Risultati per: Nelle donne lo stress danneggia la salute dell’intestino

Il 12 e 13 novembre in piazzale Maestri del Commercio

A scienziata assegnato 1 mln euro premio “Lombardia è ricerca”

Il 12 e 13 novembre in piazzale Maestri del Commercio

Objectives
Non-alcoholic fatty liver disease (NAFLD) can persist in the stage of simple hepatic steatosis or progress to steatohepatitis (NASH) with an increased risk for cirrhosis and cancer. We examined the mechanisms controlling the progression to severe NASH in order to develop future treatment strategies for this disease.

Design
NFATc1 activation and regulation was examined in livers from patients with NAFLD, cultured and primary hepatocytes and in transgenic mice with differential hepatocyte-specific expression of the transcription factor (Alb-cre, NFATc1c.a . and NFATc1/ ). Animals were fed with high-fat western diet (WD) alone or in combination with tauroursodeoxycholic acid (TUDCA), a candidate drug for NAFLD treatment. NFATc1-dependent ER stress-responses, NLRP3 inflammasome activation and disease progression were assessed both in vitro and in vivo.

Results
NFATc1 expression was weak in healthy livers but strongly induced in advanced NAFLD stages, where it correlates with liver enzyme values as well as hepatic inflammation and fibrosis. Moreover, high-fat WD increased NFATc1 expression, nuclear localisation and activation to promote NAFLD progression, whereas hepatocyte-specific depletion of the transcription factor can prevent mice from disease acceleration. Mechanistically, NFATc1 drives liver cell damage and inflammation through ER stress sensing and activation of the PERK-CHOP unfolded protein response (UPR). Finally, NFATc1-induced disease progression towards NASH can be blocked by TUDCA administration.

Conclusion
NFATc1 stimulates NAFLD progression through chronic ER stress sensing and subsequent activation of terminal UPR signalling in hepatocytes. Interfering with ER stress-responses, for example, by TUDCA, protects fatty livers from progression towards manifest NASH.

Circulation, Volume 146, Issue 19, Page 1483-1485, November 8, 2022.

Introduction
The diagnosis, progression or recurrence of cancer is often highly traumatic for family caregivers (FCs), but systematic assessments of distress and approaches for its prevention and treatment are lacking. Acute leukaemia (AL) is a life-threatening cancer of the blood, which most often presents acutely, requires intensive treatment and is associated with severe physical symptoms. Consequently, traumatic stress may be common in the FCs of patients with AL. We aim to determine the prevalence, severity, longitudinal course and predictors of traumatic stress symptoms in FCs of patients with AL in the first year after diagnosis, and to understand their lived experience of traumatic stress and perceived support needs.

Methods and analysis
This two-site longitudinal, observational, mixed methods study will recruit 223 adult FCs of paediatric or adult patients newly diagnosed with AL from two tertiary care centres. Quantitative data will be collected from self-report questionnaires at enrolment, and 1, 3, 6, 9 and 12 months after admission to hospital for initial treatment. Quantitative data will be analysed using descriptive and machine learning approaches and a multilevel modelling (MLM) approach will be used to confirm machine learning findings. Semi-structured qualitative interviews will be conducted at 3, 6 and 12 months and analysed using a grounded theory approach.

Ethics and dissemination
This study is funded by the Canadian Institutes of Health Research (CIHR number PJT 173255) and has received ethical approval from the Ontario Cancer Research Ethics Board (CTO Project ID: 2104). The data generated have the potential to inform the development of targeted psychosocial interventions for traumatic stress, which is a public health priority for high-risk populations such as FCs of patients with haematological malignancies. An integrated and end-of-study knowledge translation strategy that involves FCs and other stakeholders will be used to interpret and disseminate study results.

Objective
Mindfulness-based stress reduction (MBSR) is a meditation-based therapy originally recommended for stress management. However, it is currently used to alleviate sleep disturbances. Therefore, this contemporary systematic review aimed to elucidate the clinical effects of MBSR on sleep quality and sleep-related daytime impairment in adults with sleep disturbances, including chronic insomnia disorders.

Design
Systematic review and meta-analysis of randomised controlled trials (RCTs).

Methods
A comprehensive search was conducted using the following databases: Ovid MEDLINE, AMED, Ovidembase, PsycINFO, Cochrane Library, CINAHL, and four domestic databases: KoreaMed, KISS, KMbase and NDSL. The final search update was performed in June 2022. Two researchers independently selected relevant studies, assessed the risk of bias and extracted the data.

Results
Of the 7516 records searched, 20 RCTs and 21 reports were included. In the subgroup analysis, MBSR did not improve objective or subjective sleep quality in chronic insomnia and cancers. However, MBSR versus waitlist control might have been effective in improving subjective sleep quality, but with substantial heterogeneity (standardised mean difference=–0.32; 95% CI: –0.56 to –0.08; I2=71%). In addition, MBSR compared with active control did not improve the sleep-related daytime impairments including depression, anxiety, stress, fatigue and quality of life. The overall risk of bias included in this review was a concern because of performance and detection bias.

Conclusions
MBSR might be ineffective for improving sleep quality in patients with chronic insomnia and cancers. In addition, more than half of the RCTs included in this review had small sample sizes and were vulnerable to performance and detection biases. Therefore, well-designed RCTs with larger sample sizes are required to confirm the clinical effects of MBSR in adults with sleep disturbances.

PROSPERO registration number
CRD42015027963.

Comunicato del 29/10/2022 n°3

Circulation, Volume 146, Issue Suppl_1, Page A14496-A14496, November 8, 2022. Introduction:Diet induced obese (DIO) mice display increased inducible atrial fibrillation (AF) and an overall increase in reactive oxygen species (ROS) production. NADPH oxidase 2 (NOX2), a major source of cytosolic ROS production in human atria, has been implicated in AF independent of obesity and is significantly increased in the atria of DIO mice. Although treatment with MitoTEMPO, a mitochondrial specific antioxidant reduced AF burden in DIO mice, the actual role of NOX2 in increasing ROS production and atrial remodeling in the context of obesity-induced AF remains unclear.Hypothesis:To test the hypothesis that increased NOX2 modulates atrial remodeling in obesity-induced AF, we used control mice, DIO andNox2-KO mice fed with a 60% HFD for 10 weeks (DIO-KO) and DIO mice treated with a NOX2 blocker, apocynin (DIO-Apocynin).Methods:Trans-esophageal rapid (TE) pacing was used to look at the AF phenotype. Cellular electrophysiology (EP), Western blotting, whole-cell patch clamping were performed to study ion channel remodeling and ROS production.Results:All three DIO mouse groups displayed significantly greater body weight compared to their respective controls (Figure A) After TE pacing, DIO-Apocynin mice displayed 28.26 ± 25.40 s and DIO-KO mice displayed 17.43 ± 31.80 s compared to 167.3 ± 168.9 s in DIO mice (Figure B). NOX2 inhibition reversed obesity-induced ion channel remodeling of potassium channels such asKCNQ1andKCNE1encoding for the IKs current andKCNA5encoding for the IKur current and also reduced mediators of oxidative stress. (Figure C-M) Lastly, voltage clamp in DIO-KO mice showed that NOX2 inhibition reverses obesity-induced IK current increase. (Figure N-O)Conclusions:Thus, these results prove that antioxidant therapy targeting Nox2 abrogated ion channel remodeling and reversed the obesity-induced AF burden. Our findings show the importance of targeting specific antioxidant pathways to manage the AF in patients with obesity.

Circulation, Volume 146, Issue Suppl_1, Page A9504-A9504, November 8, 2022. Introduction:The pathobiological mechanisms of coronary plaque erosion are unclear. Low endothelial shear stress (ESS) is a proinflammatory/proatherogenic stimulus associated with coronary plaque progression/destabilization. Intravascular imaging studies suggest that high ESS gradient (low ESS areas adjacent to high ESS areas), and steepness of plaque upslope/downslope correlate with plaque erosion. We investigated the relationship of local fluid hemodynamics to the inflammatory microenvironment at the culprit site of erosion in patients with an acute coronary syndrome.Hypothesis:ESS metrics associate with proinflammatory/proatherogenic cells and cytokines, and contribute to plaque erosion.Methods:We studied 30 patients with erosion from the OPTIcal-COherence Tomography in Acute Coronary Syndrome study (OPTICO-ACS). OCT images were segmented, co-registered with the angiogram to create a 3D-reconstruction of the coronary artery. ESS metrics were calculated by Computational Fluid Dynamics. Systemic and local blood samples and thrombectomy specimens were collected at the culprit lesion and analyzed by flow cytometry-based immunophenotyping and plasma cytokine and chemokine profiling, and statistically tested for correlations of continuous variables using Spearman rank correlation (r).Results:Proinflammatory cytokines (IL6, MIP-1, IL1β, IL2) and local concentration of T-cells, including subsets of T-cells (CD4+, CD8+, and NKT-cells), were significantly higher at the culprit site of erosion and correlate with local adverse ESS metrics (Min ESS, Max ESS, Plaque Topographical Slope) (Table).Conclusion:Biomechanical features likely trigger activation of the adaptive immune system, including T-lymphocytes and their cytotoxic effector molecules. These results provide novel insights into the links between fluid hemodynamics, inflammatory activation, and mechanisms involved in the pathogenesis of coronary plaque erosion.

Circulation, Volume 146, Issue Suppl_1, Page A15067-A15067, November 8, 2022. Introduction:Ischemia with non-obstructive coronary arteries (INOCA) is a relatively new condition, often observed in patients with angina. However, the exact pathophysiology of INOCA is not fully understood, and its management remains very debated.Hypothesis:We hypothesized that admission hyperglycemia in INOCA patients could be associated with the risk of being re-hospitalized for chest pain.Methods:We evaluated INOCA patients referred to our Institution between 2016 and 2021 for percutaneous coronary intervention (PCI). We divided our population in quintiles according to the values of the stress hyperglycemia ratio (SHR), calculated as the ratio of admission blood glucose (expressed as mmol/L) and HB1Ac (%). We calculated Kaplan-Meier product limits for cumulative ratio of reaching the endpoint and we applied the log-rank test. To further confirm our results, we performed a multivariable analysis in order to adjust for potential confounders.Results:2874 INOCA patients were enrolled in our study. At 1-year follow-up, the risk of hospitalization for chest pain was progressively higher in patients with higher SHR values (p

Circulation, Volume 146, Issue Suppl_1, Page A12932-A12932, November 8, 2022. Introduction:Exercise Stress Echocardiography (ESE) is recommended as a screening tool for the evaluation of Coronary Artery Disease (CAD) in patients with suspected Radiation-Induced Heart Disease (RIHD). Up to now, studies have only evaluated its association with the extent of CAD.HypothesisCancer survivors treated with chest Radiotherapy (RT) that undergo an ESE and have a +ESE develop more MACE than those who have -ESE.Methods:A retrospective, descriptive, cohort study was conducted. Patients who had chest RT and underwent ESE with Treadmill Bruce Stress Protocol, from 2000 to 2012, at Mayo Clinic Rochester and Mayo Clinic Health System were included. A univariate analysis was performed to characterize the population. An analysis including Kruskal Wallis and Pearson Chi-Squared tests was completed to identify variables associated with + SE (Table 1). Multivariable Cox Model for MACE was conducted and is shown in Table 2. A time-to-event curve using Kaplan-Meier estimates is shown in Figure 1.Results:We identified 113 patients, with a mean age of 67 years and a median follow-up of 15.1 years. Of those, 99% were female, 98% were breast cancer survivors, 59% had HTN, 14% DM, 11% AFib, 2% COPD, and 12% had a history of MI. All the patients received >3000cGy of Photon RT, and 57% were treated with systemic cancer therapies. A +ESE was seen in 20.3% of the patients with no significant difference in METS achieved compared with patients who had a -ESE. COPD, RT dose, and systemic therapies, specifically doxorubicin, were associated with a +ESE. The cumulative incidence of MACE was higher in the group of +ESE (p=0.029). After adjustment for HTN, DM, smoking history, hyperlipidemia, and prior MI, the HR for MACE associated with a +ESE was 1.97 (1.09-3.59).Conclusion:MACE was more frequent in patients with a +ESE who received chest RT and doxorubicin versus -ESE. These results support the usefulness of ESE in cancer survivors after RT as a cardiovascular screening tool.

Circulation, Volume 146, Issue Suppl_1, Page A10098-A10098, November 8, 2022. Introduction:Dobutamine and exercise stress echo are routinely performed on patients with advanced cirrhosis though have low sensitivity in this patient population, even when target heart rate is achieved. This is in part due to their unique cardiovascular physiology which is frequently marked by reduced peripheral vascular resistance with low blood pressure, impaired chronotropic response to stress, hyperdynamic left ventricular systolic function and elevated cardiac output. In the general population, achieving a rate pressure product (RPP), defined as peak systolic blood pressure multiplied by peak heart rate, > 25,000 is typically considered a high level of stress and is an adequate workload to detect ischemia, however this has not been validated in patients with advanced cirrhosis. We aimed to assess the impact of achieving a RPP > 25,000 on the ability of stress echo to detect obstructive coronary artery disease (CAD) in patients with advanced cirrhosis.Methods:We performed a case-control study on patients with advanced cirrhosis where 88 had and 97 did not have CAD based on invasive coronary angiography. A total of 159 patients (85.9%, 77 with CAD and 82 without) had dobutamine and 26 (14.1%, 11 with CAD and 15 without) had exercise as their stress modality. Continuous variables were compared by means of Wilcoxon Rank Sum test. Categorical variables were expressed as numbers and percentages and compared by means of chi-square and Fisher exact tests.Results:The average maximum RPP was 19,999 ± 4,969.4 with 32 patients (17.3%) achieving a RPP > 25,000 (14 with and 18 without CAD, P = 0.63). The average percent of maximum predicted HR (MPHR) achieved was 86.7 ± 9.2% with 136 patients (73.5%) achieving > 85% of MPHR. Achieving a maximum RPP > 25,000 (OR 0.83, 95% CI 0.39 – 1.79, P = 0.63) or a MPHR > 85% (OR 1.04, 95% CI 0.54 – 1.99, P = 0.92) did not improve the ability of stress echo to detect obstructive CAD.Conclusions:Achieving a maximum RPP > 25,000 did not improve the ability of stress echo to detect obstructive CAD in patients with advanced cirrhosis.

Circulation, Volume 146, Issue Suppl_1, Page A14748-A14748, November 8, 2022. Introduction:Chronic stress conditions associate with a greater incidence of hypertension (HTN).Hypothesis:We tested whether genetic risk for or neurobiological features of vulnerability to chronic stress associate with the risk for and timing of HTN.Methods:Data were obtained from Mass General Brigham Biobank participants. HTN was defined as >2 International Classification of Disease codes at least one week apart. Those with secondary HTN and those diagnosed at age

Circulation, Volume 146, Issue Suppl_1, Page A13105-A13105, November 8, 2022. Introduction:Pulmonary arterial hypertension (PAH) is a rare fatal disease with vascular remodeling leading to increased right ventricular pressure followed by fibrosis. To study PAH-induced cardiac fibrosis we develop anin vitromodel of the failing right ventricle, for which cardiac fibroblasts (cFBs) were generated from healthy subjects’ and PAH patients’ induced pluripotent stem cells (iPSC).Methods:Confluent iPSC were induced to differentiate by adding 12 μM CHIR99021 for 24h to RPMI supplemented with B27 without insulin. Next, cells recovered for 24 h in RPMI supplemented with B27 without insulin, followed by stimulation with 75 ng/ml FGF2 up to day 20. Finally, the differentiated cells were reseeded and submitted to 10% cyclic stretch at 1 Hz for 4 days using the Flexcell FX-6000 system. Control and PAH cFBs were characterized at gene and protein levels.Results:The differentiated cells had a spindle morphology typical of FBs. Furthermore, the presence of cardiac (GATA4, TCF21) and fibroblast (VIM, PDGFRα, COL1A1) markers at gene and protein levels confirmed the cFB identity. Comparable expression of fibroblast related genes was observed in PAH cFBs as well as controls. Over 4 weeks of culture, iPSC-cFBs increasingly expressed markers of activated FBs (ACTA2andPOSTN)over time, similar to in vitro adult cFBs. When exposed to mechanical stretch, cell aligned to the stretch direction. Surprisingly, no increase in gene expression of extracellular matrix (COL1A1, COL3A1) or activated fibroblasts (ACTA2, POSTN) markers was observed.Interestingly, under static and stretch conditions expression of these genes was increased in PAH cFBs compared to healthy cells.Conclusion:The cellular morphology after differentiation as well as the gene and protein analyses indicate that cFBs were successfully generated. Furthermore, cyclic stretch induced alignment of the cells but was not sufficient to stimulate fibroblast activation in either PAH or healthy cFBs.

Circulation, Volume 146, Issue Suppl_1, Page A14497-A14497, November 8, 2022. Introduction:Hypertensive response during stress echocardiography has been predominately studied in a healthy population without many comorbidities, unlike the patients for which these tests are indicated. We performed a retrospective study identifying clinical predictors of hypertensive response to both exercise (EXE) and dobutamine (DSE) stress echo.Methods:Retrospective analysis was performed on all patients who underwent stress echo from January 1, 2015 to February 28, 2017 in a tertiary care academic center. Patient demographics, comorbidities, medications and stress echo parameters were evaluated. Patients were characterized based on stress echo completed as EXE or DSE. The primary outcome was hypertensive response.Results:4670 patients were enrolled: 1238 in the DSE group and 3432 in the EXE group. On multivariable analysis, only resting SBP remained a significant predictor of hypertensive response during DSE (odds ratio (OR) per 20mmHg 3.21, CI 1.57-6.59,p=.001) with an AUC of 0.76. On multivariable analysis, obesity (OR 2.27, CI 1.08-4.8,p=.03), diabetes (OR 3.24, CI 1.22-8.6,p=.02), resting SBP (OR 4.44, CI 2.35-8.38,p