Ischemic heart diseases and heart attacks often cause irreparable damage in the heart muscle. The damage is caused by blockages in the coronary artery, which result in a lack of oxygen in the heart. These blockages can be treated with drugs, through catheterization or stenting, or a vein can be taken from another part of the body to bypass the blockages in a coronary artery bypass graft (CABG) surgery.
However, opening of the blockages does little to repair the tissue damage or the scarring of the heart muscle and the heart failure. Tissue damage and related effects cause a significant number of premature deaths and, even in milder cases, the impact on the quality of life is significant. The need for more effective treatments is clear. A new treatment method known as Cardiac Micrograft Therapy™ has been developed to make the modern treatments more effective.
The starting point of the developed treatment is to utilize the patient’s own cardiac tissue as a therapeutic graft, which can be done easily in connection to a CABG surgery. This approach is supported by the fact that, in practice, all patients approved for CABG surgery have some level of damage caused by a lack of oxygen in their heart muscle. A small sample of the patient’s cardiac tissue can be collected safely in connection to the surgery for the graft. In practice, this sample is removed from the atrial appendage, when the patient is connected to a cardiopulmonary bypass.
This treatment method has been developed so that it is possible to process this tissue into small micrografts with a diameter of a few dozen or hundreds of micrometers. In other words, the tissue is broken down into smaller pieces so that the properties of the tissue are maintained whilst the surface area increases. These grafts are then cleaned and positioned on top of the damaged area in the heart muscle with the help of a commercially available cell-free connective tissue matrix (epicardial application). In other words, the graft is made from the patient’s own cardiac tissue during the same surgery by a trained operating room nurse. The treatment supplements the CABG surgery and has practically no impact on the duration or risks of the surgery. The additional work done by the surgeon consists of attaching the graft over the damaged area with three stitches.
The basic starting points of the treatment were established around ten years ago, when an optimal approach was being sought by the researchers of the University of Helsinki and the surgeons of Helsinki University Hospital from the points of view of, e.g., the experiences gained from stem cell therapies and the practical implementation of cardiac surgeries. Laboratory tests have been completed over the years, as well as animal tests on small and larger animals and, most recently, a first-in-human study on six patients. The results have been encouraging in every phase and, subsequently, the safety of the treatment has been well established. The results gained from both animals and people indicate that the treatment has positive impacts. In the studies, the impact is visible in the walls of the heart chambers (ventricular wall) , which have become stronger, in addition to which there are indications of a reduction in the volume of scar tissue and its replacement with healthy tissue.
In the first study implemented on people, six patients were treated. The same study was also implemented on a comparison group of an equal size. Differences were observed between the treated patients and the comparison group in the thickness of the chamber wall, for example, which is critical for heart failure: Thickening was observed in all treated patients, the average growth being around 1 mm. In the comparison group, one person died of heart failure before the six-month control appointment, two manifested no change, and in three patients, the thickness of the chamber reduced (on average, by around 1.5 mm). Therefore, there are clear indications of positive impacts on the patients, but more extensive research is necessary to prove the effectiveness of the treatment reliably.
Key research results have been published in respected international peer-reviewed publication series and summarized below on this page. Case anecdotes from the first-in-human treatment was published by Lampinen et al.
The impact mechanism of the developed micrograft therapy is understood to be based on the fact that transplanted cells send signals through natural mechanisms and modulate inflammatory reactions. Various medicines and gene therapies are also being researched around the world that would enable similar effects. One approach is for example to utilize mRNA and plasmid DNA as messengers in the therapies.
EpiHeart has the expertise and equipment to support the dosing of such medicines into the heart. Already existing product portfolio enables the handling of samples parallel to the cardiac surgery and efficient delivery of the treatment. In-house product development allows also tailoring the solution for customer specific needs.
First-in-human clinical study
“Epicardial transplantation of AAMs was safe and feasible to be performed during CABG surgery. CMRI demonstrated an increase in viable cardiac tissue at the infarct site in patients receiving AAMs treatment. Transplantation of AAMs shows good clinical applicability as performed during cardiac surgery, shows initial therapeutic effect on the myocardium and has the potential to serve as a delivery platform for cardiac gene therapies.”
Nummi et al, 2021 , ' Epicardial Transplantation of Autologous Cardiac Micrografts During Coronary Artery Bypass Surgery ' , Frontiers in cardiovascular medicine , vol. 8 , 726889 . https://doi.org/10.3389/fcvm.2021.726889
LVAD + Cardiac Micrograft Therapy™ surgery with EpiHeart devices
Schmitto et al, 2023, ' Use of left atrial appendage as an autologous tissue source for epicardial micrograft transplantation during LVAD implantation ', Frontiers in cardiovascular medicine.
“In conclusion, our results demonstrate that the epicardially transplanted AAMs-enclosing matrix patch significantly improves myocardial function after ischemic damage. The composite graft’s therapeutic effect is mediated by a combination of mechanical support, via ventricular unloading, and an activation of myocardium-protecting pathways, cardio-regenerative signaling, and angiogenesis. These results strengthen the therapeutic profile of epicardial AAM patch transplantation as a cost-effective, clinically feasible cellular adjuvant therapy for myocardial rescue and repair.”
Xie et al, 2020 , ' Epicardial transplantation of atrial appendage micrograft patch salvages myocardium after infarction ' Journal of Heart and Lung Transplantation , vol. 39 , no. 7 , pp. 707-718 . https://doi.org/10.1016/j.healun.2020.03.023
Use of Left Atrial Appendage
"These studies consistently demonstrated that the LAA is a key reservoir of multiple types of progenitor cells. This is intuitive considering the unique embryonic development and fetal gene expression of the atrial appendages. The abundance of CPCs [cardiac progenitor cells] in the atrial appendages has therefore become the foundation of an evolving field of stem cell therapy: autologous atrial appendage transplantation. - AAMs [atrial appendage micrografts] activate several cardiogenic and cardioprotective pathways leading to enhanced contractility and reparative capabilities of the cardiomyocytes and decreased oxidative stress."
Alkhouli et al, 2023, 'Nonthrombogenic Roles of the Left Atrial Appendage: JACC Review Topic of the Week.' J Am Coll Cardiol. 2023;81(11):1063-1075. https://doi.org/10.1016/j.jacc.2023.01.017
“In conclusion, our results provide evidence of effectiveness and insight into the molecular mechanisms of left atrial appendage transplantation for heart failure. The therapy can easily be clinically administered, either as an epicardial tissue transplant or as epicardial left atrial appendage micrograft transplants, when mechanically minced during open heart surgery, as reported previously by us using the right atrial appendage. Given the excellent clinical applicability of atrial appendage epicardial therapy, further clinical trials evaluating therapy efficacy are warranted.”
Leinonen et al, 2022, Structural and Functional Support by Left Atrial Appendage Transplant to the Left Ventricle after a Myocardial Infarction. Int J Mol Sci. 2022 Apr 22;23(9):4661. https://doi.org/10.3390/ijms23094661
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