Obesity and diabetes are major risk factors for epicardial adipose tissue inflammation.

BACKGROUNDEpicardial adipose tissue (EAT) directly overlies the myocardium, with changes in its morphology and volume associated with myriad cardiovascular and metabolic diseases. However, EAT's immune structure and cellular characterization remain incompletely described. We aimed to define the immune phenotype of EAT in humans and compare such profiles across lean, obese, and diabetic patients.METHODSWe recruited 152 patients undergoing open-chest coronary artery bypass grafting (CABG), valve repair/replacement (VR) surgery, or combined CABG/VR. Patients' clinical and biochemical data and EAT, subcutaneous adipose tissue (SAT), and preoperative blood samples were collected. Immune cell profiling was evaluated by flow cytometry and complemented by gene expression studies of immune mediators. Bulk RNA-Seq was performed in EAT across metabolic profiles to assess whole-transcriptome changes observed in lean, obese, and diabetic groups.RESULTSFlow cytometry analysis demonstrated EAT was highly enriched in adaptive immune (T and B) cells. Although overweight/obese and diabetic patients had similar EAT cellular profiles to lean control patients, the EAT exhibited significantly (P ≤ 0.01) raised expression of immune mediators, including IL-1, IL-6, TNF-α, and IFN-γ. These changes were not observed in SAT or blood. Neither underlying coronary artery disease nor the presence of hypertension significantly altered the immune profiles observed. Bulk RNA-Seq demonstrated significant alterations in metabolic and inflammatory pathways in the EAT of overweight/obese patients compared with lean controls.CONCLUSIONAdaptive immune cells are the predominant immune cell constituent in human EAT and SAT. The presence of underlying cardiometabolic conditions, specifically obesity and diabetes, rather than cardiac disease phenotype appears to alter the inflammatory profile of EAT. Obese states markedly alter EAT metabolic and inflammatory signaling genes, underlining the impact of obesity on the EAT transcriptome profile.FUNDINGBarts Charity MGU0413, Abbott, Medical Research Council MR/T008059/1, and British Heart Foundation FS/13/49/30421 and PG/16/79/32419.

Immune checkpoint inhibitor cardiotoxicity: Breaking barriers in the cardiovascular immune landscape.

Immune checkpoint inhibitors (ICI) have changed the landscape of cancer therapy, but their use carries a high risk of cardiac immune related adverse events (iRAEs). With the expanding utilization of ICI therapy, there is a growing need to understand the underlying mechanisms behind their anti-tumor activity as well as their immune-mediated toxicities. In this review, we will focus on clinical characteristics and immune pathways of ICI cardiotoxicity, with an emphasis on single-cell technologies used to gain insights in this field. We will focus on three key areas of ICI-mediated immune pathways, including the anti-tumor immune response, the augmentation of the immune response by ICIs, and the pathologic "autoimmune" response in some individuals leading to immune-mediated toxicity, as well as local factors in the myocardial immune environment predisposing to autoimmunity. Discerning the underlying mechanisms of these immune pathways is necessary to inform the development of targeted therapies for ICI cardiotoxicities and reduce treatment related morbidity and mortality.

Recurrent disseminated Mycobacterium avium in a female patient from Thailand with anti-interferon-gamma autoantibodies: dilemma on treatment approach.

Anti-interferon-gamma (IFN-γ) autoantibodies has been recognised as an adult-onset immunodeficiency in the past decade in people who originate from Southeast Asia. These patients are susceptible to particular opportunistic infections, especially non-tuberculous mycobacteria (NTM). We present the case of a woman whom originally came from Thailand with disseminated Mycobacterium avium complex infection (pleural, pericardium, bloodstream and lung parenchymal involvement). Her infection continued to progress while receiving proper antibiotic treatment. Once high titre neutralising anti-IFN-γ autoantibodies were detected, rituximab was added as adjunctive treatment. The patient had remarkable clinical improvement against persistence of anti-IFN-γ autoantibodies. Although her lung disease has improved, the patient continues on triple therapy for NTM. The kinetics of anti-IFN-γ autoantibodies in the context of clinical progression, indication and length for rituximab and triple therapy is discussed in view of the current literature.

The autoinflammatory side of recurrent pericarditis: Enlightening the pathogenesis for a more rational treatment.

Recurrent pericarditis (RP) is a troublesome and debilitating complication of acute pericarditis. Although the etiopathogenesis of this condition remains unknown, an intricate overlap of autoimmune and autoinflammatory pathways has been hypothesized to explain its beginning and recurrence over time. The majority of cases are defined as "idiopathic", reflecting our awkwardness to unravel the intimate mechanisms of RP. Given the possible occurrence of anti-nuclear, anti-heart and anti-intercalated disk antibodies as well as the association with peculiar human leukocyte antigen haplotypes, an autoimmune contribution has been claimed to specify the nature of RP. However, the most innovative pathogenic scenario of RP has been conferred to the innate immune system, mainly involving neutrophils and macrophages that produce a large amount of interleukin (IL)-1 via inflammasome activation. The clinical resemblance of RP with autoinflammatory diseases that may be marked by symptomatic serositis, high fevers and strikingly increased inflammatory parameters further suggests a similar inflammasome-mediated pathogenesis. Aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) remain the mainstay of therapy in RP, whereas colchicine is recommended on top of standard anti-inflammatory therapy, due to its role in inhibiting the IL-1 converting enzyme (caspase 1) within the inflammasome as well as the release of additional pro-inflammatory mediators and reactive oxygen species. With regard to treatment of RP refractory to NSAIDs and colchicine, blockade of IL-1 is the most relevant advance achieved in the last decade: the outstanding effect of the short-acting IL-1 receptor antagonist anakinra has been first recognized in the pediatric population, giving a proof of its practical feasibility. Over a more recent time, a growing experience with anakinra deriving from both large and small studies has further confirmed that RP might be regarded as an IL-1-mediated disease. This review aims to provide a contemporary insight into the mechanisms leading to RP as well as into the most recent literature data showing the beneficial approach originating from IL-1 blockade in this intriguing disorder.

Responses to Treatment According to the Cytokine Profiles of Pericardial Effusion in Two Children with Idiopathic Pericarditis.

Acute pericarditis is inflammation of the pericardium with or without pericardial effusion. In the pediatric population, most patients with acute pericarditis are diagnosed with idiopathic pericarditis. Herein, we present two children with idiopathic pericarditis who underwent immunological assessment of pericardial effusion for the first time. Both patients showed equally high levels of interleukin-6 in the pericardial effusion. However, they had different treatment responses, in accordance with the pericardial effusion and serum interleukin-10 concentrations. Our present cases suggest that interleukin-10 may be associated with the response to anti-inflammatory therapy in idiopathic acute pericarditis.

Concomitant myopericarditis and takotsubo syndrome following immune checkpoint inhibitor therapy.

A 62-year-old man with metastatic hepatocellular carcinoma presented with ST elevation myocardial infarction had received one dose of nivolumab 3 weeks prior. Cardiac catheterisation was negative for obstructive coronary artery disease. He was transferred to the cardiac intensive care unit due to ventricular arrhythmias and markedly elevated troponin T levels. Transthoracic echocardiogram showed severely depressed left ventricular ejection fraction of 18% (normal 55%-70%) with mid and apical ballooning consistent with takotsubo syndrome (TTS). Intravenous glucocorticoids were administered due to suspicion for superimposed myocarditis. Cardiac MRI 3 days later showed mid-myocardial and subepicardial delayed enhancement in the inferior and lateral walls as well as apex indicative of myopericarditis. He clinically improved on steroids and was discharged with outpatient follow-up. This case highlights major cardiac complications that may arise with immune checkpoint inhibitor therapy. In addition, it emphasises the importance of assessing for concomitant myocarditis even when initial imaging suggests TTS.

Anti-inflammatory therapies for pericardial diseases in the COVID-19 pandemic: safety and potentiality.

: The COVID-19 pandemic is challenging our cardiovascular care of patients with heart diseases. In the setting of pericardial diseases, there are two possible different scenarios to consider: the patient being treated for pericarditis who subsequently becomes infected with SARS-CoV-2, and the patient with COVID-19 who develops pericarditis or pericardial effusion. In both conditions, clinicians may be doubtful regarding the safety of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, colchicine, and biological agents, such as anti-IL1 agents (e.g. anakinra), that are the mainstay of therapy for pericarditis.For NSAIDs, there is no clear scientific evidence linking ibuprofen and other NSAIDs to worsening of COVID-19; however, it seems prudent to continue them, if necessary to control pericarditis, and on the other hand, to prefer paracetamol for fever and systemic symptoms related to COVID-19. Treatments with corticosteroids, colchicine, and anakinra appear well tolerated in the context of COVID-19 infection and are currently actively evaluated as potential therapeutic options for COVID infection at different stages of the disease. On this basis, currently most treatments for pericarditis do not appear contraindicated also in the presence of possible COVID-19 infection and should not be discontinued, and some (corticosteroids, colchicine, and anakinra) can be considered to treat both conditions.

Failure of anti Interleukin-1 ß monoclonal antibody in the treatment of recurrent pericarditis in two children.

BACKGROUND: Recurrent pericarditis (RP) is a complication (15-30%) of acute pericarditis with an unknown etiology. Treatment regimen consists of a combination of non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine, with the addition of corticosteroids in resistant or intolerant cases. In the last decade anakinra was shown as an effective treatment in patients with colchicine resistant and steroid-dependent RP, initially in anecdotal reports in children and more recently in a randomized trial. Canakinumab is a monoclonal antibody selectively blocking IL-1ß and its use is only anecdotally reported to treat pericarditis. We report two pediatric patients with refractory recurrent pericarditis, who presented an optimal response to anakinra treatment but prompt relapse after switch to canakinumab. CASE PRESENTATION: The first patient is a girl with Recurrent Pericarditis started in April 2015, after heart surgery. NSAIDs and oral steroids were started, with prompt relapse after steroid suspension. The child showed a steroid-dependent RP; anakinra was therefore started with excellent response, but discontinued after 2 weeks for local reactions. In July 2016 therapy with canakinumab was started. She experienced four relapses during canakinumab therapy despite dosage increase and steroid treatment. In January 2018 a procedure of desensitization from anakinra was performed, successfully. Anakinra as monotherapy is currently ongoing, without any sign of flare. The second patient is a girl with an idiopathic RP, who showed an initial benefit from NSAIDs and colchicine. However, 10 days after the first episode a relapse occurred and therapy with anakinra was established. Two months later, while being in complete remission, anakinra was replaced with canakinumab due to patient's poor compliance to daily injections. She experienced a relapse requiring steroids 10 days after the first canakinumab injection. Anakinra was subsequently re-started with complete remission, persisting after 24 months follow-up. CONCLUSIONS: We describe two cases of failure of the treatment with anti-IL-1ß monoclonal antibodies in steroid- dependent idiopathic RP. This anecdotal and preliminary observation suggests a different efficacy of the two IL-1 blockers in the management of RP and support a possible pivotal role of IL-1α in the pathogenesis of this condition.

Acute Effects of Interleukin-1 Blockade Using Anakinra in Patients With Acute Pericarditis.

Interleukin-1 (IL-1) receptor antagonist (anakinra) has been shown to be effective in steroid-dependent recurrent pericarditis resistant to nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine. We sought to evaluate the acute efficacy of anakinra given early in patients with acute pericarditis. We enrolled patients within 24 hours of presentation of a first or recurrent episode of acute pericarditis who were experiencing severe pain (≥6 in 11-point Likert scale), despite treatment with at least one dose of NSAIDs and of colchicine. The primary outcome was pain relief at 24 hours. Subcutaneous anakinra 100 mg was administered in all patients, whereas NSAIDs and colchicine were suspended for 24 hours. Serum levels of interleukin-6 (IL-6) were measured at baseline and 24 hours. Data are reported as median (interquartile range). We treated 5 patients (4 male and 1 female; 38 [31-54] years old). Anakinra significantly reduced pain from 6.0 (6.0-7.5) to 4.0 (2.5-4.0) at 6 hours (P = 0.012 vs. baseline) and to 2.0 (1.5-2.5) at 24 hours (P = 0.0025 vs. baseline). No patients required rescue pain medication. IL-6 levels were also significantly reduced from 95.3 (24.2-155.1) to 23.9 (4.5-71.9) pg/mL at 24 hours (P = 0.037). The reduction in pain intensity paralleled the reduction in IL-6 serum levels (R = +0.966, P = 0.007). No adverse events related to treatment occurred. The administration of anakinra given early in acute pericarditis treatment course rapidly and significantly improved chest pain from acute pericarditis. The improvement is correlated with a reduction in IL-6 levels.

Anakinra in Recurrent Pericarditis: Current Evidence on Clinical Use, Effectiveness, and Safety.

Anakinra is a recombinant human interleukin 1 receptor antagonist that competes and blocks the biologic effects of interleukin 1, reducing systemic inflammatory responses. In the 2015 guidelines for the diagnosis and management of pericardial diseases of the European Society of Cardiology, anakinra was established as a third-line therapy option for refractory recurrent pericarditis (RP). Recently, important studies that investigates the effect and safety of anakinra in RP were published, such as the AIRTRIP trial and the International Registry of Anakinra for Pericarditis. This article presents the current evidence about the effectiveness and safety of anakinra in RP and discusses its clinical application and mechanisms.

Innate Lymphoid Cells Play a Pathogenic Role in Pericarditis.

We find that cardiac group 2 innate lymphoid cells (ILC2s) are essential for the development of IL-33-induced eosinophilic pericarditis. We show a pathogenic role for ILC2s in cardiac inflammation, in which ILC2s activated by IL-33 drive the development of eosinophilic pericarditis in collaboration with cardiac fibroblasts. ILCs, not T and B cells, are required for the development of pericarditis. ILC2s transferred to the heart of Rag2-/-Il2rg-/- mice restore their susceptibility to eosinophil infiltration. Moreover, ILC2s direct cardiac fibroblasts to produce eotaxin-1. We also find that eosinophils reside in the mediastinal cavity and that eosinophils transferred to the mediastinal cavity of eosinophil-deficient ΔdblGATA1 mice following IL-33 treatment migrate to the heart. Thus, the serous cavities may serve as a reservoir of cardiac-infiltrating eosinophils. In humans, patients with pericarditis show higher amounts of ILCs in pericardial fluid than do healthy controls and patients with other cardiac diseases. We demonstrate that ILCs play a critical role in pericarditis.

Meta-analysis for the value of colchicine for the therapy of pericarditis and of postpericardiotomy syndrome.

BACKGROUND: Colchicine has been used as anti-inflammatory agent in pericardial effusion (PE). We sought to perform a meta-analysis of randomized trials assessing the efficacy and safety of colchicine in patients with pericarditis or postpericardiotomy syndrome (PPS). METHODS: In the systematic literature search following the PRISMA statement, 10 prospective randomized controlled studies with 1981 patients with an average follow-up duration of 13.6 months were identified. RESULTS: Colchicine reduced the recurrence rate of pericarditis in patients with acute and recurrent pericarditis and reduced the incidence of PPS (RR: 0.57, 95% CI: 0.44-0.74). Additionally, the rate of rehospitalizations as well as the symptom duration after 72 h was significantly decreased in pericarditis (RR 0.33; 95% CI 0.18-0.60; and RR 0.43; 95% CI 0.34-0.54; respectively), but not in PPS. Treatment with colchicine was associated with significantly higher adverse event (AE) rates (RR 1.42; 95% CI 1.05-1.92), with gastrointestinal intolerance being the leading AE. The reported number needed to treat (NNT) for the prevention of recurrent pericarditis ranged between 3 and 5. The reported NNT for PPS prevention was 10, and the number needed to harm (NNH) was 12, respectively. Late colchicine administration > 7 days after heart surgery did not reduce postoperative PE. CONCLUSIONS: Our meta-analysis confirms that colchicine is efficacious and safe for prevention of recurrent pericarditis and PPS, while it reduces rehospitalizations and symptom duration in pericarditis. The clinical use of colchicine for the setting of PPS and postoperative PE after heart surgery should be investigated in further multicenter RCT.

The Heart Matters: Contribution of Genetic Factors in Recurrent Pericarditis.

BACKGROUND: Recurrent pericarditis is a state of repetitive inflammation of the pericardium with intervals of remission. The etiology of recurrent pericarditis is still largely unknown, yet most causes are presumed to be immune mediated. Genetic factors, including human leukocyte antigen (HLA) haplotypes, can be involved in dysregulation of the immune system and as a predisposition to several autoimmune conditions, including recurrent pericarditis. Several diseases are frequently associated with such manifestations. They include systemic lupus erythematosus, familial Mediterranean fever, and tumor necrosis factor receptor-associated periodic syndrome. However, idiopathic recurrent pericarditis remains the most frequently observed clinical condition and the conundrum of this disease still needs to be solved.

PD-1+CXCR5-CD4+T cells are correlated with the severity of systemic lupus erythematosus.

OBJECTIVES: PD-1+CXCR5-CD4+T peripheral helper (Tph) cells, a recently identified T cell subset, are proven to promote B cell responses and antibody production in rheumatoid arthritis, but their role in the pathogenesis of SLE is unknown. We explored the role of Tph in lupus disease development. METHODS: This cohort study included 68 patients with SLE and 41 age- and sex-matched healthy individuals. The frequency of PD-1+CXCR5-CD4+T cells was analysed in peripheral blood by flow cytometry. Inducible T-cell costimulator, CD38, MHC-II, IL-21, CXCR3 and CCR6 expression were measured in Tph cells. Comparisons between the two groups were performed, and correlations between Tph cells and other parameters were investigated. RESULTS: We revealed a markedly expanded population of Tph cells (8.31 ± 5.45 vs 2.86 ± 1.31%, P < 0.0001) in the circulation of patients with SLE (n = 68), compared with healthy controls (n = 41). Tph cells were much higher in the active group than in the inactive group (14.21 ± 5.21 vs 5.49 ± 2.52%, P < 0.0001). Tph cells were significantly associated with SLEDAI score (r = 0.802), ESR (r = 0.415), IgG (r = 0.434), C3 (r = -0.543), C4 (r = -0.518) and IL-21 level (r = 0.628), and ANA titre (r = 0.272). Furthermore, Tph cells were much higher in lupus patients with arthritis, nephritis, rash, alopecia, pleuritis, pericarditis and haematological involvement. Tph cells were associated with CD138+/CD19+ plasma cells (r = 0.518). Furthermore, MHC-II, inducible T-cell costimulator, CD38, and IL-21 expression were all higher in Tph cells from SLE patients compared with healthy controls. CXCR3+CCR6-Tph (Tph1) cells were expanded in the SLE patients. CONCLUSION: Our data show that relative number of Tph cells is correlated with disease measures in patients with SLE, suggesting an important role in lupus disease development.

Idiopathic Pericarditis-an Autoinflammatory Disease?

PURPOSE OF THE REVIEW: Idiopathic acute and recurrent pericarditis are rare diseases of unknown origin. Here, we review trigger factors, pathomechanism, and treatment options for acute and recurrent pericarditis. RECENT FINDINGS: Acute pericarditis can be triggered by viral infections, myocardial ischemia, heart catheter interventions, cardiac surgery or seem to occur without any trigger. Earlier reports about viral nucleic acids in the effusion or myocardial autoantibodies in serum were detected only in a minority of patients. The current pathomechanistic concept focuses on the innate immune system. Clinical trials revealed that colchicine and anti-IL1ß-targeted medication were effective to control acute and recurrent attacks. Activation of the innate immune system in pericarditis suggests that autoinflammation contributes to acute and recurrent pericarditis. The efficacy of colchicine and anti-IL1ß-targeted medication in clinical trials indicates that acute and recurrent pericarditis should be regarded as an autoinflammatory disease. Therefore, idiopathic pericarditis should be considered as an autoinflammatory disease.

Immune Checkpoint Inhibitor-Associated Pericarditis.

Side effects of immune checkpoint inhibitors, termed immune-related adverse events, are relatively common, but immune checkpoint inhibitor-mediated cardiotoxicities are rare; however, they can be serious and potentially fatal. Pericarditis is an infrequent cardiac toxicity of immunotherapy and predisposing factors remain unknown. Here we report three patients with NSCLC who developed pericarditis during therapy with programmed death 1/programmed death ligand 1+/- CTLA-4 inhibitors. We review the clinical presentation of these three cases and histopathologic findings from autopsies from the first two patients and a pericardial sampling that has been obtained from a pericardial window procedure in the third patient who recovered from the pericarditis episode. We also discuss the potential mechanisms, as well as what is known about pericarditis secondary to immune-related adverse events.