Curbing inflammation could reduce heart disease risk linked to blood disorder

More than 1 in 10 adults over the age of 70 have a blood disorder called clonal hematopoiesis of indeterminate potential, or CHIP, in which some blood stem cells become too abundant because of acquired cancer-predisposing mutations. CHIP can lead to cancer, but the biggest health risk from the disorder may be a heart attack or stroke.

Researchers from the Broad Institute of MIT and Harvard and Massachusetts General Hospital (MGH) have found that a common variant in the gene for an inflammatory molecule reduces that risk, suggesting that therapeutically blocking inflammation could help prevent cardiovascular disease in some patients with CHIP.

“In the clinic, we now use a fairly standard cocktail of medicines such as statins and aspirin to prevent cardiovascular events, and those can be beneficial for people with CHIP,” said Pradeep Natarajan, associate member at the Broad Institute, director of preventive cardiology at MGH, and assistant professor of medicine at Harvard Medical School. “Here we’ve defined a subset of individuals who may one day benefit even more from an additional completely different therapy.”

Featured in Circulation, the work builds upon years of research by MGH, Broad, Brigham & Women’s Hospital, and Dana-Farber Cancer Institute scientists, who first identified CHIP as a risk factor for cancer. In this condition, some blood stem cells acquire mutations in the TET2 and DNMT3A genes that allow them to divide more rapidly in the blood, which can lead to blood cancer.

But the greater health risk from CHIP may be cardiovascular disease. Natarajan and other Broad and MGH scientists, including institute members Ben Ebert and Sekar Kathiresan (on leave), previously showed that having one of the CHIP-related mutations nearly doubles the risk for coronary heart disease. The affected stem cells also appeared to be “hyper-inflammatory,” expressing high levels of inflammatory molecules that can lead to the buildup of plaques that clog arteries.

In the new study, Natarajan and his team, including Broad researchers Alexander Bick, an internal medicine resident at MGH, and James Pirruccello, a cardiology fellow at MGH, tested whether curbing inflammation could help reduce cardiovascular disease risk in people with CHIP. They examined exome sequence data from 35,000 participants in the UK Biobank who did not have cardiovascular disease at study baseline, and followed their health for an average of seven years.

The team found that people with CHIP at the start of the study had a greater future risk of a cardiovascular event (heart attack, coronary revascularization, stroke, or death) during the seven-year follow-up period. One third of those with the condition carried CHIP-related mutations in more than 10% of their blood cells, and these patients had an even greater risk of a cardiovascular event.

To test whether decreasing inflammation could reduce this risk, the researchers conducted a kind of natural experiment. Roughly one-third of people in the UK Biobank carry a common genetic variant in the gene for the inflammatory molecule known as the interleukin-6 (IL-6) receptor. The mutation disrupts IL-6 signaling in the cell to a similar degree as an FDA-approved IL-6 receptor inhibitor, so having the variant serves as a genetic proxy to inhibiting the inflammatory pathway with the drug.

The researchers found that among people with more advanced CHIP, those who carry the IL-6-inhibiting DNA variant had a 40 percent lower risk of future cardiovascular events than people who lack the variant. The reduced risk brought their rate of cardiovascular events down to that of individuals without CHIP. In people who don’t have CHIP, however, those who carry the IL-6 receptor variant didn’t see any significant reduction in cardiovascular risk — the variant seems to clearly be protective only for those with CHIP.

The findings suggest that blocking the IL-6 inflammatory cascade with a drug could help reduce heart disease risk in patients with CHIP, especially those who have the more advanced form of the condition. Additionally, the findings indicate that IL-6 inflammatory signaling blockade may be better suited for individuals with CHIP compared to those without for the purposes of reducing cardiovascular disease risk. Many drugs that target inflammatory pathways are on the market or in development, but more work is needed to test whether they could benefit people with CHIP.

“The goal of precision medicine is to identify patients who may uniquely benefit from specific therapies,” said Bick, a co-first author on the study who will present the work at the 2019 American Heart Association annual meeting. “For the past several decades, we’ve given everybody the same therapy because everyone benefits more or less equally. This paper shows for the first time that there may be a very specific targeted therapy that can further lower the risk of life-threatening cardiac events in some people with CHIP.”

The work was supported in part by a grant from the Fondation Leducq Transatlantic Networks of Excellence and the National Heart, Lung, and Blood Institute.