Early fibrotic gene activation precedes structural remodeling in the heart of cardiac myosin binding protein-C knockout mice.

Abstract

Hypertrophic cardiomyopathy (HCM) is the leading genetic cause of heart disease. Although research has been focused on HCM for the past several decades, clinical treatments for patients remain limited. The heart comprises several myofilament proteins that work together to facilitate proper contraction and relaxation to pump blood throughout the body. Cardiac myosin binding protein-C (cMyBP-C) is a thick-filament regulatory protein, and mutations in cMyBP-C are frequently linked with clinical cases of HCM. To further understand the role of cMyBP-C and its contribution to cardiac disease, we assessed the progressive development of molecular and morphological biomarkers associated with HCM in a cMyBP-C knockout mouse model. We assessed gene expression associated with hypertrophy, fibrosis, and sarcomeric proteins at 21, 60, and 183 days of age via a custom NanoString nCounter gene panel designed from clinically relevant human cardiac disease panels. Cardiac morphology and tissue remodeling were evaluated using biochemical and histological assays. Our findings unveil significant dysregulation in genes associated with hypertrophy and fibrosis in cMyBP-C deficient mice at 21 days old, which precedes irreversible overt fibrosis in the cardiac tissue. However, changes in sarcomeric gene expression only appeared after hypertrophy and fibrosis were established. The early changes in gene expression underscore the need for better understanding the mechanisms driving HCM development, which may offer potential avenues for therapeutic intervention before pathological remodeling occurs. Pharmaceutical interventions that target cardiac dysfunction may be most effective before cardiac remodeling, highlighting the potential utility for early screening and preventative strategies to manage genetic-based cardiomyopathies.The effect of cMyBP-C ablation in the cardiac sarcomere induces cell-signaling changes that precede significant overt fibrosis. These data indicate that early clinical screening may allow for treatment before irreversible, pathological remodeling of the heart takes place.