Myocardial inflammation and non-ischaemic heart failure: is there a role for C-reactive protein?

Whereas C-reactive protein (CRP) is acknowledged as a cardiovascular risk marker, there is ongoing discussion about its role as a risk factor. Previous studies focused on the effects of CRP on ischaemic heart failure and atherosclerosis. In this study we investigated distribution of CRP, the Terminal Complement Complex (C5b-9) and macrophages (CD68) in the myocardium of patients suffering from non-ischaemic heart failure and their implication on clinical parameters. Endomyocardial biopsies were taken from 66 patients suffering from dilated cardiomyopathy (DCM). Biopsies were analysed by immunohistochemical and immunofluorescent staining for CRP, C5b-9 and CD68. Viral DNA/RNA for adenovirus, enterovirus, parvovirus B19 and human herpes virus 6 was detected by PCR and Southern blot analysis. Myocardial biopsy findings were correlated with plasma level of hsCRP and NT-proBNP as well as echocardiography, exercise test and NYHA class. In 18 (27%) patients, a positive staining for CRP and in 57 (86%) patients a positive staining for C5b-9 was detected. All patients showed myocardial infiltration with macrophages with an average of 39 cells/mm². CRP, C5b-9 and CD68 co-localised within the myocardium. No correlation was observed for inflammatory proteins and plasma level of hsCRP, NT-proBNP and clinical parameters. CRP is frequently present in the myocardium of patients suffering from DCM and co-localises with C5b-9 and macrophages. CRP may contribute to myocardial damage in DCM via activation of the complement system and chemotaxis of macrophages. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Is there a role for adaptive immunity in nonalcoholic steatohepatitis?

The growing diffusion of nonalcoholic fatty liver disease (NAFLD) is a consequence of the worldwide increase in the prevalence of obesity. Oxidative stress is widely recognized to play a pivotal role in NAFLD evolution to nonalcoholic steatohepatitis (NASH). Here we review recent evidence suggesting that oxidative stress-derived antigens originating within fatty livers stimulate both humoral and cellular adaptive immune responses and the possible mechanisms involved in sustaining hepatic inflammation in NASH.     

Is there a role for cardiomyocyte toll-like receptor 4 in endotoxemia?

Lipopolysaccharide (LPS) is thought to be an important molecule in myocardial depression in sepsis. Toll-like receptor 4 (TLR4), the lipopolysaccharide receptor, is known to underlie these responses. Because TLR4 is expressed on both cardiac myocytes and immune cells, it is unclear as to which cell type is responsible for myocyte depression. In this article, we present evidence that the early response is likely related to TLR4 on immune cells and most likely macrophages, whereas the more delayed response may involve various immune cells as well as myocytes.     

A role for innate immunity in type 1 diabetes?

Two arms of the immune system, innate and adaptive immunity, differ in their mode of immune recognition. The innate immune system recognizes a few highly conserved structures on a broad range of microorganisms. On the other hand, recognition of self or autoreactivity is generally confined to the adaptive immune response. Whilst autoimmune features are relatively common, they should be distinguished from autoimmune disease that is infrequent. Type 1 diabetes is an immune-mediated disease due to the destruction of insulin secreting cells mediated by aggressive immune responses, including activation of the adaptive immune system following genetic and environmental interaction. Hypotheses for the cause of the immune dysfunction leading to type 1 diabetes include self-reactive T-cell clones that (1) escape deletion in the thymus, (2) escape from peripheral tolerance or (3) escape from homeostatic control with an alteration in the immune balance leading to autoimmunity. Evidence, outlined in this review, raises the possibility that changes in the innate immune system could lead to autoimmunity, by either priming or promoting aggressive adaptive immune responses. Hostile microorganisms are identified by genetically determined surface receptors on innate effector cells, thereby promoting clearance of these invaders. These innate effectors include a few relatively inflexible cell populations such as monocytes/macrophages, dendritic cells (DC), natural killer (NK) cells, natural killer T (NKT) cells and gammadelta T cells. Recent studies have identified abnormalities in some of these cells both in patients with type 1 diabetes and in those at risk of the disease. However, it remains unclear whether these abnormalities in innate effector cells predispose to autoimmune disease. If they were to do so, then modulation of the innate immune system could be of therapeutic value in preventing immune-mediated diseases such as type 1 diabetes.     

Is there a role for estrogen and progesterone receptors in gall bladder cancer?

Background/Aims. The concept of metaplastic and non-metaplastic types of gall bladder cancer and the likelihood of hormone receptor expression in the nuclei of tumour cells raised the possibility of a potential role for anti-estrogen therapy in gall bladder cancer. This study was carried out to determine the hormone receptors (ER/PR) expression level in gall bladder cancer using specific immunohistochemical assays and correlate it with patient and tumour histopathological characteristics. Patients and methods. Histopathological tumour specimens of 62 patients who underwent a radical cholecystectomy were analysed. Pronase pretreatment and primary monoclonal antibodies were used to perform immunohistochemical analysis for ER and PR. Results. The histology was adenocarcinoma – predominantly, moderately to poorly differentiated (91%). Gallstones were present in 90% of the individuals. Of the 62 specimens analysed, 62 (100%) and 61 (98%) were negative for ER and PR, respectively. Conclusion. The high incidence of gallstone-related gall bladder cancer in India is associated with metaplasia and a tendency to poorer differentiation in the tumour histology. These tumours are consequently less likely to express hormone receptors. Thus, there does not seem to be a role for anti-hormone therapy in patients with histogenesis similar to that seen in India.     

Hydroxychloroquine: is there a role in long COVID?

Clinical Rheumatology -     

Macrolides in cystic fibrosis: is there a role?

A spectrum of anti-inflammatory properties, evidence of anti-infective action against Pseudomonas aeruginosa at sub-inhibitory concentrations and positive clinical experience in patients with diffuse panbronchiolitis, a disease with features in common with cystic fibrosis (CF), has prompted research to evaluate the role of macrolide therapy in patients with CF. Newer macrolides such as azithromycin have the advantage of improved tolerability and a prolonged intracellular half-life requiring an infrequent dosing regimen. Results from initial studies suggest a benefit from several months of macrolide therapy in patients with CF. An improvement in lung function was initially shown in a small open study in children, while maintenance of lung function compared with placebo, reduced acute respiratory exacerbations, and reduced systemic markers of inflammation were demonstrated in a randomized, placebo-controlled study of macrolide therapy in adult patients with CF. Additional controlled studies are required to determine optimal drug, dosage, and duration of therapy, and long-term adverse effects of prolonged therapy with macrolides in patients with CF. The potential, with long-term use, to induce resistance against other bacteria colonizing the upper respiratory tract e.g. pneumococci has not been explored. Measurement of cytokines and inflammatory mediators from the sputum of patients with CF is technically difficult and does not correlate with disease activity. There is a need for easily measurable, reproducible and clinically meaningful end-points for evaluation of new therapies in CF. The choice of appropriate outcome measures, apart from lung function, to monitor disease activity needs careful consideration in clinical trials determining the efficacy of macrolides in patients with CF. Evidence-based recommendations for the use of macrolides in the treatment of CF are not expected for some years although macrolides are already being prescribed for long-term use in some centers. There is a need for further research into mechanisms of anti-inflammatory action of macrolides in the lungs of patients with CF and whether or not such therapy may be beneficial in the long term.     

Acute heart failure: is there a role for surgery?

Many of the disorders and lesions leading to acute heart failure can be treated surgically. Modern surgical techniques like the off pump coronary surgery, newer techniques for the surgical treatment of the mechanical complications of acute MI and valvular reparative techniques have been added to the surgical armamentarium in recent years. Modern ventricular assist devices have started their career in the clinical arena promising to be less invasive. At the same time the spectrum of indications for mechanical circulatory support continues to witness a rapid expansion. Technical advances have led to an evolution of surgical strategies. Heart failure surgery is now in a position to offer improved outcomes, avoidance of recurrence of acute heart failure or the development of advanced chronic heart failure.     

Toll-like receptor-2 expression is upregulated in antigen-presenting cells from patients with psoriatic arthritis: a pathogenic role for innate immunity?

OBJECTIVE: To study Toll-like receptor-2 (TLR-2) and TLR-4 expression in antigen-presenting cells from patients with psoriatic arthritis (PsA). METHODS: We measured expression of TLR-2 and TLR-4 in monocyte-derived dendritic cells from patients with PsA and with rheumatoid arthritis (RA), and in healthy controls. Dendritic cells were obtained from freshly isolated monocytes, stimulated with granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin 4 (IL-4) after 6 days in culture. To obtain mature dendritic cells, lipopolysaccharide stimulation and 2 additional days in culture were necessary. The expression of TLR-2, TLR-4, HLA-DR, and CD86 was studied at baseline, at 6 days, and at 8 days by flow cytometry. To establish the functional properties of TLR expression we studied the following cytokines in cell supernatants: tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, and GM-CSF. TLR-2 expression was confirmed by Western blot analysis. RESULTS: Ten PsA patients with active disease and 8 healthy controls were studied, along with 4 patients with RA. TLR-2 expression was increased in immature dendritic cells from patients with PsA. Monocytes and mature dendritic cells did not show statistically significant differences. No difference was observed in the expression of TLR-4 in any cell type. The supernatant expression of cytokines showed a Th1 pattern, mostly with increased expression of TNF-alpha, IFN-gamma, and IL-2. Western blot analysis confirmed the increased expression of TLR-2. CONCLUSION: Upregulation of TLR-2 expression provides support for a role of the innate immune system in the pathogenesis of PsA.     

Primary and secondary prevention of atherosclerosis: is there a role for antioxidants?

Elevated plasma free radical concentration (expression of enhanced oxidative stress) is related to different pathophysiological conditions such as ageing, cancer and diabetes. Nevertheless, even in healthy subjects a rise in plasma free radicals is due to hyperglycaemia, elevated free fatty acids and hyperinsulinaemia. Once elevated oxidative stress occurs, accelerated atherosclerosis may be present. Thus, antioxidants might potentially be useful in preventing or delaying the development of atherosclerosis. Several epidemiological studies have provided conflicting results, whereas interventional studies have demonstrated that antioxidant administration at pharmacological doses is useful for secondary prevention of atherosclerosis. The role of antioxidants in diabetic patients is still debatable, and it is too early to suggest this means for the prevention of atherosclerosis. Concerning trace elements, several studies have indicated that iron, copper, zinc and selenium may play a role in the pathogenesis of atherosclerosis. Nevertheless, only future longitudinal studies can provide a final response. In conclusion, the whole body of studies to date clearly demonstrates that antioxidants may be useful for secondary prevention of coronary heart disease.     

Cardiac vascular calcification and QT interval in ESRD patients: is there a link?

We will present our experience and our preliminary data about the correlation between cardiac calcification and QT interval (and QT dispersion) in uraemia. We studied 32 haemodialysis (HD) patients (age 69 +/- 16 years, time on dialysis 32 +/- 27 months) and 12 chronic kidney disease stage 4 (CKD-4) patients (age 66 +/- 17 years, uraemia duration 38 +/- 16 months). The patients were characterized by a good mineral control, as shown by serum phosphate levels (3.6 +/- 1.3 mg/dl in CKD-4 and 4.3 +/- 1.6 mg/dl in HD patients) and Ca x P product (46 +/- 17 and 49 +/- 16 mg(2)/dl(2), respectively). The parathyroid hormone levels were higher in HD than CKD-4 patients (p < 0.0001). A TC score >400 was found to be highly prevalent in both groups. Significantly more HD patients (62.5%) showed cardiac calcification than CKD-4 patients (33%; p = 0.01). The patients were matched for TC scores higher or lower than 400. The two groups differed by gender (p < 0.05), age (p = 0.026), frequency of diabetes mellitus (p < 0.01), uraemia follow-up period (p < 0.001), low-density lipoprotein cholesterol level (p = 0.009), Ca x P product (p = 0.002), parathyroid hormone level (p < 0.0001), and corrected QT dispersion (p < 0.0001). The QT interval was higher in HD and CKD-4 patients with higher TC scores (approximately 11%), but QT interval dispersion was significantly higher in patients with TC scores >400. QT dispersion showed a linear correlation with TC scores in both groups (r = 0.899 and p < 0.0001 and r = 0.901 and p < 0.0001). Male gender, age, time (months) of uraemia, low-density lipoprotein cholesterol, albumin, calcium x phosphorus product, parathyroid hormone, and TC score are important determinants of QT dispersion. Our data show that it is possible to link dysrhythmias and cardiac calcification in uraemic patients.     

Innate immunity and hepatocarcinoma: Can toll-like receptors open the door to oncogenesis?

Hepatocarcinoma (HCC) is a highly prevalent cancer worldwide and its inflammatory background was established long ago. Recent studies have shown that innate immunity is closely related to the HCC carcinogenesis. An effective innate immunity response relies on the toll-like receptors (TLR) found in several different liver cells which, through different ligands and many signaling pathways can elicit, not only a pro-inflammatory but also an oncogenic or anti-oncogenic response. Our aim was to study the role of TLRs in the liver oncogenesis and as a consequence their value as potential therapeutic targets. We performed a systematic review of PubMed searching for original articles studying the relationship between HCC and TLRs until March 2015. TLR2 appears to be a fundamental stress-sensor as its absence reveals an augmented tendency to accumulate DNA-damages and to cell survival. However, pathways are still not fully understood as TLR2 up-regulation was also associated to enhanced tumorigenesis. TLR3 has a well-known protective role influencing crucial processes like angiogenesis, cell growth or proliferation. TLR4 works as an interesting epithelial-mesenchymal transition’s inducer and a promoter of cell survival probably inducing HCC carcinogenesis even though an anti-cancer role has already been observed. TLR9’s influence on carcinogenesis is also controversial and despite a potential anti-cancer capacity, a pro-tumorigenic role is more likely. Genetic polymorphisms in some TLRs have been found and its influence on the risk of HCC has been reported. As therapeutic targets, TLRs are already in use and have a great potential. In conclusion, TLRs have been shown to be an interesting influence on the HCC’s microenvironment, with TLR3 clearly determining an anti-tumour influence. TLR4 and TLR9 are considered to have a positive relationship with tumour development even though, in each of them anti-tumorigenic signals have been described. TLR2 presents a more ambiguous role, possibly depending on the stage of the inflammation-HCC axis.     

Editorial: is there a role for angiography in patients with obscure overt bleeding?

Obscure gastrointestinal hemorrhage remains a challenging but uncommon clinical scenario. Video capsule endoscopy (VCE) has been recommended as the third diagnostic test after normal upper and lower endoscopic examinations. A recent randomized controlled trial comparing immediate VCE to angiography demonstrated a superior diagnostic yield for VCE compared with angiography. However, long-term outcomes, including rebleeding, hospitalization rates, and death, did not differ between the two cohorts. Although VCE appears to be superior to other testing modalities for overall diagnostic yield, the clinical outcomes ultimately depend upon the type of lesion detected. Vascular lesions, mainly small bowel angiodysplasia, can be expected to have the highest rates of rebleeding, despite endoscopic therapy, and have been associated with the presence of comorbid conditions.