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Laser-supported CD133+ cell therapy in patients with ischemic cardiomyopathy: initial results from a prospective phase I multicenter trial.

ABSTRACT: This study evaluates the safety, principal feasibility and restoration potential of laser-supported CD133+ intramyocardial cell transplantation in patients with ischemic cardiomyopathy.Forty-two patients with severe ischemic cardiomyopathy (left ventricular ejection fraction (LVEF) >15% and <35%) were included in this prospective multicenter phase I trial. They underwent coronary artery bypass grafting (CABG) with subsequent transepicardial low-energy laser treatment and autologous CD133+ cell transplantation, and were followed up for 12 months. To evaluate segmental myocardial contractility as well as perfusion and to identify the areas of scar tissue, cardiac MRI was performed at 6 months and compared to the preoperative baseline. In addition, clinical assessment comprising of CCS scoring, blood and physical examination was performed at 3, 6 and 12 months, respectively.Intraoperative cell isolation resulted in a mean cell count of 9.7±1.2×106. Laser treatment and subsequent CD133+ cell therapy were successfully and safely carried out in all patients and no procedure-related complications occurred. At 6 months, the LVEF was significantly increased (29.7±1.9% versus 24.6±1.5% with p?=?0.004). In addition, freedom from angina was achieved, and quality of life significantly improved after therapy (p<0.0001). Interestingly, an extended area of transmural delayed enhancement (>3 myocardial segments) determined in the preoperative MRI was inversely correlated with a LVEF increase after laser-supported cell therapy (p?=?0.024).This multicenter trial demonstrates that laser-supported CD133+ cell transplantation is safe and feasible in patients with ischemic cardiomyopathy undergoing CABG, and in most cases, it appears to significantly improve the myocardial function. Importantly, our data show that the beneficial effect was significantly related to the extent of transmural delayed enhancement, suggesting that MRI-guided selection of patients is mandatory to ensure the effectiveness of the therapy.EudraCT 2005-004051-35) Controlled-Trials.com ISRCTN49998633.

SUBMITTER: Assmann A

PROVIDER: S-EPMC4084817 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Laser-supported CD133+ cell therapy in patients with ischemic cardiomyopathy: initial results from a prospective phase I multicenter trial.

Assmann Alexander A Heke Michael M Kröpil Patric P Ptok Lena L Hafner Dieter D Ohmann Christian C Martens Andreas A Karluβ Antje A Emmert Maximilian Y MY Kutschka Ingo I Sievers Hans-Hinrich HH Klein Hans-Michael HM

PloS one 20140707 7

<h4>Objectives</h4>This study evaluates the safety, principal feasibility and restoration potential of laser-supported CD133+ intramyocardial cell transplantation in patients with ischemic cardiomyopathy.<h4>Methods</h4>Forty-two patients with severe ischemic cardiomyopathy (left ventricular ejection fraction (LVEF) >15% and <35%) were included in this prospective multicenter phase I trial. They underwent coronary artery bypass grafting (CABG) with subsequent transepicardial low-energy laser tre ...[more]

PMID: 25000346

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Project description:Backgroundc-kit-positive, lineage-negative cardiac stem cells (CSCs) improve post-infarction left ventricular (LV) dysfunction when administered to animals. We undertook a phase 1 trial (Stem Cell Infusion in Patients with Ischemic cardiOmyopathy [SCIPIO]) of autologous CSCs for the treatment of heart failure resulting from ischaemic heart disease.MethodsIn stage A of the SCIPIO trial, patients with post-infarction LV dysfunction (ejection fraction [EF] ?40%) before coronary artery bypass grafting were consecutively enrolled in the treatment and control groups. In stage B, patients were randomly assigned to the treatment or control group in a 2:3 ratio by use of a computer-generated block randomisation scheme. 1 million autologous CSCs were administered by intracoronary infusion at a mean of 113 days (SE 4) after surgery; controls were not given any treatment. Although the study was open label, the echocardiographic analyses were masked to group assignment. The primary endpoint was short-term safety of CSCs and the secondary endpoint was efficacy. A per-protocol analysis was used. This study is registered with ClinicalTrials.gov, number NCT00474461.FindingsThis study is still in progress. 16 patients were assigned to the treatment group and seven to the control group; no CSC-related adverse effects were reported. In 14 CSC-treated patients who were analysed, LVEF increased from 30·3% (SE 1·9) before CSC infusion to 38·5% (2·8) at 4 months after infusion (p=0·001). By contrast, in seven control patients, during the corresponding time interval, LVEF did not change (30·1% [2·4] at 4 months after CABG vs 30·2% [2·5] at 8 months after CABG). Importantly, the salubrious effects of CSCs were even more pronounced at 1 year in eight patients (eg, LVEF increased by 12·3 ejection fraction units [2·1] vs baseline, p=0·0007). In the seven treated patients in whom cardiac MRI could be done, infarct size decreased from 32·6 g (6·3) by 7·8 g (1·7; 24%) at 4 months (p=0·004) and 9·8 g (3·5; 30%) at 1 year (p=0·04).InterpretationThese initial results in patients are very encouraging. They suggest that intracoronary infusion of autologous CSCs is effective in improving LV systolic function and reducing infarct size in patients with heart failure after myocardial infarction, and warrant further, larger, phase 2 studies.FundingUniversity of Louisville Research Foundation and National Institutes of Health.

Project description:BackgroundGlaucoma is a leading cause of global blindness, especially preventable blindness. The increased prevalence of glaucoma has led to a growing demand for newer, safer, more rapid, and simpler treatments for the reduction of intraocular pressure (IOP). In this study, we evaluated the safety and feasibility of performing filtration glaucoma surgery with an Ab-Interno Er:YAG laser in rabbits.MethodsNine New Zealand White rabbits age 16 weeks were studied. After subconjunctival injection of mitomycin C (MMC), a novel Ab-Interno Er:YAG laser probe was inserted into the anterior chamber (AC) through a clear corneal 1 mm paracentesis and directed at the trabecular meshwork adjacent to the MMC injection area. A pulsed laser beam was applied to create a patent sclerostomy connecting the AC to the subconjuctival space, resulting in a filtering bleb. The laser system used was the Er:YAG laser system - LAS25-FCU, (Pantec Biosolutions AG, Liechtenstein). Parameters used: Wave lengh: 2940 nm, Pulse length: 100-400 μsec,frequency: 250 Hz. Average laser power in accordance to the fiber tip diameter: 0.85 W(range 0.8-0.92 W). Complete ocular exams, including IOP measurements, were performed on 1, 7, 14, and 23 days postoperatively. Three rabbits were sacrificed on days 1, 14, and 23, and histological examinations were performed on all nine eyes.ResultsAll procedures resulted in a functional medium-large superior bleb without significant complications. The bleb was sustained in all rabbits by day 14 and in one of the three rabbits that reached the last follow-up at 23 days. No cases of postoperative hypotony were observed. There was a transient significant reduction in mean IOP on postoperative days 5 and 7 (P = 0.028). Histopathological analysis revealed a patent full-thickness scleral tunnel with only a minor degree of surrounding coagulation necrosis.ConclusionsThe Ab-Interno laser sclerostomy procedure is potentially safe and effective based on initial experience in an in-vivo rabbit animal model.

Project description: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.

Dataset Information

Laser-supported CD133+ cell therapy in patients with ischemic cardiomyopathy: initial results from a prospective phase I multicenter trial.

Publications

Laser-supported CD133+ cell therapy in patients with ischemic cardiomyopathy: initial results from a prospective phase I multicenter trial.

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