[Interventional left atrial appendage occlusion : alternative to oral anticoagulation for stroke prevention in atrial fibrillation]. / Interventioneller Vorhofohrverschluss : Alternative zur Antikoagulation in der Schlaganfallprophylaxe bei Vorhofflimmern.

Stroke prevention in patients with atrial fibrillation is one of the greatest challenges in modern cardiology. Interventional left atrial appendage occlusion is an alternative to oral anticoagulation in patients with non-valvular atrial fibrillation. This procedure is currently used mainly for patients with elevated risk for bleeding complications (HAS-BLED score ≥3) or other contraindications for oral anticoagulation. The novel anticoagulants dabigatran, rivaroxaban and apixaban carry a risk for major bleeding for 2-3% of patients per year. The indications for an interventional left atrial appendage closure are therefore not affected by these substances. Several devices have been developed for this purpose; however, currently only the WATCHMAN® and AMPLATZER® cardiac plug are used in the clinical routine in Germany. The WATCHMAN® device proved to be non-inferior to oral anticoagulation with warfarin in the PROTECT-AF trial in terms of safety and efficacy. These findings are supported by data from registries with up to 5 years follow-up. For the second device currently used in clinical practice, the AMPLATZER® cardiac plug, there is increasing data from registries suggesting comparable safety and efficacy. Both devices necessitate anticoagulation during the first 3-6 months after implantation until endothelialization is completed. Due to the anatomical complexity the implantation should be performed in experienced centers with reduction of the periprocedural risk to <1%. Thus, interventional left atrial appendage occlusion is a valid option to prevent stroke or other thromboembolic events in non-valvular atrial fibrillation especially for elderly patients or those with a history of bleeding complications.

[Volume regulation in cardiac insufficiency : possibilities of telephone coaching and peritoneal dialysis]. / Volumenregulation bei Herzinsuffizienz : Möglichkeiten des Telefon-Coachings sowie der Peritonealdialyse.

Volume retention is the hallmark of progressive heart failure, both systolic and diastolic (heart failure with preserved ejection fraction). It represents the cause of the main symptoms (dyspnea, edema, liver synthesis) and also the main target of drug therapy. Antagonizing excessive volume retention is also the most important therapy element. Many patients can be stabilized with sequential nephron blockade (thiazide + loop diuretics) combined with afterload reduction [blockade of the RAAS (renin-angiotensin-aldosterone) system]. Personal patient coaching combined with telemetric components (weight, blood pressure) has evolved as another cornerstone of treatment in heart failure patients. If these measures are insufficient to control volume retention, renal replacement therapy is effective and can improve quality of life. More specifically, aquaresis via peritoneal dialysis has been shown to be effective and adequate to control volume overload. Many patients may qualify for this evolving therapy as it effectively prevents repeat hospitalization for heart failure decompensation, can be performed in an out-patient setting and has a low complication rate, thus significantly improving quality of life.

[Interventional, intramyocardial stem cell therapy in ischemic cardiomyopathy: update 2010]. / Aktuelle Datenlage zur interventionellen, intramyokardialen Stammzelltherapie bei ischämischer Kardiomyopathie.

BACKGROUND: The intracoronary application of autologous bone marrow cells has proven hitherto to be safe but not sufficiently effective in patients with ischemic cardiomyopathy. The interventional application of cells injected directly into the myocardium represents one possible approach to improve effectiveness. TECHNIQUES: The NOGA method is based on the CARTO technique, which has been evaluated extensively for safety and feasibility in patients with heart failure. In a first step, an electrically and anatomically exact map of the left ventricle is obtained. Guided by this three-dimensional map direct injection of the cells into the ischemic area can be easily performed. CLINICAL STUDIES: Since its introduction in 2002 many studies have proven the safety, feasibility and effectiveness of NOGA-guided regenerative therapy to the left ventricle. While several studies also suggest effectiveness regarding various parameters of left ventricular function, no larger multicenter study is available to date. Such studies with also clinical endpoints are currently ongoing. CONCLUSION: The currently available data support, but do not yet prove, the hypothesis that intramyocardial stem cell therapy using NOGA-guided injection into the myocardium is safe and feasible in both acute and chronic ischemic cardiomyopathy. Ongoing trials will reveal whether this approach will become the standard form for applying cell therapy to the heart.

In cardiomyocyte hypoxia, insulin-like growth factor-I-induced antiapoptotic signaling requires phosphatidylinositol-3-OH-kinase-dependent and mitogen-activated protein kinase-dependent activation of the transcription factor cAMP response element-binding protein.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

Treating resistant hypertension with new devices.

Arterial hypertension is a frequent, chronic disease, which is one of the main risk factor for cardiovascular and renal diseases such as heart failure, chronic kidney disease, hypertensive heart disease, stroke as well as cardiac arrhythmias. In the clinical setting it remains challenging to accomplish the thresholds of guideline blood pressure (BP) levels now defined as office based BP to be below <140 mmHg. Patients on three or more antihypertensive drugs, with systolic BP values above ≥160 mmHg (≥150 mmHg for patients with type 2 diabetes) are classified as having resistant hypertension. In the past six years the development of interventional sympathetic renal artery denervation (RDN) opened a new treatment option targeting the afferent and efferent sympathetic nerves of the kidney to reduce BP. A large variety of devices are available on the market. Newly developed devices try to focus on new strategies such as ultrasound or irrigated catheters, which might reduce the post-procedural complications and increase the success rate. The first generation SymplicityTM device (Medtronic, Palo Alto, CA, USA) was shown to be safe, with side effects rarely occurring. Clinical trials demonstrate that this procedure is successful in about 70% of patients. However current data from Simplicity HTN-3 with 25% african-americans and a massive BP-lowering effect in the control "sham" group was not able to find a significant effect in the overall patient cohort. Possibly devices which allow to safely destroy sympathetic renal innervation more efficiently might allow for a higher responder rate. Irrigated RDN and ultrasound devices could deliver more energy to deeper tissue levels. This article provides an overview of currently available data on devices.

Risk factors for clinical events at 1-year follow-up after drug-eluting stent implantation: results from the prospective multicenter German DES.DE registry.

BACKGROUND: Drug-eluting stents (DES) have substantially reduced target vessel revascularization (TVR) after percutaneous coronary interventions. Risk factors for clinical events need to be redefined with this treatment option. METHODS AND RESULTS: In the prospective DES.DE registry, baseline clinical and angiographic characteristics as well as in-hospital and follow-up events were recorded for all enrolled patients. Between October 2005 and May 2009, 21,774 patients receiving DES were enrolled at 98 DES.DE sites. The composite of death, myocardial infarction (MI) and stroke defined as major adverse cardiac and cerebrovascular events (MACCE) and TVR were predefined as primary endpoints. At 1-year follow-up rates for overall death, MI, stroke, MACCE, TVR and definite stent thrombosis were 2.7, 3.1, 1.4, 7.1, 11.5 and 0.6 %, respectively. Aside from well-known risk factors like age, diabetes mellitus and triple-vessel disease, stratification in patients with or without MACCE revealed atrial fibrillation, non-ST-segment elevation myocardial infarction, renal failure, impaired ejection fraction and peripheral vascular disease as strong predictors of MACCE at 1 year. CONCLUSION: Data collected in the DES.DE registry, reflecting the clinical practice in Germany, revealed favorable clinical outcomes after DES implantation in a real world setting but also identifying several high-risk populations.

Effect of NF-kappa B Inhibition on TNF-alpha-induced apoptosis and downstream pathways in cardiomyocytes.

Heart-specific inhibition of survival pathway gp130 was recently shown to sensitize transgenic mice towards stress stimuli, resulting in rapid onset of cardiac dilatation and heart failure. In order to identify further survival pathways we evaluated the role of transcription factor nuclear factor-kappa B (NF-kappa B) in tumour necrosis factor-alpha (TNF-alpha)-induced apoptosis of cardiomyocytes. TNF-alpha stimulation (10 ng/ml) of both H9c2 cells and primary cardiomyocytes isolated from neonatal Wistar rats resulted in rapid nuclear translocation of NF-kappa B complexes. The NF-kappa B complexes consisted of rel-proteins p50 and p65, as revealed by supershift analysis. Addition of proteasome inhibitor MG132 or adenoviral expression of a truncated I kappa B alpha (I kappa B Delta N) inhibited TNF-alpha-induced NF-kappa B nuclear translocation in a dose-dependent manner. Both neonatal cardiomyocytes and H9c2 cells were resistant to TNF-induced apoptosis. However, specific inhibition of NF-kappa B activation by Ad5-I kappa B alpha Delta N (MOI=50) or MG132 (5 microm) increased apoptosis as measured by subG1-assay (H9c2 cells) and annexin V binding/propidium iodide (neonatal cardiomyocytes, FACS-analysis: 7+/-2% to 26+/-5% annexin V positive/PI negative), respectively. TUNEL-assay double-stained with anti-alpha-sarcomeric actin confirmed apoptosis of neonatal cardiomyocytes. Furthermore, caspase-3 activation was increased by 52+/-7% in neonatal cardiomyocytes after TNF alpha+Ad5-I kappa B alpha Delta N compared to TNF alpha+Ad5-control treatment. Protein levels of hiAP1, hiAP2, x-iAP, bcl-2 and bcl-x(L) were neither downregulated by NF-kappa B inhibition nor upregulated by TNF-alpha stimulation. In summary, cardiomyocytes utilize transcription factor NF-kappa B to activate survival factors in the context of TNF-alpha stimulation. As locally increased levels of TNF-alpha have been detected in heart failure, NF-kappa B activity is essential for cellular homeostasis in the heart.

GM-CSF expression in pulmonary epithelial cells is regulated negatively by posttranscriptional mechanisms.

Incubation of pulmonary A549 cells with D609, a phosphatidyl-choline specific phospholipase C (PC-PLC)-inhibitor, or the anti-oxidant, pyrrolidine dithiocarbamate (PTDC), markedly increased IL-1beta-induced GM-CSF elaboration. This effect was observed at the mRNA level and could be partially reproduced by the protein synthesis inhibitor, cycloheximide. Following the peak in GM-CSF mRNA, the mRNA half-life (t(1/2)) was 0.5-1 h. This was increased to around 3 h by cycloheximide, whilst following D609 or PDTC treatment there was essentially no degradation. These data suggest the existence of inhibitory pathways that posttranscriptionally regulate GM-CSF expression via new protein synthesis and D609- and PDTC-sensitive steps. These observations may have important clinical implications. First, drugs that target gene induction may also knock out these inhibitory pathways to lessen their effect. Second, defects in such pathways could lead to overexpression of cytokines or growth factors and contribute to the pathogenesis of inflammatory or proliferative diseases.