Atrial Appendage Micrograft Transplants to Assist Heart Repair After Cardiac Surgery

Summary

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.

Conditions

• Ischemic Heart Disease
• Ischemic Cardiomyopathy
• Heart Failure, Systolic
• Heart Failure NYHA Class III
• Heart Failure NYHA Class II
• Heart Failure NYHA Class IV
• Coronary Artery Disease

Interventions

PROCEDURE

Epicardial AAMs-patch transplantation

Perioperative assembly of an AAMs-patch with epicardial transplantation onto the epicardium of the scarred myocardium at the end of CABG surgery

DIAGNOSTIC_TEST

RNA-stabilized whole blood sampling

Collection (preoperative and at 6-month-follow-up) of TEMPUS(TM) stabilizing whole blood for epitranscriptomics-oriented measurements

DIAGNOSTIC_TEST

Plasma sampling

Collection (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

DIAGNOSTIC_TEST

Transthoracic echocardiography

To assess cardiac structure and function both pre- and postoperatively (at both hospital discharge and 3-month follow-up)

DIAGNOSTIC_TEST

Late-gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMRI)

To assess detailed cardiac structure (i.e. interstitial fibrosis) and function both preoperatively and at 6-month follow-up postoperatively.

OTHER

Symptom-scaling

Standardised 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).

OTHER

6-minute walking test (6MWT)

Standardised assessment of physcial capacity pre- and postoperatively (at 6-month follow-up)

DIAGNOSTIC_TEST

Blood sampling (NT-proBNP)

Collection of a blood sample measurement of NT-proBNP by an accredited hospital laboratory pre- and postoperatively (at both 3- and 6-month follow-up).

DIAGNOSTIC_TEST

Transesophageal echocardiography

Performed 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.

PROCEDURE

Epicardial collagen-based patch transplantation

Epicardial transplantation of the collaged-based patch material without the AAMs onto the epicardium of the scarred myocardium at the end of CABG surgery.

Sponsors & Collaborators

• University of Helsinki

  collaborator OTHER

• Oulu University Hospital

  collaborator OTHER

• Hospital District of Helsinki and Uusimaa

  lead OTHER

Principal Investigators

• Antti Nykänen, Docent · Hospital District of Helsinki and Uusimaa

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

75 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2024-04-01

Primary Completion

2026-01-31

Completion

2026-12-31

Countries

• Finland

Study Locations