Abstract
Background: Endocardial fibroelastosis (EFE) frequently associated with development of HLHS or critical AS, restricting growth of the left ventricle (LV). The mechanism of EFE formation is the transition from endocardial endothelial cells to mesenchymal cells (EndMT). Regulation of EndMT in cardiac fibrosis is mainly through the TGF-β pathway, and upregulated Krüppel-like factor 2 (KLF2) inhibits the TGF-ß pathway by blocking SMAD2/3. Besides their plasma lipid-lowering effect, statins (e.g. Atorvastatin) directly upregulate KLF2 and are thereby atheroprotective (i.e., inhibit EndMT). The aim was to evaluate whether the upregulation of KLF2 with Atorvastatin inhibits EFE formation. Methods: Heterotopic rat heart transplantation was performed using 2-4 day-old donor hearts into adolescent recipients, which induces LV EFE growth. Atorvastatin (n=7) was administered daily at 3 mg/kg intraperitoneally for two weeks and compared to untreated/vehicle (n=5) controls. At postoperative day 14, LV EFE thickness was determined on Masson’s trichrome-stained slides. Gene expression of KLF2 was analyzed by qRT-PCR and protein expression by Westernblot and quantified via densitometry for SMAD2/3 and collagen. Results: Mean LV EFE thickness was significantly decreased in the Atorvastatin group (22.3±2.5μm) compared to 176.8±22.6μm in the untreated/vehicle-treated group (p<0.0001, A ). KLF2 was significantly upregulated in Atorvastatin treated hearts (p=0.0173, B ). SMAD2/3 and collagen were significantly elevated in the control group, p=0.0014 and p=0.048, respectively ( C, D ). Conclusion: LV growth restriction through EFE formation precludes patients from biventricular repair. Until now, surgical resection has been the only available therapeutic option. With this study, we show that Atorvastatin impedes EFE formation within the LV cavity in neonatal rat hearts through the upregulation of KLF2. Atorvastatin is, therefore a promising therapeutic agent.
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