Abstract 18649: Tracking Spironolactone-Induced Regression of Myocardial Fibrosis and Myocyte Hypertrophy in Mice With Contrast-Enhanced Magnetic Resonance Imaging
Background: In heart failure (HF) with preserved left ventricular ejection fraction, interstitial fibrosis and cellular hypertrophy are early markers of the adverse tissue remodeling in response to pressure-overload.
Methods: Wild-type mice were assigned to three experimental groups: placebo (n=15), receiving tap water for 7 weeks; L-NG-Nitroarginine methyl ester (L-NAME) (n=22) (3mg/ml of L-NAME in drinking water, Sigma, USA) for 7 weeks; and L-NAME (3mg/ml) + spironolactone (n=21) (L-NAME-S), with spironolactone delivered by subcutaneous pellets at 50mg/kg/day. Extracellular volume (ECV) expansion, as a measure of interstitial fibrosis, and intracellular lifetime of water, τic, as a measure of cardiomyocyte hypertrophy, were assessed by pre and post-contrast T1 measurements. Minor (Dmin) and major (Dmaj) cell-diameters were measured on FITC-wheat germ agglutinin stained sections.
Results: L-NAME without spironolactone increased mean arterial pressure (86.8±7.4 mmHg at baseline to 124.4±6.1 mmHg after 7 weeks of L-NAME therapy, P<0.001) and left venrtciular (LV) mass (162.9±19.4 μg for L-NAME vs. 98.5±14.4 μg for placebo, P<0.001), with a modest decrease in LV systolic function (LV ejection fraction 51.3±8.2% for L-NAME vs. 60.3±3.2% for placebo, P<0.001). Spironolactone reduced the mean arterial pressure and LV mass in L-NAME-treated mice. Spironolactone also reduced the myocardial ECV (0.43±0.09 for L-NAME vs. 0.25±0.03 for L-NAME+S, P<0.001), myocyte hypertrophy (τic, 0.42±0.11 for L-NAME vs. 0.12±0.05 for L-NAME+S). The on-therapy effect of spironolactone on myocardial ECV and τic was observed even after adjustment for mean arterial pressure in linear regression (myocardial ECV: adjusted multiple R2 = 0.71, P<0.001). ECV and τic had strong correlations with connective tissue fraction and cell size, measured by histology.
Conclusion: CMR can track the progression and regression of interstitial fibrosis, cellular and LV hypertrophy in a murine model of hypertensive heart disease on exposure to spironolactone. This ability to non-invasively phenotype changes in cellular and tissue-based ventricular remodeling with therapy is critical to furthering our understanding of pathobiology of HF progression and its reversal.
- © 2013 by American Heart Association, Inc.