Alirocumab prevents atrial fibrillation in hypertension and obese mice through alleviation of PCSK9 induced atrial remodeling by regulating arachidonic acid metabolism

Abstract Background Atrial fibrillation, the world’s most common arrhythmia, has long been consider a leading cause of stroke and heart failure. Obesity and hypertension are widely approved risk factors of atrial fibrillation. Former meta analysis have demonstrated the protective effect of Alirocumab, a kind of Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on atrial fibrillation. Actually, the underlying molecular and pathophysiological mechanism of such a phenomenon still remain unclear. Objectives To explore the role of PCSK9 in the occurrence of AF induced by hypertension and obesity and decipher the underlying mechanism. Methods and Results We combined hypertension and obesity in mice to mimics hypertension and obesity patients, who have a higher vulnerability to atrial fibrillation in bedside and proved that 16 weeks of obesogenic diets and angiotensin 2 induced hypertension increased the atrial fibrillation inducibility and burden, while shortened the RR interval. Besides, hypertension elicited a higher individual risk factor than obesity alone. Alirocumab (ALI), a kind of PCSK9 inhibitor, were used to treat ALI group mice through intraperitoneal injection, once a week, for 12 weeks, in a dosage of (25μl/mouse). We detected the protein level of PCSK9 in atrium and liver tissue using Western Blot, which the expression level significantly increased in obesity and obesity+hypertension group. Sirius Red and Masson were observed to examine the histological changes in the atrium. Hypertension and obesity have increased fibrosis and enlarged atrial myocytes. Echocardiography data showed a restricted diastolic and systolic cardiac function caused by hypertension and obesity, while ALI has alleviated these pathological changes in the atrium. A n analogous tendency was presented in markers for fibrosis, αSMA and collegan1A, and markers for electrophysiology, CamkII, L type calcium channel, and Serca2A. To further investigate the mechanism and the downstream signal pathways of PCSK9 and atrial fibrillation, we used RNA-seq and Metabolomics, targeting to poly unsaturated fatty acid according to the RNA-seq analysis, to analyse atrium tissues. Taken the intersection of both analysis, arachidonic acid metabolism is the pathway enriched with mostly differently gene expressions. Finally, we use Elisa to detect the level of PCSK9 and arachidonic acid in serum of 94 inpatients, after trimming confounding factors, including sex, age, history of hypertension, diabetes, heart failure, stroke and hyperlipemia.ect a significantly increased level of PCSK9 and decreased level of arachidonic acid were found in patient with atrial fibrillation. Conclusion Elevated PCSK9 can cause atrial fibrosis and structural remodeling by inhibiting the arachidonic acid metabolism through downregulating the express of Ptgs1 and Ptgs2 in atria, and Alirocumab can prevent obesity and hypertension mice from atrial fibrillation.picture 1 picture 2