Int J Cardiol. 2013 Dec 10;170(2):246-51. doi: 10.1016/j.ijcard.2013.10.079. Epub 2013 Oct 28.
Autotransplantation of mesenchymal stromal cells from bone-marrow to heart in patients with severe stable coronary artery disease and refractory angina–final 3-year follow-up.
1Cardiac Stem Cell Laboratory, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Cardiac Catheterization Laboratory 2014, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
BACKGROUND: The study assessed long-term safety and efficacy of intramyocardial injection of autologous bone-marrow derived mesenchymal stromal cells (BMMSCs) in patients with severe stable coronary artery disease (CAD) and refractory angina.
METHODS: Thirty-one patients with severe stable CAD and refractory angina were included. Patients had reversible myocardial ischemia and no further revascularization options. Autologous BMMSCs were isolated, culture expanded and stimulated with vascular endothelial growth-factor to facilitate endothelial differentiation. BMMSCs were injected into an ischemic, viable region of the myocardium. Patients were followed for 3 years.
RESULTS: We found significant clinical improvements in exercise time (p=0.0016), angina class (CCS) (p<0.0001), weekly number of angina attacks (p<0.0001) and use of nitroglycerine from (p=0.0017). In the Seattle Angina Questionnaire there were significant improvements in physical limitation score, angina stability score, angina frequency score and quality of life score (all p<0.0001). When comparing all hospital admissions from 3 years before to 3 years after treatment, we observed highly reduced admission rates for stable angina (p<0.0001), revascularization (p=0.003) and overall cardiovascular disease (p<0.0001). No early or late side-effects of the treatment were observed.
CONCLUSIONS: The final 3-year follow-up data after intramyocardial injection of autologous BMMSCs, in patients with severe CAD and refractory angina, demonstrated sustained clinical effects, reduced hospital admissions for cardiovascular disease and excellent long-term safety. The results indicate that autotransplantation of BMMSCs to the heart does not only improve symptoms but also slows down disease progression. TRIAL REGISTRATION: ClinicalTrials.gov NCT00260338.
KEYWORDS: Angiogenesis; Chronic myocardial ischemia; Mesenchymal stromal cell; Refractory angina; Stem cell; Stem cell therapy
Cell Transplant. 2013;22(3):521-8. doi: 10.3727/096368912X636830. Epub 2012 Apr 2.
Direct intramyocardial mesenchymal stromal cell injections in patients with severe refractory angina: one-year follow-up.
1Cardiac Stem Cell Laboratory and Catheterization Laboratory, The Hearth Centre, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark.
In patients with stable coronary artery disease (CAD) and refractory angina, we performed direct intramyocardial injections of autologous mesenchymal stromal cells (MSC) and followed the safety and efficacy of the treatment for 12 months. A total of 31 patients with stable CAD, moderate to severe angina, normal left ventricular ejection fraction, and no further revascularization options were included. Bone marrow MSCs were isolated and culture expanded for 6-8 weeks and then stimulated with vascular endothelial growth factor (VEGF) for 1 week. The 12-month follow-up demonstrated that it was safe to culture expand MSCs and use the cells for clinical treatment. The patients’ maximal metabolic equivalent (MET) during exercise increased from 4.23 MET at baseline to 4.72 MET at 12-month follow-up (p < 0.001), Canadian Cardiovascular Society Class (CCS) was reduced from 3.0 to 0.8 (p < 0.001), angina attacks per week from 13.8 to 3.2 (p < 0.001), and nitroglycerin consumption from 10.7 to 3.4 per week (p < 0.001). In addition, Seattle Angina Questionnaire (SAQ) evaluations demonstrated highly significant improvements in physical limitation, angina stability, angina frequency, and quality of life (p < 0.001 for all). It is safe in the intermediate/long term to treat patients with stable CAD using autologous culture expanded MSCs. Previously reported, early and highly significant improvements in exercise capacity and clinical symptoms persist after 12 months. The results are encouraging, and a larger controlled study is warranted.
J Mol Cell Cardiol. 2011 Feb;50(2):258-65. doi: 10.1016/j.yjmcc.2010.06.010. Epub 2010 Jun 30.
Cardiac cell therapy: lessons from clinical trials.
1Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiovascular Surgery, Université Paris Descartes, INSERM U 633, Paris, France.
Cardiac cell therapy has now been in clinical use since 10 years. Both autologous skeletal myoblasts and bone marrow-derived different cell subsets (mononuclear cells, hematopoietic progenitors, mesenchymal stem cells) have been investigated in different settings (acute myocardial infarction, refractory angina and chronic heart failure). Despite the huge variability in cell processing techniques, dosing, timing of delivery and route for cell transfer, some lessons can yet be drawn, primarily from randomized controlled trials and summarized as follows: Techniques used for cell preparation are reasonably well controlled although better standardization and improvement in scale-up procedures remain necessary; cell therapy is overall safe, with the caveat of ventricular arrhythmias which still require careful scrutinization; the cell type needs to be tailored to the primary clinical indication, whereas the paracrine effects of bone marrow cells may be therapeutically efficacious for limitation of remodelling or relief of angina, only cells endowed with a true cardiomyogenic differentiation potential are likely to effect regeneration of chronic scars; autologous cells are primarily limited by their variable and unpredictable functionality, thereby calling attention to banked, consistent and readily available allogeneic cell products provided the immunological issues inherent in their use can be satisfactorily addressed; regardless of the cell type, a meaningful and sustained therapeutic benefit is unlikely to occur until cell transfer and survival techniques are improved to allow greater engraftment rates; and trial end points probably need to be reassessed to focus on mechanistic issues or hard end points depending on whether new or already extensively used cells are investigated. Hopefully, these lessons may serve as a building block whose incorporation in the design of second-generation trials will help making them more clinically successful. This article is part of a special issue entitled, “Cardiovascular StemCells Revisited”.