The heartbreak of depression: ‘Psycho-cardiac’ coupling in myocardial infarction

Abstract

Ample evidence identifies strong links between major depressive disorder (MDD) and both risk of ischemic or coronary heart disease (CHD) and resultant morbidity and mortality. The molecular mechanistic bases of these linkages are poorly defined. Systemic factors linked to MDD, including vascular dysfunction, atherosclerosis, obesity and diabetes, together with associated behavioral changes, all elevate CHD risk. Nonetheless, experimental evidence indicates the myocardium is also directly modified in depression, independently of these factors, impairing infarct tolerance and cardioprotection. It may be that MDD effectively breaks the heart's intrinsic defense mechanisms. Four extrinsic processes are implicated in this psycho-cardiac coupling, presenting potential targets for therapeutic intervention if causally involved: sympathetic over-activity vs. vagal under-activity, together with hypothalamic-pituitary-adrenal (HPA) axis and immuno-inflammatory dysfunctions. However, direct evidence of their involvement remains limited, and whether targeting these upstream mediators is effective (or practical) in limiting the cardiac consequences of MDD is unknown. Detailing myocardial phenotype in MDD can also inform approaches to cardioprotection, yet cardiac molecular changes are similarly ill defined. Studies support myocardial sensitization to ischemic insult in models of MDD, including worsened oxidative and nitrosative damage, apoptosis (with altered Bcl-2 family expression) and infarction. Moreover, depression may de-sensitize hearts to protective conditioning stimuli. The mechanistic underpinnings of these changes await delineation. Such information not only advances our fundamental understanding of psychological determinants of health, but also better informs management of the cardiac consequences of MDD and implementing cardioprotection in this cohort.

Chronic stress: a crucial promoter of cell apoptosis in atherosclerosis

“…More obvious apoptosis (with changes in Bcl-2 family expression), worsened oxidative and nitrosative damage, and infarction have been observed in models of moderate depression than in the normal group; thus, the vessel's sensibility to protective conditioning stimuli is attenuated in response to depression. [20][21][22] In the present study, the serum TC and LDL-C levels were 25 times higher in the OPþHD group than in the CG. Furthermore, the effects of CS were indicated by the higher levels of TC and LDL-C in the OPþHDþCS than OPþHD group.…”

From feedback loop transitions to biomarkers in the psycho-immune-neuroendocrine network: Detecting the critical transition from health to major depression

“…The physiology underlying MDD consists of multiple interlocking pathways (e.g. see Stapelberg et al, 2011;Stapelberg et al, 2015, Headrick et al, 2017 and we assert here that the complex physiology underlying critical transition to MDD involves multiple feedback loop transitions (FLTs) from negative to positive feedback. We propose that these FLTs destabilise the PINE network, creating an unstable pre-disease state which can be measured using biomarkers, and that the FLTs of multiple physiological regulatory loops leads to positive feedback loop dominance and critical transition of the PINE network to the pathological state of MDD.…”

The brain-adipocyte-gut network: Linking obesity and depression subtypes

“…This paper focuses on plausible biological mechanisms leading from obesity to MDD (obesity-associated depression), before considering the less typical depression-toobesity relationship (depression-associated obesity in MDD-AF). Mechanisms are presented using a systems biology framework, as employed previously in exploring physiological relationships between depressive illness and other comorbid conditions (Stapelberg et al, 2015;Stapelberg et al, 2011;Headrick et al, 2017). While obesity also is linked to other mental illnesses, for example anxiety symptoms (Sullivan et al, 1993;Wing et al, 1991) and disorders (Barry, Pietrzak, & Petry, 2008), these specific relationships are beyond the scope of the present discussion.…”

“…Examples of biological systems amenable to exploration using network theory include gene (Kitano, 2002;Alm and Arkin, 2003), protein and enzymatic (Nikolsky et al, 2005;Alm and Arkin, 2003), and metabolic networks (Kitano, 2002). Systems biology can also be applied to complex disease states involving multiple pathogenic determinants (Noorbakhsh et al, 2009) and highly interrelated mechanisms (Stapelberg et al, 2015;Stapelberg et al, 2011;Headrick et al, 2017).…”

“…The ranking of MDD has increased since 1990 (Charlson et al, 2013) with recent estimates and projections (Vos et al, 2016) placing MDD as the second-leading cause of disability-adjusted life years (DALYs) through 2020, behind ischaemic heart disease (Murray & Lopez, 1997). The latter also is strongly associated with MDD (Stapelberg et al, 2015;Headrick et al, 2017). There has been a simultaneous increase in obesity, with overweight and obesity significant problems worldwide (Ng et al, 2014).…”