Background. How low-level psychological stress and overnutrition interact in influencing cardiometabolic disease is unclear. Mechanistic overlaps suggest potential synergies, however findings are contradictory. We test whether low level stress and Western diet (WD) feeding synergistically influence homeostasis, mood and myocardial ischemic tolerance. Methods. Male C57Bl6/J mice were fed a control or WD (32%/57%/11% calories from fat/carbohydrates/protein) for 12 wks, with subgroups restrained for 30 min/day over the final 3 wks. Metabolism, behavior, tolerance of perfused hearts to ischemia/reperfusion (I/R), and cardiac 'death proteins' were assessed. Results. The WD resulted in insignificant trends to increased body weight (+5%), glucose (+40%), insulin (+40%), triglycerides (+15%) and cholesterol (+20%), and reduced leptin (-20%), while significantly reducing insulin sensitivity (100% rise in HOMA-IR, P<0.05). Restraint did not independently influence metabolism, while increasing HOMA-IR a further 50% (and resulting in significant elevations in insulin and glucose to 60-90% above control) in WD mice (P<0.05), despite blunting weight gain in control and WD mice. Anxiogenesis with restraint or WD was non-additive, whereas anhedonia (reduced sucrose consumption) only arose with their combination. Neuroinflammation markers (hippocampal TNF-a, Il-1b) were unchanged. Myocardial I/R tolerance was unaltered with stress or WD alone, while combination worsened dysfunction and oncosis (LDH efflux). Apoptosis (nucleosome accumulation) and death protein expression (BAK, BAX, BCL-2, RIP-1, TNF-α, cleaved caspase-3 and PARP) were unchanged. Conclusion. Mild, anxiogenic yet cardio-metabolically 'benign' stress interacts synergistically with a WD to disrupt homeostasis, promote anhedonia (independently of neuroinflammation), and impair myocardial ischemic tolerance (independently of apoptosis and death protein levels).

New Findings What is the central question of this study?What is the impact of chronic adult‐onset diabetes on cardiac ischaemic outcomes and preconditioning? What is the main finding and its importance?Chronic adult‐onset type 2 but not type 1 diabetes significantly impairs myocardial ischaemic tolerance and ischaemic preconditioning. Preconditioning may be detrimental in type 2 diabetes, exaggerating nitrosative stress and apoptotic protein expression. Abstract Effects of diabetes on myocardial responses to ischaemia–reperfusion (I–R) and cardioprotective stimuli remain contentious, potentially reflecting influences of disease duration and time of onset. Chronic adult‐onset type 1 diabetes (T1D) and type 2 diabetes (T2D) were modelled non‐genetically in male C57Bl/6 mice via 5 × 50 mg kg−1 daily streptozotocin (STZ) injections + 12 weeks’ standard chow or 1 × 75 mg kg−1 STZ injection + 12 weeks’ obesogenic diet (32% calories as fat, 57% carbohydrate, 11% protein), respectively. Systemic outcomes were assessed and myocardial responses to I–R ± ischaemic preconditioning (IPC; 3 × 5 min I–R) determined in Langendorff perfused hearts. Uncontrolled T1D was characterised by pronounced hyperglycaemia (25 mm fasting glucose), glucose intolerance and ∼10% body weight loss, whereas T2D mice exhibited moderate hyperglycaemia (15 mm), hyperinsulinaemia, glucose intolerance and 17% weight gain. Circulating ghrelin, resistin and noradrenaline were unchanged with T1D, while leptin increased and noradrenaline declined in T2D mice. Ischaemic tolerance and IPC were preserved in T1D hearts. In contrast, T2D worsened post‐ischaemic function (∼40% greater diastolic and contractile dysfunction) and cell death (100% higher troponin efflux), and abolished IPC protection. Whereas IPC reduced post‐ischaemic nitrotyrosine and pro‐apoptotic Bak and Bax levels in non‐diabetic hearts, these effects were reduced in T1D and IPC augmented Bax and nitrosylation in T2D hearts. The data demonstrate chronic T1D does not inhibit myocardial I–R tolerance or IPC, whereas metabolic and endocrine disruption in T2D is associated with ischaemic intolerance and inhibition of IPC. Indeed, normally protective IPC may exaggerate damage mechanisms in T2D hearts.

Psychosocial stress promotes and links mood and cardiovascular disorders in a sex‐specific manner. However, findings in animal models are equivocal, in some cases opposing human dimorphisms. We examined central nervous system (CNS), behavioral, endocrine, cardiac, and hepatic outcomes in male or female C57Bl/6 mice subjected to chronic social stress (56 days of social isolation, with intermittent social confrontation encounters twice daily throughout the final 20 days). Females exhibited distinct physiological and behavioral changes, including relative weight loss, and increases in coronary resistance, hepatic inflammation, and thigmotaxic behavior in the open field. Males evidence reductions in coronary resistance and cardiac ischemic tolerance, with increased circulating and hippocampal monoamine levels and emerging anhedonia. Shared CNS gene responses include reduced hippocampal Maoa and increased Htr1b expression, while unique responses include repression of hypothalamic Ntrk1 and upregulation of cortical Nrf2 and Htr1b in females; and repression of hippocampal Drd1 and hypothalamic Gabra1 and Oprm in males. Declining cardiac stress resistance in males was associated with repression of cardiac leptin levels and metabolic, mitochondrial biogenesis, and anti‐inflammatory gene expression. These integrated data reveal distinct biological responses to social stress in males and females, and collectively evidence greater biological disruption or allostatic load in females (consistent with propensities to stress‐related mood and cardiovascular disorders in humans). Distinct stress biology, and molecular to organ responses, emphasize the importance of sex‐specific mechanisms and potential approaches to stress‐dependent disease.

Linoleic acid (LA), an essential n-6 fatty acid (FA), is critical for fetal growth and development. We investigated the effects of maternal high LA (HLA) diet on offspring cardiac development and how it relates to circulating FAs and cardiovascular function in adolescent offspring, and the ability of the postnatal diet to reverse any adverse effects. Female Wistar Kyoto rats were fed low LA (LLA; 1.44% energy from LA) or HLA (6.21% energy from LA) diets for 10 weeks before pregnancy, and during gestation/lactation. Offspring, weaned at postnatal day 25 (PN25), were fed LLA or HLA diets and euthanised at PN40 (n = 6-8). Maternal HLA diet decreased circulating total cholesterol and HDL-cholesterol in females and decreased total plasma n-3 FA in males, while maternal and postnatal HLA diets decreased total plasma n-3 FA in females. Alpha- linolenic acid (ALA) and eicosapentaenoic acid (EPA) were decreased by postnatal but not maternal HLA diets in both sexes. Maternal and postnatal HLA diets increased total plasma n-6 and LA, and a maternal HLA diet increased circulating leptin, in both male and female offspring. Maternal HLA decreased slopes of systolic and diastolic PVRs, and increased cardiac Col1a1, Col3a1, Atp2a1 and Notch1 in males. Maternal and postnatal HLA diets left-shifted the diastolic PVR in female offspring. Coronary reactivity was altered in females, with differential effects on flow repayment after 10–20 sec occlusions. In conclusion, maternal HLA diets impact lipids, fatty acids and cardiac function in offspring, with postnatal diet modifying fatty acids and cardiac function in the female offspring.

Stress is an important risk factor for modern chronic diseases, with distinct influences in males and females. The sex specificity of the mammalian stress response contributes to the sex-dependent development and impacts of coronary artery disease (CAD). Compared to men, women appear to have greater susceptibility to chronic forms of psychosocial stress, extending beyond an increased incidence of mood disorders to include a 2- to 4-fold higher risk of stress-dependent myocardial infarction in women, and up to 10-fold higher risk of Takotsubo syndrome—a stress-dependent coronary-myocardial disorder most prevalent in post-menopausal women. Sex differences arise at all levels of the stress response: from initial perception of stress to behavioural, cognitive, and affective responses and longer-term disease outcomes. These fundamental differences involve interactions between chromosomal and gonadal determinants, (mal)adaptive epigenetic modulation across the lifespan (particularly in early life), and the extrinsic influences of socio-cultural, economic, and environmental factors. Pre-clinical investigations of biological mechanisms support distinct early life programming and a heightened corticolimbic-noradrenaline-neuroinflammatory reactivity in females vs. males, among implicated determinants of the chronic stress response. Unravelling the intrinsic molecular, cellular and systems biological basis of these differences, and their interactions with external lifestyle/socio-cultural determinants, can guide preventative and therapeutic strategies to better target coronary heart disease in a tailored sex-specific manner.