By Christine Haran
Just when we've mastered the difference between good and bad cholesterol, researchers have introduced a host of new risk factors for heart disease. While the major risk factors such as family history and elevated LDL cholesterol are still the strongest predictors of risk, emerging factors such as high levels of homocysteine and C-reactive protein may also play a role in the development of heart disease. Doctors can now use these extra clues to better determine if patients need treatment and how aggressive the treatment should be.
Below, MacRae F. Linton, MD, a professor of medicine and pharmacology in the division of cardiovascular medicine at Vanderbilt University Medical Center, discusses how heart disease is assessed and when the emerging risk factors should be considered.
What are the major risk factors for coronary artery disease?
The major cardiovascular risk factors can be divided into modifiable and non-modifiable risk factors. The non-modifiable ones include age; for a man, age 45 and for a woman, age 55 or older. Family history, having a parent or sibling who has had premature coronary disease, is another non-modifiable risk factor.
The modifiable risk factors include elevated LDL cholesterol, or the bad cholesterol, and low HDL cholesterol, which is the good cholesterol. Other major risk factors are hypertension, diabetes and cigarette smoking.
How is risk assessed?
According to the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III), you first count the traditional risk factors, and if somebody has fewer than two risk factors, they're at low risk. And if they have two or more risk factors, they're potentially at high risk or intermediate risk. If they already have evidence of coronary disease, they're in the highest risk category. In addition, you are also put in the highest risk category if you have diabetes mellitus, atherosclerosis (plaque build-up) in non-heart blood vessels, or a 10-year risk of coronary heart disease (CHD) events that is greater than 20 percent.
The treatment of hypercholesterolemia is based on the level of LDL cholesterol and risk, so the goal for your LDL cholesterol is determined by your level of risk. For people who are in the highest risk categories, the goal for their LDL cholesterol is less than 100 mg/dL, whereas if you're in the intermediate category, the goal is less than 130 mg/dL, and if you're in the low-risk category, it's less than 160 mg/dL.
What are some lifestyle risk factors?
The lifestyle cardiovascular risk factors are obesity, physical inactivity and a diet that promotes plaque buildup in the arteries; this is basically a high-fat, high-cholesterol typical American diet.
What are the emerging risk factors for heart disease?
All the emerging risk factors appear to contribute to heart disease risk and are mentioned in the formal guidelines as things to consider in situations where doctors feel like they need more information to stratify the patient's risk.
Elevated levels of triglycerides, high LDL and low HDL cholesterol are often referred to as the lipid triad. This lipid triad is clearly associated with plaque buildup. The role of triglycerides as a risk factor for CHD has been somewhat controversial because they have not been found to be independent risk factors in all studies. A major reason for this is the inverse relationship between triglyceride levels and HDL cholesterol levels (when triglycerides are high HDL cholesterol is usually low).
Another independent risk factor that's particularly important in people who have a high LDL cholesterol is lipoprotein a, Lp(a).
Another risk factor is the metabolic syndrome, which is a clustering of a lot of these risk factors; it's also been called the insulin resistance syndrome, or syndrome X. It includes high triglycerides, low HDL, high LDL, hypertension and abdominal obesity. When we're in our 20s, about 5 percent of the population has it. By the time we're in our 60s, about 40 percent of the population has it. Metabolic syndrome clearly confers an increased risk, both for cardiovascular events and diabetes.
The other non-lipid risk factors include homocysteine, fibrinogen and inflammatory markers such as C-reactive protein (CRP).
What is homocysteine?
Homocysteine is an amino acid, and interest in it came from observations of a rare genetic disorder called homocystinuria; children who had it developed premature atherosclerosis and vascular events and recurrent thrombosis. You can lower homocysteine levels by taking folic acid and B vitamins. Outcomes studies to evaluate the benefits of lowering homocysteine in terms of reducing CHD events are in progress, so there's really not definitive proof of that yet.
What is C-reactive protein?
C-reactive protein (CRP) is a nonspecific marker for inflammation. It's an acute phase protein, which means that in situations of stress, trauma, injury or infection, it can go up enormously, 1,000-fold. It's produced by the liver but may also be relevant when it's produced elsewhere. It's been looked at in a number of large studies, and it's been shown that it's an independent risk factor for cardiovascular events.
In order to accurately measure CRP, you have to use a high-sensitivity assay, and individuals need to basically be free of infection or other kinds of acute traumas that may cause it to go up. Right now, we're still figuring out how to use it.
What they've recommended now is to use CRP in that intermediate risk category to stratify people further in terms of how aggressively they should be treated to lower their cholesterol.
What is fibrinogen?
When you think about myocardial infarctions or heart attacks, the underlying process is atherosclerosis, which is plaque buildup in the artery. But what causes the heart attack is when the plaque ruptures and you form a clot. Fibrinogen plays a role in clot forming, so it's a risk factor for heart attacks.
When is use of the emerging risk factors appropriate?
You use these emerging risk factors in situations where you're concerned that there may be more risk than is apparent. So doctors might consider them in individuals who have a strong family history, yet their risk comes out to be low when the traditional risk calculation is done.
A lot of people who have either very high risk because they have very high cholesterol, or a very strong family history are now being referred to preventive cardiology clinics and lipid clinics or cholesterol clinics. In those settings, there's probably more use of the emerging risk factors.
How would the presence of emerging risk factors affect treatment recommendations?
You'd be more likely to upgrade people into a category where they might be treated. If you had somebody who's young, with a couple of risk factors such as low HDL cholesterol and a strong family history of premature heart attacks, their overall risk calculation may put them in the low or intermediate risk group. If their LDL cholesterol isn't that high, the guidelines might indicate that you do not need to treat them. But if you found that their CRP level or another one of the emerging risk factors that you're concerned about is positive, you might use it to upgrade their risk and go ahead and treat them.
If someone has high levels of homocysteine, you can treat them with the vitamin supplement folic acid. Even though we don't really have definitive evidence yet that it reduces the risk, I think in patients in whom you're concerned about the risk of cardiovascular events, if you find that they have an elevated homocysteine, treating it with folic acid is probably a reasonable approach.
What is your advice to people at risk for heart disease?
People should be aware that there are effective ways to prevent cardiovascular events, and they should be proactive and make sure that they get screened for the major risk factors, particularly if they have a family history.
There have been studies to look at how much you miss if you just use the major risk factors, and it varies, but some of these studies say that you can pick up 80 percent of people at risk just by using the traditional risk factors. I think the real issue is that we aren't even screening enough for the traditional risk factors, and then we're not implementing appropriate treatment.
So the place to start is with the traditional risk factors. If your traditional risk factors put you in a high-risk category, then you need to take preventive measures, which include lifestyle modification in addition to medications.
When you look at what's happening now in terms of obesity in our country, this is going to create a huge increase in the number of patients who have diabetes and are at risk for cardiovascular disease. And a lot of that is due to our lifestyles, which involve physical inactivity and a high-caloric, high-fat diet. These are things that we can modify, along with cigarette smoking. This seems to be something that's widely known but hard for people to put into practice.
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