Abstract 19851: A Novel Inotropic Class With Unique Mechanism of Action Identified by a Phenotypic Screen
Introduction: Heart failure (HF) is a leading cause of disability and mortality in US, and there is tremendous unmet need for therapies targeting advanced systolic HF (SHF) or HF with preserve ejection fraction (HFpEF). Within this backdrop, we have utilized human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as a high-content (HC) phenotyping platform to discover small molecules with therapeutic potential for HF.
Methods and Results: To facilitate this approach, we deployed a Matrigel Mattress method to assess both systolic and diastolic functions in hiPSC-CMs. Using this innovative chemical phenotyping approach, we identified a novel class of inotrope, represented by EGM, with a unique pharmacological profile. In both isolated mouse cardiomyocytes and hiPSC-CMs, EGM enhances contractility (inotropy) by ~50% versus vehicle and relaxation rate (lusitropy) by 2-fold, without increasing beating rate (chronotropy) (Figure A). Consistent with the in vitro data, EGM enhances systolic function in mice with failing hearts without increasing the heart rate (Figure B). In contrast to traditional inotropes, EGM had no significant effect on intracellular cAMP or calcium levels. In addition, EGM did not directly increase myofilament calcium sensitivity. Our proteomic analysis of molecules bound to EGM has identified several candidate target molecules, which reveal a novel mechanism of action.
Conclusion: EGM represents a novel inotropic class that exerts positive inotropic and lusitropic effects in vitro and in vivo, without the deleterious chronotropic effects. Thus, this pharmaceutical class may be useful as an inotropic therapy for SHF and as a lusitropic therapy for HFpEF. A better understanding of its unique mechanism of action may lead to future HF therapies which avoids the pitfalls of traditional inotropes, whose utility has been limited by tachycardia, tolerance and cardiotoxicity.
Author Disclosures: J.E. Hempel: None. C.H. Williams: None. T.K. Feaster: None. A.G. Cadar: None. H.S. Hwang: None. J.M. Metzger: None. B.K. Knollmann: None. C.C. Hong: None.
- © 2016 by American Heart Association, Inc.