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Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction.
Cardiovasc Res. 2005 Jul 01; 67(1):97-105.CR

Abstract

OBJECTIVES

The mechanisms underlying the clinical benefits of mineralocorticoid receptor antagonism in patients with left ventricular (LV) dysfunction and heart failure (CHF) after myocardial infarction (MI) are poorly understood.

METHODS

We investigated whether long-term (9 weeks) aldosterone antagonism with eplerenone (100 mg/kg/day) provides additional benefit to angiotensin II type 1 (AT1) receptor inhibition with irbesartan (50 mg/kg/day) on cardiac remodeling after MI in rats.

RESULTS

Eplerenone monotherapy, like AT1 receptor blockade, significantly reduced LV end-diastolic pressure (LVEDP), end-systolic volume (LVESV) and end-diastolic volume (LVEDV) compared to placebo. Improvement of LV dilation by aldosterone antagonism was associated with a significant reduction of increased AT1 receptor, angiotensin-converting enzyme (ACE) and endothelin-1 gene expression in the noninfarcted LV myocardium. Combination therapy with irbesartan led to a substantial further leftward shift of the LV pressure-volume curve and decrease in LVEDP, LVESV and LVEDV. Moreover, combination therapy significantly improved LV systolic and diastolic function and reversed LV alterations of alpha- and beta-myosin heavy-chain isoforms, ANF and SERCA2 ATPase expression more effectively than monotherapies. LV collagen type I and type III expression as well as interstitial fibrosis were substantially increased in placebo CHF rats, similarly decreased by eplerenone and irbesartan, and further reduced by eplerenone/irbesartan. However, no additive effects of eplerenone/irbesartan on myocardial AT1 receptor, ACE and endothelin-1 mRNAs were observed.

CONCLUSIONS

Aldosterone receptor antagonism provides additional benefit to AT1 receptor blockade on LV function and remodeling associated with improvement of molecular alterations responsible for progressive contractile dysfunction post-MI.

Authors+Show Affiliations

Medizinische Klinik I, Universitätsklinikum, Julius-Maximilians-Universität Würzburg, Würzburg, Germany. Fraccaroll_d@medizin.uni-wuerzburg.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15949473

Citation

Fraccarollo, Daniela, et al. "Additive Amelioration of Left Ventricular Remodeling and Molecular Alterations By Combined Aldosterone and Angiotensin Receptor Blockade After Myocardial Infarction." Cardiovascular Research, vol. 67, no. 1, 2005, pp. 97-105.
Fraccarollo D, Galuppo P, Schmidt I, et al. Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction. Cardiovasc Res. 2005;67(1):97-105.
Fraccarollo, D., Galuppo, P., Schmidt, I., Ertl, G., & Bauersachs, J. (2005). Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction. Cardiovascular Research, 67(1), 97-105.
Fraccarollo D, et al. Additive Amelioration of Left Ventricular Remodeling and Molecular Alterations By Combined Aldosterone and Angiotensin Receptor Blockade After Myocardial Infarction. Cardiovasc Res. 2005 Jul 1;67(1):97-105. PubMed PMID: 15949473.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction. AU - Fraccarollo,Daniela, AU - Galuppo,Paolo, AU - Schmidt,Isabel, AU - Ertl,Georg, AU - Bauersachs,Johann, Y1 - 2005/04/07/ PY - 2004/11/30/received PY - 2005/02/22/revised PY - 2005/03/01/accepted PY - 2005/6/14/pubmed PY - 2005/12/15/medline PY - 2005/6/14/entrez SP - 97 EP - 105 JF - Cardiovascular research JO - Cardiovasc. Res. VL - 67 IS - 1 N2 - OBJECTIVES: The mechanisms underlying the clinical benefits of mineralocorticoid receptor antagonism in patients with left ventricular (LV) dysfunction and heart failure (CHF) after myocardial infarction (MI) are poorly understood. METHODS: We investigated whether long-term (9 weeks) aldosterone antagonism with eplerenone (100 mg/kg/day) provides additional benefit to angiotensin II type 1 (AT1) receptor inhibition with irbesartan (50 mg/kg/day) on cardiac remodeling after MI in rats. RESULTS: Eplerenone monotherapy, like AT1 receptor blockade, significantly reduced LV end-diastolic pressure (LVEDP), end-systolic volume (LVESV) and end-diastolic volume (LVEDV) compared to placebo. Improvement of LV dilation by aldosterone antagonism was associated with a significant reduction of increased AT1 receptor, angiotensin-converting enzyme (ACE) and endothelin-1 gene expression in the noninfarcted LV myocardium. Combination therapy with irbesartan led to a substantial further leftward shift of the LV pressure-volume curve and decrease in LVEDP, LVESV and LVEDV. Moreover, combination therapy significantly improved LV systolic and diastolic function and reversed LV alterations of alpha- and beta-myosin heavy-chain isoforms, ANF and SERCA2 ATPase expression more effectively than monotherapies. LV collagen type I and type III expression as well as interstitial fibrosis were substantially increased in placebo CHF rats, similarly decreased by eplerenone and irbesartan, and further reduced by eplerenone/irbesartan. However, no additive effects of eplerenone/irbesartan on myocardial AT1 receptor, ACE and endothelin-1 mRNAs were observed. CONCLUSIONS: Aldosterone receptor antagonism provides additional benefit to AT1 receptor blockade on LV function and remodeling associated with improvement of molecular alterations responsible for progressive contractile dysfunction post-MI. SN - 0008-6363 UR - https://www.unboundmedicine.com/medline/citation/15949473/Additive_amelioration_of_left_ventricular_remodeling_and_molecular_alterations_by_combined_aldosterone_and_angiotensin_receptor_blockade_after_myocardial_infarction_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1016/j.cardiores.2005.03.001 DB - PRIME DP - Unbound Medicine ER -