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Good Medicine: Affair of the Heart

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By Greg Critser, Photos by David Miezal

Published Jan 1, 2011 8:00 AM


A New Direction

But by the late 1990s, Fogelman was asking a new and very uncomfortable question: If statins and such were so good at driving up HDL and driving down LDL, why did we still have so much heart disease?

He theorized that HDL might be much more complicated than previously imagined, and then launched a new effort to characterize the molecule, from outer membrane to nucleus.

What emerged was a complex molecule — the enzymes and antioxidants carried by normal HDL did turn out to prevent or reverse some of the consequences of the "bad" cholesterol, LDL.

In the process, however, Fogelman discovered something else: In a number of scenarios, HDL morphed into something entirely different. After the trauma of a surgery, for example, good cholesterol behaved even worse than the bad cholesterol. Why?

Thanks in part to the use of lab-bench techniques developed in his laboratory, Fogelman began teasing out the phenomenon. He found that for several weeks after someone comes down with the flu, the "fighter" enzymes inside HDL become dysfunctional. That wasn't all. Bad HDL started popping up in the blood of patients with common chronic diseases — uncontrolled diabetes, kidney disease and rheumatoid arthritis. Hence, the higher levels of HDL caused inflammation and atherosclerosis.

The Good, the Bad and the Healthy

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Perhaps this was why torcetrapib had failed as a cardiovascular drug: The compound pushed up HDL levels in such a way as to be inflammatory. Although Fogelman cautions that these observations are not ready for use in public-health policy, they may have an impact on postsurgical care, wherein standard practice now encourages physicians to prescribe statins.

A New Discipline

Fogelman's expertise in HDL dynamics has also enabled UCLA to advance a huge and promising new medical discipline: environmental cardiology, the study of how one's surroundings interact with genes and behavior to instigate heart disease.

A remarkable example was a study that came out in 2008 by UCLA researcher Dr. Jesus Araujo Ph.D. '04, a Fogelman colleague. Like Fogelman, Araujo was taken with the question: Why had heart disease remained so prevalent? Perhaps, he thought, it might have to do with smog. Epidemiologists had long posited a link between the two, but never found a causal explanation for it.

To find out, Araujo placed cages of genetically altered mice in two distinct locations — one alongside the Harbor Freeway and one in Santa Monica. He then used a machine to collect and analyze the exhaust fumes the animals were breathing. When Araujo later examined the mouse arteries, he found advanced artery disease in the ones parked next to the freeway.

One other thing: Their HDL had become inflammatory.

Might there be a way to restore HDL's good characteristics? That is exactly what Fogelman and his colleagues are now trying to do. Currently, there is at least one commercial study of a molecule from Fogelman's research that mimics some of the good properties of HDL. Another, an HDL mimetic peptide, was able to turn "bad" HDL into "good" HDL in lab animals. Both compounds are being developed by Bruin Pharma, a commercial venture in which Fogelman is a principal and an officer. Executive Jerry A. Magnin heads the company.

What are the HDL peptide's chances?

"It is so early to try to tell something like that," Fogelman says. "We have no idea where that effort will take us, or whether it will hit the target we hope for. We have to wait for the trials.

"After all, HDL — it's a chameleon."

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