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Abstract

Clinical studies have established an inherent comorbidity between depression and the development of cardiovascular disease (CVD). Furthermore, this comorbidity seems to be more amplified in women than in men. To further investigate this comorbidity, a thorough literature review was conducted on studies from 1992 to date. The PubMed database was accessed using the keywords: cardiovascular disease, inflammation, depression, and sex differences. Both human and animal studies were considered. This review takes the standpoint that depression and CVD are both inflammatory disorders, and that their co-occurrence may be related to how the hypothalamic–pituitary–adrenal axis, serotonergic transmission and circulation, and the renin–angiotensin–aldosterone system via angiotensin II are affected by the excess secretion of proinflammatory cytokines. More recently, preliminary research attributes this systemic inflammation to a global deficiency in CD4+CD25+FOXP3 regulatory T cells. 17-β estradiol and progesterone mediated modulation of cytokine secretion may partially explain the sex differences observed. These hormones and reproductive events associated with hormonal fluctuations are discussed in depth, including the analysis of perinatal models of depression and CVD, including preeclampsia. However, as evidenced by this review, there is a need for mechanistic research in humans to truly understand the nature and directionality of the relationship between depression and CVD.

Keywords

cardiovascular disease depression proinflammatory cytokines regulatory T cells sex differences

Introduction

Depression and cardiovascular disease (CVD) are conditions that are both associated with significant medical and psychiatric morbidity, as well as reduced quality of life [Ay-Woan et al. 2006; Swenson and Clinch, 2000]. Depression and ischemic heart disease are also among the five leading causes of disability-adjusted life years in women worldwide [Murray et al. 2013]. The impact of each of these disorders independently is enormous, and research examining depression and CVD has increased exponentially in the past three decades. However, it was not until more recently that the comorbidity of these two conditions has been more widely acknowledged, and research has begun to focus on the possibility that the two disorders may have a common origin.

Though depression and CVD are perceptibly distinct, it is possible that the two disorders represent separate manifestations of a single underlying dysfunction [Huffman et al. 2013; Nemeroff and Goldschmidt-Clermont, 2012]. Individuals who have suffered from depression are at increased risk for CVD [Schnatz et al. 2011; Glassman, 2007], and up to 35 % of those with CVD develop depressive symptoms, which are in turn associated with an increased risk of cardiac morbidity and mortality [Mastrogiannis et al. 2012; Rallidis et al. 2011; Freedland and Carney, 2013]. Elevated levels of systemic inflammation have also been reported in both patients with depression and those with CVD [Hansson and Hermansson, 2011; Zunszain et al. 2011].

There are marked sex differences among people with depression and those with CVD. It is well established that depression is more prevalent in women [Kessler et al. 2005]. This is especially true when periods of hormonal transition are considered. Findings of elevated rates of depression during the perinatal and perimenopausal periods suggest that steroid hormones (17-β estradiol and progesterone) may be involved [Steiner et al. 2003]. Similarly, Roger and colleagues reported the emerging trend of increasing CVD-related mortality in women compared with men [Roger et al. 2011]. Such evidence suggests that the cooccurrence of depression and CVD may be amplified in women. Rutledge and colleagues reported that the costs of providing healthcare to women with CVD is increased significantly for women with a past history of depression compared with women without [Rutledge et al. 2009].

Though increased levels of proinflammatory cytokines have been noted in patients with depression and with CVD, the relevance of cytokines in the etiology of CVD and depression in humans is not well understood. While proinflammatory cytokine secretion is a healthy immune response, when chronically elevated, cytokine production becomes maladaptive. Chronic proinflammatory cytokine secretion contributes to autoimmune responses and diseases, and alters bodily functioning to a defensive and ‘sickness‘ state [Layé, 2010]. Proinflammatory cytokines are of particular interest in the comorbidity of depression and CVD because they interact globally in the body, indicating many pathways through which they may mediate cardiovascular and neurological processes, as well as the clinical observance of elevations of proinflammatory cytokines in each of the two disorders separately [Dowlati et al. 2010; Hansson and Hermansson, 2011]. The purpose of this review is to summarize the evidence suggesting that chronic elevations in proinflammatory cytokine levels are a key link in the comorbidity of depression and CVD in women. We will review findings from both human and animal literatures to examine the interaction of proinflammatory cytokines with the hypothalamic–pituitary–adrenal (HPA) axis, the hypothalamic–pituitary–gonadal (HPG) axis, in particular we focus on 17-β estradiol and progesterone, central and peripheral serotonin (5-HT) transmission, and angiotensin II. Perinatal depression and preeclampsia and their relationship with proinflammatory cytokines will be discussed as sex-specific models of this comorbidity. A better understanding of the mechanisms underlying the comorbidity of depression and CVD in women, as it may facilitate early detection, better prevention, and treatments for these disorders.

Proinflammatory cytokines and the HPA axis

The HPA axis is vital for human responses to acute stress. The primary product of the HPA axis is cortisol, which facilitates responses to and recovery from stressors. Disruption of HPA axis function can lead to hyper- or hypocortisol secretion, affecting an individual’s ability to cope with future stresses [Watson and Mackin, 2006]. Depression has consistently been associated with increased baseline HPA axis functioning, and hypercortisolemia [Herbert, 2013; Brown et al. 2004], as well as overproduction of corticotrophin-releasing hormone (CRH) [Holsboer and Ising, 2008]. Furthermore, patients with depression may have impaired negative feedback of the HPA axis [Anacker et al. 2011]. In these cases, chronic HPA axis activation becomes maladaptive and results in the oversecretion of cortisol, which can lead to memory deficits, as well as depressive symptoms [Lupien et al. 2009].

The HPA axis is involved in the regulation of cardiovascular function. The hypothalamus is specifically responsible for the maintenance of autonomic nervous system functioning [Ramchandra et al. 2013], including heart rate variability [Mastelari et al. 2012]. The HPA axis is also involved in the regulation of blood pressure and blood vessel dilation in response to stress [Steptoe and Kivimäki, 2012]. As with depression, CVD is also associated with HPA axis hyperactivity [Hamer and Malan, 2010; Meyburgh et al. 2012]. More specifically, increased cortisol response is positively correlated with the presence and development of carotid atherosclerotic plaques and calcification of the coronary arteries [Dekker et al. 2008; Hamer et al. 2012].

Thus, HPA axis dysfunction and chronically elevated cortisol levels may be important in the development of the depression–CVD comorbidity [Messerli-Buergy et al. 2012; Otte et al. 2004], and proinflammatory cytokines may be a driver of these associations [Figure 1(a)]. Interleukin 1 (IL-1) receptors are located on both the hypothalamus and the pituitary glands of rats, indicating a direct pathway by which cytokines may act on the HPA axis [Gadek-Michalska et al. 2011]. Receptor sites for IL-1 in the paraventricular nucleus of the hypothalamus directly stimulate the production of CRH, ultimately leading to increased cortisol secretion [Sim et al. 2012; Toftegaard et al. 2002]. This increase in stress hormone secretion has also been noted in response to elevations in other proinflammatory cytokines, including tumor necrosis factor α (TNFα) and IL-6 [Silverman et al. 2005; Raison et al. 2008], suggesting that chronic elevation of proinflammatory cytokines can lead to overactivation of the HPA axis.

Figure 1.

The relationship between inflammation and comorbid depression and cardiovascular disease (CVD). Decreases in levels of regulatory T cells and consequent increases in proinflammatory cytokine secretion may contribute to the development of depression and CVD by increasing HPA axis activity (a), reducing central 5-HT (b), increasing peripheral 5-HT (c), and increasing levels of angiotensin II (d).

However, the relationship between the HPA axis and proinflammatory cytokines may be bidirectional. In rats, HPA axis stimulation leads to an increased production of proinflammatory cytokines [Velickovic et al. 2009]. Fluctuations in salivary cortisol responses in humans also correlate with changes in peripheral levels of proinflammatory cytokines [DeSantis et al. 2012]. This bidirectional interaction between the HPA axis and inflammatory markers allows for no direction of causality to be determined, but it is clear that the two have significant effects on one another.

Clinical studies have also tied systemic inflammation and HPA axis hyperactivity to the comorbidity of depression and CVD [Munk et al. 2012; Messerli-Buery et al. 2012; Otte et al. 2004]. Remission from depression is accompanied by normalization in function of the HPA axis, and coincides with a decrease in the proinflammatory cytokine TNFα [Himmerich et al. 2006]. Moreover, low heart rate variability, a hallmark of both CVD and depression, is correlated with hypercortisolemia and chronic elevation of TNFα levels [Weber et al. 2010].

Proinflammatory cytokines and 5-HT

Central nervous system 5-HT transmission

Numerous studies have established that there are decreased levels of 5-HT both in the hypothalamus and hippocampus of people with depression [Grippo and Johnson, 2009]. The involvement of 5-HT in mood regulation is further supported by the success of selective serotonin reuptake inhibitors (SSRIs) in alleviating depressive symptoms by increasing the synaptic availability of 5-HT [Hamon and Blier, 2013]. Animal models suggest that proinflammatory cytokines may downregulate levels of 5-HT in the central nervous system (CNS). Two hypotheses have been put forth to explain this [Figure 1(b)]. The first suggests that proinflammatory cytokines activate 2,3-indoleamine dioxygenase (IDO) [Fallarino and Grohmann, 2011]. This is a compound that readily metabolizes tryptophan, the precursor of 5-HT. When proinflammatory cytokines such as IL-2 or TNFα activate IDO, the amount of available tryptophan for conversion into 5-HT is drastically reduced [Müller et al. 2011]. A primary product of IDO’s metabolism is kynurenine. Kynurenine readily crosses the blood–brain barrier, and stimulates the formation of microglia in the CNS. In a cyclic manner, microglia activate the immune system, leading to the production of more proinflammatory cytokines [Dantzer et al. 2008]. Significant elevations of kynurenine within the CNS are thought to represent a neurotoxic state, and a cascade of maladaptive changes including hypercortisolemia and neuronal apoptosis may result. It is suggested that this neurotoxic state may also be associated with a vulnerability to the developing of major depression [Myint et al. 2012].

The second mechanism by which proinflammatory cytokines affect serotonergic signaling is by affecting 5-HT receptor density. Interferon α significantly downregulates the expression of hippocampal 5-HT_1a receptors in both mice and humans [Ping et al. 2012; Cai et al. 2005]. These 5-HT_1a receptors are located in various areas of the brain, including the raphe nuclei, the hypothalamus, and the entorhinal cortex, all of which are known to be involved in both mood regulation and cardiac function. These receptors have an excitatory effect on the cardiac vagal preganglionic neurons, and affect cardiac innervation [Dergacheva et al. 2011]. In the paraventricular nucleus and the dorsomedial hypothamalmus, 5-HT_1a receptors reduce heart rate and blood pressure [Carnevali et al. 2012; Villalon and Centurion, 2007; Horiuchi et al. 2011]. These receptors also happen to be the target of many successful antidepressant and anxiolytic medications [Scorza et al. 2012; Hensler, 2003; Blier and Ward, 2003]. Wang and colleagues also suggest that the efficacy of SSRIs in patients with treatment-resistant depression may be increased through augmentation with acetylsalicylic acid, a common medication with anti-inflammatory properties [Wang et al. 2011].

A decrease of 5-HT_1a receptor density may also further increase the HPA axis hyperactivity common to depression and CVD. Mice who have the 5-HT_1a receptor knocked out demonstrate excessive secretion of CRH. Behaviorally, these mice are anxious and have a heightened stress response, suggesting hyperactivity of the HPA axis [Groenink et al. 2003].

Peripheral 5-HT circulation

Most research studies involving serotonin focus on the CNS, but peripheral 5-HT is also thought to be heavily involved in the maintenance of cardiac and mental health [Sanner and Frazier, 2011]. Higher peripheral 5-HT levels have also been hypothesized to link the comorbidity seen between depression and CVD [Figure 1(c)] [Steiner, 2011; Sanner and Frazier, 2011; Schins et al. 2004].

Outside of the CNS, 5-HT is stored and transported in platelets. Peripheral 5-HT is crucial to the immune system’s defenses, as it facilitates the clotting of vessel tissue to prevent the invasion of pathogens. Increases in peripheral 5-HT may be involved in the formation of atherosclerotic plaques via the release of cellular adhesion molecules. Peripheral 5-HT is also important to the maintenance of vascular tone through its effects on vessel constriction and dilation [Cote et al. 2004]. Elevated platelet activation has also been observed in patients with depression [Neubauer et al. 2013]. Mendelson reported that the platelets of people with depression have higher densities of circulating 5-HT_2a binding sites, specifically in women [Mendelson, 2000]. Additionally, patients with existing CVD who develop depression have higher mean levels of peripheral 5-HT than those without depression [Wulsin et al. 2009].

Peripheral serotonin is a necessary component of the immune response to vessel and endothelial injury [Mitsuashi et al. 2001]. 5-HT_2a receptors have been distinctively identified as the primary active receptors in the stimulation of platelet adhesion and cytokine secretion in response to injury [Nishiyama, 2009; Jaffre et al. 2004, 2009]. Specifically, the production of IL-1, IL-6, TNFα, and IL-10 have been linked to 5-HT_2a receptor activity [Schäfer et al. 2010; Durk et al. 2005; Katoh et al. 2006]. Excess proinflammatory cytokine secretion may be responsible for the elevation of 5-HT_2a receptor density and activity observed in both depression and CVD [Meyer, 2013; Uchiyama et al. 2007]. However, more extensive research in humans is required to further confirm the link between peripheral 5-HT activity, immune functioning, and the comorbidity of depression and CVD.

Proinflammatory cytokines and angiotensin II

The renin–angiotensin–aldosterone system (RAAS) is a biological circuit that is crucial for the maintenance of cardiovascular function. Activation of the RAAS increases blood pressure and chronic activation leads to hypertension. Angiotensin II is a hormone released upon the activation of the RAAS. It is synthesized through the conversion of angiotensin I by angiotensin-converting enzyme (ACE). ACE is a rate-limiting enzyme and thus the production of angiotensin II is dependent on the availability of ACE.

Clinical studies have demonstrated that chronic heart failure is associated with significant elevations in circulating angiotensin II [Ito et al. 2013]. Many pharmacologic treatments for CVD either aim to block angiotensin II receptors or target ACE. ACE inhibitors medications are effective in reducing the risks associated with CVD and have been shown to reduce carotid intima media thickness [Ferrairo and Strawn, 2006; Ruschitzka and Taddei, 2012]. Angiotensin II is also associated with an increased thickness of vessel walls, the facilitation of endothelial cell apoptosis and aggregation, and the formation of atherosclerotic plaques [Neutel, 2004; Liu et al. 2011; Schmidt-Ott et al. 2000]. The efficacy of such medications suggests that increases in levels of angiotensin II may be involved in the development of CVD.

Systemic inflammation is a potential avenue for abnormal increases in levels of angiotensin II and ACE [Figure 1(d)] [Sriramula et al. 2013]. In vitro experiments indicate that the cytokines IL-1, IL-6, IL-8, and TNFα upregulate the expression of ACE [Carl-McGrath et al. 2009]. Proinflammatory cytokines also increase angiotensin II receptor density. Sasamura and colleagues note that administration of IL-1 to rats is associated with up to a 1.7-fold increase in angiotensin II 1 receptor [Sasamura et al. 1997].

The relationship between angiotensin II and cytokines may also be bidirectional. Research shows that angiotensin II is a major regulator of the production of proinflammatory cytokines. Administration of angiotensin II stimulates the production of TNFα and IL-6 [Ruiz-Ortega et al. 2002]. Additionally, administration of an enzyme that metabolizes angiotensin II to hypertensive mice attenuates hypertension and is correlated with the normalization of levels of circulating proinflammatory cytokines [Sriramula et al. 2011]. Human studies also suggest that increases in IL-6 and IL-8 are the consequence of angiotensin II administration [Skurk et al. 2004]. It is proposed that angiotensin II and proinflammatory cytokines influence each other through nuclear factor κB (NFκB), which is a liver protein that facilitates immune response and cardiovascular regulation [Henry, 1992].

To a lesser extent, angiotensin II and ACE have been linked to depression. Functional polymorphisms and hypermethylation of the ACE gene have both been associated with the occurrence of depression [Zill et al. 2012]. Such polymorphisms in depression have further been correlated with increases of serum ACE and angiotensin II concentrations [Firouzabadi et al. 2012]. Polymorphisms of the ACE gene are also associated with hypercortisolemia in depression, indicating that the HPA axis may be the facet through which the ACE genotype and depression interact [Baghai et al. 2006], In addition, angiotensin type 1 receptor C/C polymorphism, which is associated with angiotensin II activation, is significantly correlated with the occurrence of depression [Saab et al. 2007].

T-regulatory cells

A small body of research highlights that CD4⁺CD25⁺FOXP3 T-regulatory (Treg) cells may be a possible mechanism underlying chronic proinflammatory cytokine secretion, and thus the comorbidity of depression and CVD. Treg cells are synthesized during inflammation to regulate the production of proinflammatory cytokines. These cells act as a key messenger in the feedback loop of immune response and are therefore necessary for the prevention of excessive autoimmune induced damage. Deficiencies in Treg cells have been observed in a wide variety of disorders, including dermatitis [Verhagen et al. 2006], gastrointestinal tumor development [Sasada et al. 2003], and amyotrophic lateral sclerosis [Beers et al. 2011]. Decreases in Treg cell populations have also been noted in both depression and CVD independently, in which they may have an etiological role.

Animal research consistently demonstrates associations between deficiencies in Treg cells and poor cardiovascular health. Klingenberg and colleagues described a significant depletion of Treg cells in mice with atherosclerotic plaques [Klingenberg et al. 2013]. When these mice received transplants of external Treg cell populations, an attenuation of these plaques was observed. Foks and colleagues also noted that manual reduction of Treg cells in mice enhance arterial plaque formation, while treatment with Treg cell populations stabilizes and even reduces atherosclerosis [Foks et al. 2011]. It is hypothesized that the association between decreased Tregs and atherosclerosis may be due to the dysregulation and oversecretion of proinflammatory cytokines [Hansson and Hermansson, 2011].

Kim and colleagues described similar deficiencies of Tregs using an animal model of depression [Kim et al. 2012]. CD4+CD25+FOXP3 Treg knockout mice demonstrated anxious and depressive behaviors in the elevated plus maze, the tail suspension task, and the forced swim test. It has also been reported that human patients with major depressive disorder have decreased levels of circulating Treg cells [Li et al. 2010], while successful treatment with antidepressants increases the Treg cell populations and decreases the plasma concentration of the proinflammatory cytokine IL-1 [Himmerich et al. 2010].

Treg cell deficiencies appear to be present in both depression and CVD. This cell population’s functional role in the regulation of proinflammatory cytokines makes it a factor that may be involved in etiopathogenesis of the comorbidity of these two disorders. However, more research is required to validate this hypothesis.

Sex-specific modulation of proinflammatory cytokines

Though the comorbidity of depression and CVD is not exclusive to women, it seems to be more prevalent in women [Möller-Leimkühler, 2010]. This raises the question of how the interaction of the HPG axis and proinflammatory cytokines may be involved.

Yuan and colleagues reported the effects of estradiol and progesterone on proinflammatory cytokine secretion (TNFα, IL-1, IL-8) by peripheral blood mononuclear cells [Yuan et al. 2008]. In their work, estradiol attenuated cytokine production, while progesterone stimulated secretion. It is suggested that some of the mechanisms through which estradiol attenuates proinflammatory cytokines are decreases in stimulatory cytokines and the suppression of NFκB [Puder et al. 2001; Murphy et al. 2010]. Progesterone is considered to promote oxidative stress, ultimately giving way to increased inflammation [Huang et al. 2008]. Overall, women have lower levels of circulating Tregs than men, and it is hypothesized that this may be why women are more susceptible to autoimmune diseases in general [Afshan et al. 2012]. The literature on the specific impact of estradiol and progesterone on Treg populations is sparse, but it suggests that both estradiol and progesterone readily promote Treg population increases [Xiong et al. 2013; Lee et al. 2012].

Estradiol and progesterone also have interactions with the HPA axis, 5-HT transmission, and angiotensin II (Table 1), and thus they may exasperate or attenuate the inflammatory interactions with these systems.

Table 1.

Interaction of steroid hormones with biological systems.

	17-β Estradiol	Progesterone
HPA axis	Increase HPA activation through the upregulation of CRH gene expression in response to stress [Kageyama and Suda, 2008]	Decrease CRH secretion and HPA axis activity through its product allopregnanolone [Wirth, 2011]
Central 5-HT	Decreases monoamine oxidases which degrade 5-HT, and promoting tryptophan hydroxylase secretion, the rate-limiting enzyme of 5-HT synthesis [Lokuge et al. 2010], mediates both pre- and postsynaptic 5-HT receptors [Östlund et al. 2010]	Mild promotion of 5-HT synthesis through upregulation of tryptophan hydroxylase [Bethea et al. 2000]
Peripheral 5-HT	Upregulates peripheral 5-HT activity and levels through increases in tryptophan hydroxylase, and 5-HT transporter expression in pulmonary arterial muscles cells [White et al. 2011]	Not well established
Angiotensin II	Beneficial to cardiovascular health, estradiol attenuates angiotensin II induced hypertension [Xue et al. 2013]	Not well established

5-HT, serotonin; CRH, corticotropin-releasing hormone; HPA, hypothalamic pituitary adrenal.

Given this information, it may be suggested that periods in a woman’s life marked by increased levels of progesterone or decreases in estradiol (such as the luteal phase of the menstrual cycle and the perinatal period) represent times of increased risk for systemic inflammation and perhaps even depression and CVD. In humans, the luteal phase of the menstrual cycle is correlated with increases in IL-6, IL-4, and TNFα [O’Brien et al. 2007], and with negative mood symptoms [Andreen et al. 2009; Steiner et al. 2006]. The progesterone elevation seen in the luteal phase of the menstrual cycle is also associated with increases in resting heart rate and decreased heart rate variability [Bai et al. 2009], factors suggestive of increased cardiovascular risk.

Perinatal models of depression and CVD

Pregnancy is a valuable model to consider when focusing on sex differences and the comorbidity of CVD and depression.

Perinatal depression

In pregnancy, progesterone levels are elevated to levels not replicated at any other period in a woman’s life. Depression during pregnancy and the early postpartum period is up to 10% more prevalent than rates in the general population [Gavin et al. 2005]. This may be due to progesterone’s agonistic action on cytokine secretion, but to date the data on cytokine levels in perinatal depression are inconclusive. However, links between perinatal exposures and disorders and CVD, particularly preeclampsia, have been more extensively studied. The prevalence of preeclampsia ranges from 3% to 3.7% [Delahaije et al. 2013; Mbachu et al. 2013]. Preeclampsia may provide insight into the comorbidity of depression and CVD, as it has been linked to both perinatal depression and risk for CVD in later life.

Preeclampsia and depression

Women who experience mild to severe depressive symptoms in the prenatal period are at more than double the risk [odds ratio 2.95, 95% confidence interval (CI) 1.26–6.89] of developing preeclampsia [Kim et al. 2013]. Research suggests that the association between depression and preeclampsia is also bidirectional. Preeclampsia has been linked to the development of depressive symptoms in the postpartum period [Blom et al. 2010]. It is unclear, however, whether this association is due to a shared biological mechanism or rather the impact of the stress associated with having preeclampsia, including bed rest or a newborn’s admission to the neonatal intensive care unit [Hoedjes et al. 2011].

The presence of depressive symptoms in the perinatal period may be an early marker of cardiovascular risk, as suggested by increases in platelet aggregation and increases in peripheral 5-HT activity [Neubauer et al. 2013]. Platelet aggregation is a risk factor in the development of hypertension, suggesting a potential physiological pathway by which depression and preeclampsia may be linked. Treatment of depression during pregnancy, however, is difficult. The use of SSRIs, SNRIs, or tricyclic antidepressants was associated with relative risks of developing preeclampsia (1.22, 95% CI 0.97–1.54; 1.95, 95% CI 1.25–3.03; 3.23, 95% CI 1.87–5.59 respectively), relative to women with untreated depression [Palmsten et al. 2012]. These increased risks may be due to the antagonist effect such medications have on the 5-HT2 receptors, which are the primary serotonergic receptors activated for both vasodilation and vasoconstriction, and general cardiovascular function [Pytliak et al. 2011].

Preeclampsia and risk for CVD

The effect of preeclampsia on cardiovascular health may extend past the perinatal period. Preeclampsia is positively correlated with the occurrence of CVD and hypertension in later life. Both preeclampsia and CVD share common risk factors and physiological underpinnings, including pre-existing high blood pressure, immune dysfunction, and diabetes mellitus. The Framingham 10-year risk score is a common model used to evaluate the risk ratio of the future occurrence of CVD in an individual’s life [D’Agostino et al. 2001] and preeclampsia is associated with a (95% CI 3.70–4.52) increase in Framingham risk ratio relative to healthy, nonhypertensive pregnancies [Bhasin and Kapoor, 2013; Hermes et al. 2013]. However, the underlying mechanism of this risk elevation is unclear.

Östlund and colleagues assessed women 11 years after they developed preeclampsia and found that cardiovascular risk factors, such as vascular inflammation and decreased glucose tolerance, were still present [Östlund et al. 2013]. However, in this study, endothelial tissue dysfunction seemed to have normalized from their previous preeclamptic state. This suggests that preeclampsia is associated with an increased risk for CVD, but that it may not permanently alter vascular structure or function. Other studies support this, indicating that preeclampsia is associated with chronic hypertension after delivery and increased waist and hip circumferences, but that it was not associated with thickening of the carotid intima media 20 years after the adverse pregnancy [McDonald et al. 2013]. Finally, genetic studies suggest a possible link between preeclampsia and CVD. Polymorphisms of the C-reactive protein gene, which have previously been identified in CVD phenotypes, were associated with preeclampsia or hypertensive complications during pregnancy [Best et al. 2013].

Preeclampsia–immune system interactions

Pregnancy is a time of balanced immune–body interaction. The implantation of the fertilized egg in the uterine wall is interpreted as an invasion by the maternal immune system. For the survival of the fetus, it is very important to have high levels of Treg cells to actively suppress proinflammatory cytokine secretion and reduce inflammation. Preeclampsia has also been tied to chronic inflammation [Laresgoiti-Servitje et al. 2013] and linked to increased levels of IL-6, IL-8 [Ellis et al. 2001], TNFα [Conrad et al. 1998], IL-2, and IL-4 [Molvarec et al. 2011]. Furthermore, the onset of preeclampsia has been linked to deficiencies in maternal Tregs both peripherally and decidually, and to decreased suppression of proinflammatory cytokines [Teles et al. 2013; Steinborn et al. 2012]. In fact, women who have preeclampsia have Treg cell population frequencies more similar to nonpregnant women than to healthy pregnant women [Santer-Nanan et al. 2009]. Other researchers theorize that at implantation, maternal Treg cells migrate to the decidua to protect the area of the fetus. Thus, there would be significant decreases in maternal Treg circulation, leaving the mother vulnerable to disease and autoimmune reactions [Tilburgs et al. 2008]. This suggests that improper regulation of the immune system at implantation may precipitate the development of preeclampsia in later pregnancy. As Treg cell deficiencies are also implicated in antepartum depression and CVD, further research is required to determine how this deficiency and these disorders may interact.

The elevation of proinflammatory cytokines and deficits in Treg cell populations may be a predisposing factor to the comorbidity of depression and CVD. Further research in these areas could provide additional insights into the prevention and treatment of this comorbidity.

Discussion

We outlined in this synthesis three mechanisms by which the excess and chronic hypersecretion of proinflammatory cytokines could contribute to the development of depression and CVD (Figure 1). Though we acknowledge that there is obvious crosstalk between the HPA axis, the 5-HT system, and the RAAS system, it is beyond the scope of this review to discuss these in depth.

We suggest that depression and CVD are both inflammatory disorders and that their cooccurrence may be related to how the HPA axis, the serotinergic system, and the RAAS via angiotensin II are affected by the excess secretion of proinflammatory cytokines.

As described, proinflammatory cytokines are modulators of many biological systems. These interactions are almost always bidirectional and we do not claim any direction of causality. As with many other illnesses, it is likely that the chronic secretion of proinflammatory cytokines observed in depression and CVD is both a precipitating and maintenance factor of this comorbidity. It has been the attempt of this review to synthesize current animal, ex vivo, in vivo, and human studies to gain insight into the comorbidity of depression and CVD.

Footnotes

Funding

This research was supported by a grant from the Society for Women’s Health Research (SWHR) ISIS Network (grant number 1001_S32).

Conflict of interest statement

The authors declare that there is no conflict of interest.

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Depression and cardiovascular disease in women: is there a common immunological basis? A theoretical synthesis

Abstract

Keywords

Introduction

Proinflammatory cytokines and the HPA axis

Proinflammatory cytokines and 5-HT

Central nervous system 5-HT transmission

Peripheral 5-HT circulation

Proinflammatory cytokines and angiotensin II

T-regulatory cells

Sex-specific modulation of proinflammatory cytokines

Perinatal models of depression and CVD

Perinatal depression

Preeclampsia and depression

Preeclampsia and risk for CVD

Preeclampsia–immune system interactions

Discussion

Footnotes

Funding

Conflict of interest statement

References