Mineralocorticoid accelerates transition to heart failure with preserved ejection fraction via "nongenomic effects"

Selma F. Mohammed, Tomohito Ohtani, Josef Korinek, Carolyn S P Lam, Katarina Larsen, Robert D. Simari, Maria L. Valencik, John C Jr. Burnett, Margaret May Redfield

Research output: Contribution to journalArticle

53 Citations (Scopus)

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-β 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. Methods and 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.

Original languageEnglish (US)
Pages (from-to)370-378
Number of pages9
JournalCirculation
Volume122
Issue number4
DOIs
StatePublished - Jul 27 2010

Fingerprint

Mineralocorticoids
Mineralocorticoid Receptors
Desoxycorticosterone
Heart Failure
Hypertrophy
Oxidative Stress
Constriction
Acetates
Fibrosis
Salts
Heart Diseases
11-beta-Hydroxysteroid Dehydrogenases
Genes
Blood Pressure
Osteopontin
Cardiomegaly
Ventricular Pressure
Nephrectomy
Diet
Inflammation

Keywords

  • deoxycorticosterone acetate
  • heart failure
  • hypertrophy
  • mineralocorticoids
  • stress
  • ventricular ejection fraction

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Mineralocorticoid accelerates transition to heart failure with preserved ejection fraction via "nongenomic effects". / Mohammed, Selma F.; Ohtani, Tomohito; Korinek, Josef; Lam, Carolyn S P; Larsen, Katarina; Simari, Robert D.; Valencik, Maria L.; Burnett, John C Jr.; Redfield, Margaret May.

In: Circulation, Vol. 122, No. 4, 27.07.2010, p. 370-378.

Research output: Contribution to journalArticle

Mohammed, Selma F. ; Ohtani, Tomohito ; Korinek, Josef ; Lam, Carolyn S P ; Larsen, Katarina ; Simari, Robert D. ; Valencik, Maria L. ; Burnett, John C Jr. ; Redfield, Margaret May. / Mineralocorticoid accelerates transition to heart failure with preserved ejection fraction via "nongenomic effects". In: Circulation. 2010 ; Vol. 122, No. 4. pp. 370-378.
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AU - Larsen, Katarina

AU - Simari, Robert D.

AU - Valencik, Maria L.

AU - Burnett, John C Jr.

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