Abstract 254: Losartan Improves Disease Outcome in a Double-Mutant Model of Severe Hypertrophic Cardiomyopathy
INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is an inherited disease of the myocardium, caused by sarcomere mutations. Multiple causal mutations in HCM patients correlates with disease severity, including increased LV hypertrophy, early disease onset and elevated incidence of sudden cardiac death events. There are currently no pharmacological therapies that have definitively been shown to prevent or cause regression of HCM.
OBJECTIVE: To investigate losartan as a preventative therapy in a severe mouse model of HCM.
METHODS: This study used the TnI-203/MHC-403 mouse model, which expresses two HCM-causing mutations resulting in severe disease phenotype and 100% mortality by 21 days. This model recapitulates a subgroup of HCM patients who progress to a dilated phenotype and heart failure. TnI-203/MHC-403 and non-transgenic mice were treated with losartan or water from a pre-disease time-point. Measures of outcome included survival analysis, cardiac function, whole heart morphology, fibrosis and hypertrophy. miRNA and mRNA profiling was performed on ventricle RNA of the TnI-203/MHC-403 mice, and miRNAs with modified expression were cross-referenced to predicted, differentially expressed target mRNAs.
RESULTS: Losartan treatment improved disease outcome in the TnI-203/MHC-403 mice, including increased survival by 35% (mean, 23.3±1.4 days vs 17.3±6 days; P<0.0001), improved cardiac function (fractional shortening, 54±4% vs 40±14%, P<0.01), normalized gross heart morphology and heart-weight:body-weight ratios, decreased interstitial fibrosis at 14 days (0.84±0.12% vs 7.81±2.25%, P<0.01) and 17 days (2.30±0.36% vs 8.98±1.73%, P<0.0001), and reduced expression of pro-fibrotic- and pro-hypertrophic- molecules. Expression profiling showed six miRNAs (miR-30c, miR-203, miR-21, miR-214, miR-31, miR-199a-3p) were significantly altered with treatment, and their predicted targets within the differentially expressed mRNAs were identified.
CONCLUSION: Early treatment with losartan improves disease outcome in this double-mutant mouse model of severe HCM. miRNAs that play a potentially beneficial role in this improvement, have been identified and may be promising as new therapeutic targets.
- © 2012 by American Heart Association, Inc.