Exploring the Relationship Between Heart, Brain, and Depression

Abstract

Background:

Depression is a condition which is characterized by an everlasting feeling of sadness and hopelessness and a lack of interest in activities has affected more than 300 million people in the world in2010. The burden of depression increases for people with chronic diseases. In the case of cardiovascular disease (CVD), the prevalence of depression is nearly double when compared with people without CVD. The presence of depression along with cardiovascular disease leads to poorer outcomes due to not sticking with treatment and bad lifestyle behavior.

Objective:

The objective of this study is to synthesize the evidence on: the prevalence of CVD and cardio metabolic risk factors, the bi directional mechanisms between depression and cardiac pathology, clinical consequences of outcomes due to under diagnosed depression, practical implications for integrated detection and management.

Methods:

For analyzing the already existing epidemiologic and mechanistic evidence about depression, heart disease, and cardiometabolic risk factors (diabetes, hypertension, dyslipidemia) impact on comorbidity, mortality, and health behaviors were explored.

Results:

People with heart disease are about two times more likely to have depression than those without it. The presence of depression along with chronic medical conditions like CVD can make illnesses worse than they would otherwise be and can lead to death. This also increases non-compliance with therapy and is associated with increased smoking, lack of physical activity, and alcohol use. People with classic heart problems like diabetes, high blood pressure, or high cholesterol are much more likely to be depressed. Recent studies show how brain-heart circuitry can dysregulate mood and cardiac function. Even though there are treatments available for cardiac patients, many suffer from depression diagnosis remains difficult.

Conclusion:

Depression is widespread, it has serious consequences, and often goes unnoticed. Regular screening and timely diagnosis, along with integrated cardio-behavioral care, are critical to improving clinical outcomes and adherence, as well as differentiating pathological depression from normative illness-related emotion.

1. BACKGROUND

Depression is a common psychological disorder with unknown aetiology, a population prevalence between 3 to 20% and an incidence peak at around the age of 30 years (1). Major depression disorder (MDD) is 3 times more prevalent in individuals diagnosed with cardiovascular disease (CVD) than in otherwise healthy individuals (1). It is important to investigate the biological mechanisms leading to the high incidence of MDD in this patient group due to the observational studies which find that depression significantly increases the morbidity and mortality in individuals with CVD (2). Other studies also note a higher risk of CVD in individuals diagnosed with depressive disorders, including the population-based study where women with MDD had an elevated incident CVD risk (3). Additionally, many patients with CVD consider their diagnosis and treatment so stressful they develop anxiety states (4).

2. OBJESCTIVE:

The objective of this study is to synthesize the evidence on: the prevalence of CVD and cardio metabolic risk factors, the bi directional mechanisms between depression and cardiac pathology, clinical consequences of outcomes due to under diagnosed depression, practical implications for integrated detection and management.

3. MATERIAL AND METHODS

For analyzing the already existing epidemiologic and mechanistic evidence about depression, heart disease, and cardiometabolic risk factors (diabetes, hypertension, dyslipidemia) impact on comorbidity, mortality, and health behaviors were explored.

4. RESULTS AND DISCUSSION

The Heart-Brain Connection

A better understanding of heart-brain interactions and their implications for cardiovascular treatment strategies is needed (5). Two key hypotheses have been more fully explored through neuroimaging studies (5). First, there is clear, albeit indirect, evidence of a link between heart disease and depression (6). Brain regions operating on the collateral pathway from the heart that are linked to depressive disorder were more active in depression-prone patients following acute myocardial infarction (AMI), suggesting that depression-prone patients reacting to AMI use a different strategy for coping with their emotions (5). Affective deficits in heart disease patients extending to hindrance of emotional regulation and impairments in deciding and coping with emotionally charged events may contribute towards the onset of clinical depression (7).

Other consequences of AMI not related to the likely affective consequences, such as a change in bodily awareness, may initiate symptoms falling under the diagnostic criteria for anxiety disorder (8). The results showed that the brain’s emotion-related areas differed with respect to mental effort in coping with emotional stimuli in healthy participants experiencing increased heartbeat awareness, compared with an unlikely pattern of brain activation during normal heartbeat awareness or the absence of heartbeat awareness (1). Thus, at least two key links exist between heart disease and depression that would need to be taken into consideration in future studies of heart-brain interactions (9). Furthermore, autonomic activity may benefit or constrain the heart-brain link as a formative factor in depression when local regulation of autonomic activity is impaired, and with respect to neural mechanisms involved in the connection (10).

Understanding Depression

As if heart catastrophes alone do not present enough trouble, a great majority of heart disease victims begin to suffer from unabated depression soon thereafter (4). All studies to date demonstrate that people with cardiovascular disease (CVD) have an increased probability of developing major depressive disorder (MDD) as compared to the general population (11). Epidemiological studies suggest that while heart disease increases the risk of developing a depressive disorder by 2-3 times in the general population, the picture is even bleaker in those people who have already developed heart disease (7). Simply put, MDD is a very poorly understood but more prevalent consequence of a heart catastrophe (1). Still worse, depression significantly and substantially increases the morbidity and mortality in individuals with CVD, making continued research in this area a significant need (12).

With respect to how depression arises after heart injury, very little is known (13). In fact, many people who suffer from heart catastrophes report feeling and demonstrating a flattened mood or depression (14). The symptoms often arise quickly: within days or weeks of the disease start (15). Thus, heart disease presents a compelling clinical paradigm for studying the relationship between the heart, the brain, and a depressive disorder (16). Depression is a disorder that has long, indirect effects on the cellular machinery of both the brain and the heart (17). Thus, it is expected that heart disease would impact the brain and give rise to an almost immediate depressive disorder (18).

Most neuroanatomical studies showing that heart injury causes depression have focused on the hippocampus (19). Several studies in which post-mortem human depression brains have been compared to post-mortem control brains have shown that the hippocampus is a likely candidate for changes arising from cardiovascular disease and giving rise to depression (20). Most notably, it has been determined that hippocampal brain-derived neurotrophic factor and inflammatory profiles are altered in depression (21). However, findings are somewhat inconsistent regarding cellular pathology in human depression and these studies do not corroborate preclinical results that show a decrease in the density of a specific subset of neurons in a specific layer of the hippocampus (22). Given the differences in depression and physiology between humans and experimental models, it was hypothesized that different brain areas might be impacted by heart disease itself in addition to those that could be impacted by depression (23).

Physiological Mechanisms Linking Heart and Brain

Research suggests that the heart and brain communicate directly through some mechanistic interactions (24). One such mechanism is an increase in the sympathetic nervous system activity of the heart (1). This, in turn, can induce an increase in the activity of norepinephrine neurons and a long-term elevation in the concentration of norepinephrine in both the amygdala and the hippocampus (25). Depression is linked to both a loss of brain-derived neurotrophic factor (BDNF) and low activity of the human neurotrophic tyrosine kinase receptor type 2 (TrkB) receptor (26). Research indicates that an increase in heart rate, pressure overload, or both can increase levels of amygdaloid noradrenergic signaling and downregulate TrkB activity via catecholamine-mediated receptor endocytosis (27). These two seemingly isolated domains of cognition, memory, and mood control may converge upon a common physiological mechanism with potential implications for the treatment of cardiovascular disease and major depressive disorder (28).

The recently observed parallel development of models of depression and heart disease presents an opportunity to investigate the physiological links between these diseases further (29). In terms of pathophysiology, heart disease, and depression may comprise shared risks in altered heart rate variability, low-grade inflammation, atypical neural circuits, and neurotransmitter systems with implications for cognition (30). The risk for developing MDD has been shown to increase following the diagnosis of CVD; likewise, depression significantly increases the morbidity and mortality of individuals with CVD (31). The need for continued research in this area is apparent; however, deepening the understanding of the normalized mechanistic relationships between myocardial insult and neurobiological changes may reveal new avenues of research (32).

The Role of Neurotransmitters

In the brain, neurotransmitters are key players in regulating emotions, behavior, and mood (33). The disturbances of monoamine neurotransmitter systems, including norepinephrine (NE), serotonin (5-hydroxytryptamine [5-HT]), and dopamine (DA), are associated with major depressive disorders (MDDs) (33). MDDs is a common mental disorder which significantly impairs people’s daily lives (34). It is estimated that 350 million people worldwide suffer from MDD (35). This disorder receives extensive attention because patients are less responsive to current medications and treatments (35). The most important feature of depression is the absence of joyful emotions (35). The emotional effect of dopamine (DA) has been studied for more than half a century, and it has become a synonym of joy and reward, thus why the DBS of VTA is exciting and mainly releases dopamine (36). Mesocortical dopamine pathway has been known as the pathway of cognition and behavior, while mesolimbic dopamine pathway (NAc and VTA) is known as the pathway of emotion, and through the motivation of reward, DA might improve the mood (37). This simple view suggests that increasing DA might be a good way for treating MDD (37). Drug: Ketamine, an anesthetic drug, was used to induce dissociative anesthesia by inhibiting N-methyl-D-aspartate receptors (37). The acute and chronic administration of Ketamine blockers induces different EEG oscillation changes (38). Interestingly, ketamine is a drug and a stimulant (38). It has many rapid effects after administration, like psychostimulation, dissociation, and hallucination (39). Based on rat study, the low-dose ketamine stimulation increased release of dopamine in NAc and this effect lasted about 2 h. Moreover, blocked DA receptors partly attenuated the acute expression of antidepressant effect (39). Under clinical trial, the major reason for ketamine to exert its antidepressant effect is related to DA release (39). The increased release of DA is mainly mediated by pre-synapse mechanisms, possibly by activating astrocytic Ca2+ signaling and changing the bursting of neurons in the Habula nucleus (40). The combination treatment with low-dose dopamine D2-receptor agonist and NMDA antagonists rapidly improves the mood of depression susceptible rats and causes DA hyperactivity much more than alone NMDA antagonists administration (40). Thus, raising brain dopamine is certainly a quick way to change the depressed mood (40).

Impact of Cardiovascular Health on Mental Well-being

About one in three patients reporting chest pain who undergo coronary artery angiography have no significant coronary artery stenosis (41). Various noninvasive tests are used to assess additional cardiovascular disease (CVD) risk (42). However, little attention has been devoted to evaluating the psychological aspects of patients with cardiac symptoms (43). There is a growing body of evidence that mental health support is vital in the assessment and treatment of post-heart attack depression (44).

Many adult CVD patients were first or second generation Polish immigrants from Eastern Europe who could not speak English fluently or read this language (45). Among patients with reduced heart function, a growing number receive heart pump devices that help their heart pump blood more efficiently to vital organs (45). Therapy to support implanted devices was developed and that many patients engaged in a partial inpatient treatment (45). Information about treatment was initially only available in English and translated into Polish later (45). Therefore, many patients experienced stress and anxiety while acclimating to treatment and the health care system (46). Another immediate reaction was “stress”, which is the natural reaction to a stressful encounter, such as receiving a CVDs diagnosis (46). Then stress events seldom appear in life, at least from breast-feeding through early adulthood (47). In those patients who experienced stress, it usually faded with time, but this new stress was continuous (47). Some felt worried day and night and engaged in discussions with families, friends, and medical staff about their health (47). Continuous stress and worries cause anxiety, which is one of the synaptic reasons for health deterioration (48). Suffering from anxiety leads to disrupted comfort during the day, interrupted sleep at night, and limits social interactions (49). Some patients with CVDs experienced debilitating anxiety disorders, which would be classified as general anxiety disorder if the patient sought treatment for mental difficulties (49). Living with anxiety disorders deteriorates health in multiple ways (50). Some become more inactive and avoid going outdoors because they are afraid of being unable to cope (50). Some become less organized and make arrangements last minute (50). Some smoke or drink more and are worried about health, outcomes, and relationships (45).

Depression as a Risk Factor for Heart Disease

In the past decade, the association between depression and cardiovascular disease (CVD) has garnered significant interest and has been the subject of numerous scientific investigations (51). CVD encompasses both coronary artery disease (CAD) and cardiac heart failure (HF) (52). It is increasingly recognized that depression is significantly, and independently, associated with CVD, including increased risk of incident CVD and adverse postevent outcomes (51). The consequences of this association are significant (51). Depression is a common mental disorder, affecting 21% of the United States population at some point in their life (53). Twelve-month prevalence rates are also high, with estimates ranging from 7% to 9% (53). Costs related to depression and its comorbidities are conservatively estimated at $83 billion per year in the United States alone (54). With a growing epidemic of obesity and other cardiovascular (CV) risk factors, CVD will likely become a greater societal burden, heightening the importance of better understanding the links between these two major public health disorders (55).

Psychological Factors Influencing Cardiac Health

Psychological factors that influence cardiac health and outcomes have been recognized for decades (55). Important psychosocial factors associated with coronary artery disease (CAD) include anxiety, depression, social support and isolation, chronic stress, coping styles and mechanisms, and personality traits (56). While traditional risk factors account for the majority of CVD predictable by risk prediction models, measures of personality traits, depression, anxiety, social support, coping resources, and others, add to that predictive ability (57). Unaccounted variance in traditional risk factors, or ‘residual risk,’ accounts for a large effect (57). Several additional factors have also been associated with worse outcomes (57). Acute myocardial infarction (MI) develops from a stable atherosclerotic lesion following plaque rupture and thrombosis (58). Although classical risk factors have been studied extensively, the vast majority of patients with atherosclerosis exhibit none of the classical risk factors. Similarly, after controlling for traditional factors, depression emerges as a significant predictor of new-acquired CAD (58).

There are several proposed physiologic and behavioral processes bridging the association between depression and cardiac disease. Inflammation: The contribution of inflammation to the overall development of cardiac disease—and especially to acute cardiac events—is well documented (59).

Depression processes have also been linked to increased levels of cytokines (specifically CRP, IL-1, and IL-6), both in patients with and without a history of cardiac disease (60). Results of these studies suggest a link between depression and inflammation (60). This is plausible, as stressors impact circulating pro-inflammatory cytokines and C-reactive protein (61).

Stress and Its Effects on Heart and Brain

Imbalances in the body’s regulatory systems, which result from genetics and the environment (epigenetics), may lead to symptoms and disorders (62). These include maladaptive responses to stress that are responsible for most forms of psychopathology, such as anxiety and mood disorders (62). In addition, evidence is accumulating that these imbalances involve interactions between the brain and peripheral physiological systems such as the autonomic nervous system, the heart, and the immune system (63). There is also increasing appreciation that such imbalances play a significant role in health risks, including cardiovascular disease and metabolic syndrome (63). Given the difficulty of drawing together diverse insights from a wide variety of disciplines, there is a need to develop a working model of a health burden of specific translational endpoints (64). This would provide a structure for integrating diverse pieces of information coming from many areas of research (64). Importantly, this model must take into account individual differences in risk dispositions rooted in genetics and epigenetics and their interactions with environmental factors, including developmental trajectories (64).

Heart and brain growth and functioning are both regulated by internal and external factors that develop throughout the course of a lifetime (65). Stress exposures alter structure and functioning in both of these organs (65). Dysregulation of the heart and brain from interactions among environmental risk factors and pathologies in individual growth curves, i.e. allostasis, gradually emerge and become maladaptive (66). Misregulation of the heart contributes to development of cardiovascular disease and misregulation of the brain contributes to development of anxiety and mood disorders (67). Theoretical models highlight how stressors amplify these original individual characteristics into distinct physiological profiles such as cardiac and brain vulnerabilities to further risk exposures like chronic psychological stress (67).

5. CONCLUSION

This article explored the relationship between heart, brain, and the experience of depression (68). The first section described the various common pathological mechanisms of depression and cardiovascular disease (69). The second section explored the heart-brain cross-talks such as neuroplasticity, neuroinflammation, and the neuroendocrine system, and their implications for the comorbidity of depression and heart disease (70). Finally, it highlights the need for future studies to investigate the mechanistic role of heart-brain cross-talks in the relationship between heart disease and depression and the untargeted treatments for both conditions (71).

Depression is a leading cause of disability and affects more than 264 million people globally (72). The psychopathological experience of depression is multifaceted and includes various biological and psychological aspects including inhibition of neuroplastic change, chronic low-grade brain inflammation, and increased feelings of helplessness, hopelessness and worthlessness, leading to anhedonia, apathy, cognitive impairments, and suicidal ideation (73). Depression is also common after cardiovascular disease, which is a leading cause of death worldwide, and has various common pathological triggers including increased systemic inflammation, the perturbation of the neuroendocrine system and autonomic dysfunction, leading to arrhythmias and/or sudden cardiac death (74).

Author’s Contribution:

The all authors were involved in all steps of preparation of this article. Final proofreading was made by the first author.

Conflicts of interest:

There are no conflicts of interest.

Financial support and sponsorship:

This work was supported and funded by the Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University (IMSIU) (grant number IMSIU-DDRSP2501).