title: Cardiovascular Impacts of Stress and a Western Diet: Synergistic Effects of Lifestyle Risk Factors on Infarct Tolerance and Cardioprotection
Creators: name: Nicholas, Makayla J
Publisher: name: Griffith University
Year: 2022
Subjects: subject: Ischemic heart disease (IHD)
subject: mood disorders
subject: weight gain
subject: diet
subject: chronic stress (CS)

description: Introduction: Ischemic heart disease (IHD) is one of the leading causes of death from a non-communicable disease globally. Multimorbidity - the co-occurrence of two or more chronic conditions - is becoming highly prevalent in patients suffering IHD. Recently, mood and metabolic disorders have been found to share mechanistic pathways in disease progression, with mood disorders such as major depressive disorder (MDD) and chronic stress (CS), and metabolic disorders such as obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome (MetS) contributing to cardiovascular disease (CVD) risk and development, and worsening cardiovascular outcomes in IHD sufferers. The intertwining pathological mechanisms of how these metabolic and mood disorders promote cardiovascular disease (perhaps synergistically) is not well known and is currently under investigation. Emerging research suggests that subclinical levels of CS and consumption of a Western diet promote pathological impairments in cardiac infarct tolerance and may diminish the heart’s innate protective signalling pathways. We further investigated these claims and examined the impacts of CS exposure and/or WD consumption on cardiometabolic risk factor development, mood impairment, and cardiac responses to classical pre-conditioning stimuli. Methods: 64 male C57BL/6J 8-week-old mice were randomly allocated to one of four groups (control diet, CD; Western diet, WD; control diet + restraint stress, CD + RS; or a Western diet + restraint stress, WD + RS). Mice were fed either a CD (calorie content: 14% fat, 59% carbohydrates, and 19% protein) or a WD (57% carbohydrates, 32%, fat, and 11% from protein) for 17 weeks. At week 15, mice in RS groups were exposed to 14 days of twohour daily RS in a clear Perspex restraint device. Behavioural analyses (open field test and sucrose preference test) were undertaken at baseline (week 0) and post-intervention (week 17) to determine if these interventions had an impact on markers of mood. Fasted circulating glucose was measured at baseline and post-intervention, with serum samples taken at these times for subsequent assessment of fasted insulin, triglycerides, and cholesterol. After postintervention behavioural assessment and blood collection, mice were anaesthetised and euthanised via heart excision. Serum samples were taken from the thoracic cavity immediately after heart removal for assessment of circulating markers. These hearts were used for immediate Langendorff perfusion experiments. Hearts were divided into two groups: one group that underwent ischemia and reperfusion (I/R), and one that was subjected to an ischaemic preconditioning (IPC) protocol (3x cycles of 5 minutes ischemia/5 minutes reperfusion) before exposure to I/R. Myocardial ventricular tissue was isolated and underwent analysis via ELISA and Western Blot assessment. Efflux of the two cell damage markers, lactate dehydrogenase (LDH) and cardiac troponin, was assessed. Results and conclusions: The WD resulted in significant weight gain and development of insulin resistance, without changes in the lipid profile. RS alone did not have an impact on metabolic parameters. Mood disturbances were found in the mice exposed to RS, however the WD did not improve or worsen behaviour (in the absence or presence of RS). No differences were found in intrinsic cardiac function between the control or the intervention groups. The protective efficacy of IPC was reduced in hearts from WD vs. control diet animals. However, WD hearts were nonetheless able to be pre-conditioned, with improvements found in % recovery of left ventricular developed pressure (LVDP) and absolute recovery of end-diastolic pressure (EDP). Regardless of diet, chronic RS impaired or eliminated reperfusion function protective effects of IPC, an inhibitory effect associated with reduced AKT expression and a trend to increased GSK-3b phosphorylation (significant in WD+RS hearts). Thus, both a WD and chronic stress are detrimental to cardioprotection and kinase signalling, with these adverse effects of stress more pronounced than those of diet.