Increased haemodynamic adrenergic load with isoflurane anaesthesia in type 2 diabetic and obese rats in vivo.

BACKGROUND: Increasing numbers of type 2 diabetic and obese patients with enhanced rates of cardiovascular complications require surgical interventions, however they have a higher incidence of perioperative haemodynamic complications, which has been linked to adrenergic dysfunction. Therefore, we aimed to determine how α- and ß-adrenoceptor (AR)-mediated haemodynamic responses are affected by isoflurane anaesthesia in experimental type 2 diabetes and obesity in vivo. METHODS: Sixteen-week old male Zucker type 2 Diabetic Fatty (ZDF) rats, Zucker Obese rats and their lean counterparts (n = 7-9 per group) were instrumented with radio telemeters to record blood pressure and heart rate and with vascular access ports for non-invasive intravenous drug delivery in vivo. Haemodynamic effects of α-AR (phenylephrine; 1-100 µg x kg(-1)) or ß-AR (dobutamine; 2-120 µg x kg(-1)) stimulation were assessed under conscious and anaesthetised (isoflurane; 2%) conditions. RESULTS: Vascular α-AR sensitivity was increased in both diabetic (non-diabetic 80 ± 3 vs. diabetic 95 ± 4 ΔmmHg at 100 µg x kg(-1); p < 0.05) and obese (lean 65 ± 6 vs. obese 84 ± 6 ΔmmHg at 20 µg x kg(-1); p < 0.05) conscious rats. Interestingly, anaesthesia exacerbated and prolonged the increased α-AR function in both diabetic and obese animals (non-diabetic 51 ± 1 vs. diabetic 68 ± 4 ΔmmHg, lean 61 ± 5 vs. obese 84 ± 2 ΔmmHg at 20 µg x kg(-1); p < 0.05). Meanwhile, ß-AR chronotropic sensitivity was reduced in conscious diabetic and obese rats (non-diabetic 58 ± 7 vs. diabetic 27 ± 8 Δbpm, lean 103 ± 12 vs. obese 61 ± 9 Δbpm at 15 µg x kg(-1); p < 0.05). Anaesthesia normalised chronotropic ß-AR responses, via either a limited reduction in obese (lean 51 ± 3 vs. obese 66 ± 5 Δbpm; NS at 15 µg x kg(-1)) or increased responses in diabetic animals (non-diabetic 49 ± 8 vs. diabetic 63 ± 8 Δbpm, at 15 µg x kg(-1); NS at 15 µg x kg(-1)). CONCLUSIONS: Long term metabolic stress, such as during type 2 diabetes and obesity, alters α- and ß-AR function, its dynamics and the interaction with isoflurane anaesthesia. During anaesthesia, enhanced α-AR sensitivity and normalised ß-AR function may impair cardiovascular function in experimental type 2 diabetes and obesity.

Maternal Migration, Prenatal Stress and Child Autistic Traits: Insights From a Population-Based Cohort Study.

OBJECTIVE: There is emerging evidence for an increased prevalence of autism in children of mothers with a migration background. To date, the mechanisms underlying this relationship are poorly understood. We investigated whether prenatal stress exposure mediates the association between maternal migration and child autistic traits, assessing first- and second-generation migrant mothers in the Netherlands and their children. METHOD: The study was embedded in the prospective population-based Generation R cohort. Of the 4,727 participants, 1,773 mothers (38%) had a migration background. Prenatal stress was assessed using questionnaires related to stressful life events, family functioning, self-esteem, long-lasting difficulties, symptoms of psychopathology, social support, and perceived discrimination. Autistic traits were measured at age 6 years with the parent-reported Social Responsiveness Scale exclusively. Longitudinal multiple mediation analyses were performed. Analyses were stratified by migration origin (Europe and outside Europe) because of differences in migration characteristics. RESULTS: Maternal migration background was associated with more experienced stress and with higher child autistic trait scores (Europe: mean = 0.42, SD = 0.25; outside Europe: mean = 0.50, SD = 0.24) compared to no migration background (Netherlands: mean = 0.38, SD = 0.23; both p < .01). Prenatal stress, especially perceived discrimination and maternal psychopathology, accounted for up to half of the total effect of maternal migration, which remained after adjusting for sociodemographic factors (Bindirect = 0.035, 95% CI = 0.027, 0.043, Btotal = 0.074). CONCLUSION: Stress during pregnancy mediated the association between maternal migration status and child autistic traits. Future research should focus on early interventions to assess whether reducing prenatal stress exposure among women with a migration background can result in lower offspring autistic traits. DIVERSITY & INCLUSION STATEMENT: We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We actively worked to promote sex and gender balance in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Hypoxia-responsive zinc finger E-box-binding homeobox 2 (ZEB2) regulates a network of calcium-handling genes in the injured heart.

AIMS: Intracellular calcium (Ca2+) overload is known to play a critical role in the development of cardiac dysfunction. Despite the remarkable improvement in managing the progression of heart disease, developing effective therapies for heart failure (HF) remains a challenge. A better understanding of molecular mechanisms that maintain proper Ca2+ levels and contractility in the injured heart could be of therapeutic value. METHODS AND RESULTS: Here, we report that transcription factor zinc finger E-box-binding homeobox 2 (ZEB2) is induced by hypoxia-inducible factor 1-alpha (HIF1α) in hypoxic cardiomyocytes and regulates a network of genes involved in Ca2+ handling and contractility during ischaemic heart disease. Gain- and loss-of-function studies in genetic mouse models revealed that ZEB2 expression in cardiomyocytes is necessary and sufficient to protect the heart against ischaemia-induced diastolic dysfunction and structural remodelling. Moreover, RNA sequencing of ZEB2-overexpressing (Zeb2 cTg) hearts post-injury implicated ZEB2 in regulating numerous Ca2+-handling and contractility-related genes. Mechanistically, ZEB2 overexpression increased the phosphorylation of phospholamban at both serine-16 and threonine-17, implying enhanced activity of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), thereby augmenting SR Ca2+ uptake and contractility. Furthermore, we observed a decrease in the activity of Ca2+-dependent calcineurin/NFAT signalling in Zeb2 cTg hearts, which is the main driver of pathological cardiac remodelling. On a post-transcriptional level, we showed that ZEB2 expression can be regulated by the cardiomyocyte-specific microRNA-208a (miR-208a). Blocking the function of miR-208a with anti-miR-208a increased ZEB2 expression in the heart and effectively protected from the development of pathological cardiac hypertrophy. CONCLUSION: Together, we present ZEB2 as a central regulator of contractility and Ca2+-handling components in the mammalian heart. Further mechanistic understanding of the role of ZEB2 in regulating Ca2+ homeostasis in cardiomyocytes is an essential step towards the development of improved therapies for HF.

Single-cell transcriptomics provides insights into hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a genetic heart disease that is characterized by unexplained segmental hypertrophy that is usually most pronounced in the septum. While sarcomeric gene mutations are often the genetic basis for HCM, the mechanistic origin for the heterogeneous remodeling remains largely unknown. A better understanding of the gene networks driving the cardiomyocyte (CM) hypertrophy is required to improve therapeutic strategies. Patients suffering from HCM often receive a septal myectomy surgery to relieve outflow tract obstruction due to hypertrophy. Using single-cell RNA sequencing (scRNA-seq) on septal myectomy samples from patients with HCM, we identify functional links between genes, transcription factors, and cell size relevant for HCM. The data show the utility of using scRNA-seq on the human hypertrophic heart, highlight CM heterogeneity, and provide a wealth of insights into molecular events involved in HCM that can eventually contribute to the development of enhanced therapies.

Sodium-glucose cotransporter 2 inhibition: cardioprotection by treating diabetes-a translational viewpoint explaining its potential salutary effects.

Diabetes is a growing epidemic worldwide characterized by an elevated concentration of blood glucose, associated with a high incidence of cardiovascular disease and mortality. Although in general reduction of hyperglycaemia is considered a therapeutic goal, hypoglycaemic therapies do not necessarily reduce cardiovascular mortality and may even aggravate cardiovascular risk factors, such as body weight. A new class of antidiabetic drugs acts by inhibition of the sodium-glucose cotransporter 2 (SGLT2), which (partially) prevents reabsorption of glucose from the renal filtrate. The induction of glucose excretion via the urine (glycosuria) was turned into an effective strategy to reduce blood glucose. Ancillary advantages are the caloric and volumetric loss and thereby the reduction of body weight and blood pressure. Additionally, SGLT2 inhibition has been suggested to exert direct cardioprotective effects by the reduction of cardiac fibrosis, inflammation, and oxidative stress. This article summarizes the functional consequences of SGLT2 inhibition on the diabetic and hyperglycaemic organism. We especially focused on the effects on the kidney and the cardiovascular system as described in experimental studies. The interesting observations in experimental studies may extend to clinical medicine, as a recent trial reported a decrease in heart failure outcomes in patients at high cardiovascular risk. In conclusion, SGLT2 inhibition represents a novel treatment, which might be a promising target not only to (further) reduce blood glucose but also to target other cardiovascular risk factors. More research and long-term follow-ups will reveal the specific influence of SGLT2 inhibition on the circulatory system and cardiovascular outcomes.