Autologous Atrial Appendage Micrografts Transplanted During Coronary Artery Bypass Surgery: the AAMS2 Randomized, Double-blinded, and Placebo-controlled Trial
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 50
- 试验地点
- 2
- 主要终点
- Change in the amount of myocardial scar tissue
研究概览
简要总结
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.
详细描述
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. While 126.5 million patients suffer from IHD worldwide, in Europe 30.3 million patients are afflicted.
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. 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. HF due to an ischemic etiology has been reported to vary from 29% to 45%. 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.
CABG surgery is the preferred revascularization method for patients with severe progressed IHD. In Europe, more than 245,000 CABG surgeries were carried out in 2016. Regardless of age, CABG surgery has been shown to have an overall beneficial effect on ischemic symptoms and mortality.
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. Very early in life, also the human heart seems to possess capacity to regenerate after ischemia.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Outcomes Assessor)
盲法说明
Patients are randomized to CABG or AAMs groups using block randomization via the online tool at www.sealedenvelope.com with block sizes 2 and 4, and stratification to sex (female, male). Randomization is carried out by the study nurse, who texts the Sealed Envelope service phone number 'AAMS2' and a command 'randomise', and the participant pseudonym. The allocation is received by a text message. The study nurse oversees the allocation in a double-blinded manner, where the patient and the evaluating cardiologist and radiologists remain blinded. Given the nature of the treatment (AAMs-processing vs. no processing) it is impossible to blind the operating surgeon or the study nurse to the allocations intraoperatively. However, the surgeon is blinded when planning the anastomoses. All LGE-CMRI and TTE measurements as well as laboratory analyses are done by those blinded to the allocations.
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
- •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 or LVEF ≥ 50% in preoperative LGE-CMRI
- •Preoperative LGE-CMRI has not been performed prior scheduled CABG
结局指标
主要结局
Change in the amount of myocardial scar tissue
时间窗: 6 months
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
时间窗: 6 months
Measured from blood sample at preoperative visit, 3-month, and 6-month follow-ups
次要结局
- Efficacy: Change in left ventricular ejection fraction(6 months)
- Efficacy: Change in Canadian Cardiovascular Society (CCS) class(6 months)
- Efficacy: Deaths due to primary cardiovascular cause(6 months)
- Efficacy: Changes in the quality of life(6 months)
- Efficacy: Change in left ventricular wall thickness(6 months)
- Efficacy: Change in New York Heart Association (NYHA) class(6 months)
- Efficacy: Local changes in systolic and diastolic function(6 months)
- Efficacy: Changes in myocardial strain and LVEF(6 months)
- Safety; in-hospital infections(1 week, up to 10 days)
- Efficacy: Change in viable left ventricular myocardium(6 months)
- Efficacy: Change in movement, systolic or diastolic function of the left ventricle(6 months)
- Efficacy: Major adverse cardiovascular and cerebrovascular events (MACCE)(6 months)
- Efficacy: Postoperative days in hospital(1 week, up to 10 days)
- Feasibility: Waiting time for the AAMs patch(75-90 minutes from the start of CABG operation)
- Safety: telemetric monitoring of rhythm(4 days)
- 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)
- Feasibility: Waiting time in minutes for the heart(75-90 minutes from the start of CABG operation)
- Feasibility: Closing the right atrial appendage(1-5 minutes, at the decannulation phase at the end of CABG)
- Safety; need for vasoactive medication(up to 2 days after CABG)
- Observational: Blood and plasma long-read RNA sequencing, proteomics, and/or metabolomics(6 months)
研究者
Antti Nykanen
Docent Antti Nykänen, MD PhD
Hospital District of Helsinki and Uusimaa