Magician Clinician

When Howard Hodis first entered a laboratory, he knew that science was the rational foundation on which to test his curiosity and theories

by Alicia Di Rado

 

He is a professor. Physician. Researcher. Husband and father.

But to many, Howard Hodis, M.D., could very well have a more colorful title: The Wizard of Clogs.

Clogged arteries, that is.

Patients consult him for help in lowering cholesterol levels that seem impossible to drop, and investigators know him for his meticulous, inventive research—all in the name of battling a deadly foe, atherosclerosis.

Atherosclerosis is a condition in which the arteries thicken and narrow as fatty plaques accumulate along their inner walls. What makes atherosclerosis so dangerous is that it is the underlying cause of heart attacks and stroke, something too many Americans discover firsthand.

One in every two Americans will die as a result of the complications from atherosclerosis. “It’s that simple,” says Hodis, professor of medicine and preventive medicine at the Keck School of Medicine of USC and director of the USC Atherosclerosis Research Unit.

Now if only the causes and mechanisms of atherosclerosis could magically become clear. No one is quite sure why atherosclerotic lesions form or why they pose more risk for some people than for others.

But the enigma only makes the hunt for the origins of atherosclerosis more tantalizing to Hodis. The truth is out there, and until Hodis and his colleagues find it, he refuses to give up.

Hodis’ scientific dedication and persistence is remarkable for someone with no family background in medicine who was not the least interested in science as a child.

That changed when he entered a laboratory for the first time as a teen. Through USC’s Edmondson Fellowship program, which aims to introduce high school and college students to scientific research, Hodis spent a summer in a USC neuropathology lab. Then, as an undergraduate at USC, he worked in the Keck School labs of neurosurgeon Martin Weiss, M.D., neurologist Leslie Weiner, M.D., and ophthalmologist Ronald Smith, M.D.

“They were great influences on me, in my discipline, knowledge and scientific development,” says Hodis, who grew up in Anaheim, Calif. “I had this curiosity—a need to understand how things work. I had to gain the skill, discipline and focus to do it.”

Science became the rational foundation on which to test his theories. “With science as a basis, even if someone disagrees or rejects your ideas, you can be persistent and educate people to see your point,” says Hodis.

That perseverance has boosted his success in a field buffeted by competing theories, opinions and vogues.

This much we know about atherosclerosis, Hodis says: It starts early, it affects everyone and it is part of aging.

Even before a child is born, fatty plaque slowly begins to coat the child’s blood vessels. Over years and decades, that plaque thickens. When it chokes blood flow or blocks it altogether, that can rob the heart, brain or other parts of the body of much-needed oxygen and nutrients.

Physicians recommend several steps for fighting atherosclerosis. Hodis creates plans with patients to help maintain a healthy weight, lower blood pressure, exercise regularly and adopt a diet that raises levels of HDL, the so-called “good” cholesterol, while lowering levels of LDL, the “bad” cholesterol, and other dangerous fats in the blood. As a busy professional, spouse and father of three boys, he understands that patients need realistic, practical lifestyle changes that can be adopted wholeheartedly.

Quitting smoking also is key, and for those who still have high blood pressure or cholesterol despite healthy habits, medications can help too. But even these measures and medicine’s growing body of knowledge about atherosclerosis fall short in fully protecting patients.

That is why Hodis needs to know more. He and fellow scientists are exploring other interventions, studying whether certain hormones, vitamins and other substances might block the process.

Hormones, specifically estrogen, seem to hold promise, Hodis says: Women generally develop heart disease about 10 years after men do, and scientists believe that the estrogen that surges through women’s bodies protects them from cardiovascular disease until the hormone’s levels dip at menopause.

If estrogen could spring back to youthful levels in postmenopausal women, perhaps it could slow atherosclerosis progression. So Hodis’ group conducted the Estrogen in the Prevention of Atherosclerosis Trial, or EPAT, the first randomized controlled trial to test estrogen’s effectiveness in deterring atherosclerosis progression in healthy women.

They found that women taking estrogen (synthetic 17beta-estradiol, to be specific, which is just like human estrogen) had their atherosclerosis reversed slightly during the trial’s two years, while atherosclerosis progression continued unimpeded among women not on the hormone.

However, recent debate over hormone replacement therapy, or HRT, has prompted great sensitivity in medicine about hormone use. HRT is meant to ease the discomforts of menopause. But in 2002, women abandoned HRT in droves after the National Institutes of Health halted a part of the Women’s Health Initiative HRT trial in postmenopausal women because of increased risks of breast cancer and cardiovascular problems.

Those risks occurred among women taking both a type of estrogen and progestin. Most of the women in the trial had been in menopause for decades.

But EPAT tested only estrogen. (Estrogen alone is usually recommended only for women with hysterectomies, because it can cause uterine cancer unless closely monitored or taken with progestin.) His study also included women closer to the beginning of menopause.

“The greatest problems we deal with today in terms of HRT are the unsubstantiated overgeneralizations of the data. For example, the ideas that all treatment regimens are the same and that all women at any stage of menopause will derive the same benefits and/or have the same side-effects,” Hodis says. “This is not the case, and current data, including even the WHI, support our hypothesis. Sorting out the contradictory data will be the mandate for all future research in this important public health area.”

To that end, Hodis and his colleagues plan to study whether taking estrogen slows down atherosclerosis among women just entering menopause. That is the critical time period when he suspects it is likely to be the most beneficial.

Hodis has no trouble testing theories—or conjuring ideas for new approaches.

Take vitamin E, for instance. Back in the 1990s, research touted vitamin E’s heart-helping power. As a potent antioxidant, the vitamin—found in vegetable oils, nuts and green leafy vegetables—fights cellular damage caused by free radicals, unstable oxygen molecules that are byproducts of the body’s metabolism. Many believe that the combination of free radicals, LDL and other fatty molecules in the blood promotes processes that result in atherosclerosis.

Hodis and colleagues including USC antioxidant expert Alex Sevanian, Ph.D., launched the Vitamin E Atherosclerosis Prevention Study to test the vitamin’s potential. Over three years, they measured atherosclerosis progression in healthy men and women over age 40 who took either a daily vitamin E supplement or a placebo pill for comparison.

Just as expected, the vitamin E consumers had lower levels of oxidatively damaged cholesterol in the blood. But the vitamin E group experienced just as much atherosclerosis as the comparison group—and in the end that is what matters.

Hodis was undefeated, though. The results just meant that perhaps vitamin E helps a different group of people, he surmised. Or, perhaps researchers need to revise their theories about how human atherosclerosis develops. Regardless, Hodis chalked it up to science: “We just have to reflect, rethink and figure out where to go next.”

Hodis’ team is unafraid to turn to novel ideas in this cardiovascular quest, tackling risk factors such as homocysteine, a substance found in the blood.

Research shows that higher homocysteine levels mean more cardiovascular-disease risk. So Hodis is studying lowering homocysteine levels in healthy patients by giving them a daily dose of vitamins B6 and B12 and folate. If homocysteine levels drop, perhaps atherosclerosis also will slow.

The team also will soon start a study to see if regularly consuming certain substances from soybeans can slow atherosclerosis in healthy people.

But risk comes not only from without, Hodis says; it also comes from within, in the form of genes and their products and regulators. “Atherosclerosis is a process of aging that is genetically programmed but modified by many environmental factors,” he says. “The process is different—but pre-programmed—in each of us,” and diet, smoking and other factors may speed it along.

Along with colleagues from other institutions, Hodis’ group has been identifying genes involved with the process of atherosclerosis and aging. “Genetics controls how the vasculature responds to the causes of atherosclerosis in each of us as individuals,” says Hodis, “but that is uncharted territory and a theory that we are slowly and methodically studying.”

Already, Hodis and colleagues have found that people with a certain genetic makeup are more likely to have a high proportion of certain lipoproteins—tiny globules of fat, cholesterol, protein and triglycerides—floating around in their blood. Their bodies may make too many of these particles and have difficulty clearing them. The particles irritate blood vessel walls, possibly playing a part in atherosclerosis.

“This is a very exciting area,” says Hodis. “As we get closer to understanding the relationships of factors that drive wall thickening, we get closer to designer therapy to fight it.”

And it will be scientific wizardry through careful research—not magic—that will get them there