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Baroreflex Sensitivity Is Reduced in Depression

From the Heart and Lung Unit, Torbay Hospital, Torquay, UK (A.J.M.B.); Department of Cardiovascular Medicine, University of Birmingham, UK (M.P.F.); Biostatistics Bioinformatics Unit, Cardiff University, Cardiff, UK (V.M.); Princess of Wales Hospital, Bridgend, UK (C.J.H.J.); and Centre for Psychiatry, Bart’s and The London, Queen Mary’s School of Medicine and Dentistry, London, UK (A.K.)

Address correspondence and reprint requests to Ania Korszun, MD, Reader in Psychiatry, Barts and The London, Queen Mary’s School of Medicine and Dentistry, Mile End Road, London E1 4NS. E-mail: a.korszun{at}qmul.ac.uk

	ABSTRACT

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Objectives: Depression is independently associated with increased cardiovascular morbidity and mortality, including sudden cardiac death, and this risk is observed even in patients who have been successfully treated for depression. Recent studies have emphasized the importance of impaired baroreceptor sensitivity (BRS) as a predisposing factor for sudden death in patients with manifest cardiac disease. Our objective was to test the hypothesis that BRS is impaired in subjects with depression in remission and with no other cardiac risk factors.

Methods: We measured BRS by the sequence method in 36 patients with treated recurrent depression, who were euthymic at the time of study and with no manifest cardiac disease or "conventional" cardiac risk factors, compared with 39 healthy controls. Exclusion criteria included manifest heart disease or any risk factor for IHD (smoking, hypertension, diabetes, hypercholesterolemia, or body mass index >30). Nine subjects were not on any medication, and 22 were taking antidepressants. None of the controls was taking any medication.

Results: BRS was significantly lower in patients than in controls (19.5 [1.78] versus 25.4 [1.69] ms/mm Hg, p = .017). Analysis of covariance, in which age, sex, cholesterol, and body mass index were included, also showed that depression was a significant (p = .027) predictor of BRS. There was no significant difference in BRS adjusted by age and sex between the subjects taking antidepressants compared with those on no medications (p = .40).

Conclusions: These data indicate that BRS is impaired in otherwise healthy patients with depression and may contribute to their increased cardiac risk.

Key Words: Baroreflex sensitivity • cardiac risk • ischemic heart disease • depression

Abbreviations: IHD = ischemic heart disease; MI = myocardial infarction; SSRI = selective serotonin reuptake inhibitor; HR = heart rate; BP = blood pressure BRS = baroreflex sensitivity; ANCOVA = analysis of covariance.

	INTRODUCTION

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There is now robust evidence that depression is an independent risk factor for ischemic heart disease (IHD) (1,2) and that the greater the exposure to depression, the higher the incidence of coronary events, including acute myocardial infarction (MI) and sudden cardiac death (3). A lifetime history of recurrent depression is also associated with development of carotid atherosclerotic plaques (4). Although the exact nature of the underlying mechanisms is unknown, several factors, such as abnormal platelet function and endothelial dysfunction, have been suggested. Whereas the abnormality in platelet function improves on treatment of depression with selective serotonin uptake inhibitors (SSRI) (5), this may not be the case for endothelial dysfunction as both treated (6) and untreated (7) depressed patients show endothelial dysfunction.

Depression also predicts increased mortality in those with established IHD (8,9) and is associated with a >4-fold increased risk of death following MI. Again, in a recent large controlled clinical trial, it was found that the increased risk persisted even in patients who had received treatment for depression, and those who were treatment refractory were at even higher risk than treatment responders (10).

Sympathetic nervous system activation predisposes to post-MI ventricular arrhythmias and sudden cardiac death, and several parameters of sympathoexcitation have been described in depressed patients (11). Heart rate (HR) and peripheral vascular resistance are regulated on a beat-by-beat basis by the "baroreflex" system that buffers changes in blood pressure (BP). Acute increases in BP lead to reflex slowing of the heart and a reduction in artery tone, via increased vagal and reduced sympathetic efferent activity, whereas decreased BP results in opposite changes. Baroreflex sensitivity (BRS) is a measure of the gain of the baroreflex. Following MI, and in other cardiac syndromes such as chronic heart failure, BRS is typically impaired. Impaired BRS promotes sympathoexcitation and sympathoexcitation in turn impairs the cardiac baroreflex (12). An important causal link between impaired BRS and post-MI risk of sudden cardiac death is supported by both human (13) and animal studies (12).

We hypothesized that impaired BRS may underlie the autonomic abnormalities observed in depressed patients and that this might contribute to their known increased risk of sudden cardiac death. In patients with manifest IHD and depressive symptoms, BRS is indeed impaired (14), but to our knowledge, there have been no prior studies of BRS in young patients with depressive disorders and without manifest cardiac disease. Furthermore, as we had previously shown that endothelial dysfunction persists after successful treatment for depression, our aim was to assess whether BRS was also impaired in euthymic patients with recurrent major depression. We therefore compared BRS in patients with well-defined prior depression but who were currently euthymic and who had no other "conventional" cardiac risk factors, to a group of healthy controls.

	METHODS

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The Local Research Ethics Committee approved our work, and all participants gave informed consent.

Subjects
Subjects were identified from psychiatric clinics, hospitals, general medical practices and from volunteers responding to media advertisements. They were aged 18 to 55 with a history of two or more episodes of unipolar depression (15) of at least moderate severity diagnosed using the Schedule for Clinical Assessments in Neuropsychiatry (16). All subjects had received treatment for depression and were in remission at the time of the study. Exclusion criteria included psychotic symptoms present outside a mood disturbance and depression occurring secondary to alcohol, substance abuse, or medical illness. Poster and word of mouth were used to recruit control subjects from the general public, hospital (but not Research Institute) staff, medical students, and visitors of patients. Controls were of similar age to subjects with no history of psychiatric illness. Exclusion criteria for both groups included a history of heart disease, any traditional risk factor for IHD [smoking, hypertension, diastolic blood pressure >85 bpm; diabetes or total cholesterol >5.7 mmol/l], body mass index >30 or any other condition or drug treatment likely to affect BRS.

Baroreflex Sensitivity
Subjects were studied at 8:30 AM, after fasting, and after having avoided alcohol for 24 hours and caffeine for 12 hours. After venesection, attachment to an ECG monitor, and fitting of a Portapres (TNO Biomedical Instrumentation, Affligem, Belgium) noninvasive continuous blood pressure (BP) monitor, subjects rested supine in a quiet, temperature-controlled environment for 20 minutes. For the next 10 minutes heart rate (HR) and BP were recorded. Analog outputs were fed into an analog-to-digital converter (Biopac, Biopac Systems Inc., Goleta, CA), and output from the converter fed into a PC and recorded at 500 Hz using AcqKnowledge software (Biopac Systems Inc.) for later calculation of BRS by the "sequence" method (17). BPs were calibrated using an automated sphygmomanometer (Omron 705 CP, Matsusaka Company Limited, Matsusaka, Japan).

Briefly, each systolic BP measurement was matched with the following RR interval on the ECG. A proprietary program was then used to seek "sequences" in which both systolic BP and RR interval increased or decreased together for 3 beats, with a (correlation coefficient < 0.85). Minimum increments were 1 mm Hg and 2 milliseconds. The mean sequence gradient, expressed in milliseconds/mm Hg, was taken as BRS.

Statistical Analysis
Data are expressed as mean (standard error of mean). Comparison between groups was by the independent samples t test. The difference in BRS between patients and controls was tested using analysis of covariance (ANCOVA). Age, sex, BMI, and cholesterol level can influence BRS, thus they were included in the analysis. Age, cholesterol, and body mass index were included as covariates in the model; sex and diagnosis were included as fixed effects. p < .05 was considered significant.

	RESULTS

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Thirty-six patients (28 women) and 39 controls (20 women) met the entry criteria and had BRS measured successfully; all BRS measurements made were of sufficient technical quality for inclusion. There was no difference in age, BMI, and cholesterol between the patients and controls (Table 1). Diastolic BP and HR were significantly higher in patients. BRS was significantly lower in patients (19.5 [1.78] versus 25.4 [1.69] ms/mm Hg, p = .017). BRS correlated with age (–0.43, p < .001), systolic BP (–0.19, p = .108), diastolic BP (–0.30, p = .01) and HR (–0.45, p < .001).

ANCOVA in which age, sex, cholesterol, and BMI were included showed that depression was a significant (p = .027) predictor of BRS. BP and HR are partially dependent on BRS; therefore, they were not included in the analysis because this would underestimate the strength of any effect of depression.

To study the influence of antidepressant medication on BRS, subjects were analyzed separately according to treatment status (Table 2). ANCOVA showed no significant difference in BRS adjusted by age and sex between the group with medications versus the group without medication (p = .4) nor between groups on different medications (SSRI versus others p = .57, SSRI versus nil p = .28, others versus nil p = .75).

	DISCUSSION

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Our principal finding is that BRS is impaired in patients with a prior history of recurrent major depression but who were euthymic at the time of the study and who had no other risk factors for IHD. This finding is consistent with our earlier observation that endothelial dysfunction persists in patients with treated depression (6), and together these findings may explain why patients with depression remain at increased risk of cardiovascular disease, including sudden cardiac death. It is a limitation of the study that there is a predominance of women in the sample; however, the unequal sex distribution is adequately accommodated by using ANCOVA and by including sex as a covariate. In addition, although sex influences BRS, it is of note that in an extensive study of BRS in 1,134 healthy subjects, gender accounted for only 1% of the total BRS variability (18). A further limitation of the study is that there were no depression rating scores available for subjects and controls at the time of BRS measurement although all subjects had been screened for depressive symptoms before entry and were euthymic.

In this population, BRS was not significantly different between those receiving no treatment and those taking antidepressants, and although the numbers were small, there appeared to be no difference in BRS according to the class of antidepressants used. Of those on medication, the largest group was taking SSRI. To the best of our knowledge, no studies have assessed the effects of SSRI on BRS; however, SSRI have been shown either to have no effect on (19) or to increase (20) heart rate variability. Increased heart rate variability is consistent with increased cardiac vagal tone, an observation usually associated with an increase in BRS.

Low BRS would be expected to result in, or at least contribute to, a higher HR and BP, and indeed these two measures were slightly but significantly higher in patients although still remained, in every case, within the normal range. It is another limitation of our study that patients with the greatest sympathoexcitation may have been excluded because such patients might have been hypertensive, and this may have led to an underestimation of the effect of depression on BRS.

BRS, like HR and BP, can vary within an individual as a consequence of psychological stress, and the modest differences we observed between subjects and controls may reflect greater residual anxiety in the former group in the laboratory setting. Six of the individuals in the control group were medical staff or students who might have been more accustomed to the experimental setting used, but elimination of these subjects from the analysis did not alter any of the findings. It may be that patients with a history of depression are generally more stressed or anxious and that this is a feature of their disease, via various mechanisms, contributing to their increased risk of IHD, and in this particular study, stress and anxiety were reflected in poorer relaxation under laboratory conditions.

Impaired BRS in post-MI patients strongly predicts mortality, independent of other known predictors such as impaired left ventricular function. The increased mortality predicted by low BRS in this population appears to be attributable largely to an increase in sudden cardiac death (13). In such a population sudden death is almost always arrhythmic, and this is consistent with impaired BRS being a cause and indicator of increased sympathoexcitation, thus predisposing patients to malignant ventricular arrhythmias (21). It is not known whether BRS is premorbidly low in those with impaired BRS in association with IHD. However, in a dog model of MI, low premorbid BRS predicted post-MI arrhythmias and a high premorbid BRS was protective (12).

It should be noted that BRS is largely a measure of cardiac vagal control of heart period, and although vagal and sympathetic control are usually reciprocal, this is not always the case. The higher heart rate and diastolic BP in the patient group probably reflects increased sympathetic tone as well as decreased cardiac vagal tone. While impaired BRS promotes sympathoexcitation (12), sympathoexcitation impairs cardiac vagal control. This makes it problematic to distinguish between sympathoexcitation and baroreflex impairment as the primary mechanism in these patients.

Notwithstanding this, these data indicate that BRS is impaired in depressed patients even when they are in remission, and thus BRS appears to be a "trait" rather than a "state" effect, which may contribute to their continued increased IHD risk. Potential contributory mechanisms, such as BRS, endothelial dysfunction (6), and platelet abnormalities (5), and a tendency toward an adverse lifestyle profile, including smoking, poorer diet and less physical activity, appear to be additive (22). Therefore, some depressed patients may be at greatly increased risk for cardiovascular disease.

The authors would like to thank Emma Dunn, Vicky Swainson, Anna Smith, John Tredget, and Debra Woolway for help in recruitment of subjects.

	NOTES

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A.J.M.B. and M.P.F. contributed equally to this manuscript.

This study was funded by the British Heart Foundation.

Received for publication August 20, 2004; revision received March 4, 2005.

DOI:10.1097/01.psy.0000170829.91643.24

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