Cedars-Sinai Investigators Uncover Earliest Changes in Coronary Heart Disease

Researchers have identified molecular changes that appear to trigger atherosclerosis years before inflammation—the long-recognized hallmark of the disease—takes hold, according to a Cedars-Sinai Health Sciences University-led study.

The multi-institutional study offers one of the clearest pictures of what happens during the earliest stages of disease. The findings could help researchers develop new ways to detect and prevent heart disease before plaque builds up inside arteries.

“This suggests that changes in cellular metabolism and communication begin before the inflammation long considered a hallmark of the disease.”

Published in the European Heart Journal, the study findings point to previously unrecognized molecular pathways—and a potential “master regulator” called MLXIPL—that could become targets for therapies aimed at preventing plaque from developing.

The Cedars-Sinai Newsroom spoke with Parker about the findings and how proteomics—the study of proteins—is helping researchers rethink the earliest stages of heart disease.

Why are proteins so important in understanding heart disease?

Proteins are the molecules that make cells function. They tell us how the body’s cells are responding to risk factors like cholesterol, blood pressure or smoking. Two people can have identical cholesterol levels, yet only one develops plaque.

Proteins may help explain why. They provide a much more direct picture of what's happening inside the artery wall and may reveal why some people are more vulnerable to heart disease than others.

What did this most recent study reveal about the earliest stages of atherosclerosis?

Previous studies had shown that the earliest artery lesions can appear in the first decade of life. What we haven’t understood is what causes those early changes to progress into dangerous plaques that lead to heart attacks.

In studying coronary artery tissue before people ever developed symptoms, we were able to capture some of the earliest molecular changes that appear to set the disease in motion.

To be clear, inflammation remains a defining feature of advanced atherosclerosis. What our study suggests is that important molecular changes begin much earlier. If we want to prevent plaque from forming, we need to understand those earliest changes—not just what happens after inflammation has already taken hold.

Explain MLXIPL, the potential ‘master regulator’ you identified.

We performed a master regulator analysis to identify the genes that may be coordinating these early events. Some of the regulators we found were exactly what we expected. But one stood out. MLXIPL is a transcription factor gene involved in cellular metabolism.

Previous genetic studies have linked it to coronary artery disease through its role in the liver. Our findings suggest it may also play an important role directly within the artery wall. When we altered MLXIPL activity in lab-grown human artery tissue, we saw the protein changes we predicted. That makes it an exciting candidate for future therapies that interrupt disease before plaque develops.

How could these findings change atherosclerosis prevention?

Today, we estimate cardiovascular risk using factors such as high cholesterol, diabetes, smoking, age and family history. By the time plaque is visible on imaging, disease often is well underway. We hope to identify protein biomarkers in the blood that reveal what’s happening inside the artery wall much earlier.

That said, our findings do not change current prevention recommendations. Managing cholesterol, blood pressure, diabetes, smoking, exercise and diet remain essential.

This study relied on a decades-long collaboration. Why was that essential?

This is a collaboration more than 20 years in the making. The project was spearheaded by proteomics pioneer Jennifer Van Eyk. (Van Eyk, PhD, is director of the Advanced Clinical Biosystems Research Institute in the Smidt Heart Institute at Cedars-Sinai and co-director of the Proteomics and Metabolomics Core.)

Our collaborators included investigators from many other institutions across the country. What began as a small group has grown into an ecosystem of investigators, trainees and collaborators. This kind of large-scale molecular study simply isn’t possible without that level of long-term partnership and shared expertise.

(Newswise/SR)