Short-term Rapid Atrial Pacing Alters the Gene Expression Profile of Rat Liver: Cardiohepatic Interaction in Atrial Fibrillation

Background: Atrial fibrillation (AF) activates the coagulation system, leading to hypercoagulation of the blood. The liver is a major source of prothrombotic molecules.

Objective: This study aimed to clarify whether cardiohepatic interactions are involved in AF-related hypercoagulation.

Methods: We compared gene expression profiles of human liver tissue between patients with AF and sinus rhythm. An AF model was created by rapid atrial pacing (RAP) at a frequency of 1200 beats/min in anesthetized 10-week-old Sprague-Dawley rats. Livers, atria, and peripheral blood cells were collected and analyzed after 12 hours of RAP.

Results: DNA microarray analysis revealed marked changes in the gene expression profile of human liver of patients with AF. The extrinsic prothrombin activation pathway showed the most prominent change in 354 BioCarta pathways. Twelve hours of RAP also markedly altered the gene expression profile of rat liver. RAP markedly augmented the hepatic messenger RNA expression of fibrinogen chains, prothrombin, coagulation factor X, and antithrombin III. The augmented fibrinogen production by RAP was accompanied by increased of interleukin 6 (IL-6) messenger RNA expression in peripheral blood cells, enhanced monocyte chemoattractant protein-1 expression in the liver, infiltrated cluster of differentiation 11b-positive mononuclear cells in the liver, and enhanced signal transducer and activator of transcription 3 (STAT3) phosphorylation in the nuclei of hepatocytes. STAT3 phosphorylation and increased fibrinogen and coagulation factor X production by RAP were suppressed by pretreatment with IL-6 neutralizing antibody.

Conclusion: Rapid atrial excitation mimicking paroxysmal AF remotely altered the hepatic gene expression of prothrombotic molecules. Increased fibrinogen expression in the liver by RAP was mediated by activation of the IL-6/STAT3 signaling pathway in the peripheral blood and liver.