Improvement of Local Cell Delivery Using Helix Transendocardial Delivery Catheter in a Porcine Heart

Mitsutake, Yoshiaki; Pyun, Wook Bum; Rouy, Didier; Foo, Cheryl Wong Po; Stertzer, Simon H.; Altman, Peter; Ikeno, Fumiaki

doi:10.1536/ihj.16-179

Cited by 24 publications

(11 citation statements)

References 31 publications

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“…Additionally, reliable cell delivery systems also need to be developed as with other cell therapy. 33) In summary, HCN4-overexpressing mESC-CMs produced a new ectopic rhythm. The results suggest that HCN4 overexpression can improve the pacemaking ability of mESC-CMs in vivo and that HCN4-overexpressing mESC-CMs can partially function as a biological pacemaker.…”

Section: Discussionmentioning

confidence: 92%

HCN4-Overexpressing Mouse Embryonic Stem Cell-Derived Cardiomyocytes Generate a New Rapid Rhythm in Rats with Bradycardia

et al. 2018

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A biological pacemaker is expected to solve the persisting problems of an artificial cardiac pacemaker including short battery life, lead breaks, infection, and electromagnetic interference. We previously reported HCN4 overexpression enhances pacemaking ability of mouse embryonic stem cell-derived cardiomyocytes (mESC-CMs) in vitro. However, the effect of these cells on bradycardia in vivo has remained unclear. Therefore, we transplanted HCN4-overexpressing mESC-CMs into bradycardia model animals and investigated whether they could function as a biological pacemaker. The rabbit Hcn4 gene was transfected into mouse embryonic stem cells and induced HCN4-overexpressing mESC-CMs. Non-cardiomyocytes were removed under serum/glucose-free and lactate-supplemented conditions. Cardiac balls containing 5 × 10 mESC-CMs were made by using the hanging drop method. One hundred cardiac balls were injected into the left ventricular free wall of complete atrioventricular block (CAVB) model rats. Heart beats were evaluated using an implantable telemetry system 7 to 30 days after cell transplantation. The result showed that ectopic ventricular beats that were faster than the intrinsic escape rhythm were often observed in CAVB model rats transplanted with HCN4-overexpressing mESC-CMs. On the other hand, the rats transplanted with non-overexpressing mESC-CMs showed sporadic single premature ventricular contraction but not sustained ectopic ventricular rhythms. These results indicated that HCN4-overexpressing mESC-CMs produce rapid ectopic ventricular rhythms as a biological pacemaker.

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Section: Discussionmentioning

confidence: 92%

HCN4-Overexpressing Mouse Embryonic Stem Cell-Derived Cardiomyocytes Generate a New Rapid Rhythm in Rats with Bradycardia

et al. 2018

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“…Overall, in our experience, the fluoroscopy-based approach has confirmed feasibility, safety and practicality as previously reported in larger studies [ 44 , 45 ]. Moreover, the unique design of the Helical Infusion Catheter has been recently proved to provide a cell retention 3-fold higher than a straight needle approach [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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BackgroundCell 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.MethodsIn 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.ResultsPatients 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).ConclusionResults 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 registrationClinicalTrials.gov, NCT02059681. Registered 11 February 2014.

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“…CardiAMP HF is the first investigational cell therapy trial to test a multi-step, point of care kit to harvest, isolate and deliver high dose autologous BM MNC in post MI HF patients who were selected based on a bone marrow potency. This kit consists of tools to i) collect the 5 mL bone marrow sample for the cell potency assay, ii) harvest and process 60 mL of BM MNC for transendocardial injections and iii) deliver isolated BM MNCs using innovative, corkscrew shaped needle tipped transendocardial injection catheters that are designed to ensure high cell retention in the myocardium [25,26].…”

Section: Autologous Bone Marrow Mononuclear Cell Treatmentmentioning

confidence: 99%

Point of care, bone marrow mononuclear cell therapy in ischemic heart failure patients personalized for cell potency: 12-month feasibility results from CardiAMP heart failure roll-in cohort

Raval

Johnston

Duckers

et al. 2021

International Journal of Cardiology

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Heart failure following myocardial infarction (MI) is a potentially lethal problem with a staggering incidence. The CardiAMP Heart Failure trial represents the first attempt to personalize marrow-derived cell-based therapy to individuals with cell characteristics associated with beneficial responses in prior trials. Before the initiation of the randomized pivotal trial, an open-label "roll-in cohort" was completed to ensure the feasibility of the protocol's procedures. Methods: Patients with chronic post-MI heart failure (NYHA class II-III) receiving stable, guideline-directed medical therapy with a left ventricular ejection fraction between 20 and 40% were eligible. Two weeks prior to treatment, a~5 mL bone marrow aspiration was performed to examine "cell potency". On treatment day, a 60 mL bone marrow aspiration, bone marrow mononuclear cell (BM MNC) enrichment and transendocardial injection of 200 million BM MNC's was performed in a single, point of care encounter. Patients were then followed to assess clinical outcomes. Results: The cell potency small volume bone marrow aspirate, the 60 mL bone marrow aspirate, and transendocardial injections were well tolerated in 10 patients enrolled. There were no serious adverse events related to bone marrow aspiration or cell delivery. Improvement in 6-min walk distance was observed at 6 months (+47.8 m, P = 0.01) and trended to improvement at 12 months (+46.4, P = 0.06). Similarly, trends to improved NYHA heart failure functional class, quality of life, left ventricular ejection fraction and recruitment of previously akinetic left ventricular wall segments were observed. Conclusion: All CardiAMP HF protocol procedures were feasible and well tolerated. Favorable functional, echo and quality of life trends suggest this approach may offer promise for patients with post MI heart failure. The randomized CardiAMP Heart Failure pivotal trial is underway to confirm the efficacy of this approach.

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Improvement of Local Cell Delivery Using Helix Transendocardial Delivery Catheter in a Porcine Heart

Cited by 24 publications

References 31 publications

HCN4-Overexpressing Mouse Embryonic Stem Cell-Derived Cardiomyocytes Generate a New Rapid Rhythm in Rats with Bradycardia

HCN4-Overexpressing Mouse Embryonic Stem Cell-Derived Cardiomyocytes Generate a New Rapid Rhythm in Rats with Bradycardia

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

Point of care, bone marrow mononuclear cell therapy in ischemic heart failure patients personalized for cell potency: 12-month feasibility results from CardiAMP heart failure roll-in cohort

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