Detecting new risks for heart disease

Times Staff Writer

Given all that doctors know about the effects of cholesterol, blood pressure, body weight and smoking, predicting who will have a heart attack should be easier than it is.

Winston Churchill, for example, exhibited several risk factors for heart trouble. He smoked. He was overweight. And he lived until age 90. Celebrated runner Jim Fixx looked to be in perfect health and dropped dead from a massive coronary at 52.

“Obviously, everyone with risk factors doesn’t get a heart attack,” says Dr. P.K. Shah, director of cardiology at Cedars-Sinai Medical Center. “Our traditional risk factors are very weak overall predictors of future risk. They are the best we have, but they are very weak.”

Doctors typically assess a person’s chances of having a heart attack based on cholesterol, blood pressure, weight, diabetes or insulin resistance, smoking habits and family history. All these factors can cause damage to the coronary arteries, commonly defined as heart disease, increasing the likelihood of a heart attack or stroke. But other variables are involved too.


Scores of researchers are trying to pin down those variables in an attempt to better predict risk. Within a few years, new factors probably will be added to the list of traditional warning signs for at least some patients.

“We are looking for markers to help improve our discrimination and accuracy, to help show us who is at risk and who is not at risk,” says Dr. Gregg C. Fonarow, a professor of cardiology at the David Geffen School of Medicine at UCLA. “There is a lot of interest and excitement around other markers that we may be able to utilize.”

Doctors are already debating whether C-reactive protein, a substance found in the blood, should be routinely measured in all adults. Previous research suggested that high levels of CRP raise the risk of heart disease, and last month, two studies published in the New England Journal of Medicine showed that lowering CRP levels with statins (drugs that help lower cholesterol) can reduce the risk of a heart attack.

The recognition of risk factors such as CRP reflects a deepening understanding of heart disease, says Dr. Richard M. Fleming, director of the Fleming Heart and Health Institute in Omaha, Neb.


Heart disease is known to be linked to the accumulation of plaque in the coronary arteries, but inflammation in the arteries also appears to play a role. The inflammation is thought to cause a weakening of the artery walls and ruptures in the plaque that could lead to a heart attack. CRP is a warning sign that inflammation may be present.

“Heart disease is not what we thought it was,” says Fleming. “It’s not just a narrowing of the arteries. Seventy-five percent to 80% of people who have a heart attack have 30% or less narrowing of the arteries. And for many people who have heart attacks, cholesterol is not elevated.”

CRP is produced by the liver and plays a role in fighting inflammation wherever it occurs in the body, but using the protein to assess heart attack risk is difficult. Levels can rise in people with lupus, rheumatoid arthritis and other conditions. Moreover, although lowering CRP in large groups of people appears to lower heart attack rates overall, it’s hard to predict the effect of lowering it in a particular patient.

“CRP seems to add to our ability to predict risk, but not by much,” Shah says. “Measuring CRP in the blood may be insufficient to know what is going on in the vessel wall.”


Shah says he does not routinely check CRP levels in his patients. People with the traditional risk factors for heart disease should be treated regardless of their CRP status, he says. People with no risk factors other than an elevated CRP pose a dilemma. Although CRP can be lowered through diet, exercise and quitting smoking, there’s no proof that lowering it will reduce the risk of a heart attack.

Nevertheless, some doctors are enthusiastic about the value of measuring CRP. The new studies demonstrate that it can help predict the prognosis of a patient who is already taking statins, says Fonarow.

“It opens up an avenue for patients where you already know they have disease and are following them, using CRP to reassess the patients,” he says.

The American Heart Assn. and the federal Centers for Disease Control and Prevention issued guidelines in 2003 on whose CRP levels should be checked. The experts did not recommend the test for the general public. But CRP measurement could be useful, they said, if a patient has an intermediate risk of developing heart disease within the next 10 years. The test can help a doctor choose between further evaluation and more aggressive therapy.


Those guidelines are expected to evolve as more information on CRP emerges. And expect the list of risk factors for heart disease to grow. Other potential risk factors include:

* Myeloperoxidase, or MPO. This enzyme, found in white blood cells, helps fight infection. Researchers believe it accumulates in the arteries and helps convert low-density lipoprotein (LDL) cholesterol into a more destructive form. In a 2003 study in the New England Journal of Medicine, researchers at the Cleveland Clinic showed that high levels of MPO could predict future heart attack.

* Lipoprotein phospholipase A2, or Lp-PLA2. This enzyme is linked to a greater risk of plaque formation and rupture in blood vessel walls. People with higher levels of Lp-PLA2 appear to be at greater risk for cardiac problems. The Food and Drug Administration in 2003 approved a blood test to measure the enzyme.

* Interleukin-6. Interleukins are chemical messengers. Elevated levels of a particular one, called interleukin-6, could be a marker for inflammation -- most likely from heart disease.


* Fibrinogen. This protein increases the blood’s tendency to form clots. Higher levels could mean a greater risk for heart attack.

* Homocysteine. This amino acid, found in the blood, appears to harm artery walls and cause inflammation. A study last month in the Lancet showed that people with high concentrations of homocysteine have an increased risk of stroke. Taking folic acid and other B vitamins can lower homocysteine levels.

These emerging markers “are about being proactive rather than reactive,” says Fleming, the author of a new book on cardiac inflammation called “Stop Inflammation Now!”

“We’ve spent a lot of time dealing with what to do when someone has a heart attack. Now we know the disease is a dysfunction of the artery as a result of inflammation,” he says. “So instead of allowing a disease to smolder, we can address it by making the right types of changes so you don’t have a heart attack.”


Doctors are also looking for genes that will show whether specific individuals are at higher risk and for markers that suggest a problem is imminent. Most traditional risk factors predict the risk of having a heart attack within 10 years.

“What we’d like to have is something to raise an immediate red light,” says Fonarow. “Something that is not going to happen five years down the road but will help us know who is at risk in the next few months.”

But doctors are debating the usefulness of any new marker for heart disease in light of a sobering fact: We don’t make good use of the information we have now.

“The challenge is that, even for traditional markers like cholesterol and blood pressure, we have done a very poor job in controlling these modifiable risk factors,” says Fonarow. “The majority of patients have an LDL cholesterol well above optimal levels even though there is no question that cholesterol plays a role in determining risk and that lowering LDL lowers the risk.”


A recent study showed that of the four major modifiable risk factors -- smoking, diabetes, high LDL cholesterol and high blood pressure -- 80% of a group of 100,000 people had one or more, says Fonarow. Altering any of these risk factors, he adds, could have a huge effect on the prevalence of heart disease in the United States: “These big four modifiable risk factors are driving the majority of the events.”