2024-09-05 09:45:06
To the already known cardiovascular risk factors such as high blood pressure, high cholesterol, diabetes, obesity and overweight, smoking and physical inactivity, we must add a new one: clonal hematopoiesis. Clonal hematopoiesis is caused by acquired mutations in blood stem cells. It is known that this phenomenon is associated with a greater risk of cardiovascular disease, but until now it has not been clarified whether it is the cause or the result of cardiovascular disease. In a new study, published in the journal Nature Medicine, it has finally been clarified that it is the cause of cardiovascular disease and not the result.
This study was carried out by researchers from the National Center for Cardiovascular Research (CNIC) in Spain and several groups from the Biomedical Research Network for Cardiovascular Diseases (CIBERCV) in Spain.
Also, in a second study, published in the academic journal of the European Heart Journal, CNIC experts suggest an old drug, colchicine, as a personal strategy to reduce the effects of clonal hematopoiesis associated with changes of you get the TET2 gene.
The results of these two important studies were presented at the Congress of the European Society of Cardiology held recently in London (United Kingdom).
Acquired changes in blood: a new cause of atherosclerosis
We know that an adult produces hundreds of billions of blood cells every day, which leads to the accumulation of changes in the DNA of some of these cells. These changes are called somatic and they are acquired, not inherited. “Although most of them are harmless, some give the affected cells a competitive advantage that allows them to expand continuously, producing clonal populations of blood cells that reproduce, a phenomenon known in clonal hematopoiesis,” explained José Javier Fuster, researcher at CIBERCV at CNIC and director of the study published in Nature Medicine.
Although these mutations have previously been proposed as a possible cardiovascular risk factor, the exact nature of the relationship between clonal hematopoiesis and cardiovascular disease is unclear. José Javier Fuster points out that some studies “suggest that somatic mutations linked to clonal hematopoiesis contribute directly to cardiovascular disease by increasing the development of atherosclerosis. “In contrast, others suggest that atherosclerosis actually causes clonal hematopoiesis by increasing the proliferation of red blood cells, leading to a higher percentage of differentiated blood cells.”
In a study published in Nature, the relationship between clonal hematopoiesis and atherosclerosis was described. To this end, a longitudinal study was conducted using data from PESA-CNIC-Santander (Progression of Early Subclinical Atherosclerosis). PESA is a prospective study of more than 4,000 apparently healthy participants who have been periodically examined with advanced imaging techniques since 2010 to detect the presence and development of of atherosclerosis. PESA is the result of a collaboration between CNIC and Banco Santander. “The PESA study has made very important contributions to our knowledge of cardiovascular disease and its long-term nature and unique characteristics provide the best framework to conduct this important research on the relationship between clonal hematopoiesis and atherosclerosis,” says Valentin Fuster. of CNIC, principal investigator of PESA and co-chair of the study.
The team uses highly sensitive DNA sequencing techniques to detect somatic mutations in blood samples and non-invasive sequencing techniques to assess the presence and progression of atherosclerosis. “This work has been a multidisciplinary effort, in which basic scientists and cardiologists have participated, as well as technical experts from the Bioinformatics, Genomics and Clinical Trials Units of the CNIC,” said José Javier Fuster.
Two of the study authors published in Nature Medicine. From left to right: Valentin Fuster and José Javier Fuster. (Photo: CNIC)
The results of the study are clear: people with mutations linked to clonal hematopoiesis at the beginning of the study are more likely to develop atherosclerosis in the following years. However, the presence or extent of atherosclerosis does not affect the proliferation of altered blood cells. “These data show that these changes contribute to the development of atherosclerosis, but not its result,” explained Miriam Díez-Díez, co-author of the study. “We cannot exclude, however, that other conditions, such as genetic inheritance or lifestyle, can change the effects of clonal hematopoiesis, a possibility that will be examined in the near future,” Beatriz L. Ramos, co- add. author of the study.
For the research group, clinical effects are evident. Clonal hematopoiesis is a new cardiovascular risk factor, completely different from the traditional risk factors studied in recent decades. Therefore, it is promising for the development of new strategies for the prevention of cardiovascular diseases. “By demonstrating that mutations linked to clonal hematopoiesis precede and contribute to the development of atherosclerosis, our study suggests that attacking the effects of these somatic mutations may help prevent cardiovascular disease, ” stressed José Javier Fuster.
A second study by CNIC researchers in which CIBERCV researchers also participated, published in the European Heart Journal, laid the foundations for this.
An ancient medicine for the last prevention of cardiovascular risk
Among the mutations linked to clonal hematopoiesis, the best characterized are those affecting the TET2 gene. In a 2017 study by José Javier Fuster, published in the journal Science, it was shown that mutations in this gene increase the development of atherosclerosis in animal models by causing negative inflammatory responses of the muscle. In a new study, published in the European Heart Journal, José Javier Fuster’s team, in collaboration with Pradeep Natarajan’s team, from the Broad Institute in the American city of Boston, suggests that the adverse effects of TET2 mutations on heart disease health and bleeding may decrease. including the anti-inflammatory drug, colchicine.
In studies in animal models, CNIC researchers demonstrated that treatment with colchicine attenuates inflammatory responses and the development of atherosclerosis in animals with mutant TET2 cells, making them comparable to those of non-mutant animals. In comparison, analyzes carried out at the Broad Institute showed that the risk of having a heart attack was reduced in people with TET2 mutations who were treated with colchicine for other diseases.
Five of the study authors published in the European Heart Journal. From left to right: Marta Amorós Pérez, Beatriz L. Ramos-Neble, Rosa Moro, Marian Zuriaga and José Javier Fuster. (Photo: CNIC)
Colchicine is a drug of plant origin, found in medicinal plants that have been used for thousands of years in traditional medicine. It is often used as an anti-inflammatory in other pathologies such as gout. “The most important thing is that it is a very cheap drug, available to almost everyone, and it has already been approved to prevent cardiovascular disease by the European and American Medicines Agency (FDA), which will be so that its use allows you to prevent the risk in one of the people who have changes. in TET2”, emphasizes María Ángeles Zuriaga, co-author of the study and responsible for the test analyzes at CNIC.
José Javier Fuster also highlighted the importance of the study in the field of personalized medicine: “In clonal hematopoiesis we found that each gene acts through different mechanisms and, therefore, different interventions are probably needed to reduce the your role. “This study raises the first stone for the use of colchicine as a personal treatment in people who carry TET2 mutations, but new clinical trials will be necessary to demonstrate its effectiveness.”
The study published in Nature Journal is titled “Unidirectional Association of Clonal Hematopoiesis with Atherosclerosis Development.”
The study published in the European Heart Journal is titled “Colchicine prevents accelerated atherosclerosis in TET2-mutant clonal hematopoiesis.” (Source: CNIC / CIBERCV)
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