The Persistent Impact of Atherosclerosis

Mauricio Wajngarten, MD


October 20, 2021

Atherosclerosis accounts for thousands of deaths around the world. Some degree of atherosclerosis was reported in more than 42% of Swedes 50 to 64 years of age with no known heart disease, according to data from the Swedish CArdioPulmonarybioImage Study (SCAPIS). This corroborates results from the Cardiovascular Health Study, which revealed a high prevalence of atherosclerosis with prognostic impact in people older than 65 years.

Despite advances in the prevention and treatment of atherosclerosis and cardiovascular disease, challenges remain.

A timeline of the two types of advances — those derived from clinical studies and those derived from basic research on the pathogenesis and physiopathology of atherosclerosis — is outlined in a recent commentary, published in Nature Reviews Cardiology, by Peter Libby, MD, from Brigham and Women’s Hospital in Boston.

Clinical studies drive laboratory research, which, in turn, leads to practical applications, he explains. On the timeline of clinical advances, Libby touches on pivotal moments, from the description of angina by William Heberden in 1772 all the way to the CANTOS trial in 2017 that established the efficacy of anti-inflammatory therapy in atherosclerosis.

In the search for ways to reduce the impact of atherosclerosis, we have seen (only) three basic research studies in the 21st century. It is worth paying attention to them.

The first, which defined the role of PCSK9 in the cellular regulation of low-density lipoprotein (LDL), was incorporated into clinical practice with the approval of PCSK9 inhibitors in 2015.

The second, which led to the recognition of clonal hematopoiesis as a risk factor, has not yet been incorporated into practice. (Note that in a previous commentary published on Medscape, I mentioned this biological phenomenon when discussing whether or not aging is a disease.)

The process of clonal hematopoiesis is characterized by somatic mutations in hematopoietic stem cells that then replicate the same mutations. Over time, these cells make up an increasing percentage of stem cells and can accelerate inflammation. Although clonal hematopoiesis is rare in young people, it affects up to 10% of people older than 70 years and is associated with increases in coronary artery calcification and significant increases in the risk for myocardial infarction.

The third, and most recent, basic-research advance mentioned by Libby was CRISPR editing of the PCSK9 gene in primates.

The impact of a single-nucleotide loss-of-function CRISPR-induced PCSK9 mutation on LDL-cholesterol levels in nonhuman primates is explored in a recent study by Musunuru et al published in Nature. That team demonstrated that lipid nanoparticles could deliver CRISPR adenine base editors to monkeys and induce the mutation. These base editors were confirmed in primary human hepatocytes, primary monkey hepatocytes, and mice.

In vivo CRISPR delivery led to a near-complete knockdown of PCSK9 in the liver after a single infusion of lipid nanoparticles, with concomitant reductions in blood levels of PCSK9 and LDL cholesterol of about 90% and 60%, respectively. These changes were sustained for at least 8 months. No relevant adverse effects were seen in the animals treated with CRISPR. Off-target gene editing was found at only one site in monkey liver; no off-target editing was found in human hepatocytes.

Some key points from this loss-of-function study were simplified for clinicians in a commentary by Francesco Paneni, MD, from the Center for Molecular Cardiology at the University of Zürich, and Massimo Volpe, MD, from the Department of Clinical and Molecular Medicine, Sapienza University of Rome.

"Individuals with spontaneous loss-of-function PCSK9 mutations experience a significant reduction of both LDL cholesterol levels (∼30–40%) as well as cardiovascular disease risk (88%), and appear free from adverse clinical consequences," the pair write.

"Gene-editing technologies, which include CRISPR-Cas nucleases and CRISPR base editor, have the potential to permanently modify disease-causing genes. The demonstration of durable editing of PCSK9 in target organs is a key step before in vivo administration of specific gene editors in clinical trials," they add.

The commentary concludes that the CRISPR study paves the way for a broad application of CRISPR editor delivery for the treatment of dyslipidemia, as well as a wide panel of monogenic human diseases. However, the text emphasizes that the potential risks of this approach must be carefully weighed against their benefits.

Have we found a new way, a new avenue, to combat atherosclerosis? Let’s hope so!

This article originally appeared in the Portuguese edition of Medscape.

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