Eplerenone enhances cardioprotective effects of standard heart failure therapy through matricellular proteins in hypertensive heart failure.
OBJECTIVE
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 β-blocker) in the progression of heart failure in spontaneously hypertensive heart failure (SHHF) rats.


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 (Eple+ST-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 + 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.


CONCLUSIONS
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.
aVascular Biology Research Laboratory, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos bDepartment of Animal Medicine and Surgery, School of Veterinary Science, Universidad Complutense de Madrid cDepartment of Pathology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos dLaboratory of Renal and Vascular Pathology, IIS-Fundación Jiménez Díaz, Universidad Autónoma eFacultad de Medicina, Department of Internal Medicine, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain *In memoriam.
Paloma
P
Muñoz-Pacheco
Adriana
A
Ortega-Hernández
Alicia
A
Caro-Vadillo
Sebastian
S
Casanueva-Eliceiry
Paloma
P
Aragoncillo
Jesús
J
Egido
Arturo
A
Fernández-Cruz
Dulcenombre
D
Gómez-Garre
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004359:Drug Therapy, Combination / Q000379:methods; D000077545:Eplerenone; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000209:etiology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009206:Myocardium / Q000201:enzymology; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D000077545:Eplerenone; D020782:Matrix Metalloproteinases