Mutated stem cells emerge as a major cause of heart attacks and stroke, as deadly as high blood pressure or cholesterol

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It’s widely known that cancer is driven by the build-up of mutations in the DNA of cells. Everything from pollutants to cigarettes to exposure to everyday chemicals can alter genes, and continued exposure over a lifetime can lead to a critical mass of mutations. Research now shows that the same process can cause heart disease and stroke. 

One of the more enduring puzzles in medicine has been why so many people who have heart attacks or strokes have few or no conventional risk factors. These are patients with normal levels of cholesterol and blood pressure, no history of smoking or diabetes, and no family history of cardiovascular disease. This hidden risk has been the “dark matter” of cardiology - an invisible force that lands tens of thousands of patients in hospital each year. But now researchers may have gotten a glimpse of part of it.

In a paper published in the New England Journal of Medicine, Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease (available on NEJM in full text via CKN), a team of researchers led by Dr. Sekar Kathiresan, from the Broad Institute of Harvard and MIT, and Dr. Benjamin Ebert from Brigham and Women’s Hospital in Boston, found cumulative gene mutations that build up over a lifetime can double the risk of heart events. They discovered an age-related condition in which mutated hematopoietic stem cells (found in bone marrow) gradually take over, increasing a person’s risk of dying within a decade by 40% to 50% - usually from a heart attack or stroke. The condition, called “clonal hematopoiesis of indeterminate potential” (CHIP) has emerged as a major risk for heart attack and stroke that is as powerful as high LDL or high blood pressure. 

CHIP was discovered independently by several groups of researchers who were not even investigating heart disease. Mostly, they were looking at the genes of patients who might develop leukaemia or, in one research project, schizophrenia. The researchers investigated datasets from four large genetic studies involving over 8,000 people whose genomes had been sequenced. To their great surprise, the teams converged on the same phenomenon. Unexpectedly large numbers of study participants had blood cells with mutations linked to blood cancers — but they did not have cancer. Instead, they had just one or two mutation clusters. In those clusters the four most common driver mutations were in the DNMT3A, TET2, ASXL1, and JAK2 genes, which were already individually associated with coronary disease as well as preclinical disease in terms of coronary-artery calcification.

Dr. Benjamin Ebert, chair of medical oncology at the Dana-Farber Cancer Institute, was the first to see the link. He turned for help to Dr. Sekar Kathiresan.

Kathiresan and his team actually identified the gene mutations several years ago when they linked it to a 10-fold higher risk of developing blood cancers, such as leukaemia, lymphoma and myeloma. Although the mutations increased cancer risk, the cancers were still relatively rare, but people who had them had a 40% higher risk of dying of other causes. Among those was heart disease, and the mutations seem to have a stronger effect on heart disease than cancer.

The investigators mapped out the broad outline of what was happening. White blood cells, the attack dogs of the immune system, arise from stem cells in the bone marrow. Every day, a few hundred such stem cells produce blood cells that begin dividing rapidly into the 10 billion needed to replace those that have died. Sometimes, by chance, one of those marrow stem cells acquires a mutation, and the white blood cells it produces carry the same mutation.

Some mutations are just markers of past events without any lasting consequence. But others, especially those linked to leukaemia, seem to give stem cells a new ability to accumulate in the marrow. The result is a sort of survival of the fittest, or fastest growing, stem cells in the marrow. The mutated stem cells outlast normal stem cells in the marrow, and their progeny — an increasing percentage of white blood cells — show up in the blood with mutations.

The big surprise came when the researchers looked at the medical records of people with these white blood cell mutations. They had a 54% increase in the chances of dying within the next decade, compared to people without CHIP. And the cause: heart attacks and strokes.

They confirmed that CHIP doubled the risk of a heart attack in typical patients, and increased the risk fourfold in those who had had heart attacks early in life. The condition becomes more likely with age. Up to 20% of people in their 60s have it, and perhaps 50% of those in their 80s.

“This is a totally different type of risk factor than hypertension or hypercholestserolemia or smoking,” Kathiresan said.

“And since it’s a totally different risk factor that works through a different mechanism, it may lead to new treatment opportunities very different from the ones we have for heart disease at present."

But how might mutated white blood cells cause heart disease? One clue intrigued the researchers. Artery-obstructing plaque is filled with white blood cells, smouldering with inflammation and subject to rupture. Perhaps mutated white cells were causing atherosclerosis or accelerating its development.

When the researchers gave mice a bone-marrow transplant containing stem cells with a CHIP mutation they learned more about how a cancer-causing gene can contribute to heart disease. Mutated blood cells began proliferating in the mice, and they developed rapidly growing plaques that were burning with inflammation. It appears that the CHIP mutations cause atherosclerotic plaques in the blood vessels, which contributes inflammation and hardening of the arteries that can trigger heart attacks. It also raises the possibility that CHIP may be involved in other inflammatory diseases, like arthritis.

There’s still a lot to learn. As exciting as the findings are, it’s still too early to add CHIP testing to routine blood screening to identify people at higher risk of having heart problems. And because CHIP contributes to heart disease in a new way, it’s possible that the mechanisms to control CHIP-related heart events have nothing to do with cholesterol, exercise and blood pressure. “The mouse work suggests that the path to heart disease is something different from what we have been working on so far,” says Kathiresan.

For now the researchers advise against testing for CHIP, since there is nothing specific to be done to reduce the increased risks of cancer or heart disease that it confers. At the moment, CHIP is mostly found accidentally in patients who are genetically tested for other reasons. While there are genes associated with greater heart disease risk, most of them are inherited. The new mutations linked to heart problems are among the first known to be acquired, or picked up over a lifetime — most likely by bad luck or exposure to toxins like cigarette smoke. There is little that patients can do.

More work needs to be done to determine if there are ways to counteract the effect of the mutation on plaques or control the rate at which the mutations build up in these cells. “Currently there isn’t a drug that’s safe enough or efficacious enough to treat people with CHIP,” says Ebert. “But it’s a very active area of research to identify interventions that can decrease the size of the mutated cell population or potentially eliminate them.”

For people who do have CHIP, the best advice is to control all heart disease risks, like cholesterol and blood pressure, with a healthy diet and exercise – something that we should all be doing anyway. 

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