Baroreflex mechanisms in major depression

Abstract

Background

Recent studies have shown that depressive disorder is associated with impaired baroreceptor or baroreflex sensitivity, which is proposed to be a predisposing factor for sudden death in patients with manifest cardiac disease. These studies have not evaluated the afferent and efferent components of the cardiac baroreflex loop or other baroreflex mechanisms that regulate target processes (cardiac metabolism and blood pressure variability) related to the impairment. The objective of this study was to gain more insight into autonomic functioning in depressive disorder to more fully examine the potential basis for increased cardiac mortality.

Methods

The subjects were 28 women and men with unipolar major depression who were taking antidepressant medications and who were in partial remission and free of cardiovascular or other serious disease, and 28 healthy control subjects matched for sex, age, and ethnicity. The two samples were compared for negative affective dispositions (anger expression, hostility, defensiveness, anxiety), spontaneous (closed-loop) baroreflex activity, heart rate, heart rate variability, systolic blood pressure, and heart rate-systolic blood pressure double product under resting conditions.

Results

Depressed patients showed a general disposition to anger suppression coupled with higher hostility and anxiety, and lower defensiveness. The patients showed higher general sympathetic activity (high levels of blood pressure, low-frequency heart rate variability) and lower parasympathetic-related activity (high heart rate and reduced high frequency heart rate variability) with affected cardiac metabolism estimated by the double product. Depressed patients had lower baroreflex sensitivity related to a higher gain of the afferent component of the baroreflex without respective gain adjustment of its efferent component (reflex gain ‘de-afferentation’). It was coupled with a compensatory higher number of effective baroreflex reactions (reflex gating ‘re-afferentation’). Antidepressant agents and depressed mood had additional independent effects on baroreflex sensitivity through the efferent component of the cardiac baroreflex loop.

Conclusions

The data indicate that different baroreflex components and mechanisms may be impaired in patients with depression and may contribute to their increased cardiac risk.

Introduction

There is emerging evidence that depressed patients have a significant loss of cells in the prefrontal cortex (Rajkowska, 2000), a brain area important in mood regulation and in cortical control of the hypothalamic–pituitary–adrenal axis and the sympathetic nervous system. The evidence supports the concept of depression as a systemic disease with primary medical manifestations. Depression is associated with cardiovascular disease, diabetes, and osteoporosis (Carney et al., 2005, Grippo and Johnson, 2002). Prospective treatment of depressed patients with comorbid cardiovascular pathology may increase the chances of good medical outcome and survival (Gold and Charney, 2002, Carney et al., 2005).

The prefrontal cortex is part of the limbic system and assumed to be involved in the modulation of autonomic responses to stress and emotional stimuli, thus considered a visceral-motor cortical region. Ineffective coping strategies may lead to mood disturbance (e.g., depression) coupled with disorganized prefrontal cortex activity, which affects cortisol and norepinephrine secretion and, in turn, produces a highly adverse biochemical environment with negative metabolic outcomes (McEwen, 2004). Moreover, the prefrontal cortex directly modulates cardiovascular control (Resstel et al., 2004), and cardiac autonomic activity (e.g., related to baroreflex) is sensitive to the early stage of dysregulation of emotions and cognition.

There is considerable evidence of autonomic cardiovascular dysregulation in depressed patients, including elevated resting and 24-h heart rate, increased heart rate responses to physical stressors, reduced respiration-related high-frequency component of heart rate variability (HF-HRV), and high variability in ventricular repolarization (see, e.g., Carney et al., 2005). These dysregulations have been associated with increased mortality and cardiac morbidity, especially in vulnerable populations such as depressed patients (see Grippo and Johnson, 2002). HF-HRV is one of the most widely used measures of cardiac autonomic activity in humans (Task Force Report, 1996). Beat-to-beat variability in the heart's rhythm is determined primarily by autonomic modulation of the intrinsic cardiac pacemakers. Low HF-HRV suggests insufficient cardiac parasympathetic modulation (Task Force Report, 1996). Many studies, although not all (Yeragani et al., 1992), have found HF-HRV to be lower in depressed psychiatric patients than in controls (Dallack and Roose, 1990, Imaoka et al., 1985, Rechlin, 1994a). HRV is lower in depressed than in nondepressed patients with stable coronary disease (Carney et al., 1995, Krittayaphong et al., 1997) and is reduced in patients with a recent history of acute myocardial infarction (Carney et al., 2001).

The arterial baroreflex contributes substantially to parasympathetic regulation of the heart (La Rovere et al., 1995). Although HF-HRV and baroreflex sensitivity (BRS) are correlated, BRS has been shown to be a better predictor of parasympathetic tone during parasympathetic blockade (Reyes del Paso et al., 1996). BRS is a measure of the functioning of a reflex loop involving pressure-sensitive nerves (i.e., baroreceptors) mainly in the carotid arteries and the aorta. Reduced baroreflex sensitivity (BRS) may be a marker of increased cardiac risk associated with depression or comorbid anxiety (Broadley et al., 2005, Carney et al., 2005, Grippo and Johnson, 2002, Hughes et al., 2006, Watkins et al., 1998, Watkins et al., 1999, Watkins and Grossman, 1999, Pitzalis et al., 2001). This association may be secondary to metabolic changes, mainly related to age (Hunt et al., 2001, Sposito and Barreto-Filho, 2004). The reduction in BRS may not be a pathological process, but rather a physiological adaptation (i.e., the baroreflex gain ‘de-afferentation’ mechanism between afferent and efferent components of the baroreflex) to reduced blood pressure (BP) variation, changed BP steady state, or to other baroreflex and non-baroreflex processes to achieve BP and cardiac work stabilization (see Burattini et al., 2004).

Thus, the activity of different (afferent, efferent, peripheral, and central) components of the baroreflex loop in their impact on BRS and HRV measures should be assessed to distinguish primary and secondary factors in baroreflex impairment related to cardiovascular function in affective states. As BRS is derived from the central integration of two separate gains in the afferent and efferent phases of a loop, an independent impact of the afferent and efferent components of the spontaneous baroreflex on its integrated gain may help uncover the basis of altered BRS in its relation to affective condition.

Moreover, the effectiveness of baroreflex mechanisms of BP stabilization should be evaluated to distinguish pathological and normal physiological processes in the cardiovascular system during affective states. The effectiveness of the buffering action of the baroreflex in BP stabilization has not been evaluated in most studies of patients with depressive symptoms (see, e.g., Broadley et al., 2005, Carney et al., 2005, Pitzalis et al., 2001, Watkins and Grossman, 1999). Watkins and Grossman (1999) suggested that low BRS may be a marker of increased risk of cardiac events associated with depression, but in their comparison of patients with many or few depressive symptoms, the decline of BRS was not associated with significant changes in BP variability. That fact questions whether decreased BRS is a pathological process in all cases. The reduced effectiveness of the arterial baroreflex in humans leads to an increase in BP variability, and mean BP levels remain largely unchanged in chronic conditions (Cowley et al., 1973, Ramirez et al., 1985). Thus, the role of baroreflex activity in regulating BP may be important for the prognosis of cardiac morbidity in patients with depression. The impairment of BP stability, but not a change of BRS itself, may introduce an additional strain on myocardial energy balance, which can cause transient subendocardial ischemia, tissue hypoxia, and myocardial dysfunction (Feigl, 1983, Gamble et al., 1974, Walston et al., 1978).

Blood pressure variability within a steady state (e.g., standard deviation of BP) may reflect the effectiveness of baroreflex mechanisms in BP regulation (Mancia et al., 1986). Because the baroreflex is known to impose an inverse relationship between HR and BP, this implies that it should attenuate variations in their product. The extent to which such variations will be reduced depends on the size of the reflex adjustment of HR for a given change in BP. Thus, the baroreflex may help isolate the heart from the metabolic impact of sudden hemodynamic disturbances not only by attenuating perturbations of BP but also by stabilizing the double product (Van Vliet and Montani, 1999, Van Vliet et al., 2002).

However, the baroreflex mechanism is a more complex physiological process and is not restricted to the baroreflex sensitivity function. Recent physiological studies (Carr et al., 2001, Harper, 1991, Paton and Kasparov, 2000, Resstel et al., 2004, Snitsarev et al., 2002) revealed a critical role for other mechanisms in baroreflex control. With a primary effect on central functional unbalance, these mechanisms suggest an additional etiological factor for cardiac risk in mood disorders. For example, high basal sympathetic activation (e.g., high circulating norepinephrine and angiotensin II levels), a condition frequently found in depressed patients (see, e.g., Grippo and Johnson, 2002), leads to a decline in the effective baroreflex sequences by a partial (gain) or total (gating) central ‘de-afferentation’ mechanism to allow for the maturational rise in arterial pressure (Airaksinen et al., 2001, Paton and Kasparov, 2000).

The sequence technique of BRS evaluation offers a means of quantifying the central gating process using the so-called baroreflex effectiveness index (BEI), which measures the number of times the baroreflex is effective in overcoming the non-baroreflex influences that regulate the sinus node (Di Rienzo et al., 2001b). A reduction of the BEI may occur in conjunction with an increase in BRS (Di Rienzo et al., 2001b). Thus, the number of times the baroreflex inhibits the sinus node (the baroreflex ‘gating’ mechanism) may be taken as another measure of its effectiveness in controlling the circulation (Di Rienzo et al., 2001b, Parati et al., 2000, Rüdiger and Bald, 2001).

Recent findings (see, e.g., Di Rienzo et al., 2001a, Halamek et al., 2003) raise questions about the phase relationship between BP and the cardiac inter-beat interval (R-wave to R-wave interval, RRI). In the case of baroreflex, gain (i.e., sensitivity) might correspond to the magnitude of change in RR-interval for a given change in blood pressure, but the phase relation is described by quantifying the phase shift (delay) between systolic blood pressure (SBP) and RR-interval coupling. If the phase of transfer function is not steady from the point of view of hemodynamic stability, then it is conceivable that any benefits of increased gain of the baroreflex control of heart rate might be less apparent. Both baroreflex gain and variability of phase may provide important and independent information about circulatory control and stability (Di Rienzo et al., 2001a) and provide important additional information regarding the risk of sudden cardiac death (Halamek et al., 2003). Indeed, in some conditions, the RR-interval is in phase with or slightly leads arterial pressure changes, but in others, it follows pressure changes (Cohen and Taylor, 2002, De Boer et al., 1987). These baroreflex heart reaction delays were found unrelated to fast versus slow heart rates (Di Rienzo et al., 2001a). Thus, baroreflex buffering measured by the gain in cardiac feedback may be redistributed among different phase shifts (lags with 0, 1, or 2 beats, Di Rienzo et al., 2001b) related to BP changes by the baroreflex ‘phase’ mechanism.

All these baroreflex mechanisms serve to control the arterial pressure, i.e., to steer the pressure toward some “normal” steady state (e.g., mean SBP), to diminish BP fluctuation around it (e.g., BP variability) or to keep BP fluctuation within a range between the “up” and “down” SBP set points. The term “set point” denotes the operating point of the cardiovascular system related to a BP level within an SBP range, which is determined by physiological parameters and mechanisms (e.g., baroreflex regulatory up or down reactions). To keep BP within the set point range, the baroreflex mechanisms should control the balance of number, gain, and phase of SBP-RRI sequences during hemodynamic load and unload on baroreceptors.

We evaluated baroreflex mechanisms by retrieving and calculating baroreflex variables from sequences of spontaneous baroreflex reactions. Up to now, the method of spontaneous baroreflex evaluation has been used to derive baroreflex sensitivity (gain) in the same way that pharmacological (phenylephrine hydrochloride and sodium nitroprusside) manipulation techniques have been used. However, the method of spontaneous baroreflex evaluation makes it possible to assess additional components of cardiac baroreflex regulation. A major objective of the present study was to introduce and examine these additional physiological components as a means of exploring mechanisms in the relationship between depression and cardiac functioning.

We hypothesized that impaired baroreflex is related to compensated and de-compensated interactions between more central (e.g., gain of the efferent component of the baroreflex loop) and more peripheral (e.g., gain of the afferent component of the baroreflex loop) processes underlying the autonomic abnormalities observed in depressed patients, a condition which may contribute to increased risk of cardiac pathology. This study was conducted to examine the coupling of different baroreflex components (e.g., afferent and efferent) and mechanisms (e.g., ‘gain’, ‘phase’, and ‘gating’) with biomarkers of increased cardiac risk (e.g., instability in BP and HR-BP ‘double’ product) in patients with major depressive disorder (MDD) and to determine if a similar coupling occurs in healthy subjects.

We predicted that patients with the negative affect structure related to major depression (a general disposition to higher hostility, anger, and anxiety) would have reduced HRV and BRS (baroreflex gain) compared to healthy people. We also predicted that impairment in other baroreflex mechanisms (e.g., an increase in BEI or a phase delay in baroreflex cardiac feedback) and instability in target (SBP) processes would differentiate patients with depression from healthy subjects. The blood pressure instability would be reflected in the effectiveness of different baroreflex mechanisms and might be evaluated by BP variability, stability in “up” and “down” SBP set points for cardiac baroreflex regulatory reactions, and the HR-BP ‘double’ product. Thus, the main focus of the study was the effectiveness of mechanisms of baroreflex functioning associated with depressive mood disorder.