Abstract 21671: Diastolic Dysfunction Triggers Chemotactic Activity and Accumulation of Extracellular Matrix by Activating Myofibroblasts in Patients With Heart Failure and Normal Ejection Fraction. An in vivo and in vitro Approach.
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. Moreover, endomyocardial biopsies were obtained and analyzed. Furthermore, primary human cardiac fibroblasts were outgrown from the endomyocardial biopsies to investigate the gene expression of ECM proteins after stimulation with TGF-beta or mechanical stretch. In endomyocardial biopsies of HFNEF patients we found an accumulation of collagen (+78%), p>0.05), which was accompanied with a decrease in the major collagenases system (MMP-1, -250%, p>0.05). Moreover, an increment of inflammatory cells (increased CD4, CD68 and CD45 positive cells), which expressed the pro-fibrotic growth factor TGF-β, could be documented in the HFNEF patients. Stimulation of primary human cardiac fibroblasts from HFNEF patients with TGF-β resulted in a transdifferentiation to myofibroblasts (increase of alpha-SMA), which produced more collagen (+250%, p>0.05) and decreased the amount of MMP-1. Interestingly, myofibroblasts also produced chemokines (MCP-1 +550%, p>0.05), which were chemotactic active in migration assays suggesting the myofibroblast as inflammatory supporter cells in HFNEF. Importantly, mechanical stretch in vitro mimicking diastolic dysfunction and wall stress as one hall mark in HFNEF also activated fibroblasts to myofibroblast (alpha SMA) and increased gene expression of collagen and chemokines significanty. This suggests that diastolic dysfunction triggers invasion of inflammatory cells, which deteriorate ECM production and quality.
Conclusions: Cardiac inflammation contributes to diastolic dysfunction in HFNEF by triggering the accumulation of ECM and chemokines by activating fibroblast to myofibroblast. Moreover, mechanical stretch mimicking diastolic dysfunction alone activated myofibroblast and increased chemotactic activity suggesting that diastolic dysfunction starts the inflammatory cascade resulting in a stiff and non compliant heart.
- © 2010 by American Heart Association, Inc.