Are we mice or men? Gene mutation linked to improving heart failure in mice proves lethal in humans

ardiac hypertrophy in which mice destined to develop cardiac hypertrophy were also genetically modified to lack the PLN gene. They found that the absence of the PLN gene restored impaired calcium signaling and muscle contraction in individual heart cells, however there was no reversal or prevention of hypertrophy of the whole heart.

In the second study, the authors found that individuals with naturally occurring mutations in the human PLN gene develop heart failure. Individuals that lacked the PLN gene suffered fatal heart failure. The results indicate that PLN is essential for cardiac health in humans and its absence is lethal the direct opposite of the results observed in mice.

In contrast to earlier successful studies in mice in which genetic manipulation was able to prevent or reverse heart failure, "these two studies provide a sobering reminder of heart failure's complexity" writes Jonathon Lederer, a heart specialist at the University of Maryland Biotechnology Institute. "By examining both animal models and human disease, these papers indicate that the role of PLN in the pathogenesis of heart failure might be more complicated than previously thought". The two studies also indicate that we need to better understand inherent differences in cardiac physiology between mice and humans. Dr. Kranias concluded that "these data emphasize a general concern that targeted therapies whose design is based exclusively on results of studies in rodent models, in which phenotypes can differ radically from those observed in the corresponding human genetic condition, may not ultimately be successful in human disease.

Evangelia G. Kranias
University of Cincinnati Medical Center
Dept Of Pharmacology & Cell Biophysics
231 Albert Sabin Way
ML 0575
Cincinnati, OH 45267-0575
Phone 1-513-558-2377
Fax 1-513-558-2269

Contact: Brooke Grindlinger
Journal of Clinical Investigation

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