Depression and cardiovascular disease: Shared molecular mechanisms and clinical implications

Psychiatry Research 285 (2020) 112802

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Review article

Depression and cardiovascular disease: Shared molecular mechanisms and clinical implications

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Shao Mingjinga,1, Lin Xiaodongb,1, Jiang Deguob,1, Tian Hongjunc, Xu Yongd, Wang Linac, ⁎ Ji Fenge, Zhou Chunhuaf,2, Song Xueqingg,2, Zhuo Chuanjune,b,g,d, a

National Integrated Traditional and Western Medicine Center for Cardivascular Disease, China-Japan Friendship Hospital, Beijing 100101, China Department of Psychiatric-Neuroimaging-Genetics Laboratory (PNG_Lab), Wenzhou Seventh People's Hospital, Wenzhou, Zhejiang Province 325000, China c PNGC-Lab, Tianjin Mental Health Centre, Tianjin Anding Hospital, Tianjin, 300222, China d Department of Psychiatry, First Hospital of Shanxi Medical University, Tainyuan, 030001, China e Department of Psychiatry, School of Mental Health, Jining Medical University, Jining, Shandong Province 272100, China f Department of Pharmacology, The first Hospital of Hebei Medical University, Shijiazhuang, Hebei Province 37000,China g Department of Psychiatry, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China b

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A B S T R A C T

Keywords: Cardiovascular disease Depression Inflammation Interleukin-6 C-reactive protein

Depression is a highly prevalent risk factor for both the onset of cardiovascular disease (CVD) and the mortality of CVD patients, and people suffering from CVD are more likely to develop depression than healthy individuals. The aim of this review is to summarize recent findings regarding the underlying relationship between CVD and depression. Literature search and review were conducted using PubMed, Google Scholar, Wanfang Med Online, and Baidu Scholar databases. CVD and depression are intimately related and researchers from around the world have proposed and validated various mechanisms that may potentially explain the comorbidity of CVD and depression. Recent studies have suggested that depression and CVD may manifest as two distinct clinical conditions in two different organs, the brain and the heart, respectively, but may also be linked by shared mechanisms. Of these, inflammation involving the immune system is thought to be a common mechanism of depression and heart disease, with specific inflammatory cytokines or pathways being potential targets for the prevention and treatment of the concurrent diseases. Therefore, inflammation may play an important role in bridging the link between depression and CVD, a finding that can have important clinical implications for the prevention and early intervention of these conditions.

1. Introduction Depression is the most prevalent mental illness with a lifetime risk of 6–25% across the general population, and is projected to be the leading causes of disability worldwide by 2030 (Kessler and Bromet, 2013; Murray and Lopez, 2013). Cardiovascular disease (CVD), also simply referred to as heart disease, includes conditions such as coronary heart disease (CHD), stroke, heart failure, and many other dysfunctions of the heart and surrounding vessels. CVD remains the leading global cause of death for both adult males and females (Lozano et al., 2012; Mozaffarian et al., 2015). A great number of studies have shown that these two clinical conditions are intimately related, suggesting a physiological link between CVD and depression (Hare et al., 2014; Xue et al., 2019; Okunrintemi et al., 2019;

Graham et al., 2019; Almeida et al., 2019; Jee et al., al.,2019). For instance, CVD patients are more likely to develop depression than individuals without CVD, while people suffering from depression are at higher risk of developing CVD compared to healthy individuals (Frasure-Smith and Lesperance, 2005; Musselman et al., 1998; Carney and Freedland, 2017). It has also been evident that patients with more severe depression are at higher risk of developing CVD (Whooley and Wong, 2013). Additionally, depression is a strong risk factor for both increased morbidity and mortality of patients with CVD (Huang et al., 2009; Colquhoun et al., 2013). Despite the comorbidity between CVD and depression, the mechanism underlying the link between these two conditions is largely unknown. To understand such mechanism(s), extensive studies have been conducted and recent progress has been made that may explain, at

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Corresponding author. E-mail address: [email protected] (C. Zhuo). 1 This authors contributed equally to this work and should be the co-first authors of this work. 2 These authors are the co-corresponding authors. https://doi.org/10.1016/j.psychres.2020.112802 Received 18 September 2019; Received in revised form 19 January 2020; Accepted 19 January 2020 Available online 21 January 2020 0165-1781/ © 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

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(Whooley and Wong, 2013), and that there is compelling evidence regarding the association between the two conditions. In this section, we review the results obtained from studies of different populations and summarize the connection between CVD and depression. First, depression is more prevalent among patients diagnosed with CVD compared to the general population. The high prevalence of depression in CVD patients was first noted in 1967 by Wynn et al., in which nearly 40% of patients reported depression after myocardial infraction (Wynn, 1967). In the study conducted by Cay and colleagues in 1972, following acute myocardial infraction (AMI), two-thirds of patients were found to present symptoms of mild depression (Cay et al., 1972). Overall, the prevalence of depression among CVD patients has been variable, ranging from 10% to 40%, with greater prevalence in patients with more severe heart disease, such as chronic heart failure (CHF) (Colquhoun et al., 2013; Rutledge et al., 2006). In patients who received an implantable cardioverter defibrillator, more than 25% of the patients were depressed, and those individuals who experienced an increased prevalence of shock were more likely to develop depression (Suzuki et al., 2010). Among CVD patients who were treated with coronary artery bypass surgery, 15–25% of the patients experienced major depression, and another 15% developed significantly depressed moods or minor depression after the surgery (Tully and Baker, 2012). Although the prevalence of depression varies in patients with different types of CVD, it is generally recognized that approximately 15% of CVD patients suffer from depression (Colquhoun et al., 2013), which is nearly three times greater than that of the general population. Second, compiled findings to date suggest a significantly increased prevalence of CVD in patients with depression, who are more likely to develop and to die from CVD compared to healthy individuals. In the

least in part, why depression and CVD are so intimately correlated. Of these, a number of longitudinal studies have connected significantly elevated levels of systematic inflammatory markers, interleukin 6 (IL-6) and C-reactive protein (CRP) in particular, with the subsequent risk of developing CVD (Danesh et al., 2008, 2004; Emerging Risk Factors et al., 2012; Miller et al., 2009; Pradhan et al., 2001, 2002). Inflammatory pathways involving the human immune system may therefore offer novel targets for the early intervention and prevention of the comorbidity of CVD and depression. In this review, we summarize recent studies on the shared mechanisms between depression and CVD. These findings have important clinical implications for proposing new approaches for the prevention and early intervention of either or both diseases. 2. Methods Literature search and review were conducted in the core databases (PubMed, Wanfang Med Online), and other sources (Google Scholar, Baidu Scholar) in which the keywords, such as “cardiovascular disease”, “heart disease”, “depression”, “mental disorders”, “inflammation”, “interleukin-6”, “C-reactive protein”, were used. We had included the most relevant original research articles but excluded relatively less relevant articles. A flow diagram of the articles selected and eliminated in this review was presented in Fig. 1. 3. Connection between depression and CVD Over the past two decades, extensive epidemiological studies have demonstrated that depression and CVD are highly comorbid

Fig. 1. Flow diagram of literature selection process for this review. A literature search was performed in core databases (PubMed, Wanfang Med Online), and in other sources (Google Scholar, Baidu Scholar). Duplicate publications were initially removed to avoid reviewing duplicate articles. Among 597 publications, 389 publications, including abstracts presented in workshops, annual meetings, as well as conferences, correspondences, editorials, book chapters, and publications written in non-English languages, were subsequently excluded. In the final step of selection for literature, 138 full articles were finally eliminated mainly based on the relevance. A total of 70 publications were included in this review. 2

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disease (CHD) and depression. A Mendelian randomization analysis revealed potential molecular pathways contributing to the comorbidity between the two conditions, and found that the three conventional cardiovascular risk factors of TG, CRP and IL-6 were likely to be causally linked to depression (Khandaker et al., 2019). These findings suggest that inflammation involving the immune system may be a common mechanism shared by depression and heart disease (Khandaker et al., 2019). Previous studies have also shown that elevated levels of IL-6 and CRP are associated with depression in patients diagnosed with depression alone (Howren et al., 2009) and in those diagnosed with depression and CHD (Danesh et al., 1998; Howren et al., 2009; Miller et al., 2003, 2005; Ridker et al., 1998, 2000a, 2000b; Ridker et al., 2000c). In an effort to understand the extent to which inflammation mediates the link between depression and heart disease, several studies have found that the various inflammatory markers account for a proportion of the total effect (Davidson et al., 2009; Empana et al., 2005; Hiles et al., 2015; Kop et al., 2010; Surtees et al., 2008; Vaccarino et al., 2007). For example, individuals with abnormally high levels of CRP and IL-6 are more likely to suffer from depression (Valkanova et al., 2013), supporting the hypothesis that depression and heart disease manifest as different clinical conditions related to the distinct organs of the brain and heart, respectively. However, we must realize the limitations of this population-based study as the included cohort was restricted to individuals of European ancestry and the role of inflammation in comorbid depression and heart disease may depend on race or ethnicity (Carney and Freedland, 2017; Stewart, 2016). In a meta-analysis with moderate heterogeneity conducted by Valkanova and colleagues, a significant correlation between increased levels of CRP and IL-6 and depressive symptoms can be accounted for (Valkanova et al., 2013). These results support, at least in part, the hypothesis that inflammation involving the immune system and its response might be a causal pathway to developing depression (Valkanova et al., 2013). Stress-induced inflammation in patients with depression might also reveal a causal pathway to the development of heart disease, as the body may lose its capability of regulating the inflammatory response. As extensive literature and evidence exists on the topic of stress and depression, it is well-known that stress is closely associated with depression and other stress-induced psychological conditions. It is evident that stress-induced inflammation is partly modulated by cortisol, a glucocorticoid (steroid hormone) secreted by the two adrenal glands in humans (Black and Garbutt, 2002; Cohen et al., 2012). Under normal physiological conditions, cortisol can reduce inflammation; however, in patients with depression, chronic stress persists and maintains elevated levels of cortisol in the blood. This phenomenon continuously attempts to drive down inflammation which can eventually wear down the immune system. Over time, immune cells become insensitive to the regulatory effects of cortisol and cause chronic inflammation and an increased susceptibility to diseases, including heart disease in patients with depression (Black and Garbutt, 2002; Cohen et al., 2012). Cortisol can constrict blood vessels and elevates blood pressure (BP) to enhance the circulation of oxygenated blood. Nevertheless, over time, when cortisol levels in the blood remain high, the effect on both blood vessel constriction and BP elevation can cause blood vessel damage and plaque buildup, which is the scenario for CVD. This scientific evidence may explain why patients with depression are at a significantly higher risk than healthy individuals for developing CVD (Sher, 2005). New findings in a recent study from Boston's Brigham and Women's Hospital in the US appear to confirm the hypothesis that inflammation may play a significant role in CVD (Ridker et al., 2017). In this study, 10,061 patients from different populations in 39 countries were randomized to receive injections at different doses (50, 150, and 300 mg every three months) of the antiinflammation drug, canakinumab, a monoclonal antibody specifically targeted for IL-1β in humans (Ridker et al., 2017). The medical status of these patients was followed for up to four years and the results indicated that significantly more

United States alone, the prevalence of CVD in adult patients with major depression is nearly 3-fold higher than control individuals without mood disorders (Frasure-Smith and Lesperance, 2005; Goldstein et al., 2009; Musselman et al., 1998). Further, the association between depression and increased cardiovascular mortality was also noted in a study with more than 1000,000 participants of all ages from Taiwan (Huang et al., 2009) that spanned 4 years. Huang and colleagues examined the relationship between CVD and mood disorders, including major depressive disorder (MDD), and found that the prevalence of CVD significantly increased in all age groups for those patients also diagnosed with a mood disorder. The MDD patients at the age of <20 years displayed the greatest prevalence of ischemic heart disease (IHD) among patients with MDD (Goldstein et al., 2009). Additionally, an observational study involving 7641 participants between the ages of 17 and 39 years also revealed a significant correlation between MDD and an increased risk for CVD and mortality (Shah et al., 2011). After adjusting for many individual factors, including income, education, alcohol consumption, body mass index (BMI) and sedentary lifestyle, the findings remained unaffected (Shah et al., 2011). When these results, based on large patient samples in different populations, are considered together, as in this section, it becomes evident that MDD confers and increased risk of CVD and cardiovascular mortality in adolescents and young adult depression patients (Huang et al., 2009; Shah et al., 2011). In addition to the link between CVD and depression, there is the possibility that antidepressants can cause cardiac effects. In a recent case-control study, Chou et al. from Taiwan examined 34,053 patients with atrial fibrillation (AF), a common form of atrial arrhythmia associated with an increased risk of stroke (5-fold) and long-term mortality (2-fold) (Michelsen and Meyer, 2007), and reported that antipsychotic drugs, including antidepressants, significantly increased the risk of developing AF, clearly linking medications for depression and heart disease (Chou et al., 2017). Furthermore, Chou and colleagues noted that a higher dose of anti-depressant drugs was related to a greater risk of developing AF (Chou et al., 2017). In a recent examination of the long-term cardiotoxicity of antidepressants, it was found that some patients experienced myocarditis at the onset of treatment, suggesting a connection between antidepressants and CVD that supports the necessity for monitoring hearth health during the early treatment period with such medications (Michelsen and Meyer, 2007). It can be clearly seen that depression and CVD are highly comorbid and that patients with both conditions are more likely to expire than those with only CVD (Whooley and Wong, 2013). Furthermore, it is evident that the more severe the depression, the more likely the person will develop CVD and be at risk of death (Huang et al., 2009; Colquhoun et al., 2013). 4. Molecular mechanisms underlying the link between CVD and depression As previously discussed, the comorbidity of CVD and depression has already been well established by extensive studies. However, the mechanisms explaining the link between the two clinical conditions are complex and remain unclear. As studies accumulate, some potential mechanisms have emerged that mainly include behavioral, biological, and medication-related mechanisms. This section offers an overview of potential molecular mechanisms that may bridge depression and CVD, with a focus on inflammation-related interleukins such as interleukin-6 (IL-6) and IL-1β, C-reactive protein (CRP) (a protein released from the liver in response to inflammation) and triglycerides (TG) in lipid metabolism. Most recently, a research team at the University of Cambridge analyzed data on 367,703 unrelated people of European ancestry of ages 40–69 years old in a large population-based cohort study. (Khandaker et al., 2019) The data were obtained from the United Kingdom (UK) Biobank and are publicly available online (https://www. ukbiobank.ac.uk). The researchers in this study conducted various analyses to identify the potential mechanisms shared by coronary heart 3

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dysfunctions through targeting inflammation (Halaris et al., 2016; Zuzarte et al., 2018). This section highlights the opportunities presented to help clinicians identify individuals that are highly susceptible to developing both conditions, to prevent one or both conditions, and to provide interventions throughout the progression of the diseases. In finding shared mechanisms of CVD and depression, preventing the development of both conditions can be more easily achieved. The biochemical mechanisms causing and abating inflammation are multifaceted and complex, and fortunately, there are effective approaches to maintaining cortisol levels within a normal range and to managing stress. For example, one strategy for effective stress management is to adopt an anti-inflammatory diet to decrease inflammation and minimize stress. Based on various properties of food, a low-inflammation diet is generally characterized by maximizing the amount of anti-inflammatory foods ingested and to minimize the intake of foods with pro-inflammatory properties. Since lifestyle is also believed to be one of the most significant contributors to inflammation, a healthy lifestyle can also help in preventing the comorbidity of these two conditions. The findings involving the potential shared mechanisms based on inflammation pathways or specific cytokines, such as IL-6, may also lead to early intervention, prevention, and/or treatment. These downstream effects are discussed in this section and are summarized in Fig. 3.

favorable clinical outcomes were seen for the patients who were given injections of various doses of canakinumab compared to the control individuals who received a placebo (Ridker et al., 2017). Notably, the patients who were injected with 150 mg or 300 mg of canakinumab saw an approximately 15% lower risk of having another heart attack, a 30% drop in the requirement for bypass surgery and angioplasty interventional procedures, and a 17% reduction in hospitalization for unstable angina (Ridker et al., 2017). These findings from such a large sample size and diverse population in different countries demonstrate that antiinflammation treatment with canakinumab can significantly lower the risk of suffering from recurrent heart attacks and CVD-related deaths in individuals who have abnormally high levels of high-sensitivity CRP (hsCRP) (Ridker et al., 2017). Discovering a significant role of inflammation in heart disease is important because it may also open a novel avenue for the treatment of CVD as a comorbidity of other diseases, such as depression. In addition, the same research team at Cambridge University revealed an association between higher levels of IL-6 in childhood and an increased risk for depression in young adulthood (Khandaker et al., 2014). Greater levels of IL-6 in childhood were significantly associated with the subsequent increased risk of depression in a dose-dependent manner; patients with MDD have elevated levels of IL-6, which is likely to contribute to worsening mood. Compared with IL-6, CRP is more likely to be linked to depressive symptoms. There is a possibility that CRP may act as an important driver of inflammatory processes with depressive symptoms (Valkanova et al., 2013). It is evident that IL-6 can stimulate the liver to produce CRP and is considered the most potent inducer of CRP, however, it is difficult to know whether the elevation of CRP levels is secondary to that of IL-6. Despite of the complex and unvalidated mechanisms in humans, accumulating evidence indicates, as summarized and discussed above, that inflammation may play an important role in the link between CVD and depression. Accordingly, we propose that a shared mechanism involving inflammation is behind the comorbidity of CVD and depression, which is presented as a schematic diagram in Fig. 2.

5.1. Nutritional interventions with anti-inflammatory foods and supplements A wide range of foods and supplements, including omega-3 (ω−3) polyunsaturated fatty acids, coenzyme Q10 (CoQ10), turmeric, black pepper and antioxidant vitamins (VE and VC) have been found to suppress the formation and ultimate level of IL-6. For instance, the ω−3 polyunsaturated fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), have all been well-documented to suppress the formation of IL-6 and reduce levels of CRP (Khalfoun et al., 1997). Thus, several promising studies support the hypothesis that supplementing a diet with ω−3 polyunsaturated fatty acids, such as DHA and EPA, can attenuate the production of IL-6 (Khalfoun et al., 1997; Bersch-Ferreira et al., 2017). A wealthy body of research has also shown that ω−3 fatty acids, when given to heart disease patients, significantly lowers the levels of IL-6 (Bersch-Ferreira et al., 2017; Khalfoun et al., 1997; Zhang et al., 2012). In addition, antioxidant supplementation can quench free radicals such as reactive oxygen species and thereby reduce the production of IL-6 and CRP.

5. Clinical implications of the shared mechanism The potential shared mechanism of CVD and depression carries important clinical implications, which may offer potential therapeutic approaches for prevention and early intervention of one or both

5.2. Practicing relaxation as a lifestyle modification Lifestyle modification using such a strategy as improved stress management through mind-body practices (e.g. yoga, Tai Chi, meditation) may help lower levels of IL-6. This intervention merits attention as yoga has been shown to significantly reduced levels of IL-6 by 41% in a study comparing individuals who do and don't practice yoga (KiecoltGlaser et al., 2010). Like yoga, any relaxation practice may be helpful for reducing levels of IL-6 and in turn to reducing the risk of concurrent depression and CVD 5.3. Treatment with specific anti-inflammatory medications As described earlier in this review, the anti-inflammatory medication, canakinumab, which targets IL-1β, has shown promising results for lowering the risk of recurrent heart attacks and heart disease-associated deaths among patients with high levels of inflammation (Ridker et al., 2017). These important findings may also have implications as a new treatment of CVD with various mental disorder comorbidities (e.g. depression, anxiety, bipolar disorders) (Ridker et al., 2017). It should be noted that canakinumab carries a risk for infection and that patients taking this medication must be carefully monitored. In

Fig. 2. Schematic of a mechanism that may bridge cardiovascular disease and depression. 4

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Fig. 3. Schematic diagram for targeting inflammation in the co-treatment of cardiovascular disease and depression.

loop recorder (Koshy et al., 2018) but much more convenient. To date, a majority of studies have focused on assessing the utility of these smart watches for monitoring the sinus rhythm (SR) (Cadmus-Bertram et al., 2017; Koshy et al., 2018; Wallen et al., 2016; Wang et al., 2017) in patients with atrial arrhythmias. In a study by Koshy (Koshy et al., 2018) involving 102 patients, [SR (n = 50), atrial fibrillation (n = 32), or atrial flutter (n = 20)], the analysis revealed a high agreement with ECG in patients with atrial flutter and SR, but with an underestimation of HR in AF. It must be pointed that this study is in its infancy and that future clinical trials will be required to evaluate the efficacy of the use of these devices in the management of comorbid CVD in depression patients.

addition, as canakinumab is used to treat patients who have already had a heart attack and are at a high risk of recurrent events due to elevated levels of inflammation, it is highly recommended that appropriate tests for inflammation are performed and that the patient's medical history is considered when developing a treatment plan. Although this discovery may reveal a new intervention, more clinical studies are needed in the future to confirm the findings for the treatment of comorbid CVD in patients with depression. 5.4. Treatment with traditional Chinese medicine (TCM) It has long been recognized that some TCM techniques have antiinflammatory properties (Li et al., 2019; Lin and Ren, 2009; Wu et al., 2017; Zheng et al., 2009; Zhou et al., 2007). Recent clinical studies have confirmed the effectiveness of TCMs targeting inflammation for the treatment of CVD (Li et al., 2019; Lin and Ren, 2009; Zheng et al., 2009). These findings suggest that TCM is a promising adjuvant therapy for CVD regarding patient safety and clinical effects that include pleiotropic anti-inflammation, lipid regulation, endothelium protection, and microcirculation improvement. This may also imply that TCMs, alone or in combination with other medications, might offer a new treatment of CVD in depression patients. Regarding the management of comorbid CVD in patients with depression, wrist-worn devices such as smartwatches, recently developed by high-tech companies, allow patients to monitor their own heat rate (HR) and electrocardiogram (ECG) (Cadmus-Bertram et al., 2017; Koshy et al., 2018; Rumsfeld et al., 2016; Wallen et al., 2016; Wang et al., 2017). Although future studies will be needed to test the efficacy, these wearable devices hold promise to predict and manage CVD in patients with depression. Of these devices, the Apple Watch Series 4′s ECG feature has become available for capturing CVD-related signals, such as abnormal HR and irregular heart rhythm (arrhythmias) and is expected to bring new hope for the autonomous management of CVD in patients with depression. Additionally, the continuous pulse and ECG monitoring features can provide physicians with trends of the HR and ECG of their patients; this technology is similar to an implanted

6. Conclusions Taken together, depression and heart disease are intimately related, and the comorbidity between the two clinical conditions has been confirmed through many years of research. Of the theorized mechanisms, inflammation involving specific cytokines is proposed to play an important role in bridging the link between depression and CVD. Although further studies are needed for confirmation, new findings regarding such shared mechanisms may help in crafting approaches to the prevention and early intervention of these diseases, as well as open a novel avenue for the treatment of CVD as a comorbidity of other diseases, such as depression. Authors’ contributions All authors made substantial and intellectual contributions to the writing of this manuscript. In particular, CZ contributed to conception of the review, drafted the manuscript, and made critical revisions to the manuscript. Funding statement This work was supported by grants from the National Natural 5

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Science Foundation of China (81871052 to C.Z., 81801679 and 81571319 to Y.X.), the Key Projects of the Natural Science Foundation of Tianjin, China(17JCZDJC35700 to C.Z.), the Tianjin Health Bureau Foundation(2014KR02 to C.Z.), the National Key Research and Development Program of China (2016YFC1307004 to Y.X.), the Shanxi Science and Technology Innovation Training Team's Multidisciplinary Team for Cognitive Impairment(201705D131027 to Y.X.), Zhejiang Public Welfare Fund Project(LGF18H090002 to D.J.) and the Wenzhou Science and Technology Bureau key project fund (ZS2017011 to X.L.).

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