Cardiac Inflammation Contributes to Changes in the Extracellular Matrix in Patients with Heart Failure and Normal Ejection Fraction Running Title: Westermann et al: Inflammation and Fibrosis in HFNEF

Background The pathophysiology of heart failure with normal EF (HFNEF) is still under discussion. Here we study the influence of cardiac inflammation on extracellular matrix (ECM) remodeling in patients with HFNEF. Methods and Results We investigated the left ventricular systolic and diastolic function in 20 patients with HFNEF and 8 control patients by conductance catheter and echocardiography. Moreover, endomyocardial biopsies were obtained and ECM proteins as well as cardiac inflammatory cells were investigated. Furthermore, primary human cardiac fibroblasts were outgrown from the endomyocardial biopsies to investigate the gene expression of ECM proteins after stimulation with TGF. Diastolic dysfunction was present in the HFNEF patients compared to the control patients. In endomyocardial biopsies of HFNEF patients we found an accumulation of cardiac collagen, which was accompanied with a decrease in the major collagenases system (MMP-1) in the heart. Moreover, an increment of inflammatory cells, which expressed the pro-fibrotic growth factor TGF, could be documented in the HFNEF patients. Stimulation of primary human cardiac fibroblasts from HFNEF patients with TGFresulted in a transdifferentiation of fibroblasts to myofibroblasts, which produced more collagen and decreased the amount of MMP-1, the major collagenases in the human heart. A positive correlation of cardiac collagen as well as the amount of inflammatory cells to diastolic dysfunction was evident and suggests a direct influence of inflammation to fibrosis triggering diastolic dysfunction. Conclusions Cardiac inflammation contributes to diastolic dysfunction in HFNEF by triggering the accumulation of extracellular matrix.