Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Eplerenone enhances cardioprotective effects of standard heart failure therapy through matricellular proteins in hypertensive heart failure Paloma Mun˜ oz-Pacheco a , Adriana Ortega-Herna´ ndez a , Alicia Caro-Vadillo b , Sebastian Casanueva-Eliceiry a , Paloma Aragoncillo c,  , Jesu´ s Egido d , Arturo Ferna´ ndez-Cruz e , and Dulcenombre Go´ mez-Garre a Aims: The addition of an aldosterone receptor antagonist on top of current optimal therapy (based on angiotensin II inhibition) has demonstrated an important clinical benefit in heart failure patients with systolic dysfunction. Whether this finding also applies to heart failure patients with preserved systolic function is unknown. Therefore, we have studied the effect of adding eplerenone to standard pharmacological heart failure therapy (angiotensin- converting enzyme inhibitor/angiotensin receptor blocker and diuretic and b-blocker) in the progression of heart failure in spontaneously hypertensive heart failure (SHHF) rats. Methods and results: Two-month-old SHHF rats were randomized to receive no treatment (SHHF group), a standard heart failure therapy (quinapril-torasemide- carvedilol; ST-SHHF group), or the combination of eplerenone and standard heart failure therapy (EpleRST- SHHF group) for 20 months. Untreated SHHF was characterized by progressive left ventricular hypertrophy, fibrosis, and myocardial contractile and relaxation abnormalities, leading to pulmonary congestion. Despite similar blood pressure control, the addition of eplerenone to standard heart failure therapy further prevented left ventricular hypertrophy, contractile and relaxation alterations, and pulmonary congestion than standard heart failure therapy alone. ST-SHHF and Eple R ST-SHHF rats showed similar inhibition of structural extracellular matrix proteins collagen I, collagen III and fibronectin and metalloproteinase (MMP)-2, MMP-7, MMP-12, and MMP- 13. However, only the coadministration of eplerenone with standard heart failure therapy normalized the expression of matricellular proteins thrombospondin 1, tenascin C, periostin, and secreted protein acidic rich in cysteine/ osteonectin to values comparable to normotensive rats. Conclusion: In a hypertensive heart failure rat model, the addition of eplerenone to conventional heart failure therapy further improves cardiac structural and functional parameters, delaying the progression of heart failure. These beneficial effects of eplerenone were associated with normalization of matricellular protein expression. Keywords: cardiac remodeling, eplerenone, matricellular proteins, preserved systolic function heart failure Abbreviations: ACE, angiotensin-converting enzyme; Ang II, angiotensin II; ARBs, angiotensin receptor blockers; BP, blood pressure; ECM, extracellular matrix; MMPs, matrix metalloproteinases; mwFS, midwall fractional shortening; RAAS, renin–angiotensin–aldosterone system; RT-PCR, real-time-PCR; SHHF, spontaneously hypertensive heart failure INTRODUCTION A ldosterone is a mediator of the renin–angiotensin– aldosterone system (RAAS) involved in a variety of pathophysiological processes associated with car- diovascular events such as vascular inflammation, endo- thelial dysfunction and cardiac fibrosis, and hypertrophy [1]. Both in heart failure patients and in several experimental models, elevated levels of cardiac aldosterone have been demonstrated in failing hearts, and the organ-protection effect of aldosterone antagonism has been well described [1,2]. Thus, the importance of aldosterone in the patho- physiology of heart failure was evidenced in a meta- analysis of 19 clinical trials showing a 20% reduction in all-cause mortality with the use of aldosterone blockade in a clinically heterogeneous group of heart failure patients with left ventricular dysfunction [3]. Journal of Hypertension 2013, 31:2309–2319 a Vascular Biology Research Laboratory, Hospital Clı´nico San Carlos, Instituto de Investigacio´n Sanitaria del Hospital Clı´nico San Carlos, b Department of Animal Medicine and Surgery, School of Veterinary Science, Universidad Complutense de Madrid, c Department of Pathology, Hospital Clı´nico San Carlos, Instituto de Inves- tigacio´n Sanitaria del Hospital Clı´nico San Carlos, d Laboratory of Renal and Vascular Pathology, IIS-Fundacio´ n Jime´nez Dı´az, Universidad Auto´ noma and e Facultad de Medicina, Department of Internal Medicine, Hospital Clı´nico San Carlos, Universidad Complutense de Madrid, Instituto de Investigacio´n Sanitaria del Hospital Clı´nico San Carlos, Madrid, Spain Correspondence to Dulcenombre Go´mez Garre, PhD, Laboratorio de Biologı´a Vas- cular, planta baja sur (Pabellon B), Hospital Clı´nico San Carlos, C/Martı´n Lagos s/n, 28040-Madrid, Spain. E-mail: mgomezg.hcsc@salud.madrid.org  In memoriam. Received 22 November 2012 Revised 31 May 2013 Accepted 28 June 2013 J Hypertens 31:2309–2319 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0b013e328364abd6 Journal of Hypertension www.jhypertension.com 2309 Original Article