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(Circulation. 2002;106:I-151.)
© 2002 American Heart Association, Inc.

Thoracic Transplantation and Mechanical Support for Congestive Heart Failure

Cardiac Grafting of Engineered Heart Tissue in Syngenic Rats

Wolfram-Hubertus Zimmermann, MD; Michael Didié, BS; Gerald H. Wasmeier, MD; Uwe Nixdorff, MD; Andreas Hess, PhD; Ivan Melnychenko, MD; Oliver Boy, BS; Winfried L. Neuhuber, MD; Michael Weyand, MD; Thomas Eschenhagen, MD

From the Institute of Experimental and Clinical Pharmacology and Toxicology (W.-H.Z., M.D., A.H., I.M., O.B., T.E.); Medical Clinic II, Nuremberg, Germany (G.H.W., U.N.); Institute of Anatomy (W.L.N.); Clinic for Cardiac Surgery (M.W.), Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.

Correspondence to Thomas Eschenhagen, MD, Department of Clinical Pharmacology and Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Fahrstraße 17, 91054 Erlangen. E-mail eschenhagen{at}pharmakologie.uni-erlangen.de

Abstract

Background Cell grafting has emerged as a novel approach to treat heart diseases refractory to conventional therapy. We hypothesize that survival and functional and electrical integration of grafts may be improved by engineering cardiac tissue constructs in vitro before grafting.

Methods and Results Engineered heart tissue (EHT) was reconstituted by mixing cardiac myocytes from neonatal Fischer 344 rats with liquid collagen type I, matrigel, and serum-containing culture medium. EHTs were designed in circular shape (inner/outer diameter: 8/10 mm; thickness: 1 mm) to fit around the circumference of hearts from syngenic rats. After 12 days in culture and before implantation on uninjured hearts, contractile function of EHT was measured under isometric conditions. Baseline twitch tension amounted to 0.34±0.03 mN (n=33) and was stimulated by Ca²⁺ and isoprenaline to 200±12 and 185±10% of baseline values, respectively. Despite utilization of a syngenic model immunosuppression (mg/kg BW: azathioprine 2, cyclosporine A 5, methylprednisolone 2) was necessary for EHT survival in vivo. Echocardiography conducted 7, 14, and 28 days after implantation demonstrated no change in left ventricular function compared with pre-OP values (n=9). Fourteen days after implantation, EHTs were heavily vascularized and retained a well organized heart muscle structure as indicated by immunolabeling of actinin, connexin 43, and cadherins. Ultrastructural analysis demonstrated that implanted EHTs surpassed the degree of differentiation reached before implantation. Contractile function of EHT grafts was preserved in vivo.

Conclusions EHTs can be employed for tissue grafting approaches and might serve as graft material to repair diseased myocardium.

Key Words: cells • transplantation • contractility • echocardiography • tissue