Psychocardiology: Understanding the Heart-Brain Connection: Part 1

September 20, 2018

To goal of this activity is to understand the bidirectional relationship between depression and cardiovascular disease.

Premiere Date: September 20, 2018
Expiration Date: March 20, 2020

This activity offers CE credits for:

1. Physicians (CME)
2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

ACTIVITY GOAL

To goal of this activity is to understand the bidirectional relationship between depression and cardiovascular disease.

LEARNING OBJECTIVES

At the end of this CE activity, participants should be able to:

• Explain the reasons for the high comorbidity between depression and cardiovascular disease

• Understand the role of the autonomic nervous system in regulating heart function

• Assess autonomic nervous system activity through measurement of heart rate variability

TARGET AUDIENCE

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

CREDIT INFORMATION

CME Credit (Physicians): This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of CME Outfitters, LLC, and Psychiatric Times. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

CME Outfitters designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note to Nurse Practitioners and Physician Assistants: AANPCP and AAPA accept certificates of participation for educational activities certified for AMA PRA Category 1 Credit™.

DISCLOSURE DECLARATION

It is the policy of CME Outfitters, LLC, to ensure independence, balance, objectivity, and scientific rigor and integrity in all of their CME/CE activities. Faculty must disclose to the participants any relationships with commercial companies whose products or devices may be mentioned in faculty presentations, or with the commercial supporter of this CME/CE activity. CME Outfitters, LLC, has evaluated, identified, and attempted to resolve any potential conflicts of interest through a rigorous content validation procedure, use of evidence-based data/research, and a multidisciplinary peer-review process.

The following information is for participant information only. It is not assumed that these relationships will have a negative impact on the presentations.

Angelos Halaris, MD, has no conflicts to report.

Ebrahim Haroon, MD (peer/content reviewer), reports that he receives funding from the NIH.

Applicable Psychiatric Times staff and CME Outfitters staff, have no disclosures to report.

UNLABELED USE DISCLOSURE

Faculty of this CME/CE activity may include discussion of products or devices that are not currently labeled for use by the FDA. The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational uses (any uses not approved by the FDA) of products or devices. CME Outfitters, LLC, and the faculty do not endorse the use of any product outside of the FDA-labeled indications. Medical professionals should not utilize the procedures, products, or diagnosis techniques discussed during this activity without evaluation of their patient for contraindications or dangers of use.

For content-related questions, email us at editor@psychiatrictimes.com; for questions concerning CME credit – Call us at 877.CME.PROS (877.263.7767)

Every affection of the mind that is attended with either pain or pleasure, hope or fear, is the cause of an agitation whose influence extends to the heart.
   William Harvey1

Heart-brain interactions have been known to mankind since Hippocratic times and written about extensively in the medical and nonmedical literature over the centuries. The epigraph by the 17th century physician holds great validity and urgency in the present day. Heart-brain interactions are now recognized to be complex and multifaceted, and to engulf several functions and systems of the body. At least in certain conditions, as will be described below, they appear to be bidirectional. The consequences of heart-brain dysfunction can lead to pathological manifestations involving many organ systems, with dire consequences.

There is evidence that cardiovascular disease (CVD) and psychiatric disorders are far more closely interrelated than had been assumed. Moreover, findings indicate that CVD and psychiatric disorders, notably depressive and anxiety disorders, have a bidirectional relationship. A common pathophysiological link underlying this comorbidity is mental stress and stress susceptibility that is confounded by genetic and epigenetic factors, psychosocial and environmental influences, and lifestyle choices. In recognition of the multifactorial complexity underlying these high rates of comorbidity and associated patient needs for management and recovery, the term “psychocardiology” was coined.

In Part 1 of this 2-part CME article, the following topics are discussed: key epidemiological data to illustrate the high comorbidity between CVD and depression, mental stress as a common instigator behind the comorbidity, and the autonomic nervous system. In Part 2, the following will be discussed: the concept of endothelial dysfunction as a preamble to atheromatosis and atherosclerosis; depression in association with myocardial infarction; the role of inflammation in heart disease and heart failure as well as non-cardiac chest pain.

Epidemiology

CVD and depression are two of the world’s leading health problems. CVD is the leading cause of mortality worldwide and accounts for approximately 16.7 million deaths every year.2 The most common types of CVD are coronary artery disease and cerebrovascular disease.

It has been estimated that CVD is responsible for close to 1 million deaths and more than six million hospital admissions with an annual cost to the US economy in excess of $350 billion.3 In the US, major depressive disorder (MDD) afflicts approximately 17 million people annually with a direct and indirect cost to the nation exceeding $50 billion in today’s dollar estimates.4

The incidence of MDD has been steadily increasing over the past decades. Using the Disability Adjusted Life-Years measure, MDD was classed as the fourth leading burden of disease worldwide for both sexes in 1990. By 2004, it advanced to third place, and according to the World Health Organization’s estimate, will rank second to CVD by the year 2020 and will be the leading cause of disease burden by 2030.

Numerous studies published over the past two decades have confirmed the bidirectional association between CVD and depression. In a meta-analysis, clinical depression was identified as a significant risk factor for mortality in patients with coronary heart disease.5 The Multiple Risk Factor Intervention Trial (MRFIT) of middle-aged men established an association between depressive symptoms and all-cause mortality with a higher risk of CVD-related death and more specifically stroke mortality.6

 

Mental stress and its consequences

Mental stress can produce profound alterations in the physiology and chemistry of the CNS and the autonomic nervous system, peripheral organs, and the endocrine, vascular, and immune systems. The perception of mental stress is subject to high individual variability and vulnerability, which is based, in part, on genetically determined and epigenetically modified stress susceptibility and stress resilience. Chronic and inescapable stress ultimately lead to pervasive mental status changes and pathological alterations to the cardiovascular system that may lead to irreversible tissue and organ damage.

The autonomic nervous system and heart rate variability

In addition to activating the hypothalamic-pituitary-adrenal axis (HPA), stress activates the sympathetic branch of the autonomic nervous system. This activation leads to a reduction in vagal tone that can have consequences in the body’s immune responses. The imbalance in autonomic nervous system function, especially if prolonged, has profound effects on cardiovascular physiology and the immune system. These pathophysiological changes contribute significantly to the comorbidity between CVD and psychiatric disorders. Thus, the autonomic imbalance and decreased parasympathetic activity may be the final common pathway to numerous diseases and conditions associated with increased morbidity and mortality.7

Psychophysiological consequences of stress include sympathoadrenal hyperactivity, with a concomitant decrease in vagal tone, increases in plasma catecholamines, vasoconstriction, elevated heart rate, and platelet activation. The Heart and Soul Study clearly established that in patients with coronary artery disease, depressive symptoms are associated with elevated levels of norepinephrine.8 These changes, singly and additively, exert adverse effects on the cardiovascular system. Elevated and sustained catecholaminergic action on the heart, blood vessels, and platelets leads to changes in hemodynamic factors with increased shear stress. The decrease in parasympathetic tone may predispose to ventricular arrhythmias and possibly explain the excessive cardiovascular mortality found in patients with CVD and comorbid depression.

Heart rate variability (HRV) is an index of a healthy heart and good cardiac function with the ability to adapt to external and internal stressful demands. Diminished high-frequency HRV reflects decreased parasympathetic tone and has been observed at least in some depressed patients. The results of a large cohort study demonstrated that depressed patients, when compared with healthy controls, have significantly both lower total HRV and lower HRV in the respiratory frequency range.9 These findings are compatible with theoretical models, notably the polyvagal theory coined by Porges.10 These models have linked the parasympathetic system to the etiopathology of depression based on the premise that low vagal tone is associated with reduced social engagement and an impaired response to environmental stimuli and challenges.

Heart rate variability can also be significantly decreased in severe coronary artery disease or heart failure. The risk of sudden death after acute myocardial infarction is significantly higher with decreased HRV. Indeed, HRV is a post-myocardial infarction prognostic factor (along with age, left-ventricular ejection fraction, frequency of arrhythmia). In patients with coronary artery disease, diminished HRV is far more common in depressed patients.11

Our group has recently published studies in which we included HRV measurements along with inflammation biomarkers and relevant rating instruments before and after pharmacological treatment of unipolar or bipolar depressed patients.12,13 We also addressed methodological issues such as duration of ECG monitoring and recording and corrections for respiratory and muscular artifacts. We are encouraged by our findings, which confirm in large part and expand on previously published studies of HRV in psychiatric cohorts. Taken together, with further research and methodological refinements, HRV measurements could be introduced into the diagnostic and prognostic armamentarium for the evaluation and management of stress-related disorders, notably depression and comorbid heart disease.

It is now possible to obtain accurate readings after short ECG tracings obviating the need for time intensive Holter monitors. The raw data must be subjected to correction of tracing artifacts by means of commercially available software programs. For the rationale of conducting such measurements and detailed description of data processing, the reader is referred to our recently published work. It is also noteworthy and of potential clinical significance that administration of therapeutic compounds with anticholinergic activity as part of their pharmacologic profile may exert unwanted and possibly deleterious effects over prolonged exposure to such agents.

The role of inflammation

The autonomic nervous system is involved in exerting regulatory input to the immune system. Simultaneous and sustained reduction in parasympathetic tone due to illness chronicity, recurrence, and severity may lead to disinhibition of the body’s inflammatory response as the immune system becomes overactive. Vagal nerve efferent inputs that regulate inflammation via the cholinergic anti-inflammatory pathway are well documented and measurements of inflammatory biomarkers in mood disorders can differentiate at least some of these patients from healthy subjects.14,15

Amongst the various pathophysiological processes that have been identified as playing major contributory roles to the comorbidity between CVD and depression is inflammation. The inflammatory response aims to restore homeostasis and health; however, inflammation can persist and expand, both centrally and peripherally, especially in instances of chronic physical or mental illnesses that perpetuate the stressful condition. The relationship between stressful events and the onset of inflammation-related diseases, notably cardiovascular, neurological, and immunological, has been documented in the literature. A growing body of evidence has also identified inflammatory events associated with affective, anxiety, and psychotic disorders.

Evidence for a connection between mood disturbances and the immune system dates back more than two decades, and the connection continues to be studied.16 Activation of inflammatory processes as a common link between depression and CVD has received increased attention. Proinflammatory cytokines have been implicated in the pathogenesis of atherosclerosis and CVD.17,18 Endothelial damage leads to the release of pro-inflammatory cytokines that induce a sequence of events leading ultimately to thrombus formation and vascular occlusion.

Inflammation is a major contributing causal factor to depression and has been thought to play a major role in endothelial damage of the cerebral vasculature. This has led to the designation of “vascular depression” that presents with many of the typical symptoms of depression. Interleukin-6 (IL-6), secreted in response to stress, is one of the most potent stimulators of the HPA axis and induces the release of other pro-inflammatory cytokines. It is postulated that depression is a disease of inflammation in response to chronic psychological stress.19

Cardiovascular pathology and inflammation

Inflammation plays a major role in the development of atherosclerosis and atherothrombosis with the associated clinical sequelae that lead to high morbidity and mortality. Immune-competent cells are involved both in the early stages of atherosclerosis and the subsequent events leading to plaque formation and rupture and the ensuing acute coronary syndromes.20

During the past two decades, circulating compounds have been identified as markers of inflammation and atherosclerosis. These compounds include acute phase proteins, C-reactive protein (CRP), fibrinogen, immunoglobulins, adhesion molecules, and cytokines. Most of these biomarkers have also been shown to be abnormally regulated in many, but not all, patients with depressive syndromes without any evidence of other inflammatory processes, cardiovascular, or immune system pathology. Fibrinogen, CRP, tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and IL-6 have been discussed extensively in the cardiovascular literature. Indeed, a case has been made that CRP and depression have prognostic value in predicting adverse cardiac events.21 The literature is replete with findings that indicate persisting CVD vulnerability after full recovery from a depressive episode, although there appears to be a time lag between mood improvement and immune marker normalization. However, the role of CRP in mediating inflammatory response and whether elevated blood levels in depression or CVD should always be considered a risk factor must be reexamined in view of findings that there is a pentameric and a monomeric CRP with the latter posing a toxic threat.

Focusing on CRP

A growing field of research involves CRP levels posttreatment with antidepressants. Several studies have sought to answer whether CRP levels change with various MDD treatments. Pizzi and colleagues22 randomized patients with coronary heart disease and MDD to receive sertraline or placebo for 20 weeks. At 20 weeks, levels of CRP decreased significantly from baseline with sertraline treatment, whereas they did not significantly change in the placebo group. Moreover, patients treated with sertraline demonstrated a decrease in depressive symptoms with a lower Beck Depression Inventory score.

Similar results were obtained from a meta-analysis conducted by Hiles and colleagues.23 The researchers considered various antidepressant treatment studies in patients with MDD that measured CRP, IL-10, and IL-6 at baseline and posttreatment. The results showed that treatment with antidepressants resulted in a significant reduction in CRP levels with the most notable reductions obtained after treatment with TCAs. As CRP levels decreased there was an accompanying reduction in depressive symptoms. While these co-occurring reductions may be correlated, it is not clear whether a reduction in CRP is indicative of response to treatment.

Chavda and colleagues24 treated patients with 20-mg fluoxetine or 20-mg escitalopram daily for two months. The results showed a significant decrease in CRP levels from baseline with both fluoxetine and escitalopram. However, unlike the results of other studies, the decrease in CRP was independent of the medication effects on depression symptoms. As indicated by the Hamilton Depression Rating Scale for depression, there was no notable response.

Findings from the three studies suggest that antidepressants can exert an anti-inflammatory effect as evidenced by a reduction in CRP levels. Whether this reduction in CRP is related to a reduction in depressive symptoms remains unclear. (For further discussion of this issue, the reader is referred to Halaris.25)

CRP isomers

CRP polymorphisms help explain variations in CRP levels at the gene level, but differences in CRP also exist in the structure of the protein itself. CRP is present in two different forms: the pentameric (pCRP) and the monomeric (mCRP) isomer. These isomers are structurally unique from one another. CRP is believed to circulate as a pentamer in plasma, while mCRP is known to have limited solubility. Recently, it has been recognized that mCRP and pCRP have different biological activities, which raises questions about the role of each isomer in the inflammatory process. The differing biological activities of mCRP and pCRP may help explain the discrepancies in reported findings. Clearly more research focused on elucidating these issues must be completed before routine measurements of CRP in psychiatric patients can be justified.

 

CME POST-TEST

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Disclosures:

Dr Halaris is Professor of Psychiatry and Behavioral Neuroscience, Loyola University Stritch School of Medicine, Loyola University Medical Center, Maywood, IL.

References:

1. Harvey W. The circulation of the blood is further confirmed by probably reasons. On the Motion of the Heart and Blood in Animals. March 2016. https://ebooks.adelaide.edu.au/h/harvey/william/motion/chapter15.html. Accessed August 1, 2018.

2. Waldman SA, Terzic A. Cardiovascular health: the global challenge. Clin Pharmacol Ther. 2011;90:483-485.

3. American Heart Association: Heart Disease and Stroke Statistics: 2004 Update. Dallas, TX: American Heart Association; 2004.

4. Demyttenaere K, Bruffaerts R, Posada-Villa J, et al. Prevalence, severity, and unmet need for treatment of mental disorders in the World Health Organization World Mental Health surveys. JAMA. 2004;291:2581-2590.

5. Barth J, Schumacher M, Herrmann-Lingen C. Depression as a risk factor for mortality in patients with coronary heart disease: a meta-analysis. Psychosom Med. 2004;66:802-813.

6. Gump BB, Matthews KA, Eberly LE, Chang YF, for the MRFIT Research Group. Depressive symptoms and mortality in men: results from multiple risk factor intervention trial. Stroke. 2005;36:98-102.

7. Thayer JF, Lane RD. The role of vagal function in the risk for cardiovascular disease and mortality. Biol Psychol. 2007;74:224-242.

8. Otte C, Neylan TC, Pipkin SS, et al. Depressive symptoms and 24-hour urinary norepinephrine excretion levels in patients with coronary disease: findings from the Heart and Soul Study. Am J Psychiatry. 2005;162:2139-2145.

9. Licht CM, de Geus EJC, Zitman FG, et al. Association between major depressive disorder and heart rate variability in the Netherlands Study of Depression and Anxiety (NESDA). Arch Gen Psychiatry. 2008;65:1358-1367.

10. Porges SW. Cardiac vagal tone; a physiological index of stress. Neurosci Biobehav Rev. 1995;19:225-233.

11. Kop WJ, Stein PK, Tracy RP, et al. Autonomic nervous system dysfunction and inflammation contribute to the increased cardiovascular mortality risk associated with expression. Psychosom Med. 2010;72:626-635.

12. Hage B, Britton B, Daniels D, et al. Low cardiac vagal tone index by heart rate variability differentiates bipolar from major depression. World J Biol Psychiat. October 2017;1-9.

13. Hage B, Britton B, Daniels D, et al. Heart Rate Variability predicts treatment outcome in major depression. J Psychiat Brain Sci. 2017;2:1-13.

14. Pavlov V, Tracey K. The cholinergic anti-inflammatory pathway. Brain Behav Immun. 2009;19:493-499.

15. Halaris A. Myint A-M, Savant V et al. 2015. Does escitalopram reduce neurotoxicity in major depression? J Psychiat Res. 2015;66-67:118-126.

16. Wichers M, Maes M. The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. Int J Neuropsychopharmacol. 2002;5:375-388.

17. Koenig W. Inflammation and coronary heart disease: an overview. Cardiol Rev. 2001;9:31-35.

18. Mulvihill NT, Foley JB. Inflammation in acute coronary syndromes. Heart. 2002;87:201-204.

19. Connor TJ, Leonard BE. Depression, stress and immunological activation: the role of cytokines in depressive disorders. Life Sci. 1998;62:583-606.

20. Lind L. Circulating markers of inflammation and atherosclerosis. Atheroscler. 2003;169:203-214.

21. Frasure-Smith N, Lespérance F, Irwin MR, et al. Depression, C-reactive protein and two-year major adverse cardiac events in men after acute coronary syndromes. Biol Psychiat. 2007;62:302-308.

22. Pizzi C, Mancini S, Angeloni L, et al. Effects of selective serotonin reuptake inhibitor therapy on endothelial function and inflammatory markers in patients with coronary heart disease. Clin Pharmacol Therap. 2009;86:527-532.

23. Hiles SA, Baker A, de Malmanche T, et al. Interleukin-6, C-reactive protein and interleukin-10 after antidepressant treatment in people with depression: a meta-analysis. Psychol Med. 2012;42:2015-2026.

24. Chavda N, Kantharia ND, Jaykaran. Effects of fluoxetine and escitalopram on C-reactive protein in patients of depression. J Pharmacol Pharmacother. 2011;2:11-16.

25. Halaris A. Do antidepressants exert effects on the immune system? In: Mueller N, Myint A-M, Schwarz MJ, Eds. Immunology and Psychiatry, Current Topics in Neurotoxicity. Berlin: Springer Verlag; 2015:339-350.

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