Epicardial Transplantation of Autologous Cardiac Micrografts During Coronary Artery Bypass Surgery

Annu Nummi, Severi Mulari, Juhani A Stewart, Sari Kivistö, Kari Teittinen, Tuomo Nieminen, Milla Lampinen, Tommi Pätilä, Harri Sintonen, Tatu Juvonen, Markku Kupari, Raili Suojaranta, Esko Kankuri, Ari Harjula, Antti Vento, AADC consortium, Annu Nummi, Severi Mulari, Juhani A Stewart, Sari Kivistö, Kari Teittinen, Tuomo Nieminen, Milla Lampinen, Tommi Pätilä, Harri Sintonen, Tatu Juvonen, Markku Kupari, Raili Suojaranta, Esko Kankuri, Ari Harjula, Antti Vento, AADC consortium

Abstract

Background: Cardio-regenerative cell therapies offer additional biologic support to coronary artery bypass surgery (CABG) and are aimed at functionally repairing the myocardium that suffers from or is damaged by ischemia. This non-randomized open-label study assessed the safety and feasibility of epicardial transplantation of atrial appendage micrografts (AAMs) in patients undergoing CABG surgery. Methods: Twelve consecutive patients destined for CABG surgery were included in the study. Six patients received AAMs during their operation and six patients were CABG-operated without AAMs transplantation. Data from 30 elective CABG patients was collected for a center- and time-matched control group. The AAMs were processed during the operation from a biopsy collected from the right atrial appendage. They were delivered epicardially onto the infarct scar site identified in preoperative late gadolinium enhancement cardiac magnetic resonance imaging (CMRI). The primary outcome measures at the 6-month follow-up were (i) patient safety in terms of hemodynamic and cardiac function over time and (ii) feasibility of therapy administration in a clinical setting. Secondary outcome measures were left ventricular wall thickness, change in myocardial scar tissue volume, changes in left ventricular ejection fraction, plasma concentrations of N-terminal pro-B-type natriuretic peptide levels, NYHA class, number of days in hospital and changes in the quality of life. Results: Epicardial transplantation of AAMs was safe and feasible to be performed during CABG surgery. CMRI demonstrated an increase in viable cardiac tissue at the infarct site in patients receiving AAMs treatment. Conclusions and Relevance: Transplantation of AAMs shows good clinical applicability as performed during cardiac surgery, shows initial therapeutic effect on the myocardium and has the potential to serve as a delivery platform for cardiac gene therapies. Trial Registration:ClinicalTrials.gov, identifier: NCT02672163.

Keywords: atrial appendage; autologous micrografts; cell therapy; coronary artery bypass surgery; epicardial cell delivery; ischemic heart failure.

Conflict of interest statement

AN and EK are stakeholders in EpiHeart Ltd. developing medical devices for the operating room. HS is the developer of the 15D. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Nummi, Mulari, Stewart, Kivistö, Teittinen, Nieminen, Lampinen, Pätilä, Sintonen, Juvonen, Kupari, Suojaranta, Kankuri, Harjula, Vento and the AADC consortium.

Figures

Figure 1
Figure 1
Study outline and demographics—study outline and demographics with pre-operative and post-operative data. (A) All patients underwent pre-operative (Pre-op) echocardiography and CMRI. The Study group received AAMs therapy during coronary artery bypass (CABG) surgery, while the Control group I (Control I) only underwent CABG surgery. AAMs were harvested from the right atrial appendage, mechanically isolated, and transplanted intraoperatively (Intra-op). Patients in both groups were examined 3-months post-operatively (Post-op) by echocardiography and 6 months after the operation using CMRI. (B) Demographics, pre- and post-operative data of the AAMs group (AAMs) and both control groups (Control I and Control II). 1ACE, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; CAD, coronary artery disease; CCB, calcium channel blockers; CK-MB, creatine kinase myocardial band; CMRI, cardiac magnetic resonance imaging; COPD, chronic obstructive pulmonary disease; GFR, glomerular filtration rate; MRA, mineralocorticoid receptor antagonists; NT-Pro-BNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; PCI, percutaneous coronary intervention. Results are presented as median (IQR), group comparisons were performed with the Kruskal-Wallis test. Mann Whitney U-test was used for the variables in only Study and Control group I results, or Chi Square for ordinal variables. Significant results after correction (Bonferroni) for multiple comparison are marked by an asterisk (*), with the results of post-hoc between-group analyses found in the text.
Figure 2
Figure 2
Cardiac magnetic resonance imaging—evaluation of function and structure by cardiac magnetic resonance imaging. (A) Comparison of the AAMs group patients with the Control group I patients. For all variables, a preoperative and post-operative value is presented, followed by the absolute change (Δ) of these values. Results presented as median and IQR, group comparison performed with the Mann Whitney U-test (Bonferroni adjusted P of 0.002). (B) Single parameter comparison of post-operative-preoperative change in viable left ventricle thickness at infarct scar site. (C) Single parameter comparison of post-operative-preoperative change in myocardial scar mass. 1EDV, end diastolic volume; EF, ejection fraction; ESV, end systolic volume; LV, left ventricle; FWHM, full width with half maximum; SD, standard deviation.
Figure 3
Figure 3
Infarct site in cardiac magnetic resonance imaging—representative pictures from cardiac magnetic resonance imaging illustrating infarct size and site (white lines) at pre- (A,C) and post-operative (B,D) time-points. (A,B) AAMs group and (C,D) Control group I. Arrow shows an apical thrombus that was removed during the coronary artery bypass surgery.
Figure 4
Figure 4
Graphical presentation of quality of life—health-related quality of life QoL in the AAMs group and the Control group I. (A) Graphical presentation of 15D QoL scores preoperatively and at the 6-month follow-up in the AAMs group. (B) Selected parameters of the 15D QoL in the AAMs group. White bars represent preoperative values, black bars represent values at 6-months follow-up and gray bars represent the respective parameter's 15D QoL score in the general population. (C) Graphical presentation of 15D QoL scores preoperatively and at the 6-month follow-up in the Control group I (Control I). (D) Selected parameters of the 15D QoL in the Control I group. White bars represent preoperative values, black bars represent values at 6-months follow-up and gray bars represent the respective parameter's 15D QoL score in the general population.

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