Abstract 18753: Mechanisms of Left Ventricular Reverse Remodeling: Insights From a Novel Murine Model of Hypertensive Ischemic Cardiomyopathy
Background: All approved therapies for heart failure (HF) lead to reverse LV remodeling (LVRR). The lack of genetically tractable animal models of LVRR has prevented further understanding of the biology of LVRR. Here we present a murine model of HF that mimics hypertensive ischemic cardiomyopathy, which undergoes LVRR with hemodynamic unloading.
Methods: Wild type mice were subjected to Sham (n=6), or transverse aortic constriction (TAC) with LAD ligation (MI), leading to progressive LV remodeling (n=12). Hemodynamic unloading was accomplished by debanding (DB) the aorta 2 wks post MI/TAC (n=6), whereas the band remained intact in the HF group (n=6). Both DB and HF groups were followed for 4 more weeks. 2D echo speckle tracking was performed at 1 & 14 days post-MI/TAC, and at 4 wks post-DB. Hearts were analyzed by LV morphometry, histology and transcriptional profiling.
Results: 2-D echo at 1 and 14 days post-MI/TAC showed progressive LV dilatation (1d=34ul, 14d=62ul; p<0.01). LVRR occurred 4 wks post-DB, with near normalization of LV volumes (p=NS vs sham). In contrast, LV volumes increased ~ 3-fold (p<0.01 vs sham) in the HF group. LV ejection fraction (LVEF) continued to decrease over 4 weeks in HF hearts (36% vs 31%, p<0.05), whereas LVEF increased in post-DB hearts (33% vs 42%, p<0.01). LV weights were significantly (p < 0.05) smaller in the DB group (85±13g) compared to the HF group (133±16g) at 4 weeks. Myocyte size decreased significantly (p<0.05) in DB hearts (409±41μ2) compared to HF hearts (446±41μ2), whereas interstitial fibrosis was not different (p > 0.05). Transcriptional profiling showed that, relative to HF hearts, LVRR in post DB hearts was accompanied by significant (p < 0.05) decreases in extracellular matrix gene expression, and significant increases in α-myosin heavy chain, calcium channels and adenylate cyclase gene expression.
Conclusion: We developed a genetically tractable mouse model of hypertensive ischemic cardiomyopathy that undergoes LVRR following unloading. LVRR is accompanied by favorable changes in LV structure and function, myocyte size, as well as changes in contractile protein and calcium handling genes. Genetic manipulation of this model will permit a clearer understanding of the molecular mechanisms responsible for LVRR.
- © 2013 by American Heart Association, Inc.