Anti-inflammatory and pro-angiogenic effects of beta blockers in a canine model of chronic ischemic cardiomyopathy: comparison between carvedilol and metoprolol
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There is controversy regarding the superiority of carvedilol (C) over metoprolol (M) in congestive heart failure. We hypothesized that C is superior to M in chronic ischemic cardiomyopathy because of its better anti-inflammatory and pro-angiogenic effects. In order to test our hypothesis we used a chronic canine model of multivessel ischemic cardiomyopathy where myocardial microcatheters were placed from which interstitial fluid was collected over time to measure leukocyte count and cytokine levels. After development of left ventricular dysfunction, the animals were randomized into four groups: sham (n = 7), placebo (n = 8), M (n = 11), and C (n = 10), and followed for 3 months after treatment initiation. Tissue was examined for immunohistochemistry, oxidative stress, and capillary density. At 3 months both rest and stress wall thickening were better in C compared to the other groups. At the end of 3 months of treatment end-systolic wall stress also decreased the most in C. Similarly resting myocardial blood flow (MBF) improved the most in C as did the stress endocardial/epicardial MBF. Myocardial interstitial fluid showed greater attenuation of leukocytosis with C compared to M, which was associated with less fibrosis and oxidative stress. C also had higher IL-10 level and capillary density. In conclusion, in a chronic canine model of multivessel ischemic cardiomyopathy we found 3 months of C treatment resulted in better resting global and regional function as well as better regional function at stress compared to M. These changes were associated with higher myocardial levels of the anti-inflammatory cytokine IL-10 and less myocardial oxidative stress, leukocytosis, and fibrosis. Capillary density and MBF were almost normalized. Thus in the doses used in this study, C appears to be superior to M in a chronic canine model of ischemic cardiomyopathy from beneficial effects on inflammation and angiogenesis. Further studies are required for comparing additional doses of these drugs.
KeywordsIschemic cardiomyopathy Beta blockers Regional flow Regional function Cytokines Angiogenesis
The authors would like to thank Craig Goodman, B.S. for his expert technical assistance with the experiments. We are also grateful to Melissa Bevard, Helen Liu, and Yan Zhao for their assistance with the histology and immunohistochemistry work and to Jay Phillips, Robert Webber, Lisa Bleyle and Dennis Koop from the Bioanalytical Shared Resource/Pharmacokinetics Core University Shared Resources at OHSU for their assistance with the oxidative stress assessment.
Supported in part by grants from the National Institutes of Health (K-08-HL0742901, D. Elizabeth Le and R01-HL660346, Sanjiv Kaul). The radiolabeled microspheres were provided by Dupont Pharmaceuticals, North Billerica, MA, and the ultrasound equipment was supplied by Philips Ultrasound, Andover, MA.
Conflicts of interest
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