Long-term cerebral thromboembolic complications of transapical endocardial resynchronization therapy

Purpose: Cardiac resynchronization therapy (CRT) is an established therapeutic option in selected heart failure patients (pts). However, the transvenous left ventricular (LV) lead implantation remains ineffectual in a considerable number of pts. Transapical LV (TALV) lead implantation is an alternative minimally invasive, surgical, endocardial implantation technique. The aim of the present prospective study is to determine the long-term outcome, including the cerebral thromboembolic complications, of pts

Investigation of the Antiremodeling Effects of Losartan, Mirabegron and Their Combination on the Development of Doxorubicin-Induced Chronic Cardiotoxicity in a Rat Model

Despite the effectiveness of doxorubicin (DOXO) as a chemotherapeutic agent, dose-dependent development of chronic cardiotoxicity limits its application. The angiotensin-II receptor blocker losartan is commonly used to treat cardiac remodeling of various etiologies. The beta-3 adrenergic receptor agonist mirabegron was reported to improve chronic heart failure. Here we investigated the effects of losartan, mirabegron and their combination on the development of DOXO-induced chronic cardiotoxicity. Male Wistar rats were divided into five groups: (i) control; (ii) DOXO-only; (iii) losartan-treated DOXO; (iv) mirabegron-treated DOXO; (v) losartan plus mirabegron-treated DOXO groups. The treatments started 5 weeks after DOXO administration. At week 8, echocardiography was performed. At week 9, left ventricles were prepared for histology, qRT-PCR, and Western blot measurements. Losartan improved diastolic but not systolic dysfunction and ameliorated SERCA2a repression in our DOXO-induced cardiotoxicity model. The DOXO-induced overexpression of Il1 and Il6 was markedly decreased by losartan and mirabegron. Mirabegron and the combination treatment improved systolic and diastolic dysfunction and significantly decreased overexpression of Smad2 and Smad3 in our DOXO-induced cardiotoxicity model. Only mirabegron reduced DOXO-induced cardiac fibrosis significantly. Mirabegron and its combination with losartan seem to be promising therapeutic tools against DOXO-induced chronic cardiotoxicity.Peer reviewe

Comparison of the antiremodeling effects of losartan and mirabegron in a rat model of uremic cardiomyopathy

Uremic cardiomyopathy is characterized by diastolic dysfunction (DD), left ventricular hypertrophy (LVH), and fibrosis. Angiotensin-II plays a major role in the development of uremic cardiomyopathy via nitro-oxidative and inflammatory mechanisms. In heart failure, the beta-3 adrenergic receptor (beta 3-AR) is up-regulated and coupled to endothelial nitric oxide synthase (eNOS)-mediated pathways, exerting antiremodeling effects. We aimed to compare the antiremodeling effects of the angiotensin-II receptor blocker losartan and the beta 3-AR agonist mirabegron in uremic cardiomyopathy. Chronic kidney disease (CKD) was induced by 5/6th nephrectomy in male Wistar rats. Five weeks later, rats were randomized into four groups: (1) sham-operated, (2) CKD, (3) losartan-treated (10 mg/kg/day) CKD, and (4) mirabegron-treated (10 mg/kg/day) CKD groups. At week 13, echocardiographic, histologic, laboratory, qRT-PCR, and Western blot measurements proved the development of uremic cardiomyopathy with DD, LVH, fibrosis, inflammation, and reduced eNOS levels, which were significantly ameliorated by losartan. However, mirabegron showed a tendency to decrease DD and fibrosis; but eNOS expression remained reduced. In uremic cardiomyopathy, beta 3-AR, sarcoplasmic reticulum ATPase (SERCA), and phospholamban levels did not change irrespective of treatments. Mirabegron reduced the angiotensin-II receptor 1 expression in uremic cardiomyopathy that might explain its mild antiremodeling effects despite the unchanged expression of the beta 3-AR.Peer reviewe

Bidirectional Relationship Between Reduced Blood pH and Acute Pancreatitis: A Translational Study of Their Noxious Combination

Acute pancreatitis (AP) is often accompanied by alterations in the acid-base balance, but how blood pH influences the outcome of AP is largely unknown. We studied the association between blood pH and the outcome of AP with meta-analysis of clinical trials, and aimed to discover the causative relationship between blood pH and AP in animal models. PubMed, EMBASE, and Cochrane Controlled Trials Registry databases were searched from inception to January 2017. Human studies reporting systemic pH status and outcomes (mortality rate, severity scores, and length of hospital stay) of patient groups with AP were included in the analyses. We developed a new mouse model of chronic metabolic acidosis (MA) and induced mild or severe AP in the mice. Besides laboratory blood testing, the extent of pancreatic edema, necrosis, and leukocyte infiltration were assessed in tissue sections of the mice. Thirteen studies reported sufficient data in patient groups with AP (n = 2,311). Meta-analysis revealed markedly higher mortality, elevated severity scores, and longer hospital stay in AP patients with lower blood pH or base excess (P < 0.001 for all studied outcomes). Meta-regression analysis showed significant negative correlation between blood pH and mortality in severe AP. In our mouse model, pre-existing MA deteriorated the pancreatic damage in mild and severe AP and, vice versa, severe AP further decreased the blood pH of mice with MA. In conclusion, MA worsens the outcome of AP, while severe AP augments the decrease of blood pH. The discovery of this vicious metabolic cycle opens up new therapeutic possibilities in AP

Energy Policies in the European Union

textabstractBackground: Coronary sinus lead placement for transvenous left ventricular (LV) pacing in cardiac resynchronization therapy (CRT) has a significant failure rate at implant and a considerable dislocation rate during follow-up. For these patients epicardial pacing lead implantation is the most frequently used alternative. Recent data support endocardial lead implantation through the atrial septum and the mitral valve, because this method provides further hemodynamic advantages. On the other hand transseptal CRT carries a significant risk for device related infective endocarditis of the mitral valve. The aim of this prospective, nonrandomized study was to demonstrate the feasibility of a fundamentally new approach for endocardial LV lead implantation. Methods: We performed 12 transapical LV lead implantations in 10 end-sta

New method for cardiac resynchronization therapy: Transapical endocardial lead implantation for left ventricular free wall pacing

Coronary sinus lead placement for transvenous left ventricular (LV) pacing in cardiac resynchronization therapy (CRT) has a significant failure rate at implant and a significant dislocation rate during follow-up. For these patients, epicardial pacing lead implantation is the most frequently used alternative. The aim of this case report is to describe

Comparison of the Efficacy of Two Surgical Alternatives for Cardiac Resynchronization Therapy: Trans-Apical versus Epicardial Left Ventricular Pacing

Background: Epicardial pacing lead implantation is the currently preferred surgical alternative for left ventricular (LV) lead placement. For endocardial LV pacing, we developed a fundamentally new surgical method. The trans-apical lead implantation is a minimally invasive technique that provides access to any LV segments. The aim of this prospective randomized study was to compare the outcome of patients undergoing either trans-apical endocardial or epicardial LV pacing. Methods: In group I, 11 end-stage heart failure (HF) patients (mean age 59.7 +/- 7.9 years) underwent trans-apical LV lead implantation. Epicardial LV leads were implanted in 12 end-stage HF patients (group II; mean age 62.8 +/- 7.3 years). Medical therapy was optimized in all patients. The following parameters were compared during an 18-month follow-up period: LV ejection fraction (LVEF), LV end-diastolic diameter (LVEDD), LV end-systolic diameter, and New York Heart Association (NYHA) function Results: Nine out of 11 patients responded favorably to the treatment in group I (LVEF 39.7 +/- 12.5 vs 26.0 +/- 7.8%, P < 0.01; LVEDD 70.4 +/- 13.6 mm vs 73.7 +/- 10.5 mm, P = 0.002; NYHA class 2.2 +/- 0.4 vs 3.5 +/- 0.4, P < 0.01) and eight out of 12 in group II (LVEF 31.5 +/- 11.5 vs 26.4 +/- 8.9%, P = < 0.001; NYHA class 2.7 +/- 0.4 vs 3.6 +/- 0.4, P < 0.05). During the follow-up period, one patient died in group I and three in group II. There was one intraoperative LV lead dislocation in gr Conclusions: Our data suggest that trans-apical endocardial LV lead implantation is an alternative to epicardial LV pacing. (PACE 2012;35:124-130

Rational design of balanced dual-targeting antibiotics with limited resistance

Antibiotics that inhibit multiple bacterial targets offer a promising therapeutic strategy against resistance evolution, but developing such antibiotics is challenging. Here we demonstrate that a rational design of balanced multitargeting antibiotics is feasible by using a medicinal chemistry workflow. The resultant lead compounds, ULD1 and ULD2, belonging to a novel chemical class, almost equipotently inhibit bacterial DNA gyrase and topoisomerase IV complexes and interact with multiple evolutionary conserved amino acids in the ATP-binding pockets of their target proteins. ULD1 and ULD2 are excellently potent against a broad range of gram-positive bacteria. Notably, the efficacy of these compounds was tested against a broad panel of multidrug-resistant Staphylococcus aureus clinical strains. Antibiotics with clinical relevance against staphylococcal infections fail to inhibit a significant fraction of these isolates, whereas both ULD1 and ULD2 inhibit all of them (minimum inhibitory concentration [MIC] ≤1 μg/mL). Resistance mutations against these compounds are rare, have limited impact on compound susceptibility, and substantially reduce bacterial growth. Based on their efficacy and lack of toxicity demonstrated in murine infection models, these compounds could translate into new therapies against multidrug-resistant bacterial infections

MOBILITY4EU - D2.1 - Societal needs and requirements for future transportation and mobility as well as opportunities and challenges of current solutions

Mobility4EU is a Coordination and Support Action of the European Commission started in January 2016 and lasting for 3 years, until 31 December 2018. The project will deliver a vision for the European transport system in 2030 and an action plan including a roadmap to implement that vision. The work towards that vision and action plan is based on the identification and assessment of societal challenges that will influence future transport demand and supply and the compilation of a portfolio of promising cross-modal technical and organisational transport solutions. The entire process from studying trends and options for solutions, developing a vision and finally the action plan are organized within a structured participatory approach that focuses on user-centeredness and that aims to engage a broad stakeholder community into the consultation processes. A further goal is to build a European Transport Forum that continues the work beyond the project duration and works on complementing the action plan. The present document reports on the results of researching trends and societal drivers impacting mobility demands and transport in Europe until 2030