'Good' Cholesterol: What's in a Number?

Parag Joshi

Deemed "good" cholesterol, high-density lipoprotein, or HDL, has earned a reputation as a guardian of cardiac health, countering the damage caused by other lipids, chief among them low-density lipoprotein, or "bad" cholesterol.

Indeed, a number of studies over the past few decades have demonstrated the benefits of higher HDL levels, highlighting HDL's ability to mop up bad cholesterol from the walls of blood vessels -- the chief culprit in heart attacks and strokes. Thus, the conventional wisdom that boosting HDL levels can ward off heart attacks and strokes. But there is growing evidence suggesting that how we go about increasing HDL may matter more than the numbers themselves.

Cholesterol: a Primer

Despite its bad rap, small amounts of cholesterol are essential to human health. However, many people end up with far more cholesterol than their bodies need or can handle due to a combination of modern diets, sedentary lifestyles and genetics.

Like water and oil, cholesterol -- a fatty, waxy substance -- doesn't mix well with our blood. To get around this problem and make its way to various organs, cholesterol hitches a ride via transport vehicles -- protein particles such as LDL and HDL -- which travel freely in the bloodstream.

LDL and HDL pick up and interact with cholesterol differently, behave differently and have different effects on the body. For example, LDL's chemical structure allows it to "dump" its cargo inside the walls of the blood vessels. Over time, this leads to buildup of cholesterol in the arteries, rendering them narrowed, hardened and clogged -- a process known as atherosclerosis, the leading cause of heart attacks and strokes worldwide.

HDL, on the other hand, acts as a chemical vacuum cleaner, drawing cholesterol from the walls of blood vessels and transporting it to the liver for disposal.

What's in a Number?

Ever since evidence of HDL's cardioprotective effects began piling up, health experts have recommended that men aim for HDL above 40 milligrams per deciliter and that women aim for 50 milligrams per deciliter. Indeed, the risk of suffering a heart attack is higher when HDL is below the recommended level. By contrast, those with HDL above 60 have a decidedly lower risk of heart attacks and strokes. But HDL levels are far from a perfect predictor of cardiovascular health. People with high HDL levels have heart attacks, and some individuals with dismally low HDL never suffer one.

A small town in northern Italy between Milan and Venice called Limone sul Garda provides a perfect illustration of this paradox. The region is well-known for its many centenarians who make it into old age with plaque-free, healthy arteries despite HDL levels that hover around 10 to 15 milligrams per deciliter. We now know that these people carry a particular genetic mutation, dubbed Apo A1-Milano, marked by very low HDL levels and high triglycerides -- another fatty substance known to fuel cardiovascular damage -- but no heart disease. Why?

The leading theory is that people who carry the mutation have a form of HDL that is super efficient in removing cholesterol and reducing plaque. Their HDL is rapidly ferrying cholesterol from the arteries to be dumped in the liver and purged from the body. This rapid movement and high efficiency renders their circulating HDL levels in the blood very low. In this case, lower HDL signals higher performance and better cardiovascular health.

Standard cholesterol tests measure the cholesterol content inside LDL and HDL (LDL-C and HDL-C), not the number or quality of LDL and HDL particles that carry cholesterol. In other words, they capture the total load of cholesterol, but not the size or efficiency of the fleet required to carry the cargo. For example, two people with "low" HDL-C levels of 35 milligrams per deciliter could fare differently depending on how nimble and efficient their fleet of HDL-carrying vehicles is. A few high-performing "vehicles" can be much more efficient than a fleet of low-performing carriers.

"Good" Cholesterol's Dark Side

While most of HDL's effects are clearly beneficial, emerging evidence suggest it has a dark side. A form of HDL, called "dysfunctional" HDL, fails to remove cholesterol from the arteries and instead builds up inside blood vessels, fueling inflammation. Standard cholesterol tests capture the total content of HDL and do not differentiate between dysfunctional HDL and beneficial HDL, a discrepancy that can explain why people with very high levels of "good" cholesterol can still suffer heart attacks.

Scientists are actively developing a test that measures HDL efficiency rather than total HDL content as a more accurate bellwether of cardiac risk. Recent studies of this test have shown dramatic results supporting the idea that while HDL cholesterol levels predict risk, HDL efficiency is a far better predictor and should likely be our focus for future therapies. If we can improve the efficiency of our HDL, we will be much more likely to reduce our risk for heart disease.

What Should My HDL Be? healthy diet

For starters, don't obsess over a number. Aim to reduce your overall cardiac disease risk by ensuring you exercise regularly, eat a and don't smoke. These lifestyle modifications can improve your overall lipid profile by reducing bad cholesterol, boosting good cholesterol and even lowering disease-causing chronic inflammation. More importantly, adopting healthy habits translates to a lower risk of heart attacks and strokes.

Those who are at high risk due to family history, genetic cholesterol anomalies and/or the presence of other conditions, such as diabetes or high blood pressure, can gain powerful health benefit from treatment with cholesterol-lowering statins.

It is natural to assume that increasing HDL through medications will improve cardiovascular health, but as it turns out, this is not necessarily the case. Although higher HDL is associated with better health, increasing it doesn't necessarily cause better health. Instead, higher levels may simply be a marker of healthier habits. Several recent trials of drugs designed to raise HDL levels demonstrate that just increasing the number didn't produce major health benefits.

Niacin, which has historically been prescribed to boost HDL levels, led to a 15 to 20 percent increase in HDL in recent studies when added to statins. However, it failed to reduce the number of heart attacks and strokes in people with good control of their LDL levels.

Another class of medications called CETP inhibitors is being tested to reduce heart attacks and strokes in people whose LDL levels remain stubbornly high even on statins. Although these medications can more than double HDL, the jury is still out on their ability to prevent heart attacks and strokes when added to statins, as two trials so far have been disappointing. The niacin and CETP inhibitor trial results underscore the importance of HDL function rather than total HDL content.

The human body is astounding in its complexity, so treating a disease or defining risk by a number can be dangerously reductive. While important guideposts on our journey to improving cardiac health, cholesterol levels are not the end-all and be-all in risk reduction.

There is little doubt that "good" cholesterol can help foretell cardiovascular risk, but recent evidence tells us moving forward we should focus on understanding the relationship between HDL performance and HDL content, for how we go about raising HDL is, indeed, turning out to be more important than the number itself.

As the science on HDL moves forward, it is clear that lifestyle modifications remain the best way to improve your risk profile, your HDL and, ultimately, your overall health.

Dr. Parag Joshi is a Pollin Fellow with the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease and a cardiology fellow in the Johns Hopkins Division of Cardiology. His research interests within preventive cardiology specifically focus on risk assessment for heart attacks and strokes, non-invasive cardiac CT imaging and cholesterol disorders.