Anemia in chronic heart failure: etiology and treatment options

PURPOSE OF REVIEW: Anemia is common in patients with chronic heart failure, and is related to increased morbidity and mortality. The etiology of anemia in heart failure is complex and still not fully resolved. The review will describe current advances in the understanding of the pathophysiology of anemia and the potential therapeutic effects of recombinant human erythropoietin. RECENT FINDINGS: Recent attempts to resolve the preponderant etiology of anemia in chronic heart failure have further defined its multifactorial nature. Impaired renal perfusion and function resulting in blunted erythropoietin production as well as impaired erythropoiesis in the bone marrow account for a vulnerable erythropoietic system. Moreover, fluid retention causes hemodilutional anemia. Correction of anemia with recombinant human erythropoietin seems feasible and is currently being evaluated in a phase 3 clinical trial. In addition, recombinant human erythropoietin improves cardiac function in chronic heart failure through the recruitment of endothelial progenitor cells and exerts cytoprotective effects during acute myocardial infarction. Although recombinant human erythropoietin shows great promise, we should not neglect other treatable causes of anemia. SUMMARY: Although the etiology of anemia in chronic heart failure is clearly multifactorial, correction of anemia with recombinant human erythropoietin seems promising. In addition to correction of anemia, recombinant human erythropoietin might exert important protective and regenerative effects on the myocardium.     

CCL17/thymus and activation–related chemokine in Churg‐Strauss syndrome

Objective

Churg‐Strauss syndrome (CSS) is a Th2‐mediated systemic vasculitis characterized by eosinophilic infiltration, blood eosinophilia, and high IgE levels. CCL17/thymus and activation–regulated chemokine (TARC) is a chemokine responsible for the recruitment of Th2 cells. This study was undertaken to explore a possible role of CCL17/TARC in CSS.

Methods

CCL17/TARC levels in serum from patients with active or inactive CSS, hypereosinophilic syndrome, systemic small‐vessel vasculitis other than CSS, other types of eosinophilia, and healthy controls were determined by enzyme‐linked immunosorbent assay. Biopsy samples of affected tissue from CSS patients were examined by immunohistochemical staining for Th2 infiltration and CCL17/TARC expression.

Results

Serum CCL17/TARC levels were significantly elevated in CSS patients with active disease (mean ± SEM 1,122.0 ± 422.7 pg/ml) compared with controls (220.6 ± 27.9 pg/ml) and patients with inactive disease (388.9 ± 72.6 pg/ml) (P < 0.001 and P < 0.05, respectively). These levels correlated with the clinical disease course of CSS and with absolute eosinophil counts as well as IgE levels. Infiltrating Th2 cells in active CSS lesions were evidenced by CD294 staining. CCL17/TARC in the affected tissue of CSS patients was readily identified by immunohistochemical analysis. Elevated CCL17/TARC levels were also noted in patients with hypereosinophilic syndrome (794.5 ± 294.8 pg/ml) and other disorders associated with eosinophilia (1,096.0 ± 345.3 pg/ml) (both P < 0.005 versus controls).

Conclusion

CCL17/TARC may contribute to CSS pathogenesis by recruitment of Th2 cells into affected tissue. Serum CCL17/TARC levels reflect disease activity, and further studies to validate its use as an activity marker in CSS are warranted.

     

Mild renal dysfunction is associated with electrocardiographic left ventricular hypertrophy

BACKGROUND: Both renal dysfunction and left ventricular hypertrophy (LVH) are signs of end-organ damage, risk markers of cardiovascular (CV) disease and chronic heart failure. In selected populations such as those with diabetes or hypertension, renal dysfunction was found to be related to LVH. We studied the relation between renal dysfunction and LVH in a cross-sectional study in 8592 inhabitants from Groningen, The Netherlands. METHODS: Standard 12-lead electrocardiograms were recorded, and LVH was classified using the Cornell voltage duration product. Renal dysfunction was defined as creatinine clearance <60 mL/min/1.73 m(2) or microalbuminuria (30 to 300 mg/24 h). RESULTS: Electrocardiographic signs of LVH were present in 396 of subjects (5.3%). Subjects with LVH were older and had a more extensive CV risk profile. We found that LVH was more prevalent in subjects with renal dysfunction than in those without (8% v 4%, P < .001). Multivariate regression analysis demonstrated that renal dysfunction was independently related to a 1.47-fold increased risk of the presence of LVH (95% CI = 1.15 to 1.88, P = .009). In addition, both creatinine clearance (OR = 1.56, 95% CI = 1.07 to 2.2, P = .044) and microalbuminuria (OR = 1.37, 95% CI = 1.04 to 1.80, P = .024) were independently associated with the presence of LVH. CONCLUSION: Subjects with mild renal dysfunction have a substantially higher risk of LVH on electrocardiography than those without renal dysfunction.     

Aging,telomeres and heart failure

During normal aging, the heart undergoes functional, morphological and cellular changes. Although aging per se does not lead to the expression of heart failure, it is likely that age-associated changes lower the threshold for the manifestation of signs and symptoms of heart failure. In patients, the susceptibility, age of onset and pace of progression of heart failure are highly variable. The presence of conventional risk factors cannot completely explain this variability. Accumulation of DNA damage and telomere attrition results in an increase in cellular senescence and apoptosis, resulting in a decrease in the number and function of cells, contributing to the overall tissue and organ dysfunction. Biological aging, characterized by reduced telomere length, provides an explanation for the highly interindividual variable threshold to express the clinical syndrome of heart failure at some stage during life. In this review, we will elaborate on the current knowledge of aging of the heart, telomere biology and its potential role in the development of heart failure.     

MCS-18, a natural product isolated from Helleborus purpurascens, inhibits maturation of dendritic cells in ApoE-deficient mice and prevents early atherosclerosis progression

Introduction

Inflammation accelerates both plaque progression and instability in the pathogenesis of atherosclerosis. The inhibition of dendritic cell (DC) maturation is a promising approach to suppress excessive inflammatory immune responses and has been shown to be protective in several autoimmune models. The aim of this study was to investigate the immune modulatory effects of the natural substance MCS-18, an inhibitor of DC maturation, regarding the progression of atherosclerosis in ApoE-deficient mice.

Materials and methods

ApoE-deficient mice were fed for twelve weeks with a Western-type diet (n = 32) or normal chow (control group; n = 16). Animals receiving high-fat diet were treated with MCS-18 (500 μg/kg body weight, n = 16) or saline (n = 16) twice a week. After 12 weeks, animals were transcardially perfused and sacrificed. The percentage of mature DCs (CD3⁻/CD19⁻/CD14⁻/NK1.1⁻/CD11c⁺/MHCII⁺/CD83⁺/CD86⁺) and T cell subpopulations (CD4⁺/CD25⁺/Foxp3⁺, CD3/CD4/CD8) was analyzed in peripheral blood and in the spleen using flow cytometry. Plaque size was determined in the aortic root and the thoracoabdominal aorta using en-face staining. Immunohistochemical stainings served to detect inflammatory cells in the aortic root. Several cytokines and chemokines were determined in serum using multiplex assays.

Results

In splenic cells derived from saline-treated atherosclerotic mice an increased DC maturation, reflected by the upregulation of CD83 and CD86 expression, was observed. The enhanced expression of both maturation markers was absent in MCS-18 treated atherosclerotic mice. While the percentage of splenic Foxp3 expressing Treg was increased in animals receiving MCS-18 compared to saline-treated atherosclerotic mice, cytotoxic T cells were reduced in the spleen and in atherosclerotic lesions of the aortic root. Furthermore, proatherogenic cytokines (e.g. IL-6 and IFN-γ) and chemokines (e.g. MIP-1β) were decreased in serum of MCS-18-treated animals when compared to saline-treated atherosclerotic mice. Also plaque size in the aortic root and the thoracoabdominal aorta was significantly lower following administration of MCS-18.

Conclusion

This study provides for the first time evidence that MCS-18 is able to prevent the onset of atherosclerosis in ApoE-deficient mice. The observed anti-atherogenic effect is associated with the suppression of DC maturation and an inhibited migration and proliferation of cytotoxic T cells.     

Contrast-Enhancing Meningeal Lesions Are Associated with Longer Survival in Breast Cancer-Related Leptomeningeal Metastasis

BACKGROUND: Leptomeningeal metastasis (LM) is a devastating complication of advanced cancer. Despite aggressive therapy survival is very poor. METHODS: Data of all breast cancer patients with LM were retrospectively analyzed (n = 27). RESULTS: Median survival was 9 weeks. Patients with contrast-enhancing meningeal lesions (n = 11) detected by MRI had a median survival of 33 weeks versus 8 weeks for patients without contrast-enhancing lesions (n = 9; p = 0.0407). Patients who received systemic chemotherapy (n = 18) had a median survival of 15 weeks versus 7 weeks (n = 9; p = 0.0106). Patients undergoing radiotherapy (n = 8) had a median survival of 17 weeks as compared to 5 weeks for patients without radiotherapy (n = 18; p = 0.0188). In a multiple Cox regression analysis, lack of systemic therapy (hazard ratio, HR 89.5; p = 0.002) and negative hormone receptor status (HR 4.2; p = 0.027) emerged as significant main risk factors, together with contrast-enhancing lesion as effect modifier for systemic therapy (p = 0.03). CONCLUSION: Contrast-enhancing meningeal lesions, systemic therapy, and radiotherapy were significantly associated with longer survival. Patients with contrast-enhancing lesions who were treated systemically had the longest survival. Evidence is increasing that systemic therapy plays an important role and should be applied in breast cancer patients with LM.     

Prion infection of mice transgenic for human APPSwe: increased accumulation of cortical formic acid extractable Aβ(1–42) and rapid scrapie disease development

Neuropathological, epidemiological and experimental data indicate a potential interrelationship between Alzheimer's disease and prion diseases. Proteolytic processing of amyloid precursor protein (APP) by β-secretase was recently suggested to be controlled by prion protein expression. Here, we characterized the prion infection of Tg2576 mice, which overexpress the human APP_Swe protein. Prion infection of Tg2576-mice led to an early death of the animals, which was preceded by a relatively short symptomatic stage. However, disease-associated gliosis and deposition of misfolded prion protein PrP^Sc were identical in infected Tg2576-mice and non-transgenic littermate controls. To analyze the effect of prion infection on APP processing and generation of β-amyloid we determined cortical levels of SDS- and formic acid (FA)-extractable forms of β-amyloid (1–40) and (1–42) by ELISA. Formic acid-extractable Aβ (1–42) levels were 10-fold higher in infected versus uninfected Tg2576 mice whereas other forms of Aβ were essentially unaffected by the prion infection. Hence, the experimental model demonstrates that a prion infection of the CNS promotes selectively formation of FA-extractable Aβ(1–42) in Tg2576 mice.     

Prevalence of Parkinson symptoms in patients with different peripheral vestibular disorders

Journal of Neurology -