Linking cell function with perfusion: insights from the transcatheter delivery of bone marrow-derived CD133 + cells in ischemic refractory cardiomyopathy trial (RECARDIO)

Stem Cell Res Ther. 2018 Sep 14;9(1):235. doi: 10.1186/s13287-018-0969-z.

Abstract

Background: Cell therapy with bone marrow (BM)-derived progenitors has emerged as a promising therapeutic for refractory angina (RA) patients. In the present study, we evaluated the safety and preliminary efficacy of transcatheter delivery of autologous BM-derived advanced therapy medicinal product CD133+ cells (ATMP-CD133) in RA patients, correlating perfusion outcome with cell function.

Methods: In the phase I "Endocavitary Injection of Bone Marrow Derived CD133+ Cells in Ischemic Refractory Cardiomyopathy" (RECARDIO) trial, a total of 10 patients with left ventricular (LV) dysfunction (ejection fraction ≤ 45%) and evidence of reversible ischemia, as assessed by single-photon emission computed tomography (SPECT), underwent BM aspiration and fluoroscopy-based percutaneous endomyocardial delivery of ATMP-CD133. Patients were evaluated at 6 and 12 months for safety and preliminary efficacy endpoints. ATMP-CD133 samples were used for in vitro correlations.

Results: Patients were treated safely with a mean number of 6.57 ± 3.45 × 106 ATMP-CD133. At 6-month follow-up, myocardial perfusion at SPECT was significantly ameliorated in terms of changes in summed stress (from 18.2 ± 8.6 to 13.8 ± 7.8, p = 0.05) and difference scores (from 12.0 ± 5.3 to 6.1 ± 4.0, p = 0.02) and number of segments with inducible ischemia (from 7.3 ± 2.2 to 4.0 ± 2.7, p = 0.003). Similarly, Canadian Cardiovascular Society and New York Heart Association classes significantly improved at follow-up vs baseline (p ≤ 0.001 and p = 0.007, respectively). Changes in summed stress score changes positively correlated with ATMP-CD133 release of proangiogenic cytokines HGF and PDGF-bb (r = 0.80, p = 0.009 and r = 0.77, p = 0.01, respectively) and negatively with the proinflammatory cytokines RANTES (r = - 0.79, p = 0.01) and IL-6 (r = - 0.76, p = 0.02).

Conclusion: Results of the RECARDIO trial suggested safety and efficacy in terms of clinical and perfusion outcomes in patients with RA and LV dysfunction. The observed link between myocardial perfusion improvements and ATMP-CD133 secretome may represent a proof of concept for further mechanistic investigations.

Trial registration: ClinicalTrials.gov, NCT02059681 . Registered 11 February 2014.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen / genetics
  • AC133 Antigen / metabolism
  • Aged
  • Angina Pectoris / diagnostic imaging
  • Angina Pectoris / genetics
  • Angina Pectoris / pathology
  • Angina Pectoris / therapy*
  • Becaplermin / genetics
  • Becaplermin / metabolism
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism
  • Bone Marrow Transplantation / methods*
  • Cardiomyopathies / diagnostic imaging
  • Cardiomyopathies / genetics
  • Cardiomyopathies / pathology
  • Cardiomyopathies / therapy*
  • Chemokine CCL5 / genetics
  • Chemokine CCL5 / metabolism
  • Endocardium
  • Gene Expression
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Male
  • Myocardial Ischemia / diagnostic imaging
  • Myocardial Ischemia / genetics
  • Myocardial Ischemia / pathology
  • Myocardial Ischemia / therapy*
  • Patient Safety
  • Percutaneous Coronary Intervention / methods*
  • Prospective Studies
  • Tomography, Emission-Computed, Single-Photon
  • Transplantation, Autologous
  • Treatment Outcome
  • Ventricular Dysfunction, Left / diagnostic imaging
  • Ventricular Dysfunction, Left / genetics
  • Ventricular Dysfunction, Left / pathology
  • Ventricular Dysfunction, Left / therapy*

Substances

  • AC133 Antigen
  • CCL5 protein, human
  • Chemokine CCL5
  • HGF protein, human
  • IL6 protein, human
  • Interleukin-6
  • PROM1 protein, human
  • Becaplermin
  • Hepatocyte Growth Factor

Associated data

  • ClinicalTrials.gov/NCT02059681