Early safety and feasibility of atrial appendage-derived micrografts for the treatment of ischemic heart failure

Cardiovascular diseases are the leading causes of death worldwide. Ischemic heart failure due to coronary artery disease is one of the most common reasons for mortality. Drug therapy, transcatheter procedures, and surgery cannot restore the functional cell loss of the dead myocardium. Instead, the traditional treatment consensus focuses on delaying the progression of the disease and diminishing the symptoms. Eventually, ventricular dysfunction develops when the heart suffers from inadequate blood flow. Only a ventricular assist device or heart transplantation can treat end-stage heart failure. The vision of restoring structural and functional myocardium after ischemic damage and scarring has fascinated the cardiac regeneration research community for decades and driven the search for a clinically feasible, reliable, and effective treatment for repairing and replacing damaged heart tissue. Epicardial transplantation of atrial appendage micrografts (AAMs) is a newly adopted surgical technique with cardio regenerative potential and can, as a straightforward method, be readily adopted worldwide. As myocardial support therapy, performing AAMs transplantation with open heart surgery is feasible—such as coronary artery bypass grafting (CABG) surgery. This PhD thesis aims to assess the safety of the epicardial delivered AAMs with CABG surgery and evaluate the procedure’s feasibility in a clinical setting. Patients and methods Study I assessed the safety and feasibility of epicardial transplanted AAMs in pigs after coronary artery ligation. First, the right atrial appendage was harvested and mechanically processed into AAMs. The left descending coronary artery was ligated to experimentally model myocardial infarction and heart failure. AAMs with fibrin gel were placed on an extracellular matrix patch and transplanted epicardially onto the infarct area. Four pigs received an AAMs patch, and four received similarly prepared patches without AAMs. Open heart echocardiography was performed preoperatively and at three weeks follow-up to evaluate the cardiac function and dimensions of the infarcted ventricular wall. The primary outcome measures were the safety and feasibility of therapy administration during open heart surgery. Studies II, III, and IV included 12 ischemic heart failure patients scheduled for elective CABG surgery. Late gadolinium enhancement cardiac magnetic resonance imaging (CMRI) was performed preoperatively and six months postoperatively. As well as the standard clinical treatment protocol, six patients received an AAM patch, and six were operated on according to the standard clinical treatment protocol without AAMs patch transplantation. Clinical data of 30 elective CABG patients, without any additional follow-up or imagining, was collected from hospital records; this group formed another control group. A sample of the right atrial appendage was mechanically processed to generate the AAMs. The micrografts were applied with a fibrin gel onto a tissue-engineered extracellular matrix sheet and further epicardially onto the infarct scar site identified in the preoperative CMRI. Laboratory tests and quality-of-life questionnaires (QoL) were performed preoperatively and at a six-month follow-up. The primary outcome measures were I) patient safety concerning hemodynamic and cardiac function over the follow-up time and II) feasibility of therapy administered 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 the hospital, and changes in QoL. Results Study I showed no arrhythmias, complications, or increased mortality among the pigs receiving epicardial AAMs or control patches. According to processing time and sterility, AAMs patch preparation was feasible to be conducted simultaneously with heart surgery. AAMs suppressed the overall inflammation (foreign body reaction) caused by the matrix as measured by the amount of infiltrated inflammatory cells and the size of the inflammation area. Immunohistochemistry showed increased CD3+ cell (T-lymphocyte) density in the AAMs patch group. In Studies II, III, and IV, epicardial transplantation of AAMs for patients was safe and feasible to be performed with open heart surgery. Patient recovery was the same in all groups. CMRI demonstrated that patients receiving AAMs treatment had a greater volume of viable cardiac tissue at follow-up. Conclusions According to the results, epicardial transplantation of AAMs is safe, clinically feasible, and shows good clinical applicability during open heart surgery. As the results from the safety and feasibility trial suggest, the therapy’s regenerative efficacy should be evaluated in a larger randomized clinical trial. Moreover, epicardial transplantation of AAMs may be a delivery platform for future cell-, drug-, or gene-based cardiac therapies.