Autoantibody Signature in Cardiac Arrest

Background: Cardiac arrest is a tragic event that causes one death roughly every 90 seconds

worldwide. Survivors generally undergo a work-up to identify the etiology of arrest. However, 5-

10% of cardiac arrest remain unexplained. As cardiac arrhythmias mostly underlie cardiac arrest

and increasing evidence strongly supports the involvement of autoantibodies in

arrhythmogenesis, a large-panel autoantibody screening was performed in cardiac arrest patients.

Methods: This is an observational, cross-sectional study of patients from the Montreal Heart

Institute (MHI) hospital cohort, a single center registry of participants. A peptide microarray was

designed to screen for IgG targeting epitopes from all known cardiac ion channels with

extracellular domains. Plasma samples from 23 patients with unexplained cardiac arrest were

compared to 22 cardiac arrest cases of ischemic origin and a group of 29 age-, sex- and BMImatched

healthy subjects. The false discovery rate (FDR), LASSO logistic regression and

random forest methods were jointly carried out to find significant differential IgG responses.

Results: The autoantibody against the pore domain of the L-type voltage-gated calcium channel

(Cav1.2) was consistently identified as a biomarker of idiopathic cardiac arrest (P=0.002,

FDR=0.007, classification accuracies ≥0.83). Functional studies on human induced pluripotent

stem cell-derived cardiomyocytes demonstrated that the anti-Cav1.2 IgG purified from patients

with idiopathic cardiac arrest is proarrhythmogenic by reducing the action potential duration

through calcium channel inhibition.

Conclusions: The present report addresses the concept of autoimmunity and cardiac arrest.

Hitherto unknown autoantibodies targeting extracellular sequences of cardiac ion channels were

detected. Moreover, the study identified an autoantibody signature specific to patients with

cardiac arrest.