Irregular bone marrow cells may increase heart disease risk

Lowering blood pressure and cholesterol levels, quitting smoking, managing diabetes: these evidence-backed approaches remain key ways to reduce the risk of cardiovascular disease (SN: 11/9/15).

But an unexpected contributor to that risk has emerged in the past decade. Nothing can be done to specifically tackle this risk factor yet, but the discovery offers a new angle to understanding cardiovascular disease. And it might partly explain why some people develop the disease even when they don’t check the familiar boxes on the modifiable risk list. A 2021 Lancet study found that of just over 62,000 people who had had serious heart attacks from 2005 to 2018, 15 percent did not smoke and did not have high cholesterol, high blood pressure or diabetes.

The newly found risk arises from specialized cells, called stem cells, that live in the bone marrow. These cells can make copies of themselves or transform into blood and immune cells. Over time, the stem cells acquire genetic mistakes, giving some an edge in terms of self-renewal. Eventually, those stem cells can outnumber others in the bone marrow, providing more opportunities to pass the genetic errors on to blood and immune cells. This state, called clonal hematopoiesis of indeterminate potential, or CHIP, is one step on the path to potentially developing blood cancer.

But CHIP has also turned out to be linked to an increased risk of cardiovascular disease. And in terms of that risk, “it’s up there,” says Amy Lin, a cardiologist and physician-scientist at the University of California, San Fransisco. High blood pressure, excessive cholesterol and current or former smoking each increase the risk by a factor of 1.2 to 1.4, while CHIP ups the risk by a factor of almost 2. (Diabetes and older age, especially at 70 years and older, contribute even more to risk.)

Studies of CHIP in animals suggest what may be going on in people’s bodies to boost risk. In mice, CHIP increases inflammation and accelerates the buildup of fat-laden plaques in arterial walls, a process called atherosclerosis, which can lead to a heart attack.

As scientists develop a better understanding of its impact on inflammation and atherosclerosis, it’s possible that CHIP could be a target for treatment. “We‘ve got 10 [or] 15 years of really new science to do,” says cardiologist and physician-scientist Peter Libby of Brigham and Women’s Hospital and Harvard Medical School in Boston. Studying clonal hematopoiesis and how it influences the development of cardiovascular disease, Libby says, “is going to open up many many doors.”

CHIP and its tie to cardiovascular disease

The genetic errors connected to CHIP are not inherited. Instead, these mutations pop up over time. “As we age, we get mutations,” says oncologist and physician-scientist Kelly Bolton of the Washington University School of Medicine in St. Louis. “It’s just by chance.” When this happens in particular genes in a bone marrow stem cell, “it can lead that cell to have an advantage” in its ability to renew itself. The copies have the errors, as do the blood or immune cells derived from these stem cells.

Many people have CHIP by adulthood, “but it’s present at very low levels,” Bolton says. The degree of CHIP — and its overall prevalence — generally increases with age, as it can take time for a population of clones to grow. The larger the proportion of cells with errors in the genes tied to CHIP, the greater the risk of health issues, says Bolton. It’s a continuum.

Of the genes connected to CHIP so far, those that are most commonly mutated regulate other genes or respond to genetic damage. It takes additional genetic errors beyond the ones that kick off CHIP to develop cancer. People can have CHIP and never get cancer.

And it has turned out that there is more to CHIP than meets the eye. In 2014 in the New England Journal of Medicine, researchers reported on an analysis of DNA data from past studies totaling more than 5,000 people. The likelihood of dying from any cause was higher, by a factor of 1.4, for people with CHIP compared with people without it, over a period of roughly eight years. In a twist, “it wasn’t cancer-related deaths that people were dying of most often when they had CHIP,” says physician-scientist Siddhartha Jaiswal of the Stanford School of Medicine. “It was actually cardiovascular causes.”

“That was interesting to us,” Jaiswal says. In a follow-up study published in 2017 in the same journal, Jaiswal and colleagues analyzed DNA data from past studies of people with and without coronary heart disease, which occurs when plaques form in the arteries that provide blood to the heart. People with CHIP had a risk of developing coronary heart disease almost two times as high as those without. Forty of the 443 with coronary heart disease had CHIP compared with 37 of the 577 without the disease.

In the same study, Jaiswal and colleagues also investigated the impact of CHIP on mice bred to be more susceptible to developing plaques in their arteries. The mice received bone marrow transplants that either would or would not initiate CHIP. Then the mice were fed a high-cholesterol diet. The mice with CHIP had larger plaques and more inflammation compared with the mice without CHIP.

Molecular biologist Ken Walsh of the University of Virginia School of Medicine in Charlottesville and his colleagues reported similar findings in their 2017 Science study on the impact of CHIP in atherosclerosis-prone mice. Walsh’s team’s work also nodded toward the possibility that something could be done about the increased risk of cardiovascular disease from CHIP. When the researchers blocked excessive inflammation that occurred in the CHIP mice, there was no longer a difference in the size of their plaques compared with the non-CHIP mice. “We could reverse the effect” that CHIP had on the development of atherosclerosis in the mice, Walsh says.

CHIP as a potential treatment target

Research over the last few decades has indicated that chronic inflammation is a risk factor for cardiovascular disease. In general, plaques start forming with the accumulation of “bad” cholesterol and immune cells in the arterial wall, including cells called macrophages that try to gobble up the cholesterol. Inflammation plays a role in the formation of the plaque, and as the plaque comes together, it kick-starts a series of cellular actions that further amplify inflammation.

It looks like having CHIP adds even more inflammation, driven by the immune cells derived from the mutated stem cells. That’s suggested in the studies in mice, and in research on macrophages with errors in genes tied to CHIP, which has found the cells become “hyper-inflammatory,” Jaiswal says. “We think that having more immune cells in your blood vessel wall is bad. [CHIP] increases the amount of inflammation that the immune cells have. That leads to even more immune cells going to the area,” he says. “So it kind of just speeds the whole process” of plaque development.

It might be possible to block extra inflammation that comes from CHIP in people. That hint came from a large clinical study that began before the link between CHIP and cardiovascular disease was reported. The trial enrolled more than 10,000 participants who previously had had a heart attack; some received one of three doses of a treatment that blocks an inflammatory protein. The participants on 150 mg of the treatment had a slight reduction, 15 percent, in the risk of developing another heart attack or stroke or dying from cardiovascular issues compared with those not on the treatment. There were close to four of these cardiovascular events per 100 people per year in the treated group versus 4.5 events per 100 per year in the group not given the treatment.

However, the inflammatory protein targeted in the trial is also important for an effective immune response, and the treatment led to more fatal infections. In the end, the heart health benefit wasn’t enough to counter that infection risk.

But when the clinical trial team learned of the effect of CHIP on cardiovascular disease, the group, which included Peter Libby, wondered: “If CHIP is involved in inflammation and we’ve got an anti-inflammatory, could we get a bigger bang in people who had CHIP?” Libby says.

Although the clinical trial had concluded, the team had blood samples for nearly 4,000 participants. There were 338 with CHIP. Those who had errors in one of the main genes tied to CHIP, called TET2, had a 62 percent reduction in the risk of developing a heart attack or stroke or dying from cardiovascular issues, Libby and colleagues reported in 2022 in JAMA Cardiology. “Lo and behold,” Libby says, people with TET2 CHIP “had an outsized benefit” from the treatment.

Figuring out how inflammation and CHIP are involved in cardiovascular disease “does not displace or demote” contributions from excessive cholesterol, high blood pressure or other modifiable risk factors, Libby says. “By no means do we think CHIP is the be–all and end–all or the only cause of atherosclerosis — it works together with the standard risk factors to boost your risk.”

As of now, there isn’t a way to specifically temper CHIP’s impact on cardiovascular disease risk. So it would not be helpful for most people to learn whether they have CHIP. Nor is that testing widely available. CHIP tends to be discovered when people undergo genetic testing because they have cancer or symptoms suggestive of cancer. At this point, trying to prevent cardiovascular disease in those with CHIP relies on modifying the standard risk factors.

Beyond the treatment potential, research into CHIP may also prove helpful in explaining two mysteries: why some people who don’t have the familiar risk contributors can still develop cardiovascular disease, and why the likelihood of developing the disease increases with age. “People have always thought that there’s still some sort of dark matter out there,” Walsh says. “So maybe what’s filling some of this void — some — is clonal hematopoiesis.”