Scientists pinpoint location of plaque ruptures, and a protein that predicts them

Scientists have uncovered new details about the mechanisms that cause plaques in arteries to rupture, paving the way for new tests to predict which patients are most at risk of a heart attack or stroke.

In the results of a study published June 5 in the Journal of the American College of Cardiology, researchers from Sweden’s Lund University described how they figured out precisely where plaques break away from arteries. Their experiments also reinforced a link between plaque rupture and increased levels of the enzyme MMP-9, which could be eventually used as a biomarker—or even a treatment target.

“Sadly, those of us who work clinically discover the plaque too late, when it has already ruptured and caused serious complications like sudden death, heart attack or a stroke,” lead researcher Isabel Gonçalves, M.D., Ph.D., said in a press release. “If we can learn more about the underlying mechanisms, we can initiate preventative measures or treat the dangerous plaques in time.”

Gonçalves’ team examined plaques in the carotid arteries from 188 individuals who had undergone carotid endarterectomy, a surgical procedure to remove plaque from the carotid artery. The carotid arteries are on each side of the neck, where they supply blood to the brain. Buildup of plaque there—called carotid artery disease—is behind up to a third of all strokes.

To carry out their research, the scientists started by using immunohistochemistry and electron microscopy to look at the plaques. They found that ruptures most often took place near the start of the plaque along the direction of blood flow, or the proximal portion of the plaque in the artery—the side closest to the heart. RNA sequencing showed that this area also had greater expression of genes associated with macrophages and other immune cells, making it more inflamed and rupture-prone.

There were other differences in gene expression too. One gene in particular, matrix metalloproteinase-9, or MMP9, was expressed at much higher levels in the area where the plaques were most likely to rupture. The MMP9 gene expresses the MMP-9 protein, which previously was found to be involved in the formation of rupture-prone plaques. Some scientists have claimed circulating levels of MMP-9 may even be a better predictor of cardiac events than troponin, the current biomarker for ischemic heart damage.

The Gonçalves lab reinforced the connection between MMP9 and plaque rupture by showing that gene expression of MMP9 was higher in plaque tissue from patients who had symptomatic carotid artery disease than in those who didn’t have symptoms. High MMP9 levels were also associated with a greater risk for future cardiovascular events. Going a step further, they used data from the UK Biobank to show a causal link between higher levels of circulating MMP-9 and the risk of developing coronary atherosclerosis.

“Our findings, using several different perspectives, suggest a strong role for MMP-9 as a prognostic marker and therapeutic target for [cardiovascular disease],” the researchers wrote in their paper.

The results come with limitations. For one, the team identified several other genes besides MMP-9 that were upregulated in the area where plaques most frequently ruptured, but it isn’t clear how involved they are in developing cardiovascular disease. (That said, genetic analysis showed that variants of these genes were linked to cardiovascular events, making a connection likely, the paper noted.) The findings also can’t be applied to other vascular regions where plaques form or earlier phases of atherosclerosis.

While there’s still much more to learn about the mechanisms behind plaque rupture, the researchers hope to see whether MMP-9 levels can be used to predict heart attack or a stroke. The team is also working on finding out if the protein could be targeted by therapies, though they’ll need to tread carefully due to its involvement in other processes, Gonçalves noted in the press release.