Delineating the Link Between Dilated Cardiomyopathy and Arrhythmogenic Symptoms

Abstract

Dilated cardiomyopathy (DCM) is a common cause of heart failure and frequently involves life‐threatening ventricular arrhythmia and sudden cardiac death. In addition, DCM patients often show a heightened susceptibility to drug‐induced arrhythmia. The mechanisms that link DCM to ventricular arrhythmia are not well understood but are thought to involve structural alterations in the heart wall and in the ion channel makeup of individual cardiomyocytes. About 50 genetic mutations are known to cause congenital forms of DCM. Induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) generated from patient tissue recapitulate many pathophysiological phenotypes characteristic of congenital heart disease and offer an unprecedented tool to study disease mechanisms. To model DCM, we used iPSC‐CMs harboring a DCM‐causing mutation in phospholamban (PLN), a protein involved in calcium regulation. Using the PLN mutant cells, we tested whether the disease would increase arrhythmic susceptibility to drugs that target certain ion channels. Initial experiments from my internship found that both Sodium and human Ether‐à‐go‐go Related channel agonists elicited an exacerbated proarrhythmic response from mutant cells. Action potential durations were disproportionately increased in the DCM‐afflicted mutants. If these data are sustained throughout the experiment, they support the model that the PLN mutant DCM involves a channelopathy that increases proarrhythmic sensitivity to drugs.Support or Funding InformationTM acknowledges support from the American Heart Association and the Stanford Cardiovascular Institute.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.