Furosemide and the progression of left ventricular dysfunction in experimental heart failure
John M. McCurley, MD*,
Stephen U. Hanlon, MD*,
Shao-kui Wei, MD*,
Erich F. Wedam, MD ,
Michael Michalski, MD and
Mark C. Haigney, MD*,*
* Division of Cardiology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
Division of Cardiology, National Naval Medical Center, Bethesda, Maryland, USA
Division of Cardiology, Naval Medical Center, San Diego, California, USA
View larger version (11K):
[in a new window]
|
Figure 1 Cumulative probability of the development of severe systolic dysfunction as defined as a fractional shortening (FS) of <0.16 in placebo-treated (blue line) and furosemide-treated animals (red line) (n = 16 for both groups). p = 0.038 from log-rank statistics.
|
|
View larger version (28K):
[in a new window]
|
Figure 2 (A) Comparison of mean ± SEM of serum aldosterone measured in both groups at implantation (yellow), at day 14 of pacing (red), and at sacrifice (purple). Serum aldosterone in placebo animals did not increase at day 14 (n = 11), while aldosterone increased significantly in furosemide-treated animals both compared with implant and compared with placebo (n = 9, *p < 0.05 compared with implantation; #p < 0.05 with respect to placebo). (B) Comparison of mean ± SEM of serum norepinephrine measured in both groups at implantation (yellow), at day 14 of pacing (red), and at sacrifice (purple). Serum norepinephrine increased equally in both placebo- and furosemide-treated animals at day 14 (n = 11, *p < 0.05 compared with implantation).
|
|
View larger version (19K):
[in a new window]
|
Figure 3 The mean change in fractional shortening (FS) as a function of the change in end-diastolic dimension index (EDDI) from baseline to day 14 and to sacrifice (day 34 ± 5, n = 15) in placebo-treated (black squares) versus furosemide animals (red circles). Furosemide group measurements were made at day 13 (±1) and sacrifice (day 23 ± 4, n = 14). Despite its diuretic action, furosemide was associated with similarly increased end-diastolic dimension and reduced FS compared with placebo, indicating that the reduced systolic performance in the furosemide group was not due to a drop in presystolic chamber volume. The change in FS at sacrifice was marginally greater in the furosemide group (p = 0.07). Sacrifice occurred at different time points due to the earlier development of systolic dysfunction in the furosemide group.
|
|
View larger version (43K):
[in a new window]
|
Figure 4 (A and B) Representative traces of the sodium-calcium exchange current elicited by voltage ramp in a myocyte from a failing placebo-treated animal (A) and a failing furosemide-treated animal (B). Basal currents are seen in black, and the current in the same cell after stimulation with 2 µM isoproterenol (ISO) are presented in red. (C) Comparison of mean ± SEM peak outward sodium-calcium exchanger currents elicited from myocytes from nonfailing controls (yellow, n = 42 cells from 11 pigs), failing placebo-treated (red, n = 40 cells from 8 pigs), and furosemide-treated animals (purple, n = 50 cells from 9 pigs). Heart failure was associated with a significantly greater peak current, but furosemide use was associated with significantly greater current compared with placebo (*different compared with both failure groups, p < 0.05; #different from placebo cells, p < 0.05). (D) Comparison of mean ± SEM ratio of peak outward sodium-calcium exchanger currents elicited in response to ISO divided by basal current from failing myocytes from placebo- and furosemide-treated animals. Furosemide use was associated with significantly less inducible current compared with placebo and nonfailing controls, consistent with a reduction in responsiveness to beta-adrenergic stimulation (*different compared with both failure groups, p < 0.05; #different from placebo cells, p < 0.05).
|
|
|
