Abstract: The present invention establishes a new standard for investigative studies of patient-specific, genetic cardiac diseases at a functional, tissue level by creating a novel platform for the study of cardiac related diseases, including cardiac conduction dysfunction, arrhythmias and depressed contractility for example. Provided herein are novel compositions of human engineered heart slices (EHS) formed from thin slices of decellularized cardiac tissue. Also included are compositions comprising a hybrid of decellularized tissue and organotypic organ slice technology. Intact mammalian hearts are precision cut to obtain thin slices in a range of thicknesses, decellularized, and seeded with various mammalian cells which can be from a variety of sources. Methods of investigation of many diseases and methods of use of these compositions for screening compounds for therapeutic purposes are also provided.