Introduction
Cardiomyocytes in the adult human heart show a minimal regenerative capacity. Whether this regenerative capacity of human cardiomyocytes is employed in heart failure (HF) has been controversial. Advanced HF patients can be supported with a left ventricular assist device (LVAD) and a subset of these patients show significant functional and structural cardiac improvement (termed responders). It remains unknown how mechanical unloading affects cardiomyocyte renewal, and if there is a difference between responders and non-responders.

Hypothesis
Mechanical unloading differentially induces cardiomyocyte renewal in responders and nonresponders.

Methods
We determined cardiomyocyte renewal by measuring the 14C concentration of cardiomyocyte genomic DNA. We included 52 patients with advanced HF, 28 of whom received LVAD support. Nuclear ploidy and the number of nuclei per cardiomyocyte were measured using both flow cytometry and image cytometry to distinguish the extent of non-productive cell cycle activity from proliferation. To integrate the measured 14C concentrations with the data on cardiomyocyte DNA synthesis mathematical modeling was performed and used to investigate renewal in HF, with and without mechanical unloading.

Results
Cell cycle activity increased in failing hearts rather than renewal, which was reduced >18-fold in non-ischemic and >50-fold in ischemic failing hearts compared to healthy hearts. Conversely, LVAD responders showed a >6-fold increase in cardiomyocyte renewal relative to a healthy heart.

Conclusions
LVAD-mediated functional cardiac improvement was accompanied by cardiomyocyte renewal, indicating a latent potential for regeneration in the adult heart.