For decades, doctors have tackled heart disease by focusing on well-known risk factors—high blood pressure, high cholesterol, and diabetes. Medications like aspirin and statins have helped millions, yet heart disease remains the leading cause of death in the United States. Alarmingly, many people still suffer heart attacks even when these traditional risk factors are well-managed.
Now, researchers at the University of Michigan have identified a new piece of the puzzle that could explain why.
Their study highlights a protein called suPAR (soluble urokinase plasminogen activator receptor), produced by the immune system. Unlike cholesterol or blood pressure, suPAR appears to directly cause atherosclerosis—the buildup of plaque in the arteries that can lead to heart attacks and strokes.
Atherosclerosis affects more than a billion people worldwide. It occurs when fatty deposits accumulate along artery walls, restricting blood flow and increasing the risk of serious cardiovascular events.
SuPAR is produced in the bone marrow and acts like an inflammation “thermostat” in the body. Scientists already knew that people with elevated suPAR levels had a higher risk of heart disease, but this study is the first to show that suPAR may be a direct cause of the disease.
The research began with an analysis of over 5,000 people without known heart disease. Those with higher suPAR levels were significantly more likely to develop atherosclerosis, regardless of their cholesterol or blood pressure levels.
To find out why some people have higher suPAR levels, the team examined genetic data from 24,000 individuals. They identified a specific genetic variant in the PLAUR gene, which produces suPAR. People with this variant had both higher suPAR levels and a greater risk of developing atherosclerosis.
Using a method called Mendelian randomization—which leverages genetic data to explore cause-and-effect relationships—the researchers confirmed their findings in more than 500,000 participants from the UK Biobank and two additional datasets. The link between the PLAUR variant, elevated suPAR, and atherosclerosis was consistently strong.
To further validate their discovery, the team conducted experiments on mice. Those given high levels of suPAR developed significantly more plaque in their aortas—the main arteries leading from the heart—than mice with normal levels. This provided compelling evidence that suPAR actively contributes to artery damage.
What makes this discovery particularly significant is that suPAR is not affected by current heart disease treatments. Statins, for example, do not lower suPAR levels. This opens the door to a completely new treatment approach, targeting a mechanism not addressed by existing drugs.
Led by Dr. Salim Hayek, the researchers are now working on therapies aimed at safely reducing suPAR levels, with the goal of preventing or slowing the progression of heart disease.
This breakthrough may also shed light on the close link between heart and kidney disease. Prior studies have associated suPAR with kidney damage, and in the U.S., about 1 in 7 people have kidney disease—two-thirds of whom also have heart disease. In fact, more than 40% of heart disease patients show signs of kidney dysfunction. If suPAR contributes to both, targeting it could offer dual benefits.
Published in the Journal of Clinical Investigation, this study may redefine how doctors understand and treat heart disease—offering new hope to millions of people who continue to face it, despite following all the right steps.