Role of clonal hematopoiesis as a broad driver of atherosclerosis

A group at the Centro Nacional de Investigaciones Cardiovasculares (CNIC), collaborating with institutions in the USA, has shown that acquired mutations in the gene encoding the protein p53 contribute to the onset of atherosclerotic cardiovascular disease.

Considered the Genome’s Guardian, p53 serves to protect the integrity of hereditary material within cells by controlling different cell processes in response to cellular stresses.

An adult produces hundreds of thousands of blood cells per day. While essential, this process inevitably encourages the formation of mutations in the progenitor cells that are accountable for this creation.

The presence of acquired p53 gene mutations in blood cells raises the chance of developing cancer, especially blood malignancies.

The CNIC team led by José Javier Fuster illustrates in the new research, published in Nature Cardiovascular Research, that p53 mutations also promote the onset of atherosclerosis, the actual cause of most cardiovascular disease, which is the leading cause of death worldwide and places an immense burden on health-care systems.

The researchers evaluated sequencing data from more than 50,000 people's blood cells in partnership with groups led by Derek Klarin at Universidad de Stanford, Pradeep Natarajan at Hospital General de Massachusetts, and Alexander Bick at Universidad de Vanderbilt.

We found that carriers of acquired mutations in p53 had a higher risk of developing coronary heart disease and peripheral artery disease, and this effect was independent of established cardiovascular risk factors like hypertension or elevated blood cholesterol.”

Dr José Javier Fuster, Centro Nacional de Investigaciones Cardiovasculares

In light of these findings, the CNIC researchers conducted functional experiments in animal models of atherosclerosis in which they introduced cells with p53 mutations.

The findings revealed that mice with these mutations developed cardiovascular disease more quickly, owing to an unusually high proliferation rate of immune cells in the arterial walls.

This combination of observations in humans with experimental studies in animals provides solid evidence that these mutations increase the risk of developing cardiovascular disease.”

Dr José Javier Fuster, Centro Nacional de Investigaciones Cardiovasculares

For Dr Valentín Fuster, CNIC General Director, President of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital and an author of the study, the results “broaden our knowledge of how the acquisition of mutations in blood cells, a phenomenon called clonal hematopoiesis, acts as a cardiovascular risk factor.”

Earlier research [published in 2021 in The Journal of the American College of Cardiology (JACC)] by the same group demonstrated that many of these mutations, such as those affecting the TET2 gene, contribute to the onset of cardiovascular disorders such as atherosclerosis and heart failure.

Now, “as well as validating that earlier study, our new results extend our findings to include mutations in p53 and the development of peripheral artery disease, a condition that is especially prevalent in the elderly population,” says Dr José Javier Fuster.

The researchers emphasize that mutations in different genes lead to cardiovascular disease in different ways.

In the future, this could be exploited to design personalized prevention strategies targeting the specific effects of different mutations.”

Nuria Matesanz, Study Co-First Author and Scientist, Centro Nacional de Investigaciones Cardiovasculares