bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myeloid CD40 deficiency reduces atherosclerosis by impairing macrophages’ transition into a pro-inflammatory state
Authors: Bosmans Laura A , van Tiel Claudia M , Aarts Suzanne A B M , Willemsen Lisa , Baardman Jeroen , van Os Bram W , Toom Myrthe den , Beckers Linda , Ahern David J , Levels Johannes H M , Jongejan Aldo , Moerland Perry D , Verberk Sanne G S , den Bossche Jan van , de Winther Menno M P J , Weber Christian , Atzler Dorothee , Monaco Claudia , Gerdes Norbert , Shami Annelie , Lutgens Esther 
Published: May 2022

Abstract

Aims
CD40 and its ligand, CD40L, play a critical role in driving atherosclerotic plaque development. Disrupted CD40-signalling reduces experimental atherosclerosis and induces a favourable stable plaque phenotype. We recently showed that small molecule-based inhibition of CD40-tumour necrosis factor receptor associated factor-6 interactions attenuates atherosclerosis in hyperlipidaemic mice via macrophage-driven mechanisms. The present study aims to detail the function of myeloid CD40 in atherosclerosis using myeloid-specific CD40-deficient mice.

Method and Results
Cd40flox/flox and LysM-cre Cd40flox/flox mice on an Apoe−/− background were generated (CD40wt and CD40mac−/−, respectively). Atherosclerotic lesion size, as well as plaque macrophage content, was reduced in CD40mac−/− compared to CD40wt mice, and their plaques displayed a reduction in necrotic core size. Transcriptomics analysis of the CD40mac−/− atherosclerotic aorta revealed downregulated pathways of immune pathways and inflammatory responses. Loss of CD40 in macrophages changed the representation of aortic macrophage subsets. Mass cytometry analysis revealed a higher content of a subset of alternative or resident-like CD206+CD209b− macrophages in the atherosclerotic aorta of CD40mac−/− compared to CD40wt mice. RNA-sequencing of bone marrow-derived macrophages of CD40mac−/− mice demonstrated upregulation of genes associated with alternatively activated macrophages (including Folr2, Thbs1, Sdc1, and Tns1).

Conclusions
We here show that absence of CD40 signalling in myeloid cells reduces atherosclerosis and limits systemic inflammation by preventing a shift in macrophage polarization towards pro-inflammatory states. Our study confirms the merit of macrophage-targeted inhibition of CD40 as a valuable therapeutic strategy to combat atherosclerosis.
Clinical experience with dual pathway inhibition therapy: case series and mini review
Authors: Geisler Tobias , Branch Kelley , Nikol Sigrid 
Published: May 2022

Abstract

Background
Dual pathway inhibition (DPI) with rivaroxaban 2.5 mg twice daily plus aspirin has demonstrated reductions in major adverse cardiovascular and limb events in eligible patients with chronic coronary artery disease (CAD), peripheral artery disease, or both. Patients with polyvascular disease, heart failure, renal impairment, or diabetes can benefit particularly from this therapy. We present our clinical experience to elucidate practical issues regarding the selection of patients eligible for DPI and the timing of initiation.

Case summary
The first patient was at high risk of recurrent cardiovascular events due to his history of multi-vessel CAD, myocardial infarction, heart failure, and diabetes. Following a period of post-myocardial infarction dual antiplatelet therapy, he was transitioned to DPI therapy. The second patient was at high risk of cardiovascular events due to his history of polyvascular disease, diffuse CAD, and diabetes. He was hospitalized for unstable angina, which was medically managed because no target lesion was identified. DPI was initiated a day after admission. The third patient was at high risk of cardiovascular events due to an extensive history of polyvascular disease, revascularization, and renal impairment. Although the patient was asymptomatic at routine follow-up, DPI was initiated to reduce the risk of further cardiovascular events.

Discussion
In eligible patients who are at high risk of cardiovascular events, DPI therapy with low-dose rivaroxaban should be considered. Treatment can be started at various times, including at the end of dual antiplatelet therapy, at routine follow-up, or after new events or diagnoses.
C49 SACUBITRIL–VALSARTAN IMPROVES LONGITUDINAL STRAIN AND EJECTION FRACTION IN MICE TREATED WITH DOXORUBICIN THROUGH NLRP3, MYD88 PATHWAYS RESULTING IN A REDUCTION OF MYOCARDIAL IL–1Β, IL–6, TNF–Α, G–CSF AND GM–CSF LEVELS
Authors: Quagliariello V , Iovine M , Buccolo S , Paccone A , Maurea N 
Published: May 2022

Abstract

Introduction
Doxorubicin–mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sacubitril–valsartan (LCZ 696) is a combination drug, made up of neprilysin inhibitor sacubitril and angiotensin II receptor blocker valsartan, used for the treatment of heart failure in patients with a reduced ejection fraction.

Purpose
We hypothesized that LCZ 696, administered during doxorubicin, could improve cardiac function and cardiac inflammation in preclinical models Methods Human fetal cardiomyocytes (HFC cell line) were exposed to subclinical concentration of doxorubicin (200 nM) alone or in combination with LCZ–696 (100 mM) for 72 h. After the incubation period, we performed the following tests: cell viability, apoptosis and necrosis; expression of malondialdehyde and 4–hydroxynonenal and concentration of intracellular Ca2+. Moreover, pro–inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of TLR4/MyD88; mTORC1 Fox01/3a; NF–κB). C57Bl/6 mice were untreated (Sham, n = 6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n = 6), LCZ–696 at 60 mg/kg (LCZ, n = 6) or doxorubicin combined to LCZ–696 (DOXO–LCZ, n = 6). Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd88, NF–kB and 13 chemokines (IL–1α, IL–1β, IL–2, IL–4, IL–6, IL–10, IL–12, IL17–α, IL–18, IFN–γ, TNF–α, G–CSF, and GM–CSF) were quantified.

Results
LCZ–696 exerts cardioprotective effects, enhancing cell viability of 48–54.6% compared to only doxorubicin–treated cells (p &lt; 0,001 for all); LCZ 696 decreased NLRP3, MyD88 and NF–kB expression in cardiac cells. In preclinical study, LCZ 696 improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. A reduced expression of NLRP3, MyD88 and NF–kB in cardiac tissues was seen in DOXO–LCZ group compared to DOXO mice (p &lt; 0.001). Cardiac expression of IL–1β, IL–6, TNF–α, G–CSF and GM–CSF were significantly reduced after treatment with LCZ–696 indicating anti–inflammatory properties.

Conclusion
LCZ–696 exerts direct beneficial effects in cardiomyocytes exposed to doxorubicin. In preclinical models, LCZ–696 reduced inflammation and cytokine expression involved in doxorubicin–mediated cardiotoxicity.
C50 CARDIO–ONCO–HAEMATOLOGY IN CLINICAL PRACTICE. A “CHANGELING” CASE: MORE THAN PARADOXICAL BUBBLES
Authors: Bisceglia I , Mistrulli R , Cartoni D , Buffa V , Battistini R , Proia A , Rigacci L , Petrolati S 
Published: May 2022

Abstract
39–year–old female, without cardiovascular risk factors. At the end of pregnancy she complained of progressive dyspnoea and so she was admitted to the emergency room. Blood tests showed elevated D–dimer and LDH values. A chest CT scan was performed showing a mediastinal mass of about 15 cm encompassing the ascending aorta, the left brachiocephalic trunk and the superior vena cava, both of which appeared thrombosed. Therapy with low molecular weight heparin was started. The patient underwent a mediastinal biopsy, which documented a primary mediastinal non–Hodgkin‘s lymphoma. The baseline cardiological evaluation showed a preserved ejection fraction (60%) at echocardiogram (ECHO). The first cycle of chemotherapy with R–CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine) was started. After an episode of hypoesthesia of the left upper limb, that regressed spontaneously within a few hours, she performed MRI that showed multiple areolas compatible with ischemic disease. Following these results the patient was submitted to an ECHO with saline solution injected through the right brachial vein that documented evidence of early opacification of the left atrium and subsequent opacification of the right sections (after 3 cardiac cycles) (Fig. 1–2). This finding suggested a right–to–left shunting, via the bronchial lower district to the left atrium (pulmonary veins). This suspicion was confirmed by CT angiography, which showed occlusion of the superior vena cava with passage of contrast into azygos and early opacification of peribronchial venous circles (Fig. 3). A patency of foramen ovale was ruled out by injection of saline solution through the femoral vein. After the second cycle of chemotherapy, ECHO showed diffuse hypokinesia and reduced EF to 50%. It was then decided to proceed with the third cycle according to the intensified R–DAEPOCH scheme, except for doxorubicin, because of the cardiotoxicity developed by the patient. A cardioprotective therapy was also started with bisoprolol and ramipril with rapid titration. At subsequent radiological controls, a progressive reduction of the mediastinal mass was found and after just one month, the echocardiogram showed a complete recovery of the EF. Contrast injection confirmed presence of a veno–venous shunt. Cardio–oncology is an intriguing and complex discipline that requires the development of local multidisciplinary teams for challenging situations that patients with cancer may ask us to address.
C69 EFFECTIVENESS AND SAFETY OF DISTINCT ANTIPLATELET REGIMENS AFTER TRANSCATHETER LEFT ATRIALE APPENDAGE OCCLUSION: A SINGLE CENTER REAL–WORLD EXPERIENCE
Authors: Gurgoglione F , Barocelli F , Vignali L , Maini A , Solinas E , Tadonio I , Benatti G , Coli S , Pelà G , Grassi F , Lina D , Niccoli G , Cattabiani M 
Published: May 2022

Abstract
Transcatheter left atrial appendage occlusion (LAAO) has emerged as a reliable tool to prevent thromboembolic events, in particular ischemic stroke, in patients with atrial fibrillation (AF) in the absence of mitral stenosis/valve prosthesis and contraindication to oral anticoagulation (OAC). Antiplatelet therapy (APT) is required after device implantation to prevent device–related thrombus (DRT). Previous studies provided conflicting results on the optimal APT regimen after LAAO. Thus, herein we aimed at assessing the comparative effectiveness and safety of distinct APT regimens. We conducted a real–world single–center observational study including consecutive AF patients that underwent LAAO at the University Hospital of Parma between October 2010 and June 2021. Clinical follow–up included all successfully implanted patients. Primary endpoint was net efficacy outcome, a composite of any ischemic or hemorrhagic event. Secondary endpoints were ischemic (any of the following: ischemic stroke, transient ischemic attack [TIA], DRT, systemic embolism) and hemorrhagic (major [≥3] bleedings according to Bleeding Academic Research Consortium [BARC] classification) complications alone. We enrolled a total of 130 patients (median age 77.0 [72.7;81.0] years; 78 [60.0%] men). History of hemorrhagic stroke in OAC (74 [56.9%]) was the main indication for LAAO. Technical procedure success was achieved in 123 (94.6%) patients. According to multidisciplinary team evaluation, immediately after LAAO, 39 (31.7%) patients received short (≤ 1 month)–dual APT (DAPT) consisting of cardioaspirin and clopidogrel, 35 (28.5%) long (&gt;1, ≤12 months)–DAPT and 49 (39.8%) single APT (SAPT). At a median follow–up of 32 months, the incidence of primary endpoint was significantly lower in short–DAPT group (3 [7.7%] vs. 7 [20.0%] in long–DAPT vs. 14 [28.6%] in SAPT, p = 0.049], mainly driven by a lower occurrence of bleeding endpoint (0 [0.0] vs. 4 [11.4%] in long–DAPT vs. 9 [18.4%] in SAPT, p = 0.020) without differences in the incidence of ischemic endpoint (p = 0.916). Finally, comparison of the Kaplan–Meier curves showed that short–DAPT group had a higher primary endpoint–free survival (p = 0.015) compared to the others. In summary, our study highlighted that short (≤ 1 month)–DAPT regimen after LAAO is associated with better outcomes, mainly driven by reduction of major bleedings. Strong evidences arising from randomized trials are warranted to support these findings.
C89 A CASE OF MYOPERICARDITIS RECURRENCE AFTER THIRD DOSE OF BNT162B2 VACCINE AGAINST SARS–COV–2 IN A YOUNG SUBJECT: LINK OR CASUALITY?
Authors: Mapelli M , Amelotti N , Andreini D , Baggiano A , Campodonico J , Moltrasio M , Majocchi B , Mantegazza V , Vignati C , Ribatti V , Catto V , Sicuso R , Pontone G , Agostoni P 
Published: May 2022

Abstract

Background
The rate of post–vaccine myocarditis is being studied from the beginning of the massive vaccination campaign against Sars–Cov–2, reporting a very low incidence. Although a direct cause–effect relationship has been described, in most cases the vaccine pathophysiological role is doubtful. Moreover, it is not quite as clear as having had a previous myocarditis could be a risk factor for a post–vaccine disease relapse.

Case Presentation
A 27–year–old man presented to the ED for palpitations and pericardial chest pain radiated to the upper left limb, on the 4th day after the third dose of BNT162b2 vaccine. He experienced a previous myocarditis 3 years before, with full recovery and no other comorbidities. ECG showed a diffuse ST segment elevation and a cardiac echo showed lateral hypokinesia with preserved ejection fraction. Troponine–T was elevated (160ng/l), chest x–ray was normal, and the Sars–Cov–2 molecular buffer was negative. High–dose anti–inflammatory therapy with ibuprofen and colchicine was started; in the 3rd day high sensitivity Troponin I reached a peak (hsTnI) of 23000 ng/L. No heart failure or arrhythmias were observed. A cardiac MRI was performed showing normal biventricular systolic function, areas of LGE with non–ischemic subepicardial pattern at the level of the anterior wall with increased T2 signal, suggestive for a recurrence of myocarditis. A left ventricle electroanatomic voltage mapping was negative (both unipolar and bipolar), while the endomiocardial biopsy showed a picture consistent with active myocarditis. The patient was discharged in good shape, with normal hsTnI values on bisoprolol 1.25mg, ramipril 2.5mg, ibuprofen 600 mg three times a day, colchicine 0.5 mg twice a day. Discussion: We presented the case of a young man with history of previous myocarditis, admitted with a non–complicated acute myopericarditis relapse occurred 4 days after Sars–Cov–2 vaccination (3rd dose). Despite the observed very low incidence of cardiac complications following BNT162b2 administration, and the lack of a clear proof of a direct cause–effect relationship, we think that in our patient this link can be more than likely. In the probable need for additional Sars–Cov–2 vaccine doses in the next future, studies addressing the risk–benefit balance of this subset of patient are warranted.

Conclusion
We described a multidisciplinary management of a case of myocarditis recurrence after the third dose of Sars–Cov–2 BNT162b2 vaccine.
P9 TEMPORAL TREND OF QRS VOLTAGE AMPLITUDE ON SURFACE SENSING IN PATIENTS WITH ARRHYTHMOGENIC CARDIOMYOPATHY IMPLANTED WITH A SUBCUTANEOUS ICD
Authors: Casula M , De Toni C , Pignalosa L , Savastano S , Schintu B , Scalone A , Corda M , Vicentini A , Tola G , Rordorf R 
Published: May 2022

Abstract

Introduction
Previous studies have reported a significant decrease in ventricular sensing amplitude during follow–up in patients with arrhythmogenic cardiomyopathy (ACM) implanted with trans–venous implantable cardioverter defibrillator (ICD). No data are yet available on sensing amplitude values over time for subcutaneous ICD (S–ICD). Low QRS voltage on surface ECG is one of the diagnostic clues in ACM. This, together with the progressive nature of the disease and the not–negligible incidence of inappropriate shocks due to oversensing, raise safety concerns on the use of S–ICD in this population. The aim of this study was to evaluate the trend of QRS amplitude on subcutaneous ECG (S–ECG) over time in patients with ACM implanted with S–ICD.

Methods
We conducted a retrospective analysis on a cohort of consecutive patients with ACM implanted with S–ICD in two Italian tertiary centers, prospectively enrolled in the home–monitoring program. The S–ECGs recorded at the time of first and last data transmission were analyzed. The voltage amplitude was estimated for each QRS complex available, and the values obtained were compared between the two time points (i.e. baseline and last follow–up available). The primary endpoint of our study was the proportion of patients in which the decrease of QRS amplitude during follow–up was statistically significant.

Results
Eleven patients (1 female, 9%) were enrolled in this study. The mean age was 43±10 years. An exclusive right ventricular involvement was reported in 5 patients (46%), 2 patients (18%) had an exclusive left ventricular, and 4 (36%) a biventricular involvement. Three patients (27%) were implanted in secondary prevention. During a median follow–up of 9 months (IQR 6–17), 6 patients (55%, 95%CI 24–84%) experienced a statistically significant reduction in the S–ECG QRS amplitude (Fig. A). Considering these 6 patients, the mean absolute reduction was –0.46±0.32 mV corresponding to a relative reduction of –19%±11%. Moreover, we found a statistically significant correlation between follow–up duration and QRS amplitude relative reduction (r=–0.89, p = 0.018, Fig. B). No patients experienced inappropriate shocks.

Conclusions
In a cohort of ACM patients implanted with S–ICD the majority of patients experienced a significant reduction in the amplitude of QRS voltage during follow–up, confirming a potential safety concern on the use of S–ICD in this population. Further studies are needed to investigate this issue.
P16 ATRIAL FIBRILLATION INCIDENCE IN SARS–COV–2 INFECTED PATIENTS: PREDICTORS AND RELATIONSHIP WITH IN–HOSPITAL MORTALITY
Authors: Maloberti A , Giannattasio C , Rebora P , Occhino G , Ughi N , Rizzo J , Fabbri S , Leidi F , Cartella I , Algeri M , Scarpellini S , Rossetti C , Epis O , Molon G , Bonfanti P , Valsecchi M , Genovesi S 
Published: May 2022

Abstract

Background
Among the different CardioVascular (CV) manifestation of the COronaVIrus–related Disease (COVID) particular attention has been paid to arrhythmia and particularly to Atrial fibrillation (AF). The aim of our study was to assess the incidence of AF episodes in patients hospitalized for COVID and to evaluate its predictors and its relationship with in–hospital all–cause mortality.

Methods
We enrolled 3435 cases of SARS–CoV2 infection admitted in four hospitals in Northern Italy. We collected data on clinical history, vital signs, Intensive Care Unit (ICU) admission, laboratory tests and pharmacological treatment. AF incident and all–cause in–hospital mortality were considered as outcomes.

Results
145 (4.2%) patients develop AF during hospitalization, with a median time of 3 days (IQR: 0, 11.5) from admission. Incident AF patients were older and had lower eGFR, lower platelet and lymphocytes count and higher C–Reactive Protein (CRP), were admitted more frequently to ICU and more frequently died compared to subjects that didn’t present AF. At the Cox regression model significant determinants of incident AF were older age (HR 1.070; 95% CI: 1.048, 1.092), history of AF (HR 2.800; 95% CI: 1.465, 5.351), ischemic heart disease (HR 0.324; 95% CI: 0.130, 0.811) and ICU admission (HR 8.030; 95% CI: 4.511, 14.292). Incident AF was a predictor of all–cause mortality (HR 1.679; 95% CI: 1.170, 2.410), together with age (HR 1.053; 95% CI: 1.042, 1.065), dementia (HR 1.553; 95% CI 1.151, 2.095), platelet count (HR 0.997; 95% CI: 0.996, 0.999) higher CRP (HR 1.004; 95% CI: 1.003, 1.005) and eGFR (HR: 0.991; 95% CI: 0.986, 0.996)

Conclusion
AF present as the main arrhythmia in COVID–19 patients and its development during the hospitalization strongly relates with in–hospital mortality.
P18 ATRIAL FIBRILLATION IN BETA–THALASSAEMIA: PHYSIOPATHOLOGY AND CLINICAL MANAGEMENT
Authors: Clò S , Marchini F , Sirugo P , Capanni A , Malagù M , Bertini M , Guardigli G 
Published: May 2022

Abstract
Beta–thalassaemia is an inherited blood disorder with worldwide distribution characterized by a defective synthesis of haemoglobin. Transfusions and iron–chelation therapy have radically improved the prognosis of beta–thalassaemic patients, while also allowing the development of new chronic complications, cardiac and non–cardiac (diabetes, dystyroidism, autonomic disorders and many others), among which atrial fibrillation (AF) stands out. Prevalence of AF in patients with beta–thalassemia is dramatically higher than in general population, ranging from 2 to 33%. Studies on this topic are lacking and the scarse available evidence comes from a few observational studies. The underlying pathophysiology of AF in thalassaemic is not yet well understood; responsible mechanisms are many (Figure 1) and different from those recognized in general population. Atrial iron overload appears to be the main “risk factor”, although this arrhythmia may develop even before cardiac siderosis. Clinical presentation is early and mainly paroxysmal, and patients are highly symptomatic. Furthermore, the numerous treatments available for AF (pharmacological and interventional), extensively studied in the general population, are largely unexplored in beta–thalassemia. A specific management is required for these patients (Figure 2); in particular, rhythm control should be preferred over rate control, and the most important antiarrhythmic therapy resides in iron–chelating drugs. Thromboembolic risk is also higher than in the general population and the choice of anticoagulant therapy should be considered early (well pondering the serious consequences of a haemorrhage in this setting), but the risk scores available for patients with AF are not validated in the beta–thalassemia.