Furosemide and the progression of left ventricular dysfunction in experimental heart failure.
OBJECTIVE
We tested the hypothesis that furosemide accelerates the progression of left ventricular systolic dysfunction in a tachycardia-induced porcine model of heart failure.


BACKGROUND
Furosemide activates the renin-angiotensin-aldosterone system in patients with congestive heart failure (CHF). Such activation may contribute to CHF progression, but prospective data are lacking.


METHODS
Thirty-two Yorkshire pigs were randomized to furosemide (1 mg/kg intramuscularly daily, mean 16.1 +/- 0.9 mg) or placebo. Thereafter, a pacing model of heart failure was utilized to produce systolic dysfunction in both sets of animals (fractional shortening <0.16 by echocardiogram). The goal was to determine if furosemide would accelerate the progression of left ventricular dysfunction in the "treated" group. After sacrifice, sodium-calcium exchanger currents and their responsiveness to isoproterenol were measured during voltage clamp. All investigators were blinded to treatment assignment.


RESULTS
Furosemide shortened the time to left ventricular dysfunction (35.1 +/- 5.1 days in placebo versus 21.4 +/- 3.2 days for furosemide animals; p = 0.038, log-rank test). By day 14, aldosterone levels were significantly higher in furosemide animals (43.0 +/- 11.8 ng/dl vs. 17.6 +/- 4.5 ng/dl; p < 0.05). Serum sodium was reduced (133.0 +/- 0.9 mmol/l furosemide vs. 135.7 +/- 0.8 mmol/l placebo; p < 0.05), but no difference in norepinephrine, potassium, magnesium, creatinine, or urea nitrogen was present. Basal sodium-calcium exchanger currents were significantly increased and isoproterenol responsiveness depressed by furosemide.


CONCLUSIONS
Tachycardic pigs given furosemide had significant acceleration of both contractile and metabolic features of CHF, including left ventricular systolic dysfunction, elevated serum aldosterone levels, and altered calcium handling in a controlled experimental model of heart failure.
McCurley
John M
JM
Division of Cardiology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
Hanlon
Stephen U
SU
Wei
Shao-kui
SK
Wedam
Erich F
EF
Michalski
Michael
M
Haigney
Mark C
MC
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D004232:Diuretics / Q000494:pharmacology*; D004452:Echocardiography; D004573:Electrolytes / Q000378:metabolism; D005260:Female; D005665:Furosemide / Q000494:pharmacology*; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D013223:Statistics as Topic; D013552:Swine; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D015415:Biomarkers; D004232:Diuretics; D004573:Electrolytes; D018377:Neurotransmitter Agents; D000450:Aldosterone; D005665:Furosemide; D007545:Isoproterenol