Scientists Discover New Cardiovascular Risk Factor and Identify Drug That Can Reduce Its Effects

In addition to the known risk factors for cardiovascular diseases (high blood pressure, high cholesterol, diabetes, overweight and obesity, smoking and a sedentary lifestyle), there is a new risk factor: clonal hematopoiesis. This pathology is triggered by acquired mutations in blood stem cells and was already known to be associated with a high cardiovascular risk.

However, until now it was unclear whether clonal hematopoiesis was a cause or a consequence of cardiovascular disease.

Now, a new study published in Natural medicine and carried out by researchers from the Centro Nacional de Investigaciones Cardiovasculares (CNIC), resolves this crucial debate by establishing clonal hematopoiesis as a new risk factor for atherosclerosis, the formation of lesions in the arterial wall that underlies most cardiovascular disorders.

In a second study, published in the European Heart JournalCNIC scientists propose that colchicine, an ancient drug, should be the central pillar of personalized strategies to mitigate the effects of clonal hematopoiesis associated with acquired TET2 mutations. The results of these important studies were presented at the European Society of Cardiology meeting in London, UK.

Acquired mutations in blood cell lines: a new cause of atherosclerosis

An adult produces hundreds of thousands of blood cells every day. This high rate of cell division inevitably leads to the accumulation of DNA mutations in the dividing cells. These mutations are called somatic mutations and are acquired, not inherited.

“Although most somatic mutations are harmless, some give affected cells a competitive advantage that allows them to grow and gradually accumulate, generating clonal populations of mutated blood cells, a phenomenon known as clonal hematopoiesis,” explained José Javier Fuster, who led the team. Natural medicine study.

These mutations had previously been proposed as a possible risk factor for cardiovascular disease; however, the exact nature of the relationship remained unclear.

As Dr. José Javier Fuster, coordinator of the CNIC’s “New Mechanisms of Atherosclerosis” program, explains, “some previous studies have suggested that somatic mutations related to clonal hematopoiesis contribute directly to cardiovascular diseases and thus accelerate the development of atherosclerosis.

“Others, however, have suggested that it is atherosclerosis that causes clonal hematopoiesis by increasing the proliferation of blood stem cells and thus generating a higher proportion of mutated blood cells.”

THE Natural medicine Study clarifies relationship between clonal hematopoiesis and atherosclerosis through longitudinal analysis of data from the PESA-CNIC-Santander study. PESA (Progression of Early Subclinical Atherosclerosis) is a prospective study of more than 4,000 apparently healthy middle-aged participants who have undergone periodic examinations using advanced imaging technology since 2010 to detect the presence and progression of asymptomatic atherosclerosis. PESA is a collaborative initiative of CNIC and Banco Santander.

“The PESA study has already made very important contributions to our understanding of cardiovascular disease, and its longitudinal nature and unique characteristics provide an ideal setting to carry out this important study on the relationship between clonal hematopoiesis and atherosclerosis,” said Dr. Valentín Fuster, CNIC Director General, PESA principal investigator and co-senior author of the study. Natural medicine study.

Researchers used high-sensitivity DNA sequencing technology to detect somatic mutations in blood samples and assessed the presence and progression of atherosclerosis detected by noninvasive imaging techniques in PESA participants.

“The study was the result of a multidisciplinary effort involving specialists in basic sciences and cardiology, as well as the specialized technical expertise of the CNIC’s bioinformatics, genomics and clinical trials units,” said José Javier Fuster.

The study results clearly demonstrate that participants who had clonal hematopoiesis-related mutations at the start of the study were more likely to develop atherosclerosis in the following years. In contrast, the presence and extent of atherosclerosis had no influence on the expansion of mutated blood cells.

“These results indicate that the mutations contribute to the development of atherosclerosis but are not a consequence of it,” explained co-first author Miriam Díez-Díez.

“It remains possible, however, that other factors, such as genetic profile or lifestyle, may modulate the effects of clonal hematopoiesis, and future studies are planned to examine this possibility,” added Beatriz L. Ramos-Neble, the study’s other co-first author.

The results of the study have clear clinical implications and identify clonal hematopoiesis as a cardiovascular risk factor completely different from the traditional risk factors studied in recent decades. This novelty is promising for the development of new strategies for the prevention of cardiovascular disorders.

“By demonstrating that mutations related to clonal hematopoiesis precede atherosclerosis and contribute to its development, our research suggests that blocking the effects of these somatic mutations could help prevent cardiovascular disease,” says Dr. José Javier Fuster. The second CNIC study, published in the journal European Heart Journallays the foundation for this.

Old drug to alleviate new cardiovascular risk factor

The best-characterized mutations related to clonal hematopoiesis are those affecting the TET2 gene. In a 2017 study published in ScienceDr. José Javier Fuster’s team has shown that mutations in the TET2 gene accelerate the development of atherosclerosis in animal models.

In the new study published in the European Heart JournalThe CNIC group, in partnership with the team led by Dr. Pradeep Natarajan at the Broad Institute in Boston, demonstrates that the adverse effects of TET2 mutations on cardiovascular health can be mitigated by treatment with colchicine, an anti-inflammatory drug.

The CNIC team demonstrated that administering colchicine to animals with TET2 mutations slows the development of atherosclerosis at a rate similar to that observed in non-mutated animals. In parallel, scientists at the Broad Institute showed that individuals with TET2 mutations who were treated with colchicine for other pathologies had a lower risk of myocardial infarction than untreated patients with similar mutations.

Herbal preparations containing colchicine have been used for thousands of years in traditional medicine, and the drug is used in modern medicine to treat inflammatory conditions such as gout.

“Colchicine is a very cheap drug, available worldwide, and approved for the prevention of cardiovascular diseases by the European Medicines Agency and by the FDA in the United States. Therefore, there are no major obstacles to its use for the prevention of cardiovascular diseases in people with TET2 mutations,” emphasized Dr. María Ángeles Zuriaga, who led the experimental studies at CNIC and is the first author of the study. European Heart Journal study.

Dr. José Javier Fuster highlighted the study’s important implications for personalized medicine.

“In clonal hematopoiesis, each mutated gene acts through different mechanisms and will therefore likely require specific interventions to target its effects. This study lays the foundation for the use of colchicine for/in the personalized prevention of cardiovascular disease in TET2 mutation carriers, but further clinical trials will be needed to conclusively demonstrate its efficacy in these individuals.”

Provided by the Centro Nacional de Investigaciones Cardiovasculares Carlos III (FSP)