The goal of this activity is to understand the relationship between endothelial function and arterial stiffness.
Table 1. The psychocardiology concept
Table 2. Specific short- and long-term recommendations
Table 3. Designing a comprehensive treatment plan
Earn 30 free Category 1 CME Credits
Premiere Date: October 20, 2018
Expiration Date: April 20, 2020
This activity offers CE credits for:
1. Physicians (CME)
All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.
To goal of this activity is to understand the relationship between endothelial function and arterial stiffness.
At the end of this CE activity, participants should be able to:
• Identify tools to assess endothelial dysfunction
• Understand the sequelae of comorbid ischemic heart disease and depression
• Explain the concept of psychcardiology and its role in the diagnosis and management of heart disease/psychiatric illness
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.
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The epidemiological aspects of the high comorbidity between cardiovascular disease (CVD) and major depressive disorder (MDD) were reviewed in Part 1 of this CME article in the September issue. The focus was on mental stress as a likely common instigator underlying both CVD and MDD. The role of the autonomic nervous system not only in regulating heart function but also in modulating the body’s inflammatory response to physical and mental insults threatening the integrity and the homeostatic balance of body and mind was discussed.
In Part 2, the role of the endothelium in undergoing pathological changes that lead to atheromatosis and atherosclerosis with ensuing sequelae are discussed. Endothelial dysfunction can be assessed using blood tests and applanation tonometry, the latter being a non-invasive procedure that can be carried out in ambulatory settings. Finally, the concept of psychocardiology as an emerging integrated approach to diagnose and manage heart disease patients and psychiatric patients vulnerable to heart and/or cerebrovascular disease is examined. The suggested formation of multidisciplinary teams will go a long way toward improved outcomes and a reduction in morbidity and mortality.
Endothelial dysfunction and arterial stiffness
MDD, by virtue of its proinflammatory status, leads to endothelial dysfunction that ultimately can lead to arterial stiffness. Studies have related arterial stiffness to absolute 10- to 12-year risk of stroke, coronary heart disease, and death. In addition to markers of inflammation, markers of endothelial function can be assessed in peripheral blood. Circulating biomarkers of endothelial function, include e-selectin, p-selectin, soluble intercellular adhesion molecule-1 (s-ICAM1), endothelin-1, asymmetric dimethylarginine (ADMA), von Willebrand Factor (vWF), and vascular cell adhesion molecule-1 (VCAM-1). These markers have been measured in the blood of subjects with CVD as well as in psychiatric populations with mood and anxiety disorders.
Do and colleagues1 assessed hopelessness, depression, and select endothelial markers. They found high levels of hopelessness to be significantly associated with e-selectin, whereas high levels of hopelessness were significantly associated with s-ICAM1.
In a large population-based cohort study (N=852), depressive symptoms were assessed with the Patient Health Questionnaire-9 and (major and minor) depressive disorder with the Mini-International Neuropsychiatric Interview.2 Plasma biomarkers of inflammation (hsCRP, SAA, sICAM-1, IL-6, IL-8, TNF-Î±) and endothelial dysfunction (sVCAM-1, sICAM-1, sE-selectin, vWF) were measured with immunoassays and combined into two standardized sum scores. Biomarkers of inflammation (hsCRP, TNF-Î±, SAA, sICAM-1) and endothelial dysfunction (sICAM-1, sE-selectin) were univariately associated with depressive symptoms and depressive disorder. The researchers concluded that both inflammation and endothelial dysfunction are associated with depressive disorder, independent of lifestyle factors.
In a recent study, Celano and colleagues3 assessed psychological constructs in a cohort of post-acute coronary syndrome patients and measured markers of inflammation, endothelial function, and myocardial strain. They determined that depressive symptoms were associated with elevated inflammation, endothelial dysfunction, and myocardial strain. By contrast, positive psychological constructs, such as optimism and gratitude, were linked to better endothelial function.
The index of arterial stiffness with the greatest pathophysiological and clinical background is pulse wave velocity. The shape of the arterial pressure waveform provides a measure of systemic arterial stiffness and can be assessed noninvasively by using the technique of pulse wave analysis. As determined by pulse wave analysis, arterial stiffness has been shown to be an independent marker of cardiovascular risk.4 The approach has been successfully utilized to assess arterial stiffness in depression, aging, and coronary artery disease (CAD).5,6 Our unpublished data clearly indicate that arterial stiffness increases as a function of age in physically and mentally healthy men and women. However, in the presence of MDD, arterial stiffness is significantly increased with the highest values observed in postmenopausal women with MDD whether untreated or under treatment with an antidepressant medication.
Ischemic heart disease and depression
The association between depression-and likely other psychiatric disorders-and CVD is bidirectional, with both entities sharing common pathophysiology. A 2013 study of 45 young individuals at increased risk for depression provided evidence of an altered cardiovascular risk profile in young adulthood even without overt depressive symptoms. Such vulnerability may precede or follow the onset of depression and may share common risk factors.7
Following myocardial infarction (MI) the presence of depression has a cumulative effect on mortality. The Montreal Heart Study followed 222 post-MI hospitalized patients and found that the cumulative mortality rate for depressed patients post-MI was significantly higher than the rate for non-depressed patients, with the greatest effect occurring in the first 6 months.8 Premature ventricular contractions and elevated Beck Depression Inventory (BDI) scores were significantly related to mortality at 18 months.
The Montreal group also examined longer-term survival and measured BDI scores of 892 post-MI patients at admission and again at 1 year.9 They found a significant dose-response relationship between BDI scores and cardiac mortality, and these results remained significant even after controlling for multiple measures of cardiac disease severity. Patients with the highest initial BDI scores had the worst prognosis; an improvement in depressive symptoms lessened cardiac mortality only for patients with mild depression. The researchers concluded that the link between depression and cardiac mortality may be a relatively permanent marker for long-term survival.
Heart failure is a serious syndrome that, depending on severity, interferes with normal functioning, significantly impairs the capacity of an individual to lead a normal life, and may ultimately lead to death. Close to one million new cases of heart failure will occur in the US in 2018 and, as reported at the Annual Cardiovascular Conference in Snowmass, Colorado, most of them could have been prevented.
Before discussing preventive measures, what is our understanding of the pathophysiology of this syndrome? Several models have been proposed but inflammation remains at center stage. To quote from an earlier publication by Seta and colleagues,10 “heart failure progresses, at least in part, as a result of the toxic effects exerted by endogenous cytokine cascades on the heart and the peripheral circulation.” Animal and clinical data support the presence of an inflammatory cascade that is involved at least in the progression of heart failure.11
The main risk factors for the development of heart failure are ischemic heart disease and hypertension followed by diabetes, dyslipidemia, metabolic syndrome, obesity, alcoholism, and smoking. Atherosclerotic cardiovascular disease must be diagnosed early in the process to prevent serious sequelae. Diagnostic biomarkers including assessment of arterial stiffness may eventually be introduced into psychiatric practice since stress-related illness can lead to endothelial dysfunction as a preamble to atheromatosis and atherosclerosis.
Effective management of hypertension and dyslipidemia, including education of the patient, dietary counseling, and diabetes control, especially with administration of inhibitors of the sodium-glucose transporter, are huge steps toward the prevention of heart failure. The Framingham Heart Study concluded that obese individuals had double the risk of new-onset heart failure, compared with those who were of normal weight.12 Obesity must be addressed in primary care, general medicine, cardiology, and psychiatric practices.
Psychological interventions can be effective, especially if combined with nutritional counseling and regular follow-ups. Smoking must be addressed in most all practices independent of specialty or subspecialty area. Pharmacological and psychological interventions, preferably in combination, can be quite effective in enabling permanent smoking cessation. The administration of psychotropic compounds that are known to cause weight gain and metabolic syndrome must be avoided especially since newer agents are available that do not have such an adverse effect on the organism.
Lifestyle modification with expert counseling as part of general and/or psychiatric practice can go a long way toward preventing ischemic heart disease and associated consequences. Key lifestyle factors include maintaining a normal body weight, regular exercise, smoking cessation, drinking in moderation, and a healthy diet made up primarily of vegetables and fruit.
Chest pain is a common presenting complaint in a cardiology clinic and can have numerous etiologies beyond heart disease. It is a common and potentially complex patient complaint, amounting to more than 6 million cases in the US annually. After extensive and costly evaluations, many patients receive a diagnosis of non-cardiac chest pain (NCCP). Approximately 30% of all coronary angiograms prove to be negative for significant coronary artery disease CAD, thus patients receive a diagnosis of NCCP.
Unexplained chest pain is often comorbid with anxiety, depression, and somatoform disorders. In a recent study, the comorbidity of psychiatric conditions and NCCP was examined prospectively in a cohort of 231 NCCP patients free of a current or lifetime cardiac diagnosis.13 The findings indicate that 44% of the NCCP patients suffered from a current Axis I psychiatric diagnosis; anxiety disorders (41%) and mood disorders (13%) were the most prevalent. Patients with NCCP may also have exaggerated or abnormal cardiac pain perceptions, visceral hyperalgesia, and/or abnormal cardiac sensitivity to a variety of stimuli.
Treatment of NCCP includes psychotherapy and psychotropic medications, such as antidepressant and antianxiety drugs. (For additional information, the interested reader is referred to a recently published review article on this topic.14)
The psychocardiology concept
The relationship between certain psychiatric disorders and CVD/cerebrovascular disease (CBVD) is complex. To address these issues, multidisciplinary teams of specialists in cardiology, psychiatry, and psychology as well as established researchers with diverse expertise in basic laboratory, clinical, and cardiodiagnostic methods are needed. Such integrated teams with the requisite expertise have recently begun to work collaboratively, but more needs to be done. Only through cohesive interactions of such multidisciplinary teams can we succeed in unraveling the complex relationships between mental stress, inflammation, immune responses, and psychiatric disorders and CVD/CBVD.
A number of collaborative care treatment programs have been formed that focus on the management of depression and anxiety disorders in patients with CVD as well as other conditions such as diabetes and cancer. The National Institutes of Health funded the Bypassing the Blues (BtB) study, the first trial to examine the impact of a collaborative care strategy for treating depression in patients with cardiac disease.15-17
Another relevant multicenter clinical trial is the Comparison of Depression Interventions after Acute Coronary Syndrome (CODIACS) randomized controlled trial. Results from this ambitious study demonstrated that for patients with post-acute coronary syndrome depression, active treatment had a significant beneficial effect on depressive symptoms. The researchers concluded that this kind of depression care is feasible, effective, and is likely to be cost-neutral, therefore it should be tested in a large phase 3 pragmatic trial.18,19
Last but certainly not least, TEAMcare is a highly successful model of practice-based interventions that address concomitant depression and chronic medical conditions in the primary care setting. These and others are notable examples of successful programs based on the psychocardiology concept.20-23
The psychocardiology concept would promote recognition of the high comorbidity between psychiatric disorders and CVD/CBVD and lead to more effective treatment approaches. A close interaction between the two specialties will lead to improved diagnostic and prognostic assessments, and significantly reduce patient suffering and health care costs.24
Such a concept could lead to the formation of teams of clinicians and researchers who would provide patient assessment and management and pursue multidisciplinary research. Designing and implementing training modules that focus on psychocardiology in psychiatric and internal medicine residency programs would be an excellent start. A formal subspecialty with fellowship training and board certification might follow after the successful implementation of pilot programs (Table 1).
Adoption and implementation of the psychocardiology concept will be a process over many years. The short- and long-term goals that private and hospital-based cardiology and psychiatry practices might consider are outlined in Table 2. The recommendations in Table 3 lend themselves to implementation as part of “Good Clinical Practice” regardless of whether a formal psychocardiology team has been assembled.
CVD and psychiatric disease (notably mood and anxiety disorders) comorbidity is highly prevalent and poses major and urgent challenges. Stress plays a critical role in the generation and progression of both disease entities. To address the complex factors that underlie the comorbidity, the concept of psychocardiology is proposed, which will lead to multidisciplinary teams who could be sponsored jointly by cardiology and psychiatry services/departments.
Many of the short-term recommendations can be implemented right away, while longer-term goals will have to wait for additional research and validation. To that end, federal and private funding for the establishment of pilot programs would be a highly desirable first step to prove the validity of the psychocardiology concept and the utility of the proposed tests and procedures for introduction into practice.
PLEASE NOTE THAT THE POST-TEST IS AVAILABLE ONLINE ONLY ON THE 20TH OF THE MONTH OF ACTIVITY ISSUE AND FOR 18 MONTHS AFTER.
Dr Halaris is Professor of Psychiatry and Behavioral Neuroscience, Loyola University Stritch School of Medicine, Loyola University Medical Center, Maywood, IL.
1. Do DP, Dowd JB, Ranjit N, et al. Hopelessness, depression, and early markers of endothelial dysfunction in US adults. Psychosom Med. 2010;72:613-619.
2. van Dooren FE, Schram MT, Schalkwijk CG, et al. Associations of low grade inflammation and endothelial dysfunction with depression: The Maastricht Study. Brain Behav Immun. 2016;56:390-396.
3. Celano CM, Beale EE, Beach SR, et al. Associations between psychological constructs and cardiac biomarkers after acute coronary syndrome. Psychosom Med. 2017;79:318-326.
4. Hayward CS, Kraidly M, Webb CM, et al. Assessment of endothelial function using peripheral waveform analysis: a clinical application. J Am Coll Cardiol. 2002;40:521-528.
5. I-Mei Lin, Hsueh-Chen Lu, Chih-Sheng Chu, et al. The relationship between brachial-ankle pulse wave velocity and depressive symptoms among patients with coronary artery disease. Acta Cardiol Sin. 2017;33:303-309.
6. Rybakowski JK, Wykretowicz A, Heymann-Szlachcinska A, et al. Impairment of endothelial function in unipolar and bipolar depression. Biol Psychiatry. 2006;60:889-891.
7. Mannie ZN, Williams C, Diesch J, et al. Cardiovascular and metabolic risk profile in young people at familial risk of depression. Br J Psychiatry. 2013;203:18-23.
8. Frasure-Smith N, Lesperance F, Gravel G, et al. Social support, depression, and mortality during the first year after myocardial infarction. Circulation. 2000;101:1919-1924.
9. Lesperance F, Frasure-Smith N, Talajic M et al. Five-year risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction. Circulation. 2002;105:1049-1053.
10. Seta Y, Shan K, Bozkurt B et al: Basic mechanisms in heart failure: the cytokine hypothesis. J Card Fail. 1996;2:243-249.
11. Petersen JW, Felker M. Inflammatory biomarkers in heart failure. Congest Heart Fail. 2006;12:324-328.
12. Kenchaiah S, Evans JC, Levy D. Obesity and the risk of heart failure. N Engl J Med. 2002;347:305-313.
13. White KS, Raffa SD, Jakle KR, et al. Morbidity of DSM-IV Axis I disorders in patients with noncardiac chest pain: psychiatric morbidity linked with increased pain and health care utilization. J Consult Clin Psychol. 2008;76:422-430.
14. Meresh E, Piletz J, Halaris A. Noncardiac chest pain: systematic review of the literature on prognosis. Res Rep Clin Cardiol. 2018;9:1-9.
15. Rollman BL, Belnap BH, LeMenager MS, et al. The Bypassing the Blues treatment protocol: stepped collaborative care for treating post-CABG depression. Psychosom Med. 2009;71:217-30.
16. Rollman BL, Belnap BH. The Bypassing the Blues trial: collaborative care for post-CABG depression and implications for future research. Cleve Clin J Med. 2011;78(Suppl 1): S4-12.
17. Meyer T, Belnap BH, Herrmann-Lingen C et al. Benefits of collaborative care for post-CABG depression are not related to adjustments in antidepressant pharmacotherapy. J Psychosom Res. 2014;76:28-33.
18. Whang W, Burg MM, Carney RM, et al. Design and baseline data from the vanguard of the Comparison of Depression Interventions after Acute Coronary Syndrome (CODIACS) randomized controlled trial. Contemp Clin Trials. 2012;33:1003-1010.
19. Davidson KW, Bigger JT, Burg MM et al. Centralized, stepped, patient preference-based treatment for patients with post-acute coronary syndrome depression: CODIACS vanguard randomized controlled trial. JAMA Intern Med. 2013;173:997-1004.
20. McGregor M, Lin EHB, Katon WJ. Teamcare: an integrated multicondition collaborative care program for chronic illnesses and depression. Ambul Care Manage. 2011;34:152-162.
21. Katon W, Lin EH, Von Korff M, et al. Integrating depression and chronic disease care among patients with diabetes and/or coronary heart disease: the design of the TEAMcare study. Contemp Clin Trials. 2010;31:312-22.
22. Lin EH, Von Korff M, Ciechanowski P, et al. Treatment adjustment and medication adherence for complex patients with diabetes, heart disease, and depression: a randomized controlled trial. Ann Fam Med. 2012;10:6-14.
23. Rosenberg D, Lin E, Peterson D, et al. Integrated medical care management and behavioral risk factor reduction for multicondition patients: behavioral outcomes of the TEAMcare trial. Gen Hosp Psychiatry. 2014;36:129-34.