Ginela Dela Cruz: Major Depressive Disorder and Heart Disease (MDPU)

Ginela Dela Cruz: Major Depressive Disorder and Heart Disease (MDPU)

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Ginela Dela Cruz is currently studying Neuroscience and Psychology at the University of Toronto. She is especially interested in mood disorders, complementary alternative medicine therapy, and knowledge translation. Here is her submission:

Major Depressive Disorder (MDD) is increasingly being recognized as a significant risk factor for heart disease.  For example, a recent study reported that a clinical diagnosis of MDD is a greater risk factor for coronary heart disease (CHD) compared to second hand smoke. Patients with MDD were also observed to be at significantly greater risk of dying from ischemic heart disease than their healthy counterparts.(1) Likewise; depression has also been associated with ventricular tachycardia, which usually foreshadows ventricular fibrillation and sudden cardiac death.  Even after controlling for poor health behaviours associated with MDD (e.g., poor diet or lack of exercise), studies continue to report increased risks of CHD and myocardial infarction (MI).(2)

It has been reported that psychological stress induces aggregation of adhesion cells to sites of endothelial injury, granting leukocytes access to the arterial wall.  This promotes inflammation and clot formation, which lead to narrowing of the arteries. The risk of individuals with MDD developing atherosclerotic thrombi may be attributable to this mechanism.(3)  Atherosclerosis- also known as CHD, is a disorder characterized by the formation of plaques made of cholesterol and other substances in the walls of the arteries, resulting in artery narrowing.  Atherosclerosis may develop gradually over time and present in the form of mild to severe chest pain- angina pectoris.  Plaques can rupture and trigger a coagulation cascade resulting in clotting, or thrombosis, which can result in a stroke or MI. This is because arterial constriction leads to decreased blood flow and consequently, tissue (heart) damage.(4) Inflammatory markers such as acute phase proteins (eg., C-reactive protein) are usually elevated in patients with MDD.  High levels of inflammatory agents, as well as glucocorticoids (GCs) (which are pro-inflammatory in the context of chronic stress), may thus create an internal environment in patients with MDD that is especially susceptible and conducive to cardiovascular conditions such as atherosclerosis and ischemic heart disease.(5)

In the hypothalamic-pituitary-adrenal (HPA) system, corticotropin-releasing hormone (CRH) is released from the hypothalamus into the portal venous system and acts on the adenohypophysis, or the anterior pituitary gland.  Adrenocorticotropin hormone (ACTH) is subsequently produced from its precursor, proopiomelanocortin (POMC), and acts on the adrenal cortex.  This results in the synthesis and secretion of glucocorticoids (GCs), such as cortisol.  Adrenocorticotropin hormone works with arginine vasopressin, released by the posterior pituitary gland recruited by the parvocellular cells in the thalamus, to elevate GC concentrations.  Glucocorticoids inhibit both the hypothalamus and the pituitary from releasing their respective hormones, thereby serving as a negative feedback control on the HPA system.  However, persistent corticosteroid (both GC and vasopressin) secretion may lead to damage to the hippocampus, which is a critical structure in the down-regulation of corticosteroids.  Consequently, excessive levels of GCs remain in the circulatory system, generating a pro-inflammatory environment and promoting the expression of IL-1β and TNF-α (cytokines involved in inflammation) in the context of chronic stress. (3)

The HPA system, however, is only one factor contributing to the breakdown of homeostatic stress regulation.  Hypothalamic CRH not only acts on the hypophsis, but on the locus coeruleus neurons in the brainstem as well, causing the release of norepinephrine (NE) throughout the central nervous system.  Additionally, stress triggers the release of epinephrine in the periphery, from chromaffin cells of the adrenal medulla.(3)  Taken together, these catecholamines effect the sympathetic nervous system (SNS) by increasing heart rate and blood pressure.

Elevated catecholamine levels (indicative of an overactive SNS) have been suggested to contribute to atherosclerosis by acting agonistically to platelets, acting as procoagulant agents.  Previous studies have reported elevated plasma and urinary catecholamine levels- specifically NE, in patients with MDD who are otherwise healthy.  This indicates either an increase in NE release (sympathetic activity) or a decrease in NE clearance (parasympathetic or vagal activity).In patients with MDD, an inability to “turn off” the SNS (as seen, for example, in behaviours such as rumination) may contribute to the disequilibrium of the autonomic system (the SNS and PNS).(5)  However, plasma and/or urinary NE concentrations are an insufficient proxy for autonomic functioning.  A more accurate evaluation of autonomic functioning is achieved through heart rate variability (HRV). Heart rate variability, which is calculated to represent the fluctuation in the heart’s rhythm on a beat by beat basis (i.e., between consecutive cardiac cycles), is a popular, non-invasive indicator of cardiac autonomic nervous system (ANS) activity.  Low HRV implies a shift in sympathovagal activity and has been reported in patients with MDD compared to controls.(7)  The Defibrillator in Acute Myocardial Infarction Trial (DINAMIT) reported drastic decreases in HRV in post-MI patients five minutes before an episode of fatal ischemia, which was not observed in controls who suffered from transient ischemia with no sudden death.  This suggests that a loss of ability to vary heart beat rhythm,  i.e., low HRV leads to a total loss of cardiac function in the context of a recovering and already vulnerable heart.(5)

It has been estimated that by the end of this decade, MDD and CHD will be the two leading causes of disability in the world.  While MDD and CHD are two distinct diseases, a few critical features are implicated in both of their pathophysiologies; such as chronic stress, inflammation, and disequilibrium of the ANS as indicated by low HRV.  In the future, screening for MDD in patients with CHD, and vice versa, may prove useful in ameliorating prognosis for either condition.(1)


1.Pozuelo L, Tesar G, Zhang J, Penn M, Franco K, Jian W. Depression and heart disease: what do we know and where are we headed?. Cleveland Clinic Journal of Medicine 2009; 76(1): 59-70

2.Taylor SE, Sirois FM. Health Psychology. Canada: McGraw-Hill Ryerson; 2012.

3.Gu HF, Tang CK, Yang YZ. Psychological stress, immune response and atherosclerosis. Atherosclerosis 2012; 223(): 69-77.

4. Libby P, Simon DI. Inflammation and Thrombosis. Circulation. 2001; 103:1718-1720.

5.Carney R, Freedland K, Veith RC. Depression, the autonomic nervous system, and coronary heart disease. Psychosomatic Medicine 2005; 67(1): 529-533.

6.McEwen BS. Central effects of stress hormones in health and disease: Understanding the protective and damaging effects of stress and stress mediators. Stress Hormone Actions in Brain, in Health and Disease — Possibilities for New Pharmacotherapies 2008; 583(2-3): 174-185.

7.Xhyheri B, Manfrini O, Mazzolini M, Pizzi C, Bugiandi R. Heart rate variability today. Progression in Cardiovascular Disease 2012; 55(): 321-331.