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Abstract

Objective:

To examine the evidence for shared pathophysiological pathways in acute coronary syndrome and major depression and to conceptualise the dynamic interplay of biological systems and signalling pathways that link acute coronary syndrome and depression within a framework of neuro-visceral integration.

Methods:

Relevant articles were sourced via a search of published literature from MEDLINE, EMBASE and PubMed using a variety of search terms relating to biological connections between acute coronary syndrome and depression. Additional articles from bibliographies of retrieved papers were assessed and included where relevant.

Results:

Despite considerable research efforts, a clear understanding of the biological processes connecting acute coronary syndrome and depression has not been achieved. Shared abnormalities are evident across the immune, platelet/endothelial and autonomic/stress-response systems. From the available evidence, it seems unlikely that a single explanatory model could account for the complex interactions of biological pathways driving the pathophysiology of these disorders and their comorbidity.

Conclusion:

A broader conceptual framework of mind–body or neuro-visceral integration that can incorporate the existence of several causative scenarios may be more useful in directing future research and treatment approaches for acute coronary syndrome–associated depression.

Keywords

Depression acute coronary syndrome biological mechanisms inflammatory response autonomic nervous system

Introduction

Depression and cardiovascular disease (CVD) are prevalent and highly disabling disorders (Lopez et al., 2006). Patients who suffer an acute coronary syndrome (ACS; e.g. myocardial infarction or unstable angina) experience a threefold increased risk of developing depression (15–20% versus 6%) compared to the general population (Davidson et al., 2010; De Jonge et al., 2010; Glassman, 2007; Nemeroff and Goldschmidt-Clermont, 2012). Moreover, it is well documented that the emergence of a major depressive episode around the time of the ACS significantly increases the risk of a poor cardiac outcome, including mortality (Freedland and Carney, 2013; Parker et al., 2008). In response to these findings, a scientific statement from the American Heart Association advised that the strength of the evidence justifies formal acknowledgement of depression as a risk factor for poor medical outcomes after an ACS (Lichtman et al., 2014). The underlying pathophysiological mechanisms responsible for the bidirectional link between depression and ACS remain poorly understood (Baune et al., 2012; De Jonge et al., 2010; Freedland and Carney, 2013; Pereira et al., 2013; Stapelberg et al., 2011; Whooley, 2013) and led to this review of candidate mechanisms.

Behaviour has a clear influence. Patients with depression are more inclined to smoke, have a poor diet and be physically inactive – behaviours predisposing to cardiac events (Glassman, 2007; Joynt et al., 2003; Lane et al., 2001). After ACS, depression may lead to behaviours that increase the risk of further cardiovascular events, including a lack of self-care, reduced social interaction, underutilisation of healthcare services such as cardiac rehabilitation and poor medication adherence (Cowan et al., 2008; Lane et al., 2001). Psychosocial and behavioural factors ultimately translate into pathophysiological changes in biological systems to exert their effects on health. For example, lifestyle choices such as smoking and physical inactivity may act to increase cardiovascular pathophysiology directly but also contribute to risk indirectly through secondary disease processes associated with a metabolic syndrome or diabetes (Burg et al., 2013; Lopresti et al., 2013).

Several comprehensive reviews have considered candidate biological mechanisms, including inflammatory processes and dysregulation in autonomic and other stress-responsive circuits (De Jonge et al., 2010; Nemeroff and Goldschmidt-Clermont, 2012; Pereira et al., 2013; Thayer and Lane, 2007; Whooley, 2013), but few provide a persuasive conceptualisation of pathophysiological integration. Acknowledging the interaction of several causal mechanisms, rather than focussing upon a single contributor, may better describe the relationships between ACS and depression (Stapelberg et al., 2011). Furthermore, delineation of plausible explanatory models may require a deeper appreciation of the complexity of the disturbance(s) in key neurophysiological systems and their feedback circuits, and the noted reciprocal and perpetuating impact of one condition on the other. The heterogeneity in patient groups fitting the diagnostic labels ‘depression’ and ‘ACS’, although recognised (Baune et al., 2012; Davidson, 2012), is also rarely taken into account. This is despite the well-documented contribution of heterogeneity to disparate research findings in other conditions, such as the enigmatic chronic fatigue syndrome (Aslakson et al., 2009; Vollmer-Conna et al., 2006).

This review focusses on biological mechanisms with documented action in the periphery and in the central nervous system (CNS), and which may be activated by either psychological/behavioural stressors or a disruption of homeostasis in physiological systems. Existing genetic and acquired vulnerabilities unique to each individual are thought to shape the specific manifestations of the pathophysiology and symptomatology of ACS and depression.

For each candidate biological mechanism reviewed (immune, autonomic, platelet/endothelial and hypothalamic–pituitary–adrenal [HPA]-axis function), we will first evaluate the evidence of its pathophysiological importance to CVD/ACS and major depression separately and then highlight recent findings supporting a mediating role of these shared mechanisms in initiating or perpetuating disorder comorbidity. A framework of neuro-visceral integration is offered to conceptualise the complex and dynamic interplay of these biological systems and signalling pathways linking ACS and depression.

Methods

Search strategy

An initial literature search of MEDLINE, EMBASE and PubMed using the terms ‘depression’ or ‘depressive disorder’, and ‘acute coronary syndrome’, ‘myocardial infarction’ or ‘unstable angina’ was conducted. The terms ‘hypothalamus pituitary adrenal axis’, ‘autonomic nervous system’, ‘heart rate variability’, ‘inflammation’, ‘inflammatory mediators’, ‘C-reactive protein’, ‘cytokines’, ‘tumor necrosis factors’, ‘interleukins’, ‘dopamine’, ‘serotonin’, ‘brain derived neurotrophic factor’, ‘neurotransmitter agents’, ‘blood platelets’, ‘platelet aggregation’, ‘vascular endothelium’, ‘thrombocyte’, ‘thrombocyte aggregation’, ‘vascular endothelium’, ‘polymorphisms’, ‘genetic polymorphisms’ and ‘genes’ were combined in subsequent searches with the initial search terms.

A title abstract review was conducted and cross-referenced. Articles in English that focussed on biological pathways linking ACS and depression were included. Additionally, articles from bibliographies of retrieved papers were assessed and included where relevant. As this literature is extensive, we have, as far as possible, focussed on evidence of high quality.

Biological mechanisms mediating the link between depression and ACS

Immune activation and inflammation

CVD is a recognised covert inflammatory condition (Ross, 1999). Immune cells (e.g. macrophages) in and around an endothelial plaque signal and maintain an inflammatory response (Libby, 2012; Ross, 1999). The death of immune cells attempting to clear the plaque adds to its mass, further up-regulating inflammatory proteins and a cascade of pro-inflammatory activity (Joynt et al., 2003; Libby, 2012). Significant elevations in local (i.e. intracoronary) cytokine production profiles have recently been confirmed in patients with ACS (Cirillo et al., 2014), although the authors noted substantive individual variation. Inflammatory markers including C-reactive protein (CRP), interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-α have been shown to predict cardiovascular events (Kaptoge et al., 2010; Shlipak et al., 2008).

The potential immunopathological effects of intense inflammatory responses are mitigated by the up-regulation of anti-inflammatory cytokines. Patients with stable angina have higher anti-inflammatory IL-10 concentrations than those with unstable angina (Smith et al., 2001). In patients with ACS, higher levels of IL-10 were shown to correlate with lower concentrations of inflammatory proteins and better health outcomes (Chalikias et al., 2005; Heeschen et al., 2003). Conversely, two large population studies suggest that higher levels of circulating IL-10 are associated with worse outcomes after ACS (Mälarstig et al., 2008; Welsh et al., 2011). Considering the dynamic interplay between cytokines with a role in inflammation, the timing of a single blood sample in relation to ACS would greatly influence relative composition of pro- and anti-inflammatory proteins in such a snapshot assessment. Thus, it has been argued that these seemingly contradictory results can be explained in terms of the complex interactions of cytokine networks (Welsh et al., 2011). Specifically, enhanced expression of an ‘anti-inflammatory’ cytokine, such as IL-10, may indicate ongoing inflammation within the tissue, thus acting as a counter-regulatory mechanism to limit further inflammation. Consistent with such a view, Mälarstig et al. (2008) concluded that circulating IL-10 should be considered a surrogate biomarker for ongoing cardiovascular inflammation and pathology, and thus is as effective as markers of systemic inflammation in risk prediction of future cardiovascular events.

A substantive literature supports an association between inflammation and depression. For example, levels of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) were significantly higher in the blood and cerebrospinal fluid (CSF) of patients with depression compared to non-depressed controls (Dinan, 2009; Dowlati et al., 2010; Howren et al., 2009). However, considerable inter-individual variation in levels of inflammatory markers has been reported in depressed patients (Raison and Miller, 2011), and there are conflicting reports as to whether inflammatory markers revert to normal levels when depressive symptoms remit (Dinan, 2009; Miller et al., 2009).

Inflammation has been posited to link ACS/depression comorbidity. Patients with both depression and elevated inflammatory markers (e.g. CRP levels > 3 mg/L) experienced a much higher risk of ACS (Empana et al., 2005; Ladwig et al., 2005). In patients with ACS, concentrations of inflammatory markers, in particular CRP, were significantly higher in those with comorbid depression than in those without (Shimbo et al., 2006). Given the prognostic value of CRP for ACS outcome (Ramasamy, 2011), the increased morbidity and mortality risk for patients with ACS-associated depression may be mediated by an overall greater elevation in CRP levels (Shimbo et al., 2006). Other evidence has been less consistent. For example, one study showed that after adjustment for factors possibly impacting inflammation, such as smoking, physical inactivity and body mass index, the observed relationship between raised CRP and IL-6 and depression was lost (Duivis et al., 2011).

As white blood cells proliferate in response to an immunological challenge, white cell counts (WCCs) offer a simple measure of immune activation. Significantly raised WCCs have been linked to CVD with a fourfold increased risk of experiencing ACS (Brown et al., 2001; Ernst et al., 1987; Kannel et al., 1992). Additional evidence suggests that WCCs are raised as a result of distress and depression (Patterson et al., 1995; Segerstrom and Miller, 2004; Zorrilla et al., 2001). Some studies have examined the prognostic utility of WCCs for developing depression in association with ACS. Baseline WCCs predicted developing symptoms of both depression and anxiety following ACS in one study (Steptoe et al., 2013) and partially predicted cardiac mortality in patients with comorbid depression (Kop et al., 2010).

Explanations of the connection between inflammation, ACS and depression must extend beyond the direct peripheral effects of inflammation on, for example, endothelial function. Following infection or injury, immune activation and the concomitant up-regulation of pro-inflammatory proteins are typically accompanied by a set of physiological, behavioural and motivational changes, including fever, increased slow wave sleep, hyperalgesia, anorexia, anhedonia, disturbed mood and impaired concentration – termed the ‘acute sickness response’ (Hart, 1988; Vollmer-Conna, 2001). This response is triggered by the action of cytokines on CNS targets and represents a fundamental biological adaptation that shifts the organism’s priorities towards pathogen resistance, energy preservation and recovery (Poon et al., 2013). Chronic activation of inflammatory response pathways in CVD may, in vulnerable individuals, lead to the more sustained and severe pattern of behavioural and physiological changes of major depression (Gunaratne et al., 2013; Miller et al., 2013). Such complex interactions have been intensely studied, with an inflammatory contribution to neuropsychiatric conditions such as major depression being the subject of several detailed reviews (Dantzer et al., 2011; Felger and Lotrich, 2013; Liu et al., 2013; Miller et al., 2009; Raison and Miller, 2013). In essence, cytokines and their signalling pathways exert significant effects on the synthesis, release and reuptake of many neuroactive proteins including serotonin, dopamine, noradrenaline, glutamate and brain-derived neurotrophic factor (BDNF). For example, by activating the enzyme indoleamine 2,3 dioxygenase (IDO), tryptophan is converted into kynurenine instead of serotonin, a process which may affect serotonergic neurotransmission and increase the risk of depression (Dantzer et al., 2008). Kynurenine can cross the blood–brain barrier and may then be further metabolised by glial cells to generate neuroactive compounds, including quinolinic acid and kynurenic acid (Miller et al., 2013). In particular, quinolinic acid (a glutamate agonist) is well recognised for its potential to produce excitotoxicity, oxidative stress and neuronal cell death (Müller and Schwarz, 2007). Reduced levels of tryptophan and elevated kynurenine in the CSF, as well as glutamatergic hyperfunction, have been documented in depression (Capuron et al., 2003a; Müller and Schwarz, 2007; Raison et al., 2010). Additionally, the association between IDO-activity and depression was confirmed in a population-based study (Elovainio et al., 2012), although a longitudinal cohort study did not find a direct relationship between reduced tryptophan bioavailability and depression – nor establish a mediating role for tryptophan degradation in the relationship between inflammatory markers and depressive symptoms (Quak et al., 2014).

Another mechanism by which pro-inflammatory cytokines could impede monoamine function is via perturbation of tetrahydrobiopterin (BH4) activity. BH4 functions as a cofactor for several important enzyme systems involved in the biosynthesis of neurotransmitters including epinephrine, norepinephrine, dopamine and serotonin (Bendall et al., 2013). Although BH4 biosynthesis can be induced by inflammatory stimuli, pro-inflammatory cytokines also excite the activity of nitric oxide synthase (NOS) to produce nitric oxide (NO), which uses BH4 as an enzyme cofactor. Moreover, inflammatory stimuli increase oxidative stress to which BH4 is very sensitive (Bendall et al., 2013; Miller et al., 2013). Inflammation may thus increase the utilisation and ultimate degradation of BH4. BH4 is also a key regulator of endothelial NOS. Studies evaluating tissue and plasma samples from patients with CVD have revealed an inverse relationship between plasma and blood vessel BH4 levels (Antoniades et al., 2007), whereby low vascular BH4 is associated with decreased vascular function and increased vascular superoxide, and also with elevated concentrations of plasma BH4 and CRP. This example of BH4 illustrates how the same biological pathway can manifest varied localised pathologies to perpetuate CVD and/or depression.

While inflammatory proteins can impact brain functioning, acute or chronic psychological trauma and depression can in turn significantly increase inflammatory responses, decreasing neurotrophic support and the availability of serotonin and glutamate, as well as increasing apoptosis and oxidative stress (Catena-Dell’Osso et al., 2013). Up-regulated inflammatory processes may therefore be a common feature in ACS and depression, albeit for different reasons. In individuals with both conditions, elevated levels of inflammatory proteins may be perpetuated through several different pathological processes and contribute to increased morbidity and mortality.

Twin studies suggest a genetic influence on the propensity for an exaggerated inflammatory response in patients with CVD and depression (Scherrer et al., 2003; Su et al., 2009). Specific genetic polymorphisms that may contribute to vulnerability to ACS and depression have also been identified (Mulle and Vaccarino, 2013). For example, a functional polymorphism in the TNF-α gene (-308G/A) was associated with increased production of TNF-α in response to an immune challenge (Wilson et al., 1997), cardiac risk factors (Dalziel et al., 2002), metabolic syndrome (Sookoian et al., 2005) and depression (Jun et al., 2003; Lückhoff et al., 2014). Polymorphisms in the IL-6 (-174G/C and -572G/C) and CRP genes (+1444C/T) were associated with an increased inflammatory response after coronary bypass surgery (Brull et al., 2003). Additionally, the high-producing T allele of this CRP polymorphism (+1444C/T) has been associated with increased suicidal behaviour (Suchankova et al., 2013).

Mechanisms relating to platelet and endothelial function

Platelet activation and endothelial function are dysregulated in patients with CVD. Platelet activation is a finely balanced orchestration of pro-coagulant release and platelet receptor stimulation. In the event of plaque rupture, platelets aggregate to promote healing. This activation involves platelets changing shape and releasing granules adding to the ‘stickiness’ of the milieu, which can result in an occluding thrombus (Neubauer et al., 2013). Platelet activation can thus be a precipitating factor in ACS. The endothelium reacts to platelet activation by releasing NO, a potent vasodilator, which allows blood flow to be maintained (Korszun and Frenneaux, 2006; Mombouli and Vanhoutte, 1999). Damage to the endothelium and the presence of inflammatory proteins reduce NO availability, which affects blood pressure control as well as angiogenesis (Bendall et al., 2013; Le Melledo et al., 2004; Verma et al., 2002).

Several neurotransmitters with established roles in mood regulation have a dual role in platelet and endothelial function. For example, serotonin has documented peripheral action as a platelet activation agonist, initiating vasoconstriction and coagulation (Côté et al., 2004; Ziegelstein et al., 2009), and high levels of circulating serotonin may elevate thrombotic and cardiac risks (Musselman et al., 1996; Schins et al., 2003). Additionally, BDNF plays important roles in cardiac protection and recovery by mediating endothelial function and facilitating cell regeneration (Kermani and Hempstead, 2007; Okada et al., 2012). Both endothelial cells and platelets release BDNF concomitant with platelet activation (Nakahashi et al., 2000), and animal studies have demonstrated a role for BDNF in capillarisation and recovery after ischaemia (Kermani and Hempstead, 2007; Okada et al., 2012).

Centrally, BDNF is vital for neuronal longevity and neurotransmission (Lipsky and Marini, 2007). Animal models of depression have documented reduced BDNF production in the hippocampus and altered serotonergic transmission (Hashimoto, 2010). In humans, low BDNF levels have been linked to depression (Hashimoto, 2010; Lee et al., 2007; Shimizu et al., 2003), as has a polymorphism in the BDNF gene (Val66Met), which may reduce neuro-availability of BDNF (Terracciano et al., 2010). However, recent reviews conclude that the influence of BDNF on mood regulation is complex and poorly understood, with the precursor proBDNF and the mature protein mBDNF playing opposing roles in the mediation of symptoms of mood disorders (Groves, 2007; Hashimoto, 2010; Lipsky and Marini, 2007).

Serotonergic transmission has been intensely studied in depression (Karg et al., 2011). Two meta-analyses (Karg et al., 2011; Lopez-Leon et al., 2007) but not a third (Risch et al., 2009) quantified an association between polymorphisms in the serotonin transporter gene (5-HTTLPR S/L) and the risk of depression, particularly in the face of repeated life stressors. It has also been shown that post-ACS patients carrying the risk-associated S allele experienced an increased likelihood of subsequent cardiac events when they also experienced depressive symptoms (Nakatani et al., 2005).

A recent review provided a detailed description of the platelet clotting cascade and subsequent dysregulation experienced in patients with ACS and depression (Nemeroff and Goldschmidt-Clermont, 2012). These authors suggest ACS-associated depression may be an age-related phenomenon, noting the increased incidence of both ACS and new-onset depression with ageing, and the age-related decreased availability of endothelial progenitor cells (EPCs) and other cells needed for arterial repair. In support, EPCs have been demonstrated to be low in patients (average age 58 years) with either ACS or depression; however, patients with comorbid ACS and depression had the lowest EPC counts (Di Stefano et al., 2014).

Platelet and endothelial dysfunction are common to ACS and depression and exacerbated by processes associated with each disorder (Sherwood et al., 2005; Von Känel et al., 2001). Patients experiencing depression showed higher cardiac risk factors related to platelet dysfunction such as elevated fibrinogen; when re-assessed 6 months later, depression symptom remission and fibrinogen decreases were correlated (Mclean et al., 2007). Some evidence suggests a cumulative risk of platelet dysfunction resulting from comorbid ACS and depression (Kuijpers et al., 2002; Serebruany et al., 2003). However, a review (Nemeroff and Musselman, 2000) and large cohort study (Gehi et al., 2010) examining whether platelet activation functions as a mediator between CVD and depression found the evidence inconclusive.

The importance of autonomic regulation

The autonomic nervous system (ANS) is pivotal in the maintenance of body integrity, self-regulation and adaptation (Thayer et al., 2012; Tracey, 2009). Autonomic response pathways have evolved to favour sympathetic dominance to ensure adaptive survival. Experience of severe and/or persistent stress and trauma may cause prolonged reduction in prefrontal inhibitory control of stress-responsive neural circuits (Maier and Watkins, 2010), leading to an imbalance in ANS function characterised by a dominance of sympatho-excitatory circuits and loss of parasympathetic (vagal) tone. This engenders a hyper-vigilant physiological state, lacking adaptive flexibility, which has been linked to the severity and outcome of a large spectrum of diseases including ACS and depression (Hillebrand et al., 2013; Kemp et al., 2012; Pereira et al., 2013; Stapelberg et al., 2012; Thayer and Lane, 2007). In addition, the sympathetic branch of the ANS is understood to play a role in enhancing the intensity of the host response to immunogenic stimuli (Grebe et al., 2010; Kin and Sanders, 2006; Thayer et al., 2012), while the parasympathetic vagus nerve contributes to the containment of inflammatory responses (Andersson and Tracey, 2012; Tracey, 2009).

Cardiac autonomic functioning, in particular vagal modulation, can be reliably inferred from measures of beat-to-beat heart rate variability (HRV; Task Force of the European Society of Cardiology the North American Society of Pacing (Electrophysiology), 1996). One of the earliest large-scale investigations of a role for HRV in post-ACS mortality (Kleiger et al., 1987) reported a highly significant fourfold increase in mortality risk for those in the lowest quadrant of HRV over the 4-year follow-up study period. The predictive value of HRV was independent of other relevant risk factors, and its impact increased over time. Since that report, evidence has accumulated supporting a connection between low HRV and cardiovascular morbidity and mortality (Hillebrand et al., 2013; Stapelberg et al., 2012; Taylor, 2010; Thayer and Lane, 2007).

Thayer and Lane (2007) noted that all modifiable risk factors for CVD (e.g. diabetes, smoking, high cholesterol, insufficient exercise) are linked to low HRV. A reduction of HRV has been associated with poor modulation of cardiovascular responses, an increased propensity to inflammation and poorer health outcomes in ACS patients (Carney et al., 2007; Thayer and Lane, 2007). Low HRV has also been recognised as an important covariate of major depressive disorder (Kemp et al., 2012; Wang et al., 2013) and is hypothesised to underlie the link between depression and cardiovascular events (Huikuri and Stein, 2012; Stapelberg et al., 2012; Taylor, 2010). HRV parameters have been shown to negatively correlate with depression severity in patients with CVD (Stein et al., 2000) and after ACS (Carney et al., 2001), and reduced HRV persists in patients with depression following cardiac surgery (Patron et al., 2012). In patients with ACS assessed 2 months after discharge, a negative correlation between HRV and the inflammatory markers CRP and IL-6 was shown to be strongest in depressed participants (Frasure-Smith et al., 2009). While these data provide circumstantial support for an anti-inflammatory role of vagal nerve activity, no direct relationship with HRV and depression symptoms was found.

As is the case when examining the impact of inflammation on ACS and depression, the relationships between autonomic dysfunction, ACS and depression are best considered within a framework of neuro-visceral connectivity. Traditional cardiovascular research has linked altered autonomic activity to its localised effects on vascular, endothelial or cardiac function (Xhyheri et al., 2012). Similarly, reduced HRV in depression has typically been interpreted in a top-down fashion, as a reflection of ongoing psychosocial stress and associated state of hyper-vigilance (Thayer and Lane, 2007; Thayer and Sternberg, 2006). A meta-analysis documenting the failure of anti-depressant medication to enhance HRV, even when symptoms of depression are significantly improved (Kemp et al., 2010), underscores cognitive explanations of the depression–low HRV association as being in themselves insufficient. A study linking a disturbance in autonomic balance to inflammatory processes suggests that low-grade inflammation may be an additional, independent driver for centrally mediated reduction of HRV – including in those with depressive disorder (Harrison et al., 2013). An ‘internal stressor’ of ongoing inflammation may thus contribute to low HRV in both CVD and depression, while sustained low HRV, and associated reduced vagal activity, may perpetuate a physiological state unable to contain excessive inflammatory responses. Adding the neural and physiological changes associated with major depression to this mix creates a vicious feedback cycle that sustains, and possibly potentiates, autonomic imbalance and chronic inflammation, particularly in patients with comorbid ACS and depression.

HPA-axis and glucocorticoid sensitivity

Glucocorticoids function to contain the inflammatory response via a feedback loop where HPA-axis activity is induced by high levels of pro-inflammatory cytokines (particularly IL-6), and the released cortisol in turn, down-regulates further production of pro-inflammatory cytokines (Nijm and Jonasson, 2009; Walker, 2007). Administration of glucocorticoids has been associated with an increased risk of experiencing a cardiovascular event (Souverein et al., 2004; Wei et al., 2004) and the progression of atherosclerosis (Dekker et al., 2008). In patients receiving interferon (IFN)-α therapy, responders with hyper-activation of the HPA-axis were more likely to develop depression in subsequent weeks (Capuron et al., 2003b), indicating a role for HPA-axis sensitivity in immunologically triggered depression. HPA-axis dysregulation may contribute to the increased morbidity and mortality risk in patients with ACS-associated depression, although this has not been examined in any depth.

Perspectives on neuro-visceral integration as it relates to CVD/ACS-associated depression

Contemporary research has significantly advanced our understanding of the functional complexities of the major regulatory and signalling systems connecting the human mind and body. Reciprocal and dynamic influences are nowhere more apparent than in the comorbidity of medical disease and psychiatric syndromes, such as ACS and depression. Many of the biological processes previously described as important in the development and progression of either ACS or depression are now recognised as playing a role in both conditions and may be critical for understanding their linked pathogeneses.

Endothelial and vascular pathologies characteristic of ACS engage local and systemic inflammation, change autonomic reactivity and advance dysregulation of oxidative, essential enzyme and cofactor systems, including BH4 and NOS (Bendall et al., 2013). Moreover, elevation of inflammatory proteins in ACS can reduce the bioavailability and functioning of key neurotransmitter and neurotrophic systems involved in mood regulation and depression. Systemic immune activation additionally elicits a classical stress response characterised by activation of the HPA-axis and a shift in autonomic balance towards sympathetic dominance (Maier and Watkins, 2010). Reduced parasympathetic (vagal) signalling and enhanced catecholamine release from sympathetic neurons in turn perpetuate the release of pro-inflammatory proteins (Andersson and Tracey, 2012; Grebe et al., 2010; Pereira et al., 2013) and impact adversely on local cardiovascular pathology (Korszun and Frenneaux, 2006).

The premise that inflammatory processes may increase cardiovascular risk through centrally mediated mechanisms has been strengthened by a recent human neuroimaging experiment documenting that elevation of peripheral inflammatory proteins elicited distinct CNS-mediated effects on cardiovascular autonomic reactivity (Harrison et al., 2013).

Psychological stress and depression directly impact neural circuits and neurotransmitter pathways involved in the regulation of emotional and behavioural responses and activate regulatory systems that influence both local and distant mechanisms (Broadley et al., 2005; Burg et al., 2011; Maier and Watkins, 2010). Prolonged sympathetic activity can cause adverse local cardiovascular effects, with evidence from experimental studies in humans documenting a direct role for cortisol in stress-induced endothelial dysfunction and impaired baroreflex sensitivity (Broadley et al., 2005). Mental stress and depression severity have also been related to elevated endothelin-1, a potent vasoconstrictor, known to play an important role in CVD progression (Burg et al., 2011). Cardiovascular reactivity to stress has been found to be genetically influenced. A meta-analytic review of twin studies comparing heart rate and blood pressure responses to stressors demonstrated strong heritability (Wu et al., 2010). This research documents a spectrum of biological mechanisms through which depression and emotional stress directly contribute to ACS outcome.

Taken together, the accumulated evidence supports the hypothesis that disturbances in peripheral systems, notably the inflammatory response, engage similar neural networks as do psychosocial stressors and that both may ultimately affect the function of signalling pathways regulating homeostasis and body integrity, as well as mood, motivation and behaviour. As ACS constitutes a fundamental stressor of some psychological and physiological magnitude, it is important to consider the combined impact of stressors on neuro-visceral systems (Beaumont et al., 2012; Thayer et al., 2012). From the available evidence, it is clear that not all individuals with ACS have substantively raised inflammatory markers, and that those with increased inflammation do not all develop depression, so these contingencies depend on the interplay of a spectrum of factors (Figure 1). These include the severity of ACS and existing comorbidities, vulnerabilities in immune and/or behavioural genes (which can influence the intensity of the inflammatory response and endow a person with more or less resilient stress-responsive regulatory systems), as well as developmental and current life stressors, and the coping strategies (including health behaviours) adopted by each individual (Felger and Lotrich, 2013; Gunaratne et al., 2013; Raison and Miller, 2013).

Figure 1.

Schematic representation of the complex changes in biological signalling and response pathways potentially associated with ACS and depression comorbidity.

Translational implications

As highlighted throughout this review, ACS-associated depression is likely to arise from interactions between several bio-behavioural systems. It is therefore not surprising that identifying interventions that effectively address mortality and morbidity risk in this group has so far proved challenging. Large randomised controlled trials (RCTs) assessing the effects of anti-depressant treatment on cardiac mortality outcomes have largely proved ineffective (Carney et al., 2004; De Jonge et al., 2007; Van Melle et al., 2007). A recent meta-analysis concluded that well-conducted RCTs revealed no difference in mortality between selective serotonin reuptake inhibitors (SSRIs) and placebo in patients with ACS (Pizzi et al., 2011). However, SSRIs can only be expected to be effective if disrupted serotonergic transmission is an underlying contributor to depression.

Similarly, an initial RCT in a small number of patients with treatment-resistant depression using the anti-inflammatory agent infliximab revealed that this treatment was only beneficial for those participants whose baseline levels of CRP showed moderate elevation (i.e. CRP > 5 mg/L). By contrast, those with low baseline levels of CRP fared worse (Raison et al., 2013). Several non-pharmacological interventions designed to enhance vagal nerve activity appear to improve both HRV and depressive symptoms: for example, vagal nerve stimulation for treatment-resistant depression (Aaronson et al., 2012; Nahas et al., 2005). Patients with ACS and depression, who also have significantly reduced HRV, may find vagal nerve stimulation an effective treatment.

The findings reviewed here argue the need to individualise treatment for patients with ACS-associated depression. This could be addressed by routine testing of key biological parameters identified in ACS-associated depression (e.g. including markers of immune, HPA-axis and autonomic functioning, and metabolites of key neurotransmitters). Finally, researchers and clinicians need to be mindful that increased inflammation, autonomic dysfunction and a host of other pathophysiological changes with putative roles in ACS-associated depression can be related to poor health generally, rather than depression specifically. Improvements to diet, exercise and sleep will undoubtedly contribute to regulating these biological systems in a positive way.

Conclusion

It has become increasingly apparent that the traditional classification of ACS as a purely medical disease and depression as a mental/psychiatric condition is not helpful in guiding research efforts towards a clearer understanding of the pathophysiological mechanisms underlying each of these disorders and their frequent association. The time has come to embrace a broader integrated systems perspective of health and disease. Such a perspective will open new avenues for multidisciplinary research that, with time and discernment, will allow us to see the bigger picture. Such an approach promises greater clarity to both the assessment of risk around further cardiac events and survival following ACS and direct clinical practice towards more effective, personalised treatments for CVD/ACS and depression.

Footnotes

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Funding

This work was funded by a NHMRC Programme Grant (1037196) and by the Commonwealth Department of Health and Ageing.

References

Aaronson

Carpenter

Conway

. (2012) Vagus nerve stimulation therapy randomized to different amounts of electrical charge for treatment-resistant depression: Acute and chronic effects. Brain Stimulation 6: 631–640.

Andersson

Tracey

(2012) Reflex principles of immunological homeostasis. Annual Review of Immunology 30: 313–335.

Antoniades

Shirodaria

Crabtree

. (2007) Altered plasma versus vascular biopterins in human atherosclerosis reveal relationships between endothelial nitric oxide synthase coupling, endothelial function, and inflammation. Circulation 116: 2851–2859.

Aslakson

Vollmer-Conna

Reeves

. (2009) Replication of an empirical approach to delineate the heterogeneity of chronic unexplained fatigue. Population Health Metrics 7: 17–27.

Baune

Stuart

Gilmour

. (2012) The relationship between subtypes of depression and cardiovascular disease: A systematic review of biological models. Translational Psychiatry 2: e92.

Beaumont

Burton

Lemon

. (2012) Reduced cardiac vagal modulation impacts on cognitive performance in chronic fatigue syndrome. PLoS ONE 7: e49518.

Bendall

Douglas

McNeill

. (2013) Tetrahydrobiopterin in cardiovascular health and disease. Antioxidants and Redox Signaling 20: 3040–3077.

Broadley

Korszun

Abdelaal

. (2005) Inhibition of cortisol production with metyrapone prevents mental stress-induced endothelial dysfunction and baroreflex impairment. Journal of the American College of Cardiology 46: 344–350.

Brown

Giles

Croft

(2001) White blood cell count: An independent predictor of coronary heart disease mortality among a national cohort. Journal of Clinical Epidemiology 54: 316–322.

10.

Brull

Serrano

Zito

. (2003) Human CRP gene polymorphism influences CRP levels implications for the prediction and pathogenesis of coronary heart disease. Arteriosclerosis, Thrombosis, and Vascular Biology 23: 2063–2069.

11.

Burg

Edmondson

Shimbo

. (2013) The ‘perfect storm’ and acute coronary syndrome onset: Do psychosocial factors play a role? Progress in Cardiovascular Diseases 55: 601–610.

12.

Burg

Martens

Collins

. (2011) Depression predicts elevated endothelin-1 in patients with coronary artery disease. Psychosomatic Medicine 73: 2–6.

13.

Capuron

Neurauter

Musselman

. (2003a) Interferon-alpha-induced changes in tryptophan metabolism: Relationship to depression and paroxetine treatment. Biological Psychiatry 54: 906–914.

14.

Capuron

Raison

Musselman

. (2003b) Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. American Journal of Psychiatry 160: 1342–1345.

15.

Carney

Blumenthal

Freedland

. (2004) Depression and late mortality after myocardial infarction in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study. Psychosomatic Medicine 66: 466–474.

16.

Carney

Blumenthal

Stein

. (2001) Depression, heart rate variability, and acute myocardial infarction. Circulation 104: 2024–2028.

17.

Carney

Freedland

Stein

. (2007) Heart rate variability and markers of inflammation and coagulation in depressed patients with coronary heart disease. Journal of Psychosomatic Research 62: 463–467.

18.

Catena-Dell’Osso

Rotella

Dell’Osso

. (2013) Inflammation, serotonin and major depression. Current Drug Targets 14: 571–577.

19.

Chalikias

Tziakas

Kaski

. (2005) Interleukin-18: Interleukin-10 ratio and in-hospital adverse events in patients with acute coronary syndrome. Atherosclerosis 182: 135–143.

20.

Cirillo

Cimmino

D’Aiuto

. (2014) Local cytokine production in patients with acute coronary syndromes: A look into the eye of the perfect (cytokine) storm. International Journal of Cardiology 176: 227–229.

21.

Côté

Fligny

Fromes

. (2004) Recent advances in understanding serotonin regulation of cardiovascular function. Trends in Molecular Medicine 10: 232–238.

22.

Cowan

Freedland

Burg

. (2008) Predictors of treatment response for depression and inadequate social support – The ENRICHD randomized clinical trial. Psychotherapy and Psychosomatics 77: 27–37.

23.

Dalziel

Gosby

Richman

. (2002) Association of the TNF-alpha -308 G/A promoter polymorphism with insulin resistance in obesity. Obesity Research 10: 401–407.

24.

Dantzer

O’Connor

Freund

. (2008) From inflammation to sickness and depression: When the immune system subjugates the brain. Nature Reviews Neuroscience 9: 45–56.

25.

Dantzer

O’Connor

Lawson

. (2011) Inflammation-associated depression: From serotonin to kynurenine. Psychoneuroendocrinology 36: 426–436.

26.

Davidson

(2012) Depression and coronary heart disease. ISRN Cardiology 2012: Article ID 743813.

27.

Davidson

Rieckmann

Clemow

. (2010) Enhanced depression care for patients with acute coronary syndrome and persistent depressive symptoms: Coronary psychosocial evaluation studies randomized controlled trial. Archives of Internal Medicine 170: 600–608.

28.

De Jonge

Honig

van Melle

. (2007) Nonresponse to treatment for depression following myocardial infarction: Association with subsequent cardiac events. American Journal of Psychiatry 164: 1371–1378.

29.

De Jonge

Rosmalen

JGM

Kema

. (2010) Psychophysiological biomarkers explaining the association between depression and prognosis in coronary artery patients: A critical review of the literature. Neuroscience & Biobehavioral Reviews 35: 84–90.

30.

Dekker

Koper

Van Aken

. (2008) Salivary cortisol is related to atherosclerosis of carotid arteries. Journal of Clinical Endocrinology and Metabolism 93: 3741–3747.

31.

Di Stefano

Felice

Pini

. (2014) Impact of depression on circulating endothelial progenitor cells in patients with acute coronary syndromes: A pilot study. Journal of Cardiovascular Medicine 15: 353–359.

32.

Dinan

(2009) Inflammatory markers in depression. Current Opinion in Psychiatry 22: 32–36.

33.

Dowlati

Herrmann

Swardfager

. (2010) A meta-analysis of cytokines in major depression. Biological Psychiatry 67: 446–457.

34.

Duivis

de Jonge

Penninx

. (2011) Depressive symptoms, health behaviors, and subsequent inflammation in patients with coronary heart disease: Prospective findings from the Heart and Soul study. American Journal of Psychiatry 168: 913–920.

35.

Elovainio

Hurme

Jokela

. (2012) Indoleamine 2,3-dioxygenase activation and depressive symptoms: Results from the Young Finns Study. Psychosomatic Medicine 74: 675–681.

36.

Empana

Sykes

Luc

. (2005) Contributions of depressive mood and circulating inflammatory markers to coronary heart disease in healthy European men. Circulation 111: 2299–2305.

37.

Ernst

Hammerschmidt

Bagge

. (1987) Leukocytes and the risk of ischemic diseases. Journal of the American Medical Association 257: 2318–2324.

38.

Felger

Lotrich

(2013) Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications. Neuroscience 246: 199–229.

39.

Frasure-Smith

Lespérance

Irwin

. (2009) The relationships among heart rate variability, inflammatory markers and depression in coronary heart disease patients. Brain, Behavior, and Immunity 23: 1140–1147.

40.

Freedland

Carney

(2013) Depression as a risk factor for adverse outcomes in coronary heart disease. BMC Medicine 11: 131.

41.

Gehi

Musselman

Otte

. (2010) Depression and platelet activation in outpatients with stable coronary heart disease: Findings from the Heart and Soul Study. Psychiatry Research 175: 200–204.

42.

Glassman

(2007) Depression and cardiovascular comorbidity. Dialogues in Clinical Neuroscience 9: 9–17.

43.

Grebe

Takeda

Hickman

. (2010) Cutting edge: Sympathetic nervous system increases proinflammatory cytokines and exacerbates influenza A virus pathogenesis. The Journal of Immunology 184: 540–544.

44.

Groves

(2007) Is it time to reassess the BDNF hypothesis of depression? Molecular Psychiatry 12: 1079–1088.

45.

Gunaratne

Lloyd

Vollmer-Conna

(2013) Mood disturbance after infection. Australian and New Zealand Journal of Psychiatry 47: 1152–1164.

46.

Harrison

Cooper

Voon

. (2013) Central autonomic network mediates cardiovascular responses to acute inflammation: Relevance to increased cardiovascular risk in depression? Brain, Behavior, and Immunity 31: 189–196.

47.

Hart

(1988) Biological basis of the behavior of sick animals. Neuroscience & Biobehavioral Reviews 12: 123–137.

48.

Hashimoto

(2010) Brain-derived neurotrophic factor as a biomarker for mood disorders: An historical overview and future directions. Psychiatry and Clinical Neurosciences 64: 341–357.

49.

Heeschen

Dimmeler

Hamm

. (2003) Serum level of the antiinflammatory cytokine interleukin-10 is an important prognostic determinant in patients with acute coronary syndromes. Circulation 107: 2109–2114.

50.

Hillebrand

Gast

de Mutsert

. (2013) Heart rate variability and first cardiovascular event in populations without known cardiovascular disease: Meta-analysis and dose–response meta-regression. Europace 15: 742–749.

51.

Howren

Lamkin

Suls

(2009) Associations of depression with C-reactive protein, IL-1, and IL-6: A meta-analysis. Psychosomatic Medicine 71: 171–186.

52.

Huikuri

Stein

(2012) Clinical application of heart rate variability after acute myocardial infarction. Frontiers in Physiology 3: 41.

53.

Joynt

Whellan

O’Conner

(2003) Depression and cardiovascular disease: Mechanisms of interaction. Biological Psychiatry 54: 248–261.

54.

Jun

Pae

Chae

. (2003) Possible association between -G308A tumour necrosis factor-α gene polymorphism and major depressive disorder in the Korean population. Psychiatric Genetics 13: 179–181.

55.

Kannel

Anderson

Wilson

(1992) White blood cell count and cardiovascular disease. Journal of the American Medical Association 267: 1253–1256.

56.

Kaptoge

Di Angelantonio

Lowe

. (2010) C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: An individual participant meta-analysis. The Lancet 375: 132–140.

57.

Karg

Burmeister

Shedden

. (2011) The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: Evidence of genetic moderation. Archives of General Psychiatry 68: 444–454.

58.

Kemp

Quintana

Felmingham

. (2012) Depression, comorbid anxiety disorders, and heart rate variability in physically healthy, unmedicated patients: Implications for cardiovascular risk. PLoS ONE 7: e30777.

59.

Kemp

Quintana

Gray

. (2010) Impact of depression and antidepressant treatment on heart rate variability: A review and meta-analysis. Biological Psychiatry 67: 1067–1074.

60.

Kermani

Hempstead

(2007) Brain-derived neurotrophic factor: A newly described mediator of angiogenesis. Trends in Cardiovascular Medicine 17: 140–143.

61.

Kin

Sanders

(2006) It takes nerve to tell T and B cells what to do. Journal of Leukocyte Biology 79: 1093–1104.

62.

Kleiger

Miller

Bigger

Jr . (1987) Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. The American Journal of Cardiology 59: 256–262.

63.

Kop

Stein

Tracy

. (2010) Autonomic nervous system dysfunction and inflammation contribute to the increased cardiovascular mortality risk associated with depression. Psychosomatic Medicine 72: 626–635.

64.

Korszun

Frenneaux

(2006) Stress – The battle for hearts and minds: Links between depression, stress and ischemic heart disease. Future Cardiology 2: 571–578.

65.

Kuijpers

Hamulyak

Strik

. (2002) Beta-thromboglobulin and platelet factor 4 levels in post-myocardial infarction patients with major depression. Psychiatry Research 109: 207–210.

66.

Ladwig

K-H

Marten-Mittag

Löwel

. (2005) C-reactive protein, depressed mood, and the prediction of coronary heart disease in initially healthy men: Results from the MONICA–KORA Augsburg Cohort Study 1984–1998. European Heart Journal 26: 2537–2542.

67.

Lane

Carroll

Ring

. (2001) Predictors of attendance at cardiac rehabilitation after myocardial infarction. Journal of Psychosomatic Research 51: 497–501.

68.

Le Melledo

Mahil

Baker

(2004) Nitric oxide: A key player in the relation between cardiovascular disease and major depressive disorder? Journal of Psychiatry and Neuroscience 29: 414–416.

69.

Lee

B-H

Kim

Park

S-H

. (2007) Decreased plasma BDNF level in depressive patients. Journal of Affective Disorders 101: 239–244.

70.

Libby

(2012) Inflammation in atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology 32: 2045–2051.

71.

Lichtman

Froelicher

Blumenthal

. (2014) Depression as a risk factor for poor prognosis among patients with acute coronary syndrome: Systematic review and recommendations – A scientific statement from the American Heart Association. Circulation 129: 1350–1369.

72.

Lipsky

Marini

(2007) Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticity. Annals of the New York Academy of Sciences 1122: 130–143.

73.

Liu

Luiten

PGM

Eisel

ULM

. (2013) Depression after myocardial infarction: TNF-α-induced alterations of the blood–brain barrier and its putative therapeutic implications. Neuroscience & Biobehavioral Reviews 37: 561–572.

74.

Lopez

Mathers

Ezzati

. (2006) Global and regional burden of disease and risk factors, 2001: Systematic analysis of population health data. The Lancet 367: 1747–1757.

75.

Lopez-Leon

Janssens

Ladd

AMGZ

. (2007) Meta-analyses of genetic studies on major depressive disorder. Molecular Psychiatry 13: 772–785.

76.

Lopresti

Hood

Drummond

(2013) A review of lifestyle factors that contribute to important pathways associated with major depression: Diet, sleep and exercise. Journal of Affective Disorders 148: 12–27.

77.

Lückhoff

Van Rensburg

Botha

. (2014) The pro-inflammatory TNFA-308G> A (rs1800629) polymorphism is associated with an earlier age at onset in patients with major depressive disorder. Journal of Psychiatry 17: 124.

78.

Mclean

Tennant

Ward

. (2007) Sick at heart? Results of a longitudinal interventional case-control study in to the prothrombotic links between depression and heart disease. Australian and New Zealand Journal of Psychiatry 41: A58.

79.

Maier

Watkins

(2010) Role of the medial prefrontal cortex in coping and resilience. Brain Research 1355: 52–60.

80.

Mälarstig

Eriksson

Hamsten

. (2008) Raised interleukin-10 is an indicator of poor outcome and enhanced systemic inflammation in patients with acute coronary syndrome. Heart 94: 724–729.

81.

Miller

Haroon

Raison

. (2013) Cytokine targets in the brain: Impact on neurotransmitters and neurocircuits. Depression and Anxiety 30: 297–306.

82.

Miller

Maletic

Raison

(2009) Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression. Biological Psychiatry 65: 732–741.

83.

Mombouli

J-V

Vanhoutte

(1999) Endothelial dysfunction: From physiology to therapy. Journal of Molecular and Cellular Cardiology 31: 61–74.

84.

Mulle

Vaccarino

(2013) Cardiovascular disease, psychosocial factors, and genetics: The case of depression. Progress in Cardiovascular Diseases 55: 557–562.

85.

Müller

Schwarz

(2007) The immune-mediated alteration of serotonin and glutamate: Towards an integrated view of depression. Molecular Psychiatry 12: 988–1000.

86.

Musselman

Tomer

Manatunga

. (1996) Exaggerated platelet reactivity in major depression. The American Journal of Psychiatry 153: 1313–1317.

87.

Nahas

Marangell

Husain

. (2005) Two-year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes. The Journal of Clinical Psychiatry 66: 1097–1104.

88.

Nakahashi

Fujimura

Altar

. (2000) Vascular endothelial cells synthesize and secrete brain-derived neurotrophic factor. FEBS Letters 470: 113–117.

89.

Nakatani

Sato

Sakata

. (2005) Influence of serotonin transporter gene polymorphism on depressive symptoms and new cardiac events after acute myocardial infarction. American Heart Journal 150: 652–658.

90.

Nemeroff

Goldschmidt-Clermont

(2012) Heartache and heartbreak – The link between depression and cardiovascular disease. Nature Reviews Cardiology 9: 526–539.

91.

Nemeroff

Musselman

(2000) Are platelets the link between depression and ischemic heart disease? American Heart Journal 140: 57–62.

92.

Neubauer

Petrak

Zahn

. (2013) Newly diagnosed depression is associated with increased beta-thromboglobulin levels and increased expression of platelet activation markers and platelet derived CD40-CD40L. Journal of Psychiatric Research 47: 865–871.

93.

Nijm

Jonasson

(2009) Inflammation and cortisol response in coronary artery disease. Annals of Medicine 41: 224–233.

94.

Okada

Yokoyama

Toko

. (2012) Brain-derived neurotrophic factor protects against cardiac dysfunction after myocardial infarction via a central nervous system-mediated pathway. Arteriosclerosis, Thrombosis, and Vascular Biology 32: 1902–1909.

95.

Parker

Hilton

Walsh

. (2008) Timing is everything: The onset of depression and acute coronary syndrome outcome. Biological Psychiatry 64: 660–666.

96.

Patron

Messerotti Benvenuti

Favretto

. (2012) Association between depression and heart rate variability in patients after cardiac surgery: A pilot study. Journal of Psychosomatic Research 73: 42–46.

97.

Patterson

Matthews

Allen

. (1995) Stress-induced hemoconcentration of blood cells and lipids in healthy women during acute psychological stress. Health Psychology 14: 319–324.

98.

Pereira

Cerqueira

Palha

. (2013) Stressed brain, diseased heart: A review on the pathophysiologic mechanisms of neurocardiology. International Journal of Cardiology 166: 30–37.

99.

Pizzi

Rutjes

AWS

Costa

. (2011) Meta-analysis of selective serotonin reuptake inhibitors in patients with depression and coronary heart disease. American Journal of Cardiology 107: 972–979.

100.

Poon

DC-H

Y-S

Chiu

. (2013) Cytokines: How important are they in mediating sickness? Neuroscience & Biobehavioral Reviews 37: 1–10.

101.

Quak

Doornbos

Roest

. (2014) Does tryptophan degradation along the kynurenine pathway mediate the association between pro-inflammatory immune activity and depressive symptoms? Psychoneuroendocrinology 45: 202–210.

102.

Raison

Miller

(2011) Is depression an inflammatory disorder? Current Psychiatry Reports 13: 467–475.

103.

Raison

Miller

(2013) Malaise, melancholia and madness: The evolutionary legacy of an inflammatory bias. Brain, Behavior, and Immunity 31: 1–8.

104.

Raison

Dantzer

Kelley

. (2010) CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: Relationship to CNS immune responses and depression. Molecular Psychiatry 15: 393–403.

105.

Raison

Rutherford

Woolwine

. (2013) A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: The role of baseline inflammatory biomarkers. JAMA Psychiatry 70: 31–41.

106.

Ramasamy

(2011) Biochemical markers in acute coronary syndrome. Clinica Chimica Acta 412: 1279–1296.

107.

Risch

Herrell

Lehner

. (2009) Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression. Journal of the American Medical Association 301: 2462–2471.

108.

Ross

(1999) Atherosclerosis – An inflammatory disease. New England Journal of Medicine 340: 115–126.

109.

Scherrer

Xian

Bucholz

. (2003) A twin study of depression symptoms, hypertension, and heart disease in middle-aged men. Psychosomatic Medicine 65: 548–557.

110.

Schins

Honig

Crijns

. (2003) Increased coronary events in depressed cardiovascular patients: 5-HT2A receptor as missing link? Psychosomatic Medicine 65: 729–737.

111.

Segerstrom

Miller

(2004) Psychological stress and the human immune system: A meta-analytic study of 30 years of inquiry. Psychological Bulletin 130: 601–630.

112.

Serebruany

Glassman

Malinin

. (2003) Enhanced platelet/endothelial activation in depressed patients with acute coronary syndromes: Evidence from recent clinical trials. Blood Coagulation and Fibrinolysis 14: 563–567.

113.

Sherwood

Hinderliter

Watkins

. (2005) Impaired endothelial function in coronary heart disease patients with depressive symptomatology. Journal of the American College of Cardiology 46: 656–659.

114.

Shimbo

Rieckmann

Paulino

. (2006) Relation between C-reactive protein and depression remission status in patients presenting with acute coronary syndrome. Heart 92: 1316–1318.

115.

Shimizu

Hashimoto

Okamura

. (2003) Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biological Psychiatry 54: 70–75.

116.

Shlipak

Bibbins-Domingo

. (2008) Biomarkers to predict recurrent cardiovascular disease: The Heart and Soul Study. The American Journal of Medicine 121: 50–57.

117.

Smith

Irving

Sheldon

. (2001) Serum levels of the antiinflammatory cytokine interleukin-10 are decreased in patients with unstable angina. Circulation 104: 746–749.

118.

Sookoian

González

Pirola

(2005) Meta-analysis on the G-308A tumor necrosis factor α gene variant and phenotypes associated with the metabolic syndrome. Obesity Research 13: 2122–2131.

119.

Souverein

Berard

Van Staa

. (2004) Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case – Control study. Heart 90: 859–865.

120.

Stapelberg

Hamilton-Craig

Neumann

. (2012) Mind and heart: Heart rate variability in major depressive disorder and coronary heart disease – A review and recommendations. Australian and New Zealand Journal of Psychiatry 46: 946–957.

121.

Stapelberg

Neumann

Shum

. (2011) A topographical map of the causal network of mechanisms underlying the relationship between major depressive disorder and coronary heart disease. Australian and New Zealand Journal of Psychiatry 45: 351–369.

122.

Stein

Carney

Freedland

. (2000) Severe depression is associated with markedly reduced heart rate variability in patients with stable coronary heart disease. Journal of Psychosomatic Research 48: 493–500.

123.

Steptoe

Wikman

Molloy

. (2013) Inflammation and symptoms of depression and anxiety in patients with acute coronary heart disease. Brain, Behavior, and Immunity 31: 183–188.

124.

Miller

Snieder

. (2009) Common genetic contributions to depressive symptoms and inflammatory markers in middle-aged men: The Twins Heart Study. Psychosomatic Medicine 71: 152–158.

125.

Suchankova

Holm

Träskman-Bendz

. (2013) The +1444C>T polymorphism in the CRP gene: A study on personality traits and suicidal behaviour. Psychiatric Genetics 23: 70–76.

126.

Task Force of the European Society of Cardiology the North American Society of Pacing (Electrophysiology) (1996) Guidelines: Heart rate variability – standards of measurement, physiological interpretation, and clinical use. European Heart Journal 17: 354–381.

127.

Taylor

(2010) Depression, heart rate related variables and cardiovascular disease. International Journal of Psychophysiology 78: 80–88.

128.

Terracciano

Martin

Ansari

. (2010) Plasma BDNF concentration, Val66Met genetic variant and depression-related personality traits. Genes, Brain and Behavior 9: 512–518.

129.

Thayer

Åhs

Fredrikson

. (2012) A meta-analysis of heart rate variability and neuroimaging studies: Implications for heart rate variability as a marker of stress and health. Neuroscience & Biobehavioral Reviews 36: 747–756.

130.

Thayer

Lane

(2007) The role of vagal function in the risk for cardiovascular disease and mortality. Biological Psychology 74: 224–242.

131.

Thayer

Sternberg

(2006) Beyond heart rate variability. Annals of the New York Academy of Sciences 1088: 361–372.

132.

Tracey

(2009) Reflex control of immunity. Nature Review Immunology 9: 418–428.

133.

Van Melle

de Jonge

Honig

. (2007) Effects of antidepressant treatment following myocardial infarction British Journal of Psychiatry 190: 460–466.

134.

Verma

Wang

C-H

S-H

. (2002) A self-fulfilling prophecy C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation 106: 913–919.

135.

Vollmer-Conna

(2001) Acute sickness behaviour: An immune system-to-brain communication? Psychological Medicine 31: 761–767.

136.

Vollmer-Conna

Aslakson

White

(2006) An empirical delineation of the heterogeneity of chronic unexplained fatigue in women. Pharmacogenomics 7: 355–364.

137.

Von Känel

Mills

Fainman

. (2001) Effects of psychological stress and psychiatric disorders on blood coagulation and fibrinolysis: A biobehavioral pathway to coronary artery disease? Psychosomatic Medicine 63: 531–544.

138.

Walker

(2007) Glucocorticoids and cardiovascular disease. European Journal of Endocrinology 157: 545–559.

139.

Wang

Zhao

O’Neil

. (2013) Altered cardiac autonomic nervous function in depression. BMC Psychiatry 13: 187.

140.

Wei

MacDonald

Walker

(2004) Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Annals of Internal Medicine 141: 764–770.

141.

Welsh

Murray

Ford

. (2011) Circulating interleukin-10 and risk of cardiovascular events: A prospective study in the elderly at risk. Arteriosclerosis, Thrombosis, and Vascular Biology 31: 2338–2344.

142.

Whooley

(2013) Depression and cardiovascular disorders. Annual Review of Clinical Psychology 9: 327–354.

143.

Wilson

Symons

McDowell

. (1997) Effects of a polymorphism in the human tumor necrosis factor α promoter on transcriptional activation. Proceedings of the National Academy of Sciences of the United States of America 94: 3195–3199.

144.

Snieder

de Geus

(2010) Genetic influences on cardiovascular stress reactivity. Neuroscience & Biobehavioral Reviews 35: 58–68.

145.

Xhyheri

Manfrini

Mazzolini

. (2012) Heart rate variability today. Progress in Cardiovascular Diseases 55: 321–331.

146.

Ziegelstein

Parakh

Sakhuja

. (2009) Platelet function in patients with major depression. Internal Medicine Journal 39: 38–43.

147.

Zorrilla

Luborsky

McKay

. (2001) The relationship of depression and stressors to immunological assays: A meta-analytic review. Brain, Behavior, and Immunity 15: 199–226.

Acute coronary syndrome and depression: A review of shared pathophysiological pathways

Abstract

Objective:

Methods:

Results:

Conclusion:

Keywords

Introduction

Methods

Search strategy

Biological mechanisms mediating the link between depression and ACS

Immune activation and inflammation

Mechanisms relating to platelet and endothelial function

The importance of autonomic regulation

HPA-axis and glucocorticoid sensitivity

Perspectives on neuro-visceral integration as it relates to CVD/ACS-associated depression

Translational implications

Conclusion

Footnotes

Declaration of interest

Funding

References