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Glucose-guzzling immune cells may drive coronary artery disease, Stanford study finds

Hyper-aggressive immune cells parked in arterial plaque and bingeing on glucose appear to be major drivers of coronary artery disease, Stanford University School of Medicine investigators have found.

The discovery, detailed in a study to be published online Feb. 29 in The Journal of Experimental Medicine, could lead to new therapeutic interventions that provide some protection from the disease, which is the No. 1 cause of death in America.

“We’ve pinpointed a defect in glucose metabolism by a class of arterial-plaque-associated immune cells as a key factor driving those cells into a hyper-inflammatory state,” said Cornelia Weyand, MD, professor and chief of immunology and rheumatology, who is the study’s senior author. The lead author is postdoctoral scholar Tsuyoshi Shirai, MD, PhD.

Blocking that glucose overconsumption or, for that matter, a couple of other downstream links in the chain of ensuing biochemical events, prevented this hyper-inflammatory activation, the researchers discovered.

The findings support a growing recognition that it’s not just arterial deposition of fatty materials called lipids that causes coronary heart disease, but also underlying chronic inflammation. “It’s been unclear where the inflammation comes from,” Weyand said.

The puzzle of heart attacks

Coronary artery disease, which accounts for nearly half of all deaths in the United States, arises when blood flow through the arteries that supply oxygen-rich blood to the heart is impaired. The underlying process — the buildup of plaque inside the arteries — is called atherosclerosis.

“Most of us develop arterial plaque over the course of our lifetimes,” Weyand said. Plaque accumulation can begin early in life, with deposits sometimes evident in individuals as young as 15 to 20 years old, and progresses steadily with advancing age.

When these deposits become severe enough, they can restrict blood flow. It used to be thought that this occlusion triggered heart attacks. But a puzzle remained: If this process is so gradual, why are heart attacks so sudden?

While lipids are a prime constituent of arterial plaque, it’s now understood that plaque also contains immune cells — chiefly, a type called macrophages. These cells wear many hats. They attack and ingest invading bacteria, repair tissue, clean up detritus left behind after injury or infection, and more.

“We can’t live without them,” said Weyand.

Macrophages generally fall into two broad categories: The kinder, gentler ones — so-called M2 macrophages — are like construction engineers, nibbling cellular debris, releasing factors that encourage new cell growth and stimulate blood flow, and otherwise overseeing tissue repair.

So-called M1 macrophages, on the other hand, are inflammatory: As hard-boiled as traffic cops who’ve heard every excuse, they blow the whistle on pathogens, recruiting other types of immune cells to the scene. In addition, they attack the invaders themselves by spitting out nasty little clouds of biohazardous chemicals called free radicals. And they squirt out proteins that act both locally and systemically to ramp up the entire immune system to high-alert status.