Marfan syndrome is a systemic disorder caused by defects in fibrillin-1, a matrix protein. Cardiovascular manifestations, particularly in the aorta, are the most life-threatening consequences. Moreover, accumulating evidence indicates that Marfan syndrome is causing a primary cardiomyopathy. Importantly, the cardiac stroma, consisting of cardiac fibroblasts, is increasingly considered to be an active player in heart development, cardiac repair, and disease. Insight in the precise effect of the extracellular matrix (ECM) on the cardiac muscle cells is lacking. Therefore, the Poznan group, proficient in advanced disease modeling using these ECM-producing cardiac fibroblasts, and the Ghent group are uniting their strengths in cardiac research to provide a better understanding of Marfan cardiomyopathy. We aim to generate advanced in vitro heart tissue models, comprising both muscle cells and fibroblasts to create representative Marfan models. Three fribillin-1 variants described in patients with confirmed cardiomyopathy will be expressed in heart muscle cells and fibroblasts. Two- and three-dimensional models will be created. These Marfan heart models will be dissected in a molecular, electrophysiological and transcriptional way using state-of-the art techniques. Moreover, these experiments will define the underlying pathophysiology, and the contribution of the distinct cardiac components, being muscle and matrix.