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, the patient's own tissue from the right atrial appendage (RAA) is 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. Recently, the safety and feasibility of AAMs therapy was demonstrated in an open-label clinical study. 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 a collaged-based matrix sheet, which is then epicardially sutured in place at the end of CABG surgery. The location is determined by preoperative late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMRI) to pinpoint the ischemic scar. The controls receive the collagen-based patch, but without the AAMs. 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.
Informed consent obtained
Left ventricular ejection fraction (LVEF) between ≥ 15% and ≤ 40% at recruitment (transthoracic echocardiography)
New York Heart Association (NYHA) Class II-IV heart failure symptoms
Heart failure due to left ventricular outflow tract obstruction
Acute myocardial infarction (AMI) within last 30 days
History of life-threatening and possibly repeating ventricular arrhythmias or resuscitation, or an implantable cardioverter-defibrillator
Stroke or other disabling condition within 3 months before screening
Parallel
Epicardial AAMs-patch transplantation
Procedure/SurgeryPerioperative assembly of an AAMs-patch with epicardial transplantation onto the epicardium of the scarred myocardium at the end of CABG surgery
RNA-stabilized whole blood sampling
Diagnostic testCollection (preoperative and at 6-month-follow-up) of TEMPUS(TM) stabilizing whole blood for epitranscriptomics-oriented measurements
Plasma sampling
Diagnostic testCollection (preoperative and at 6-month follow-up) of blood-derived both RNA-stabilized and non-stabilized plasma aliquots for epitranscriptomic-oriented and other CVD biomarker oriented measurements, respectively
Transthoracic echocardiography
Diagnostic testTo assess cardiac structure and function both pre- and postoperatively (at both hospital discharge and 3-month follow-up)
Late-gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMRI)
Diagnostic testTo assess detailed cardiac structure (i.e. interstitial fibrosis) and function both preoperatively and at 6-month follow-up postoperatively.
Symptom-scaling
Other interventionStandardised evaluation of IHD and HF-related angina pectoris (CCS) and dyspnea (NYHA) and life quality (RAND36) pre- and postoperatively (at both 3- and 6-month follow-up).
6-minute walking test (6MWT)
Other interventionStandardised assessment of physcial capacity pre- and postoperatively (at 6-month follow-up)
Blood sampling (NT-proBNP)
Diagnostic testCollection of a blood sample measurement of NT-proBNP by an accredited hospital laboratory pre- and postoperatively (at both 3- and 6-month follow-up).
Transesophageal echocardiography
Diagnostic testPerformed by the perfusion-anesthesiologist at the beginning of the CABG surgery to evaluate both LAA and RAA for blood flow velocities, anatomy, possible sludge and thrombus.
Epicardial collagen-based patch transplantation
Procedure/SurgeryEpicardial transplantation of the collaged-based patch material without the AAMs onto the epicardium of the scarred myocardium at the end of CABG surgery.
Change in the amount of myocardial scar tissue
Measured by LGE-CMRI preoperatively and at the 6-month-follow-up
Change in plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels
Measured from blood sample at preoperative visit, 3-month, and 6-month follow-ups
Efficacy: Change in left ventricular wall thickness
Measured by LGE-CMRI preoperatively and at the 6-month-follow-up
Efficacy: Change in viable left ventricular myocardium
Measured by LGE-CMRI preoperatively and at the 6-month-follow-up
Efficacy: Change in movement, systolic or diastolic function of the left ventricle
Measured by LGE-CMRI preoperatively and at the 6-month-follow-up
Efficacy: Change in left ventricular ejection fraction
Measured by LGE-CMRI preoperatively and at the 6-month-follow-up
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Hospital District of Helsinki and Uusimaa
Lead sponsor
University of Helsinki
Collaborator
Oulu University Hospital
Collaborator
