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 A10014-A10014, November 8, 2022. Background:Work-related stress is a psychosocial risk factor linked to a higher risk of adverse health outcomes, especially cardiovascular disease (CVD). However, the association between work-related stress and ideal cardiovascular health (CVH) is not well established. We examined whether work-related stress was negatively associated with favorable CVH in a multi-ethnic population of adults free of CVD at baseline.Methods:We analyzed cross-sectional data of 6,486 men and women aged 45-84 years. Work-related stress was assessed by the presence or absence of ongoing job difficulty and ongoing job difficulty for >6 months. CVH was measured by a scoring system that assigned points to 7 metrics (smoking, physical activity, body mass index, diet, total cholesterol, blood pressure and blood glucose). Each metric had 3 categories: poor (0 points), intermediate (1 point) and ideal (2 points). The total score attainable was 14 points, categorized as inadequate (0-8 points), average (9-10 points) and optimal (11-14 points). We used polytomous logistic regression to examine the association of work-related stress with the CVH score and number of ideal metrics, adjusted for sociodemographic factors.Results:The mean age (SD) was 62 (10) years and 53% were women. Ongoing job difficulty was reported by 14% of participants while 13% reported ongoing job difficulty for >6 months. Participants who reported ongoing job difficulty had 21% and 24% lower odds of having average and optimal CVH scores, respectively(Table).Additionally, the presence of ongoing job difficulty for >6 months was associated with 23% and 24% lower odds of having average and optimal CVH scores, respectively. A similar trend was observed for the association of work-related stress with the number of ideal metrics.Conclusion:Work-related stress was negatively associated with favorable CVH. Stress reduction and CVH promotion programs in the workplace may decrease the incidence of CVD.

Circulation, Volume 146, Issue Suppl_1, Page A14807-A14807, November 8, 2022. Introduction:Stress-induced cardiomyopathy (SIC) is a form of transient non-ischemic cardiomyopathy that is precipitated in the setting of acute emotional or physical stress. Postulated hypothesis implicated catecholaminergic excess and a role of the brain-heart axis behind its pathogenesis. The impact of different psychiatric illnesses on the outcomes of SIC is not clear.Method:We conducted a retrospective study using National Readmission Database (NRD) from 2011 to 2019 using ICD-10-CM (International Classification of Diseases, 10th Edition, Clinical Modification) and ICD-9-CM codes to identify the admissions with the discharge diagnosis of SIC and stratified them based on the presence of psychiatric illnesses. The primary outcome was six-month readmission and predictors of readmission.Result:We included a total of 98,721 admissions with a diagnosis of SIC. Among them, 12.9% had major depression, 1.8% had bipolar disorder, 17.6% had an anxiety disorder, and 0.6% had schizophrenia. Overall, patients with psychiatric illnesses were younger. Patients with psychiatric illnesses had a higher burden of comorbidities. Patients with schizophrenia had higher in-hospital mortality. Patients with psychiatric illnesses had a higher likelihood of getting readmitted within six months (p

Circulation, Volume 146, Issue Suppl_1, Page A9608-A9608, November 8, 2022. Background:Recent evidence highlights oxidative stress as an important mechanism to cardiac dysfunction in type 2 diabetes (T2D) and altered β3-adrenergic receptor (AR)-activated nitric oxide synthase (NOS) pathway contributing to this process. However, the NOS isoforms involved are controversial. The mechanism of how β3-AR stimulation impacts ROS, SERCA2a, and cardiac function in T2D is unclear. We tested the hypothesis that oxidant stress from upregulation of LV β3-AR-activated iNOS uncoupling promotes T2D cardiomyopathy.Methods:We compared myocyte β1- and β3-AR, NOS, peroxynitrite (NT), NADPH and SERCA2a expressions and myocyte functional responses to β- and β3-AR stimulation with isoproterenol (ISO,10-8M) and BRL-37344 (BRL,10-8M), respectively, in the absence and presence of iNOS inhibitor, 1400W (10-5M) of female mice over 14 weeks (W): 7 normal and 7 with T2D induced by 14 W high-fat diet (HFD) intake, but after HFD for 4 W receiving streptozotocin (STZ, 40 mg/kg/day, i.p. 5 days).Results:Versus normal myocytes, T2D myocytes had significantly increased protein levels of β3-AR (0.25 vs 0.14) and iNOS (0.25 vs 0.15) accompanied with increased oxidative stress indicated by significantly-elevated NT formation, NADPH (P67-phox, 33% and p22-phox, 29%) and decreased GTPCH expression (0.43 vs 0.85) and activity. T2D myocytes had significantly decreased β1-AR (0.35 vs 0.49) and SERCA2a (0.19 vs 0.29). These changes were associated with reduced cell contraction (dL/dtmax, 75.4 vs 133.7 μm/s), relaxation (dR/dtmax, 59.6 vs 113.8 μ m/s), and [Ca2+]iT(0.16 vs 0.21) accompanied by diminished β-AR-stimulated positive inotropic response, but enhanced β3-AR-induced negative inotropic response. Only in T2D myocytes, pretreatment with 1400W improved basal cell function and augmented ISO-increased dL/dtmax(64.5%) and [Ca2+]iT(29.2%), but significantly limited BRL-induced decrease in dL/dtmax(12.7%) and [Ca2+]iT(9.8%).Conclusions:T2D is associated with contrasting changes on myocyte β1- and β3-AR expression with decreased SERCA2a and increased iNOS. Upregulation of β3-AR triggers iNOS uncoupling, leading to oxidative stress, thus promoting intrinsic myocyte dysfunction with impaired [Ca2+]iregulation and reduced β-AR reserve.

Circulation, Volume 146, Issue Suppl_1, Page A11734-A11734, November 8, 2022. Introduction:Chest pain is common in patients with Post-acute Sequelae of SARS-CoV-2 (PASC), also known as long COVID, but the mechanism is unknown.Hypothesis:We hypothesized that PASC patients with chest pain have impaired myocardial perfusion reserve (MPR) measured by stress perfusion cardiovascular magnetic resonance (CMR) imaging.Methods:We retrospectively identified the first 30 consecutive patients who underwent clinically ordered adenosine stress perfusion CMR for chest pain persisting >4 weeks after SARS-CoV-2 infection (PASC). Patients with a history of coronary artery disease (CAD) or left ventricular ejection fraction (LVEF) 2 SD below mean MPR for controls.Results:In 30 PASC (67% female, age 43±13) and 13 controls (54% female, age 50±12), with LVEF (61±6% vs 59±8%), native T1 (1001±49 vs 992±57 ms), T2 (49.5±3.7 vs 48.0±3.3 ms), and ECV (24.6±2.9 vs 24.6±2.6%) were similar (p >0.2 for all). Prior pericarditis (n=2) or prior myocarditis (n=3) were infrequent, with no acute disease by CMR. PASC patients had significantly lower global MPR than controls (1.54±0.25 vs. 2.20±0.36, p

Circulation, Volume 146, Issue Suppl_1, Page A11502-A11502, November 8, 2022. Background -Mitral valve prolapse (MVP) is a common valvular abnormality found in approximately 2.4% of the population. Whereas the majority of cases are benign, an increasingly recognized sequela of MVP is sudden cardiac death (SCD), but triggers and risk factors for SCD are not well-defined. It is theorized that increased stretch on the papillary muscles due to MVP leads to papillary muscle fibrosis and cellular changes of local conduction properties, increasing the risk of ventricular arrhythmias and SCD.Hypothesis- We hypothesized that patients with MVP and SCD would have increased ventricular arrhythmias and ECG changes compared to MVP controls during exercise stress testing.Methods -The study population was generated from the Duke Epic. Patients were included if they had guideline-based diagnosis of MVP on echocardiogram or cardiac magnetic resonance imaging. Increase in ventricular arrhythmias during exercise was defined as >/= 10 PVCs per minute, multifocal PVCs, or >/= 2 PVCs in a row.Results-A total 2,513 patients with MVP were screened. 18 patients with SCD. Patients with SCD were younger [(47.22 +/- 12.2 ) vs. (58.0 +/- 18.7), p=0.02], more likely to be female (89.9% vs 64%, p=0.04) and had increased rate of bileaflet prolapse (72% vs. 40%, p=0.01) compared to controls. Patients with sudden cardiac death had either dynamic T wave changes or increased ventricular arrhythmias with stress testing versus controls [12/18 (66.7%) vs 17/75 (22.6%), p

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 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 A14778-A14778, November 8, 2022. Introduction and Hypothesis:Arterial healing following stent implantation involves a series of biological reactions such as thrombosis, inflammation, neointimal regeneration. Clinical evidences have shown favorable arterial healing after thin-strut stents, however, there has been a lack ofin vivoimaging evidence on how strut thickness affect vascular healing process. We evaluated local endothelial shear stress (ESS) and healing response of a thin-strut bioresorbable scaffold (BRS, 100μm) compared to first-generation 157μm-thickness ABSORB.Methods and Results:BRS and ABSORB were simultaneously implanted in left coronary arteries of the same pigs (n=7). Detailed scaffolded-artery 3D model was reconstructed based on OCT and angiography. Scaffold-related inflammation response was serially assessed by dual-modal OCT-near-infrared fluorescence (OCT-NIRF) molecular imaging using macrophage-mannose receptor-Cy7 as an inflammation-targeting agent. On ESS analysis, regions with athero-prone low ESS were significantly greater in thick-ABSORB compared to BRS. Dual-modal OCT-NIRF imaging visualized arterial inflammation activity at peri-strut regionsin vivo(Figure). Based on coregistered ESS-NIRF data, we found a significant inverse correlation was found between ESS and NIRF activity (p