The latest research has found a possible way to prevent long-lasting scarring and heart failure after a heart attack. A recent study conducted by Massachusetts General Hospital (MGH), which is part of the Mass General Brigham (MGB) healthcare system, has identified a crucial step in aiding the human heart in regenerating after a heart attack. This study involved comparing the formation of scar tissue in the injured hearts of zebrafish and mice, and has potentially unlocked the key to reversing the permanent scarring that can be detrimental to mammal hearts.The findings of the research are now available in Nature Communications.
Lead author Eman A. Akam-Baxter, PhD, who is an investigator at the MGH Cardiovascular Research Center and instructor in Medicine at Harvard Medical School, comments, “We have become the first to directly compare and demonstrate significant differences in the formation of scar tissue between zebrafish and mammals. The results of our study suggest a potential new target for reversing scarring after myocardial infarction, which has not been previously demonstrated.”
When a myocardial infarction occurs, it leads to the death of a large number of heart cells. In order to repair the damage, the body replaces the damaged and dead cells.Scars are a normal part of the healing process after a heart injury. They help to initially keep the heart intact, but over time they can make it harder for the heart to pump blood effectively. This can lead to permanent damage as the scar tissue expands due to an overworked heart.
Unlike other mammals, zebrafish have the unique ability to completely remove scar tissue after a heart injury. This allows new cardiac cells to regenerate and fully regrow a healthy heart. Researchers have been studying the properties of zebrafish in hopes of finding ways to apply this regenerative ability to human hearts.David Sosnovik, MD, the senior author of the paper, explained that they studied the cardiomyocytes (heart muscle cells) and immune cells in the zebrafish heart to understand this phenomenon. He also mentioned that previous studies did not characterize the nature of the collagen scar in zebrafish, but with the expertise of Dr. Akam-Baxter in synthetic and analytical chemistry, they were able to approach the problem from a new angle.
Up until now, it was not possible to examine scar tissue formation in the small zebrafish heart through imaging. In order to do so, the researchers had to develop a molecular imaging probe called TMR-O, which allowed them to see details of the process.The research focused on the scarring found in the hearts of zebrafish and mouse models after cardiac injury. Scar tissue is mainly made up of collagen, which is a protein that forms long strands and binds together to create the structure of scar tissue. The process of collagen molecules binding is known as cross-linking. The researchers designed a probe that attaches to each hand of the cross-linked collagen, producing a fluorescent response. Akam-Baxter explained that cross-linked collagen can be visualized as a network of long protein strands linked together with hands clasping each other like a handshake.Researchers have long thought that the level of collagen cross-linking determines whether a scar is permanent or can be absorbed. However, when MGH investigators tested this theory, they found that the zebrafish and mice had similar amounts of cross-linking after cardiac injury, but the type of cross-link was different. In the mouse heart, the collagen cross-links were highly mature and formed a structure that couldn’t be broken down by the body’s antifibrotic enzymes. In contrast, the zebrafish had looser cross-links.andshake,” states Akam-Baxter. “The connections in the zebrafish heart remained in an immature chemical form that can be broken down, allowing the fibrotic scars to be absorbed and replaced with regenerated heart cells.”
The researchers also demonstrated that the connections that develop in mouse hearts are due to a chemical alteration (lysine hydroxylation) of the collagen strands in mice, which does not occur to the same extent in the zebrafish heart.
This alteration is carried out by an enzyme called lysyl hydroxylase 2; this enzyme is associated with permanent scarring in other organs in.disease caused by fibrosis.”
Akam-Baxter states, “No one has explored the impact of blocking this enzyme in the context of a heart attack.” Her team is currently researching whether inhibiting this enzyme can effectively prevent permanent scarring in the heart following a heart attack. Additionally, the researchers will be examining the possibility of reversing scar tissue in other organs.
“The significant number of deaths and the extent of heart failure that arises from scarring after a heart attack are alarming,” explains Akam-Baxter. “Furthermore, fibrotic diseases are responsible for a substantial number of deaths. If we can identify a common factor for reversing scar tissue in multiple organs, it could potentially lead to groundbreaking treatments.”The research conducted at MGH was highly multidisciplinary and made possible by the unique research environment. Dr. Sosnovik, the director of the Program in Cardiovascular Imaging in the Martinos Center for Biomedical Imaging, stated that researchers from the Cardiovascular Research Center, the Institute for Innovation in Imaging, and the Martinos Center for Biomedical Imaging all contributed different skills that allowed them to collaboratively address a challenging scientific question.
