Risultati per: Le sigarette light sono più pericolose di quelle normali

Circulation, Volume 146, Issue Suppl_1, Page A13258-A13258, November 8, 2022. Introduction:Atrial fibrillation (AF) is the most common sustained arrhythmia, with an estimated prevalence in the U.S. of 6.1 million . AF increases the risk of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. We have recently identified protein phosphatase 1 subunit 12c (PPP1R12C) as a key molecule targeting myosin light chain phosphorylation in AF.ObjectiveWe hypothesize that the overexpression of PPP1R12C causes hypophosphorylation of atrial myosin light chain 2 (MLC2a), thereby decreasing atrial contractility in AF.Methods and ResultsLeft and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluate the role of the PP1c-PPP1R12C interaction in MLC2a de-phosphorylation, we utilized Western blots, co-immunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12CPP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A) PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls.ConclusionThe overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, associated with a reduction in atrial contractility and increase in AF inducibility. All these discoveries suggest that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

Circulation, Volume 146, Issue Suppl_1, Page A12887-A12887, November 8, 2022. The most common subsets of amyloidosis that affect the heart include light chain (AL) and transthyretin (ATTR). While both types cause diffuse amyloid fibril deposition within the interstitial space of the myocardium, they arise from two different precursors. AL amyloidosis results from misfolded monoclonal light chains, whereas ATTR amyloidosis results from misfolded transthyretin monomers. This distinction is essential as it suggests that a diagnosis of one disease does not exclude the existence of the other. We present a unique case of a patient with evidence of both systemic ATTR and AL amyloidosis occurring concurrently.An 80-year-old male with a past medical history of severe mitral regurgitation S/p mechanical mitral valve replacement, rotator cuff tear, bilateral carpal tunnel syndrome, and multiple hospitalizations for decompensated systolic heart failure was referred to cardiomyopathy clinic. He presented with class III New York Heart Association (NYHA) symptoms, including significant limitations in activity due to dyspnea. An echocardiogram demonstrated severe left ventricular hypertrophy with a low global longitudinal strain, an apical sparing pattern suspicious of amyloidosis. Monoclonal gammopathy workup showed an elevated lambda free light chain. Subsequent bone marrow biopsy demonstrated plasma cell dyscrasia and amyloid deposition in hypocellular bone marrow. Mass spectrometry showed both lambda light chain and transthyretin amyloid protein. He had elevated cardiac biomarkers, speaking for advanced cardiac involvement, together with nephrotic range proteinuria. He was started on chemotherapy/immunotherapy, with daratumumab, bortezomib and dexamethasone. He was in end stage heart failure requiring inotropic support. Few weeks after chemotherapy, he transitioned toward hospice care.In conclusion, we present a rare case of ATTR and AL amyloidosis coinciding simultaneously that demonstrates the importance of having high index of suspicion for this disease, a stepwise and thorough diagnostic approach highlighting the importance of mass spectroscopy after amyloid protein detection.

Circulation, Volume 146, Issue Suppl_1, Page A10310-A10310, November 8, 2022. Introduction:Untreated, light-chain (AL) cardiac amyloidosis is associated with a median survival of 6-months when diagnosed in advanced stage. However, current plasma cell-targeting therapies have drastically improved end-organ function and life expectancy. Yet, a portion still die despite appropriate treatment. We hypothesize this is from sudden cardiac death (SCD).Aim:To determine the incidence of and clinical characteristics associated with 90-day SCD after diagnosis of AL amyloidosis.Methods:Clinical, electrocardiographic, imaging, treatment, and outcomes were abstracted from consecutive patients diagnosed with AL amyloidosis from 2014-2022 at UT Southwestern Medical Center. Statistics were reported as mean and standard deviation.Results:In our study cohort (N=189) patients with AL amyloidosis, 18 patients (66% male, age 65 ± 9.5 y) died by 90-days (9.5%). Of these, 14 patients died by 60-days (7.3%), and 10 patient died by 30-days (5.2%). There were 7 cardiac deaths (3.6%): including one PEA arrest (0.5%), one in-hospital cardiac arrest (0.5%) and five unwitnessed out-of-hospital cardiac arrests (2.6%). Among cardiac deaths, 3 patients had endomyocardial tissue consistent with AL. Revised Mayo Stage was 66% III, 33% IV. Six patients had at least one dose of chemotherapy with bortezomib, cyclophosphamide and dexamethasone (CyBorD), Velcade/Dexamethasone, or Daratumumab/CyBorD, and 5 had at least one full cycle. The LVEF was 48.9 ± 8.1, QTc 483 ± 50 ms, interventricular septal thickness was 1.2 cm ± 0.4 cm. CMR was obtained in 4 of 7 patients, with late gadolinium enhancement present in a diffuse pattern in 75%, average LVEDV 59 ± 9.5 mL. Mean time to death was 37.2 ± 21 days.Conclusions:Sudden cardiac death may be a significant contributor to mortality among patients with newly diagnosed AL amyloidosis. These observations warrant confirmation in larger cohorts and may identify an unmet need to enhance risk stratification for SCD in this population.

Circulation, Volume 146, Issue Suppl_1, Page A15402-A15402, November 8, 2022. Introduction:Smooth muscle (SM) contraction is regulated by an increase in [Ca2+],activation of myosin light chain kinase (MLCK) and phosphorylation of myosin regulatory light chain (RLC20) activating myosin crossbridge cycling. MLCK null mice die at birth, but SM retains the ability to contract suggesting the presence of another kinase(s). Based on studies with WT and p90 ribosomal S-6 kinase (RSK2) null mice, we reported that RSK2 activity accounts for ~ 25% of maximal contractile force in wild type (WT) resistance arteries.Hypothesis:RSK2 confers contractility via RLC20activation in smooth muscle cells of MLCK null mice.Methods:Tension was measured on E18 aorta, bladder, and umbilical artery from WT and MLCK-/-embryos, in response to phenylephrine, carbachol, high potassium, SM myosin phosphatase, calyculinA (10 uM), as well as Ca2+following permeabilization with α-toxin. VSMCs were cultured from E18 MLCK-/-aortae and from WT and RSK2-/-mouse mesenteric arteries. Serum starved cells were stimulated with serum and LPA (0.5 uM), in the presence and absence of RSK2 inhibitor, LJH685 (10 μM). Protein-protein interactions were assessed by in-situ PLA assay and immunoprecipitation. On-goingin-vitrostudies using purified myosin and kinases address RSK2 direct regulation of MLCK activity.Results:Strips from bladder SM and umbilical artery from WT and MLCK-/-embryos (E18), contracted in response to agonists and high [K]. pCa-tension curves showed the same sensitivity to Ca2+in MLCK-/-and WT. Maximal force induced by calyculinA was also the same indicating an intact normal contractile apparatus in the MLCK-/-. Significant phosphorylation of RLC20at Ser19 occurred in LPA- and serum-stimulated MLCK-/-SM cells, which was significantly inhibited by the RSK2 inhibitor, LJH685 (n=3). PLA assay showed co-localization of RSK2 and MLCK (

Circulation, Volume 146, Issue Suppl_1, Page A11818-A11818, November 8, 2022. Background:Immunoglobulin light-chain (AL) amyloidosis is a lethal condition resulting from misfolded immunoglobulin ALs produced by clonal CD38-positive plasma cells. Daratumumab, an anti-human CD38 monoclonal antibody, led to higher frequencies of complete hematologic responses and better clinical outcomes compared to conventional treatment. Therefore, daratumumab-containing regimens has become the standard of care in patients with systemic AL amyloidosis and multiple myeloma. This study sought to evaluate the survival benefit of daratumumab-containing regimens in patients with AL cardiac amyloidosis. Methods and Results: We examined 65 consecutive patients with AL cardiac amyloidosis (mean age: 67.2±10.4 years old, male: 69%) who underwent chemotherapy. We divided the patients into two groups, daratumumab group (n=32: treated with daratumumab containing regimens within the first two lines of chemotherapy) and conventional treatment group (n=33). Compared to conventional treatment group, daratumumab group tended to be older (69.2±9.6 vs. 65.2±11.0; p=0.12), while no significant differences in biomarkers and echocardiographic parameters were observed. A total of 26 patients (40%) were deceased (median follow up period: 395 days). Kaplan-Meier survival curves showed that daratumumab group had significantly lower mortality compared to conventional treatment group (p=0.04; log-rank test; Figure). Cox hazard analysis revealed that daratumumab containing regimens were associated with lower mortality after adjustment for revised Mayo staging system for AL amyloidosis (hazard ratio: 0.32; 95% confidence interval: 0.12 to 0.85; p=0.02).Conclusion:Daratumumab containing regimens might be associated with improved survival in AL cardiac amyloidosis.

Circulation, Volume 146, Issue Suppl_1, Page A13860-A13860, November 8, 2022. Introduction:Cardiac amyloidosis is a clinical disorder defined as an extracellular deposition of protein in the heart. Typically, signs and symptoms of heart failure develop in the advanced disease. High index of suspicion is required for the diagnosis of this disorder.Results:A 62 years old male came to the cardiology clinic due to lower extremity edema, fatigue, dyspnea on exertion. He had a 3 month history of progressive lower leg edema. On physical examination he had a positive S4; lung sounds were diminished and there was dullness to percussion over the lower two thirds; and bilateral lower extremity edema. Hospital admission was decided for management of decompensated heart failure. On admission, the surface ECG showed normal sinus rhythm with low QRS voltage in the limb leads, a RBBB and LPFB. Initial laboratory reported elevated NT-proBNP: 13,816 pg/mL. Chest x-ray demonstrated right interstitial infiltration and bilateral pleural effusion. The echocardiogram revealed severe concentric hypertrophy of the left ventricle, an apical sparing left ventricle longitudinal strain, and an ejection fraction of 68%. A cardiac MRI showed concentric biventricular hypertrophy associated with extensive diffuse late gadolinium enhancement, suggestive of cardiac amyloidosis. Screening resulted in a Perugini score of 1 on Tc-PYP scintigraphy, elevated Kappa and Lambda light chains on serum, and kidney biopsy positive for amyloidosis. Hematology-oncology consultation was done and a daratumumab-CyBorD protocol was started.Conclusions:This case elucidated a stepwise diagnostic approach of cardiac amyloidosis in a patient presenting with signs and symptoms of heart failure. Amyloid AL cardiac amyloidosis and its repercussions are severe because it not only compromises by being infiltrative but also by its toxic capacity. A high index of suspicion and a multidisciplinary approach is needed in order to improve quality of life and prolong survival.

Introduction
Fatigue is one of the most commonly recorded patient symptoms that can result in deficits in aspects of psychomotor functioning, cognition, work performance and mood. Research shows that bright light and dim light therapy may be an efficacious way to reduce symptoms of fatigue. Still, the feasibility, scalability, individual treatment effects and adverse event heterogeneity of these treatments are unknown.

Methods and analysis
The current study evaluates the feasibility, acceptability and effectiveness of a series of personalised (N-of-1) interventions for virtual delivery of bright light therapy and dim light therapy versus usual care treatment for fatigue in 60 participants. We hypothesise that this study will provide valuable information about implementing virtual, N-of-1 randomised controlled trials (RCTs) for fatigue. It will also offer results about determining participants’ ratings of usability and satisfaction with the virtual, personalised intervention delivery system; evaluating participants’ improvement of fatigue symptoms; and, in the long term, identify ways to integrate N-of-1 light therapy trials into patient care.

Ethics and dissemination
This trial was approved by the Northwell Health Institutional Review Board. The trial results will be published in a peer-reviewed journal. All publications resulting from this series of personalised trials will follow the Consolidated Standards of Reporting Trials extension for N-of-1 trials CENT 2015 reporting guidelines.

Registration details
This trial is registered in www.ClinicalTrials.gov (number NCT04707846).

Trial registration number
NCT04707846.

Introduction
Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes that strongly impact the patients’ quality of life and working ability. Evidence indicated that low level light therapy (LLLT)/photobiomodulation might be effective for neuropathy. However, the effect of LLLT for DPN is not clear. The objective of this systematic review and meta-analysis is to determine the effects and safety of LLLT/photobiomodulation for DPN, in comparison with other methods such as sham light, no treatment, other active treatment and LLLT as an additional treatment compared with another treatment alone.

Methods and analysis
We will search eight databases from their inception to the date before the review submission. Randomised controlled trials (RCTs) will be included. Two reviewers will independently extract data using a structured data extraction method and assess the risk of bias in the included studies. Data will be synthesised using standardised mean difference or risk ratio with 95% CIs for continuous and dichotomous data, respectively. The primary outcome will be change in pain and secondary outcomes will include global symptom improvement, functional impairment and disability, impairment of sensation, quality of life, nerve conduction, and adverse events. Sensitivity and subgroup analysis will be employed to explore the influence of possible clinical and methodological characteristics. Publication bias will be assessed using funnel plot. We will conduct meta-analysis with RevMan V.5.4 and evaluate quality of the evidence using GRADE approach.

Ethics and dissemination
This study does not require ethics approval. Our findings will be disseminated in the peer-reviewed publications.

PROSPERO registration number
CRD42021276056.

Stroke, Volume 53, Issue Suppl_1, Page AWP258-AWP258, February 1, 2022. Introduction:The spatiotemporal pattern of microvascular reperfusion in vivo after large vessel recanalization is poorly understood. Combining chronic cranial window with embedded microprism (CCW-MP) and visible-light optical coherence tomography angiography (Vis-OCTA) enables the study of mouse cortical cerebrovasculature up to 60 days post-stroke. Vis-OCTA/CCW-MP can identify the presence or absence of microvascular flow, without labelling, up to 1 mm in cortical depth of the mouse brain at 1.3 micron resolution. We sought to build on these findings to understand the pattern of microvascular no-reflow in a mouse model of stroke that simulates large vessel occlusion and reperfusion.Hypothesis:Different regions of the cortex have striking variation in flow characteristics after macrovascular reperfusion.Methods:All mice studied were 3-4 mo old, C57/Bl6 background, and subject to IMPROVE guideline. Control mice (n=3) were studied to confirm absence of cortical or vascular changes induced by CCW-MP surgery. Test mice (n =6) underwent CCW-MP as previously published. After 2 weeks to allow for healing post-surgery, mice were subject to transient middle cerebral artery occlusion (tMCAO) to model large vessel occlusion and reperfusion. Vis-OCTA measured cortical flow at baseline, 24 hours post-stroke, and 72 hours post-stroke. Cortical mouse vascular regions were divided into layers 1-3: layer 4 : layer 5-6 from top to bottom.Results:Control mice showed no neuronal death, astrogliosis, microgliosis, or neutrophil recruitment induced by CCW-MP implantation. There was no significant difference between vascular density for prism-adjacent cortex and prism-remote cortex. We also determined that the CCW-MP images cortical vascular territory supplied by the middle cerebral artery. For the test mice, all six mice survived combined surgery. Vis-OCTA showed four of six mice had reduction of microvascular flow > 20% from baseline by 72h post-stroke at layer 5-6.Conclusions:Microvascular reperfusion post large vessel recanalization can be incomplete up to 72 hours post-stroke, especially at deeper cortical levels. Further studies should define associated changes in inflammatory cells as well as oxygenation of vessels.