Mineralocorticoid Accelerates Transition to Heart Failure With Preserved Ejection Fraction Via 'Nongenomic Effects'
| Autor: | Carolyn S.P. Lam, John C. Burnett, Robert D. Simari, Selma F. Mohammed, Josef Korinek, Tomohito Ohtani, Maria L. Valencik, Katarina Larsen, Margaret M. Redfield |
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| Rok vydání: | 2010 |
| Předmět: |
Male
medicine.medical_specialty Heart disease medicine.drug_class Diastole Mice Inbred Strains Ventricular Function Left Article Mice chemistry.chemical_compound Mineralocorticoids Physiology (medical) Internal medicine medicine Animals RNA Messenger Desoxycorticosterone Aldosterone Heart Failure Inflammation Membrane Glycoproteins Ejection fraction Reverse Transcriptase Polymerase Chain Reaction business.industry NADPH Oxidases Stroke Volume Cytochrome b Group medicine.disease Hypertensive heart disease Capillaries Oxidative Stress Endocrinology chemistry NADPH Oxidase 4 Mineralocorticoid Heart failure NADPH Oxidase 2 Cardiology RNA Osteopontin Collagen Cardiology and Cardiovascular Medicine business Heart failure with preserved ejection fraction Atrial Natriuretic Factor |
| Zdroj: | Circulation. 122:370-378 |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circulationaha.109.915215 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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