Mar. 25, 1998 SANTA FE, N.M., March 20 -- Sex-related differences in an enzyme that breaks down blood fats -- particularly "bad cholesterol" known as LDL -- may explain why men develop heart disease earlier than women, said scientists March 20 at the American Heart Association's epidemiology and prevention conference.
"There are gender differences in the risk of coronary artery disease, the cause of heart attack. Pre-menopausal women have lower cholesterol levels and higher HDL levels (the good cholesterol) and lower heart disease rates than men," says the study's lead author, John E. Hokanson, Ph.D.
"We have observed in the past that there are higher levels of the enzyme hepatic lipase in men than in women. We asked the question, does hepatic lipase account for these lipid differences in men and women, and, if so, to what extent?" adds Hokanson, research scientist in the department of medicine at the University of Washington, Seattle.
Hokanson's research -- the first to focus on hepatic lipase and gender in heart disease -- could point to a new mechanism for increased risk for heart disease that characterizes men, when compared to women, before age 55. The research could suggest new ways to intervene to reduce that risk, he says.
In the study, scientists tested 25 men, 21 to 59 years old, and 39 pre-menopausal women, 21 to 51 years old. Both groups had normal cholesterol levels. Hepatic lipase activity was 53.4 percent higher in men than in women.
"The differences in the type of cholesterol we see in men and women appear to be related to hepatic lipase, and differences in this enzyme's activity may account for much of the difference in heart disease risk between men and pre-menopausal women," Hokanson says.
Researchers have in recent years been studying what they call the atherogenic phenotype, also called LDL subclass pattern B, which is characterized by predominantly small, dense LDL, low levels of the protective HDL cholesterol component and high triglycerides. The researchers found that men had significantly lower amounts of HDL, higher triglyercides and more small, compact LDL.
"One of the regulators of hepatic lipase appears to be estrogen," he says. "A crucial question would be to look at post-menopausal women, because women's heart disease risk increases after menopause, and some women have changes in their lipoproteins like those associated with higher hepatic lipase. It would be very interesting to know whether hepatic lipase is involved in the difference in coronary disease risk between pre-menopausal and post-menopausal women. We are, in fact, looking into issues related to that question.
"Another very interesting question is how estrogen replacement therapy might affect HDL and small dense LDL in post-menopausal women," he adds. Evidence is mounting that small, dense LDL particles are the "baddest of the bad" because they are most likely to clog the arteries, Hokanson says. Having a predominance of small, compact LDL particles causes about a three-fold increase in a person's risk of heart disease compared to people whose LDL particles tend to be the larger kind.
"The density of LDL is crucial," he says. "Small, dense LDL is more atherogenic (likely to clog blood vessels), but the mechanism is unclear." Cholesterol and other fats cannot dissolve in the blood and must be transported by special carriers made in the liver called lipoproteins -- fats surrounded by proteins. Enzymes such as hepatic lipase, which is also made in the liver, break down the lipoproteins so the fats can be metabolized or used by the body.
Cholesterol metabolism has many steps. First, the liver turns food ingested into fatty acids, carbohydrates, alcohol and some cholesterol into very low-density lipoprotein (VLDL), the largest type of lipoprotein. VLDL is transported through the bloodstream to the body's tissues, which release triglycerides, fats used for energy or stored in muscle or fat cells. Lipoprotein lipase breaks down the VLDL into intermediate-density lipoprotein. Hepatic lipase is the enzyme that breaks the intermediate-density particles down into LDL, which carries 60 to 80 percent of the cholesterol in the blood.
Some lipoproteins are more dangerous than others. LDL is called the "bad" cholesterol because excess LDL particles stick to the inner walls of the blood vessels to form plaque. These particles help form the plaque obstructions in the blood vessels that can block blood flow and trigger heart attacks and strokes. LDL comes in different sizes, or densities, and everyone's cholesterol profile contains different ratios of the different sizes of LDL.
Reverse cholesterol transport doesn't sound very heroic, but that's the role of high-density lipoprotein (HDL), the so-called "good" cholesterol. HDL clears fragments of proteins, fats and cholesterol from the bloodstream before they can damage arteries. Low levels of HDL have been linked to increased heart disease risk.
Researchers have been able to show that they can intervene in men and change hepatic lipase levels, he says. In a previous study, co-author Alberto Zambon, a senior researcher at the University of Washington, found that intensive therapy with lipid-lowering drugs decreases hepatic lipase in men and causes coronary artery disease regression.
Hepatic lipase activity must be measured in a test tube and requires more than a simple blood test. Because it binds to the endothelium, the inner lining of blood vessels, people must first submit to an injection of the blood thinner heparin to release hepatic lipase into the bloodstream. The complexity of the test, which temporarily thins a person's blood but has no other side effects, makes large studies difficult, he says. "That has been an important limitation to the research."
This study was presented at the American Heart Association's 38th Annual Conference on Cardiovascular Disease Epidemiology and Prevention.
Hokanson and Zambon's co-author was John D. Brunzell, M.D.
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