A new cardiovascular risk factor and a drug capable of treating it have been discovered

In addition to the already known cardiovascular risk factors such as high blood pressure, high cholesterol, diabetes, obesity and overweight, smoking and physical inactivity, a new one must be added: clonal haematopoiesis. Clonal haematopoiesis is caused by acquired mutations in blood stem cells. It was known that this phenomenon is associated with a higher cardiovascular risk, but until now it had not been defined whether it is a cause or consequence of cardiovascular disease. In a new study, published in the academic journal Nature Medicine, it has finally been clarified that it is a cause of cardiovascular disease and not a consequence.

This study was carried out by research staff from the National Centre for Cardiovascular Research (CNIC) in Spain and several groups from the Biomedical Research Centre on Cardiovascular Diseases (CIBERCV) in Spain.

In addition, in a second study, published in the academic journal European Heart Journal, CNIC specialists propose an ancestral medicine, colchicine, as a personalized strategy to mitigate the effects of clonal hematopoiesis associated with acquired mutations in the TET2 gene.

The results of these two important investigations were presented at the European Society of Cardiology Congress recently held in London (United Kingdom).

Acquired mutations in blood: a new cause of atherosclerosis

It is known that an adult person generates hundreds of billions of blood cells every day, which leads to the accumulation of mutations in the DNA of some of these cells. These mutations are called somatic and are acquired, not inherited. “Although most of them are harmless, some give the affected cells a competitive advantage that allows them to expand progressively, generating clonal populations of mutant blood cells, a phenomenon known as clonal hematopoiesis,” explains José Javier Fuster, a CIBERCV researcher at the CNIC and leader of the research published in Nature Medicine.

Although these mutations had already been proposed as a possible new cardiovascular risk factor, the exact nature of the relationship between clonal hematopoiesis and cardiovascular disease was not clear. José Javier Fuster points out that some studies “suggest that somatic mutations linked to clonal hematopoiesis directly contribute to cardiovascular disease by accelerating the development of atherosclerosis. In contrast, others propose that atherosclerosis actually causes clonal hematopoiesis by increasing the proliferation of blood stem cells, which leads to a higher proportion of mutant blood cells.”

The study published in Nature Medicine clarifies the relationship between clonal hematopoiesis and atherosclerosis. To do so, a longitudinal study was conducted using data from the PESA-CNIC-Santander (Progression of Early Subclinical Atherosclerosis) study. PESA is a prospective study of more than 4,000 apparently healthy middle-aged participants who have been periodically examined with advanced imaging technologies since 2010 to detect the presence and development of atherosclerosis. PESA is the result of a collaboration between the CNIC and Banco Santander. “The PESA study has already made very important contributions to our knowledge of cardiovascular disease and its longitudinal nature and unique characteristics provided an ideal framework to carry out this important study on the relationship between clonal hematopoiesis and atherosclerosis,” says Valentín Fuster, director general of the CNIC, principal investigator of PESA and co-leader of the study.

The team used highly sensitive DNA sequencing techniques to detect somatic mutations in blood samples and noninvasive imaging techniques to assess the presence and progression of atherosclerosis. “This work has been a multidisciplinary effort, involving basic scientists and cardiologists, as well as technical experts from the CNIC’s Bioinformatics, Genomics and Clinical Trials Units,” says José Javier Fuster.

Two of the authors of the study published in Nature Medicine. From left to right: Valentín Fuster and José Javier Fuster. (Photo: CNIC)

The results of the study are clear: people with mutations linked to clonal haematopoiesis at the start of the study were more likely to develop atherosclerosis in the following years. However, the presence or extent of atherosclerosis did not influence the expansion of mutated blood cells. “These data indicate that these mutations contribute to the development of atherosclerosis, but are not a consequence of it,” explains Miriam Díez-Díez, co-author of the study. “We cannot rule out, however, that other conditions, such as genetic inheritance or lifestyle, may modulate the effects of clonal haematopoiesis, a possibility that will undoubtedly be examined in the near future,” adds Beatriz L. Ramos-Neble, co-author of the study.

For the research team, the clinical implications are clear. Clonal hematopoiesis is a new cardiovascular risk factor, completely different from the traditional risk factors studied in recent decades. This makes it promising for the development of new strategies for preventing cardiovascular disease. “By demonstrating that mutations linked to clonal hematopoiesis precede and contribute to the development of atherosclerosis, our research suggests that attacking the effects of these somatic mutations could help prevent cardiovascular disease,” stresses José Javier Fuster.

The second study by CNIC researchers, in which CIBERCV researchers also participated, published in the European Heart Journal, lays the foundations for this.

An ancestral drug for the prevention of the last cardiovascular risk factor

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 academic journal Science, it was shown that mutations in this gene accelerate the development of atherosclerosis in animal models by causing exacerbated inflammatory responses in the artery wall. In the new study, published in the European Heart Journal, José Javier Fuster’s group, in collaboration with Pradeep Natarajan’s group from the Broad Institute in the American city of Boston, proposes that the adverse effects of TET2 mutations on cardiovascular health could be mitigated with an 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 TET2 mutant cells, making them comparable to that of non-mutant animals. In parallel, analyses carried out at the Broad Institute demonstrated that the risk of having a heart attack is attenuated in people with TET2 mutations treated with colchicine for other diseases.

Five of the authors of the study 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 plant-derived drug, found in medicinal plants that have been used for thousands of years in traditional medicine. It is frequently used as an anti-inflammatory in other pathologies such as gout. “The most remarkable thing is that it is a very cheap drug, accessible in almost the entire world, and already approved to prevent cardiovascular disease by the European Medicines Agency and the United States Food and Drug Administration (FDA), which would facilitate its use to prevent cardiovascular risk in people with TET2 mutations,” highlights María Ángeles Zuriaga, co-author of the study and responsible for the experimental analyses at the CNIC.

José Javier Fuster also highlights the importance of the study in the field of personalized medicine: “In clonal hematopoiesis, we find that each mutated gene acts through different mechanisms and, therefore, different interventions are probably required to alleviate its effects. This study lays the first stone for using colchicine as a personalized treatment in people with TET2 mutations, but new clinical trials will be necessary to demonstrate its efficacy conclusively.”

The study published in Nature Medicine is titled “Unidirectional Association of Clonal Hematopoiesis with Atherosclerosis Development.”

The study published in the European Heart Journal is entitled “Colchicine prevents accelerated atherosclerosis in TET2-mutant clonal haematopoiesis”. (Source: CNIC / CIBERCV)