Mutated leukocytes as a cardiovascular risk factor

Unidirectional association between CHIP and atherosclerosis

In the current Spanish longitudinal cohort study, CHIP clones were detected by DNA sequencing of blood samples and atherosclerosis was detected by ultrasound examination of the femoral artery. The study was published in the journal Nature Medicine. The study period was six years. 3,692 healthy people took part. At the start, the participants were between 40 and 55 years old.

The results: CHIP increased the risk of developing atherosclerosis in the femoral artery within three years by a factor of 2.1. Conversely, no increase in blood cell clones was found in people who already had atherosclerosis. The researchers concluded from this that CHIP promotes unidirectional atherosclerosis. Previously, it was assumed that there was a mutual interaction between vascular damage and CHIP.

In addition, the prevalence of CHIP in middle age is 6%, three times higher than previously thought. Deep genome-wide sequencing revealed at least one mutation associated with CHIP in 25% of the participants. Somatic mutations in DNMT3A-Gen and TET2-Gene were the most common. Women had a 64% higher risk, regardless of age DNMT3Agene mutation than men. Otherwise, the research group does not report any gender-specific differences.

The study results suggest that CHIP is an independent risk factor for atherosclerosis and related diseases [5].

Prevention of CHIP mutation

The “classic” risk factors for atherosclerosis account for approximately 50% of cases, says Prof. Dr. Stefanie Dimmeler, Director of the Institute for Cardiovascular Regeneration at the Johann Wolfgang Goethe University in Frankfurt am Main. Obesity, high blood pressure, elevated non-HDL cholesterol levels, smoking and diabetes increase the likelihood of a cardiovascular event and overall mortality. [1]CHIP could be one of the previously unknown additional “unmodifiable” risk factors and play an effective role in prevention.

Targeted prevention strategies that address the mutated leukocytes could reduce the risk of suffering a stroke or heart attack in mutation carriers. However, current guidelines do not provide any recommendations for screening or treatment of CHIP. Dr. Moritz von Scheidt, Specialist in cardiology and head of the special Clonal Hematopoiesis course at the German Heart Center Munich, summarizes the prevention potential as follows: “The automatic speech recognition [von Blutzell-Klonen] could make it possible to develop and implement targeted prevention strategies before cardiovascular events occur. Screening in population groups at risk would be practical, particularly in elderly patients or those with previous cardiovascular disease (for example, in patients aged 50 and over with proven atherosclerosis or in patients aged 60 and over with two cardiovascular risk factors).”

Soon a medicine at CHIP?

The interleukin-1 beta antibody canakinumab targets the NLRP3 inflammasome-mediated signaling pathway and therefore has an anti-inflammatory effect. In a multicenter study with 338 heart attack patients who received canakinumab once daily for three months, participants with CHIP had fewer serious cardiovascular events than patients without CHIP. In particular, participants with TET2-Mutation and CHIP substances from the active substance, compared with patients without CHIP [3].

The alkaloid colchicine is often discussed in CHIP, but randomized studies are lacking. In studies, the active ingredient was able to reduce the occurrence of cardiovascular events regardless of CHIP status. [4]

^literature

^{[1] The Global Cardiovascular Risk Consortium. Global impact of modifiable risk factors on cardiovascular disease and mortality. Global impact of modifiable risk factors on cardiovascular disease and mortality | New England Journal of Medicine (nejm.org}

^{[2] What is CHIP? German CHIP Register eV 2023, What is CHIP? – German Chip Register – German CHIP Register (chip-register.de)}

^{[3] Svensson EC et al. TET2-driven clonal hematopoiesis and response to canakinumab. JAMA 2022, TET2-driven clonal hematopoiesis and response to canakinumab: an exploratory analysis of the CANTOS randomized clinical trial | Genetics and Genomics | JAMA Cardiology | JAMA Network}

^{[4] Tardif J et al. Efficacy and safety of low-dose colchicine after myocardial infarction. The New England Journal of Medicine 2019, doi: 10.1056/NEJMoa19123}

^{[5] Diez-Diez M et al. Unidirectional association of clonal hematopoiesis and atherosclerosis development. Unidirectional association of clonal hematopoiesis with the development of atherosclerosis | Nature Medicine}