Abstract Body: Background: Hypertrophic cardiomyopathy (HCM), primarily driven by mutations in the cardiac myosin binding protein-C (MYBPC3) and beta-myosin heavy chain (MYH7) genes, presents with diverse clinical phenotypes that often result in heart failure (HF). Importantly, compared with MYH7 clinical variants, MYBPC3 variants are predominantly associated with C′-terminal truncation and haploinsufficiency, leading to HCM and frequently progressing to HF. Tissue-level inflammation, immune activation, and neutrophil extracellular traps (NETs) have been reported in HCM. However, the role of NETosis in the phenotypic transition from HCM to HF remains unclear. In the present study, we hypothesized that neutrophil infiltration and NETosis amplify HCM pathology and progress to HF secondary to chronic inflammation, immune responses, and tissue damage.
Methods and Results: To investigate this hypothesis, we used a homozygous mouse model expressing a C′-terminal truncation of cMyBP-C (cMyBP-C^t/t) to assess inflammation, immune responses, NETosis, and their relationships with cardiac remodeling during the transition from HCM to HF between 1 and 3 months of age. Mixed-sex cMyBP-C^t/t mice, compared with age-matched wild-type controls, underwent echocardiography at 1, 2, and 3 months of age. Blood and hearts were collected for hemostatic assays, coagulation marker profiling, transcriptomics, and cardiac immune phenotyping. Echocardiography revealed concentric hypertrophy at one month and a clear eccentric hypertrophy by three months in cMyBP-C^t/t mice. These mice exhibited elevated white blood cell counts, including lymphocytes and monocytes, along with time-dependent increases in plasma microvesicle tissue factor activity, thrombin–antithrombin complexes, and D-dimer levels. RNA-Seq analysis identified key pathways associated with HCM-to-HF progression, including immune activation, NETosis, and inflammation. Flow cytometry analysis of mononuclear cells from three-month-old hearts showed an increased proportion of neutrophils and inflammatory monocytes, and a reduced proportion of CD206⁺ resident macrophages.
Conclusions: Together, these findings indicate that inflammation-driven innate immune responses are closely linked to ventricular remodeling and the transition from HCM to HF, highlighting immune dysregulation as a potential mechanistic driver and therapeutic target in haploinsufficiency-associated HCM caused by MYBPC3 variants.