Abstract 4343931: The Inflammasome and Fibroblast Transdifferentiation and Activation in Heart Failure with Reduced Ejection Fraction

Background: Heart failure with reduced ejection fraction (HFrEF) is often caused by a precedent myocardial infarction (MI). While exogenous inflammatory cascades are well recognized to occur with MI and HFrEF, innate immune system activation, specifically the inflammasome NOD-like receptor protein 3(NOD-, LRR- and pyrin domain-containing protein 3; NLRP-3) with HFrEF is less well understood. Moreover, the downstream signaling cascades caused by NLRP-3 such as proteolytic pathways and fibroblast activation with the development of HFrEF remain unexplored. This study tested the hypothesis that the emergence of NLRP-3 occurs within the LV myocardium with HFrEF and causes a cascade of events including inducing fibroblast activation protein (FAP). Methods and Results: MI was induced in pigs (25kg, n=10) and additional pigs served as referent controls (n=9). At 28 days post-MI, the HFrEF phenotype was observed with a reduced EF (43±4 vs 64±3%, p=<0.05). NLRP-3 expression increased within the MI region as did indices of fibroblast activation such as smooth muscle actin (SMA), P311 and vimentin (VIM).(Table) NLRP-3 has been shown to cause increased levels of the profibrotic cytokines IL-1 β and TGF- β, and indeed both were increased with HFrEF. (Table). Finally, in LV fibroblast cultures (n=6) IL-1 β (25 ng/mL, 24 hrs) induced NLRP-3 and FAP by over 3-fold, respectively at 24hrs. Conclusions: The unique findings from this study were 2-fold. First, the emergence of NLRP-3 was associated with fibroblast transdifferentatioin and the induction of FAP. Second, fibroblast studies identified that both IL-1 β /TGF-β can stimulate the production of NLRP-3 as well as /FAP. These findings suggest that a potent positive feedback loop consisting of an NLRP-3/IL-1 β /TGF-β/FAP axis occurs with HFrEF.