Published Online
on July 14, 2008

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Original Article

Chronic Glucagon-like Peptide-1 (GLP-1) Infusion Sustains LV Systolic Function and Prolongs Survival in the Spontaneously Hypertensive-Heart Failure Prone Rat

Indu Poornima¹; Suzanne Brown²; Siva Bhashyam¹; Pratik Parikh¹; Hakki Bolukoglu¹ and Richard Patrick Shannon^3,4

¹ Department of Medicine, Allegheny General Hospital, Pittsburgh;
² Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia;
³ Depts. of Medicine, Allegheny General Hospital, Pittsburgh; Hospital of the Uni. of PA, Philadelphia

⁴ E-mail: richard.shannon{at}uphs.upenn.edu

Background—GLP-1 treatment leads to short-term improvements in myocardial function in ischemic and non-ischemic cardiomyopathy. It is unknown whether GLP-1 improves survival when administered over a longer time period. Spontaneously hypertensive, heart failure prone rats (SHHF) progress to advanced heart failure and death over a 15 month period. We 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 had greater survival (72% vs. 44%, p=0.008) at 12 months of age. In addition, GLP-1 treatment led to higher plasma insulin, lower plasma triglycerides, and preserved 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 developed pressure were greater in the GLP-1 group. Myocardial glucose uptake was also increased in GLP-1 treated SHHF.

Conclusions—Chronic GLP-1 treatment prolongs survival in obese, hypertensive SHHF. 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