London – Clonal genetic changes in blood or bone marrow cells are apparently a relevant risk factor for atherosclerosis. Nature Medicine Published Spanish study presented at the European Society of Cardiology (ESC) 2024 Congress reinforces the evidence for CHIP as a cardiovascular risk factor [1,2]CHIP stands for “clonal hematopoiesis of indeterminate potential” (see box on the last page for definition).
In their longitudinal cohort study, Dr. Miriam Diez-Diez and her colleagues enrolled 3,692 participants who were between 40 and 55 years old at the start of the study and were examined three times during the 6-year study. The subjects’ DNA was sequenced and imaging was used to look for atherosclerotic plaques in the femoral artery.
The researchers were able to show that CHIP increases the risk of developing atherosclerosis in the femoral artery in 3 years by a factor of 2.1. However, no increase in blood cell clones could be detected due to existing atherosclerosis.
Study shows: CHIP promotes atherosclerosis
“The study shows that people with clonal hematopoiesis actually have a higher risk of developing atherosclerosis. It thus refutes the assumption that clonal hematopoiesis is only a sign of existing atherosclerosis. The point of contention of the past 2 or 3 years as to whether there is exclusively reverse causality has thus been put to rest,” explains Prof. Dr. Andreas M. Zeiherinternist and cardiologist, who has held a Distinguished Professorship at Goethe University Frankfurt since 2021.
The study shows that people with clonal hematopoiesis actually have a higher risk of developing atherosclerosis. Prof. Dr. Andreas M. Zeiher
He refers to a recent paper in Nature Communications with over 4,000 patients who were examined over 20 years, which reached similar results to the Spanish study. “This is certainly a first step towards establishing clonal hematopoiesis as a risk factor in the foreseeable future,” says Zeiher to Medscape.
Also Prof. Dr. Stefanie DimmelerDirector of the Institute for Cardiovascular Regeneration at the Johann Wolfgang Goethe University in Frankfurt am Main, assesses the Science Media Center (SMC) the study results confirm that CHIP promotes atherosclerosis.
As an “important further development” Prof. Dr. Christoph Binderdeputy head of the Department of Medical and Chemical Laboratory Diagnostics at the Department of Laboratory Medicine, Medical University of Vienna, the results. Due to the highly sensitive sequencing method, both the prevalence of CHIP and the pathophysiological relevance of clone size have been redefined, said Binder.
According to Dr. Moritz von Scheidtspecialist in cardiology and head of the special consultation on clonal hematopoiesis (CHIP) at the German Heart Center in Munich, the study provides crucial new insights into the temporal connection between CHIP and atherosclerosis. “The current results suggest that a relevant proportion of CHIP mutations were simply not detected in previous studies,” says Scheidt. He describes CHIP as a “relevant, clinically neglected cardiovascular risk factor”. One in three CHD patients, he reports, is affected by CHIP.
It is still too early to include it as a risk factor in the guidelines
The fact that CHIP is associated with atherosclerosis, stroke, heart attack and a shortened overall survival is knownAnimal studies have shown that CHIP mutations trigger inflammatory reactions in the body. This promotes cardiovascular risk processes. In a feedback mechanism, these could then again trigger CHIP support financially.
The currently known “classic” risk factors such as hypercholesterolemia or high blood pressure are only responsible for about 50% of the resulting cases of atherosclerosis. According to Zeiher, we are not yet ready to include CHIP as an independent risk factor – comparable to smoking, hypertension, diabetes and hypercholesterolemia – in the guidelines. There is still a lot of information missing on this.
“We will get this evidence, possibly not only for atherosclerosis itself, there is also evidence that the progression of heart failure is accelerated via CHIP. But at the moment, classifying clonal hematopoiesis as a risk factor would be too early,” Zeiher clarifies.
At the moment, it would be too early to classify clonal hematopoiesis as a risk factor. Prof. Dr. Andreas M. Zeiher
Another aspect that is not yet clear is the amount of mutated blood cells that must be present for atherosclerosis to develop. The Spanish paper provides evidence that progression is less with fewer mutated blood cells, but more with more mutated cells. “You would have to create and set a cut-off for this – for example for troponin or NT-proBNP,” explains Zeiher.
In Germany, 8 million people are affected by clonal hematopoiesis
According to estimates by the Society for Hematology and Oncology, around 8 million people in Germany are affected by clonal hematopoiesis. In comparison, around 5.7 million people in Germany suffer from type 2 diabetes. What is particularly worrying is that one in three patients with established coronary heart disease is also affected by CHIP.
“Despite this prevalence, current guidelines do not provide specific recommendations for screening or therapy for CHIP. This underscores the urgent need to develop and implement targeted prevention and treatment strategies,” explains Scheidt.
Despite this prevalence, current guidelines do not provide specific recommendations for screening or treatment of CHIP. Dr. Serena L. Orr
According to Binder’s assessment, the identification of CHIP in patients can contribute to risk stratification, while Dimmeler sees CHIP as a previously unknown additional “unmodifiable” risk factor that could play a significant role in prevention. Scheidt also emphasizes that early detection of CHIP could enable targeted prevention before cardiovascular events occur.
General screening is still premature
At the initiative of the German Center for Cardiovascular Research, CHIP clinics have been set up in Frankfurt, Munich and Heidelberg, where patients are examined for the presence of mutated blood cells. However, the costs of sequencing are still very high. According to Dimmeler, however, cheaper alternatives are already being developed that should cost less than 100 euros.
Scheidt can imagine screening population groups at risk, such as those with previous cardiovascular diseases. “However, I think general screening for CHIP is premature, especially since we currently have only limited therapeutic options,” emphasizes Zeiher.
However, I think that general screening for CHIP is premature, especially since we currently have only limited therapeutic options. Prof. Dr. Andreas M. Zeiher
2 studies with new anti-inflammatory drugs are underway
Clonal hematopoiesis is probably associated with increased inflammatory activity of the blood cells, so an anti-inflammatory therapy would be appropriate, explains Zeiher. This is also supported by the results of a study in European Heart Journal showing that patients with clonal hematopoiesis who received colchicine for gout had fewer cardiovascular events.
There are some indications that anti-inflammatory therapy is particularly effective, but this also needs to be investigated prospectively, says Zeiher. Two larger Studies with new anti-inflammatory drugs. Zeiher expects that reliable results will be available in 2 to 3 years.
Scheidt, who is also chairman of the non-profit German CHIP Register which cares for over 2,500 patients, reports that current therapy consists of adjusting lifestyle and medication to reduce cardiovascular risk factors. Potential anti-inflammatory therapies target NLRP3 inflammasome-mediated signaling pathways. This includes specific (e.g. canakinumab – an antibody against interleukin-1-beta) and non-specific (e.g. colchicine) therapy options.
What does CHIP mean?
Clonal hematopoiesis of indeterminate potential (CHIP) refers to the presence of clonal genetic alterations in blood or bone marrow cells in the absence of signs of hematological neoplasia and the absence of cytopenia.
CHIP is a benign phenomenon that occurs in some people during the aging process: mutations occur in one or more blood stem cells or blood precursor cells. The resulting blood cells are called blood cell clones. However, mature blood cells can also develop mutations.
If the proportion of blood cells that belong to the blood cell clone reaches at least 4% of the blood cells, this means a variant allele frequency (VAF) of 2%. From this value onwards, the condition is referred to as CHIP. Every 10th person over the age of 60 has CHIP, and the frequency increases with age.
CHIP is rare in people under 40 years of age and increases steadily after 65 years of age. In older people, it affects between 10 and 40%, although the prevalence also depends on the sensitivity of the diagnostic sequencing method. dependsBut younger people can also develop smaller blood cell clones.
There are numerous CHIP mutations, the most common of which include changes in the DNMT3A and TET2 genes. DNA sequencing These CHIP mutations can be found in the blood.