The Inventors developed conditions allowing to efficiently detect differences in cardiomyocytes relaxation phases associated with increased cardiomyocytes stiffness. Theyused a library of patient-specific human induced pluripotent stem cells (hiPSC) either from healthy donors or carrying mutations (i.e., MYH7 and BRAF mutations) associated with hypertrophic cardiomyopathy, a condition typically associated with impaired diastolic function as well as an increase in cardiomyocytes passive stiffness. They performed a high throughput screening on hiPSC-derived cardiac cells to identify microRNAs capable of modifying the relaxation rates of cardiomyocytes. In particular, they set up a large-scale functional genomics using miRNAs screening. All identified miRNAs were tested for their impact on cardiac cells movement and calcium transient. miRNAs with the highest impact were in particular tested on ECTs and changes in diastolic function, were measured and compared to the results obtained at the cell level. They manipulated the most interesting ’hits’ in 3D models using similar readouts as in primary assays. They tested the impact of the positive ’hits’ in mechanical models (developed during the exploratory part) and establish physiological and biochemical mechanisms of action of the identified key proteins. They finally identified two promisingmiRNAs that could be used for improving striated myocytes relaxation and, more generally, to alleviate symptoms related to striated muscle stiffness, in particular in the context of heartfailure with a preserved ejection fraction (HFpEF).