Olalla Radio and his brother Esteban carry traces of the same disease in their genes: hypertrophic cardiomyopathy, the most common of hereditary heart conditions. But far from following the same path, the ailment that both suffer from has shown two very different faces: while she remains invisible and asymptomatic for Olalla, she has presented herself to Esteban in the most severe and disabling way.
Now science has illuminated the cause of this catastrophe. Thanks to experiments with a heart model made with stem cells from the brothers, researchers from the Bellvitge Biomedical Research Institute (Idibell) and the Family Heart Disease Unit of the Hospital of A Coruña (CHUAC), have discovered that an additional genetic variation in Esteban's disease is responsible for the fact that, in his case, the heart disease is expressed more severely.
The hypertrophic cardiomyopathy of these brothers from O Grove (Pontevedra) showed its face when Esteban, at just 15 years old, began to feel unwell and an electrocardiogram revealed that “there was something strange,” according to himself. Subsequent studies confirmed that he did indeed suffer from the disease, which involves a thickening of the muscle that surrounds the heart (myocardium) and can make it difficult for blood to leave the organ. The family also underwent genetic testing and both his sister Olalla and his father had the same diagnosis. Only the eldest brother was saved from this inheritance.
The disease, which affects one in every 500 people, is very complex, with different manifestations and many associated genetic variants. “There are patients who may be asymptomatic and others who may develop obstructive hypertrophic cardiomyopathy: the thickness is increased and the place where blood has to leave the heart is narrowed. The person has fatigue, chest pain, or syncope. And it is the most common cause of sudden death in athletes,” explains Roberto Barriales, coordinator of the Family Heart Disease Unit of the CHUAC and doctor of the Radio brothers.
Esteban, who is now 41 years old, says that in his case, it was not until he was well into his twenties that he began to present the most serious symptoms and, over the years, things have gotten worse. “I felt fatigue, it made me tired, I got dizzy… But until seven or eight years ago I started to get arrhythmias, I lived a more or less normal life. Between 2014 and 2019 I had a bad time because my heart was losing its youth and I began to notice palpitations and discomfort,” he says.
Barriales explains that hypertrophic cardiomyopathy is a family disease, which each patient has a 50% chance of transmitting to their descendants: “There are different pathogenic genetic variants, different genes involved. In 60% of cases we identify the genetic variant of the disease and this is very good because it helps with the prognosis and with family follow-up.” It may also happen, the doctor admits, “that the variant has been inherited and the disease is not going to develop. You can be a healthy carrier of a variant, but you can pass it on to your descendants. Because? Intrafamilial variability is something that is being studied and there may be another variant in another gene that causes you to modulate the disease. “You may need more than one pathogenic variant.”
The very different manifestations of the disease in this Galician family always caught the attention of their doctors. “Esteban had a severe phenotype and his sister and his father had a very mild form. “Esteban had a lot of hypertrophy, malignant ventricular arrhythmias, fatigue…” Barriales recalls. In fact, they had to give him an implantable automatic defibrillator (ICD) to restore his normal heart rhythm when he suffered from an arrhythmia. “The DAI saved my brother's life. He didn't find out, he thought he had syncope, but no. He has been given life for six years by the DAI,” says Olalla, who is now 43 years old and the disease, in his case, still does not show its face. “I have not had any type of symptoms. But since my offspring had a 50% chance of having the disease, I did the preimplantation genetic diagnosis and my daughter is now genetically free of this,” she says, relieved. Esteban's daughter does not have the disease either.
In search of individual genetic variants
Barriales remembers when Dr. Ángel Raya, coordinator of the Idibell Regenerative Medicine Program, contacted him in search of patients with the same characteristics as the brothers; That is, carriers of the same mutation that causes the disease but with different manifestations of the disease. The scientists' intention was to find the individual genetic variants responsible for each of the pathological manifestations. And the brothers threw themselves headlong into the studio: “We always lend ourselves to everything. I did it because of blind trust in the entire team [de Barriales]. Thanks to them, we have a serious disease under great control,” explains Olalla.
The idea was to use a heart model, with stem cells from Esteban and Olalla, to explain all these symptomatic differences between the brothers. “We had been generating genetically based disease models for some time using induced pluripotent cells, similar to those of patients. With organs like the brain or the heart you can't take out a piece and study it, so we use that trick of creating stem cells and seeing how they work,” explains Raya, leader of this project and researcher at ICREA (Catalan acronym for the Catalan Institution). of Research and Advanced Studies).
Each brother underwent a skin tissue biopsy and the cells obtained became stem cells, which have the ability to differentiate into any other type of cell. “Using skin cells, which are extracted from the buttock, they were dedifferentiated into stem cells and then differentiated again into cardiomyocytes, which are the cells of the heart,” describes Barriales. Using genetic editing techniques, such as the CRISPR tool, the researchers tried to identify the genetic variants of each brother and played by removing them and putting them in those heart models to see which ones caused each symptom.
With a specific variant, only present in Esteban's cells, the scientists saw “that the cardiomyocytes contracted abnormally, they had hyperexcitability,” Raya explains. And in subsequent tests with the heart models, they verified that, indeed, the brother's more severe symptoms were explained by the presence of this additional mutation. The research led by Idibell and which included the participation of CHUAC, the Josep Trueta Hospital of Girona and the National Center for Cardiovascular Research, has been published in the journal Circulation Research.
A much more accurate forecast
“The study with Raya has allowed us to answer the question of why the presentation is different in this family. And this can be repeated in other families to see what other variants of
uncertain significance can modify the phenotype of the disease to a more severe one,” reflects Barriales. The study sheds light on the prognosis of the disease and also opens the door to identifying potential therapeutic targets to find new drugs, adds the cardiologist: “We know that Olalla is not going to have a severe presentation because it lacks the other variant and now we also know that your prognosis is going to be good. For Esteban we do not have any genetic treatment to offer him, but he is in a trial for non-obstructive hypertrophic cardiomyopathy, with a drug that tries to take a little force from the heart so that it works better, because the excess force does not allow the organ to relax well.”
Raya believes that, in effect, her studies open a therapeutic door, but clarifies that it will be in the future. “We stay with diagnosis and prognosis,” she points out, but she does not rule out the study of “a collection of heart models with different mutations and testing new drugs that are coming out.”
This is not the first time that science has turned to modeling genetic diseases to unravel some of their enigmas. It has already been done with Fanconi anemia or Parkinson's, explains the researcher. And while it's a promising strategy, he admits it also has its limitations. “The main drawback is that a model is simplified versions of what you are modeling. If you need a lot of complexity, it's very difficult to model it. And there are also diseases that need very mature cells and the cells that we make are immature,” explains Raya.
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