Atrial Appendage Micrograft Transplants to Assist Heart Repair After Cardiac Surgery

Ischemic heart disease (IHD) leads the global mortality statistics. Atherosclerotic plaques in coronary arteries hallmark IHD, drive hypoxia, and may rupture to result in myocardial infarction (MI) and death of contractile cardiac muscle, which is eventually replaced by a scar. Depending on the extent of the damage, dysbalanced cardiac workload often leads to emergence of heart failure (HF).The atrial appendages, enriched with active endocrine and paracrine cardiac cells, has been characterized to contain cells promising in stimulating cardiac regenerative healing.In this AAMS2 randomized controlled and double-blinded trial, we use the patient's own tissue from the right atrial appendage (RAA) for therapy. A piece from the RAA can be safely harvested upon the set-up of the heart and lung machine at the beginning of coronary artery bypass (CABG) surgery. In the AAMS2 trial, a piece of the RAA tissue is processed and utilized as epicardially transplanted atrial appendage micrografts (AAMs) for CABG-support therapy.In our preclinical evaluation, epicardial AAMs transplantation after MI attenuated scarring and improved cardiac function. Proteomics suggested an AAMs-induced glycolytic metabolism, a process associated with an increased regenerative capacity of myocardium. In an open-label clinical trial, we have demonstrated the safety and feasibility of AAMs therapy. Moreover, as this study suggested increased thickness of the viable myocardium in the scarred area, it also provided the first indication of therapeutic benefit.Based on randomization with estimated enrolment of a total of 50 patients with 1:1 group allocation ratio, the piece of RAA tissue is either perioperatively processed to AAMs or cryostored. The AAMs, embedded in a fibrin matrix gel, are placed on an extracellular matrix sheet (ECM), which is then epicardially sutured in place. The location is determined by preoperative late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMRI) to pinpoint the ischemic scar. Study blood samples, transthoracic echocardiography (TTE), and LGE-CMRI are performed before and at 6-month follow-up after the surgery.The trial's primary endpoints focus on changes in cardiac fibrosis as evaluated by LGE-CMRI and circulating levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP). Secondary endpoints center on other efficacy parameters, as well as both safety and feasibility of the therapy.

Inclusion Criteria:Informed consent obtainedLeft ventricular ejection fraction (LVEF) between ≥ 15% and ≤ 40% at recruitment (transthoracic echocardiography)New York Heart Association (NYHA) Class II-IV heart failure symptomsExclusion Criteria:Heart failure due to left ventricular outflow tract obstructionHistory of life-threatening and possibly repeating ventricular arrhythmias or resuscitation, or an implantable cardioverter-defibrillatorStroke or other disabling condition within 3 months before screeningSevere valve disease or scheduled valve surgeryRenal dysfunction (GFR <45 ml/min/1.73m2)Other disease limiting life expectancyContraindications for coronary angiogram or LGE-CMRIParticipation in some other clinical trialScreening Failure:After optimization of medications, no visible scar and LVEF ≥ 50% in preoperative LGE-CMRIPreoperative LGE-CMRI has not been performed prior scheduled CABG