Published Online
on April 29, 2002

A more recent version of this article appeared on May 21, 2002

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Submitted on December 31, 2001
Revised on March 1, 2002
Accepted on March 1, 2002

Cellular Cardiomyoplasty Improves Survival After Myocardial Injury

Wilhelm Roell MD, Zhong J. Lu MD, Wilhelm Bloch MD, Sharon Siedner MS, Klaus Tiemann MD, Ying Xia MD, Eva Stoecker VMD, Michaela Fleischmann VMD, Heribert Bohlen MD, Robert Stehle PhD, Eugen Kolossov MD, Gottfried Brem VMD, Klaus Addicks MD, Gabriele Pfitzer MD, Armin Welz MD, Juergen Hescheler MD, and Bernd K. Fleischmann MD^*

From the Department of Cardiac Surgery (W.R., A.W.) and the Department of Cardiology (K.T.), University of Bonn, Bonn, Germany; the Institute of Neurophysiology (Z.J.L., Y.X., J.H., B.K.F.), Institute of Anatomy I (W.B., E.S., K.A.), and Institute of Vegetative Physiology (S.S., R.S., G.P.), University of Cologne, and Axiogenesis AG (H.B., E.K.), Cologne, Germany; and the Department of Biotechnology in Animal Production, Tulln, Austria (M.F., G.B).

^* To whom correspondence should be addressed. E-mail: akp17{at}uni-koeln.de.

Background—Cellular cardiomyoplasty is discussed as an alternative therapeutic approach to heart failure. To date, however, the functional characteristics of the transplanted cells, their contribution to heart function, and most importantly, the potential therapeutic benefit of this treatment remain unclear.

Methods and Results—Murine ventricular cardiomyocytes (E12.5--E15.5) labeled with enhanced green fluorescent protein (EGFP) were transplanted into the cryoinjured left ventricular walls of 2-month-old male mice. Ultrastructural analysis of the cryoinfarction showed a complete loss of cardiomyocytes within 2 days and fibrotic healing within 7 days after injury. Two weeks after operation, EGFP-positive cardiomyocytes were engrafted throughout the wall of the lesioned myocardium. Morphological studies showed differentiation and formation of intercellular contacts. Furthermore, electrophysiological experiments on isolated EGFP-positive cardiomyocytes showed time-dependent differentiation with postnatal ventricular action potentials and intact ß-adrenergic modulation. These findings were corroborated by Western blotting, in which accelerated differentiation of the transplanted cells was detected on the basis of a switch in troponin I isoforms. When contractility was tested in muscle strips and heart function was assessed by use of echocardiography, a significant improvement of force generation and heart function was seen. These findings were supported by a clear improvement of survival of mice in the cardiomyoplasty group when a large group of animals was analyzed (n=153).

Conclusions—Transplanted embryonic cardiomyocytes engraft and display accelerated differentiation and intact cellular excitability. The present study demonstrates, as a proof of principle, that cellular cardiomyoplasty improves heart function and increases survival on myocardial injury.

Key words: transplantation • cells • electrophysiology • contractility • survival

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