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Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts

Nature Medicine volume 12, pages 452–458 (2006)Cite this article

Abstract

The concept of regenerating diseased myocardium by implantation of tissue-engineered heart muscle is intriguing, but convincing evidence is lacking that heart tissues can be generated at a size and with contractile properties that would lend considerable support to failing hearts. Here we created large (thickness/diameter, 1–4 mm/15 mm), force-generating engineered heart tissue from neonatal rat heart cells. Engineered heart tissue formed thick cardiac muscle layers when implanted on myocardial infarcts in immune-suppressed rats. When evaluated 28 d later, engineered heart tissue showed undelayed electrical coupling to the native myocardium without evidence of arrhythmia induction. Moreover, engineered heart tissue prevented further dilation, induced systolic wall thickening of infarcted myocardial segments and improved fractional area shortening of infarcted hearts compared to controls (sham operation and noncontractile constructs). Thus, our study provides evidence that large contractile cardiac tissue grafts can be constructed in vitro, can survive after implantation and can support contractile function of infarcted hearts.

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Figure 1: Construction of optimized EHTs. Effects of oxygen, load and insulin were analyzed by isometric contraction experiments in EHT rings.
Figure 2: EHT morphology 4 weeks after engraftment.
Figure 3: Electrical integration of EHTs in vivo.
Figure 4: Changes in left ventricular function after EHT implantation.
Figure 5: Influence of EHT grafting on left ventricular hemodynamics.

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Acknowledgements

This work is part of the doctoral thesis of I.M. at the Universities of Erlangen-Nuremberg and Hamburg. We acknowledge the technical assistance of S. John and F. Bussmann (University of Erlangen; MRI data evaluation) and T. Müller (University of Erlangen; construction of stretch devices). The help from H. Rütten and D. Gehling (Aventis, Frankfurt) in echocardiography and pressure-volume loop recordings is appreciated. This study was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft; Es 88/8-2 to T.E. and FOR 604/1-1 to T.E. and H.E.), the German Ministry for Education and Research (Bundesministerium für Bildung und Forschung 01GN 0124 and BMBF 01GN 0520 to T.E. and W.-H.Z.), the Deutsche Stiftung für Herzforschung (W.-H.Z.) and the Minerva foundation (W.-H.Z.).

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Author notes

  1. Wolfram-Hubertus Zimmermann and Ivan Melnychenko: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg, 20246, Germany

    Wolfram-Hubertus Zimmermann, Ivan Melnychenko, Michael Didié, Hiroshi Naito & Thomas Eschenhagen

  2. Medical Clinic II, Friedrich-Alexander-University of Erlangen-Nuremberg, Ulmenweg 18, Erlangen, 91054, Germany

    Gerald Wasmeier & Uwe Nixdorff

  3. Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University of Erlangen-Nuremberg, Fahrstraße 17, Erlangen, 91054, Germany

    Andreas Hess, Lubos Budinsky & Kay Brune

  4. Department of Cardiac Surgery, Heart Center, University of Leipzig, Strümpellstraße 39, Leipzig, 04289, Germany

    Bjela Michaelis & Stefan Dhein

  5. Institute of Vegetative Physiology and Pathophysiology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg, 20246, Germany

    Alexander Schwoerer & Heimo Ehmke

Authors
  1. Wolfram-Hubertus Zimmermann
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Corresponding authors

Correspondence to Wolfram-Hubertus Zimmermann or Thomas Eschenhagen.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Relating functional effects of optimized EHTs to molecular alterations in EHTs. (PDF 115 kb)

Supplementary Fig. 2

Cell composition of multi-unit EHTs. (PDF 114 kb)

Supplementary Fig. 3

Echocardiography assessment. (PDF 398 kb)

Supplementary Fig. 4

DAPI labeling of EHT grafts. (PDF 17896 kb)

Supplementary Fig. 5

Ambulatory echocardiogram telemetry. (PDF 101 kb)

Supplementary Table 1

Summary of the experimental outline. (PDF 23 kb)

Supplementary Table 2

Echocardiography data. (PDF 267 kb)

Supplementary Table 3

MRI data. (PDF 115 kb)

Supplementary Table 4

Catheterization data. (PDF 151 kb)

Supplementary Video 1

Multiunit engineered heart tissue. (MOV 6008 kb)

Supplementary Methods (PDF 47 kb)

Supplementary Note (PDF 59 kb)

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Zimmermann, WH., Melnychenko, I., Wasmeier, G. et al. Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts. Nat Med 12, 452–458 (2006). https://doi.org/10.1038/nm1394

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