Changes in Circulating Biomarkers in Patients With Ischemic Heart Failure After Treatment With Autologous Mesenchymal Stromal Cells and c‐Kit‐Positive Cardiac Cells, Alone or in Combination: Results From the Cardiovascular Cell Therapy Research Network CONCERT‐HF Clinical Trial

Journal of the American Heart Association, Volume 15, Issue 9 , May 5, 2026. BackgroundIn ischemic heart failure, the biological mechanisms underlying the benefits of mesenchymal stromal cells (MSCs) and c‐kit–positive cardiac progenitor cells (CPCs) remain incompletely understood.MethodsIn this predefined secondary biomarker analysis of 96 patients from the multicenter, randomized, double‐blind, placebo‐controlled Cardiovascular Cell Therapy Research Network CONCERT‐HF (Combination of Mesenchymal and c‐Kit+ Cardiac Stem Cells as Regenerative Therapy for Heart Failure) trial, plasma biomarkers were measured at baseline and at days 7, 30, and 180.

Changes were assessed using 2‐sample randomization median tests and multivariate 2‐sample Cramér–von Mises tests to evaluate time point–specific and trajectory‐level effects. Complementary longitudinal mixed‐effects models were used to assess treatment×time interactions.ResultsCell therapy induced distinct, time‐dependent biomarker changes.

Significant reductions were observed in TRAIL‐R1 (tumor necrosis factor receptor superfamily member 10A; MSCs+CPCs), IL‐33 (interleukin‐33), and GDF‐15 (growth differentiation factor 15; MSCs, CPCs), PTX3 (pentraxin 3; MSCs, and MSCs+CPCs), TNF‐α (tumor necrosis factor‐alpha; MSCs and MSCs+CPCs), and PDGF‐BB (platelet‐derived growth factor‐BB; all cell therapy groups). VEGF‐A (vascular endothelial growth factor A), HGF (hepatocyte growth factor), and BMP‐9 (bone morphogenetic protein 9) also decreased significantly in the MSCs cohort.

Multivariate 2‐sample Cramér–von Mises test confirmed significant treatment‐related shifts in biomarker trajectories for PTX3, TNF‐α, PDGF‐BB, GDF‐15, BMP‐9, and MMP‐1 (matrix metalloproteinase‐1). Complementary longitudinal mixed‐effects modeling demonstrated significant treatment×time interactions for TNF‐α, MMP‐1, and BMP‐9.

Among individual contrasts, PDGF‐BB showed the most consistent treatment effect, including a reduction in the MSCs group versus placebo at day 30 (estimate, −157.98 [95% CI, −286.04 to −29.91];P=0.01). Time‐specific treatment contrasts for most other biomarkers were modest with wide CIs.

Greater increases in PDGF‐BB at day 180 were associated with smaller improvements in Minnesota Living With Heart Failure Questionnaire scores.ConclusionsMSCs, CPCs, and their combination are associated with selective, time‐dependent modulation of inflammatory and matrix remodeling biomarkers in ischemic heart failure. These findings provide mechanistic insight into cell therapy effects and identify PDGF‐BB, PTX3, TNF‐α, MMP‐1, and BMP‐9 as candidate biomarkers for response monitoring and hypothesis generation in future regenerative trials.RegistrationURL:https://clinicaltrials.gov; Unique Identifier: NCT02501811.