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

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.

SUBMITTER: Bassetti B

PROVIDER: S-EPMC6137884 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Bassetti Beatrice B Carbucicchio Corrado C Catto Valentina V Gambini Elisa E Rurali Erica E Bestetti Alberto A Gaipa Giuseppe G Belotti Daniela D Celeste Fabrizio F Parma Matteo M Righetti Stefano S Biava Lorenza L Arosio Maurizio M Bonomi Alice A Agostoni Piergiuseppe P Scacciatella Paolo P Achilli Felice F Pompilio Giulio G

Stem cell research & therapy 20180914 1

<h4>Background</h4>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<sup>+</sup> cells (ATMP-CD133) in RA patients, correlating perfusion outcome with cell function.<h4>Methods</h4>In the phase I "Endocavitary Injection of Bone Marrow Derived CD133<sup>+</ ...[more]

PMID: 30217223

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Project description:Whether culture-expanded mesenchymal stem cells or whole bone marrow mononuclear cells are safe and effective in chronic ischemic cardiomyopathy is controversial.To demonstrate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy.A phase 1 and 2 randomized, blinded, placebo-controlled study involving 65 patients with ischemic cardiomyopathy and left ventricular (LV) ejection fraction less than 50% (September 1, 2009-July 12, 2013). The study compared injection of MSCs (n=19) with placebo (n?=?11) and BMCs (n?=?19) with placebo (n?=?10), with 1 year of follow-up.Injections in 10 LV sites with an infusion catheter.Treatment-emergent 30-day serious adverse event rate defined as a composite of death, myocardial infarction, stroke, hospitalization for worsening heart failure, perforation, tamponade, or sustained ventricular arrhythmias.No patient had a treatment-emergent serious adverse events at day 30. The 1-year incidence of serious adverse events was 31.6% (95% CI, 12.6% to 56.6%) for MSCs, 31.6% (95% CI, 12.6%-56.6%) for BMCs, and 38.1% (95% CI, 18.1%-61.6%) for placebo. Over 1 year, the Minnesota Living With Heart Failure score improved with MSCs (-6.3; 95% CI, -15.0 to 2.4; repeated measures of variance, P=.02) and with BMCs (-8.2; 95% CI, -17.4 to 0.97; P=.005) but not with placebo (0.4; 95% CI, -9.45 to 10.25; P=.38). The 6-minute walk distance increased with MSCs only (repeated measures model, P?=?.03). Infarct size as a percentage of LV mass was reduced by MSCs (-18.9%; 95% CI, -30.4 to -7.4; within-group, P?=?.004) but not by BMCs (-7.0%; 95% CI, -15.7% to 1.7%; within-group, P?=?.11) or placebo (-5.2%; 95% CI, -16.8% to 6.5%; within-group, P?=?.36). Regional myocardial function as peak Eulerian circumferential strain at the site of injection improved with MSCs (-4.9; 95% CI, -13.3 to 3.5; within-group repeated measures, P?=?.03) but not BMCs (-2.1; 95% CI, -5.5 to 1.3; P?=?.21) or placebo (-0.03; 95% CI, -1.9 to 1.9; P?=?.14). Left ventricular chamber volume and ejection fraction did not change.Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach.clinicaltrials.gov Identifier: NCT00768066.

Project description:ObjectiveWe tested the hypothesis that direct intramyocardial injection of bone marrow mononuclear cells in patients with non-ischemic dilated cardiomyopathy can improve left ventricular function and physical capacity.MethodsThirty non-ischemic dilated cardiomyopathy patients with left ventricular ejection fraction <35% were randomized at a 1:2 ratio into two groups, control and treated. The bone marrow mononuclear cells group received 1.06±108 bone marrow mononuclear cells through mini-thoracotomy. There was no intervention in the control group. Assessment was carried out through clinical evaluations as well as a 6-min walk test, nuclear magnectic resonance imaging and echocardiogram.ResultsThe bone marrow mononuclear cells group showed a trend toward left ventricular ejection fraction improvement, with magnectic resonance imaging - at 3 months, showing an increase from 27.80±6.86% to 30.13±9.06% (P=0.08) and returning to baseline at 9 months (28.78%, P=0.77). Magnectic resonance imaging showed no changes in left ventricular ejection fraction during follow-up of the control group (28.00±4.32%, 27.42±7.41%, and 29.57±4.50%). Echocardiogram showed left ventricular ejection fraction improved in the bone marrow mononuclear cells group at 3 months, 25.09±3.98 to 30.94±9.16 (P=0.01), and one year, 30.07±7.25% (P=0.001). The control group showed no change (26.1±4.4 vs 26.5±4.7 and 30.2±7.39%, P=0.25 and 0.10, respectively). Bone marrow mononuclear cells group showed improvement in New York Heart Association functional class, from 3.40±0.50 to 2.41±0.79 (P=0.002); patients in the control group showed no change (3.37±0.51 to 2.71±0.95; P=0.17). Six-minute walk test improved in the bone marrow mononuclear cells group (348.00±93.51m at baseline to 370.41±91.56m at 12 months, P=0.66) and there was a non-significant decline in the control group (361.25±90.78m to 330.00±123.42m after 12 months, P=0.66). Group comparisons were non-significant.ConclusionThe trend of intragroup functional and subjective improvement was not confirmed when compared to the control group. Direct intramyocardial application of bone marrow mononuclear cells in non-ischemic dilated cardiomyopathy was not associated with significant changes in left ventricular function. Differences observed within the bone marrow mononuclear cells group could be due to placebo effect or low statistical power.

Dataset Information

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

Publications

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

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