Skip to comments.Protein Is Factor in Heart Disease, Researchers Say
Posted on 01/05/2005 4:19:08 PM PST by neverdem
Reducing the levels of a protein secreted by the body during inflammation may be as powerful in slowing heart disease and preventing heart attacks and deaths as lowering cholesterol, two teams of researchers are reporting.
The studies, published in Thursday's issue of The New England Journal of Medicine, provide the strongest evidence yet for the role of the protein, known as CRP for C-reactive protein, in heart disease. The participants were patients with severe heart disease who were taking high doses of statin drugs, which lower both cholesterol and CRP. Lower CRP levels, the researchers found, were linked to a slower progression of atherosclerosis and fewer heart attacks and deaths. And this effect was independent of cholesterol's effect on heart disease.
"What we now have is hard clinical evidence that reducing CRP is at least as important as lowering cholesterol," said Dr. Paul Ridker, of Brigham and Women's Hospital in Boston, who was the lead author on one of the studies.
But other heart disease researchers cautioned that more research was needed to prove that CRP directly causes heart disease. And most agreed that because the new studies involved only people with severe heart disease, it remains unknown whether healthy people would benefit from reducing their levels of CRP.
Still, the study investigators said they suspect that the results will be shown to apply more broadly. If they are correct, it could open a huge new market for the already popular statins - people whose cholesterol levels are normal but who have high levels of CRP. Of people who have heart attacks, half have normal cholesterol readings.
Dr. Ridker's study addressed the question of whether CRP levels independently predicted heart attacks and deaths. The second study, by Dr. Steven Nissen of the Cleveland Clinic and his colleagues, asked whether CRP independently predicted heart disease progression.
In both cases, the investigators concluded, the answer was yes. They, like most researchers in this field, have received support from drug companies and Dr. Ridker also is an inventor of a test for CRP, which his university licensed. He and his lab profit from the use of the test.
CRP is made in the liver and also in the walls of coronary arteries and possibly elsewhere in the body. Its levels, which can be measured with a simple blood test, often rise and remain high in patients who have chronic inflammation from conditions like rheumatoid arthritis, for example, or periodontal disease. Patients with chronic inflammation also have an increased risk of heart disease. Some heart disease experts said the new studies offered persuasive evidence that doctors should focus on keeping CRP levels low in patients with severe disease.
"This is missing link evidence," said Dr. Sidney Smith, a cardiologist at the University of North Carolina who is a past president of the American Heart Association and co-chairman of a committee of the heart association and the American College of Cardiology that that sets treatment guidelines.
But others said that CRP could instead be a marker for something else that statin drugs are doing to reduce heart disease risk.
"These are very important papers," said Dr. James Cleeman, who is coordinator of the National Cholesterol Education Program at the National Heart, and Blood Institute. "They are provocative. But we need to recognize that the relationship between CRP and heart disease is a developing story. This adds to the evidence but I'm not sure it settles the issue."
CRP levels in healthy young people are low, usually less than 1 milligram per liter of blood, but they rise with age and with obesity, diabetes, smoking, and a sedentary life. A third of the population has levels greater than 3, which have been associated with heart disease risk, Dr. Ridker said.
If people lose weight, stop smoking, exercise or take oral diabetes drugs, their CRP levels fall.
The evidence is increasing that CRP and heart disease are somehow linked. More than 30 studies have found that the higher the level of CRP, the greater the risk of heart disease and that CRP predicts risk independently of other factors, including cholesterol. Scientists have developed hypotheses to explain why, proposing that the protein could cause plaque to develop in coronary arteries, leading plaque to burst open and blood clots to form that then block arteries and cause heart attacks.
Some drug companies have started programs to develop drugs that specifically target CRP and prevent its synthesis.
But what these findings mean remains uncertain. The fact that CRP levels drop with exercise and weight loss, for example, has led some experts to argue that the protein is a marker of heart disease risk, not a cause, as gray hair is a marker but not a cause of aging .
CRP was discovered about 70 years ago by scientists who were trying to understand why some strep bacteria caused disease and others did not. It was named because it was found in the third band on an electrophoresis gel, referred to as band C by scientists. About half a century ago, doctors noticed that CRP flooded the blood after a heart attack and, for a while, they used it to help diagnose heart attacks.
Dr. Ridker's study involved 3,745 patients who had been hospitalized with heart attacks or severe chest pain from blocked coronary arteries and then were followed for two and a half years. Dr. Ridker said that when the study, sponsored by Bristol-Myers Squibb, was being planned several years ago, the thought was that it would ask whether moderate statin therapy - 40 milligrams a day with the company's Pravachol - was as effective in preventing heart attacks as more intense therapy with 80 milligrams a day of Pfizer's statin, Lipitor.
"I said, 'This is a good study, but it can be better,' " Dr. Ridker said. He proposed also asking about CRP - would people in the study with lower CRP levels have fewer heart attacks and deaths?
"My idea at the time was that I would be happy to find a 10 percent residual benefit or a 20 percent residual benefit," from low CRP levels, Dr. Ridker said. "We never dreamed we'd get a risk reduction as large as the risk reduction from lowering LDL cholesterol."
Dr. Nissen's study, sponsored by Pfizer, examined plaque in the coronary arteries of 502 patients with heart disease, comparing intense to moderate statin therapy and using the same doses of the same drugs as Dr. Ridker's study used. Intense therapy resulted in lower cholesterol levels and slower growth of plaque, Dr. Nissen reported. But he also suspected that something else was going on, because some patients seemed to be doing much better than others with the same cholesterol levels.
Upon further analysis, Dr. Nissen found that levels of CRP dropped independently of cholesterol, and were independently associated with a slowing of disease progression. In patients who achieved both low levels of CRP and low levels of cholesterol, plaque actually regressed in their coronary arteries, Dr. Nissen found.
"I'm looking right at the plaque and when your CRP level is reduced, you are stopping the disease," Dr. Nissen said. "We are saying that CRP is a direct participant in atherosclerosis."
The next step, Dr. Ridker said, is to see if reducing CRP levels can prevent heart attacks in healthy people. His new study will enroll 15,000 people with normal cholesterol levels but higher than average levels of CRP, above 2 milligrams per liter of blood. The participants will be randomly assigned to take 20 milligrams a day of a statin, AstraZeneca's Crestor, or a placebo.
Some experts say the new findings make it clear that doctors should monitor CRP levels in patients with severe heart disease and do whatever it takes, including giving high doses of the most powerful statins, to get levels below 2 milligrams per liter of blood.
"What these two papers are saying is that not only is CRP a risk factor on its own, but we should be aggressively treating it," said Dr. Valentin Fuster, a past president of the American Heart Association and director of the cardiovascular institute at Mount Sinai School of Medicine in New York.
But Dr. Daniel Rader, a heart disease researcher at the University of Pennsylvania, said that may not be so easy in patients who are already doing everything possible.
"You've already counseled them about life style, you've already given a statin, you're already targeting LDL cholesterol to less than 70," a very low level that is recommended by the current guidelines," he said. "So if you find a high CRP, what do you do? Do you tell the patient, 'Oh, this is bad. You're at high risk?' "
A difficult question, Dr. Ridker said, but one he predicted will not arise too often.
Most patients with severe heart disease are not taking high doses of statins, he said, so there is room for doctors to experiment with higher doses and different drugs to reduce CRP levels, if necessary.
"There is a huge payoff if physicians understand that they need to titrate not just the cholesterol but also the CRP," Dr. Ridker said. "That alone will save tens of thousands of lives, right there."
YES....I am on doxycycline ....I refused to go the HEAVY DRUG route....after doing research of my own, and finding a like minded doctor. (Too bad it takes soooo long to make you feel better, though!)
I was recently diagnosed with RA also, but because I have been taking aspirin 3x day for ordinary arthritis, I still had a low CRP. I now take it 4x per day, on schedule and with food.
Statins aren't the only way to lower CRP. ;-D
How's your stomach doing? And, how's your RA? (My condolences for the diagnosis....I KNOW what IT'S like!)
It apparently works better when combined with Roxithromycin. Ask your doc if he's willing to try combined therapy.
The aspirin will reduce the inflammation but not kill the microbacteria that is probably causing the inflammation. Ask your doc about adding an antibiotic like doxycycline.
Are YOU a doctor?....I've done LOTS of research...never heard of Roxithromycin.....going to check now. THANKS.
RA is an auto immune disease caused by a prior strep infection long gone.
RA could be MANY things.....what makes you so CERTAIN it's from "strep?"
Arthritis is caused by many things. Rhumatoid arthritis is a specific arthritis caused by strep infection. It is a unique arthritis with it's own characteristics. Other organisms, such as B. burgdorferi, (lyme disease) can cause similar autoimmume diease.
Hmmmm....so YOU are a doctor? If it's caused by strep (which I had when I was in my 20's).....and it comes back to haunt you by the immune system.....then WHY don't doctors SAY that? NO doctor I've read of, talked to, or heard of has EVER said "strep" was the cause of RA....in fact, I'll go to the roadback.org....and see what everyone THERE says.
I went and reviewd "The New Arthritis Breakthrough" Book I have....and Yes, strep CAN be an RA instigator, but I doubt that it ALWAYS is....if it is, amoxicillin should cure me, right?
Post 32 was for you.
I'm not sure how similar the arthritis of RA and that from B.burg. are.
Very interesting. I guess one can ask their doctor for a blood test that would indicate the levels discussed.
No. The infection is almost always gone, or at least almost total remission by the time RA developes. RA devlopes at a later time, sometimes decades after the infection. RA is actually an autoimmune disease where the body's own immune system is doing the attack and damage. It's usually controlled by reducing the immune response with corticosteroids and anti-inflamatories.
Where do you get YOUR information? I will not use corticosteroids.....I WILL get to the bottom of the problem....likely mycoplasma within cells (strep gone hiding?)....
Infla-Zyme is one of more popular enzymes used here as well as in Europe.
"If it's caused by strep (which I had when I was in my 20's).....and it comes back to haunt you by the immune system.....then WHY don't doctors SAY that?"
They do. Their lit. is where I got my info. From immunology and infectious disease lit., not athritis lit. My childhood doc also thought so.
"likely mycoplasma within cells (strep gone hiding?)."
There's no mycoplasma there. It's an immune attack on the synovia and smooth muscle at least. The joints and smooth muscle are usually aseptic-no bugs whatsoever. It's similar to MS, where intermittent immune attack occurs on the myelin sheaths of nerve cells.
"I will not use corticosteroids"
They are of little help in the long run. They are a short term fix that opens one up to infection, because of reduced immune response. Aspirin and nutrients, like geletin and glucosamine and chondroitin are effective in the long run. I know little of any other meds.
Could Lyme Disease cause this inflamation?