Effects of spironolactone alone and in addition to a β-blocker on myocardial histological and electrical remodeling in chronic severe failing rat hearts.
BACKGROUND
Aldosterone antagonists (AAs) have beneficial effects on ventricular histological and electrical remodeling and improve noradrenaline uptake. Adding an AA to a beta-blocker (BB) further improves cardiac mortality in heart failure patients. We investigated if adjunction of a BB modifies beneficial effects of spironolactone on different parameters of the ventricular remodeling.


METHODS
A severe myocardial infarction (MI) was produced in rats. Three months after surgery, left ventricular (LV) function was assessed by echocardiography. Fifty-five rats with heart failure were then randomized in 5 groups: sham, MI, and MI treated for 4 weeks with spironolactone (10 mg·kg·d), atenolol (1 mg·kg·d), or both. Holter transducers were implanted to record 24-hour ventricular electrical parameters, mean cycle length (RR) and SD of RR. Before killing, invasive left ventricular end diastolic pressure (LVEDP) was recorded. LV samples were used for histological analysis and catecholamine assay.


RESULTS
Rats with MI had significantly increased LVEDP (32 ± 3 vs. 14 ± 1 mm Hg), LV, collagen content (5.8% ± 1.4% vs. 3.6% ± 0.7%), ventricular premature complexes (2.5 10 ± 10 vs. 30 ± 13), and decreased meanRR (164 ± 2 vs. 169 ± 1 milliseconds) and SDRR (3.9 ± 0.2 vs. 5.4 ± 0.2 milliseconds) compared with sham. At nonhypotensive doses, spironolactone and atenolol similarly improved LVEDP. Compared with MI, although spironolactone significantly decreased ventricular premature complexes, LV collagen and noradrenaline contents, and improved meanRR and SDRR, atenolol had effects only on meanRR and SDRR. Addition of atenolol to spironolactone further improved spironolactone effects on all these parameters.


CONCLUSIONS
AA improved, independently of the cardiac function, histological and electrical remodeling after MI. A BB added to an AA did not blunt these beneficial effects; furthermore, it improved these effects related to spironolactone.
INSERM U942, University Paris-Diderot, Lariboisiere University Hospital, Paris, France. milliez-p@chu-caen.fr
Paul
P
Milliez
Sophie
S
Gomes
Laure
L
Champ-Rigot
Jacques
J
Callebert
Jane-Lise
JL
Samuel
Claude
C
Delcayre
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage*; D000818:Animals; D002908:Chronic Disease; D004359:Drug Therapy, Combination; D006333:Heart Failure / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000473:pathology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D013148:Spironolactone / Q000008:administration & dosage*; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
D000319:Adrenergic beta-Antagonists; D013148:Spironolactone