Impact of left atrial appendage morphology on indication and procedural outcome after interventional occlusion: results from the prospective multicentre German LAARGE registry.

AIMS: Interventional left atrial appendage closure (LAAC) is an emerging alternative to oral anticoagulation (OAC) for stroke prevention in atrial fibrillation (AF) in concomitance with a contraindication for standard OAC. This sub-analysis of the LAARGE registry aimed to investigate differences between different LAA morphologies in a real-world setting. METHODS AND RESULTS: This prospective, multicentre, observational registry included 562 patients from 37 centres with ineligibility for long-term OAC between April 2014 and January 2016. Baseline characteristics, indications, procedural data and complications were registered according to each LAA morphology (i.e., chicken wing, cauliflower, windsock, cactus and atypical morphologies). Implantation success was high across the four typical anatomies (≥97.5%, p=n.s.); only atypical anatomies exhibited a lower success rate (94%). The cactus-shaped LAA was linked to a trend indicating a shorter fluoroscopy time, while the atypical LAA was linked to a significantly prolonged fluoroscopy time (p=0.089 and p=0.025 versus the overall mean, respectively). Periprocedural and intra-hospital complications were generally rare, with no differences among the different morphologies (p=n.s.). CONCLUSIONS: Procedural success as well as the complication rates of LAAC were not different among the four typical LAA morphologies. A lower implantation success rate was only obvious in patients with atypical LAA morphologies.

Percutaneous left atrial appendage closure with a novel self-modelizing device: a pre-clinical feasibility study.

The aim of the study is to evaluate the feasibility and safety of a new left atrial appendage (LAA) occluder. Twelve pigs were included. In 2 pigs the implantation process failed due to pericardial tamponade in 1 pig and device embolization in the other pig. The placement of the devices was controlled via TEE and fluoroscopy. After 6 weeks of implantation the hearts were explanted. The devices were found to be easy to deploy and showed a very good adaptation to the LAA tissue. Eight out of 10 pigs had full closure of the LAA directly after implantation. After six weeks, due to the self-modelizing properties of the device, all pigs had a full closure of the LAA. The macroscopic evaluation of the explanted hearts showed that all devices were securely integrated in LAA tissues. There was one case of mild pericarditis but no macroscopic signs of inflammation on the device surrounding endocardium. The explantation revealed that device loops had penetrated the LAA tissue in three pigs. However, no signs of bleeding, pericardial effusion, or other damage to the LAA wall could be detected and the pigs were in good condition with normal weight gain and no clinical symptoms. The Occlutech® LAA occluder achieved complete closure of the LAA in all pigs, and remained in the LAA, with benign healing and no evidence of new thrombus or damage to surrounding structures. Moreover, the uncompromised survival of all implanted pigs demonstrates the feasibility and safety of the device.

Simvastatin increases fibrinolytic activity in human peritoneal mesothelial cells independent of cholesterol lowering.

BACKGROUND: The continuous physical and chemical irritation of the peritoneum in peritoneal dialysis patients can result in a nonbacterial serositis with increased fibrin deposition, thus promoting peritoneal fibrosis and adhesion development. By expressing the fibrinolytic enzyme tissue-type plasminogen activator (t-PA) and its specific inhibitor, plasminogen activator inhibitor-1 (PAI-1), human peritoneal mesothelial cells (HMC) play an important role in regulating peritoneal fibrinolysis. METHODS: Cultured HMC were used to examine the effect of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, simvastatin, on the expression of t-PA and PAI-1. Antigen concentrations in the cell supernatants were measured by ELISA and Northern blot analysis was conducted for mRNA expression. RESULTS: Simvastatin time- and concentration-dependently increased t-PA and decreased PAI-1 synthesis, reaching maximal effects after 48 hours, when simvastatin (1 micromol/L) increased t-PA levels 5.1 +/- 0.1-fold and suppressed PAI-1 levels 2.6 +/- 0.2-fold. This was accompanied by a twofold increase in mesothelial cell-associated t-PA activity. Qualitatively similar results were obtained in cultured human endothelial cells, but the effects were less pronounced and required higher simvastatin concentrations. Northern blot analysis revealed that the action of simvastatin on t-PA and PAI-1 expression in HMC can be explained by parallel changes in t-PA and PAI-1 mRNA. The effects of simvastatin were prevented in the presence of mevalonate and geranylgeraniol, suggesting that the effect of simvastatin on t-PA and PAI-1 synthesis is mediated through geranylgeranyl-modified intermediates. Experiments using specific inhibitors of geranylgeranylated Rho GTPases excluded a role of members of this family of small GTP-binding proteins in simvastatin action in HMC. The effects of simvastatin on t-PA and PAI-1 expression as well as on cell shape were completely mimicked by cytochalasin D, a disrupter of cellular actin filaments, but not by colchicine, a disrupter of microtubules. CONCLUSIONS: In conclusion, the cholesterol-lowering drug simvastatin is an effective stimulator of local peritoneal fibrinolytic activity, as it increases t-PA and decreases PAI-1 production in mesothelial cells by a mechanism involving geranylgeranyl-modified intermediates and actin skeleton perturbation. These results provide a new rationale to prevent peritoneal fibrin deposition and adhesion development in peritoneal dialysis patients.