Hereditary cardiomyopathies represent a major cause of cardiac disease, often manifesting as early as adolescence or young adulthood. Among them, dilated cardiomyopathy is characterized by left ventricular dilation, impaired systolic function, and myocardial fibrosis. Mutations in the LMNA gene, which encodes the A-type lamins that make up the nuclear lamina, are the second most common genetic cause of the familial forms of this condition. The LMNA-associated form is clinically distinguished by its rapid progression, early and extensive myocardial fibrosis, a high arrhythmic burden, and accelerated onset of heart failure. Despite a well-established genetic origin, the molecular and cellular mechanisms underlying its progression remained poorly understood, hampering the development of treatments.
To investigate these mechanisms, the authors combined two models carrying the same point mutation (c.665A>C, p.His222Pro): patient-derived human induced pluripotent stem cells (hiPSCs), together with an isogenic corrected control line, and an Lmna H222P mouse model. Cardiomyocytes and engineered cardiac tissues derived from the mutant cells exhibited elevated diastolic calcium levels, reduced sensitivity to external calcium, and hypocontractility. These cells also displayed nuclear shape abnormalities, a hallmark of the disease, in both two and three dimensions. This work provides the first demonstration that the LMNA mutation alters chromosome positioning within the nucleus, reflecting a disorganization of chromatin normally regulated by the nuclear lamina and associated with altered gene expression profiles.
Transcriptomic analysis revealed a dysregulation of extracellular matrix remodeling and a marked overexpression of Loxl2 in mutant hiPSC cardiomyocytes, engineered cardiac tissues, and the mouse model. In the context of heart failure, excessive extracellular matrix deposition increases myocardial stiffness and disrupts signal transmission to cardiomyocytes, ultimately impairing contractility. Loxl2, already identified as a biomarker of heart failure, is here associated for the first time with LMNA-related dilated cardiomyopathy. Treatment of mice with simtuzumab, a Loxl2 inhibitor, prevented cardiac dysfunction and fibrosis in vivo: left ventricular parameters remained stable between four and five months in treated animals, whereas they deteriorated in untreated animals, along with a decrease in the expression of the Myh7 and Nppa genes.
The authors acknowledge several limitations: a short-duration pilot study requiring long-term follow-up, the use of male mice only, the relative immaturity of hiPSC-derived cardiomyocytes, and the value of a complementary genetic approach to strengthen these observations. Nevertheless, this work identifies Loxl2 as a promising therapeutic target for preserving cardiac function in LMNA-associated dilated cardiomyopathy.