No abstract

Recently, the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) showed the successful anti-inflammatory benefit of canakinumab, a monoclonal antibody targeting interleukin-1ß (IL-1ß) towards major cardiovascular events (MACE) in patients with a previous myocardial infarction. The magnitude of reduction in MACE was directly attributed to a reduction witnessed in IL-6 and CRP and highlighted the therapeutic potential of selectively targeting IL-1ß for atherosclerotic disease, a notion previously introduced in animal models. IL-1ß is involved in the downstream activation of the IL-6 receptor, which itself has been previously implicated as a target for atherothrombosis from Mendelian randomization studies. Further support has been garnered with the results of CIRT (Cardiovascular Inflammation Reduction Trial), which showed the inability of low-dose methotrexate to reduce IL-1ß, IL-6, or hsCRP in addition to MACE among patients with prior MI or multivessel coronary artery disease (CAD) but with normal hsCRP levels. Therefore, elucidation of therapeutic targets against the IL-1ß pathway are of immense interest currently in treating atherothrombosis. Upstream and serving as an activator of IL-1ß lies the nucleotide-binding oligomerization domain-like (NOD) receptor protein 3 (NLRP3) inflammasome that has been well described in animal models to be activated by cholesterol crystals or hypoxia to promote cleavage and secretion of IL-1ß and IL-18 that lead to atherosclerotic deposition in arteries. Given the direct implication of an atherogenic role to the NLRP3 inflammasome in generating these cytokines, NLRP3 inhibitors are of interest with the consideration to move upstream from the initial success of anti-IL-1ß therapy. With further discussion of the existing knowledge on the proinflammatory relationship of the NLRP3 *

Introduction: Despite advances in drug eluting technologies, neointimal hyperplasia (NIH) and restenosis still plagues endovascular therapy in atherosclerotic diseases. By appreciating atherosclerosis and NIH as complex inflammatory processes, specialized pro-resolving mediators (SPMs) are a superfamily of endogenous unsaturated fatty-acid derived lipids with the potential for inflammatory resolution. Areas covered: Inquiry into SPMs in this context is a novel approach and is the focus of this review, with emphasis on our understanding with NIH. Prior mechanistic understandings of SPM deficiency with atherosclerosis has offered insight, as well as the complexity and diversity of the SPM superfamily. Therapeutic investigation using SPMs to combat NIH is also evaluated here. Expert commentary: Endogenous deficiency of SPMs synthesis by 12/15-lipoxygenase underlies resolution deficits in atherosclerosis and NIH. Upstream PDGF inhibition by SPMs, most notably RvD1 and LXA4, confers a multifactorial attenuation of NIH that involves interconnected anti-inflammatory efforts, most notably switch pro-resolving smooth muscle cells (vSMCs) and macrophages. The ALX/ FPR2 is one receptor system identified on vSMCs that interacts with these SPMs to promote NIH resolution. Therapeutically, while shown to be promising with less stent burden or cytotoxicity, SPMs must be balanced by necessary mechanistic, pharmacokinetic and anatomical considerations.

Background Comorbidity burden is associated with development of cancer, stage at diagnosis, and treatment outcomes. We evaluated the association between comorbidity burden, receipt of adjuvant immunotherapy, and survival in patients with stage III melanoma. Methods Using the National Cancer Database, we identified 16,906 patients with stage III melanoma who underwent surgery of the primary site. Outcomes included receipt of adjuvant immunotherapy and overall survival; independent variables included Charlson/ Deyo comorbidity index (CDI) and receipt of adjuvant immunotherapy. Results Patients with CDI scores of two or more averaged 30.0% and 30.9% lower adjusted odds of receiving adjuvant immunotherapy relative to patients with a CDI score of zero or one, respectively (P = 0.001 and 0.002, respectively). Longer survival was associated with lower CDI scores (all P < 0.001) and receipt of adjuvant immunotherapy (P < 0.001). Patients who received adjuvant immunotherapy averaged 16.0% lower adjusted risk of death compared to patients who did not (P < 0.001), which was constant within all CDI cohorts. Patients with a CDI score of two or more averaged 53.4% and 39.1% higher adjusted risk of death relative to patients with a CDI score of zero or one (both P < 0.001). Conclusion Greater comorbidity burden was associated with lower receipt of adjuvant immunotherapy; however, adjuvant immunotherapy provided similar survival benefit for patients' irrespective comorbidity burden. Our findings suggest that patients with stage III melanoma who have a greater comorbidity burden may benefit from adjuvant immunotherapy but should not replace careful patient selection by the clinician.

Introduction: Due to shared risk factors and pathophysiology, atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) frequently coexist. However, the prognostic implications of AF in HFpEF are unclear with conflicting data. Herein, we conducted a systematic review and meta-analysis to assess the impact of concomitant AF on cardiovascular outcomes in patients with HFpEF. Methods: PubMed, Scopus, and Google Scholar were comprehensively searched through May 7th, 2020 for studies comparing outcomes of HFpEF patients with and without AF. Outcomes assessed were all-cause mortality and a composite of HF hospitalization or cardiovascular (CV) mortality. Data from selected studies were abstracted and pooled using a random-effects meta-analysis to calculate odds ratios (ORs) and 95% confidence intervals [CIs] for each of the outcomes. Results: Our final analysis included 10 studies with 27,440 HFpEF patients (43.2% with AF). AF was associated with significantly increased risk of all-cause mortality (OR 1.37 [1.17-1.61], p < 0.001, Fig. 1A), HF hospitalization or CV mortality (OR 1.66 [1.16-2.36], p = 0.005, Fig. 1B), and HF hospitalization alone (OR 1.34 [1.03-1.76], p = 0.03, Fig. 1C). However, AF was not associated with excess risk of CV mortality alone (OR 1.10 [0.79-1.52], p = 0.57, Fig. 1D). Conclusions: In patients with HFpEF, concomitant AF is associated with an increased risk of all-cause mortality and HF hospitalization. Further research into the mechanisms and interventions to mitigate this excess risk is necessary.