br Acknowledgements This work was

Acknowledgements This work was supported by a grant from the National Science Foundation (IOS- 1353366), the Hatch Program of the National Institute of Food and Agriculture (VA-135908) and the Virginia Agricultural Experiment Station, to G.P.
Introduction With steadily rising number of affected patients, atrial fibrillation is the most frequent arrhythmia in the Western World. Complications may be life-threatening including stroke, worsening of VX-765 failure and sudden death. [1] The main hallmarks of the management of non-valvular AF are rhythm control, heart rate control and stroke prevention depending on the CHA2DS2-VASc score. The left atrial appendage (LAA) plays a pivotal role in stroke development. In the last years the interventional exclusion of the LAA has risen to an established alternatively method to prevent strokes in patients with non-valvular AF. [2] Left atrial appendage closure (LAAC) is recommended in patients with a contraindication for oral anticoagulation (OAC) or in patients who suffered from a stroke despite OAC treatment. [1,2] However, LAAC might affect cardiac pathophysiology. Cardiac biomarkers such as Atrial natriuretic peptide (ANP) and B-type natriuretic Peptide (BNP) may decrease after LAAC. [3,4] Several studies demonstrated that cardiac interventions may influence cardiac remodeling. [[5], [6], [7]] Other studies showed that cardiac surgery influences gene and protein expression. [6,8] Metabolomics have become of high interest in the last decades and are implemented in modern cardiovascular research. [[9], [10], [11]] It was described recently, that cardiac resynchronization therapy (CRT) might alter metabolomic profiles. [7,12] The heart represents one of the most metabolically demanding organs, and therefore associations between metabolomics and cardiovascular diseases rise certain hope for novel diagnostic and prognostic tools. [9,13] In a prospective study including 212 patients with acute decompensated heart failure, Wang et al. could demonstrate that a metabolic score consisting of butyrylcarnitine, dimethylarginine/arginine ratio, spermidine, and total essential amino acids was associated with a worse outcome and a higher incidence for AF. [14] Furthermore, a sub-analysis of the Framingham study population, showed no association of tested metabolites including amino acids, organic acids and lipids in patients with new onset of atrial fibrillation. [15] This shows the controversial data existing in metabolomic profiling of patients with AF. However, we recently demonstrated significant changes of metabolites of nutrient processing, namely glycolysis, tricarboxylic acid and protein metabolism, potentially mirroring remodeling processes of the left atrium and ventricle ongoing after LAAC. [16,18] Based on our experience in this field, this study therefore evaluates whether LAAC might affect metabolism of essential amino acids, kynurenine and creatinine, potentially reflecting alterations of bioenergetics efficacy and myocardial contraction.
Methods
Results
Discussion The prospective, hypothesis generating, observational “LABEL” study evaluates changes of metabolomics in patients with non-valvular AF undergoing successful percutaneous LAAC. It was demonstrated that LAAC affects the metabolism of essential amino acids and kynurenine at mid-term follow-up. Results were proven in univariable and multivariable regression models. Therefore, this data supports the hypothesis that LAAC might affect the metabolism of essential amino acids and bioenenergetic efficacy. These findings are in line with recently published data from our working group, expanding the knowledge about the impact of LAAC on metabolism at mid-term follow-up, as recently demonstrated for MR-proANP, acetylcarnitines, tricarboxylic acid and urea metabolism. [16,18,24] Specific pathophysiological alterations were recently proven to occur after successful LAAC: (1) neo-endothelization; (2) local stretch within the LAA; (3) ongoing myocardial contraction of the LAA.