Glucose In, Heart Disease Out

    Coronary artery disease (CAD) accounts for nearly half of all deaths in the United States and 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,” explained senior study author Cornelia Weyand, M.D., professor and chief of immunology and rheumatology at Stanford University School of Medicine.

    Accumulation of arterial plaques can begin early in life, with deposits sometimes evident in individuals as young as 15–20 years old, and progresses steadily with advanced age.

    Yet, for many years, researchers have speculated that it’s not just arterial deposition of lipids that causes coronary heart disease, but also underlying chronic inflammation. “It’s been unclear where the inflammation comes from,” Dr. Weyand remarked.

    Now, Dr. Weyand and her team believe they have evidence showing hyperaggressive immune cells that reside in arterial plaque and binge on glucose to be major drivers of CAD. The investigators are hopeful that their study results will lead to future therapeutic interventions that provide some protection from the disease.

    “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 hyperinflammatory state,” Dr. Weyand noted.

    The findings from this study were published recently in the Journal of Experimental Medicine in an article entitled “The Glycolytic Enzyme PKM2 Bridges Metabolic and Inflammatory Dysfunction in Coronary Artery Disease.”

    When the deposits for those with CAD become severe enough, they can restrict blood flow. Researchers often thought that this occlusion triggered heart attacks. However, a nagging conundrum remained: If this process is so gradual, why are heart attacks so sudden?

    Over the past several years, scientists have come to understand that arterial plaques also contain immune cells—mainly macrophages.

    Macrophages typically fall into two broad categories—M2 macrophages, which grind up cellular debris releasing factors that encourage new cell growth, stimulate blood flow, and otherwise oversee tissue repair, and M1 macrophages, which are inflammatory, excreting out proteins and molecules that act both locally and systemically to ramp up the entire immune system.

    “Some believe that coronary artery disease patients’ macrophages are so preoccupied with their inflammatory power trip they neglect their clean-up tasks,” Dr. Weyand stated, which ultimately allows plaque to continue building up in arteries. The ensuing inflammation renders the plaque increasingly brittle, sometimes culminating in a piece breaking off suddenly and wounding the artery wall. The resultant rapid formation of a clot can often trigger a heart attack.

    Dr. Weyand and her colleagues began their study by comparing monocytes (which are the progenitor cells to macrophages) harvested from the blood of 140 patients with CAD, each of whom had experienced at least one heart attack, with those from 105 healthy, demographically matched control subjects.

    The researchers cultured the monocytes and used standard laboratory methods to differentiate them into macrophages. To their surprise, they observed that the monocytes from patients with CAD had a pronounced predisposition to develop into inflammatory, interleukin-6 (IL-6)-producing M1 macrophages.

    “We also found that macrophages from people with type 2 diabetes, hyperlipidemia, or hypertension—each of these a known risk factor for coronary artery disease—were making more IL-6,” said Weyand. Interestingly, the greater the number of risk factors the subjects had, the more IL-6 their macrophages produced.

    “Even before taking up residence in arterial plaque and becoming full-fledged macrophages, these patients’ monocytes were already leaning toward becoming inflammatory,” Dr. Weyand stated. “If you simply overfeed normal monocytes or macrophages, they don’t turn in into high IL-6 producers. We wondered why.”

    In a series of follow-up experiments, Dr. Weyand, and her colleagues discovered the reason. They found that the macrophage mitochondria were producing excessive amounts of free radicals driven by extreme uptakes of glucose within those cells, which they attributed to a faulty overproduction of proteins responsible for importing glucose into cells.

    “The primary problem, we learned, is that these macrophages take up glucose at a higher rate than normal cells do,” said Dr. Weyand. “That causes them to break it down faster, overheating their mitochondria, which then produce too many free radicals.”

    Dr. Weyand and her team were excited by their findings, as there are already several interventions that can block glucose uptake and mop up free radicals, which in turn should reduce the macrophages’ excess inflammatory activity, thus leading to new therapeutic approaches.