Cardiac myofibroblasts enhance hypertrophy and systolic dysfunction, but not fibrosis in experimental autoimmune myocarditis

P­08.3­45

K. TkaczI, A. Jaźwa­KusiorII, F. RolskiI, E. DziałoI, K. WęglarczykI, M. CzepielI, M. SiedlarI, G. KaniaIII, P. BłyszczukI

IJagiellonian University Medical College, Department of Clinical Immunology, Cracow, Poland, IIJagiellonian University, Faculty of Biochemistry, Biophysics and Biotechnology, Department of Medical Biotechnology, Cracow, Poland, IIIUniversity Hospital Zurich, Division of Rheumatology, Zurich, Switzerland

Myocarditis is a common cause of dilated cardiomyopathy which is characterized by ventricular stiffening, cardiac fibrosis and heart failure. In experimental autoimmune myocarditis (EAM) susceptible mice are immunized with alpha myosin heavy chain (αMyHC) and complete Freund's adjuvant (CFA). CD4+ T cell­mediated acute cardiac inflammation is followed by fibrosis and systolic dysfunction. The aim was to investigate the role of fibroblasts and myofibroblasts in myocarditis and postinflammatory cardiomyopathy in EAM model. EAM was induced in BALB/c mice by immunization with αMyHC/CFA. We used reporter strains expressing EGFP under the type I collagen promoter and RFP under α­smooth muscle actin (αSMA) promoter and transgenic αSMA­TK mice with ganciclovir­inducible myofibroblasts ablation. Comparing unaffected heart, the number of cardiac fibroblasts (EGFP+) and the subset of myofibroblasts (EGFP+αSMA+) was unchanged at inflammatory (day 21) and fibrotic stages (day 40). EGFP+ fibroblasts were sorted from control and myocarditis­positive hearts (d21) and analyzed for the whole genome transcriptomics by RNA sequencing. Analysis of differentially expressed genes (min. 2x fold change, p value < 0.05) suggested activation of immune processes (mainly chemokine production), response to stress, cytoskeletal and extracellular matrix re­organization in cardiac fibroblasts in response to myocarditis. Ablation of myofibroblasts in αSMA­TK mice with ganciclovir at the acute myocarditis (day 21 of EAM) showed no effect on cardiac fibrosis (Trichrome Masson’s staining, hydroxyproline assay), but markedly reduced heart weight, decreased cardiomyocyte hypertrophy and improved ejection fraction and cardiac output at day 40. In EAM model cardiac fibroblasts participate in proinflammatory and profibrotic responses, while activated myofibroblasts drive progression of myocarditis to dilated cardiomyopathy phenotype independently of cardiac fibrosis.