April 3, 2008

"Good" Cholesterol, Heart Attack Risk and Prevention

By Jeffrey Norris Keeping "bad" cholesterol in check can aid arteries and help hearts. But now there also is increasing interest in boosting the "good" cholesterol. The "good" cholesterol is high-density lipoprotein cholesterol, or HDL. HDL in the bloodstream is now regarded as being at least as important an indicator of heart disease risk as levels of "bad" low-density lipoprotein cholesterol, or LDL. "Low HDL cholesterol levels are the most prevalent lipid abnormality in people who have had heart attacks - much more common than elevated LDL cholesterol levels," says Thomas Bersot, MD, PhD, clinical professor of medicine at UCSF, cholesterol researcher at the Gladstone Institute of Cardiovascular Disease and head of the Lipid Clinic at San Francisco General Hospital Medical Center. Through the Gladstone-initiated Turkish Heart Study, Bersot is investigating the causes and consequences of genetic variations that lead many Turks to have low levels of HDL. UCSF researchers are at the forefront among those conducting research on HDL and what it does in human artery walls. Studies range from investigating its contribution to risk and identifying new forms of HDL to imaging HDL molecules with the aid of powerful electron microscopes. Does Raising HDL Lower Heart Risk? Even though low HDL is a marker for coronary heart disease risk, it does not automatically follow that raising HDL by any means will reduce risk. Some researchers go as far as to suggest that low HDL might only be a risk marker, not an actual cause of more heart attacks. But biological research strongly implicates HDL in arterial disease. Evidence indicates that some HDL acts in the "cholesterol retrieval pathway" to help remove plaque-forming cholesterol particles from artery walls. There are older drugs that raise HDL. These drugs appear to lower heart attack risk. However, these same drugs also affect other blood fats in potentially beneficial ways. So, it's not clear whether the positive health outcomes observed in these studies are due solely or even primarily to raising HDL. Furthermore, raising HDL may not always be the most important objective of treatment. Among patients who already have had a heart attack, for instance, beta-blockers have been shown to reduce the incidence of second heart attacks, even though they lower HDL levels. Drug Development Aimed at Boosting HDL There are newer drugs in development that aim to specifically raise HDL levels. But there have been setbacks. In 2006, the experimental HDL-raising Pfizer drug torcetrapib failed dramatically in a clinical trial. For still unexplained reasons, there were significantly more deaths among the experimental group in comparison with the control group, and there was no apparent reduction in coronary heart disease-related medical events. Knowledge gaps in understanding HDL biochemistry and metabolism in cardiovascular disease may be increasing the costs of new drug development.

"Low HDL cholesterol levels are the most prevalent lipid abnormality in people who have had heart attacks - much more common than elevated LDL cholesterol levels," says Thomas Bersot, MD, PhD.

Researchers who study cholesterol are sorting out many details. It turns out that there are multiple types of cholesterol, including different species of LDL and HDL. The different types may play different roles, which have yet to be fully unraveled. With his colleagues at the UCSF Cardiovascular Research Institute (CVRI), John P. Kane, MD, PhD, leads research aimed at identifying molecules and genes implicated in the progression of heart disease. "We have discovered many new molecular species of HDL, whereas people used to say there were probably two species, HDL2 and HDL3," he says. "We discovered prebeta-1 HDL, which is the major form of HDL that acquires cholesterol coming back out of the arterial wall." UCSF researcher Gang Ren, PhD, is learning more about HDL and LDL metabolism by studying their structures using one of the most powerful electron microscopes in the world. "Function is based on structure," he explains. "People have studied HDL and LDL metabolism for 30 years, but we still know little about their structures." At the UCSF Mission Bay site of the California Institute for Quantitative Biosciences, Ren is observing individual lipoprotein molecules and the distinct shapes they assume during different molecular interactions. Ren also is studying interactions of HDL, LDL and the protein targeted by the failed drug torcetrapib. The protein, called cholesterol ester transfer protein, moves cholesterol from HDL to LDL - thereby lowering HDL levels and raising LDL levels. Using the electron microscope, Ren hopes to uncover the finer details of the molecular interactions that result in this cholesterol transfer. The results might lead to better drug designs, he suggests. Older Treatments Getting a Closer Look While new HDL-raising drugs are being developed, clinical trials also are underway to more thoroughly evaluate older HDL-raising treatments. For instance, formulations of niacin, used since the 1950s to treat cholesterol imbalances, are undergoing new clinical trials. Niacin also lowers LDL, as well as triglycerides, another category of fat associated with obesity, diabetes and heart disease. In a 1990 study of 72 patients with a hereditary form of high cholesterol, a UCSF team led by Kane and former CVRI Director Richard Havel, MD, historically demonstrated that arterial blockage can sometimes be reversed; in this case, by a low-fat diet and a combination of three drugs - niacin, a statin and a less popular type of treatment called a bile acid-binding resin. The benefits in that study were associated with lowering LDL. A few follow-up studies also seem to suggest that combination therapies may do more to ward off heart attacks than statins alone in high-risk patients - spurring interest in the larger clinical trials underway today.

"Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens" J. P. Kane, M. J. Malloy, T. A. Ports, N. R. Phillips, J. C. Diehl and R. J. Havel JAMA, vol. 264, no. 23, Dec. 19, 1990 Abstract

"Is Raising HDL a Futile Strategy for Atheroprotection?" Tisha Joy and Robert A. Hegele Nature Reviews Drug Discovery, vol. 7, February 2008 Full Text