Percutaneous stent-supported angioplasty is a treatment option for atherosclerotic ostial renal artery stenosis. Improvement of renal function by such intervention, however, is controversial and ...thought to be limited to specific subsets, such as nondiabetic patients and bilateral stenoses. In this prospective study, we investigated predictors for improvement of renal function and blood pressure after renal artery stent placement.
The study included 215 consecutive patients with ostial renal artery stenosis of > or =70% diameter stenosis undergoing stent-supported angioplasty. The primary end point was decrease in serum creatinine concentration at 1 year; the secondary end point, decrease in average mean arterial blood pressure assessed by 24-hour monitoring. One-year follow-up was complete in 191 surviving patients. In 52% (99/191) of the patients, serum creatinine concentration decreased during 1-year follow-up. Median serum creatinine concentration dropped significantly from 1.21 mg/dL (quartiles: 0.92, 1.60 mg/dL) at baseline to 1.10 mg/dL (quartiles: 0.88, 1.50 mg/dL) at 1 year (P=0.047). On average, mean arterial blood pressure decreased significantly, from 102+/-12 mm Hg (mean+/-SD) at baseline to 92+/-10 mm Hg at 1 year (P<0.001). Significant independent predictors of improved renal function were baseline serum creatinine (odds ratio 95% CI, 2.58 1.35 to 4.94, P=0.004) and left ventricular function (OR 1.51 1.04 to 2.21, P=0.032). Female sex, high baseline mean blood pressure, and normal renal parenchymal thickness were independent predictors for decreased mean blood pressure.
Stent-supported angioplasty for severe ostial renal artery stenosis improves renal function and blood pressure in a broader spectrum of patients than previously thought.
The endoplasmic reticulum (ER) is the site of synthesis and folding of membrane and secretory proteins. The fraction of protein passing through the ER represents a large proportion of the total ...protein in the cell. Protein folding, glycosylation, sorting and transport are essential tasks of the ER and a compromised ER folding network has been recognized to be a key component in the disease pathogenicity of common neurodegenerative, metabolic and malignant diseases. On the other hand, the ER protein folding machinery also holds significant potential for therapeutic interventions. Many causes can lead to ER stress. A disturbed calcium homeostasis, the generation of reactive oxygen species (ROS) and a persistent overload of misfolded proteins within the ER can drive the course of adisease. In this review the role of ER-stress in diseases of the liver and pancreas will be examined using pancreatitis and Wilson´s disease as examples. Potential therapeutic targets in ER-stress pathways will also be discussed.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Atrial fibrillation (AF) is the most common sustained arrhythmia in the general population. As an age-related arrhythmia AF is becoming a huge socio-economic burden for European healthcare systems. ...Despite significant progress in our understanding of the pathophysiology of AF, therapeutic strategies for AF have not changed substantially and the major challenges in the management of AF are still unmet. This lack of progress may be related to the multifactorial pathogenesis of atrial remodelling and AF that hampers the identification of causative pathophysiological alterations in individual patients. Also, again new mechanisms have been identified and the relative contribution of these mechanisms still has to be established. In November 2010, the European Union launched the large collaborative project EUTRAF (European Network of Translational Research in Atrial Fibrillation) to address these challenges. The main aims of EUTRAF are to study the main mechanisms of initiation and perpetuation of AF, to identify the molecular alterations underlying atrial remodelling, to develop markers allowing to monitor this processes, and suggest strategies to treat AF based on insights in newly defined disease mechanisms. This article reports on the objectives, the structure, and initial results of this network.
HDL, through sphingosine-1-phosphate (S1P), exerts direct cardioprotective effects on ischemic myocardium. It remains unclear whether other HDL-associated sphingophospholipids have similar effects. ...We therefore examined if HDL-associated sphingosylphosphorylcholine (SPC) reduces infarct size in a mouse model of transient myocardial ischemia/reperfusion. Intravenously administered SPC dose-dependently reduced infarct size after 30 minutes of myocardial ischemia and 24 hours reperfusion compared to controls. Infarct size was also reduced by postischemic, therapeutical administration of SPC. Immunohistochemistry revealed reduced polymorphonuclear neutrophil recruitment to the infarcted area after SPC treatment, and apoptosis was attenuated as measured by TUNEL. In vitro, SPC inhibited leukocyte adhesion to TNFα-activated endothelial cells and protected rat neonatal cardiomyocytes from apoptosis. S1P3 was identified as the lysophospholipid receptor mediating the cardioprotection by SPC, since its effect was completely absent in S1P3-deficient mice. We conclude that HDL-associated SPC directly protects against myocardial reperfusion injury in vivo via the S1P3 receptor.
Full text
Available for:
DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Background and methods Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice. The substrate of AF is composed of a complex interplay between structural and ...functional changes of the atrial myocardium often preceding the occurrence of persistent AF. However, there are only few animal models reproducing the slow progression of the AF substrate to the spontaneous occurrence of the arrhythmia. Transgenic mice (TG) with cardiomyocyte-directed expression of CREM-IbΔC-X, an isoform of transcription factor CREM, develop atrial dilatation and spontaneous-onset AF. Here we tested the hypothesis that TG mice develop an arrhythmogenic substrate preceding AF using physiological and biochemical techniques. Results Overexpression of CREM-IbΔC-X in young TG mice (< 8 weeks) led to atrial dilatation combined with distension of myocardium, elongated myocytes, little fibrosis, down-regulation of connexin 40, loss of excitability with a number of depolarized myocytes, atrial ectopies and inducibility of AF. These abnormalities continuously progressed with age resulting in interatrial conduction block, increased atrial conduction heterogeneity, leaky sarcoplasmic reticulum calcium stores and the spontaneous occurrence of paroxysmal and later persistent AF. This distinct atrial remodelling was associated with a pattern of non-regulated and up-regulated marker genes of myocardial hypertrophy and fibrosis. Conclusions Expression of CREM-IbΔC-X in TG hearts evokes abnormal growth and development of the atria preceding conduction abnormalities and altered calcium homeostasis and the development of spontaneous and persistent AF. We conclude that transcription factor CREM is an important regulator of atrial growth implicated in the development of an arrhythmogenic substrate in TG mice.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
CAP7.1 is a novel topoisomerase II inhibitor, converted to active etoposide via carboxylesterase 2 (CES2), with signals of efficacy in treatment-refractory solid tumours. In a Phase II trial, 27 ...patients with advanced biliary tract cancers (BTC) were randomised 1:1 to CAP7.1 plus best supportive care (BSC), or BSC alone, with crossover to CAP7.1 upon disease progression. The primary objective was disease control rate (DCR) following 28-day cycles of CAP7.1 (200/150 mg/m2; iv), or BSC until progression. Secondary objectives included progression-free survival (PFS), time-to-treatment failure (TTF), overall survival (OS) and safety. Fourteen patients received CAP7.1 and 13 BSC. DCR favoured CAP7.1 vs. BSC (50% vs. 20%; treatment difference: 30%, 95%CI −18.44, 69.22, full analysis set FAS), with disease progression in 40% vs. 70%, respectively. Significantly longer median PFS was achieved for CAP7.1 vs. BSC: 66 vs. 39 days, respectively (hazard ratio HR 0.31; 95%CI 0.11, 0.86; p = 0.009; FAS). Similar trends were observed for TTF and OS. CES2-positive patients had longer median PFS (158 vs. 56 days) and OS (228 vs. 82 days) vs. CES2-negative patients. Adverse events were predictable, dose-dependent and consistent with those previously observed with etoposide. These efficacy and safety findings in second-line BTC warrant further clinical investigation of CAP7.1.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A variety of pathologic stimuli lead to apoptosis of cardiomyocytes. Survival factors like insulin-like growth factor-I (IGF-I) exert anti-apoptotic effects in the heart. Yet the underlying signaling ...pathways are poorly understood.
In a model of hypoxia-induced apoptosis of cultured neonatal cardiomyocytes, IGF-I prevented cell death in a dose-dependent manner. Antiapoptotic signals induced by IGF-I are mediated by more than one signaling pathway, because pharmacological inhibition of the phosphatidylinositol-3-OH-kinase (PI3K) or the mitogen-activated protein kinase kinase (MEK1) signaling pathway both antagonize the protective effect of IGF-I in an additive manner. IGF-I-stimulation was followed by a PI3K-dependent phosphorylation of AKT and BAD and an MEK1-dependent phosphorylation of extracellular signal-regulated kinase (ERK) 1 and ERK2. IGF-I also induced phosphorylation of cAMP response element-binding protein (CREB) in a PI3K- and MEK1-dependent manner. Ectopic overexpression of a dominant-negative mutant of CREB abolished the antiapoptotic effect of IGF-I. Protein levels of the antiapoptotic factor bcl-2 increased after longer periods of IGF-I-stimulation, which could be reversed by pharmacological inhibition of PI3K as well as MEK1 and also by overexpression of dominant-negative CREB.
In summary, our data demonstrate that in cardiomyocytes, the antiapoptotic effect of IGF-I requires both PI3K- and MEK1-dependent pathways leading to the activation of the transcription factor CREB, which then induces the expression of the antiapoptotic factor bcl-2.
Purpose:
To compare acute and long-term outcomes of endovascular therapy for TASC (TransAtlantic Inter-Society Consensus) A and B lesions versus TASC C and D lesions.
Methods:
Based on a ...prospectively maintained database, a retrospective analysis was conducted of 375 symptomatic patients (335 men; mean age 63±8 years) who underwent 438 interventions for aortoiliac arterial obstructions. Lesions were stratified according to the TASC II classification: 259 (59%) procedures involved TASC A/B lesions, while 113 (26%) were for TASC C and 66 (15%) for TASC D lesions.
Results:
The baseline characteristics of patients with TASC A/B lesions differed significantly in the ankle-brachial index (ABI), occurrence of renal insufficiency, and lesion characteristics from those with TASC C or D lesions. Acute treatment success, defined as residual stenosis <30%, was 100%, 96%, 93%, and 100% for TASC A, B, C, and D lesions, respectively. The primary 1-year patency rate, which was 86% for the entire study cohort, was similar for all TASC classifications (89%, 86%, 86%, 85% for TASC A to D lesions, respectively). In the TASC A/B cohort, the 5-year event-free survival (70%) was not significantly better than in the C/D cohort (57%, p=0.124). The clinical outcome, as measured by Rutherford stage and ABI, improved significantly in all TASC subgroups after successful intervention and was maintained up to 1 year. Stenting was an independent predictor for lower restenosis rates (HR 0.517, 95% CI 0.317 to 0.842; p=0.008).
Conclusion:
In experienced hands, endovascular therapy of aortoiliac lesions can be successfully performed with sustained long-term outcome independent of the TASC II classification, even in class D lesions.
Full text
Available for:
NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
PDF
