AAMS2: Atrial Appendage Micrograft Transplants to Assist Heart Repair After Cardiac Surgery

• Sponsor: Hospital District of Helsinki and Uusimaa (Other)
• Overall Status: Not yet recruiting
• CT.gov ID: NCT05632432
• Collaborator: University of Helsinki (Other)
• Enrollment: 50
• Arms: 2
• Anticipated Duration (Months): 37

Study Details

Study Description

Brief 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, 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.

Condition or Disease	Intervention/Treatment	Phase
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	Procedure: Epicardial AAMs-patch transplantation; Diagnostic Test: RNA-stabilized whole blood sampling; Diagnostic Test: Plasma sampling; Diagnostic Test: Transthoracic echocardiography; Diagnostic Test: Late-gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMRI); Other: Symptom-scaling; Other: 6-minute walking test (6MWT); Diagnostic Test: Blood sampling (NT-proBNP); Diagnostic Test: Transesophageal echocardiography	N/A

Detailed Description

BACKGROUND AND SIGNIFICANCE

Globally, each year 17.9 million people die of cardiovascular diseases. Ischemic heart disease (IHD) is the cause in half of these cases, thus making it the global leading single cause of death [GBD 2017]. While 126.5 million patients suffer from IHD worldwide, in Europe 30.3 million patients are afflicted [Timmis 2018].

IHD is hallmarked by progressively enlarging atherosclerotic coronary plaques. These disease hotspots not only drive myocardial hypoxia, cardiomyocyte hibernation, apoptosis and interstitial fibrosis but are prone for erosion and rupture. Plaque rupture forcefully activates the hemostatic system resulting in thrombotic coronary occlusion, myocardial infarction (MI), and death of cardiac tissue. Due to improved acute care, the patients increasingly survive the acute phase, and the site of injury eventually gets replaced by a scar that typically restricts the filling and pumping of the heart [Cohn 2000]. Depending on the extent of injury and the resulting scar, eventually the increased workload leads to adverse remodeling and emergence of heart failure (HF), an irreversible and incapacitating clinical syndrome with poor prognosis [Taylor 2017, Cohn 2000]. HF due to an ischemic etiology has been reported to vary from 29% to 45% [Groenewegen 2020]. For instance, a recent meta-analysis suggests the "all-type" HF prevalence, including the previously unrecognized cases via population-based echocardiographic screening, to be as high as 11.8% among general population aged above 65 years [van Riet 2016].

CABG surgery is the preferred revascularization method for patients with severe progressed IHD [Rihal 2003]. In Europe, more than 245,000 CABG surgeries were carried out in 2016 [Eurostat 2015]. Regardless of age, CABG surgery has been shown to have an overall beneficial effect on ischemic symptoms and mortality [Freitas 2019].

Cardiac healing by regeneration rather than scarring could tilt the IHD with its complications towards an increasingly manageable, even curable, disease. While the hearts of some vertebrates heal by regeneration throughout their lifespan, in rodents this capacity is limited to the first week of life [Cutie 2021]. Very early in life, also the human heart seems to possess capacity to regenerate after ischemia [Haubner 2016].

It has proved complex to activate cardiac regenerative repair in adult human heart. Many stem, progenitor and differentiated cells have been tested in this regard [Cambria 2017]. While these investigations have provided promising results, the therapies remain complex and costly, highlighting the need for more clinically straightforward approaches. Cells derived from atrial appendages have been shown to be capable of stimulating regenerative cardiac healing in the context of ischemic cardiac damage [Koninckx 2013, Detert 2018, Evens 2021]. As positioned by the European Society of Cardiology, many tissue-engineered approaches, including epicardial extracellular matrix (ECM) patch transplantation, are highlighted as promising future therapies for ischemic HF [Madonna 2019]. These approaches could improve the local persistence and viability of the co-transplanted cells-a major obstacle identified in previous studies.

GENERAL CONCEPT

We use the patient's own heart tissue from the right atrial appendage for therapy. Neither the left nor the right atrial appendage (LAA and RAA, respectively) directly contribute to the heart's pumping function. A piece of the RAA can be safely harvested upon insertion of the right atrial cannula during the set-up of the heart and lung machine at the beginning of CABG [Lampinen 2017, Nummi 2017, Nummi 2021]. In the AAMS2 trial, a piece of the RAA tissue is used as epicardially transplanted, patch-encased, and mechanically expanded atrial appendage micrografts (AAMs). This therapy can be administered during single CABG surgery.

PREVIOUS RESULTS

In a preclinical mouse model of MI and HF, the effects of epicardial AAMs-patches were compared to acellular ECM patches. The results demonstrated myocardial tissue protection, attenuated scarring, and retained cardiac function [Xie 2020]. Further, mass-spectrometry-based quantitative proteomics demonstrated widespread regenerative and cardioprotective effects in the myocardium, including decreased oxidative stress and AAMs-mediated induction of myocardial glycolytic metabolism, a process associated with an increased regenerative capacity of myocardium [Lalowski 2018, Nakada 2017, Kimura 2015, Puente 2014].

The AAMs-patch therapy has proceeded to clinical use. Following the first-in-man application of AAMs [Nummi 2019], the safety and feasibility of the epicardial AAMs transplantation during CABG was recently confirmed [Nummi 2021]. Moreover, as this study suggested increased thickness of the viable myocardium in the scar zone, it provided the first indication of therapeutic benefit [Nummi 2021].

OBJECTIVES AND OVERVIEW

This AAMS2 randomized double-blinded and controlled trial evaluates the effect of epicardially transplanted AAMs as an adjuvant therapy to CABG surgery. The trial's primary endpoints are changes in cardiac function and structure as evaluated using late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMRI) at 6-month follow-up after surgery as compared to preoperative LGE-CMRI.

The trial enrolls 50 patients in a 1:1 group allocation ratio to the study groups (CABG or AAMs patch with CABG). Autologous RAA tissue is harvested from the RAA during CABG from all participants and based on randomization, the piece of RAA tissue is either processed to AAMs perioperatively or cryostored for biochemical analyses. The AAMs, embedded in fibrin matrix gel, are placed on an ECM sheet, which is then epicardially sutured in place. To pinpoint the ischemic scar area as the epicardial transplantation site, LGE-CMRI is done preoperatively. Study blood samples are collected preoperatively as well as at 3- and 6-month follow-up after surgery. Transthoracic echocardiography (TTE), LGE-CMRI, symptom-scaling measures, and 6-minute walking test (6MWT) are performed preoperatively and at the 6-month follow-up.

METHODS

1. Patient selection, enrolment, ethics, and timeline-The patients meeting the eligibility and exclusion criteria, as evaluated by a cardiologist, are selected from the hospital's list of elective cardiac surgeries. The patients' medication is optimized according to the current guidelines by the treating cardiologist. The usual waiting time on the list ranges between 2 and 8 weeks. This time allows medication changes to take effect before surgery. Later, the recruited patients are called for a clinical control visit (denoted as the 3-month follow-up) and a dedicated trial visit (at 6-8 months postoperatively, denoted as the 6-month follow-up).

All patients are provided with information describing the trial. Before a subject undergoes any study procedure, an informed consent discussion will be conducted and written informed consent to participate is required. The trial will be conducted following the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects [World Medical Association 2013]. The study has been approved by the Ethics Committee of Hospital District of Helsinki and Uusimaa (HUS; Dnr. HUS/12322/2022). The estimated start of the patient recruitment is December 2022 with an estimated full study completion date on December 2025. The participant is excluded from the trial (screening failure), if after optimization of medications, a visible scar cannot be identified and left ventricular ejection fraction (LVEF) is ≥50% in preoperative LGE-CMRI. This applies also if the LGE-CMRI has not been performed prior to CABG.

1. Endpoints-The trial endpoints are listed in a separate section. The 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). The secondary endpoints center on other efficacy parameters as well as both safety and feasibility of the therapy.

2. Randomization and blinding-Patients are randomized into CABG or AAMs groups using sex-stratified block randomization via the openly available online tool at www.sealedenvelope.com with block sizes 2 and 4, and stratification according to sex (female, male). Randomization is carried out by the University of Helsinki (person-in-charge docent Esko Kankuri). Running-numbered sealed envelopes with the randomized allocation information are handed out to the study nurse, who opens each respective envelope at the beginning of each patient's surgery. The study nurse oversees the allocation in a double-blinded manner, where the patient and the evaluating cardiologist and radiologists remain blinded to the study group allocation. Given the nature of the treatment (transplant vs. no transplant) it is impossible to blind the operating surgeon or the study nurse to the allocations. All LGE-CMRI and TTE measurements as well as laboratory analyses are done by researchers blinded to the group allocations.

3. Preparation and administration of atrial appendage micrografts-A piece of the RAA is harvested at the beginning of cardiac surgery upon right atrial cannulation. The RAA tissue is weighed and mechanically processed into micrografts as previously described [Lampinen 2017, Nummi 2017, Nummi 2021] by using the Rigeneracon blade (Rigenera-system, HBW s.r.l., Turin, Italy). Dedicated CE-marked instrumentation kits to support tissue processing in the operating room are obtained from EpiHeart Oy (Helsinki, Finland). The micrografts are spread onto a pericardial matrix sheet (Equine Pericardium Patch, Autotissue GmbH, Berlin, Germany) and are embedded in a small amount of diluted fibrin tissue glue (Tisseel, Baxter AG, Vienna, Austria). The AAMs-patch is maintained cooled (+6 - +8C), covered, and sterile when waiting for transplantation.

4. General data protection regulation-The data collected during the trial will fulfil EU regulations for personal health data protection, including General Data Protection Regulation (GDPR).

5. Blood samples-A blood sample for NT-pro-BNP measurement, a gold standard biomarker for HF evaluation [McKie 2016], is collected preoperatively and at both 3-month and 6-month follow-ups. In addition, the AAMS2 trial assesses blood, plasma, and RAA tissue samples for their contained RNA transcripts with a novel focus on their post-transcriptional modifications, as previously described [Sikorski 2021, Sikorski 2022]. However, to ensure adequate yield of native RNA, instead of collecting 3 mL x 5 of TEMPUS(TM) RNA-stabilized blood per visit, 3 mL x 8 is collected. These modifications comprise a biologic frontier in genetics that is unveiling a key contributor and regulator of many cellular functions and pathophysiologic conditions, also IHD and ischemic HF [Qin 2021, Sikorski 2022]. As the information regarding blood epitranscriptomics in human IHD and HF remains scarce [Sikorski 2022], the AAMS2 trial aims to provide insight into the AAMs-treatment-induced alterations in the blood epitranscriptomes. Especially, the focus is in the two most common modifications, N6-methyladenosine (m6A) and adenosine-to-inosine (A-to-I) editing.

6. RAA tissue samples-The removed piece of RAA tissue from the control group is collected as a sample for biochemical analyses. The piece of RAA tissue will be divided in two and stored (RNAlater or formaldehyde-ethanol) for subsequent epitranscriptomics-targeted evaluations as previously described [Sikorski 2021].

7. Echocardiography-All participants are assessed with electrocardiogram and TTE preoperatively and at 6-month follow-up postoperatively. The TTE recordings are performed with designated cardiologists. These recordings include both anatomical and functional assessments of ventricles, atria and valves. An especial focus is granted during preoperative TTE, prior to the above-described RAA sample collection for AAMs, to the atrial appendages and the atria proper for anatomic characterization. Moreover, the presence or absence of pericardial effusion, thrombus and aneurysm is recorded. Perfusion anesthesiologist will perform transesophageal echocardiography (TEE) in the operating room during anesthesia to evaluate both left and right atrial appendages for blood flow velocities, possible sludge and thrombus before CABG.

8. Late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMRI)-A whole body 1.5-T MRI scanner (Siemens Sola or Avanto-fit, Siemens AG, Erlangen, Germany) is used for LGE-CMRI image acquisition. Cardiac structure and function are evaluated with a standardized LGE-CMRI protocol using electrocardiogram and respiratory gating. Short-axis cine images are used for left and right ventricular volumetric measurements. Myocardial contractility is evaluated using longitudinal, circumferential, and radial strain measurements from short- and long-axis cine images. LGE is assessed to measure infarction volume and mass using 5-SD semiautomatic gain estimate, as previously suggested for semiautomatic thresholding for infarction detection [Schulz-Menger 2020]. Image post-processing is performed with Medis Suite software (Medis Medical Imaging Systems, Leiden, The Netherlands) with QMass and QStrain applications.

9. Quality of life assessment-Health-related quality of life (HRQoL) is measured using the RAND36 (SF36) short form questionnaire [Hays 2001]. The questionnaire is standardized with specified mean and standard deviation values for eight dimensions that range from physical functioning and subjective feeling of vitality and health to bodily pain. The obtained scores are compared to a Finnish cohort with any chronic disease. Also, a subject's symptom-evaluation is performed for the two cardinal symptoms of IHD and HF, angina pectoris and exertional dyspnea, with standardized classification systems developed by the Canadian Cardiovascular Society (CCS) and the New York Heart Association (NYHA), respectively [Campeau 1976, Russell 2009]. Finally, a six-minute walking test (6MWT) is assessed to gain objective morbidity measures [Bittner 1993]. All these parameters are assessed both preoperatively and at the 6-month follow-up visit postoperatively. NYHA and CCS classes are also recorded at 3-month clinical follow-up.

10. Statistical analyses-Power analysis was carried out using SAS 9.4 TS Level 1M4 software (SAS Institute Inc., Cary, NC, USA), the POWER Procedure Wilcoxon-Mann-Whitney Test with the fixed scenario elements O'Brien-Castelloe approximation method and two-sided statistical evaluation. Power analysis sample data was derived from the previous open-label AAMs trial [Nummi 2021]. With a total sample size of 50 (two groups, group size 25, distribution 1:1) these parameters yield a power greater than 80% at an α of 0.05. Comparisons between groups will be performed with the Mann Whitney U test. Ordinal variables are tested with the Chi-Square test. Multiple comparisons are corrected with the Bonferroni method, significant findings are further tested groupwise using the Mann Whitney U test. Quality of life data is presented as means and analyzed with the independent samples t-test (two-sided). Analyses are performed with the IBM SPSS Statistics 27 program (IBM Corp., Armonk, NY) or equivalent. The data can be analyzed and published in phases during the trial.

11. Data collection preoperatively and postoperatively during follow-up-Clinical, laboratory and drug treatment data are collected to the hospital electronic health records. After discharge and during follow-up patients can visit the primary healthcare. Any visit related to the operation or their cardiovascular system condition as well as drug treatment changes are collected by the study investigators. This data is stored pseudonymized with the other data from that patient.

12. Data storage, management and sharing-The produced data are stored in the network hard drives of HUS and UH during analyses as well as on the servers of the CSC - IT CENTER FOR SCIENCE LTD. (Finland) specifically designed for sensitive data storage, all with automated backups. Directly identifying patient data with corresponding pseudonymization keys and randomization codes are stored in a key registry located within the safe hospital systems with automated backup and access control. The accession to the registries is controlled via role-based accession rights, and only those researchers specified in the registry description approved by the HUS Ethics Committee can access the data therein. PI-researcher docent Pasi Karjalainen is the responsible party for the key registry and its contents.

The TTE data of participants is accessed via IntelliSpace software (Philips, Netherlands) that is ultimately stored on the Microsoft® Azure Cloud, which fulfills the HUS data security guidelines. The LGE-CMRI data and reports are stored to digital HUS picture archiving and communication system (PACS). When needed, the LGE-CMRI data are transferred internally between HUS Medical Imaging Center's servers to allow image analysis with appropriate CMR software. Case report formats are both physically stored in the HUS premises with an access control and electronically in the research registry.

The accessions to the research registry are controlled via role-based accession rights and only those research team members singly specified in the registry description document, approved by the HUS Ethics Committee, can access the data therein. All workstations, network drives and servers are password protected.

Prior any sharing of pseudonymized data with the academic study collaborators inside or outside European Union take place, whether performed via CSC - IT CENTER FOR SCIENCE LTD. (Finland) servers or with strong-password-protected hard drives transported by either official courier of the University of Helsinki or Helsinki University Hospital, the responsible collaborating scientist or the representative of the affiliated institution will sign Material Transfer Agreement (MTA). These MTAs will use the EU commission's Standard Contractual Clauses (SCCs) to protect the access, i.e. transfer, of the pseudonymized data. Also, all personnel handling pseudonymized data will be required to sign an official HUS secrecy and data security commitment. Moreover, the CSC

• IT CENTER FOR SCIENCE LTD. requires its own data secrecy handling agreement for each collaborator to sign prior accessing the pseudonymized data.

Principally, after the active phase of the trial, the produced data with pseudonyms will be stored on the servers of the Finnish IT Center for Science CSC (SD-Apply) for 15 years (2040). After this, the data is anonymized via erasing all the pseudonyms and curated indefinitely. A distinct Data Access Committee will monitor the re-use of the stored data. Also, the sequencing datasets with group-level anonymized metadata can be made available upon publication via uploading into repositories such as the European Nucleotide Archive (ENA) of the European Molecular Biology Laboratory European Bioinformatics Institute (EMBL-EBI, Cambridge, UK) or the Gene Expression Omnibus (GEO) functional genomics database repository (National Center for Biotechnology Information NCBI, Bethesda, MD, USA).

1. Trial monitoring-The AAMS2 trial will be externally monitored by the Clinical Research Institute, Helsinki University Central Hospital (HUCH), or equivalent monitoring service provider, to ensure trial subjects' rights, safety, and well-being. A detailed monitoring plan will be drafted with the service provider and the research group before any patient is recruited to the study.

2. Research team-The AAMS2 trial is conducted in collaboration with the HUS Heart and Lung Center (PI docent Pasi Karjalainen, and co-PI Antti Vento MD PhD) and University of Helsinki (docent Esko Kankuri MD PhD). The study nurse oversees and organizes, together with the PI, patient screening, recruitment, informing and contacting (via phone or mail), perioperative AAMs processing, and reservation of control visits. Moreover, the study nurse organizes study sample logistics in collaboration with scientists from University of Helsinki. Randomization is carried out at the University of Helsinki. The CABG surgery and application of AAMs patch is carried out by HUS Heart and Lung Center. LGE-CMRI imaging and analyses are carried by HUS Department of Radiology and University of Helsinki. The patient screening, recruitment, as well as both preoperative and postoperative clinical visits, which include TTE recordings, and clinical evaluation are conducted by the Cardiac Unit, HUS Heart and Lung Center. A heart-anesthesiologist will carry out recording of key postoperative parameters. Analysis of epitranscriptomic and other biomarkers is organized by the University of Helsinki, Faculty of Medicine, Department of Pharmacology.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: The trial enrols 50 patients in a 1:1 group allocation ratio to the study groups (CABG [control group] or AAMs patch with CABG [intervention group]). Autologous RAA tissue is harvested from the RAA during CABG from all participants. Based on randomization, the piece of RAA tissue is either processed to AAMs perioperatively or stored for biochemical analyses. The AAMs, embedded in fibrin matrix gel, are placed on an ECM patch sheet, which is epicardially sutured in place. The epicardial transplantation site is pinpointed to ischemic scar area by preoperative LGE-CMRI.The trial enrols 50 patients in a 1:1 group allocation ratio to the study groups (CABG [control group] or AAMs patch with CABG [intervention group]). Autologous RAA tissue is harvested from the RAA during CABG from all participants. Based on randomization, the piece of RAA tissue is either processed to AAMs perioperatively or stored for biochemical analyses. The AAMs, embedded in fibrin matrix gel, are placed on an ECM patch sheet, which is epicardially sutured in place. The epicardial transplantation site is pinpointed to ischemic scar area by preoperative LGE-CMRI.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Randomization is carried out by the University of Helsinki. Participants' running-numbered sealed envelopes with the randomized allocation information are handed out to the study nurse, who opens each respective envelope at the beginning of each patient's surgery. The study nurse oversees the allocation in a double-blinded manner, where the patient and the evaluating cardiologist and radiologists remain blinded to the study group allocation. Given the nature of the treatment (transplant vs. no transplant) it is impossible to blind the operating surgeon or the study nurse to the allocations.
• Primary Purpose: Treatment
• Official Title: Atrial Appendage Micrograft Transplantation in Conjunction With Cardiac Surgery-the AAMS2 Randomized Controlled Trial
• Anticipated Study Start Date: Dec 1, 2022
• Anticipated Primary Completion Date: Dec 31, 2025
• Anticipated Study Completion Date: Dec 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: CABG arm (control) In total, 25 patients are recruited to form the CABG group. During CABG surgery, RAA tissue is removed as detailed for the AAMs-patch group. However, the tissue is collected as a sample for later analyses rather than processed to AAMs (Method 4). CABG is performed without epicardial transplantation of AAMs-patch.	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 3- and 6-month of follow-up); Other Names: TTE ; 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.; Other Names: TEE
Experimental: CABG + AAMs arm (intervention) In total, 25 patients are recruited to the AAMs-patch group. Here, the AAMs are prepared from the RAA tissue sample by mechanical processing in the operating room during the CABG surgery. The RAA tissue piece is removed during right atrial cannulation, a part of the routine setup of cardiopulmonary bypass. To form an AAMs-patch, the AAMs, embedded in fibrin matrix gel, are placed onto an ECM sheet. This AAMs-patch is kept cold, covered, and sterile until the last stages of CABG surgery. After all the coronary anastomoses are done, the AAMs-patch is epicardially transplanted onto the area identified by preoperative LGE-CMRI to have most suffered from ischemia.	Procedure: Epicardial AAMs-patch transplantation; Perioperative assembly of an AAMs patch with epicardial transplantation 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 3- and 6-month of follow-up); Other Names: TTE ; 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.; Other Names: TEE

Outcome Measures

Primary Outcome Measures

1. Change in the amount of myocardial scar tissue [6 months]

   Measured by LGE-CMRI preoperatively and at the 6-month-follow-up

2. Change in plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels [6 months]

   Measured from blood sample at preoperative visit, 3-month, and 6-month follow-ups

Secondary Outcome Measures

1. Efficacy: Change in left ventricular wall thickness [6 months]

   Measured by LGE-CMRI preoperatively and at the 6-month-follow-up

2. Efficacy: Change in viable left ventricular myocardium [6 months]

   Measured by LGE-CMRI preoperatively and at the 6-month-follow-up

3. Efficacy: Change in movement, systolic or diastolic function of the left ventricle [6 months]

   Measured by LGE-CMRI preoperatively and at the 6-month-follow-up

4. Efficacy: Change in left ventricular ejection fraction [6 months]

   Measured by LGE-CMRI preoperatively and at the 6-month-follow-up

5. Efficacy: Change in New York Heart Association (NYHA) class [6 months]

   NYHA class at the 3-month and 6-month follow-ups vs NYHA peoperatively

6. Efficacy: Change in Canadian Cardiovascular Society (CCS) class [6 months]

   CCS class at the 3-month and 6-month follow-ups vs CCS preoperatively

7. Efficacy: Major adverse cardiovascular and cerebrovascular events (MACCE) [6 months]

   MACCE during the study period

8. Efficacy: Deaths due to primary cardiovascular cause [6 months]

   Deaths (and cause of death) during the study period

9. Efficacy: Postoperative days in hospital [1 week, up to 10 days]

   Measured as the CABG (and CVD) -related postoperative days spent in hospital

10. Efficacy: Changes in the quality of life [6 months]

    Measured by RAND36 questionnaire preoperatively and at the 6-month-follow-up

11. Efficacy: Local changes in systolic and diastolic function [6 months]

    Measured by transthoracic echocardiography preoperatively and at the 3 and 6-months of follow-up Measured by LGE-CMRI preoperatively and at 6-months of follow-up

12. Efficacy: Changes in myocardial strain and LVEF [6 months]

    Measured by TTE preoperatively and at the 3- and 6-months of follow-up

13. Safety: telemetric monitoring of rhythm [4 days]

    For assessing cardiac function after the CABG operation

14. Feasibility: Success in completing the delivery of the AAMs patch onto the epicardium [ Time Frame: 6 months ] [The duration of CABG operation, 3-5 hours]

    Measured in 0= success, 1= no success

15. Feasibility: Waiting time for the AAMs patch [75-90 minutes from the start of CABG operation]

    Waiting time in minutes for the atrial appendage micrograft transplant to be placed on the myocardium (placement after completion of all the required anastomoses)

16. Feasibility: Waiting time in minutes for the heart [75-90 minutes from the start of CABG operation]

    Waiting time in minutes for the heart after all the anastomoses are completed and before the AAMs patch is ready for epicardial transplantation.

17. Feasibility: Closing the right atrial appendage [1-5 minutes, at the decannulation phase at the end of CABG]

    Closing the right atrial appendage after removing the standardized tissue piece for preparing the transplant. According to the hospital protocol, appendage is closed with purse-string suture. 0 = no additional suturing needed, 1 = additional suturing needed

18. Safety; need for vasoactive medication [up to 2 days after CABG]

    For assessing haemodynamics during the operation and at the intensive care unit

19. Safety; in-hospital infections [1 week, up to 10 days]

    Transplant-related=1; Non-transplant-related=2; no infections=0 with details on organism, quantity, clinical and microbiological evaluation as well as harvesting site

20. Observational: Blood and plasma long-read RNA sequencing, proteomics, and/or metabolomics [6 months]

    Chronologic (preoperative vs. 6-month follow-up) and cross-sectional (AAMs patch vs. CABG group) correlation of blood epitranscriptomes, transcriptome, proteome and/or metabolome with the above outcomes.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 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

Exclusion Criteria:

• Heart failure due to left ventricular outflow tract obstruction

• 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

• Severe valve disease or scheduled valve surgery

• Renal dysfunction (GFR <45 ml/min/1.73m2)

• Other disease limiting life expectancy

• Contraindications for coronary angiogram or LGE-CMRI

• Participation in some other clinical trial

Screening Failure:

• After optimization of medications, no visible scar and LVEF ≥ 50% in preoperative LGE-CMRI

• Preoperative LGE-CMRI has not been performed prior scheduled CABG

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Hospital District of Helsinki and Uusimaa
• University of Helsinki

Investigators

• Principal Investigator: Pasi Karjalainen, Docent, Hospital District of Helsinki and Uusimaa

Study Documents (Full-Text)

None provided.

More Information

Publications

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• Eurostat, online material (https://ec.europa.eu/eurostat/web/health/data/database) Accessed 3.4.2022
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• Freitas P, Madeira M, Raposo L, Madeira S, Brito J, Brizido C, Gama F, Vale N, Ranchordas S, Magro P, Braga A, Goncalves PA, Gabriel HM, Nolasco T, Boshoff S, Marques M, Bruges L, Calquinha J, Sousa-Uva M, Abecasis M, Almeida M, Neves JP, Mendes M. Coronary Artery Bypass Grafting Versus Percutaneous Coronary Intervention in Patients With Non-ST-Elevation Myocardial Infarction and Left Main or Multivessel Coronary Disease. Am J Cardiol. 2019 Mar 1;123(5):717-724. doi: 10.1016/j.amjcard.2018.11.052. Epub 2018 Dec 3.
• GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018 Nov 10;392(10159):1736-1788. doi: 10.1016/S0140-6736(18)32203-7. Epub 2018 Nov 8. Erratum In: Lancet. 2019 Jun 22;393(10190):e44. Lancet. 2018 Nov 17;392(10160):2170.
• Groenewegen A, Rutten FH, Mosterd A, Hoes AW. Epidemiology of heart failure. Eur J Heart Fail. 2020 Aug;22(8):1342-1356. doi: 10.1002/ejhf.1858. Epub 2020 Jun 1.
• Haubner BJ, Schneider J, Schweigmann U, Schuetz T, Dichtl W, Velik-Salchner C, Stein JI, Penninger JM. Functional Recovery of a Human Neonatal Heart After Severe Myocardial Infarction. Circ Res. 2016 Jan 22;118(2):216-21. doi: 10.1161/CIRCRESAHA.115.307017. Epub 2015 Dec 9.
• Hays RD, Morales LS. The RAND-36 measure of health-related quality of life. Ann Med. 2001 Jul;33(5):350-7. doi: 10.3109/07853890109002089.
• Kimura W, Xiao F, Canseco DC, Muralidhar S, Thet S, Zhang HM, Abderrahman Y, Chen R, Garcia JA, Shelton JM, Richardson JA, Ashour AM, Asaithamby A, Liang H, Xing C, Lu Z, Zhang CC, Sadek HA. Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart. Nature. 2015 Jul 9;523(7559):226-30. doi: 10.1038/nature14582. Epub 2015 Jun 22. Erratum In: Nature. 2016 Apr 14;532(7598):268.
• Koninckx R, Daniels A, Windmolders S, Mees U, Macianskiene R, Mubagwa K, Steels P, Jamaer L, Dubois J, Robic B, Hendrikx M, Rummens JL, Hensen K. The cardiac atrial appendage stem cell: a new and promising candidate for myocardial repair. Cardiovasc Res. 2013 Mar 1;97(3):413-23. doi: 10.1093/cvr/cvs427. Epub 2012 Dec 19.
• Lalowski MM, Bjork S, Finckenberg P, Soliymani R, Tarkia M, Calza G, Blokhina D, Tulokas S, Kankainen M, Lakkisto P, Baumann M, Kankuri E, Mervaala E. Characterizing the Key Metabolic Pathways of the Neonatal Mouse Heart Using a Quantitative Combinatorial Omics Approach. Front Physiol. 2018 Apr 11;9:365. doi: 10.3389/fphys.2018.00365. eCollection 2018.
• Lampinen M, Nummi A, Nieminen T, Harjula A, Kankuri E; AADC Consortium. Intraoperative processing and epicardial transplantation of autologous atrial tissue for cardiac repair. J Heart Lung Transplant. 2017 Sep;36(9):1020-1022. doi: 10.1016/j.healun.2017.06.002. Epub 2017 Jun 10. No abstract available.
• Madonna R, Van Laake LW, Botker HE, Davidson SM, De Caterina R, Engel FB, Eschenhagen T, Fernandez-Aviles F, Hausenloy DJ, Hulot JS, Lecour S, Leor J, Menasche P, Pesce M, Perrino C, Prunier F, Van Linthout S, Ytrehus K, Zimmermann WH, Ferdinandy P, Sluijter JPG. ESC Working Group on Cellular Biology of the Heart: position paper for Cardiovascular Research: tissue engineering strategies combined with cell therapies for cardiac repair in ischaemic heart disease and heart failure. Cardiovasc Res. 2019 Mar 1;115(3):488-500. doi: 10.1093/cvr/cvz010.
• McKie PM, Burnett JC Jr. NT-proBNP: The Gold Standard Biomarker in Heart Failure. J Am Coll Cardiol. 2016 Dec 6;68(22):2437-2439. doi: 10.1016/j.jacc.2016.10.001. No abstract available.
• Nakada Y, Canseco DC, Thet S, Abdisalaam S, Asaithamby A, Santos CX, Shah AM, Zhang H, Faber JE, Kinter MT, Szweda LI, Xing C, Hu Z, Deberardinis RJ, Schiattarella G, Hill JA, Oz O, Lu Z, Zhang CC, Kimura W, Sadek HA. Hypoxia induces heart regeneration in adult mice. Nature. 2017 Jan 12;541(7636):222-227. doi: 10.1038/nature20173. Epub 2016 Oct 31.
• Nummi A, Mulari S, Stewart JA, Kivisto S, Teittinen K, Nieminen T, Lampinen M, Patila T, Sintonen H, Juvonen T, Kupari M, Suojaranta R, Kankuri E, Harjula A, Vento A; AADC consortium. Epicardial Transplantation of Autologous Cardiac Micrografts During Coronary Artery Bypass Surgery. Front Cardiovasc Med. 2021 Sep 14;8:726889. doi: 10.3389/fcvm.2021.726889. eCollection 2021.
• Nummi A, Nieminen T, Patila T, Lampinen M, Lehtinen ML, Kivisto S, Holmstrom M, Wilkman E, Teittinen K, Laine M, Sinisalo J, Kupari M, Kankuri E, Juvonen T, Vento A, Suojaranta R, Harjula A; AADC consortium. Epicardial delivery of autologous atrial appendage micrografts during coronary artery bypass surgery-safety and feasibility study. Pilot Feasibility Stud. 2017 Dec 20;3:74. doi: 10.1186/s40814-017-0217-9. eCollection 2017.
• Puente BN, Kimura W, Muralidhar SA, Moon J, Amatruda JF, Phelps KL, Grinsfelder D, Rothermel BA, Chen R, Garcia JA, Santos CX, Thet S, Mori E, Kinter MT, Rindler PM, Zacchigna S, Mukherjee S, Chen DJ, Mahmoud AI, Giacca M, Rabinovitch PS, Aroumougame A, Shah AM, Szweda LI, Sadek HA. The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell. 2014 Apr 24;157(3):565-79. doi: 10.1016/j.cell.2014.03.032. Erratum In: Cell. 2014 May 22;157(5):1243.
• Qin Y, Li L, Luo E, Hou J, Yan G, Wang D, Qiao Y, Tang C. Role of m6A RNA methylation in cardiovascular disease (Review). Int J Mol Med. 2020 Dec;46(6):1958-1972. doi: 10.3892/ijmm.2020.4746. Epub 2020 Oct 6.
• Rihal CS, Raco DL, Gersh BJ, Yusuf S. Indications for coronary artery bypass surgery and percutaneous coronary intervention in chronic stable angina: review of the evidence and methodological considerations. Circulation. 2003 Nov 18;108(20):2439-45. doi: 10.1161/01.CIR.0000094405.21583.7C. No abstract available.
• Russell SD, Saval MA, Robbins JL, Ellestad MH, Gottlieb SS, Handberg EM, Zhou Y, Chandler B; HF-ACTION Investigators. New York Heart Association functional class predicts exercise parameters in the current era. Am Heart J. 2009 Oct;158(4 Suppl):S24-30. doi: 10.1016/j.ahj.2009.07.017.
• Schulz-Menger J, Bluemke DA, Bremerich J, Flamm SD, Fogel MA, Friedrich MG, Kim RJ, von Knobelsdorff-Brenkenhoff F, Kramer CM, Pennell DJ, Plein S, Nagel E. Standardized image interpretation and post-processing in cardiovascular magnetic resonance - 2020 update : Society for Cardiovascular Magnetic Resonance (SCMR): Board of Trustees Task Force on Standardized Post-Processing. J Cardiovasc Magn Reson. 2020 Mar 12;22(1):19. doi: 10.1186/s12968-020-00610-6.
• Sikorski V, Karjalainen P, Blokhina D, Oksaharju K, Khan J, Katayama S, Rajala H, Suihko S, Tuohinen S, Teittinen K, Nummi A, Nykanen A, Eskin A, Stark C, Biancari F, Kiss J, Simpanen J, Ropponen J, Lemstrom K, Savinainen K, Lalowski M, Kaarne M, Jormalainen M, Elomaa O, Koivisto P, Raivio P, Backstrom P, Dahlbacka S, Syrjala S, Vainikka T, Vahasilta T, Tuncbag N, Karelson M, Mervaala E, Juvonen T, Laine M, Laurikka J, Vento A, Kankuri E. Epitranscriptomics of Ischemic Heart Disease-The IHD-EPITRAN Study Design and Objectives. Int J Mol Sci. 2021 Jun 21;22(12):6630. doi: 10.3390/ijms22126630.
• Sikorski V, Vento A, Kankuri E; IHD-EPITRAN Consortium. Emerging roles of the RNA modifications N6-methyladenosine and adenosine-to-inosine in cardiovascular diseases. Mol Ther Nucleic Acids. 2022 Jul 20;29:426-461. doi: 10.1016/j.omtn.2022.07.018. eCollection 2022 Sep 13.
• Taylor CJ, Ryan R, Nichols L, Gale N, Hobbs FR, Marshall T. Survival following a diagnosis of heart failure in primary care. Fam Pract. 2017 Apr 1;34(2):161-168. doi: 10.1093/fampra/cmw145.
• Timmis A, Townsend N, Gale C, Grobbee R, Maniadakis N, Flather M, Wilkins E, Wright L, Vos R, Bax J, Blum M, Pinto F, Vardas P; ESC Scientific Document Group. European Society of Cardiology: Cardiovascular Disease Statistics 2017. Eur Heart J. 2018 Feb 14;39(7):508-579. doi: 10.1093/eurheartj/ehx628.
• van Riet EE, Hoes AW, Wagenaar KP, Limburg A, Landman MA, Rutten FH. Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review. Eur J Heart Fail. 2016 Mar;18(3):242-52. doi: 10.1002/ejhf.483. Epub 2016 Jan 4.
• World Medical Association. Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects, 2013. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/ (Retrieved using link 3.4.2022).
• Xie Y, Lampinen M, Takala J, Sikorski V, Soliymani R, Tarkia M, Lalowski M, Mervaala E, Kupari M, Zheng Z, Hu S, Harjula A, Kankuri E; AADC consortium. Epicardial transplantation of atrial appendage micrograft patch salvages myocardium after infarction. J Heart Lung Transplant. 2020 Jul;39(7):707-718. doi: 10.1016/j.healun.2020.03.023. Epub 2020 Apr 7.

• Responsible Party: Pasi P Karjalainen, Docent Pasi Karjalainen, MD PhD, Hospital District of Helsinki and Uusimaa
• ClinicalTrials.gov Identifier: NCT05632432
• Other Study ID Numbers: AAMS2
• First Posted: Nov 30, 2022
• Last Update Posted: Nov 30, 2022
• Last Verified: Nov 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Pasi P Karjalainen, Docent Pasi Karjalainen, MD PhD, Hospital District of Helsinki and Uusimaa: Ischemic heart failure; Ischemic heart disease; Coronary artery disease; Coronary artery bypass grafting; Atrial appendage micrografts; Tissue-engineering; Ischemic cardiomyopathy; Atrial appendage; Micrografts; Cell Therapy; Epitranscriptomics
• Additional relevant MeSH terms: Heart Failure; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Heart Diseases; Cardiomyopathies; Heart Failure, Systolic; Ischemia

Study Results

No Results Posted as of Nov 30, 2022