Obese mice exposed to psychosocial stress display cardiac and hippocampal dysfunction associated with local brain-derived neurotrophic factor depletion

Introduction: Obesity and psychosocial stress (PS) co-exist in individuals of Western society. Nevertheless, how PS impacts cardiac and hippocampal phenotype in obese subjects is still unknown. Nor is it clear whether changes in local brain-derived neurotrophic factor (BDNF) account, at least in part, for myocardial and behavioral abnormalities in obese experiencing PS. Methods: In adult male WT mice, obesity was induced via a high-fat diet (HFD). The resident-intruder paradigm was superimposed to trigger PS. In vivo left ventricular (LV) performance was evaluated by echocardiography and pressure-volume loops. Behaviour was indagated by elevated plus maze (EPM) and Y-maze. LV myocardium was assayed for apoptosis, fibrosis, vessel density and oxidative stress. Hippocampus was analyzed for volume, neurogenesis, GABAergic markers and astrogliosis. Cardiac and hippocampal BDNF and TrkB levels were measured by ELISA and WB. We investigated the pathogenetic role played by BDNF signaling in additional cardiac-selective TrkB (cTrkB) KO mice. Findings: When combined, obesity and PS jeopardized LV performance, causing prominent apoptosis, fibrosis, oxidative stress and remodeling of the larger coronary branches, along with lower BDNF and TrkB levels. HFD/PS weakened LV function similarly in WT and cTrkB KO mice. The latter exhibited elevated LV ROS emission already at baseline. Obesity/PS augmented anxiety-like behaviour and impaired spatial memory. These changes were coupled to reduced hippocampal volume, neurogenesis, local BDNF and TrkB content and augmented astrogliosis. Interpretation: PS and obesity synergistically deteriorate myocardial structure and function by depleting cardiac BDNF/TrkB content, leading to augmented oxidative stress. This comorbidity triggers behavioral deficits and induces hippocampal remodeling, potentially via lower BDNF and TrkB levels. FUND: J.A. was in part supported by Rotary Foundation Global Study Scholarship. G.K. was supported by T32 National Institute of Health (NIH) training grant under award number 1T32AG058527. S.C. was funded by American Heart Association Career Development Award (19CDA34760185). G.A.R.C. was funded by NIH (K01HL133368-01). APB was funded by a Grant from the Friuli Venezia Giulia Region entitled: Heart failure as the Alzheimer disease of the heart; therapeutic and diagnostic opportunities . M.C. was supported by PRONAT project (CNR). N.P. was funded by NIH (R01 HL136918) and by the Magic-That-Matters fund (JHU). V.L. was in part supported by institutional funds from Scuola Superiore Sant\u27Anna (Pisa, Italy), by the TIM-Telecom Italia (WHITE Lab, Pisa, Italy), by a research grant from Pastificio Attilio Mastromauro Granoro s.r.l. (Corato, Italy) and in part by ETHERNA project (Prog. n. 161/16, Fondazione Pisa, Italy). Funding source had no such involvement in study design, in the collection, analysis, interpretation of data, in the writing of the report; and in the decision to submit the paper for publication

Variability in genes regulating vitamin D metabolism is associated with vitamin D levels in type 2 diabetes

Mortality rate is increased in type 2 diabetes (T2D). Low vitamin D levels are associated with increased mortality risk in T2D. In the general population, genetic variants affecting vitamin D metabolism (DHCR7 rs12785878, CYP2R1 rs10741657, GC rs4588) have been associated with serum vitamin D. We studied the association of these variants with serum vitamin D in 2163 patients with T2D from the "Sapienza University Mortality and Morbidity Event Rate (SUMMER) study in diabetes". Measurements of serum vitamin D were centralised. Genotypes were obtained by Eco™ Real-Time PCR. Data were adjusted for gender, age, BMI, HbA1c, T2D therapy and sampling season. DHCR7 rs12785878 (p = 1 x 10-4) and GC rs4588 (p = 1 x 10-6) but not CYP2R1 rs10741657 (p = 0.31) were significantly associated with vitamin D levels. One unit of a weighted genotype risk score (GRS) was strongly associated with vitamin D levels (p = 1.1 x 10-11) and insufficiency (<30 ng/ml) (OR, 95%CI = 1.28, 1.16-1.41, p = 1.1 x 10-7). In conclusion, DHCR7 rs12785878 and GC rs4588, but not CYP2R1 rs10741657, are significantly associated with vitamin D levels. When the 3 variants were considered together as GRS, a strong association with vitamin D levels and vitamin D insufficiency was observed, thus providing robust evidence that genes involved in vitamin D metabolism modulate serum vitamin D in T2D

A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death

: The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10-8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10-8). A total of 113 variants were associated with survival at P-value < 1.0 × 10-5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways

Asse Cuore-Cervello: la sinergia tra stress e obesità alla base di comorbidità cerebrali, comportamentali e cardiache nel topo.

Analisi e presentazione della letteratura inerente l'influenza negativa esercitata da stress ed obesità a carico della funzionalità cerebrale e cardiaca, con particolare attenzione all'insorgenza di psicopatologia (disturbi dell'umore, disturbi d'ansia, disturbi mnestici), disturbi cardiovascolari e alterazioni morfo-strutturali relative sia al cervello che al cuore. Tale revisione ha condotto a realizzare uno studio sul topo finalizzato alla delineazione degli effetti derivanti dalla sinergia tra stress ed obesità, nel contesto dell'asse cuore-cervello. Gli esperimenti effettuati hanno consistito in test comportamentali per la valutazione di tratti ansiosi e deficit di memoria, analisi immunoistochimiche per l'indagine di volume, neurogenesi e plasticità ippocampali, ed ecocardiografie per l'assessment della funzionalità cardiaca. I dati ottenuti sono stati infine elaborati ed interpretati in accordo con la concezione olistica che ipotizza meccanismi patogenetici comuni alla base di disturbi mentali e deficit cardiaci: il modello del Brain-Heart Axis

The Impact of Sex and Gender on Heart-Brain Axis Dysfunction: Current Concepts and Novel Perspectives

The Heart-Brain Axis (HBA) recapitulates all the circuits that regulate bidirectional flow of communication between heart and brain. Several mechanisms may underlie the interdependent relationship involving heterogeneous tissues at rest and during specific target organ injury, such as myocardial infarction, heart failure, arrhythmia, stroke, mood disorders or dementia. In-depth translational studies of the HBA dysfunction under single-organ injury should include both male and female animals to develop sex/gender-oriented prevention, diagnosis and treatment strategies. Indeed, sex and gender are determining factors since females and males exhibit significant differences in terms of susceptibility to risk factors, age of onset, severity of symptoms and outcome. Despite most studies have focused on the male population, we have conducted a careful appraisal of the literature investigating HBA in females. In particular, we have i) analysed sex-related heart and brain illnesses, ii) recapitulated the most significant studies simultaneously conducted on cardio- and cerebrovascular systems in female population, iii) hypothesised future perspectives for the development of gender-based approach to HBA dysfunction. Although sex/gender-oriented research is at its infancy, the impact of sex on HBA dysfunction is opening unexpected new avenues for managing health of female subjects exposed to risk of lifestyle multi-organ disease

Perioperative Heart-Brain Axis Protection in Obese Surgical Patients: the Nutrigenomic Approach

The number of obese patients undergoing cardiac and noncardiac surgery is rapidly increasing because they are more prone to concomitant diseases, such as diabetes, thrombosis, sleep-disordered breathing, cardiovascular and cerebrovascular diseases. Even if guidelines are already available to manage anesthesia and surgery of obese patients, the assessment of the perioperative morbidity and mortality from heart and brain disorders in morbidly obese surgical patients will be challenging in the next years. The present review will recapitulate the new mechanisms underlying the heart-brain axis (HBA) vulnerability during the perioperative period in healthy and morbidly obese patients. Finally, we will describe the nutrigenomics approach, an emerging noninvasive dietary tool, to maintain a healthy body weight and to minimize the HBA propensity to injury in obese individuals undergoing all types of surgery by personalized intake of plant compounds that may regulate the switch from health to disease in an epigenetic manner. Our review provides current insights into the mechanisms underlie HBA response in obese surgical patients and how they are modulated by epigenetically active food constituents

Barley (1,3)-β-d-Glucan Dietary Supplementation Prevents Cardiac Dysfunction in Obese Mice with Psychosocial Stress by Attenuating Myocardial Oxidative Stress

Objective: Obesity due to high fat intake and psychosocial stress (PSS) are major determinants of cardiovascular disease (CVD), particularly when combined. Long-term diets enriched with barley (1,3)-β- d-glucan (BBG), an inhibitor of the class I histone deacetylases and an antioxidant, increases post-ischemic survival rate in mice by promoting angiogenesis. However, the impact of a BBG-enriched diet on cardiac dysfunction due to conditions such as high-fat diet (HFD) and PSS, alone or in combination, is unknown. Here, we tested whether supplementing HFD-treated mice with BBG prevents HFD- or HFD/PSS induced cardiac dysfunction by attenuating myocardial oxidative stress. Methods: Controlmale C57BL/6 mice were fed with 3 different diets for 18 wks: 1) standard diet (SD; 10% kcal fromfat; n=9); 2) HFD (58%kcal from fat; n=9); or 3)HFD+3% BBG (HFD+BBG; 58% kcal from fat; n = 9). All mice were then subjected chronic PSS via a daily (10min) encounter with a male intruder (resident/intruder test, fromweek 16 to week 18). Cardiac function was evaluated by echocardiography before and after PSS, whereas left ventricle (LV) tissue was collected at study termination to assess reactive oxygen species (ROS) by emission electron paramagnetic resonance analysis. Results: At week 16, body weight was markedly higher in the HFD than in the SD group (+60.1%, P &lt; 0.001); however, BBG supplementation significantly prevented weight gain (−10% compared with HFD, P &lt; 0.05). The addition of PSS significantly worsened the LV dysfunction in HFD (LV ejection fraction (LVEF), −25%; LV fractional shortening (LVFS), −33% compared with SD (LVEF, −7%; LVFS, −10%) mice. Conversely, the LV function after PSS was significantly improved in HFD + BBG mice (LVEF, +7%; LVFS, +10%) when compared with basal values. HFD and PSS led a marked rise in LV ROS production, as compared with values found in the hearts of mice receiving SD (+76% P &lt; 0.001). However, this increment was significantly attenuated in HFD + BBG mice in which LV ROS emission rose only by 34%. Our study shows that a regular supplementation of 3% wt/vol BBG with diet prevents cardiac functional decay due to the combination of HFD and PSS, likely by countering HFD/PSS-induced myocardial ROS production. These findings may have preventative or therapeutic implications for all CVDs characterized by a cardiac, vascular, or both redox milieu

Action Observation Therapy for Arm Recovery after Stroke: A Preliminary Investigation on a Novel Protocol with EEG Monitoring

This preliminary study introduces a novel action observation therapy (AOT) protocol associated with electroencephalographic (EEG) monitoring to be used in the future as a rehabilitation strategy for the upper limb in patients with subacute stroke. To provide initial evidence on the usefulness of this method, we compared the outcome of 11 patients who received daily AOT for three weeks with that of patients who undertook two other approaches recently investigated by our group, namely intensive conventional therapy (ICT), and robot-assisted therapy combined with functional electrical stimulation (RAT-FES). The three rehabilitative interventions showed similar arm motor recovery as indexed by Fugl-Meyer’s assessment of the upper extremity (FMA_UE) and box and block test (BBT). The improvement in the FMA_UE was yet more favourable in patients with mild/moderate motor impairments who received AOT, in contrast with patients carrying similar disabilities who received the other two treatments. This suggests that AOT might be more effective in this subgroup of patients, perhaps because the integrity of their mirror neurons system (MNS) was more preserved, as indexed by EEG recording from central electrodes during action observation. In conclusion, AOT may reveal an effective rehabilitative tool in patients with subacute stroke; the EEG evaluation of MNS integrity may help to select patients who could maximally benefit from this intervention