Cardiac maturation is an important developmental phase where there are profound biological and functional changes after birth in mammals. Herein, we use our profiling of human heart maturation in vivo to identify key drivers of maturation in our human cardiac organoid (hCO) model. In this dataset, we exemplified the applicability of our mature organoids in modelling cardiovascular disease. Pathogenesis of Desmoplakin (DSP) cardiomyopathies are driven by complex cellular interplay and changes in excitation-contraction coupling. A patient (MCHTB11), was screened against a 202 cardiac gene panel for clinically-relevant rare DNA variants (frequency < 0.04%). A homozygous 2 bp deletion was identified in the DSP gene, and recapitulated in our hCOs utilising CRISPR. In this screen, we also utilised INCB054329, a bromodomain extra-terminal inhibitor, to suppress diastolic dysfunction induced by the DSP mutant. In this dataset, we evaluate the proteomic remodelling induced by DSP-mutants (DSP) versus recovered mutants (CTRL), with and without INCB (n=3-4 for each group).