The Not-So-Good News About “Good” Cholesterol

Study reviewed: Voight, B.J., et al. 2012. Plasma HDL cholesterol and risk of myocardial infarction: A mendelian randomization study. The Lancet, 380 (9841), 572–80.

Exercise professionals often inform clients that low-density lipoprotein cholesterol (LDL-C) is the “lousy,” or bad, cholesterol, while high-density lipoprotein cholesterol (HDL-C) is the “healthy,” or good, cholesterol.

Research finds a strong association between high levels of LDL-C and the buildup of arterial plaque that leads to cardiovascular disease, so exercise professionals need to keep talking about how exercise and lifestyle change can reduce LDL-C. Researchers have also noted that higher levels of HDL-C seem to negate or lessen the risk of cardiovascular disease. The standard advice for elevating “good” cholesterol is to exercise more, quit smoking and maintain a healthy weight.

A May 2012 article in The Lancet, led by Voight et al., found that a gene linked to elevated levels of HDL-C in the blood did not reduce the risk of one of cardiovascular disease’s most dangerous manifestations—the myocardial infarction, or heart attack. This column will review the function of cholesterol in the body, summarize the implications of the new Lancet study results and present consequential lifestyle changes that can lower LDL-C and reduce cardiovascular disease risk.

The body makes all the cholesterol it needs, but people get more of it from consuming animal products. Cholesterol is a building block for several body cell components, particularly cell membranes. It functions to make hormones and vitamin D, and helps in digestion. Cholesterol doesn’t mix well with blood, so it is circulated within particles called lipoproteins. Lipoproteins are made up of protein and fat, or lipids, and have different densities, or weights.

All lipoproteins transport fat molecules and cholesterol in the blood. From largest to smallest, they are categorized as chylomicrons, very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL) and high-density lipoproteins (HDL). The main metabolic role of HDL, the “good” cholesterol, is to transfer cholesterol from plaque depots (called atherosclerotic plaque or atheromas) in blood vessels to the liver for excretion, a process scientists call reverse-cholesterol transport. An HDL particle has a cholesterol core surrounded by an outer shell of phospholipids (a specific type of lipid attached to a phosphate group and nitrogen base) and apolipoproteins (proteins that bind to lipids). HDL particles are further classified into several subgroups.

Particles of LDL, the “bad” cholesterol, are formed as VLDLs deposit triglyceride in adipose (or body fat) sites, thus leaving the lipoprotein with more cholesterol. Some LDLs circulating through the bloodstream are absorbed in the walls of arteries and converted to an oxidized form. Oxidized LDL irritates the artery wall and can incite the body to release specialized proteins called cytokines. The cytokines attract white blood cells, which are inflammatory cells that try to protect arteries. These white blood cells convert to macrophages (which means “big eaters”) and try to ingest the oxidized LDL particles on the artery wall.

Sometimes the macrophages become so overloaded that they convert to foam cells, which eventually become an atherosclerotic plaque called vulnerable plaque (because it is unstable). The constant contracting and stretching of an artery, especially from high blood pressure, can rupture the thin membrane covering the vulnerable plaque, releasing some of it into the blood. The body responds by forming a clot around the loose plaque and at the site of the rupture. Loose plaque can clog a blood vessel, causing a heart attack or stroke, while arterial plaque buildup impairs blood flow.

In this landmark study (actually two studies in one), Voight and a large group of international researchers conducted an investigation using a statistical technique called mendelian randomization. This mathematical tool allowed the researchers to test the hypothesis of whether certain biomarkers were actually causal in raising (in the case of LDL-C) or lowering (in the case of HDL-C) the risk of cardiovascular disease.

The study analyzed data from 19,139 cases of heart attacks (myocardial infarctions) and 50,812 myocardial infarction–free subjects from 30 different studies. With this data, researchers tested several subcomponents of an endothelial lipase gene (in LDL and HDL) to better determine its role in heart attacks. In this very sophisticated molecular biology study, the researchers’ analysis concluded that high plasma levels of LDL-C are consistently associated with high risk of heart attacks. However, with HDL-C the researchers found that some genetic mechanisms that raise plasma HDL-C do not seem to lower risk of myocardial infarction, as was once believed. Thus, the researchers’ findings refute the notion that raising HDL-C will uniformly translate into reductions in heart attack risk.

HDL is definitely a “scavenger” particle in blood that helps to remove atherosclerotic plaque. Its “reverse-transport” role in the body is a positive and healthy mechanism. In an email interview, Ralph LaForge, MS, president of the Accreditation Council for Clinical Lipidology, said that HDL-C is a “clear marker of CVD (cardiovascular disease) risk, but not particularly a target of therapy.”

LaForge said medical professionals are “not trying to determine ways of raising HDL-C” to reduce the risk of cardiovascular disease. Much more investigation is focused on reducing harmful LDL-C and VLDL-C. LaForge went on to say that HDL is “far and away the most complex of all the lipoproteins,” suggesting there is much more to learn about its many functions in the human body.

So while attempting complex therapies to elevate levels of “good” cholesterol may be misguided, there remains little doubt that targeted therapies to lower LDL-C should be encouraged because they are so effective at improving health and lowering cardiovascular disease risk.