The Cholesterol Conundrum

Cholesterol was first discovered in 1769, but it wasn’t until the early 20th century that scientists linked these oily molecules in our blood to atherosclerosis—when artery walls become thick with plaque, potentially triggering a heart attack or stroke. Since then, many have devoted their lives to understanding cholesterol. It’s a research subject that has led to more than a dozen Nobel prizes, prompting one recipient to refer to cholesterol as “the most highly decorated small molecule in biology.”

By the 1960s, scientists thought they had a pretty good understanding that too much cholesterol floating around in our bloodstream was clogging our arteries. In the 1980s, the first cholesterol-lowering drugs, known as statins, were introduced. That same decade, the federal government began telling us to reduce our intake of cholesterol and saturated fats (which our bodies use to make cholesterol).

Since the campaign against cholesterol began, the average amount of cholesterol floating around in our collective blood has gone down. And so have death rates from heart disease.

But that’s far from the whole story.

When scientists dug deeper, they found cholesterol and its relation to cardiovascular disease to be much more complex than originally thought. For instance, when scientists began to study women (who naturally have higher cholesterol than men), they soon saw that total cholesterol levels weren’t as good at predicting who’s at risk for clogged arteries. Instead, they found it was more important to look at levels of so-called “good” versus “bad” cholesterol. Now scientists are learning that it’s just as important to look at the particles that transport cholesterol. This latter discovery came out of recent research led by the University of Pittsburgh.

Most of us have heard of “good” cholesterol. This is the cholesterol carried around on particles known as high-density lipoproteins (HDL). We’ve also heard of “bad” cholesterol, carried around on low-density lipoproteins (LDL) that can stick to our artery walls. Years ago, studies confirmed that lowering LDL cholesterol with statin drugs reduced the risk of cardiovascular disease. Despite the success of statin drugs, however, cardiovascular disease remains the nation’s leading cause of death.

So medical scientists were hopeful that the next holy grail for fighting cardiovascular disease would be drugs to significantly raise HDL cholesterol. But three failed major drug trials in recent years showed that researchers may have been barking up the wrong tree.

The disappointing HDL-raising drug trials led to a number of media reports that scientists were wrong—that HDL cholesterol wasn’t so “good” after all. These reports, however, are misleading, says Rachel Mackey, Ph.D., a cardiovascular epidemiologist with Pitt’s Graduate School of Public Health. The drugs likely failed because they aimed at the wrong HDL target.

She was probably one of the few people in the cardiovascular research community not surprised when the drug trials failed. That’s because the drugs substantially raised levels of the cholesterol carried by the HDL particles, but not the number of circulating HDL particles (in other words, the ships that carry the cholesterol cargo). Her research showed that when assessing cardiovascular disease risk, it appears more beneficial to measure—and make treatment decisions—based on HDL particles (those ships)—not just their cholesterol cargo.

“We found that higher levels of HDL cholesterol and HDL particles were both associated with less atherosclerosis (measured in the neck artery) and fewer heart attacks and other cardiovascular events,” said Mackey, lead author of a study published in the Aug. 7, 2012 edition of the Journal of the American College of Cardiology. The findings were based on analyzing blood samples of 5,598 healthy men and women.

“In our study, we found that the number of HDL particles had stronger cardio protection than HDL cholesterol,” adds Dr. Samia Mora, a physician in Brigham and Women’s Cardiovascular Division in Boston and senior author of the study’s paper.

Cholesterol is used by our bodies as a building block for estrogen, testosterone, other hormones, and for building the membranes in many of our cells, notes Excela Health cardiologist Dr. Asghar Fakhri.

He explains that we can absorb cholesterol from the food we eat, or manufacture it in our cells. Hunter-gatherer societies and people in rural China have LDL levels that are in the same range as newborn babies—about 35 to 70 mg/dL (cholesterol is measured in milligrams of cholesterol per deciliter of blood). Plaque buildup in the arteries is rare in these groups of people. Hunter-gatherer societies eat diets high in fruits, vegetables, nuts and lean meats. They also get plenty of exercise, as often they have to chase down their meals, Dr. Fakhri points out.

Most Americans have double the amount of LDL cholesterol they were born with. The average LDL cholesterol level in American adults is close to 123 mg/dL, according to the National Health and Nutrition Examination Survey.

“According to our current understanding of the science,” says Dr. Fakhri, “these high LDL levels are a big part of why we have higher rates of heart disease in America compared to societies such as rural China. We also know from studies of people born with genetic conditions with extremely high LDL levels (in the 300 range), these patients can develop heart attacks and even die at very young ages, even in their twenties. The links between high levels of LDL and risk for heart disease, stroke and dying prematurely have been proven solidly by science.”

Dr. Aryan Aiyer, a cardiologist with UPMC Heart and Vascular Institute, says, “In patients who have real heart disease (those who have had stroke, heart attack or had a need for bypass surgery or stent), then it is important to prescribe medication to get their LDL cholesterol levels to around 70.” He adds that more than 30 years’ worth of clinical data on statin medications show a “clear benefit [in] reducing all of the clinically relevant endpoints (heart attack, stroke and death).”

Despite its bad reputation in regard to cardiovascular disease, cholesterol has many health benefits. It plays a major role in brain function, seems to help fight off infections, and even protects against cancer. “Cholesterol is an essential nutrient for the body to build normal, healthy cells. But obviously, excessive amounts of cholesterol increase risk for cardiovascular disease,” says Dr. Srinivas Murali, director of the Division of Cardiovascular Medicine and Cardiovascular Institute at West Penn Allegheny.

“But having very low cholesterol is not good. One should not go below 50 [LDL cholesterol] or you are opening the door for losing some of the benefit of LDL cholesterol,” Dr. Murali notes. These very low levels “can increase the level of cancer and have been associated with depression and, in pregnant women, low birth weight.”

One company even sells cholesterol supplements, claiming that it can help relieve autism symptoms.

Dr. Aiyer concedes that “no one knows the whole story” when it comes to cholesterol and cardiovascular disease. It falls into the chicken-and-the-egg dilemma. Do high levels of cholesterol damage artery walls? Or are already damaged artery walls more susceptible to cholesterol clinging to them?

Rising rates of obesity—and related metabolic syndrome—has led to a recent puzzling finding: People with metabolic syndrome have low HDL and low LDL cholesterol levels, but they don’t have correspondingly low levels of atherosclerosis, Mackey notes. People with metabolic syndrome typically have a large waistline, high triglyceride level (a type of fat found in the blood), high blood pressure and high fasting blood sugar.

This paradox might be best explained by looking at lipoprotein particles (those ships). “We seem to be getting a much more accurate picture [of cholesterol’s impact on cardiovascular disease] if we look at the number of circulating LDL and HDL particles rather than the amount of cholesterol carried by the particles,” she says.

Just because recent HDL cholesterol-raising drug trials failed to demonstrate a reduction in cardiovascular events, Mackey says, low HDL cholesterol levels are still cause for concern. That’s because HDL particle levels will also be low. It’s important people continue to make an effort to raise them, she says. “HDL particles carry a lot of potentially beneficial things in addition to carrying cholesterol. Researchers are still working on measuring those things and figuring out what does what. Right now, we don’t have great pharmacological products that will dramatically increase the HDL particles, so quitting smoking will have a big impact. In fact, all of the lifestyle interventions—quitting smoking, watching your diet and exercising—are all still important.”

Mackey’s research has helped bring about an important question yet to be sorted out: Who should have their HDL particles measured? A test, using nuclear magnetic resonance spectroscopy, is clinically available to do that. It was developed by LipoScience Inc., a North Carolina company that partly funded Mackey’s research. The test will likely become more widely used in the coming years. But because it’s much more costly than the basic lipid profile used to measure cholesterol, Mackey says, “more research needs to be done to determine who needs to have their HDL particles measured.”

Despite the many unanswered questions, researchers have come far in their understanding of cholesterol and the lipoproteins that carry it. Mackey says, “The LDL story [cholesterol vs. particles] has been largely worked out and much of that research was done here at Pitt. HDL is a new area of interest. We still have more to learn with the HDL side of things.”