Myocarditis is an inflammatory disease of the heart with viral infections being the most common aetiology. Its complex biology remains poorly understood and its clinical management is one of the most ...challenging in the field of cardiology. Toll-like receptors (TLRs), a family of evolutionarily conserved pattern recognition receptors, are increasingly known to be implicated in the pathophysiology of viral myocarditis. Their central role in innate and adaptive immune responses, and in the inflammatory reaction that ensues, indeed makes them prime candidates to profoundly affect every stage of the disease process. This review describes the pathogenesis and pathophysiology of viral myocarditis, and scrutinises the role of TLRs in every phase. We conclude with directions for future research in this field.
Improvement of the therapeutic index of adenoviral gene transfer requires the development of strategies to abrogate adenoviral capsid-induced inflammation and cytokine production. The effect of ...monomethoxypolyethylene glycol (MPEG) conjugation to adenoviral vectors and of methylprednisolone (MP) on innate immunity, liver inflammation, and thrombocyte counts was evaluated after transfer of 1011 particles of E1/E3/E4- deleted adenoviral vector expressing human apolipoprotein A-I (apoA-I). Gene transfer with unPEGylated vectors induced peak interleukin-6 (IL-6) plasma levels that were 66-fold above baseline levels in C57BL/6 mice. PEGylation combined with 4 mg of MP 6 hr before and at the time of gene transfer suppressed IL-6 plasma levels to baseline values at all time points. This combination resulted in 24-, 28-, 5.9-, 42-, 26-, and 2.5- fold reduced mRNA expression in the liver of monocyte chemoattractant protein-1, macrophage inflammatory protein-2, interferon-inducible protein-10, macrophage inflammatory protein-1 beta, lipopolysaccharide-induced CXC chemokine, and keratinocyte-derived chemokine, respectively; abrogated neutrophil infiltration in the liver; and reduced alanine aminotransferase levels. PEGylation reduced vector uptake in the spleen and in nonparenchymal liver cells. PEGylation also inhibited the development of thrombocytopenia. In conclusion, PEGylation of adenoviral vectors combined with MP administration improves the therapeutic index of adenoviral gene transfer.
Intensive research over the last 3 decades has unequivocally demonstrated the relevance of inflammation in heart failure (HF). Despite our current and ever increasing knowledge about inflammation, ...the clinical success of antiinflammatory and immunomodulatory therapies in HF is still limited. This review outlines the complexity and diversity of inflammation, its reciprocal interaction with HF, and addresses future perspectives, calling for immunomodulatory therapies that are specific for factors that activate the immune system without the risk of nonspecific immune suppression.
Despite the ongoing global pandemic, the impact of COVID-19 on cardiac structure and function is still not completely understood. Myocarditis is a rare but potentially serious complication of other ...viral infections with variable recovery, and is, in some cases, associated with long-term cardiac remodeling and functional impairment.
To assess myocardial injury in patients who recently recovered from an acute SARS-CoV-2 infection with advanced cardiac magnetic resonance imaging (CMR) and endomyocardial biopsy (EMB).
In total, 32 patients with persistent cardiac symptoms after a COVID-19 infection, 22 patients with acute classic myocarditis not related to COVID-19, and 16 healthy volunteers were included in this study and underwent a comprehensive baseline CMR scan. Of these, 10 patients post COVID-19 and 13 with non-COVID-19 myocarditis underwent a follow-up scan. In 10 of the post-COVID-19 and 15 of the non-COVID-19 patients with myocarditis endomyocardial biopsy (EMB) with histological, immunohistological, and molecular analysis was performed.
In total, 10 (31%) patients with COVID-19 showed evidence of myocardial injury, eight (25%) presented with myocardial oedema, eight (25%) exhibited global or regional systolic left ventricular (LV) dysfunction, and nine (28%) exhibited impaired right ventricular (RV) function. However, only three (9%) of COVID-19 patients fulfilled updated CMR-Lake Louise criteria (LLC) for acute myocarditis. Regarding EMB, none of the COVID-19 patients but 87% of the non-COVID-19 patients with myocarditis presented histological findings in keeping with acute or chronic inflammation. COVID-19 patients with severe disease on the WHO scale presented with reduced biventricular longitudinal function, increased RV mass, and longer native T1 times compared with those with only mild or moderate disease.
In our cohort, CMR and EMB findings revealed that SARS-CoV-2 infection was associated with relatively mild but variable cardiac involvement. More symptomatic COVID-19 patients and those with higher clinical care demands were more likely to exhibit chronic inflammation and impaired cardiac function compared to patients with milder forms of the disease.
Recently, a new paradigm for the development of heart failure with preserved ejection fraction (HFpEF) has been proposed, which identifies a systemic pro-inflammatory state induced by comorbidities ...as the origin of microvascular endothelial cell inflammation and subsequent concentric cardiac remodeling and dysfunction. This review further discusses the pivotal role of the inflamed endothelium in the pathogenesis of HFpEF-specific cardiac remodeling. The potential importance of reciprocal interactions of the endothelium with cardiac fibroblasts and cardiomyocytes and with the cardiac neurohumoral response in this cardiac remodeling process is outlined.
Increased levels of interleukin-6 (IL-6) have been observed in patients with acute myocarditis and are associated with poor prognosis. This study was designed to examine whether treatment with ...anti-IL-6 receptor antibody improves cardiac dysfunction and left ventricular (LV) remodeling in experimental Coxsackie virus B3 (CVB3)-induced myocarditis. C57BL6/J mice were subjected to acute CVB3 infection. One day after viral infection mice were treated with a single injection of an anti-IL-6 receptor antibody (MR16-1, tocilizumab) or control IgG. Seven days after viral infection, LV function was examined by conductance catheter technique, cardiac remodeling assessed by estimation of titin phosphorylation, cardiac fibrosis, and inflammatory and antiviral response by immunohistochemistry, RT-PCR and cell culture experiments. Compared to controls, infected mice displayed an impaired systolic and diastolic LV function associated with an increase in cardiac inflammation, fibrosis and impaired titin phosphorylation. IL-6 receptor blockade led to a shift of the immune response to a Th1 direction and significant reduction of viral load. In addition, cardiac immune response, extracellular matrix regulation and titin function improved, resulting in a preserved LV function. IL-6 receptor blockade exerts cardiac beneficial effects by antiviral and immunomodulatory actions after induction of an acute murine CVB3 virus myocarditis.
The protective effects of high-density lipoprotein (HDL) under lipopolysaccharide (LPS) conditions have been well documented. Here, we investigated whether an effect of HDL on Toll-like receptor 4 ...(TLR4) expression and signalling may contribute to its endothelial-protective effects and to improved survival in a mouse model of LPS-induced inflammation and lethality. HDL cholesterol increased 1.7-fold (
p
< 0.005) and lung endothelial TLR4 expression decreased 8.4-fold (
p
< 0.005) 2 weeks after apolipoprotein (apo) A-I gene transfer. Following LPS administration in apo A-I gene transfer mice, lung
TLR4
and lung
MyD88
mRNA expression, reflecting TLR4 signalling, were 3.0-fold (
p
< 0.05) and 2.1-fold (
p
< 0.05) lower, respectively, than in LPS control mice. Concomitantly, LPS-induced lung neutrophil infiltration, lung oedema and mortality were significantly attenuated following apo A–I transfer. In vitro, supplementation of HDL or apo A–I to human microvascular endothelial cells-1 24 h before LPS administration reduced TLR4 expression, as assessed by fluorescent-activated cell sorting, and decreased the LPS-induced
MyD88
mRNA expression and NF-κB activity, independently of LPS binding. In conclusion, HDL reduces TLR4 expression and signalling in endothelial cells, which may contribute significantly to the protective effects of HDL in LPS-induced inflammation and lethality.
Left ventricular (LV) diastolic dysfunction is among others attributed to cardiomyocyte stiffness. Mesenchymal stromal cells (MSC) have cardiac‐protective properties. We explored whether intravenous ...(i.v.) application of PLacenta‐eXpanded (PLX) MSC‐like cells (PLX) improves LV diastolic relaxation in streptozotocin (STZ)‐induced diabetic mice and investigated underlying mechanisms. Diabetes mellitus was induced by STZ application (50 mg/kg body weight) during five subsequent days. One week after the first STZ injection, PLX or saline were i.v. applied. Two weeks later, mice were hemodynamically characterized and sacrificed. At this early stage of diabetic cardiomyopathy with low‐grade inflammation and no cardiac fibrosis, PLX reduced LV vascular cell adhesion molecule‐1, transforming growth factor‐β1, and interferon‐γ mRNA expression, induced the percentage of circulating regulatory T cells, and decreased the splenic pro‐fibrotic potential in STZ mice. STZ + PLX mice exhibited higher LV vascular endothelial growth factor mRNA expression and arteriole density versus STZ mice. In vitro, hyperglycemic PLX conditioned medium restored the hyperglycemia‐impaired tube formation and adhesion capacity of human umbelical vein endothelial cells (HUVEC) via increasing nitric oxide (NO) bioavailability. PLX further induced the diabetes‐downregulated activity of the NO downstream protein kinase G, as well as of protein kinase A, in STZ mice, which was associated with a raise in phosphorylation of the titin isoforms N2BA and N2B. Concomitantly, the passive force was lower in single isolated cardiomyocytes from STZ + PLX versus from STZ mice, which led to an improvement of LV diastolic relaxation. We conclude that i.v. PLX injection improves diabetes mellitus‐associated diastolic performance via decreasing cardiomyocyte stiffness. Stem Cells Translational Medicine 2017;6:2135–2145
Improvement of diabetes mellitus impaired diastolic relaxation via intravenous application of placenta‐derived mesenchymal stromal cells (MSC)‐like stromal cells. Intravenous application of placenta‐derived MSC like cells in streptozotocin‐induced diabetic mice improves diastolic relaxation at this early stage of diabetic cardiomyopathy with low‐grade inflammation and no cardiac fibrosis via decreasing cardiomyocyte stiffness (Fpassive) through increased titin phosphorylation following restoration of the activity of the nitric oxide‐downstream protein kinase G.
Abstract Objective The objective of the current study was to investigate the hypothesis that high-density lipoprotein (HDL) influences adipocyte metabolism and adiponectin expression. Therefore, HDL ...was increased in vivo via apolipoprotein (apo) A-I gene transfer and in vitro via supplementation of HDL to partly differentiated adipocytes, in the presence or absence of lipopolysaccharide (LPS), known to decrease HDL cholesterol and adiponectin levels in vivo. Methods and results Apo A-I transfer resulted in a significant increase of HDL cholesterol in control and LPS-injected C57BL/6 mice, which was paralleled by an increase in plasma adiponectin levels and adiponectin expression in abdominal fat. Triglyceride and free fatty acids levels after LPS administration were 2.2-fold ( p < 0.05) and 1.3-fold ( p < 0.05) lower, respectively, in Ad.hapoA-I -LPS than in Ad.Null -LPS mice. In parallel, the LPS-induced mRNA expression of hormone sensitive lipase was 3.5-fold ( p = 0.05) decreased in the Ad.hapoA-I -LPS group. On the other hand, apo A-I transfer abrogated the LPS-mediated reduction in lipin-1 and CD36 mRNA expression by 8.2-fold ( p < 0.05) and 18-fold ( p < 0.05), respectively. Concomitantly, the phosphorylation state of Akt was 2.0-fold ( p < 0.05) increased in the Ad.hapoA-I -LPS compared to the Ad.Null -LPS group. Pre-incubation of partly differentiated adipocytes with HDL (50 μg protein/ml) increased adiponectin expression by 1.5-fold under basal conditions ( p < 0.05) and could abrogate LPS-induced down-regulation of adiponectin, both in a phosphatidylinositol-3-kinase-dependent manner. Conclusions HDL affects adipocyte metabolism and adiponectin expression.
PDF
