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Doehner W.,Center for Stroke Research Berlin | Doehner W.,Charite - Medical University of Berlin | Erdmann E.,University of Cologne | Cairns R.,Clinical Trials Center | And 5 more authors.
International Journal of Cardiology

Context: Although weight reduction is a recommended goal in type 2 diabetes mellitus (T2DM), weight loss is linked to impaired survival in patients with some chronic cardiovascular diseases. Objective: To assess the association of weight and weight change with mortality and non-fatal cardiovascular outcomes (hospitalisation, myocardial infarction and stroke) in T2DM patients with cardiovascular co-morbidity and the effect of pioglitazone-induced weight change on mortality. Setting and participants: We assessed in a post hoc analysis body weight and weight change in relation to outcome in 5202 patients from the PROactive trial population who had T2DM and evidence of pre-existing cardiovascular disease. Patients were randomized to treatment with pioglitazone or placebo in addition to their concomitant glucose-lowering and cardiovascular medication. Mean follow up was 34.5 months. Main outcome measure: The impact of body weight and body weight change on all-cause mortality, cardiovascular mortality, on non-fatal cardiovascular events and on hospitalisation. Results: The lowest mortality was seen in patients with BMI 30-35 kg/m2 at baseline. In comparison to this (reference group), patients in the placebo group with BMI < 22 kg/m2 (Hazard Ratio (95% confidence intervals) 2.96 [1.27 to 6.86]; P = 0.012) and BMI 22 to 25 kg/m2 (HR 1.88 [1.11 to 3.21]; P = 0.019) had a higher all-cause mortality. Weight loss was associated with increased total mortality (HR per 1% body weight: 1.13 [1.11 to 1.16]; P < 0.0001), with increased cardiovascular mortality, all-cause hospitalisation and the composite of death, myocardial infarction and stroke. Weight loss of ≥ 7.5% body weight (seen in 18.3% of patients) was the strongest cut-point to predict impaired survival (multivariable adjusted HR 4.42 [3.30 to 5.94]. Weight gain was not associated with increased mortality. Weight gain in patients treated with pioglitazone (mean + 4.0 ± 6.1 kg) predicted a better prognosis (HR per 1% weight gain: 0.96 [0.92 to 1.00] P = 0.037) compared to patients without weight gain. Conclusion: Among patients with T2DM and cardiovascular co-morbidity, overweight and obese patients had a lower mortality compared to patients with normal weight. Weight loss but not weight gain was associated with increased mortality and morbidity. There may be an obesity paradox in patients with type 2 diabetes and cardiovascular risk. The original PROactive trial is registered as an International Standard Randomized Controlled Trial (Number ISRCTN NCT00174993). © 2011 Elsevier Ireland Ltd. Source

von Haehling S.,Applied Cachexia Research | von Haehling S.,Center for Cardiovascular Research | Steinbeck L.,Applied Cachexia Research | Doehner W.,Applied Cachexia Research | And 6 more authors.
International Journal of Biochemistry and Cell Biology

Patients with heart failure are frequently limited in their exercise capacity. Although this clinical phenomenon is mostly attributed to the failing myocardium, the effects of skeletal muscle wasting should not be underestimated. Muscle wasting may present in the form of loss of muscle mass and function, termed sarcopenia in healthy aging, or in the form of cachexia. Only cachexia is associated with loss of body weight. The mechanisms involved embrace an anabolic-/catabolic imbalance with increased degradation of myofibrils and myocyte apoptosis. Clinical effects include reduced muscle mass, strength and consequently reduced exercise capacity. This article describes the terminology, molecular pathways, prevalence, clinical implications and possible treatment approaches to muscle wasting in patients with heart failure. This article is part of a Directed Issue entitled: Muscle wasting. © 2013 Elsevier Ltd. All rights reserved. Source

Ebner N.,Applied Cachexia Research | Steinbeck L.,Applied Cachexia Research | Doehner W.,Applied Cachexia Research | Doehner W.,Center for Stroke Research Berlin | And 2 more authors.
Journal of Cachexia, Sarcopenia and Muscle

This article highlights preclinical and clinical studies in the field of wasting disorders that were presented at the 7th Cachexia Conference held in Kobe, Japan, in December 2013. This year, the main topics were the development of new methods and new biomarkers in the field of cachexia and wasting disorders with particular focus on inflammatory pathways, growth differentiation factor-15, myostatin, the ubiquitin proteasome-dependent pathway, valosin and the regulation of ubiquitin-specific protease 19 that is involved in the differentiation of myogenin and myosin heavy chain. This article presents highlights from the development of drugs that have shown potential in the treatment of wasting disorders, particularly the ghrelin receptor agonist anamorelin, the myostatin antagonist REGN1033, the selective androgen receptor modulators enobosarm and TEI-E0001, and the anabolic catabolic transforming agent espindolol. In addition, novel data on the prevalence and detection methods of muscle wasting/sarcopenia are presented, including the D3-creatine dilution method and several new biomarkers. © 2014 Springer-Verlag Berlin Heidelberg. Source

Jiang Q.,Max Delbruck Center for Molecular Medicine | Lagos-Quintana M.,Max Delbruck Center for Molecular Medicine | Liu D.,Max Delbruck Center for Molecular Medicine | Shi Y.,Max Delbruck Center for Molecular Medicine | And 5 more authors.

Microvascular rarefaction increases vascular resistance and pressure in systemic arteries and is a hallmark of fixed essential hypertension. Preventing rarefaction by activation of angiogenic processes could lower blood pressure. Endothelial tip cells in angiogenic sprouts direct branching of microvascular networks; the process is regulated by microRNAs, particularly the miR-30 family. We investigated the contribution of miR-30 family members in arteriolar branching morphogenesis via delta-like 4 (Dll4)-Notch signaling in a zebrafish model. The miR-30 family consists of 5 members (miR-30a-e). Loss-of-function experiments showed that only miR-30a reduced growth of intersegmental arterioles involving impaired tip cell function. Overexpression of miR-30a stimulated tip cell behavior resulting in augmented branching of intersegmental arterioles. In vitro and in vivo reporter assays showed that miR-30a directly targets the Notch ligand Dll4, a key inhibitor of tip cell formation. Coadministration of a Dll4 targeting morpholino in miR-30a morphants rescued the branching defects. Conversely, conditional overexpression of Notch intracellular domain restored arteriolar branching in miR-30a gain-of-function embryos. In human endothelial cells, loss of miR-30a increased DLL4 protein levels, activated Notch signaling as indicated in Notch reporter assays, and augmented Notch downstream effector, HEY2 and EFNB2 (ephrin-B2), expression. In spheroid assays, miR-30a loss- and gain-of-function affected tip cell behavior, consistent with miR-30a targeting Dll4. Our data suggest that miR-30a stimulates arteriolar branching by downregulating endothelial Dll4 expression, thereby controlling endothelial tip cell behavior. These findings could have relevance to the rarefaction process and, therefore, to hypertension. © 2013 American Heart Association, Inc. Source

Haeusler K.G.,Charite - Medical University of Berlin | Haeusler K.G.,Center for Stroke Research Berlin | Kirchhof P.,University of Munster | Kirchhof P.,University of Birmingham | And 2 more authors.

Left atrial catheter ablation (LACA) has become an established therapy to abolish drug-refractory symptomatic paroxysmal and persistent atrial fibrillation. Restoring sinus rhythm by LACA may help to prevent atrial fibrillation-related strokes, but presently there is no evidence from randomized clinical trials to support this notion. This review summarizes the current knowledge and uncertainties regarding LACA and procedure-related ischemic stroke. In fact, most patients who undergo LACA have a rather low annual stroke risk even when left untreated, whereas LACA imposes a risk of procedure-related stroke of ≈0.5% to 1%. In addition, LACA may cause cerebral microemboli, resulting in ischemic lesions. These cerebral lesions, detectable by high-resolution MRI, could contribute to neuropsychological deficits and cognitive dysfunction. Furthermore, recurrent atrial fibrillaton episodes can be detected up to years after LACA and might cause ischemic strokes, especially in those patients in whom therapeutic anticoagulation was discontinued. Further prospective multicenter trials are needed to identify procedure-dependent risk factors for stroke and to optimize postprocedural anticoagulation management. © 2011 American Heart Association. All rights reserved. Source

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