title: Human Organotypic Cultured Cardiac Slices: New Platform For High Throughput Preclinical Human Trials.
abstract: Translation of novel therapies from bench to bedside is hampered by profound disparities between animal and human genetics and physiology. The ability to test for efficacy and cardiotoxicity in a clinically relevant human model system would enable more rapid therapy development. We have developed a preclinical platform for validation of new therapies in human heart tissue using organotypic slices isolated from donor and end-stage failing hearts. A major advantage of the slices when compared with human iPS-derived cardiomyocytes is that native tissue architecture and extracellular matrix are preserved, thereby allowing investigation of multi-cellular physiology in normal or diseased myocardium. To validate this model, we used optical mapping of transmembrane potential and calcium transients. We found that normal human electrophysiology is preserved in slice preparations when compared with intact hearts, including slices obtained from the region of the sinus node. Physiology is maintained in slices during culture, enabling testing the acute and chronic effects of pharmacological, gene, cell, optogenetic, device, and other therapies. This methodology offers a powerful high-throughput platform for assessing the physiological response of the human heart to disease and novel putative therapies.
authors.affiliation: Washington University in St. Louis, St. Louis MO, USA.|The George Washington University, Washington DC, USA.
authors.forename: C
authors.initials: C
authors.lastname: Kang
authors.affiliation: Washington University in St. Louis, St. Louis MO, USA.|The George Washington University, Washington DC, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Washington University in St. Louis, St. Louis MO, USA.
authors.forename: G
authors.initials: G
authors.lastname: Li
authors.affiliation: Washington University in St. Louis, St. Louis MO, USA.
authors.forename: K
authors.initials: K
authors.lastname: Baechle
authors.affiliation: University of Surrey, Guildford, UK.
authors.forename: P
authors.initials: P
authors.lastname: Camelliti
authors.affiliation: Washington University in St. Louis, St. Louis MO, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rentschler
authors.affiliation: Washington University in St. Louis, St. Louis MO, USA.|The George Washington University, Washington DC, USA.|Moscow Institute of Physics and Technology, Moscow, Russia.|IHU LIRYC, Site Xavier Arnozan, Avenue du Haut Lévêque, Pessac, France.
authors.forename: I R
authors.initials: IR
authors.lastname: Efimov
mesh_terms: D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004566:Electrodes; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016276:Ventricular Function / Q000502:physiology
chemical_list: C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D007545:Isoproterenol; D002118:Calcium