by Sangrag Ganguli and Uche C. Ezeh
figures by Rebecca Clements

Every year, thousands of people are rushed into hospitals with crushing chest pain and shortness of breath. While some recognize these signs of a heart attack in time to receive proper treatment, over half a million others are not so fortunate. To combat these fatalities, doctors often warn patients about the common risk factors of cardiovascular diseases. Our understanding of these risk factors can be traced back to the long-running Framingham Heart Study. In the 1960s, this study demonstrated how certain factors such as age, smoking, obesity, high blood pressure, high cholesterol, and sedentary lifestyle can increase the risk of morbidity and mortality associated with cardiovascular diseases. While these well-known risk factors still hold true, researchers may have discovered a new risk factor that could better predict certain types of heart disease. This risk factor is called clonal hematopoiesis of indeterminate potential, commonly referred to as CHIP. Before defining CHIP in the context of heart diseases, we must first understand how cardiovascular diseases begin.

What causes cardiovascular disease?

Cardiovascular disease encompasses various conditions, many of which are linked to a process known as atherosclerosis. Atherosclerosis refers to the narrowing of blood vessels (specifically, arteries) that typically occurs due to the buildup of plaques, which are deposits of substances from the blood such as calcium, fat, and cholesterol. The likelihood of developing atherosclerosis increases with age, and scientists once believed that it was driven by a defect in fat storage; however, accumulating evidence supports the notion that inflammation may be the true culprit behind this condition.

On a biological level, inflammation is the body’s immune response to something it perceives as dangerous, such as a wound or a bacterial infection. Notably, the presence of arterial plaques can also alert the immune system, leading to the accumulation of immune cells called macrophages in the early stages of atherosclerosis. These macrophages take up residence inside the plaques, where they exacerbate plaque formation. Eventually, circulating blood that encounters this growing plaque begins to clot, and this series of events leads to a major disruption of blood flow, often resulting in a heart attack.

What is CHIP?

The critical role of the immune system in heart disease is well established, but it was not until recently that scientists began to uncover the reasons behind this maladaptive immune response. Surprisingly, the underlying problem may lie in our blood stem cells.

Blood stem cells are a very unique and specialized type of cell in the human body. These cells have two defining characteristics, the first of which is immortality. Most cell types have a set lifespan after which they cease to divide and become stagnant or die off. Stem cells, on the other hand, are able to self-renew to maintain a constant stem cell population within the body. Their second defining characteristic is the ability to develop into other types of blood cells. By their very nature, blood stem cells are undifferentiated, meaning that they do not have a specialized set of functions that, for example, a macrophage or a red blood cell could have. Blood stem cells, then, are the source of every other cell type in the blood, including all of the white blood cells that comprise our immune system (Figure 1).

Typically, this hierarchical structure of stem cell renewal and blood cell formation works very well. But what happens when a stem cell acquires a mutation, or a change to its DNA? Because of the critical role of blood stem cells in generating all other blood cell types, a mutation in a stem cell can have far-reaching consequences in an individual. Specifically, if a blood stem cells acquires a mutation, this mutation will be present in all stem cells produced through self-renewal, and it will be propagated through all other types of blood cells when the stem cell differentiates. This accumulation of mutant blood stem cells can result in a condition called CHIP, or clonal hematopoiesis of indeterminate potential (Figure 2).

The likelihood of CHIP increases dramatically with age, because the longer a person lives, the more likely it is that their blood stem cells acquire mutations and the more time there is for these stem cells to divide. In fact, CHIP mutations are present in around 10% of people aged between 71 to 80 years. Recently, researchers have begun drawing a parallel between CHIP and another common age-related disease: atherosclerosis. Although this is still a very active area of research, scientists hypothesize that CHIP mutations may impact the macrophages that infiltrate arteriole plaques to exacerbated heart disease. Specifically, imagine that a stem cell acquires a CHIP mutation and that, via differentiation, it passes this CHIP mutation down to other blood cells—including macrophages. This inherited CHIP mutation may then alter macrophage behavior in a way that favors plaque formation. For example, a common CHIP mutation in a gene called Tet2 can cause macrophages to become pro-inflammatory. High levels of inflammation then contribute to the buildup of plaques in arteries, which plays a critical role in accelerating atherosclerosis and cardiovascular disease.

Future of CHIP

While the causes and effects of CHIP is still incompletely understood, there are undoubtedly important clinical implications of these mutations. As we enter an era with the highest life expectancies ever, age-related diseases will receive more attention. We now understand that accumulated mutations in our stem cells correlate with heart diseases. Because this connection between CHIP mutations and heart diseases is mediated by inflammation, many have begun to wonder if CHIP mutations might also be relevant in other age-related inflammatory conditions. For instance, 17% of patients with rheumatoid arthritis, an inflammatory disease that causes joint swelling and pain, had these CHIP mutations. Additionally, the presence of CHIP mutations in these patients could explain why inflammatory diseases such as rheumatoid arthritis increases the risk of developing heart diseases. As such, CHIP may potentially explain the age-related prevalence of inflammatory conditions. However, more studies are necessary to confirm this speculation.

While research supports the idea that individuals with CHIP mutations are at increased risk of heart diseases as compared to those without these mutations, it begs the question of whether it is beneficial to preventatively screen for CHIP. Preventative screenings are typically performed on people who do not demonstrate clinically overt symptoms, and currently, physicians agree that it might be premature to spend thousands of dollars to determine if you contain any CHIP mutations. Although CHIP is a strong predictor of heart conditions, we are still unsure of ways of curbing the risks associated with CHIP; therefore, it may not be worthwhile to invest in screening patients without any symptoms. Given the likelihood for CHIP mutations to arise spontaneously, screening may also foster a false sense of security among patients. However, individuals who harbor these mutations are in need of monitoring for disease progression and management of risk factors associated with cardiovascular diseases.

Physicians and scientists have been fascinated by mutant blood stem cells for years, and recent research has led to many groundbreaking observations. CHIP may explain the age-related risk of cardiovascular diseases and shed light upon how macrophages drive inflammation to contribute to atherosclerosis and cardiovascular disease. Further, it is possible that CHIP underlies multiple other inflammatory disorders normally associated with the aging process. While it would be too soon to establish causality, we are excited that these new findings may open new avenues for cardiovascular research and novel treatment.

Sangrag Ganguli and Uche C. Ezeh are graduate students.

Rebecca Clements is a third-year Ph.D. candidate in the Biological and Biomedical Sciences program at Harvard. You can find her on Twitter as @clements_becca.

For more information:

• To learn more about CHIP and its relevance in heart conditions, check out this article from the New York Times.
• To learn more about the findings of research on CHIP, check out this article from the American College of Cardiology.