Beta-blocker treatment impacts on resident cardiac progenitors isolation and therapeutic features in cardiac surgery patients.

Background. Beta-blockers (BB) represent a primary pharmacological treatment for chronic heart disease (CHD), for their ability to reverse neurohormonal effects of the sympathetic nervous system. BB treatment ensures prognostic and symptomatic benefits on cardiovascular events, such as myocardial infarction and stroke. Among the most innovative therapeutic strategies for CHDs, cardiac progenitor cell (CPC) therapy has received extensive attention as a promising regenerative treatment. Purpose: The impact of patient features on resident CPCs biology represents a key issue to be addressed for the quality of the final cell product used in autologous CPC therapy. Herein, we aimed at uncovering correlations between medical/clinical records of CHD patients undergoing cardiac surgery and the yield and phenotype of CPCs isolated as cardiospheres (CSs). Methods: After Institutional review board approval and informed consent collection, CSs were isolated from 41 CHD patients’ bioptic specimens. Medical, laboratory and echographic data were collected. Immunophenotype was analyzed by cytofluorimetry. A panel of genes and microRNAs, selected for their involvement in cardiac differentiation, fibrosis and CPCs regenerative potential, was quantified by realtime qPCR. Results: We detected a statistically significant association between BB therapy and successful CS isolation. Statistical analysis revealed a significant correlation between BB assumption and: overall success in obtaining CSs from the explant; timing necessary to obtain outgrowth cells from the explant; total cell yield of CS-forming cells from each biopsy. CS-formation is a TGFβ-dependent mechanism and we observed significantly increased TGFBR2 gene expression in BB cells. We also found significant differences in the phenotype of the CPCs product with BB-CPCs containing a reduced fibrotic-like CD90+ subpopulation (7% in BB vs 23% in NBB). The B-CPCs showed reduced expression of collagen I and increased expression of collagen III and cardiac genes (MHC, nkx2.5), compared to non-BB (NBB) CPCs. Moreover the BB-CPCs population had a distinctive microRNA expression profile. Hierarchical clustering analysis showed a significant difference between BB and NBB in the global expression profile of the shortlisted miRNAs. The expression profile observed is consistent with reduced fibrotic/mesenchymal features (miR21, miR29a-b-c down-regulation), and enhanced differentiation and regenerative potential (miR1, miR133, miR101, up-regulation) within the BB vs NBB CPCs population. Conclusions: This study supports a preservative effect of BB treatment on the endogenous cardiac regenerative pool, proposing for the first time an anti-fibrotic and pro-commitment mechanism; it suggests novel speculations on BB treatments influence on the quality/quantity of resident CPCs and supports a possible adjuvant role of BB in CPC therapy applications.