Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w

Minimal Renewal of Cardiomyocytes in the Diseased Human Heart

W. Derks1, J. Rode2, S. Collin3, F. Rost2, P. Heinke2, K. Alkass3, E. Lazar3, I. Simonova1, M. Andrä4, R. Jashari5, M. Salehpour6, H. Druid3, L. Brusch2, S. Drakos7, S. Jovinge8, J. Frisen3, O. Bergmann1

1Center for Regenerative Therapies Dresden, TU Dresden, Dresden; 2Center of Information Services and High-Performance Computing, TU-Dresden, Dresden; 3Karolinska Institutet, Stockholm, SE; 4Klinikum Klagenfurt, Klagenfurt am Wörthersee, AT; 5European Homograft Bank, Brüssel, BE; 6Uppsala University, Uppsala, SE; 7University of Utah, Salt Lake City, US; 8Spectrum Health Frederik Meijer Heart and Vascular Institute and Van Andel Institute, Grand Rapids, US;

Background: Cardiomyocytes in the adult human heart are characterized by a very low renewal rate and increased ploidy levels. Previous studies in animals showed increased cell cycle activity in injured hearts. Whether the renewal capacity of human cardiomyocytes is utilized in pathologically challenged hearts or whether the increased hemodynamic stress and metabolic demands merely trigger cardiomyocyte polyploidy and exit from the cell cycle remains unknown.   Aim: We investigated cardiomyocyte renewal through retrospective 14C birth dating and mathematical modeling in patients with ischemic (ICM) and non-ischemic cardiomyopathy (NICM).   Methods: We measured the 14C concentrations of genomic DNA in cardiomyocytes from a total of 33 patients (n=33), 12 ICM (n=12), and 21 NICM (n=21) through accelerator mass spectrometry (AMS). We determined nuclear ploidy and the number of nuclei per cardiomyocyte in our samples using both flow cytometry and image cytometry. Mathematical modeling was performed to integrate 14C concentration with data on cardiomyocyte DNA synthesis to establish cardiomyocyte renewal in diseased human hearts. All experiments were performed in accordance with the ethical standards of the Declaration of Helsinki and its later amendments.   Results: Both nuclear DNA content and the number of nuclei per cardiomyocyte increased in diseased hearts compared to healthy controls. Cardiomyocyte DNA content increased from 176.9% [169.8;196.9] in healthy subjects to 216.4% [199.9;254.9] in ICM and 291.7% [250.4;341.4] in NICM (2n baseline = 100%). Isolated cardiomyocytes in ICM and NICM hearts showed significantly higher levels of binucleation, 34.6% ± 5.1% in ICM and 35.2% ± 5.5% in NICM patients compared to 19.6% ± 2.0% in healthy hearts. Applying mathematical modeling the genomic 14C levels revealed an increase in DNA synthesis in cardiomyocytes in both NICM and ICM. However, the estimated cardiomyocyte renewal in heart disease was only 0.02% per year in NICM, and 0.01% per year in ICM, compared to 0.55% per year before disease onset. More than 99.6% of all DNA synthesis activity during cardiomyopathy can be attributed to nonproductive cell cycle activity.   Conclusions: Our data show a dramatic increase in DNA synthesis activity in diseased hearts resulting in elevated nuclear ploidy and binucleation in cardiomyocytes with only minimal cardiomyocyte renewal.

https://dgk.org/kongress_programme/jt2023/aP968.html