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UCLA

Good Medicine: Affair of the Heart

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By Greg Critser, Photos by David Miezal

Published Jan 1, 2011 8:00 AM


As the master detective of "good" cholesterol, UCLA's Alan Fogelman has been tracking down the true nature of this elusive molecule — and dramatically improving our understanding of heart disease — his entire career. His latest case: how and why good cholesterol goes bad.

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In 2007, researchers released a state-of-the-art clinical study of a new Pfizer drug designed to treat high cholesterol: torcetrapib. The results were puzzling. The compound lowered low-density lipoprotein, a.k.a. LDL or "bad" cholesterol. It also substantially pushed up high-density lipoprotein, or HDL, the "good cholesterol." By all accrued medical wisdom, torcetrapib should have lowered the rate of cardiovascular events — heart attacks, strokes and, ultimately, deaths.

But it did not. Instead, to the chagrin of the entire cardio-establishment, it increased the risk of cardiovascular events like heart attacks by 25 percent. Worse: 58 percent more heart patients died than those in a control group.

What had happened? Why hadn't the "good" cholesterol improved their odds of living longer? It was a challenge tailor-made for UCLA Professor Alan Fogelman '62, M.D. '66.

A subdued, compact man who cogitates quietly in an ornately decorated office full of Churchill portraits and custom chessboards, Fogelman has pursued the elusive molecule for nearly 40 years. His quest is not unlike that of a zoologist tracking down some strange and wondrous creature.

"The reason HDL is constantly throwing a wrench into the whole business of cholesterol management is that it is not one thing all the time. It changes," he says, "like a chameleon."

Beginning the Journey

Fogelman's trek began in the late 1960s, when he was stationed at China Lake Naval Weapons Center. There, the young Navy physician was struck by a peculiar aspect of the patient population: A disproportionate number of them were dying of heart disease.

"It didn't make any sense," he recalls. "I mean, here was a pretty young population, guys in their 30s and early 40s, and they had all kinds of heart problems. I kept coming back to that picture in my mind and asking myself: What is happening here? The great minds of the day were mainly focused on heart failure, which was important, but I kept asking, 'Can't we find some way to prevent it?'"

Fogelman next landed in a perfect place to find out: the UCLA School of Medicine. Early work by UCLA pioneers and others had already elucidated the chemical structure of LDL cholesterol and showed how it might inflame arteries. What followed was a mammoth effort to characterize exactly what the molecule consisted of and how it worked.

Fogelman has pursued the elusive molecule for nearly 40 years. His quest is not unlike that of a zoologist tracking down some strange and wondrous creature.

What Fogelman et al. found was mind-boggling. LDL, at its core, is part of our innate immune system. It likely once had an important beneficial function. By oxidizing in a sudden burst, it allowed humans to fight off the enormous number of pathogens — viruses, bacteria, etc. — that were present in the premodern world, before better sanitation and antibiotics made such a robust system unnecessary. But LDL-driven inflammation led to plaque build-up, rupture and artery-clogging.

"LDL problems will be with human beings for a long, long time," Fogelman says. Evolutionary processes have yet to eliminate it, he explains, "because its ill effects come so late in life — long after the typical evolutionary sorting before reproduction takes place."

Eventually, things like lifestyle modification and drugs, mainly statins, were found to lower LDL levels and cardio risk. Similarly, LDL's sister molecule, HDL, or good cholesterol, was found to have beneficial qualities: It seemed to transport bad cholesterol back to the liver. There were more drugs and more lifestyle recommendations. HDL levels went up in sizeable populations of Americans.

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