When Good Goes Bad: The Mystery of HDL

Health Writer

We’ve come to know high-density lipoproteins (HDL) as the cholesterol “good guys” who get rid of the low-density lipoprotein (LDL) “bad guys.” The LDL bad guys earned their nickname from collecting on arterial walls, forming deposits known as plaques. The plaques narrow the arteries and can break off and flow to a major organ to cause a stroke or heart attack.

How do the HDL good guys help? They’re like the Coast Guard, cruising through arteries and picking up LDL bad guys. The “Coast Guard’s” destination is the liver, where the good guys dump the bad guys before they can do harm.

Research at the Cleveland Clinic, however, recently showed that some of the good guys can go bad. In people with heart disease, some HDL particles have become defective, moving slowly or in the wrong direction. The defective HDL particles thus create a traffic jam, preventing them from getting to the liver to dump their unhealthy LDL passengers.

What makes good guys go bad? There are several theories. An enzyme called myeloperoxidase (MPO), found in white blood cells as part of the immune system, might be a culprit because it was found in arterial plaques in 2004 by Stanley Hazen, M.D., Ph.D., and colleague. Dr. Hazen, a cardiologist and cell biologist at the Cleveland Clinic’s Lerner Research Institute, is conducting further studies to determine the impact of MPO on HDL.

There may be another culprit as well, found through research conducted by Daniel J. Rader, M.D., a geneticist and lipidologist at the University of Pennsylvania, and colleagues. They expanded on past research in which scientists had deleted the SCARB1 gene in mice, which caused them to have very high HDL levels, blocked arteries, and heart attacks. The SCARB1 gene makes a protein called SR-B1. When that protein is missing, HDL loses its ability to transport bad-guy LDL to the liver for disposal. Rader’s team looked at SR-B1 in humans by sequencing genes in nearly a thousand people who had high cholesterol. Findings showed that people with SCARB1 mutations had high levels of HDL that failed to transport LDL to the liver; thus, they had blocked arteries despite having high HDL. It is believed that the missing or mutated SCARB1 gene prevented HDL from doing its job.

People with very low HDL levels do appear to be more likely to die of complications associated with heart disease, suggesting that higher HDL is beneficial. People with an HDL level of 40 mg/Dl, however, appear to have the same risk as people with a level of 80 mg/dL. As HDL gets higher than 80, the CANHEART study by Dennis T. Ko, M.D., MS.c., and colleagues revealed increased death risks. Recent medication strategies have focused on boosting a person’s HDL or interfering with the transformation of HDL into LDL, but clinical trials have failed for every drug tested except one, Roche’s dalcetrapib, which worked in a subset of people with mutation of the ADCY9 gene. Is that because those people had a genetic mutation that makes HDL dysfunction?  Maybe, but we can’t say for sure—at least not until after research about to be launched by DalCor Pharmaceuticals, a UK company that has raised $150 million to test the drug’s impact on people with the ADCY9 mutation.

One size doesn’t fit all when it comes to clothes, shoes, and cures. Targeted therapies that fit individual genetic profiles are revolutionizing the standard of care for cancer, so why not for heart disease? There’s more to learn about HDL, and robust research is in progress. In the meantime, the guideline that has shown benefit for most still stands. HDL should be above 40 in men and above 50 in women; ideally, greater than 60. The benefit of HDL may be lost with extremely high HDL levels, for example, those over 100.

Research is in progress, and studies are focusing on the discovery of more HDL subtypes, the impact of lifestyle risk factors on HDL levels, and genetic mutations that affect people’s lipids and response to medications. Research will likely lead to biomarker-directed therapies that target people with specific gene mutations. Stay tuned, and until research yields evidence for change, follow your doctor’s instructions.