Published online before print July 14, 2008, doi: 10.1161/CIRCHEARTFAILURE.108.766402
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Original Articles |
Chronic Glucagon-Like Peptide-1 Infusion Sustains Left Ventricular Systolic Function and Prolongs Survival in the Spontaneously Hypertensive, Heart Failure–Prone Rat
From the Department of Medicine, Allegheny General Hospital, Pittsburgh, Pa (I.P., S.B., P.P., H.B., R.P.S.); and the Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa (S.B.B., R.P.S.).
Correspondence to Richard P. Shannon, MD, Hospital of the University of Pennsylvania, 3400 Spruce Street, Centex 100, Philadelphia, PA 19104. E-mail Richard.Shannon{at}uphs.upenn.edu
Received January 20, 2008; accepted July 2, 2008.
Background— Glucagon-like peptide-1 (GLP-1) treatment leads to short-term improvements in myocardial function in ischemic and nonischemic cardiomyopathy. It is unknown whether GLP-1 improves survival when administered over a longer time period. Spontaneously hypertensive, heart failure–prone (SHHF) rats progress to advanced heart failure and death over a 15-month period. The authors sought to determine whether a continuous infusion of GLP-1 would reduce mortality in this model.
Methods and Results— At 9 months of age, 50 SHHF rats were randomized to receive a 3-month, continuous infusion of either GLP-1 or saline. Metabolic parameters were measured and cardiac ultrasounds performed at study initiation and completion of treatment. Surviving rats were euthanized at 12 months. Hearts were perfused in an isolated, isovolumic heart preparation, and Tunel staining of myocardial samples was performed. Baseline metabolic and cardiac functional parameters were comparable. GLP-1–treated SHHF rats had greater survival (72% versus 44%, P=0.008) at 12 months of age. In addition, GLP-1 treatment led to higher plasma insulin, lower plasma triglycerides, and preserved left ventricular (LV) function. GLP-1–treated rats demonstrated decreased myocyte apoptosis by Tunel staining as well as reduced caspase-3 activation. No increase in p-BAD expression was seen. In isolated hearts, the LV systolic pressure and LV-developed pressure were greater in the GLP-1 group. Myocardial glucose uptake was also increased in GLP-1–treated SHHF rats.
Conclusions— Chronic GLP-1 treatment prolongs survival in obese SHHF rats. This is associated with preserved LV function and LV mass index, increased myocardial glucose uptake, and reduced myocyte apoptosis.
Key Words: apoptosis • diabetes mellitus • glucose • heart failure • mortality
CLINICAL PERSPECTIVE
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