Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation

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 proin- flammatory 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 DCMat 3 months of age. Compared towild type (WT) mice, DCMmice exhibited significantly decreased fractional shortening (36.4±2% vs. 15.5±1.0%, p b 0.0001) and significantly increased spleenweight (5.3±0.3 vs. 7.2±0.4mg/mm, p=0.002). Intriguingly, flowcytometry 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 classi- cally activated (CD45+CD11b+Ly6C−MHCII+F480+CD206−)proinflammatory (M1) macrophages (3.4±0.8% vs. 10.3±1.2%, p=0.0009) inDCMhearts as comparedwithWThearts. These resultswere further confirmed by immunofluorescence analysis of heart tissue sections. Splenic red pulp (CD11b+Ly6C+MHCIIlowF480hi)macro- phages 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 toWT animals. Furthermore, RNA-seq analysis revealed the upregula- tion of inflammatory pathways in the DCM hearts. Together, these data indicate a robust proinflammatory re- sponse in DCM hearts, likely in response to cellular damage triggered by MYBPC3 mutation and resultant contractile dysfunction.