Drug Screening Using a Library of Human Induced Pluripotent Stem Cell―Derived Cardiomyocytes Reveals Disease-Specific Patterns of Cardiotoxicity

• Published in: Circulation (New York, N.Y.) Vol. 127; no. 16; pp. 1677 - 1691
• Main Authors: PING LIANG, FENG LAN, NGUYEN, Patricia K, BERS, Donald M, ROBBINS, Robert C, WU, Joseph C, LEE, Andrew S, TINGYU GONG, SANCHEZ-FREIRE, Veronica, YONGMING WANG, DIECKE, Sebastian, SALLAM, Karim, KNOWLES, Joshua W, WANG, Paul J
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 23-04-2013
• Subjects: Action Potentials - drug effects; Addictive behaviors; Adult and adolescent clinical studies; Biological and medical sciences; Blood and lymphatic vessels; Cardiac dysrhythmias; Cardiology. Vascular system; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - pathology; Cardiomyopathy, Hypertrophic, Familial - genetics; Cardiomyopathy, Hypertrophic, Familial - pathology; Cell Differentiation; Cell Line - drug effects; Cell Line - physiology; Cell Size; Cisapride - toxicity; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Drug addiction; Drug addictions; Drug Evaluation, Preclinical - methods; Drug-Related Side Effects and Adverse Reactions - genetics; Embryoid Bodies - drug effects; Embryonic Stem Cells - cytology; Embryonic Stem Cells - physiology; Gene Expression Profiling; Genetic Predisposition to Disease; Heart; HEK293 Cells - drug effects; HEK293 Cells - physiology; Humans; In Vitro Techniques; Induced Pluripotent Stem Cells - cytology; Ion Channels - biosynthesis; Ion Channels - genetics; Kidney - cytology; Kidney - embryology; Long QT Syndrome - genetics; Long QT Syndrome - pathology; Medical sciences; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - physiology; Myofibrils - ultrastructure; Nicorandil - toxicity; Patch-Clamp Techniques; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Quinazolines - toxicity; Toxicology; Verapamil - toxicity; Heart; Human; Drug addiction; stem cells; Disease; Arrhythmia; Toxicity; Stem cell; arrhythmias, cardiac; Cardiovascular disease; Medical screening; Phlebology; Myocyte; Heart disease; induced pluripotent stem cells; Circulatory system; Cardiology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circulationaha.113.001883

Cardiotoxicity is a leading cause for drug attrition during pharmaceutical development and has resulted in numerous preventable patient deaths. Incidents of adverse cardiac drug reactions are more common in patients with preexisting heart disease than the general population. Here we generated a library of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with various hereditary cardiac disorders to model differences in cardiac drug toxicity susceptibility for patients of different genetic backgrounds.
Action potential duration and drug-induced arrhythmia were measured at the single cell level in hiPSC-CMs derived from healthy subjects and patients with hereditary long QT syndrome, familial hypertrophic cardiomyopathy, and familial dilated cardiomyopathy. Disease phenotypes were verified in long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy hiPSC-CMs by immunostaining and single cell patch clamp. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and the human ether-a-go-go-related gene expressing human embryonic kidney cells were used as controls. Single cell PCR confirmed expression of all cardiac ion channels in patient-specific hiPSC-CMs as well as hESC-CMs, but not in human embryonic kidney cells. Disease-specific hiPSC-CMs demonstrated increased susceptibility to known cardiotoxic drugs as measured by action potential duration and quantification of drug-induced arrhythmias such as early afterdepolarizations and delayed afterdepolarizations.
We have recapitulated drug-induced cardiotoxicity profiles for healthy subjects, long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy patients at the single cell level for the first time. Our data indicate that healthy and diseased individuals exhibit different susceptibilities to cardiotoxic drugs and that use of disease-specific hiPSC-CMs may predict adverse drug responses more accurately than the standard human ether-a-go-go-related gene test or healthy control hiPSC-CM/hESC-CM screening assays.