Repeated cell transplantation and adjunct renal denervation in ischemic heart failure: exploring modalities for improving cell therapy efficacy

  • David J. Polhemus
  • Rishi K. Trivedi
  • Thomas E. Sharp
  • Zhen Li
  • Traci T. Goodchild
  • Amy Scarborough
  • Geoffrey de Couto
  • Eduardo Marbán
  • David J. LeferEmail author
Original Contribution


Enthusiasm for cell therapy for myocardial injury has waned due to equivocal benefits in clinical trials. In an attempt to improve efficacy, we investigated repeated cell therapy and adjunct renal denervation (RDN) as strategies for augmenting cardioprotection with cardiosphere-derived cells (CDCs). We hypothesized that combining CDC post-conditioning with repeated CDC doses or delayed RDN therapy would result in superior function and remodeling. Wistar–Kyoto (WKY) rats or spontaneously hypertensive rats (SHR) were subjected to 45 min of coronary artery ligation followed by reperfusion for 12–14 weeks. In the first study arm, SHR were treated with CDCs (0.5 × 106 i.c.) or PBS 20 min following reperfusion, or additionally treated with CDCs (1.0 × 106 i.v.) at 2, 4, and 8 weeks. In the second arm, at 4 weeks following myocardial infarction (MI), SHR received CDCs (0.5 × 106 i.c.) or CDCs + RDN. In the third arm, WKY rats were treated with i.c. CDCs administered 20 min following reperfusion and RDN or a sham at 4 weeks. Early i.c. + multiple i.v. dosing, but not single i.c. dosing, of CDCs improved long-term left ventricular (LV) function, but not remodeling. Delayed CDC + RDN therapy was not superior to single-dose delayed CDC therapy. Early CDC + delayed RDN therapy improved LV ejection fraction and remodeling compared to both CDCs alone and RDN alone. Given that both RDN and CDCs are currently in the clinic, our findings motivate further translation targeting a heart failure indication with combined approaches.


Cellular post-conditioning Sympathetic nervous system Fibrosis Stem cells Ischemia–reperfusion injury Cell therapy Left ventricular function 



This work was supported by grants from the National Heart, Lung, and Blood Institute, Bethesda, MD (National Institutes of Health; 1R01 HL092141 (DJL), 1R01 HL093579 (DJL), 1U24 HL 094373 (DJL), 1P20 HL113452 (DJL), R01 HL133835 (EM), and 18CDA34110445 American Heart Association, Dallas, TX, Career Development Award (GdC). We are also grateful for the generous funding from the LSU Medical School Foundation and the LSU Medical School Alumni Association, New Orleans, LA. We thank Jean Carnal and Dr. Hiroshi Koiwaya for their assistance during these studies.

Compliance with ethical standards

Conflict of interest

E.M. owns founder’s equity in Capricor, Inc. GdC receives consulting fees from Capricor. D.J.P. and D.J.L have a pending patent on the use of RDN and cell therapy to treat cardiovascular diseases. R.K.T., T.E.S., A.S., and T.T.G. have nothing to disclose.

Supplementary material

395_2019_718_MOESM1_ESM.pdf (52 kb)
Supplementary material 1 (PDF 53 kb)
395_2019_718_MOESM2_ESM.docx (12 kb)
Supplementary material 2 (DOCX 12 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • David J. Polhemus
    • 1
  • Rishi K. Trivedi
    • 1
  • Thomas E. Sharp
    • 1
  • Zhen Li
    • 1
  • Traci T. Goodchild
    • 1
  • Amy Scarborough
    • 1
  • Geoffrey de Couto
    • 2
  • Eduardo Marbán
    • 2
  • David J. Lefer
    • 1
    Email author
  1. 1.Cardiovascular Center of Excellence, LSU Health Sciences CenterNew OrleansUSA
  2. 2.Smidt Heart InstituteCedars-Sinai Medical CenterLos AngelesUSA

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