title: Mineralocorticoid accelerates transition to heart failure with preserved ejection fraction via "nongenomic effects".
abstract: BACKGROUND
  Mechanisms promoting the transition from hypertensive heart disease to heart failure with preserved ejection fraction are poorly understood. When inappropriate for salt status, mineralocorticoid (deoxycorticosterone acetate) excess causes hypertrophy, fibrosis, and diastolic dysfunction. Because cardiac mineralocorticoid receptors are protected from mineralocorticoid binding by the absence of 11-beta hydroxysteroid dehydrogenase, salt-mineralocorticoid-induced inflammation is postulated to cause oxidative stress and to mediate cardiac effects. Although previous studies have focused on salt/nephrectomy in accelerating mineralocorticoid-induced cardiac effects, we hypothesized that hypertensive heart disease is associated with oxidative stress and sensitizes the heart to mineralocorticoid, accelerating hypertrophy, fibrosis, and diastolic dysfunction.
  
  
  RESULTS
  Cardiac structure and function, oxidative stress, and mineralocorticoid receptor-dependent gene transcription were measured in sham-operated and transverse aortic constriction (studied 2 weeks later) mice without and with deoxycorticosterone acetate administration, all in the setting of normal-salt diet. Compared with sham mice, sham plus deoxycorticosterone acetate mice had mild hypertrophy without fibrosis or diastolic dysfunction. Transverse aortic constriction mice displayed compensated hypertensive heart disease with hypertrophy, increased oxidative stress (osteopontin and NOX4 gene expression), and normal systolic function, filling pressures, and diastolic stiffness. Compared with transverse aortic constriction mice, transverse aortic constriction plus deoxycorticosterone acetate mice had similar left ventricular systolic pressure and fractional shortening but more hypertrophy, fibrosis, and diastolic dysfunction with increased lung weights, consistent with heart failure with preserved ejection fraction. There was progressive activation of markers of oxidative stress across the groups but no evidence of classic mineralocorticoid receptor-dependent gene transcription.
  
  
  CONCLUSIONS
  Pressure-overload hypertrophy sensitizes the heart to mineralocorticoid excess, which promotes the transition to heart failure with preserved ejection fraction independently of classic mineralocorticoid receptor-dependent gene transcription.
authors.affiliation: Cardiovascular Research, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Selma F
authors.initials: SF
authors.lastname: Mohammed
authors.forename: Tomohito
authors.initials: T
authors.lastname: Ohtani
authors.forename: Josef
authors.initials: J
authors.lastname: Korinek
authors.forename: Carolyn S P
authors.initials: CS
authors.lastname: Lam
authors.forename: Katarina
authors.initials: K
authors.lastname: Larsen
authors.forename: Robert D
authors.initials: RD
authors.lastname: Simari
authors.forename: Maria L
authors.initials: ML
authors.lastname: Valencik
authors.forename: John C
authors.initials: JC
authors.lastname: Burnett
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Redfield
mesh_terms: D000450:Aldosterone / Q000009:adverse effects; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D002196:Capillaries / Q000473:pathology; D003094:Collagen / Q000235:genetics; D003573:Cytochrome b Group / Q000235:genetics; D003900:Desoxycorticosterone / Q000494:pharmacology; D006333:Heart Failure / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D008901:Mineralocorticoids / Q000009:adverse effects*; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics; D053495:Osteopontin / Q000235:genetics; D018384:Oxidative Stress / Q000502:physiology; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
chemical_list: D003573:Cytochrome b Group; D008562:Membrane Glycoproteins; D008901:Mineralocorticoids; D012333:RNA, Messenger; D053495:Osteopontin; D003900:Desoxycorticosterone; D000450:Aldosterone; D012313:RNA; D009320:Atrial Natriuretic Factor; D003094:Collagen; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C515614:Cyba protein, mouse