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Reconstitution of the Frank-Starling Mechanism in Engineered Heart Tissues

Clara F. Asnes ^*, J. Pablo Marquez , Elliot L. Elson ^* and Tetsuro Wakatsuki 

^* Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110; and Department of Physiology and Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Correspondence: Address reprint requests to Tetsuro Wakatsuki, Tel.: 414-456-4466; Fax: 414-456-6568; E-mail: twakatsuki{at}mcw.edu.

According to the Frank-Starling mechanism, as the heart is stretched, it increases its contraction force. Reconstitution of the Frank-Starling mechanism is an important milestone for producing functional heart tissue constructs. Spontaneously contracting engineered heart tissues (EHTs) were reconstituted by growing dissociated chicken embryo cardiomyocytes in collagen matrices. Twitch and baseline tensions were recorded at precisely controlled levels of tissue strain. The EHTs showed a steep increase in twitch tension from 0.47 ± 0.02 to 0.91 ± 0.02 mN/mm² as they were stretched at a constant rate (2.67% per min) from 86% to 100% of the length at which maximum twitch force was exerted. In response to a sudden stretch (3.3%), the twitch tension increased gradually (60 s) in a Gd³⁺-sensitive manner, suggesting the presence of stretch-activated Ca²⁺ channels. A large difference in baseline tension between lengthening (loading) and shortening (unloading) was also recorded. Disruption of nonsarcomeric actin filaments by cytochalasin D and latrunculin B decreased this difference. A simple mechanical model interprets these results in terms of mechanical connections between myocytes and nonmuscle cells. The experimental results strongly suggest that regulation of twitch tension in EHTs is similar to that of natural myocardium.

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