Simtuzumab Attenuates Loxl2-Mediated Extracellular Matrix Remodeling and Preserves Cardiac Function in LMNA Mutation-Induced Dilated Cardiomyopathy

Background | Dilated cardiomyopathy (DCM) caused by LMNA mutations is a severe cardiac condition marked by arrhythmias, contractile dysfunction, and excessive myocardial fibrosis, which collectively impair left ventricular function and increase the risk of heart failure. While the disease has been well characterized, a lack of insight into the pathogenesis has impeded the development of therapies. Methods | Here, we employed induced pluripotent stem cells (hiPSCs) derived from a patient carrying a LMNA point mutation (c.665A>C, p.His222Pro), alongside a murine model carrying the same mutation, to investigate the functional and molecular abnormalities driving DCM. Results | We demonstrated that LMNA patient-derived cardiomyocytes (hiPSC-CMs) and engineered heart tissues (hiPSC-EHTs) exhibited elevated diastolic calcium levels and reduced sensitivity to external calcium, respectively, as well as hypocontractility. These cells also displayed nuclear shape abnormalities in 2D and 3D, a hallmark of LMNA-associated DCM, associated with disrupted chromosome spatial organization and altered gene expression profiles. Transcriptomic analysis revealed dysregulation of extracellular matrix remodeling and significant upregulation of Loxl2 in mutated hiPSC-CMs, hiPSC-EHTs, and mice. Treatment with Simtuzumab, a Loxl2 inhibitor, effectively prevented cardiac dysfunction and fibrosis in vivo. Conclusion | Taken together, our findings underscore the crucial role of Loxl2 as a therapeutic target and suggest that its inhibition could be a promising strategy to preserve cardiac function in LMNA-associated DCM.