Explore the vast range of titles available.

Viral infection of the heart is a common but underappreciated cause of heart failure. Viruses can cause direct cardiac damage by lysing infected cardiomyocytes. Inflammatory immune responses that limit viral replication can also indirectly cause damage during infection, making regulatory factors that fine-tune these responses particularly important. Identifying and understanding these factors that regulate cardiac immune responses during infection will be essential for developing targeted treatments for virus-associated heart failure. Our laboratory has discovered Brain Expressed X-linked protein 1 (BEX1) as a novel stress-regulated pro-inflammatory factor in the heart. Here we report that BEX1 plays a cardioprotective role in the heart during viral infection. Specifically, we adopted genetic gain- and loss-of-function strategies to modulate BEX1 expression in the heart in the context of coxsackievirus B3 (CVB3)-induced cardiomyopathy and found that BEX1 limits viral replication in cardiomyocytes. Interestingly, despite the greater viral load observed in mice lacking BEX1, inflammatory immune cell recruitment in the mouse heart was profoundly impaired in the absence of BEX1. Overall, the absence of BEX1 accelerated CVB3-driven heart failure and pathologic heart remodeling. This result suggests that limiting inflammatory cell recruitment has detrimental consequences for the heart during viral infections. Conversely, transgenic mice overexpressing BEX1 in cardiomyocytes revealed the efficacy of BEX1 for counteracting viral replication in the heart in vivo . We also found that BEX1 retains its antiviral role in isolated cells. Indeed, BEX1 was necessary and sufficient to counteract viral replication in both isolated primary cardiomyocytes and mouse embryonic fibroblasts suggesting a broader applicability of BEX1 as antiviral agent that extended to viruses other than CVB3, including Influenza A and Sendai virus. Mechanistically, BEX1 regulated interferon beta (IFN-β) expression in infected cells. Overall, our study suggests a multifaceted role of BEX1 in the cardiac antiviral immune response.

Immuno-fibrotic networks and their protein mediators, such as cytokines and chemokines, have increasingly been appreciated for their critical role in cardiac healing and fibrosis during cardiomyopathy. Immune activation, trafficking, and extravasation are tightly regulated to ensure a targeted and effective response against non-self antigens/pathogens while preserving tolerance towards self-antigens and coordinate fibrotic responses for efficient scar formation, a distinction that is severely compromised during chronic diseases. It is clear that immune cells are not only the critical regulators of post-infarct healing and scarring but are also the key players in regulating fibroblast activation during left-ventricular (LV) remodeling. Incomplete resolution coupled with sustained low-grade inflammation during dilated cardiomyopathy precipitates a “frustrated” immune cell response resulting in unconstrained pro-fibrotic and pro-hypertrophic signaling to induce maladaptive structural and functional changes in the myocardium. The aims of this review are to (i) briefly summarize the role of key immune cells that regulate wound healing during MI and fibrosis during LV remodeling; (ii) underscore phenotypic diversities in immune cells and their subsets to underscore their role in regulating fibrotic responses, and, last but not the least, (iii) highlight gaps in our understanding that restrict the translation of immuno-modulatory therapies from the preclinical models to heart failure patients.

In critically sick adults, sustained low efficiency dialysis [SLED] appears to be better tolerated hemodynamically and outcomes seem to be comparable to CRRT. However, there is paucity of data in critically sick children. In children, two recent studies from Taiwan (n = 11) and India (n = 68) showed benefits of SLED in critically sick children. The objective of the study was to look at the feasibility and tolerability of sustained low efficiency daily dialysis-filtration [SLEDD-f] in critically sick pediatric patients. Design: Retrospective study Inclusion criteria: All pediatric patients who had undergone heparin free SLEDD-f from January 2012 to October 2017. Measurements: Data collected included demographic details, vital signs, PRISM III at admission, ventilator parameters (where applicable), number of inotropes, blood gas and electrolytes before, during, and on conclusion of SLED therapy. Technical information was gathered regarding SLEDD-f prescription and complications. Between 2012-2017, a total of 242 sessions of SLEDD-f were performed on 70 patients, out of which 40 children survived. The median age of patients in years was 12 (range 0.8-17 years), and the median weight was 39 kg (range 8.5-66 kg). The mean PRISM score at admission was 8.77±7.22. SLEDD-f sessions were well tolerated, with marked improvement in fluid status and acidosis. Premature terminations had to be done in 23 (9.5%) of the sessions. There were 21 sessions (8.6%) terminated due to hypotension and 2 sessions (0.8%) terminated due to circuit clotting. Post- SLEDD-f hypocalcemia occurred in 15 sessions (6.2%), post- SLEDD-f hypophosphatemia occurred in 1 session (0.4%), and post- SLEDD-f hypokalemia occurred in 17 sessions (7.0%). This study is the largest compiled data on pediatric SLEDD-f use in critically ill patients. Our study confirms the feasibility of heparin free SLEDD-f in a larger pediatric population, and even in children weighing <20 kg on inotropic support.

In the failing heart, iNOS is expressed by both macrophages and cardiomyocytes. We hypothesized that inflammatory cell-localized iNOS exacerbates left ventricular (LV) remodeling. Wild-type (WT) C57BL/6 mice underwent total body irradiation and reconstitution with bone marrow from iNOS −/− mice (iNOS −/− c) or WT mice (WTc). Chimeric mice underwent coronary ligation to induce large infarction and ischemic heart failure (HF), or sham surgery. After 28 days, as compared with WTc sham mice, WTc HF mice exhibited significant ( p  < 0.05) mortality, LV dysfunction, hypertrophy, fibrosis, oxidative/nitrative stress, inflammatory activation, and iNOS upregulation. These mice also exhibited a ~twofold increase in circulating Ly6C hi pro-inflammatory monocytes, and ~sevenfold higher cardiac M1 macrophages, which were primarily CCR2 – cells. In contrast, as compared with WTc HF mice, iNOS −/− c HF mice exhibited significantly improved survival, LV function, hypertrophy, fibrosis, oxidative/nitrative stress, and inflammatory activation, without differences in overall cardiac iNOS expression. Moreover, iNOS −/− c HF mice exhibited lower circulating Ly6C hi monocytes, and augmented cardiac M2 macrophages, but with greater infiltrating monocyte-derived CCR2 + macrophages vs. WTc HF mice. Lastly, upon cell-to-cell contact with naïve cardiomyocytes, peritoneal macrophages from WT HF mice depressed contraction, and augmented cardiomyocyte oxygen free radicals and peroxynitrite. These effects were not observed upon contact with macrophages from iNOS −/− HF mice. We conclude that leukocyte iNOS is obligatory for local and systemic inflammatory activation and cardiac remodeling in ischemic HF. Activated macrophages in HF may directly induce cardiomyocyte contractile dysfunction and oxidant stress upon cell-to-cell contact; this juxtacrine response requires macrophage-localized iNOS.

Coronavirus disease 2019 (COVID-19) pandemic is responsible for widespread morbidity and mortality. The vaccination against the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection, the cause of the COVID-19 pandemic, is currently ongoing across the globe. Rapid vaccination is of paramount importance to mitigate this pandemic. Although considered safe in general, these vaccines have their share of rare adverse events. We report a case of antineutrophil cytoplasmic antibody (ANCA)-associated pauci-immune crescentic glomerulonephritis 15 days post 2nd dose of a killed COVID-19 (COVAXIN™ -BB152 V) vaccine. We hypothesize that vaccination triggered a systemic immune response in a susceptible patient to develop ANCA-associated vasculitis (AAV), leading to rapidly progressive glomerulonephritis (RPGN).

Although cardiac and splenic mononuclear phagocytes (MPs), i.e., monocytes, macrophages and dendritic cells (DCs), are key contributors to cardiac remodeling after myocardial infarction, their role in pressure-overload remodeling is unclear. We tested the hypothesis that these immune cells are required for the progression of remodeling in pressure-overload heart failure (HF), and that MP depletion would ameliorate remodeling. C57BL/6 mice were subjected to transverse aortic constriction (TAC) or sham operation, and assessed for alterations in MPs. As compared with sham, TAC mice exhibited expansion of circulating LyC6hi monocytes and pro-inflammatory CD206- cardiac macrophages early (1 w) after pressure-overload, prior to significant hypertrophy and systolic dysfunction, with subsequent resolution during chronic HF. In contrast, classical DCs were expanded in the heart in a biphasic manner, with peaks both early, analogous to macrophages, and late (8 w), during established HF. There was no significant expansion of circulating DCs, or Ly6C+ monocytes and DCs in the spleen. Periodic systemic MP depletion from 2 to 16 w after TAC in macrophage Fas-induced apoptosis (MaFIA) transgenic mice did not alter cardiac remodeling progression, nor did splenectomy in mice with established HF after TAC. Lastly, adoptive transfer of splenocytes from TAC HF mice into naïve recipients did not induce immediate or long-term cardiac dysfunction in recipient mice. Mononuclear phagocytes populations expand in a phasic manner in the heart during pressure-overload. However, they are dispensable for the progression of remodeling and failure once significant hypertrophy is evident and blood monocytosis has normalized.

There is a paucity of literature about the outcomes of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 after kidney transplantation in developing countries (e.g., India). We included 50 consecutive kidney transplant recipients diagnosed with COVID-19 from August 2020 to December 2020. The mean age was 50 ± 10 years, and the median interval since transplantation was 34 months. Fever (100%), cough (40%), and shortness of breath (32%) were the most common presenting symptoms. Mild disease occurred in 26 patients, moderate disease in 12, and severe disease in 12. All 24 patients with moderate-to-severe disease received remdesivir and high-dose steroids, whereas 17 of 26 patients with mild disease received favipiravir. Convalescent plasma was given to 13 of 24 patients with moderate-to-severe disease, and 7 of 12 patients with severe disease received tocilizumab. The median hospital stay was 7 days (interquartile range: 4-20 days). Of 30 patients who developed acute kidney injury, seven required renal replacement therapy and eight required mechanical ventilation. Eight patients with severe disease died. An age of >50 years, coughing, shortness of breath at presentation, C-reactive protein levels of >100 mg/dL, D-dimer levels of >1 mg/L, computed tomography severity scores of >20 at presentation, supplemental oxygen, and mechanical ventilation correlated significantly with mortality in our cohort. COVID-19 infection in kidney transplant recipients had a high mortality rate; however, remdesivir and high-dose steroids were associated with better outcomes compared with earlier studies.

Mineralocorticoid receptor antagonists (MRAs) slow cardiomyopathy in patients with Duchenne muscular dystrophy (DMD) and improve skeletal muscle pathology and function in dystrophic mice. However, glucocorticoids, known antiinflammatory drugs, remain a standard of care for DMD, despite substantial side effects. Exact mechanisms underlying mineralocorticoid receptor (MR) signaling contribution to dystrophy are unknown. Whether MRAs affect inflammation in dystrophic muscles and how they compare with glucocorticoids is unclear. The MRA spironolactone and glucocorticoid prednisolone were each administered for 1 week to dystrophic mdx mice during peak skeletal muscle necrosis to compare effects on inflammation. Both drugs reduced cytokine levels in mdx quadriceps, but prednisolone elevated diaphragm cytokines. Spironolactone did not alter myeloid populations in mdx quadriceps or diaphragms, but prednisolone increased F4/80hi macrophages. Both spironolactone and prednisolone reduced inflammatory gene expression in myeloid cells sorted from mdx quadriceps, while prednisolone additionally perturbed cell cycle genes. Spironolactone also repressed myeloid expression of the gene encoding fibronectin, while prednisolone increased its expression. Overall, spironolactone exhibits antiinflammatory properties without altering leukocyte distribution within skeletal muscles, while prednisolone suppresses quadriceps cytokines but increases diaphragm cytokines and pathology. Antiinflammatory properties of MRAs and different limb and respiratory muscle responses to glucocorticoids should be considered when optimizing treatments for patients with DMD.

In this context, the current Research Topic for Frontiers in Cell and Developmental Biology aims to collect novel evidence in the field and to help integrate the available knowledge with the final aim to reduce the global cardiovascular disease burden. Conflict of Interest LL is coinventor on the International Patent (WO/2020/226993) relating to the use of antibodies which specifically bind IL-1α to reduce various sequelae of ischemia-reperfusion injury to the central nervous system. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Excessive inflammation after myocardial infarction (MI) can promote infarct expansion and adverse left ventricular (LV) remodeling. L-4F, a mimetic peptide of apolipoprotein A-I (apoA-I), exhibits anti-inflammatory and anti-atherogenic properties; however, whether L-4F imparts beneficial effects after myocardial infarction (MI) is unknown. Here we demonstrate that L-4F suppresses the expansion of blood, splenic, and myocardial pro-inflammatory monocytes and macrophages in a mouse model of reperfused MI. Changes in immune cell profiles were accompanied by alleviation of post-MI LV remodeling and dysfunction. In vitro, L-4F also inhibited pro-inflammatory and glycolytic gene expression in macrophages. In summary, L-4F treatment prevents prolonged and excessive inflammation after MI, in part through modulation of pro-inflammatory monocytes and macrophages, and improves post-MI LV remodeling. These data suggest that L-4F could be a used as a therapeutic adjunct in humans with MI to limit inflammation and alleviate the progression to heart failure.