By Greg Critser
Cardiologist Alan Fogelman is the master detective of “good” cholesterol. His latest case: trying to determine how and why good cholesterol goes bad.
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 Alan Fogelman, M.D. ’66, a cardiologist and chair of the UCLA Department of Medicine.
Cogitating quietly in his third-floor office in the Center for Health Sciences building, Dr. 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.”
Dr. 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?’”
Dr. 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.
What Dr. 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,” Dr. 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.
BUT BY THE LATE 1990S, Dr. 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, Dr. 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, Dr. 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.
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 Dr. 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.
DR. 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 Jesus Araujo, M.D., Ph.D., whose research at UCLA focuses on environmental cardiology. Like Dr. Fogelman, Dr. 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, Dr. 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 Dr. 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 Dr. Fogelman and his colleagues are now trying to do. Currently, there is at least one commercial study of a molecule from Dr. 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.
What are the HDL peptide’s chances? “It is so early to try to tell something like that,” Dr. 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.”
Greg Critser is the author of Fat Land: How Americans Became the Fattest People in the World (Mariner, 256 pages) and Generation Rx: How Prescription Drugs are Altering American Minds (Mariner, 308 pages). This article was originally published in the January 2011 issue of UCLA Magazine.