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