Depression, Anxiety, Stress, and Spirituality in Cardiovascular Disease
Mimi Guarneri, MD, FACC
Shyamia Stone, ND, MPH
Introduction
The human heart is notoriously understood as the life-giving organ of the body. With each contraction, it sends blood and nourishment to every organ and every cell of the body. As medical professionals, we are taught about the structure and function of the heart, its capacity for disease, and its centrality to life. However, across medical and cultural traditions, the heart is given many connotations outside of its cardiovascular functions. The heart is seen as the seat of the soul, of love, pain, and general emotion. Colloquialisms such as “follow your heart” and “brokenhearted” call to mind reminiscences of intuition and emotion, evoking memories and feelings in those who hear these phrases.
It is easy for medical professionals to discount the emotional connotations of the heart as mutually exclusive concepts or social folklore, but this interconnectedness of heart, body, mind, and soul has been described by medical practitioners for hundreds of years. Traditional Chinese Medicine (TCM) discusses a connection between diseases of the heart and excess stimulation; however, it is known in TCM that all emotions affect the heart, including sadness, grief, worry, fear, pensiveness, and anger.1 Ancient Grecian physicians saw cardiovascular disease (CVD) as a manifestation of emotion and psychological disorder, and in 1937 there was a scientific correlation noted between CVD outcomes and psychological pathology, noting an increase in cardiovascular-related deaths in those with depression.2,3
Medical knowledge and literature have illustrated many structural, biochemical, and genetic etiological mechanisms of CVD. Although these are important, it is necessary to look past each of these segregated components at the whole person when attempting to paint a complete picture of underlying risk factors and comorbidities. An individual’s biology does not exist in isolation of his or her surroundings, but rather within an internal and external milieu. From a public health perspective, it is possible to see the numerous ways that environment and lifestyle factors play a role in health outcomes. We see components such as toxic exposures,4,5 nutrition, and exercise6,7 as impacting physiology and being linked to CVD risk, although an often-overlooked part of one’s environment is external stressors and internal responses, along with other mental emotional states.
Although the connections between mind and body can be seen anecdotally, we also now know that mental-emotional and psychological states contribute to physiology through very real neurotransmitter and biochemical pathways that impact pathology and/or resilience. Depression and anxiety are emotional and physiological results of various types of stress that span from the biochemical to environmental.
Purpose of the Chapter
This chapter will outline what is known about depression, anxiety, and stress as pathological states and their connection with CVD. We will then present integrative medicine treatments including conventional therapies, nutrition, lifestyle, herbal, and mind-body mechanisms. It will show the ways in which it is imperative to address depression, anxiety, stress, and CVD both symptomatically and through identifying the root cause on the levels of mind, body, and spirit.
Depression
Depression in its broadest reach may be understood as a state of being that spans from a fleeting emotional experience or mood to that of a more long-term pathological state. People often experience depressed mood as feelings of sadness, despair, emptiness, or discouragement with associated rumination and fixation on the past. When sadness is experienced as an emotion, it is important that it is acknowledged as a
normal part of the human experience, allowed to be expressed and not suppressed. However, if this state continues and is accompanied by other features, it is possible for depression to cross over into a state of pathology.
normal part of the human experience, allowed to be expressed and not suppressed. However, if this state continues and is accompanied by other features, it is possible for depression to cross over into a state of pathology.
According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), depression as a disorder may be classified as Disruptive Mood Dysregulation Disorder, Major Depressive Disorder, Persistent Depressive Disorder (Dysthymia), or Depressive Disorder Due to Another Medical Condition.8 The most commonly studied clinical diagnosis of depression related to CVD is Major Depressive Disorder (MDD). Although the DSM-58 is the gold standard in diagnosis of depressive disorders and is utilized extensively by mental health professionals, depression is often identified in medical offices through a variety of self-report measures (Table 33.1). These instruments provide information about the severity of depressive symptoms based on the frequency, severity, and impact on quality of life. Each of these measures simplify DSM criteria for self-report format and provide an estimated guideline of level of depression that may include categories such as normal/not depressed, mild, borderline, moderate, or severe depression.9,10,11,12 A measure specifically for cardiac patients has been developed that also assesses specific presentations of depression that may occur after a cardiovascular incident, including concern about health and recovery, feeling as if one is changed after their incident, fear or dread of impending health issues or dying, and loss of independence or function.13
The fact that a measure has been created for patients who have cardiac concerns shows that the presentation of depression may vary between patients and comorbidities. It is important to recognize symptoms of depression in patients even if they do not fit the criteria for diagnosis of MDD. It is not necessary for a patient to have MDD to be at risk for depressive symptoms contributing to CVD, as depressive symptoms in themselves have been correlated with adverse cardiac outcomes.14,15
Table 33.1 SCREENING MEASURES FOR DEPRESSION AND ANXIETY | ||||||||||||||
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From an etiological standpoint, studies have determined that patients with depression have twice the risk of developing new-onset CVD.16 Depression is also correlated with greater mortality in patients with a history of acute myocardial infarction (MI), with depressed patients having three times increased incidence of mortality post-MI than patients who are not depressed.16 These outcomes are not related only to the presence or absence of depression, as the 5-year mortality rate has been correlated with the severity of depression.17 Interestingly, MDD is noted as the second leading cause of disability in America, behind ischemic heart disease, which ranks number one,18 although arguably, these could be varying manifestations of related disease processes, which will be discussed in the pathophysiology section.
As depression exists on a continuum from normal emotion to pathology, with variations in clinical presentation, the etiology of depression is still being discovered with potential for differing mechanisms at work in each of the presenting criteria.19 Perhaps the most comprehensive integrative view is the biopsychosocial model of depression, which shows a multifactorial etiology including genetics,19 biochemistry, cognition, personality traits, environmental factors, trauma,20 and social interactions.21 Pathophysiological features of depression can include structural and functional brain changes as witnessed through neuroimaging studies,22,23 specifically showing reduction of dopamine network responses in the brain.22 Overall, MDD is thought to be due to deficiencies of dopamine, serotonin, and/or norepinephrine, which may occur concurrently or may lead into one another.24
Anxiety
Overlap Between Anxiety and Depression
When discussing anxiety and depression, it is difficult to draw a clear line where one ends and the other begins. There is a high level of comorbidity between depression and anxiety, even in their clinical forms of MDD and Generalized Anxiety Disorder (GAD). In fact, it has been hypothesized that MDD and GAD may be different presentations of the same disorder.25 Comorbidity rates between MDD and GAD range from 40% to 98%, with 67% of individuals with GAD reporting MDD at some point in their lives and 20% of individuals with MDD reporting GAD in the past.26 A common component between the disorders is that of general distress, yet uniquely differentiating components are that of excessive worry in GAD and anhedonia in MDD.26 In addition to common features, there also appears to be shared etiological factors, including similar genetics,27 and the trait of neuroticism that predisposes for both depression and anxiety.26 Appearance of comorbidity may also be due to overlap in the diagnostic criteria for disorders such as MDD and GAD.28 Regardless, both depression and anxiety have been shown to be correlated with CVD.
Defining Anxiety
As with depression, anxiety exists on a spectrum from that of a mental-emotional state, or a trait, to that of a psychological disorder.29 A state of anxiety is fleeting and is experienced as a momentary fear of a potential threat.30 This heightened emotional state can be a healthy part of the human experience, leading to motivation and vigilance when situationally necessary. Anxiety can also be in response to a positive event, manifesting as the stimulation of excitement. An individual with trait anxiety is predisposed to experience an anxious state of fear and/or apprehension about distant and potential threats as opposed to real ones.30 When this experience transcends into inappropriate situations and adopts a state of chronicity, anxiety can become a psychological disorder with an impact on daily functioning.
Anxiety Disorders as outlined in the DSM-5 include Separation Anxiety Disorder, Phobias, Social Anxiety Disorder, Panic Disorder, Agoraphobia, and Generalized Anxiety Disorder. The two disorders that have been the most extensively studied in conjunction with CVD are GAD and Panic Disorder (PD).8
Trait forms of anxiety may be screened in a clinical setting through use of self-report measures, which has primarily consisted of the Generalized Anxiety Disorder (GAD-7) questionnaire.31 However, recently, a combined measure called the Patient Health Questionnaire Anxiety and Depression Scale (PHQ-ADS) has been created to combine PHQ-9 and GAD-7 into one measure.32 Although the PHQ-ADS is still in its initial validation phase, it shows promise as an initial screening tool because of the overlap between anxiety and depression.
The etiology of anxiety appears to be multifactorial including inheritance, biological processes, and environmental risk factors. Some individuals with anxiety show genetic predisposition for dysregulation of serotonin33 and glutamic acid decarboxylase.34 Disturbances of neurotransmitters norepinephrine, serotonin, and gamma aminobutyric acid (GABA) have also been associated with GAD.22 Although there are widely varying experiences of anxiety that are reflected in the spectrum of state, trait, or disorder, functional magnetic resonance imaging data have shown similar neurological networks in the brain that are activated across all forms of anxiety.30 Areas of activation correspond with heightened amygdala responses and overall greater emotional responsiveness.35 Additional environmental risk factors associated with development of GAD include a greater incidence of trauma throughout life and adverse childhood events.36
Clinical presentation of anxiety may appear through emotional complaints that can be assessed through the above-mentioned DSM-5 criteria or GAD-7 assessment. However, anxiety may also present as physical symptoms such as sleep disturbance, fatigue, difficulty relaxing, muscle tension (especially in the neck, shoulders, and back), and recurrent headaches.37 It is important as a practitioner to keep anxiety in the differential diagnosis when these physical symptoms present.
Stress
Psychological stress is defined as a perceived tension or worry that impacts an individual’s behaviors and ability to traverse life events.38 In many ways, depression and anxiety are both manifestations of chronic stress and occur either as a result of the interplay of stress with the above-mentioned etiological factors or lead to a physiological state that simulates chronic stress in the body.38
Stressors
The term “stress” has also been used to describe stressors themselves, those things that one encounters that incite a stressful response. Humans exist in a context of a complex interplay of factors including internal environment, social environment, and physical environment. Stressors may exist in any of these arenas, thereby increasing the strain put on the body’s systems to come back to a point of balance, which has been termed “allostasis.”39 The concept of allostasis illustrates the way in which the body has an active regulatory process to maintain physiological balance and adapt to changing needs utilizing physiological responses such as hormones, temperature changes, and blood pressure.40 Therefore, it is possible to see that stressors have a direct impact on physiology through the body’s mechanisms to perceive these events, react, and then compensate in attempt to preserve balance. There are times when balance is unable to be achieved, and this is referred to as “allostatic load,” a state wherein the normal balancing processes are overtaxed or fail to act, leading to a lack of adaptation and dysregulation of the physiological systems that are in flux in response to stressors.41 These systems include the autonomic nervous system, hypothalamic-pituitary-adrenal (HPA) axis, sympathetic nervous system, and immune system.41
Stressors may be acute or chronic and may vary between individuals based on their perceptions of what is and is not stress. Acute stressors are encountered on a daily basis in small doses, such as having to complete tasks of daily living. They may also come in response to unexpected life changes in health, family, home, or livelihood. Acute stressors can negatively impact individuals, although chronic stressors appear to have a greater cumulative burden on the body’s ability to allostatically adjust. Chronic stressors have been shown to include low social support, low socioeconomic status, occupational stress, marital or relationship stress, and caregiver strain.15
Pathophysiology
As there is considerable overlap in the underlying processes of depression, anxiety, and stress, it makes sense that the mechanisms that correlate these emotional states/pathologies to CVD also share similarities. There is a twofold interaction between the mental-emotional states of depression, anxiety, and stress and the physical manifestation of CVD, including both biological and behavioral
mechanisms. Much of the literature regarding depression, anxiety, and chronic stress are unable to control for comorbidities, and thus mechanisms of interaction with the cardiovascular system appear to be mostly similar across these mental emotional states, although exceptions are elucidated in the following text.
mechanisms. Much of the literature regarding depression, anxiety, and chronic stress are unable to control for comorbidities, and thus mechanisms of interaction with the cardiovascular system appear to be mostly similar across these mental emotional states, although exceptions are elucidated in the following text.
Biological Mechanisms
INFLAMMATION
Inflammation is a complex process that involves the immune system’s response to potentially harmful stimuli, which triggers the signaling of various cytokines and chemokines to create a variety of protective responses within the body.42 However, when inflammatory processes are systemic, the attempt at homeostasis can lead to an increased risk of CVD. Inflammation is a common thread that appears to connect depression, anxiety, and CVD.
Various reviews have shown inflammation as a major underlying causal factor for depression,43,44 anxiety,45 and CVD.46 Xiong and colleagues found that patients with MDD and congestive heart failure (CHF) had statistically significant higher levels of inflammatory markers than patients without MDD and CHF. Elevated serum markers in depression included cytokines interleukin (IL)-1, IL-4, IL-6, IL-17, interferon (IFN)-gamma, macrophage inflammatory protein (MIP)-1, and tumor necrosis factor (TNF)-alpha.44 The Third National Health and Nutrition Examination Study had also revealed a higher serum C-reactive protein (CRP) in patients with MDD,47 a marker that is highly correlated with CVD risk.48 Elevated proinflammatory cytokines have also been found in patients with anxiety, as Godbout and Glaser38 found increased levels of IL-6 and CRP in patients who were experiencing chronic stress. Inflammatory cytokines have been found to increase autonomic imbalance, stimulate the sympathetic nervous system, cause electrical instability in the myocardium, depress cardiac function, lead to endothelial dysfunction, cause vasoconstriction, and generate atherosclerosis.46
Interestingly, Steenkamp and colleagues49 evaluated oxidative stress levels (measured by F2-isoprostanes and oxidized glutathione) in patients with MDD and found that the symptoms of anxiety that the patients experienced were more closely correlated with oxidative stress than the symptoms of depression. Oxidative stress negatively impacts cell membranes, proteins, nucleic acids, and lipids49 and has also been correlated with exacerbation of symptoms of anxiety and hypertension.45 This again shows the difficulty in disambiguating between the influence of anxiety and depression in pathogenesis of CVD, as outcomes may be symptom related as opposed to diagnosis related, and multidirectional.
PLATELET ACTIVATION
Increased inflammation may also be correlated with greater platelet activation that is found in depressed patients with CVD, leading to an increased risk of coronary artery occlusion.50 Depression has been associated with a hyperactive platelet 5-HT2A receptor signal transduction system, which leads to increased thrombosis.29 Pronounced platelet activation has been associated not only with depression but also chronic stress and anxiety symptoms.51
AUTONOMIC DYSFUNCTION
Depression and anxiety may also be correlated with CVD through their influence on altering autonomic vascular tone. This has been most directly studied through the concept of heart rate variability (HRV). HRV is a measurement of R-R intervals and the cyclic variation that reflects autonomic balance between sympathetic and parasympathetic nervous system activity.52 Autonomic nervous system imbalance comprising increased sympathetic nervous system activation with decreased vagal tone has been correlated with CVD and risk of adverse cardiac events,52 through such mechanisms as triggering atherosclerosis and/or platelet aggregation and leading to changes in lipid metabolism.53 Low HRV is related to poor cardiac outcomes and an increased risk of post-MI mortality54 and is correlated with sudden cardiac death even in those who have not been diagnosed with CVD.55 But what causes lower HRV? Mental emotional states have been shown to have a large impact on HRV, with lower HRV in patients with coronary artery disease who are depressed,54 as well as patients who present with anxiety.55
HPA AXIS DYSFUNCTION
Because HRV is a description of the sympathetic and parasympathetic nervous system balance, it is no surprise that we would see a connection between depression, anxiety, and the HPA axis. Various studies have shown increased levels of cortisol in individuals with both depression53,55,56 and anxiety,38 illustrating a correlation between HPA axis activation and emotional disorders.
Elevated cortisol leads to an increased risk of insulin resistance, central obesity, and hyperlipidemia, which are well known risk factors for CVD.29,53 Other catecholamines such as norepinephrine have also been shown to be increased in depression57,58 and chronic stress.51 Increased catecholamine levels have been found to cause damage to cardiac myocytes59 and lead to apoptosis of ventricular myocytes,60 thereby increasing the risk of adverse cardiac outcomes.57 Chronic HPA axis activation has been shown to decrease immune function and impact susceptibility to infection, as well as increase proinflammatory cytokines, feeding back into the inflammatory cycle.29
ENDOTHELIAL DYSFUNCTION
Endothelial dysfunction is the earliest indicator of vascular disease leading to atherosclerosis and adverse cardiac events including aneurysm, ischemia, and infarction. A study by van Sloten and colleagues61 illustrates a much greater level of endothelial dysfunction in elderly individuals with depression even after adjusting for those with CVD, whereas a study by Stillman and colleagues62 showed that anxiety decreased endothelial function and vascular smooth muscle function in individuals with atherosclerosis,
even in the absence of depression. Endothelial dysfunction caused by depression and anxiety may lead to even worse prognostic outcomes in CVD.
even in the absence of depression. Endothelial dysfunction caused by depression and anxiety may lead to even worse prognostic outcomes in CVD.
CARDIOVASCULAR REACTIVITY
On encountering stressors, the cardiovascular system has various compensatory mechanisms to increase perceived need. Anxiety and chronic stress have been hypothesized to increase cardiac reactivity resulting in alteration of cardiovascular mechanisms. For example, individuals with anxiety have increases in resting heart rate, dysfunction in the baroreflex, and variability in ventricular repolarization.29 All of these mechanisms increase the risk of cardiovascular events.
ACUTE EMOTIONAL EFFECTS
Although chronic depression, anxiety, and stress are shown to impact CVD through the various mechanisms described earlier, it is also possible for there to be acute effects in response to sudden emotional stress. Individuals with underlying coronary artery disease may experience adverse effects from hemodynamic stress including disrupting an atherosclerotic plaque that leads to thrombus,29 whereas another phenomenon that may occur in patients without known CVD is intense, sudden emotional stress triggering the onset of myocardial stunning.63,64 This phenomenon has been thought to be related to increased activation of the sympathoneural and adrenomedullary systems and has been termed acute myocardial stunning, left ventricular apical ballooning syndrome, takotsubo cardiomyopathy, or broken heart syndrome.64 An increase in cardiac events was seen following the terrorist attack on the World Trade Center on September 11, 2001. On the date of this event, intakes at the New York Methodist Hospital Telemetry and Coronary Care units reported significantly higher rates of acute MI (4.3% elevation) and tachyarrhythmia (6.3% elevation).65 Natural disasters such as earthquakes are associated with an increased incidence of MI and cardiac mortality. A review by Bazoukis and colleagues66 also demonstrated an increase in acute coronary syndrome after several large-scale earthquakes, including Christchurch, Great East Japan, Niigata-Chuetsu, Northridge, Great Hanshin-Awaji, Sichuan, Athens, Armenia, and Noto Peninsula.
Behavioral Mechanisms
Although there are known biological correlates between depression, anxiety, chronic stress, and CVD, these emotional states have many effects on behaviors. In depression, this occurs primarily through neglect of self-care and difficulty adhering to treatment protocols, including medication adherence and lifestyle recommendations. In a study performed by Ziegelstein and colleagues,67 within a hospital setting, patients who were found to have depression (spanning from mild depression to MDD or dysthymia) showed lower adherence to treatment protocols, including low-fat diet, exercise, stress reduction, and increasing social support. Additionally, those patients who had MDD took all prescribed medications less consistently.67
In patients with anxiety, there is also neglect of self-care, including tendencies toward lower physical activity and unhealthy eating.29 In depression, these behaviors are related to neglect and apathy, whereas in persons with anxiety they appear to be primarily due to avoidance of situations that cause worry.29 There are also additive behaviors of self-medication that serve as risk factors for CVD, such as cigarette smoking, excess alcohol consumption,68 and overeating.69
Prevention and Screening
In patients with known CVD, it is important to perform screenings for emotional disorders of depression, anxiety, and chronic stress. It is possible to utilize the self-report screening measures mentioned previously (Table 33.1) or work in collaboration with a mental health professional to determine patient risk. Although these measures may provide information regarding a patient’s emotional state, they can be impersonal, and owing to the stigma of mental health concerns, patients are not always forthcoming in this format. It is important to develop a positive relationship with the patient to facilitate trust and openness, while allowing the practitioner to attend to underlying emotional concerns.
Conversely, there is controversy regarding whether all patients with CVD should be screened for depression and anxiety, owing to potential for overdiagnosis and overtreatment in a clinical setting. It is debatable whether psychotherapy and pharmacotherapy for depression and anxiety help to mitigate CVD risk, and overtreatment may result in adverse cardiovascular side effects.70,71 It is therefore important to aim for prevention through integrative therapies, which are described in detail later.
Because the connections between depression, anxiety, chronic stress, and CVD are multidimensional and multidirectional, there are many treatment approaches that can be taken. We will begin by discussing the conventional mitigation of comorbid mental health disorders and CVD and then expand to discuss less invasive, integrative modalities to target the underlying factors that lead to these states.
Treatment
Conventional Treatment
For many patients with CVD, signs of depression and anxiety go unnoticed until after they have experienced a cardiac event. Therefore, mitigation of this comorbidity and interplay has been studied in hospital settings and specialized cardiology care. One method of treatment of depression and anxiety in CVD involves planned collaborative care, which includes screening for mental health disorders in cardiac patients, and subsequent provision of adjunctive care between cardiologists and mental health professionals or nurses.72,73 Several trials of this method have shown significant reductions in depression, as well as other cardiac risk factors (eg, low-density lipoprotein [LDL] cholesterol, blood pressure).72,73,74 Most of the studies done in this setting have
focused on depression as it is the most highly correlated with adverse cardiac outcomes, but very few have looked specifically at anxiety or chronic stress. There are potential barriers to screening anxiety in an acute care setting because many anxiety symptoms can be cardiac in nature, such as heart palpitations, tachycardia, and chest pressure.29 Some patients having panic attacks may also perceive that they are having a MI, as it is suspected that up to 25% of patients presenting to the emergency department for symptoms of MI may be experiencing a panic attack, although it is rarely diagnosed.75
focused on depression as it is the most highly correlated with adverse cardiac outcomes, but very few have looked specifically at anxiety or chronic stress. There are potential barriers to screening anxiety in an acute care setting because many anxiety symptoms can be cardiac in nature, such as heart palpitations, tachycardia, and chest pressure.29 Some patients having panic attacks may also perceive that they are having a MI, as it is suspected that up to 25% of patients presenting to the emergency department for symptoms of MI may be experiencing a panic attack, although it is rarely diagnosed.75
Conventional mental health treatment that is used in the collaborative care setting is a combination of psychotherapy and pharmacotherapy. Psychotherapy generally takes place in the form of Cognitive Behavioral Therapy (CBT) performed by a mental health professional, which focuses on identifying and altering thoughts and behaviors that lead to depression and/or anxiety,58 or Interpersonal Therapy, which involves identifying problematic social situations and developing increased social skills to mitigate depression or anxiety.76 Although these are considered safe and effective, there is a risk that symptoms may increase through increasing awareness of negative thoughts,58 but this form of therapy is still considered standard of care in the treatment of depression and anxiety and safe for those with comorbid CVD.
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