For decades, doctors have fought heart disease by managing common risk factors like high blood pressure, high cholesterol, and diabetes. Medications such as aspirin and statins have helped millions, yet heart disease remains the leading cause of death in the United States. Many people still suffer heart attacks even after keeping these traditional risks under control.
Now, scientists at the University of Michigan have discovered a new clue that could explain why heart disease continues to affect so many people.
Their research points to a protein made by the immune system called suPAR (soluble urokinase plasminogen activator receptor), which appears to directly cause atherosclerosis, the buildup of plaque that narrows and hardens the arteries.
Atherosclerosis is a major cause of heart attacks and strokes, and it affects more than a billion people around the world. It happens when fatty deposits build up in the walls of arteries, making it harder for blood to flow and increasing the risk of deadly cardiovascular events.
SuPAR is made in the bone marrow and helps control the immune system, acting like a thermostat for inflammation in the body. Scientists already knew that people with high suPAR levels were more likely to develop heart disease. But until now, no one had proven that suPAR actually causes the disease.
In this new study, the researchers first looked at data from over 5,000 people without any known heart disease. They found that people with higher levels of suPAR were much more likely to develop atherosclerosis, regardless of whether they had high cholesterol or high blood pressure.
To understand why some people have higher suPAR levels, the team studied genetic data from 24,000 people. They found a specific genetic variant in a gene called PLAUR, which is responsible for producing suPAR. People with this genetic change had higher suPAR levels, and importantly, they also had a higher risk of atherosclerosis.
The researchers confirmed these findings using Mendelian randomization, a research method that uses genetic data to study cause-and-effect relationships. In a group of 500,000 people from the UK Biobank, and in two other large datasets, they found that this genetic variant was strongly linked to both higher suPAR levels and atherosclerosis.
To back this up, the team ran experiments on mice. When the mice were given high levels of suPAR, they developed many more atherosclerotic plaques in their aortas—the major blood vessels leading from the heart—than mice with normal suPAR levels. These results provided solid evidence that suPAR plays a direct role in damaging arteries.
What makes this discovery so important is that suPAR is not affected by current heart disease treatments. Cholesterol-lowering drugs like statins do not lower suPAR. This means suPAR could be a completely new target for treatment—something doctors haven’t had until now.
The researchers, led by Dr. Salim Hayek, are now working on new treatments that could safely reduce suPAR levels to prevent or slow the development of heart disease.
This breakthrough could also help explain why kidney disease and heart disease often appear together. Earlier research had already linked suPAR to kidney damage. In the U.S., about 1 in 7 people have kidney disease, and nearly two-thirds of them also have heart disease.
In fact, over 40% of people with heart disease also show signs of kidney problems. Since suPAR may play a role in both, targeting it could help treat or prevent both conditions at once.
The study was published in the Journal of Clinical Investigation and could change the way doctors approach heart disease, offering new hope to millions of patients who continue to face this deadly illness, despite doing everything right.
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