristics of the sample for the two hypertension groups is shown in Table 1. In this sample, eleven patients did not receive any medication at the beginning of the study, and 29 patients received just one antihypertensive drug, either an angiotensinconverting enzyme inhibitor (14 patients), a calcium-channel antagonist (eight patients), a beta-blocker (six patients), or a diuretic (one patient). Two patients were on a combination of two drugs, and one patient was on a combination of three drugs, the combinations not including in all cases beta-blockers. Because beta-blockers may substantially affect the cardiovascular reactivity, the psychophysiological assessment was not administered to patients having this medication. Due to equipment errors, psychophysiological data were totally lost for one patient, and partially lost for another four. Therefore, final data for some analyses were obtained from samples that departed

Table 1 Demographic and clinical characteristics Hypertension groups Variable Age (years) Clinic systolic blood pressure (mmHg) Clinic diastolic blood pressure (mmHg) Self-measured systolic blood pressure (mmHg) Self-measured diastolic blood pressure (mmHg) Self-measured heart rate (beats/min) Duration of hypertension (months) Compliance with the medication (%)* Discomfort by medication (0–10 scale)* Number of previous treatments

Sustained (n=19)

Isolated clinic (n=24)

p†

45.6 ± 8.8 151.4 ± 9.1 99.9 ± 6.9 139.0 ± 8.9 91.0 ± 4.2 76.7 ± 9.7 74.7 ± 67.8 92.1 ± 20.4 0.0 ± 0.2 1.2 ± 1.2

45.1 ± 9.1 148.9 ± 7.8 99.0 ± 7.0 123.3 ± 6.1 78.6 ± 4.6 68.7 ± 8.1 61.6 ± 67.7 98.6 ± 3.2 0.0 ± 0.9 0.8 ± 1.0

NS NS NS -0.5) were also calculated, following the procedure proposed by Muñoz et al. (20), and each of these three variables was analyzed by a twotailed Student’s t tests with the hypertension group as between-subjects factor. Valid data from each variable measured during the psychophysiological reactivity testing were subjected to 2 × 5 MANOVAs with a between-subjects factor (hypertension group) and a within-subjects factor (tasks: baseline, relaxation, mental arithmetic, recovery, video game).

Results Demographic and Clinical Characteristics There were no significant differences between the SH and the ICH groups in such demographic and clinical variables as age, duration of hypertension, clinic SBP, clinic DBP, number of previous treatments, compliance with the medication, or discomfort by medication (see Table 1). As expected, the ICH group, in comparison to the SH group, showed lower levels of self-measured SBP, self-measured DBP, and self-measured HR (all t tests with p < 0.001). Orienting/Defense Response Pattern: HR Response to Discrete Auditory Stimuli As can be seen from Figure 1, the pattern of HR changes (post-stimulus HR minus prestimulus HR) to discrete auditory stimuli was similar for both hypertension groups. In fact, the 2 (hypertension group)×8 (auditory stimulus) MANOVA on HR changes did not reveal any significant main or interaction effect for the hypertension group factor. Consistent with these results, the t tests conducted on the number of HR accelerations (defense responses), HR decelerations (orienting responses), and undetermined responses to discrete auditory stimuli did not reveal any significant difference between the SH and the ICH groups in these three variables (see Table 3). Psychophysiological Reactivity to Laboratory Stress The effects of psychophysiological reactivity testing on HR, BVP, EMG, SCL, and breath rate are summarized in Figure 2. In all of these psychophysiological variables, there was no significant main effect of the hypertension group factor or any significant interaction effect between the hypertension group factor and the task factor. Thus, as can be seen from Figure 2, for each psychophysiological variable and for each task, the pattern of reactivity was similar for the ICH and the SH groups.

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Figure 1. Graph showing heart rate (HR) changes to discrete auditory stimuli for the isolated clinic hypertension (ICH) group (n = 19) and the sustained hypertension (SH) group (n = 13). Positive and negative values indicate cardiac accelerations (defense responses) and cardiac decelerations (orienting responses), respectively, to the auditory stimuli. The horizontal tick marks on the vertical lines (vertical lines with black squares for ICH and with black circles for SH) represent the mean HR changes for each group and each auditory stimuli, and the borders of the vertical lines are plus/minus one standard deviation of the mean.

Cardiovascular Reactivity to Stress in Daily Life: BP and HR Variability Using the standard deviation of BP values as an indicator of BP variability and, therefore, of cardiovascular reactivity to daily stress, there were no significant differences between the SH and the ICH groups in the variability of SBP or DBP during either clinic assessment or self-measurement (see Table 3). Likewise, there were no significant differences between the SH and the ICH groups in self-measured HR variability. In addition, when the differences between mean BP/HRs at work and at home were used as indicators of BP/HR variability, the ICH and the SH groups did not differ statistically (see Table 3).

Discussion The main aim of this study was to test the hypothesis that clinic BPs tend to be higher than BPs measured outside the clinic in patients with ICH because these patients show an exaggerated defense response to novel stimuli. The results failed to support this hypothesis. Patients with ICH did not differ from patients with SH on short-latency cardiac responses to discrete innocuous auditory stimuli. Negative results are always more ambiguous than difference findings, but they may be more informative and interpretable if the sensitivity of the study is adequate. The power of the study is one of the most important factors that dictate its sensitivity. In the present study, adequate power was available to find significant differences in the HR responses to auditory stimuli. Power analyses were performed with the GPOWER program (21). Analyses showed that the sample size allowed one to


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Table 3 Heart rate response to discrete auditory stimuli, as well as blood pressure and heart rate variability Hypertension groups Variable Number of heart rate responses to auditory stimuli* Number of HR acceleration responses (0–8) Number of HR deceleration responses (0–8) Number of HR indeterminate responses (0–8) Blood pressure variability SD of clinic SBP (mmHg) SD of clinic DBP (mmHg) SD of self-measured SBP (mmHg) SD of self-measured DBP (mmHg) Mean work SBP – mean home SBP (mmHg) Mean work DBP – mean home DBP (mmHg) Heart rate variability SD of self-measured HR (beats/min) Mean work HR – mean home HR (beats/min)

Sustained (n=18)

Isolated clinic (n=24)

1.4 ± 1.1 4.7 ± 1.0 1.7 ± 1.3

2.1 ± 1.0 4.3 ± 1.2 1.5 ± 1.0

6.5 ± 5.3 5.2 ± 3.3 8.7 ± 3.5 6.4 ± 2.2 0.2 ± 8.0 0.1 ± 4.5

6.7 ± 6.5 4.2 ± 3.9 8.3 ± 3.1 6.4 ± 2.8 0.3 ± 4.8 0.2 ± 2.8

7.9 ± 1.6 0.8 ± 5.9

6.7 ± 2.3 1.9 ± 3.5

Note. Data are presented as mean ± SD. Abbreviations: HR = heart rate, SD = standard deviation, SBP = systolic blood pressure, DBP = diastolic blood pressure. *n = 13 and 19 for sustained and isolated clinic hypertension groups, respectively.

find a difference of at least one orienting/defense cardiac response between the ICH and the SH groups with more than 80% power. In fact, previous studies have been able to find such as differences on the orienting/defense cardiac response pattern between headache patients and non-patients control with sample sizes as low as 18 subjects (9,10). Interestingly enough, these previous studies also suggest that further research should improve the sensitivity of the auditory stimulus task to detect differences on the orienting/defense cardiac response pattern among hypertensive patients. The mean number of defense cardiac responses for this sample of hypertensive patients was 1.8; although non-patient samples tend to show no defense cardiac responses in this type of auditory stimulus task (22), that mean is notably lower than those showed by headache patient samples (9,10). On the other hand, it is possible that patients with ICH and patients with SH initially exhibit a similar pattern of defense responses when BP is first taken, but that in the SH group, this habituates with repeated exposure, whereas in patients with ICH it may become perpetuated through classical conditioning. Several investigators have argued in favor of this conceptualization of ICH (4,5,23), although direct empirical evidence supporting it is still lacking. Moreover, it is supposed that such a conditioned cardiovascular response is resistant to extinction in ICH. This resistance may be also adequately explained by classic conditioning principles, for example, in terms of Eysenck’s theory of the incubation of anxiety/fear responses (23–25). Further research should examine whether patients with ICH acquire that kind of conditioned response more easily, or whether such patients show the psychophysiological characteristics that increase the proneness to acquire them or resistance to their extinction, such as differences on the level of neuropeptides (25).

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Figure 2. Graph showing the effects of psychophysiological reactivity testing on heart rate (HR), blood volume pulse (BVP), electromyography (EMG), skin conductance level (SCL), and breath rate for the isolated clinic hypertension (ICH) group (n = 20) and sustained hypertension (SH) group (n = 16). The horizontal tick marks on the vertical lines (vertical lines with black squares for ICH and with black circles for SH) represent the mean psychophysiological changes for each group and each task of the reactivity testing, and the borders of the vertical lines are plus/minus one standard deviation of the mean.

In conclusion, these results suggest that ICH is not a manifestation of a generalized hyperreactivity to novel stimuli, but also that it is not a manifestation of a generalized hyperreactivity to stressful situations. Indeed, concerning the second hypothesis, the results provide no evidence of differences between patients with ICH and patients with SH on five different psychophysiological responses (HR, BVP, EMG, SCL, and breath rate) to two types of mental laboratory stressors (mental arithmetic and video game). These findings seem to be in agreement with the results of previous studies reporting no differences between the two hypertension groups on HR and BP responses to mental and physical laboratory stressors, including mental arithmetic tasks (26–29). Two exceptions to this generally consistent pattern of results are those of Gerardi et al. (30) and Nakao et al. (31). Gerardi et al. (30) found that patients with ICH showed significantly greater increases in SBP than patients with SH during a mental arithmetic task, but not during two other tasks (cold pressor and stressful imagery) and not in DBP during any of the tasks. Nakao et al. (31) reported that SBP and DBP responses to mental arithmetic testing was significantly larger in females patients with ICH than in females patients with SH, but they did not find any significant difference between the two hypertensive groups on HR responses to mental arithmetic testing.


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Nakao et al. (31) proposed two explanations for the disagreement between their results and those obtained in the majority of previous studies. First, these studies had not fully controlled for the main confounding variables of ICH (i.e., sex, age, and duration of hypertension). Second, cardiovascular responses to mental arithmetic testing may be different among people from different cultures. As can be seen from Table 1, the two hypertension groups were only composed of men and did not differ on age or duration of hypertension; therefore, such variables seemed to be controlled. Thus, Nakao et al.’s second hypothesis could be more plausible than the first to explain for the disagreement between their results, obtained in an Asian culture (Japan), and those obtained by previous investigators and ourselves in Western cultures (Italy, USA, and Spain). However, this hypothesis awaits empirical testing. On the other hand, the disagreement cannot be explained in terms of lacking of statistical power. The significant differences between groups reported by Nakao et al. (31) were found with a sample size as low as 11 patients with ICH and 10 patients with SH, and results from power analyses revealed that the present sample size allowed one to find a difference in HR responses to mental arithmetic task of at least 9 beats/min between the ICH and the SH groups with over 80% power. Finally, given that only HR and BVP responses were examined in the present study, it might be that the only cardiovascular response sensitive to differences on hyperreactivity to laboratory stressful situations between ICH and SH is BP. However, this possibility is not supported by the null findings on BP responses reported by at least four previous studies (26–29). Consistent with the absence of differences on psychophysiological responses to laboratory mental stressors, the two hypertension groups did not differ on BP or HR variability, as reflected both by the standard deviation of BP/HR values and by home/work BP/ HR difference. These results replicate those reported in previous studies (29,32,33), and if BP/HR variability may be understood as an estimation of cardiovascular reactivity to stress in daily life, all of these findings support further the idea that ICH does not represent a generalized hyperreactivity to stressful situations. In sum, these results do not support the hypotheses that ICH is related to an exaggerated pattern of defense response to novel stimuli or to an enhanced psychophysiological reactivity to stress. However, the data do not preclude the possibility that such psychophysiological mechanisms are related to the white-coat effect. Although ICH is frequently confounded with the white-coat effect, they are different phenomena. The white-coat effect refers to an alerting reaction of the patient to the measurement of BP in the clinic environment and can be quantified by continuous BP monitoring before and during the physician’s visit. On the other hand, ICH (also known as white coat hypertension) is a clinical condition characterized by persistently elevated clinic BP in a patient with normal daytime ambulatory or self-measured BP values. For a long time, it was assumed that this condition could reflect the persistence over time of an alerting reaction to the physician's visit. However, results from several studies indicate that the difference between office and ambulatory or self-measured BP values does not correlate with the BP rise induced in the patient by the physician's visit (34,35). In fact, these results are the reason for the recommendation by the 1999 World Health Organization/International Society of Hypertension (WHO/ISH) guidelines (36) and reaffirmed by the 2003 WHO/ISH guidelines (12) that the condition characterized by persistently high clinic BP and persistently normal daytime ambulatory or self-measured BP values should be named “isolated clinic (or office) hypertension” instead of using the appealing, but misleading, term “white coat hypertension” (37). Therefore, it may be that the white-coat effect could be partially explained by an exaggerated pattern of defense responses to novel stimuli or an enhanced psychophysiological reactivity to stress, whereas ICH could be explained by other multiple factors,

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including, for example, factors affecting both the BP measured in the physician’s office and the BP recorded in real-life conditions. Future studies should test those hypotheses to determine the conditions and mechanisms underlying the white-coat effect and ICH; also, these two conditions need to be separately considered to avoid further misunderstandings that have often occurred over the last years. Furthermore, these data also do not preclude the possibility that an exaggerated pattern of defense response to novel stimuli or an enhanced psychophysiological reactivity to stress are related to essential hypertension in comparison to normotension. In fact, hypertensive patients exhibit greater BP and HR responses during physical or psychological stressors such as mental arithmetic, public speaking, and video game tasks than normotensive individuals, even when borderline or mildly hypertensives have been studied (38). In addition, a relation between an exaggerated response of BP to mental stress tasks and subsequent BP status has been observed in some prospective studies (39). On the other hand, some studies have found that persons showing a greater cardiac defense response to unexpected auditory stimuli tend to exhibit greater reactivity to mental stress tasks in the form of response of a variety of psychophysiological variables, including BP and HR (40). Therefore, it may be that cardiovascular reactivity to mental stress is related to a pattern of defense response to novel stimuli or to a general psychophysiological reactivity to stress. This study did not compare hypertensive versus normotensive individuals, so future research should examine whether hypertensive patients, in comparison to normotensive individuals, show an exaggerated pattern of defense response to novel stimuli or an enhanced psychophysiological reactivity to stress.

Acknowledgments This article was based on the doctoral dissertation carried out by the first author under the direction of the third author and with the support provided by a Predoctoral Fellowship from the Autonomous Community of Madrid. The authors are very grateful to José María Arribas Blanco, family physician from the Pozuelo de Alarcón Health Center, for his assistance with patient recruitment. Data analyses and article writing were supported by a grant from the Spanish Ministry of Education and Science (BSO2003-08321).

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