title: Cardiac magnetic resonance assessment of interstitial myocardial fibrosis and cardiomyocyte hypertrophy in hypertensive mice treated with spironolactone.
abstract: BACKGROUND
  Nearly 50% of patients with heart failure (HF) have preserved LV ejection fraction, with interstitial fibrosis and cardiomyocyte hypertrophy as early manifestations of pressure overload. However, methods to assess both tissue characteristics dynamically and noninvasively with therapy are lacking. We measured the effects of mineralocorticoid receptor blockade on tissue phenotypes in LV pressure overload using cardiac magnetic resonance (CMR).
  
  
  RESULTS
  Mice were randomized to l-nitro-ω-methyl ester (l-NAME, 3 mg/mL in water; n=22), or l-NAME with spironolactone (50 mg/kg/day in subcutaneous pellets; n=21). Myocardial extracellular volume (ECV; marker of diffuse interstitial fibrosis) and the intracellular lifetime of water (τic; marker of cardiomyocyte hypertrophy) were determined by CMR T1 imaging at baseline and after 7 weeks of therapy alongside histological assessments. Administration of l-NAME induced hypertensive heart disease in mice, with increases in mean arterial pressure, LV mass, ECV, and τic compared with placebo-treated controls, while LV ejection fraction was preserved (>50%). In comparison, animals receiving both spironolactone and l-NAME ("l-NAME+S") showed less concentric remodeling, and a lower myocardial ECV and τic, indicating decreased interstitial fibrosis and cardiomyocyte hypertrophy (ECV: 0.43 ± 0.09 for l-NAME versus 0.25 ± 0.03 for l-NAME+S, P<0.001; τic: 0.42 ± 0.11 for l-NAME groups versus 0.12 ± 0.05 for l-NAME+S group). Mice treated with a combination of l-NAME and spironolactone were similar to placebo-treated controls at 7 weeks.
  
  
  CONCLUSIONS
  Spironolactone attenuates interstitial fibrosis and cardiomyocyte hypertrophy in hypertensive heart disease. CMR can phenotype myocardial tissue remodeling in pressure-overload, furthering our understanding of HF progression.
authors: Cardiovascular Division, Department of Medicine, Harvard Medical School, Boston, MA (O.R.C.F., R.V.S., T.G.N., R.K.) Department of Internal Medicine, State University of Campinas (UNICAMP), São Paulo, Brazil (O.R.C.F., H.M.).
authors: Otavio R
authors: OR
authors: Coelho-Filho
authors: Cardiovascular Division, Department of Medicine, Harvard Medical School, Boston, MA (O.R.C.F., R.V.S., T.G.N., R.K.).
authors: Ravi V
authors: RV
authors: Shah
authors: Cardiovascular Division, Department of Medicine, Harvard Medical School, Boston, MA (O.R.C.F., R.V.S., T.G.N., R.K.) Division of Cardiology, Department of Medicine and the Cardiac MR PET CT Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA (T.G.N.) Division of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (T.G.N.).
authors: Tomas G
authors: TG
authors: Neilan
authors: Department of Pathology, Harvard Medical School, Boston, MA (R.M.).
authors: Richard
authors: R
authors: Mitchell
authors: Department of Internal Medicine, State University of Campinas (UNICAMP), São Paulo, Brazil (O.R.C.F., H.M.).
authors: Heitor
authors: H
authors: Moreno
authors: Cardiovascular Division, Department of Medicine, Harvard Medical School, Boston, MA (O.R.C.F., R.V.S., T.G.N., R.K.).
authors: Raymond
authors: R
authors: Kwong
authors: Department of Radiology, Harvard Medical School, Boston, MA (M.J.H.).
authors: Michael
authors: M
authors: Jerosch-Herold
mesh_terms: D000818:Animals; D057791:Cardiac Imaging Techniques / Q000379:methods; D006332:Cardiomegaly / Q000188:drug therapy / Q000473:pathology*; D005355:Fibrosis; D006321:Heart / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D051379:Mice; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D018161:Receptors, Mineralocorticoid / Q000627:therapeutic use*; D013148:Spironolactone / Q000627:therapeutic use*; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology
chemical_list: D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D019331:NG-Nitroarginine Methyl Ester
keywords: cardiac magnetic resonance imaging; hypertension; hypertrophy/remodeling