Epicardial delivery of autologous atrial appendage micrografts during coronary artery bypass surgery-safety and feasibility study

Annu Nummi, Tuomo Nieminen, Tommi Pätilä, Milla Lampinen, Miia L Lehtinen, Sari Kivistö, Miia Holmström, Erika Wilkman, Kari Teittinen, Mika Laine, Juha Sinisalo, Markku Kupari, Esko Kankuri, Tatu Juvonen, Antti Vento, Raili Suojaranta, Ari Harjula, AADC consortium, Ari Harjula, Antti Vento, Juha Sinisalo, Mika Laine, Markku Kupari, Tatu Juvonen, Kari Teittinen, Annu Nummi, Miia Lehtinen, Tuomo Nieminen, Tommi Pätilä, Eero Mervaala, Esko Kankuri, Milla Lampinen, Sari Kivistö, Miia Holmström, Raili Suojaranta, Erika Wilkman, Jari Laurikka, Shengshou Hu, Zhe Zheng, Xie Yanbo, Annu Nummi, Tuomo Nieminen, Tommi Pätilä, Milla Lampinen, Miia L Lehtinen, Sari Kivistö, Miia Holmström, Erika Wilkman, Kari Teittinen, Mika Laine, Juha Sinisalo, Markku Kupari, Esko Kankuri, Tatu Juvonen, Antti Vento, Raili Suojaranta, Ari Harjula, AADC consortium, Ari Harjula, Antti Vento, Juha Sinisalo, Mika Laine, Markku Kupari, Tatu Juvonen, Kari Teittinen, Annu Nummi, Miia Lehtinen, Tuomo Nieminen, Tommi Pätilä, Eero Mervaala, Esko Kankuri, Milla Lampinen, Sari Kivistö, Miia Holmström, Raili Suojaranta, Erika Wilkman, Jari Laurikka, Shengshou Hu, Zhe Zheng, Xie Yanbo

Abstract

Background: The atrial appendages are a tissue reservoir for cardiac stem cells. During on-pump coronary artery bypass graft (CABG) surgery, part of the right atrial appendage can be excised upon insertion of the right atrial cannula of the heart-lung machine. In the operating room, the removed tissue can be easily cut into micrografts for transplantation. This trial aims to assess the safety and feasibility of epicardial transplantation of atrial appendage micrografts in patients undergoing CABG surgery.

Methods/design: Autologous cardiac micrografts are made from leftover right atrial appendage during CABG of 6 patients. Atrial appendage is mechanically processed to micrografts consisting of atrial appendage-derived cells (AADCs) and their extracellular matrix (ECM). The micrografts are epicardially transplanted in a fibrin gel and covered with a tissue-engineered ECM sheet. Parameters including echocardiography-reflecting cardiac insufficiency-are studied pre- and post-operatively as well as at 3 and 6 months of the follow-up. Cardiac functional magnetic resonance imaging is performed preoperatively and at 6-month follow-up. The primary outcome measures are patient safety in terms of hemodynamic and cardiac function over time and feasibility of therapy administration in a clinical setting. Secondary outcome measures are left ventricular wall thickness, change in the amount of myocardial scar tissue, changes in left ventricular ejection fraction, plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, New York Heart Association class, days in hospital, and changes in the quality of life. Twenty patients undergoing routine CAGB surgery will be recruited to serve as a control group.

Discussion: This study aims to address the surgical feasibility and patient safety of epicardially delivered atrial appendage micrografts during CABG surgery. Delivery of autologous micrografts and AADCs has potential applications for cell and cell-based gene therapies.

Trial registration: ClinicalTrials.gov Identifier: NCT02672163. Date of registration: 02.02.2016.

Keywords: Atrial appendage; Autologous micrografts; Cell therapy; Coronary artery bypass surgery; Epicardial cell delivery; Heart failure.

Conflict of interest statement

The AADC consortium has been focusing on the cell therapy as a treatment for heart failure for many years. Its knowledge is based on multidisciplinary cooperation between authorities and several previous studies in this field.The trial protocol has been evaluated and approved by the Surgical Ethics Committee of the Hospital District of Helsinki and Uusimaa (number 180/13/03/02/13). Informed and written consent to participate in the study will be obtained by the main researcher from all participants.Informed and written consent for publication will be obtained from all participants.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
a Preparing the AADC-sheet. (A) The atrial appendage tissue is processed with cell therapy tissue homogenizer (Rigenera-system). (B) The micrografts are secured to extracellular matrix sheet (Cormatrix®) by using a fibrin sealant (Tisseel™). (C) The AADC sheet is placed to the myocardium in the location of infarction scar (animal model). b Administration of therapy during CABG surgery. Figure reproduced from our article by Lampinen et al. (Current Gene Therapy, 2015)
Fig. 2
Fig. 2
Timeline of the study indicating enrollment and follow-up as well as timing of laboratory tests, MRI, and echocardiographic imaging modalities

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