Abstract 13878: Activated Fibroblasts and IL-1β Mediate Fibrotic Cardiac Remodeling Observed in Premature Ventricular Contraction-Induced Cardiomyopathy

Abstract

Introduction: The relevance of fibrosis in premature ventricular contraction-induced cardiomyopathy (PVC-CM) remains unclear. Recent studies suggest that fibrosis promotes adverse extracellular matrix (ECM) remodeling that has been implicated in arrhythmogenesis. However, fibrotic areas and fibroblast activation have not been characterized in PVC-CM. The objective of this study was to assess cardiac remodeling by collagen fiber deposition, fibroblast activation (using αSMA as a marker), and the pro-fibrotic cytokine IL-1β level in LV myocardium. Hypothesis: Activation of fibroblasts promotes adverse cardiac remodeling in PVC-CM. Methods: Modified pacemakers were implanted in canines, half of them developing PVC-CM after 12 weeks of bigeminal PVCs (50% burden at 200-220 ms coupling interval), while the remaining were not exposed to PVCs (sham). Paraffin-embedded or simple formalin-fixed cardiac samples were sectioned and stained with Sirius Red/Fast Green (SR/FG) or immunofluorescence (IF) to assess collagen fiber deposits and αSMA content, respectively. Expression of IL-1β and αSMA were assessed by Western blot. Results: The percentage of fibrosis was three times greater in PVC-CM tissues compared to sham (10.2 ± 0.98 vs 3.3 ± 0.53, p = 0.014), consistent with an increase in αSMA (1 ± 0.08 vs 1.93 ±0.33, p < 0.05) and IL-1β expression (1 ± 0.09 vs 1.69 ± 0.11, p < 0.01). The figure shows differences in collagen fibers with SR/FG and αSMA with IF in (A) sham and (B) PVC-CM. Increased αSMA and IL-1β support the hypothesis that fibroblast activation is a key component in the PVC-CM phenotype. Conclusion: These findings strongly suggest that fibroblast activation during PVCs promote ECM expansion causing persistent structural remodeling which may disrupt electrical signal propagation and potentially contribute to arrhythmogenesis and worsening ventricular function associated with PVC-CM.