Table 1.

Summary of main findings in mechanisms of MDD and cardiac risk.

Reference	Objective	Subjects	Methods	Results
Stapelberg et al. (33)	To identify a model of causal mechanisms that link major depressive disorder to cardiovascular heart disease	–	A comprehensive literature review	Mechanisms linking MDD and CHD that are often discussed in the literature are genetic, behavioral, and immunological. As well as coagulation, omega-3 PUFA deficiency and vascular endothelial dysfunction. However, rather than discussing them separately, these mechanisms should be viewed as interdependent networks
Esler et al. (23)	To examine the sympathetic nervous system function in depression	11 depressed patients	Tritiated norepinephrine was used to observe the rate of norepinephrine spill over. Removal of norepinephrine from plasma was performed to assess the neuronal uptake of norepinephrine	Norepinephrine spill over was elevated in 5 of the 11 patients with depressive illness. Rapid removal phase of norepinephrine from plasma corresponded in patients with depression, suggesting increased neuronal uptake
		8 patients with other psychiatric diagnosis
		17 healthy subjects
Carney et al. (34)	To examine whether depressed patients with coronary artery disease (CAD) have lower heart rate variability compared with non-depressed CAD patients	19 depressed CAD patients	Patients underwent 24-h Holter monitoring, with SD of normal-to-normal intervals were used as the primary index of heart rate variability	Heart rate variability was significantly lower in non-depressed CAD patients
		19 non-depressed CAD patients
Spieker et al. (28)	To identify the mechanisms behind endothelial functioning in response to mental stress	23 healthy subjects	Nitroglyercin and flow-mediated (FMD) induced vasodilation were examined pre- and post-stress. FMD was also examined during stress	Endothelium-dependent vasodilation decreased by half in comparison to endothelium-independent vasodilation to nitroglyercin which remained unaffected. Intra-arterial infusion of norepinephrine for a similar duration of mental stress did not hinder FMD
Schlaich et al. (35)	To determine possible mechanisms leading to sympathetic augmentation in hypertension	22 hypertensive patients	Microneurography and radio tracer dilution were used to measure regional sympathetic activity	Patients with hypertension demonstrated reduced neuronal norepinephrine reuptake, which in turn was associated with sympathetic activation in hypertension
		11 normotensive patients
Dinan (36)	To review the biological markers of depression, specifically neuroendocrine disturbances and the hypothalamic–pituitary–adrenal axis (HPA)	–	A comprehensive literature review	Numerous studies have demonstrated that MDD results from activation from the HPA. Other biological markers may be secondary to high glucocorticoid levels
Wong et al. (37)	To examine centrally directed norepinephrine and corticotropin-releasing hormone (CRH) secretion in medication-free patients with melancholic depression	10 depressed patients	Norepinephrine and CRH were measured in lumbar cerebrospinal fluid every 30 h in addition to plasma adrenocorticotropic hormone and cortisol secretion	Depressed patients had significantly higher levels of norepinephrine and plasma cortisol yet normal levels of CRH. There was a negative correlation between plasma cortisol and CRH in healthy patients, while there was no relationship demonstrated in the depressed group
		14 healthy subjects
Barton et al. (38)	To assess the significance of the sympathetic nervous system in the promotion of cardiac risk in patients with MDD	39 depressed patients	Whole-body cardiac sympathetic activity was measured using noradrenaline isotope dilution methods and sympathetic nerve recording techniques	A bimodal distribution for whole body and heart sympathetic activity was demonstrated in patients with MDD. This subset of MDD patients had significantly high sympathetic activity
		76 healthy subjects
Ghiadoni et al. (27)	To explore whether mental stress promotes atherogenesis via the impairment of endothelium-dependent vascular homeostasis in preclinical subjects	8 non-insulin-dependent diabetic patients	Response to sublingual glyceryl trinitrate and brachial artery flow-mediated dilation (FMD) were measured before and after a mental stress test. It was measured again in the healthy group, without a stress stimuli on a separate occasion	In healthy subjects, mental stress had no effect on the response to sublingual glyceryl trinitrate; however, FMD significantly reduced after. Without the stress stimuli, FMD was unchanged. While the diabetic group had lower FMD in comparison to controls, there were no changes following the stimuli for both FMD and sublingual glyceryl trinitrate responses
		10 healthy subjects
Brown et al. (6)	To review the associations between MDD and CHD and address the clinical implications for treatment	–	A comprehensive literature review	While there is no evidence that treatment of depression will reduce this effect, it is still important to improve quality of life for those with depression through the benefits of psychological and pharmaceutical intervention
Poole et al. (39)	To review the relationship between depression and adverse outcomes from acute coronary syndrome (ACS) and coronary artery bypass graft (CABG) surgery patients	–	A comprehensive literature review	Inflammation is a frequent causal process involved in the development of depressive symptoms and for adverse cardiac outcomes