Epicardial Transplantation of Autologous Cardiac Micrografts During Coronary Artery Bypass Surgery

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.

Structural and Functional Support by Left Atrial Appendage Transplant to the Left Ventricle after a Myocardial Infarction

“…Based on our previous findings, we hypothesized that the LAA could serve as a regenerative tissue transplant after an MI [21][22][23][24][25][26][27]. The LAA is thin, exhibits a complex structure, and boasts many trabeculae, thus resembling ventricles more than the atria (Figure 1A,B and Supplementary Video S1).…”

“…Our studies on the tissue composition of the murine LAA at the cellular level revealed cellular potential for cardiac regeneration in the LAA, putatively stemming from de novo cardiomyocyte formation and/or the paracrine effect by resident heart tissue macrophages [21,22]. Atrial-appendage-derived cells have been studied, by us and others, in animal models [23] and humans with promising results [24][25][26][27]. Atrial appendage tissue or micrograft transplants provide an autologous cardiac cell source and include all cardiac cell populations with their relevant extracellular matrix support.…”

“…Atrial appendage transplantation has the potential to deliver autologous cardiac cells, including various progenitor cells, in their native environment to the injured tissue for cardiac regeneration [21][22][23][24][25][26][27]. In terms of the LAA, transplantation is further supported based on its characteristics; the most clinically relevant are its size and its potential for extensibility over the infarct area.…”

Autologous atrial appendage micrografts transplanted during coronary artery bypass surgery: design of the AAMS2 randomized, double-blinded, and placebo-controlled trial

“…Cells from the atrial appendages harbour paracrine potential and can induce cardiac regeneration (15)(16)(17)(18). In addition, the appendages can be readily harvested for cell therapies during coronary artery bypass grafting (CABG) (19,20). Recently, we reported the intraoperative grinding of right atrial appendage biopsy to micrografts (AAMs) and their epicardial transplantation safe and feasible during CABG in patients with ischemic HF with reduced ejection fraction (iHFrEF) and myocardial scar visible in cardiac magnetic resonance (CMR) with late gadolinium enhancement (n = 6, Fig.…”

“…Recently, we reported the intraoperative grinding of right atrial appendage biopsy to micrografts (AAMs) and their epicardial transplantation safe and feasible during CABG in patients with ischemic HF with reduced ejection fraction (iHFrEF) and myocardial scar visible in cardiac magnetic resonance (CMR) with late gadolinium enhancement (n = 6, Fig. 1) (19,20). Based on our clinical intraoperative processing of right atrial appendage (RAA) biopsy to AAMs and subsequent micrograft analysis, the method yielded > 90% cellular viability (n = 7) and a cell yield of 9.76 × 10 6 ± 0.53 / g of tissue (n = 11) (20).…”