Scientists are one step closer to understanding sudden cardiac death

heart attack concept

Sudden cardiac arrest is a potentially fatal condition in which your heart suddenly stops beating.

Arrhythmogenic cardiomyopathy, a heart disease that particularly affects young athletes, can lead to sudden death. The University of Basel recently developed genetically modified mice that develop a disease similar to humans. The team was able to identify previously undiscovered mechanisms and potential treatment targets.

Fans of Sevilla FC soccer team will never forget the August 2007 game when 22-year-old Antonio Puerta suffered a cardiac arrest, collapsed on the field and eventually died in hospital. It was later determined that the athlete suffered from a condition known as arrhythmogenic cardiomyopathy.

This inherited disorder affects one in 5,000 people, with men being more affected than women. “Arrhythmogenic cardiomyopathy leads to cardiac arrhythmia with loss of heart muscle cells, deposits of connective tissue and fat in the heart muscle. This can lead to sudden cardiac death, often under stress,” says Volker Spindler, anatomist and head of the Cell Adhesion working group in the Department of Biomedicine at the University of Basel.

It is now recognized that a number of gene mutations can trigger the disease. There is no treatment, even with an early diagnosis; Only symptom treatment options are available.

“Patients are advised to avoid any competitive and endurance sport and to take medication such as beta blockers. If necessary, a catheter ablation can be performed or an implantable defibrillator can be used,” says cardiologist Gabriela Kuster, head of the myocardium research group at the Institute of Biomedicine. Sometimes the only option is a heart transplant.

Heart muscle cells lose their stickiness

The project started with the idea that many of the mutations affect structures known as desmosomes. These are protein clusters on the surface of heart muscle cells that ensure a firm connection between the cells. “You can imagine these clusters as a piece of Velcro,” says Dr. Camilla Schinner, first author of the study just published in the journal Circulation. This led to the theory that the mutations reduce adhesion between cells, thus weakening the heart muscle.

To test this hypothesis, Spindler’s team introduced a patient-like mutation into the genome of mice. The heart function of these animals was then studied by Kuster’s group. The result: The genetically modified animals showed a heart disease with arrhythmia, which was similar to the arrhythmogenic cardiomyopathy in humans. In addition, microscopic and biochemical analyzes actually showed reduced adhesion between the heart muscle cells. The researchers also observed the scarring of the heart muscle that is typical of this disease.

prevent damage to heart tissue

In a next step, they investigated how a diseased heart muscle differs from a healthy one at the molecular level. Mice with the mutation showed an increased amount of a specific protein on the Klett-like structures of heart muscle cells. This leads to connective tissue deposition and scarring of the heart through a series of events. The addition of a substance that blocks this cascade prevented the disease from progressing – which is why Spindler sees a possible new treatment approach here.

“Nevertheless, there is still a long way to go before an application in humans can be considered,” he emphasizes. “But we now have better ways to study the disease in more detail to improve our understanding of the underlying mechanisms.”

Reference: “Defective Desmosomal Adhesion Causes Arrhythmogenic Cardiomyopathy by Involving an Integrin-αVβ6/TGF-β Signaling Cascade” by Camilla Schinner, Lifen Xu, Henriette Franz, Aude Zimmermann, Marie-Theres Wanuske, Maitreyi Rathod, Pauline Hanns, Florian Geier, Pawel Pelczar, Yan Liang, Vera Lorenz, Chiara Stüdle, Piotr I. Maly, Silke Kauferstein, Britt M. Beckmann, Farah Sheikh, Gabriela M. Kuster and Volker Spindler, October 21, 2022, edition.
DOI: 10.1161/CIRCULATIONAHA.121.057329

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