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Change of Heart

Daniel Steinberg, MD, PhD and Joseph Witztum, MD
Daniel Steinberg, MD, PhD (left) and Joseph Witztum, MD, shown in the Witztum lab on UC San Diego's La Jolla campus, June 6, 2013.

Discoveries in medical science are rarely made overnight; rather, pieces of the puzzle fall into place over years, often decades, of research. Perhaps even more elusive is a discovery that fundamentally changes how medicine is practiced.

Nearly 45 years ago, Daniel Steinberg, MD, PhD, came to UC San Diego to head the Division of Metabolic Disease. It was a fledgling university campus then, perched on the bluffs of La Jolla, overlooking the Pacific — and the UCSD School of Medicine had just been established.

“I had heard about San Diego from a colleague at the National Institutes of Health who had come back all aglow after a visit to this new university,” said Steinberg, now a Professor Emeritus of Medicine at UC San Diego. “I remember my first visit to my new lab in 1968. It was a nice, sunny day and the equipment consisted of an ashtray and a wastebasket.”

Despite modest beginnings, Steinberg and colleagues would become instrumental in changing how physicians look at coronary disease. But first would come an enormous battle to prove the hypothesis — that high cholesterol is a major contributing factor in the development of atherosclerosis and coronary heart disease.

The Cholesterol Wars

Daniel Steinberg, MD, PhD

Daniel Steinberg, MD, PhD

To some, it may be surprising that what today seems common sense — lowering blood LDL cholesterol to reduce the risk of coronary heart disease and stroke — would have once been so controversial. As early as 1961, the American Heart Association had accepted a causal relationship and recommended that people at high risk be advised to modify their diets to avert heart attacks. However, few physicians were paying much attention, and in 1968, the war between scientists who claimed that elevated blood cholesterol caused heart disease, and those equally respected scientists who found the idea “untenable,” was in full engagement.

In 1979, Steinberg invited Joseph L. Witztum, MD, of Washington University in St. Louis to join the UCSD School of Medicine faculty. In coming years, Witztum would become internationally recognized for his work, in collaboration with Steinberg, on the role of oxidized LDL as a major contributing factor in atherosclerosis. But in 1979 — despite an ever-increasing number of epidemiological studies, experimental animal studies and additional interventional studies here and elsewhere around the country linking high cholesterol with heart disease — “there was still no ‘you-can’t-argue-with-this’ type of study, a blockbuster,” said Steinberg.

In 1984, with Steinberg heading the nationwide study of 3,800 men at 12 centers around the country funded by the National Institutes of Health, and Witztum leading the clinical trial unit here at UC San Diego, the pair was instrumental in launching the Coronary Primary Prevention Trial. This study — the first large randomized, doubleblind study to show a statistically significant decrease in heart disease as a result of lowering cholesterol levels through drug therapy — would change how physicians treated the condition.

By 1985, while naysayers among scientists and cardiologists still existed, newspaper headlines read “Cholesterol: No more doubt about dangers.”

How Low Do We Go?

Joseph L. Witztum, MD

Joseph L. Witztum, MD

In his 2007 book, The Cholesterol Wars, Steinberg recalls, “This continuing controversy over the years made it very much an uphill battle to convince practitioners, including the cardiologists (perhaps especially the cardiologists) to pay attention to hypercholesterolemia… Today, of course, aggressive treatment of the condition has become standard medical practice, largely due to statin drugs, which became available in the late 80s.”

Witztum went on to make the seminal observation that oxidation of LDL renders it immunogenic, and he has played a key role in the recognition that immune mechanisms are an integral part of the process leading to atherosclerosis.

“In the 1980s, we also showed that oxidation of LDL converted it into a more dangerous form,” said Witztum. “Our work since then has been to understand how this happens. We don’t yet know how to prevent the process, but we have discovered that oxidized LDL is recognized by the body’s immune system as abnormal, so now we know that atherosclerosis is actually an inflammatory disease.”

3,800
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were studied at 12 U.S.
centers in the 1984 Coronary
Primary Prevention Trial

In an important set of studies, Witztum and fellow UC San Diego cardiologist Sam Tsimikas, MD, have shown that oxidized phospholipids (oxidized fats found in oxidized LDL) are very toxic and cause chronic inflammation in the artery. In 2005, Tsimikas published a seminal study in the New England Journal of Medicine, describing a novel blood test that could measure levels of oxidized phospholipids in the bloodstream, thus reflecting the amount of blockage in the coronary artery.

“We have identified antibodies that bind to oxidized LDL and can perhaps prevent it from being taken up by the macrophages — large white blood cells that play an important role in the body’s immune system,” said Witztum. “We theorize that such antibodies could be protective.” His lab is working to develop a vaccine approach that could inhibit atherosclerosis and has already succeeded in animal models. Though a human vaccine could be many years away, this is the hoped for next important step in the treatment of heart disease.

Both Steinberg and Witztum consider the other to be a world leader in solving one of the Western world’s biggest health problems. They are proud of the work that has resulted in a nearly 20 percent decrease in the rate of heart attacks in the decades since their landmark Coronary Primary Prevention Trial. They both now believe that coronary heart disease could be further reduced by treating high cholesterol levels at a very young age — perhaps beginning in adolescence.

“The question now isn’t whether low blood cholesterol levels prevent heart attacks,” said Witztum. “The question for physicians is, how low do we go?”