Response to letter to the editor: annexin A5 levels or circulating microparticles: what we see depends mainly on what we look for.

Click here to view the article Letter to the Editor by S. Shetty et al.

Circulating annexin A5 predicts mortality in patients with heart failure.

BACKGROUND: Natriuretic peptides are currently used to predict mortality in patients with heart failure (HF). However, novel independent biomarkers are needed to improve risk stratification in these patients. We hypothesized that annexin A5 (anxA5) would be highly expressed by organs which are generally affected by HF and that circulating anxA5 levels would predict mortality in HF patients. METHODS: We prospectively determined the diagnostic value of anxA5, N-terminal pro-B-type natriuretic peptide (NT-proBNP), C-reactive protein (CRP) and estimated glomerular filtration rate (eGFR) to predict mortality in 180 HF patients during a median follow-up of 3.6 years. Studies were conducted with anxA5(-/-) mice to investigate the underlying mechanisms. RESULTS: AnxA5 levels were significantly elevated in HF patients compared to healthy control subjects. Cox regression analysis demonstrated that anxA5, NT-proBNP and eGFR all predict mortality independently. AnxA5 significantly improved the diagnostic efficiency of NT-proBNP alone (improvement of c-statistic from 0.662 to 0.705, P < 0.001) and also combined with eGFR and CRP (improvement of c-statistic from 0.675 to 0.738, P < 0.001) to predict mortality in the Cox regression model. Receiver operating characteristic curve analysis showed that anxA5 predicted 3-year survival (area under curve 0.708) with an optimal cut-off value of 2.24 ng mL(-1) . Using anxA5(-/-) mice, we demonstrated that anxA5 is highly expressed in organs that are often affected by HF including lung, kidney, liver and spleen. Lysis of these organs in vitro resulted in a marked and significant increase in anxA5 concentrations. CONCLUSION: AnxA5 improves the diagnostic efficiency of conventional biomarkers to predict mortality in HF patients. Whereas natriuretic peptides originate from the myocardium, high circulating anxA5 levels in patients with HF are likely to reflect peripheral organ damage secondary to HF.

[Resuscitation]. / Reanimation.

The primary aim of cardiopulmonary resuscitation after cardiac arrest is to achieve the return of spontaneous circulation (ROSC). However, following ROSC the clinical and neurologic outcome is mainly influenced by adequate treatment in the postresuscitation period. There are several novel recommendations in the current 2010 guidelines of the European Resuscitation Council (ERC) concerning advanced life support (ALS). In addition to established standards for mechanical, electrical (defibrillation), and pharmacological resuscitation during the initial phase, the guidelines moreover deal with recommendations for standardized therapy in the postresuscitation period. Major aspects concerning the therapy of the postcardiac arrest syndrome include temperature management with therapeutic hypothermia, mechanical ventilation and the extent of oxygenation and blood glucose control. Thus, the initial cardiopulmonary resuscitation and the following postresuscitation treatment have to be considered as merging therapy concepts. Only a standardized therapeutic approach in these different phases of treatment will result in successful resuscitation with high rates of survival and good neurologic outcome.

Cardiovascular effects of GLP-1 and GLP-1-based therapies: implications for the cardiovascular continuum in diabetes?

AIMS: Glucagon-like peptide-1 receptor agonists and inhibitors of dipeptidyl peptidase-4 that increase glucagon-like peptide-1 plasma concentrations are current treatment options for patients with diabetes mellitus. As patients with diabetes are a high-risk population for the development of a severe and diffuse atherosclerosis, we aim to review the potential action of these drugs on cardiovascular disease and to summarize the potential role of present glucagon-like peptide-1-based therapies from a cardiologist's point of view. METHODS: Using a PubMed/MEDLINE search without language restriction, studies were identified and evaluated in order to review the effects of glucagon-like peptide-1-based therapy on different stages of the cardiovascular continuum. RESULTS: Recent experimental as well as clinical data suggest that dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists--in addition to their metabolic effects--may have beneficial effects on the cardiovascular continuum at multiple stages, including: (1) cardiovascular risk factors; (2) molecular mechanisms involved in atherogenesis; (3) ischaemic heart disease; and (4) heart failure. Furthermore, retrospective analysis suggested decreased cardiovascular events in patients with glucagon-like peptide-1-based therapies. CONCLUSION: There are ample data to suggest beneficial effects of glucagon-like peptide-1-based therapies on the cardiovascular continuum and large-scale clinical trials are warranted to determine whether these effects translate into improved cardiovascular endpoints in humans.

Sitagliptin reduces plaque macrophage content and stabilises arteriosclerotic lesions in Apoe (-/-) mice.

AIMS/HYPOTHESIS: Inhibitors of dipeptidyl peptidase-IV (DPP-IV), such as sitagliptin, increase glucagon-like peptide-1 (GLP-1) concentrations and are current treatment options for patients with type 2 diabetes mellitus. As patients with diabetes exhibit a high risk of developing severe atherosclerosis, we investigated the effect of sitagliptin on atherogenesis in Apoe (-/-) mice. METHODS: Apoe (-/-) mice were fed a high-fat diet and treated with either sitagliptin or placebo for 12 weeks. Plaque size and plaque composition were analysed using Oil Red O staining and immunohistochemistry. Furthermore, in vitro experiments with the modified Boyden chamber and with gelatine zymography were performed to analyse the effects of GLP-1 on isolated human monocyte migration and metalloproteinase-9 (MMP-9) release. RESULTS: Treatment of Apoe (-/-) mice with sitagliptin significantly reduced plaque macrophage infiltration (the aortic root and aortic arch both showing a 67% decrease; p < 0.05) and plaque MMP-9 levels (aortic root showing a 69% and aortic arch a 58% reduction; both p < 0.01) compared with controls. Moreover, sitagliptin significantly increased plaque collagen content more than twofold (aortic root showing an increase of 58% and aortic arch an increase of 73%; both p < 0.05) compared with controls but did not change overall lesion size (8.1 ± 3.5% vs 5.1 ± 2.5% for sitagliptin vs controls; p=NS). In vitro, pretreatment of isolated human monocytes with GLP-1 significantly decreased cell migration induced by both monocyte chemotactic protein-1 and by the protein known as regulated on activation, normal T cell expressed and secreted (RANTES) in a concentration-dependent manner. Furthermore, GLP-1 significantly decreased MMP-9 release from isolated human monocyte-derived macrophages. CONCLUSIONS/INTERPRETATION: Sitagliptin reduces plaque inflammation and increases plaque stability, potentially by GLP-1-mediated inhibition of chemokine-induced monocyte migration and macrophage MMP-9 release. The effects observed may provide potential mechanisms for how DPP-IV inhibitors could modulate vascular disease in high-risk patients with type 2 diabetes mellitus.