New studies, including catastrophic genetic heart conditions, show that mutations in adhesive proteins (molecules that should support the heart) destroy the integrity of the outermost layers of organs, leaving patients vulnerable to sudden cardiac death. It suggests that it plays a role in
Epicardium, heartThe outer cloak of the hugs the myocardium (contractor). This is the thickest layer inside the organ.
Arrhythmogenic cardiomyopathy (ACM) is a heart disease characterized by ventricular arrhythmias that usually begins in adolescence or early adulthood. Arrhythmia refers to an arrhythmia, which can be too slow or too fast. Beating mistakes occur because the heart’s electrical impulses do not work properly. In the case of ACM, this condition increases the risk of fatal arrhythmias.
However, ACM is stealth and insidious and causes few noticeable symptoms in many patients other than palpitations and fainting. For others, the first evidence of ACM is sudden death. If a young athlete suddenly dies on a basketball court or soccer field, the cause is usually ACM.
Long ago studies revealed that men were at somewhat higher risk than women and the condition was genetic, but now scientists have found that adhesive proteins (molecular adhesions designed to hold). Began to reveal how certain genetic defects, including agents) Heart cells Together — instead weakens the mind.
The latest ACM study is the result of a series of sophisticated studies in the Netherlands that not only provide new insights into the genetics of disability, but also reveal possible paths to customized treatments. ..
Arwa Kohela and Evavan Rooij of the Hubrecht Institute of the Royal Netherlands Academy of Arts and Sciences in Dr. Utrecht say that the cause of heart disease is not a predictable place. They trace the genetic origin of this disorder to mutations in the desmosome gene, which encodes an adhesive protein that functions as a supporting complex for the heart. Austrian medical scientist Josef Schaffer coined the term “desmosome” from the Greek words desmo and body (soma) a century ago.
Desmosomes are special adhesive complexes that have adhesive-like properties and are responsible for maintaining the mechanical integrity of tissues. As a complex, desmosomes are composed of multiple proteins, many of which may contain mutations that are detrimental to ACM. For people with disabilities, desmosome-expressing cells are an important source of fibroblasts (cells that produce connective tissue) and adipose tissue.
Scientists at the Yubrecht Institute focus on the epicardium of the heart because the epicardium of the heart is a continuous layer and its cells retain the ability to proliferate and differentiate into other cell types throughout life. I am. Epicardial differentiation depends on the integrity of supporting proteins, especially desmosomes. Due to the close relationship between desmosomes and the epicardium, new Dutch studies suggest that the disease originates in epicardial tissue.
“Human arrhythmogenic cardiomyopathy (ACM) is characterized by ventricular fibrofat deposits, but the mechanisms responsible for these deposits are not well understood and the current animal model of ACM is this phenotype. Does not reproduce well, “Kohela claimed. ,report Scientific translation medicine..
During early embryonic heart formation, the epicardium gives rise to coronary smooth muscle cells and myocardial fibroblasts, which provide structural support for both developing embryos and later fully formed hearts. .. Essential to a healthy heart is the development of support proteins (desmosomes) that emerge from the epicardial tissue.
A 20-year-old study of the Greek population, which has a unique tendency for ACM, pointed to a disordered desmosome mutation, but Dutch scientists say that demosome defects weiray the epicardium very deeply. Further research was carried out to clarify the reason. Indeed, scientists were surprised to identify potential genetic roots for ACM in epicardial genes. This is because the effects of the disease are felt primarily in the heart muscle (the beating layer of the heart) and are the classic “love dub, love dub”. You can hear the sounds of the organs through the stethoscope.
This study opens a portal to a keen understanding of ACM. This is a condition that is estimated to affect 1 in 5,000 people in the United States. In other parts of the world, such as northern Italy, the prevalence reaches 1 in 1000. ACM has serious consequences for young patients, accounting for 10% of sudden cardiac deaths and 17% of sudden cardiac deaths under the age of 18. Under 35 years old.
This disorder is characterized by a range of problems, including the replacement of healthy myocardium with scar tissue and fat deposits. Heart damage is further characterized by inflammation, and at worst, general degeneration of the heart, so problems that interfere with the heart do not end there.
The replacement of healthy heart tissue with scar tissue and fat is due to progressive myocardial degeneration. Recognizing the heart arrhythmia that is a major feature of this disorder, some doctors call ACM “the most arrhythmia-causing heart disease known to humans.”
Upon entering their study, Kohela and van Rooij faced a particularly difficult problem: there is no suitable animal model for studying ACM. Experimental rodents do not produce the same type of heart fat as humans.
Kohela et al. Generated stem cells with mutations in the plakophilin-2 gene in ACM patients with the aim of overcoming the lack of an effective animal model. The plakophilin 2 gene is expressed in the myocardium and is found in desmosomes. Cells containing the mutated plakophilin 2 gene differentiated into epicardial cells.
Surprisingly, suddenly, these epicardial cells spontaneously underwent remodeling of fibrous fat. This is the same change as fibrotic and fatty deposits that replace healthy heart tissue in the disease.
“We study epicardial contributions to fibrofat remodeling in ACM using heart cultures derived from human induced pluripotent stem cells, single-cell RNA sequences, and explanted human ACM hearts. I did, “Kohela wrote. “Human induced pluripotent stem cells generated from ACM patients showed spontaneous fibroadipocyte differentiation not found in homogenic control.”
Sequencing and analysis of single-cell RNA, along with examination of the heart tissue of ACM patients, further revealed that a transcription factor known as TFAP2A mediates this catastrophic epicardial translocation. A Dutch team that has unveiled the detrimental role of this factor in ACM suggests that blocking TFAP2A may be an effective way to treat ACM.
Transcription factors are regulated by the TFAP2A gene, which provides instructions for making factors that are proteins. As the name implies, this factor plays a role in mediating DNA transcription. Transcription factors bind to specific regions of DNA and help control cell division and cell death (apoptosis).
Takeaway message from Dutch study: Epicardial differentiation facilitates remodeling of fibrous fat in arrhythmogenic cardiomyopathy.
New studies are part of the growing body of studies investigating the genetic forms of heart disease that affect young people. This disorder was investigated in the 20th century, but it wasn’t until 2000 that patient studies on the island of Naxos, Greece, led scientists to identify the ACM mutation that caused the first disease. did. Researchers have found that the inhabitants of Naxos had a rare recessive form of ACM.
Dr. Angeliki Asimaki of Harvard University spoke much of the history of ACM’s genetic research in a 2014 report of the journal Progress in Pediatric Cardiology, which outlines contributions from Naxos analysis. Asimaki et al. Stated that ACM “is a disease of desmoplakin and has paved the way for identifying mutations in the desmosome genes, including the genes encoding desmoplakin, plakophilin 2, desmocollin 2, and desmoglein 2.”
Asimaki et al. “ACM-related mutations exist from conception, but clinical phenotypes do not appear at least until adolescence or, more generally, early adulthood. Therefore, ACM in young individuals is before the risk of risk. Early recognition is extremely important. Fatal arrhythmias. “
Cohera and a Dutch collaborator say their work has identified factors that may be blocked, promising ways to treat this condition. “Although further research is needed, our findings suggest that inhibition of TFAP2A may be a target for treating ACM,” they conclude.
Arwa Kohela et al, Epicardial differentiation facilitates fibrous fat remodeling in arrhythmogenic cardiomyopathy, Scientific translation medicine (2021). DOI: 10.1126 /scitranslmed.abf2750
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