An approach to study MFS cardiomyopathy could be by collecting CMs from MFS patients during surgery, transplantation or biopsy, but this is a rather invasive and limiting method to study the disease. While FBN1 appears causative for MFS cardiomyopathy, these studies also warrant the necessity for a better understanding of the underlying mechanisms. However, several independent studies have provided evidence for MFS-related cardiomyopathy unrelated to valvular disease, leading to the term Marfan cardiomyopathy 12, 16, 17, 18. Myocardial dysfunction secondary to significant valvular disease is a well-known cardiovascular complication in MFS 13, 14, 15. Due to this increased life expectancy, other clinical manifestations have arisen, among which is myocardial involvement 12. While aortic complications are still the leading cause of MFS-related mortality, advances in medical and surgical management have improved life expectancy 11. While increased TGF-ß signaling is a hallmark of MFS, uncertainty remains about the molecular mechanisms and disease progression 9, 10. Microfibrils normally act as docking sites for latent TGF-ß complexes, however, pathogenic variants in FBN1 result in release and activation of the normally bound TGF-ß 8. In addition to structural and mechanical support, fibrillin-1 also exhibits regulatory activities in growth factor signaling, ECM formation, cell behavior and the immune response 7. Due to pathogenic variants in FBN1, elastic fiber composition is suboptimal and compensated by excessive collagen and proteoglycan deposition, which leads to increased stiffness and progressive weakening of the ECM 6. The localization of fibrillin-1 in the heart also suggests a role for fibrillin-1 in myocardial tissue 5. Fibrillin-1 is a major component of the microfibrils that are important in the extracellular matrix (ECM) including the ECM of elastic tissues such as the aorta 4. Pathogenic variants in the FBN1 gene, coding for fibrillin-1, are causative for MFS 3. Aortic complications due to progressive aortic dilation leading to potential aneurysm, dissection, and rupture are the main cause of morbidity and mortality in patients with MFS. Typically, multiple organ systems are affected in MFS patients, with manifestations in the skeletal, ocular, integumentary, respiratory and cardiovascular system 2.
Marfan syndrome (MFS) is a rare systemic disorder of the connective tissue with an estimated prevalence of 1:5000–1:10,000 1. Based on these results, we postulate that impaired support from the extracellular environment plays a key role in the improper functioning of CMs in MFS. This study reports the first cardiac cell culture model for MFS, revealing abnormalities in the behavior of MFS CMs that are related to matrix defects. Isoproterenol-induced stress or cyclic strain demonstrates lack of support from the matrix in MFS CMs. Under normal culture conditions, MFS CMs show a lower beat-to-beat variability compared to corrected CMs using multi electrode array. The contraction amplitude of MFS CMs is decreased compared to corrected CMs. Atomic force microscopy revealed that MFS CMs are stiffer compared to corrected CMs. Several functional analyses are performed on this model to study MFS related cardiomyopathy. In this study, both induced pluripotent stem cells derived from a MFS-patient and the line with the corrected FBN1 mutation were differentiated to CMs. Myocardial dysfunction has been demonstrated in MFS patients and mouse models, but little is known about the intrinsic effect on the cardiomyocytes (CMs). Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by pathogenic variants in the fibrillin-1 (FBN1) gene.
Effects of fibrillin mutations on the behavior of heart muscle cells in Marfan syndrome