Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation. (January 2017) - Lynch, Thomas L.
Abstract: Cardiomyopathies are a leading cause of heart failure and are often caused by mutations in sarcomeric genes, resulting in contractile dysfunction and cellular damage. This may stimulate the production of a robust proinflammatory response. To determine whether myocardial inflammation is associated with cardiac dysfunction in dilated cardiomyopathy (DCM) caused by MYBPC3 mutation, we used the well-characterized cMyBP-C (t/t) mouse model of DCM at 3 months of age. Compared to wild type (WT) mice, DCM mice exhibited significantly decreased fractional shortening (36.4 ± 2% vs. 15.5 ± 1.0%, p < 0.0001) and significantly increased spleen weight (5.3 ± 0.3 vs. 7.2 ± 0.4 mg/mm, p = 0.002). Intriguingly, flow cytometry analysis revealed a significant increase in total (CD45 + CD11b + Ly6C − MHCII + F480 + ) macrophages (6.5 ± 1.4% vs. 14.8 ± 1.4%, p = 0.002) and classically activated (CD45 + CD11b + Ly6C − MHCII + F480 + CD206 − ) proinflammatory (M1) macrophages (3.4 ± 0.8% vs. 10.3 ± 1.2%, p = 0.0009) in DCM hearts as compared with WT hearts. These results were further confirmed by immunofluorescence analysis of heart tissue sections. Splenic red pulp (CD11b + Ly6C + MHCII low F480 hi ) macrophages were significantly elevated (1.3 ± 0.1% vs. 2.4 ± 0.1%, p = 0.0001) in DCM compared to WT animals. Serum cytokine analysis in DCM animals exhibited a significant increase (0.65 ± 0.2 vs. 2.175 ± 0.5 pg/mL, p = 0.02) in interleukin (IL)-6 compared to WT animals. Furthermore, RNA-seq analysis revealed the upregulation of inflammatory pathways in the DCM hearts. Together, these data indicate a robust proinflammatory response in DCM hearts, likely in response to cellular damage triggered by MYBPC3 mutation and resultant contractile dysfunction. Highlights: A proinflammatory cellular environment is present in cMyBP-C (t/t) hearts. The inflammatory response is linked to the infiltration and/or expansion of proinflammatory monocytes and M1 macrophages. Contractile dysfunction, cardiac remodeling, and splenic remodeling occur in cMyBP-C (t/t) mice.