Aldosterone receptor blockade improves left ventricular remodeling and increases ventricular fibrillation threshold in experimental heart failure.
OBJECTIVE
To investigate the effects of aldosterone receptor blockade in postinfarction heart failure.


METHODS
Eighty-seven rats with moderate myocardial infarction were randomized to receive either no drug or canrenone, the active metabolite of spironolactone, 20 mg/kg/day, or ramipril, 1 mg/kg/day, or a combination of the two drugs. Treatment was initiated 1 month after coronary ligation and lasted 4 weeks. Echocardiography was performed at baseline and after 4 weeks. LV catheterization, isolated heart studies, morphometric histology, myocardial norepinephrine and SERCA-2 mRNA were assessed at the end of the treatment period.


RESULTS
Infarct sizes were 33+/-3, 32+/-3, 34+/-3, and 34+/-4% in the placebo, canrenone, ramipril, and combination groups, respectively. Canrenone attenuated LV remodeling, improved LV systolic and diastolic function, and markedly reduced interstitial and perivascular fibrosis. These effects were increased by concomitant ramipril therapy. Moreover, myocardial norepinephrine content was decreased while ventricular fibrillation threshold significantly augmented by canrenone. SERCA-2 levels remained unchanged.


CONCLUSIONS
Canrenone attenuated LV dilation and interstitial remodeling, and improved LV filling dynamics and systolic function in the rat model of postinfarction heart failure. Addition of ramipril conferred further cardioprotection. Canrenone also reduced myocardial norepinephrine content and increased ventricular fibrillation threshold. The data provide a potential explanation for the decreased sudden death observed in the RALES study. The mechanisms of action of aldosterone inhibition are still poorly understood, despite its proven efficacy in heart failure. Rats with postinfarction heart failure were randomized to receive for 1 month either no drug or canrenone, or ramipril, or a combination of canrenone and ramipril. Canrenone treatment was associated with a significant attenuation of LV dilation, better LV diastolic and systolic dynamics, and a marked reduction of reactive fibrosis. These effects were enhanced by concomitant ramipril therapy. Moreover, canrenone increased ventricular fibrillation threshold and reduced myocardial norepinephrine content. The data may explain the reduced mortality demonstrated by the RALES.
Cittadini
Antonio
A
Department of Internal Medicine and Cardiovascular Sciences, University Federico II, Naples, Italy. cittadin@unina.it
Monti
Maria Gaia
MG
Isgaard
Jörgen
J
Casaburi
Cosma
C
Strömer
Hinrik
H
Di Gianni
Angela
A
Serpico
Raffaella
R
Saldamarco
Lavinia
L
Vanasia
Massimo
M
Saccà
Luigi
L
D000818:Animals; D000252:Calcium-Transporting ATPases / Q000235:genetics; D002192:Canrenone / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D017257:Ramipril / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy; D020257:Ventricular Remodeling / Q000187:drug effects
D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D002192:Canrenone; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D017257:Ramipril; D009638:Norepinephrine