Risultati per: Lo stress può essere causa di infarto ed ictus

Circulation, Ahead of Print. BACKGROUND:Excitation-contraction (E-C) coupling processes become disrupted in heart failure (HF), resulting in abnormal Ca2+homeostasis, maladaptive structural and transcriptional remodeling, and cardiac dysfunction. Junctophilin-2 (JP2) is an essential component of the E-C coupling apparatus but becomes site-specifically cleaved by calpain, leading to disruption of E-C coupling, plasmalemmal transverse tubule degeneration, abnormal Ca2+homeostasis, and HF. However, it is not clear whether preventing site-specific calpain cleavage of JP2 is sufficient to protect the heart against stress-induced pathological cardiac remodeling in vivo.METHODS:Calpain-resistant JP2 knock-in mice (JP2CR) were generated by deleting the primary JP2 calpain cleavage site. Stress-dependent JP2 cleavage was assessed through in vitro cleavage assays and in isolated cardiomyocytes treated with 1 μmol/L isoproterenol by immunofluorescence. Cardiac outcomes were assessed in wild-type and JP2CRmice 5 weeks after transverse aortic constriction compared with sham surgery using echocardiography, histology, and RNA-sequencing methods. E-C coupling efficiency was measured by in situ confocal microscopy. E-C coupling proteins were evaluated by calpain assays and Western blotting. The effectiveness of adeno-associated virus gene therapy with JP2CR, JP2, or green fluorescent protein to slow HF progression was evaluated in mice with established cardiac dysfunction.RESULTS:JP2 proteolysis by calpain and in response to transverse aortic constriction and isoproterenol was blocked in JP2CRcardiomyocytes. JP2CRhearts are more resistant to pressure-overload stress, having significantly improved Ca2+homeostasis and transverse tubule organization with significantly attenuated cardiac dysfunction, hypertrophy, lung edema, fibrosis, and gene expression changes relative to wild-type mice. JP2CRpreserves the integrity of calpain-sensitive E-C coupling–related proteins, including ryanodine receptor 2, CaV1.2, and sarcoplasmic reticulum calcium ATPase 2a, by attenuating transverse aortic constriction–induced increases in calpain activity. Furthermore, JP2CRgene therapy after the onset of cardiac dysfunction was found to be effective at slowing the progression of HF and superior to wild-type JP2.CONCLUSIONS:The data presented here demonstrate that preserving JP2-dependent E-C coupling by prohibiting the site-specific calpain cleavage of JP2 offers multifaceted beneficial effects, conferring cardiac protection against stress-induced proteolysis, hypertrophy, and HF. Our data also indicate that specifically targeting the primary calpain cleavage site of JP2 by gene therapy approaches holds great therapeutic potential as a novel precision medicine for treating HF.

Minore multimorbidità cardiometabolica

Lo rivela una ricerca sul New England Journal of Medicine

Può alterare l’rna dello sperma favorendo rischi per il cuore

Può alterare l’rna dello sperma favorendo rischi per il cuore

Circulation, Ahead of Print. BACKGROUND:The docking protein IRS2 (insulin receptor substrate protein-2) is an important mediator of insulin signaling and may also regulate other signaling pathways. Murine hearts with cardiomyocyte-restricted deletion ofIRS2(cIRS2-KO) are more susceptible to pressure overload–induced cardiac dysfunction, implying a critical protective role of IRS2 in cardiac adaptation to stress through mechanisms that are not fully understood. There is limited evidence regarding the function of IRS2 beyond metabolic homeostasis regulation, particularly in the context of cardiac disease.METHODS:A retrospective analysis of an electronic medical record database was conducted to identify patients withIRS2variants and assess their risk of cardiac arrhythmias. Arrhythmia susceptibility was examined in cIRS2-KO mice. The underlying mechanisms were investigated using confocal calcium imaging of ex vivo whole hearts and isolated cardiomyocytes to assess calcium handling, Western blotting to analyze the involved signaling pathways, and pharmacological and genetic interventions to rescue arrhythmias in cIRS2-KO mice.RESULTS:The retrospective analysis identified patients withIRS2variants of uncertain significance with a potential association to an increased risk of cardiac arrhythmias compared with matched controls. cIRS2-KO hearts were found to be prone to catecholamine-sensitive ventricular tachycardia and reperfusion ventricular tachycardia. Confocal calcium imaging of ex vivo whole hearts and single isolated cardiomyocytes from cIRS2-KO hearts revealed decreased Ca²+transient amplitudes, increased spontaneous Ca²+sparks, and reduced sarcoplasmic reticulum Ca²+content during sympathetic stress, indicating sarcoplasmic reticulum dysfunction. We identified that overactivation of the AKT1/NOS3 (nitric oxide synthase 3)/CaMKII (Ca2+/calmodulin-dependent protein kinase II)/RyR2 (type 2 ryanodine receptor) signaling pathway led to calcium mishandling and catecholamine-sensitive ventricular tachycardia in cIRS2-KO hearts. Pharmacological AKT inhibition or genetic stabilization of RyR2 rescued catecholamine-sensitive ventricular tachycardia in cIRS2-KO mice.CONCLUSIONS:Cardiac IRS2 inhibits sympathetic stress-induced AKT/NOS3/CaMKII/RyR2 overactivation and calcium-dependent arrhythmogenesis. This novel IRS2 signaling axis, essential for maintaining cardiac calcium homeostasis under stress, presents a promising target for developing new antiarrhythmic therapies.

Annals of Internal Medicine, Ahead of Print.

Annals of Internal Medicine, Ahead of Print.

Connubio trasversale tra Campidoglio e Regione per chiedere più fondi al Governo e in particolare al ministro dei Trasporti

Il decesso a marzo a 28 anni. L’ospedale, chiesta noi l’autopsia

Il decesso a marzo a 28 anni. L’ospedale, chiesta noi l’autopsia

Uno studio pubblicato su Nature Communication fa luce su Oser1

“Sistema imperfetto ma andava potenziato e non smantellato”

Introduction
The decisions of withholding or withdrawing life-sustaining treatments are difficult to make in the context of emergency departments (EDs) because most patients are unable to communicate. Relatives are thus asked to participate in the decision-making process, although they are unprepared to face such situations. We therefore aimed to develop a standardised intervention for announcing decisions of withholding or withdrawing life-sustaining treatments in EDs and assess the efficacy of the intervention on the stress of relatives.

Methods and analysis
The DISCUSS trial is a multicentre stepped-wedge cluster randomised study and will be conducted at nine EDs in France. A standardised intervention based on human simulation will be codesigned with partner families and implemented at three levels: the relatives, the healthcare professionals (HCP) and the EDs. The intervention will be compared with a control based on treatment as usual. A total of 538 families are planned to be included: 269 in the intervention group and 269 in the control group. The primary endpoint will be the symptoms of post-traumatic stress disorder (PTSD) at 90 days. The secondary endpoints will be symptoms of PTSD at 7 and 30 days, diagnosis of PTSD at 90 days and anxiety and depression scores at 7, 30 and 90 days. Satisfaction regarding the training, the assertiveness in communication and real-life stress of HCPs will be measured at 90 days.

Ethics and dissemination
This study was approved by the ethics committee Est III from Nancy and the French national data protection authority. All relatives and HCPs will be informed regarding the study objectives and data confidentiality. Written informed consent will be obtained from participants, as required by French law for this study type. The results from this study will be disseminated at conferences and in a peer-reviewed journal.

Trial registration number
NCT06071078.

Objective
To understand the current status of occupational stress, occupational burn-out and sleep quality among ambulance drivers in Hengyang, China and to analyse the relationship between occupational stress, occupational burn-out and sleep quality of ambulance drivers.

Design
A cross-sectional study.

Setting
Prehospital emergency centre of third-class hospital in Hengyang, China.

Participants
From October 2023 to December 2023, a cross-sectional survey was conducted, with 213 ambulance drivers from Hengyang, China, selected as participants.

Methods
General demographic questionnaires, the Chinese Occupational Stress Inventory, the Maslach Burnout Inventory and the Pittsburgh Sleep Quality Index were used for data collection and analysis.

Results
Occupational stress among ambulance drivers was positively correlated with occupational burn-out and sleep quality (r=0.528, 0.447, both p