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Studies raise doubt on validity of animal models in CV research
Fedorov V. J Mol Cell Cardiol. 2011;51:215-225.
Glukhov A. J Mol Cell Cardiol. 2010;48:152-160.
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Investigators of two studies published in the Journal of Molecular and Cellular Cardiology have found conflicting results of two adenosine triphosphate-regulated potassium channel openers when observed in mice vs. human hearts.
“In human hearts … the sulfonylurea receptor type 1 (SUR1) drug (pinacidil) doesn’t work in the atria at all, but it does affect the ventricles; it is the opposite of what happens in the mouse. The SUR2 drug (diazoxide) affected both the atria and the ventricles, and shortened the action potentials in the ventricles so much that it would cause fatal arrhythmias in people,” Igor R. Efimov, PhD, a biomedical engineer at Washington University, St. Louis, and researcher on both the mice and human studies, said in a press release.
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The first study, which was published in early 2010, involved intact hearts from six wild-type mice, six SUR1(-/-) mice and five Kir 6.2(-/-) mice. Efimov and colleagues observed that 300 mcM diazoxide decreased action potential duration (ADP) in the atria (P<.001) but not the ventricles among wild-type mice hearts, whereas the same dose of pinacidil lowered ventricular ADP in both wild-type and SUR1(-/-) hearts (P<.001 for both) but not atrial ADP.
In the second study, which was recently published by the journal, the investigators used hearts from patients who had congestive HF and underwent transplant (n=8) or hearts unsuitable for transplant that were donated to research either with (INF; n=2) or without (NF; n=3) infarction.
They reported that diazoxide decreased ADP in chronic HF and INF hearts in atria and ventricles (P<.01 for both) but not in NF atria. However, pinacidil lowered ADPs in the atria and ventricles of all hearts.
As a possible mechanism for the discrepancy, Efimov said a mouse heart beats on average 600 times/minute, whereas a human heart beats on average 72 times/minute, and the difference in gene expression between mice and human hearts is very large.
“You can mutate in mice the gene thought to cause HF in humans and you don’t get the same disease because the mouse is so different. So, unfortunately, even with the help of transgenic mice, very few results made it from the animal model to the clinic,” he said.
Disclosure: Dr. Efimov reports no relevant financial disclosures in either study.
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