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Cardiovascular Therapies Targeting Left Atrial Appendage. Left atrial appendage (LAA) closure has evolved as an effective strategy for stroke prevention in patients with atrial fibrillation who are considered suitable for oral anticoagulation. There is strong evidence based on randomized clinical trials with 1 percutaneous device, as well as a large registry experience with several devices, regarding the safety and efficacy of this strategy. In addition, there is encouraging data regarding the effect of epicardial LAA closure on decreasing arrhythmia burden and improvements in systemic homeostasis by neurohormonal modulation. However, there are several unresolved issues regarding optimal patient selection, device selection, management of periprocedural complications including device-related thrombus, residual leaks, and pericarditis. In this review, we summarize the rationale, evidence, optimal patient selection, and common challenges encountered with mechanical LAA exclusion.