Colitis induced ventricular alternans increases the risk for ventricular arrhythmia.

Inflammatory bowel disease was linked to an increased risk for conduction defects and ventricular arrhythmia. It coincides with dysregulation of gut microbiota, increased inflammation, and deregulation of the renin-angiotensin system. In this study, we aimed to determine the mechanism of colitis-induced electrophysiological remodeling that increases the risk for ventricular arrhythmia. In a mouse model of dextran sulfate sodium induced active colitis (3.5 %, 7 days) cardiac electrophysiological properties were quantified during active inflammation. Electrocardiographic recordings exhibited a prolonged QT duration in mice with active colitis compared to control. Field potential (FP) recordings of Langendorff perfused colitis-hearts exhibited increased FP dispersion, a reduced threshold for ventricular alternans, and an increased propensity for spatially discordant alternans. The increased propensity for alternans was also reflected in isolated ventricular myocytes where Ca2+ transient alternans occurred at lower pacing frequencies and increased alternans ratios. The action potential was unchanged during colitis but myocytes exhibited a prolonged Ca2+ transient duration that corresponded with attenuated phospholamban phosphorylation. Stimulating cellular SERCA activity (Istaroxime), normalized the propensity for alternans. Serum levels of Angiotensin II (AngII) were increased during colitis and Angiotensin-converting enzyme (ACE) inhibitor or AngII receptor type 1 blocker prevented the increased alternans inducibility in isolated myocytes and hearts. Our data demonstrate that active colitis promotes reversible remodeling of ventricular Ca2+ handling properties and increases the propensity for alternans and arrythmia. The changes can be prevented by ACE or AT1R inhibition supporting a cardiac benefit for controlling RAS signaling in patients with active colitis.