Nothing kills more guys than heart disease. It killed more than 430,000 of them in the United States in 2001. Add up all of those who died from the four next most common causes (cancers, accidents, chronic respiratory disease and diabetes) and you still don't top the heart disease body count.
Researchers have made great progress in understanding the disease and its risk factors, but we still can't predict who will get coronary heart disease, the most common form, caused by decreasing blood flow to the heart because of a narrowing or blockage of the coronary arteries. When this happens, you're often headed for a heart attack.
. As many as one of every five heart attacks occurs among apparently healthy individuals who have none of the major risk factors: smoking, high blood pressure, high cholesterol and diabetes.
. Half of all heart attacks happen to men who don't have high cholesterol, the most anxiously tracked risk factor.
. Most confounding: While the vast majority of men diagnosed with heart disease are known to have at least one risk factor, it's also true that the vast majority of men with one risk factor don't have heart disease.
"What we don't yet understand is, of those patients who do have the traditional risk factors, which [patients] are the ones who are going to have an event," said John Canto, a cardiologist at the Watson Clinic in Lakeland, Fla., and author of a Journal of the American Medical Association (JAMA) editorial about heart disease risk factors.
Researchers are turning their attention to new markers -- novel risk factors, as they are known -- to fine-tune predictions of who is headed for that first, or second, heart attack. They are also refining their understanding of some traditional risk factors. Following is a summary of the latest research into risk factors over which men have some control. None can yet predict with certainty whether you're a heart attack waiting to happen. But each can contribute to a portrait of your overall risk.
And if you are at risk? See "What Can You Do to Reduce Your Risk?" below.
C-Reactive Protein
The Update
A blood marker for inflammation, C-reactive protein (CRP) may help clarify the risk profile for some patients.
Doctors now believe inflammation in the arteries, not just the buildup of plaque, is a key contributor in the development of coronary heart disease. A number of studies have looked at whether an inexpensive ($15-$20) test for CRP can predict heart disease.
Last year the American Heart Association and the Centers for Disease Control and Prevention said doctors might consider testing CRP when they were undecided about the best treatment for someone with intermediate risk of having a heart attack -- those with a 10 to 20 percent risk for having a heart attack in the next 10 years.
What's most intriguing is the possibility that CRP could be used to predict heart disease in the 50 percent of heart attack victims who don't have high cholesterol. "I honestly believe that the CRP phenomenon has the ability to save hundreds of thousands of lives per year," said Paul Ridker, professor of medicine at Harvard Medical School and director of the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital in Boston.
Not everyone shares this enthusiasm. A study of more than 18,000 participants and 2,500 heart attacks, published last month in the New England Journal of Medicine, found that C-reactive protein was not as reliable a predictor of heart disease as high cholesterol, obesity or smoking.
"The genuine answer from the facts seems to be that CRP is a relatively modest risk factor," said Mark Pepys, head of the Department of Medicine at the Royal Free & University College Medical School in London, and one of the study's authors.
Several other cardiologists interviewed for this article do say CRP is an important predictor, particularly in patients who otherwise appear to be at moderate risk. It's still unclear how important a role CRP will play in predicting heart disease.
Homocysteine
The Update
Homocysteine, an amino acid linked to plaque buildup in the arteries, may be a disease marker in some people lacking other risk factors.
Some studies have linked high levels of homocysteine with higher rates of heart disease and death from cardiac events. But how important a risk factor homocysteine is -- and whether lowering it reduces the risk of heart disease -- remain matters of debate.
The American Heart Association does not yet consider elevated homocysteine a major risk factor. The group says homocysteine screening may be useful in people with a personal or family history of heart disease who don't have any of the other traditional risk factors.
"In groups of patients where homocysteine is increased, there seems to be increased risk, but we don't have a study [showing] that lowering homocysteine will reduce risk," said Sidney Smith, director of the Center for Cardiovascular Science and Medicine at the University of North Carolina at Chapel Hill. Smith, a spokesman for the American Heart Association, said studies must show that lowering homocysteine levels will reduce heart disease before widespread screening can be recommended.
Steve Nissen, a cardiologist at the Cleveland Clinic, is more skeptical: "It is not panning out. I think it's not a very important risk factor."
Screening for homocysteine isn't widely available, may cost $85 to $200, and usually isn't covered by insurance.
Arterial Calcium Deposits
The Update
Researchers debate whether scanning the heart for calcium yields useful information beyond traditional tests.
Some researchers and doctors say an electron-beam computed tomography scan -- commonly called a calcium scan -- can help doctors predict whether otherwise-healthy people with risk factors such as high blood pressure or high cholesterol will develop heart disease. The 10-minute scan can detect calcium deposits that result from the buildup of plaque in the arteries.
George Kondos, associate chief of the cardiology section at the University of Illinois College of Medicine in Chicago, says the scan can give doctors additional information beyond the traditional risk factors.
Last year Kondos published in the journal Circulation the results of a study in which he performed calcium scans on 5,635 people with no symptom of heart disease. More than 250 required bypass surgery or angioplasty, had a heart attack or died within 31/2 years of enrolling in the study. Kondos found that 95 percent of those who experienced such "events" had high levels of calcium in their arteries. Kondos said his research showed that the scan was a better predictor of heart problems in men than in women.
"The problem with the traditional risk factors is that they are really good, they've withstood the test of time, but we need to do better," Kondos said. "It's not uncommon for men, 25 to 30 percent of the time, that you would have somebody with absolutely no risk factors and then drop dead of a heart attack."
But not all doctors are convinced that the calcium test -- which costs about $600 and usually isn't covered by insurance -- yields valuable information. Critics say that because everyone develops calcium deposits with age, very few results are negative. And positive results have a poor predictive value, they say, certainly not better than what can be gleaned from assessing the traditional risk factors.
"The bottom line is, we have our answer in front of us with the major traditional risk factors," Canto says.
The American Heart Association published a consensus statement in 2000 saying that although the scan might help with treatment decisions in some patients, there was not enough compelling evidence to warrant its widespread use.
High Blood Pressure
The Update
A hypertension exam is not a pass-fail test. The lower your numbers, the lower your risk of heart disease.
One-quarter of adult men in the United States have high blood pressure. The risk is particularly acute for African American men, who tend to get the disease earlier and have higher rates of complications and death.
Paul Whelton, senior vice president for health sciences at the Tulane University Health Sciences Center in New Orleans, said doctors used to consider high blood pressure a disease people either had or did not have. But today we understand that the risk of dying from heart complications caused by high blood pressure is a graded risk. "The higher the pressure, the higher the risk," Whelton said. "The more you can take that pressure down, the more you can get the risk back down."
How low should you go? Blood pressure above 140/90 is considered high and current guidelines call for medication. Blood pressure of less than 120/80 is considered normal. Readings between those ranges are considered pre-hypertensive, and the guidelines recommend diet and exercise to drive the numbers to normal. People with diabetes may need to go on medication to lower these borderline pressures.
"We have primarily focused on the numbers of 140 and above," said Daniel Jones, a member of the National High Blood Pressure coordinating committee, administered by the National Heart, Lung, and Blood Institute, and dean of the University of Mississippi School of Medicine in Jackson. "But we've known for a long time that most of the risk in the population exists in high-normal or borderline blood pressures."
Diabetes
The Update
Nearly all diabetics, without regard to their cholesterol levels, are now considered candidates for statin drugs, which are ordinarily prescribed to reduce high cholesterol, as a way to reduce heart disease risk.
Approximately 9 percent of men in the United States have diabetes, according to the American Diabetes Association (ADA). Type 2 diabetes more than doubles the risk of heart disease, making it one of the most potent risk factors.
New clinical guidelines from the American College of Physicians recommend that type 2 diabetes patients with one other heart disease risk factor -- which is to say, nearly all of them -- should go on a statin medication even if they don't have high cholesterol. People with type 2 diabetes typically are obese, physically inactive and have high triglycerides, high blood pressure and insulin resistance, all of which increase risk of heart disease.
Members of the committee that published the ADA guidelines said statin use lowers cardiovascular events such as heart attacks by between 22 and 24 percent.
Cholesterol: Bad
The Update
LDL levels below previous targets reduce heart disease risks more than previously realized.
Experts agree that high levels of LDL -- the "bad" cholesterol in your bloodstream -- contribute to heart disease. But the role they play is becoming clearer and more complex.
For one, said Nissen of the Cleveland Clinic, "LDL level alone is insufficient to cause [heart] disease. It seems like [a high LDL level] is an enabler. All other things being equal, if you've got LDL cholesterol around, then you have the potential to develop the disease. If your LDL cholesterol is very, very low, then your odds are low that you'll get the disease."
It also appears the odds can be lowered more than previously thought. Nissen's latest research, published in March in the Journal of the American Medical Association, found that using potent cholesterol-lowering medications to drive LDL levels below 100 mg/dL could stop the progression of heart disease. "It's a paradigm shift like nothing we've seen in a decade, and that is that you almost can't have too low an LDL cholesterol," Nissen said.
Current treatment guidelines set by the National Cholesterol Education Program suggest an LDL target level of 100 mg/dL. But Nissen said his trial demonstrates patients need much lower LDL levels to prevent the progression of heart disease. The group that had no progression in heart disease in his most recent study had a mean LDL of 79.
"It doesn't appear that there is a lower limit of normality," Nissen said. "My guess is that we are evolved for an LDL cholesterol of 50 or 60, and anything above that is actually abnormal for how we developed as a species."
Research is also exploring a type of lipid known as Lp(a), a genetic variation of LDL cholesterol. Lp(a) levels higher than 20 to 30 mg/dl are linked to premature heart disease in men and women, and the risk goes up for those with high Lp(a) who also have high LDL and low HDL. But researchers aren't exactly sure what role Lp(a) plays in heart disease, and we don't yet whether lowering Lp(a) will prevent heart attacks. Kondos said. Because there is no national standard for measuring Lp(a), the test isn't widely performed.
Still, research continues, with the goal of determining whether Lp(a) levels can help distinguish between those likely to have events and those who are not.
Cholesterol: Good
The Update
New drugs can boost HDL considerably, but its role in the development of heart disease is not completely clear.
HDL, the "good" cholesterol, appears to sweep the blood vessels of bad cholesterol. This is why a high HDL number has long been considered protective of heart disease. But Nissen said we know less about HDL than LDL because until very recently we haven't had good drugs to raise it, and lifestyle changes such as increasing good fat in the diet and boosting exercise raise HDL only modestly.
A preliminary study has recently shown that the experimental drug torcetrapib can dramatically boost HDL levels. Nissen said that larger studies in the next several years will show whether increased levels of HDL lead to lower incidence of heart disease.
In the Pipeline
Stay tuned for a host of other novel risk factors that are being researched, as well as breakthroughs in genetic profiling. Look for more work on small LDL, a type of bad cholesterol that may speed the progression of heart disease; HDL2B, a type of good cholesterol that may be especially good at cleaning out the bad stuff; and tests that predict inflammation on the arteries better than CRP levels -- such as measurements of myeloperoxidase (MPO), an enzyme found in disease-fighting white blood cells.
Canto, the Florida cardiologist, said the new markers and genetic tests under development will allow doctors to become much more specific in their predictions.
"Right now you're hearing about the major modifiable risk factors, but we're going to get much more sophisticated," he said. "You have one of these major modifiable risk factors, in combination with these markers or this gene type?
Boom. You're going to be the one who has the heart attack."
