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Intramyocardial bone marrow cell injection does not lead to functional improvement in patients with chronic ischaemic heart failure without considerable ischaemia.

ABSTRACT: BACKGROUND:It has been suggested that bone marrow cell injection may have beneficial effects in patients with chronic ischaemic heart disease. However, previous trials have led to discrepant results of cell-based therapy in patients with chronic heart failure. The aim of this study was to evaluate the efficacy of intramyocardial injection of mononuclear bone marrow cells in patients with chronic ischaemic heart failure with limited stress-inducible myocardial ischaemia. METHODS AND RESULTS:This multicentre, randomised, placebo-controlled trial included 39 patients with no-option chronic ischaemic heart failure with a follow-up of 12 months. A total of 19 patients were randomised to autologous intramyocardial bone marrow cell injection (cell group) and 20 patients received a placebo injection (placebo group). The primary endpoint was the group difference in change of left ventricular ejection fraction, as determined by single-photon emission tomography. On follow-up at 3 and 12 months, change of left ventricular ejection fraction in the cell group was comparable with change in the placebo group (P?=?0.47 and P?=?0.08, respectively). Also secondary endpoints, including left ventricle volumes, myocardial perfusion, functional and clinical parameters did not significantly change in the cell group as compared to placebo. Neither improvement was demonstrated in a subgroup of patients with stress-inducible ischaemia (P?=?0.54 at 3?month and P?=?0.15 at 12-month follow-up). CONCLUSION:Intramyocardial bone marrow cell injection does not improve cardiac function, nor functional and clinical parameters in patients with severe chronic ischaemic heart failure with limited stress-inducible ischaemia. CLINICAL TRIAL REGISTRATION:NTR2516.

SUBMITTER: Mann I

PROVIDER: S-EPMC6352621 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Intramyocardial bone marrow cell injection does not lead to functional improvement in patients with chronic ischaemic heart failure without considerable ischaemia.

Mann I I Tseng C C S CCS Rodrigo S F SF Koudstaal S S van Ramshorst J J Beeres S L SL Dibbets-Schneider P P de Geus-Oei L F LF Lamb H J HJ Wolterbeek R R Zwaginga J J JJ Fibbe W E WE Westinga K K Bax J J JJ Doevendans P A PA Schalij M J MJ Chamuleau S A J SAJ Atsma D E DE

Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation 20190201 2

<h4>Background</h4>It has been suggested that bone marrow cell injection may have beneficial effects in patients with chronic ischaemic heart disease. However, previous trials have led to discrepant results of cell-based therapy in patients with chronic heart failure. The aim of this study was to evaluate the efficacy of intramyocardial injection of mononuclear bone marrow cells in patients with chronic ischaemic heart failure with limited stress-inducible myocardial ischaemia.<h4>Methods and re ...[more]

PMID: 30569306

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Project description:The phase III clinical trial PERFECT was designed to assess clinical safety and efficacy of intramyocardial CD133+ bone marrow stem cell treatment combined with CABG for induction of cardiac repair.Multicentre, double-blinded, randomised placebo controlled trial.The study was conducted across six centres in Germany October 2009 through March 2016 and stopped due slow recruitment after positive interim analysis in March 2015.Post-infarction patients with chronic ischemia and reduced LVEF (25-50%).Eighty-two patients were randomised to two groups receiving intramyocardial application of 5ml placebo or a suspension of 0.5-5×106 CD133+.Primary endpoint was delta (?) LVEF at 180days (d) compared to baseline measured in MRI.Safety (n=77): 180d survival was 100%, MACE n=2, SAE n=49, without difference between placebo and CD133+. Efficacy (n=58): The LVEF improved from baseline LVEF 33.5% by +9.6% at 180d, p=0.001 (n=58). Treatment groups were not different in ?LVEF (ANCOVA: Placebo +8.8% vs. CD133+ +10.4%, ?CD133+vs placebo +2.6%, p=0.4).Responders (R) classified by ?LVEF?5% after 180d were 60% of the patients (35/58) in both treatment groups. ?LVEF in ANCOVA was +17.1% in (R) vs. non-responders (NR) (?LVEF 0%, n=23). NR were characterized by a preoperative response signature in peripheral blood with reduced CD133+ EPC (RvsNR: p=0.005) and thrombocytes (p=0.004) in contrast to increased Erythropoeitin (p=0.02), and SH2B3 mRNA expression (p=0.073). Actuarial computed mean survival time was 76.9±3.32months (R) vs. +72.3±5.0months (NR), HR 0.3 [Cl 0.07-1.2]; p=0.067.Using a machine learning 20 biomarker response parameters were identified allowing preoperative discrimination with an accuracy of 80% (R) and 84% (NR) after 10-fold cross-validation.The PERFECT trial analysis demonstrates that the regulation of induced cardiac repair is linked to the circulating pool of CD133+ EPC and thrombocytes, associated with SH2B3 gene expression. Based on these findings, responders to cardiac functional improvement may be identified by a peripheral blood biomarker signature.ClinicalTrials.govNCT00950274.

Project description:Injectable biomaterials have been evaluated as potential new therapies for myocardial infarction (MI) and heart failure. These materials have improved left ventricular (LV) geometry and ejection fraction, yet there remain concerns that biomaterial injection may create a substrate for arrhythmia. Since studies of this risk are lacking, we utilized optical mapping to assess the effects of biomaterial injection and interstitial spread on cardiac electrophysiology. Healthy and infarcted rat hearts were injected with a model poly(ethylene glycol) hydrogel with varying degrees of interstitial spread. Activation maps demonstrated delayed propagation of action potentials across the LV epicardium in the hydrogel-injected group when compared to saline and no-injection groups. However, the degree of the electrophysiological changes depended on the spread characteristics of the hydrogel, such that hearts injected with highly spread hydrogels showed no conduction abnormalities. Conversely, the results of this study indicate that injection of a hydrogel exhibiting minimal interstitial spread may create a substrate for arrhythmia shortly after injection by causing LV activation delays and reducing gap junction density at the site of injection. Thus, this work establishes site of delivery and interstitial spread characteristics as important factors in the future design and use of biomaterial therapies for MI treatment.Statement of significanceBiomaterials for treating myocardial infarction have become an increasingly popular area of research. Within the past few years, this work has transitioned to some large animals models, and Phase I & II clinical trials. While these materials have preserved/improved cardiac function the effect of these materials on arrhythmogenesis, which is of considerable concern when injecting anything into the heart, has yet to be understood. Our manuscript is therefore a first of its kind in that it directly examines the potential of an injectable material to create a substrate for arrhythmias. This work suggests that site of delivery and distribution in the tissue are important criteria in the design and development of future biomaterial therapies for myocardial infarction treatment.

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Intramyocardial bone marrow cell injection does not lead to functional improvement in patients with chronic ischaemic heart failure without considerable ischaemia.

Publications

Intramyocardial bone marrow cell injection does not lead to functional improvement in patients with chronic ischaemic heart failure without considerable ischaemia.

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