C-Reactive Protein- Helpful or Hype?
Much attention has been focused in the media recently on the role of C-Reactive Protein as a predictor of cardiovascular risk. In this edition of our newsletter we explore whether the evidence has been over-blown or could this simple blood test truly predict who is at risk
C-Reactive Protein (CRP) is not a new addition to medical testing. It was first discovered in 1930 in patients with acute inflammation related to infection. CRP is a member of class of molecules commonly found in the blood known as Acute Phase Reactants. The levels of these substances increase dramatically as part of the inflammatory process, including in response to infections, some cancers and a wide variety of other less ominous conditions. CRP levels rise within hours of the start of inflammation and will return to normal within a day or two when the inflammatory stimulus is removed.
Inflammation is believed to play a role in the progression of atherosclerosis. Most importantly, inflammation may directly increase the risk of rupture of an atherosclerotic plaque already present in an artery. Plaque rupture leads to the formation of a blood clot, blocking off the blood flow in the artery and causing a heart attack or stroke.
As a marker of inflammation, CRP has shown some utility as a very mild predictor of cardiovascular risk. To measure cardiovascular risk, a “high sensitivity” CRP (hs-CRP) blood test must be done. Elevated levels, above 2.4 mg/l, have been associated in some studies with a doubling of the risk of a coronary event compared to levels below 1 mg/l. In the recently published JUPITER trial patients with elevated hs-CRP levels were given statin therapy (drugs that are commonly used to lower cholesterol) with Rosuvastatin. Statins are known to reduce inflammation and those patients who took Rosuvastatin in the study averaged a 37% decrease in their hs-CRP. The study found that those patients who had high levels of hs-CRP prior to treatment had a significant reduction in the number of cardiovascular events
So, does this mean that we should use hs-CRP as a marker for increased cardiac risk and start treating everyone with an elevated level?
As noted above, CRP levels can change very quickly and often vary from day to day. A single elevated hs-CRP is likely to be of little value. At the least, the test should be repeated several times to demonstrate that the hs-CRP remains consistently high.
The presence of visceral fat, the type of fat that occurs inside the abdomen around the internal organs as opposed to subcutaneous fat under the skin, is associated with increased levels of inflammation. Visceral fat typically accumulates in response to high carbohydrate diets, alcohol intake and insufficient exercise, among other causes. So, a change in diet, weight or exercise can cause hs-CRP levels to increase. Improving the lifestyle factors that underlie the change will bring the hs-CRP and inflammation back down. Simply having an elevated hs-CRP may not justify lifelong drug therapy when the problem may be correctable with lifestyle changes.
The bigger concern is that while inflammation is likely to play a role in both the progression of atherosclerosis and the risk of symptomatic cardiovascular events, we don’t know what role it plays in people who do not have pre-existing atherosclerosis. Studies published several years ago established that patients with plaque seen on a Heart Scan had an even higher risk of cardiac events if they also had an elevated hs-CRP. On the other hand, patients who did not have any detectable plaque on their Heart Scan had a very low risk of heart attack or stroke whether or not they had an elevated hs-CRP.
The JUPITER trial looked at all people with elevated hs-CRP but did not differentiate those who had atherosclerosis from those who didn’t. So, while a reduction in risk was seen on average across all those patients who had an elevated hs-CRP, it is very plausible that there was a very large risk reduction from treating those who have plaque while those who did not have plaque had no benefit at all.
In that case, using hs-CRP alone to determine who should be treated is very likely to result in a large number of people being treated who can not benefit because they don’t have atherosclerosis in the first place. The JUPITER trial authors estimated that 95 patients with elevated hs-CRP levels would need to be treated to prevent just 1 cardiac event over a 2 year period.
Therefore, our recommendation is that hs-CRP is not useful primarily as an initial screening tool as it does not differentiate those with high risk plaque from those without any plaque and a low risk. The initial screening step should be a Coronary Calcium Score to determine the total amount of plaque present. Those with zero scores and no detectable plaque do not need further risk stratification. Those with more than moderate amounts of plaque may benefit from measuring hs-CRP and instituting more aggressive and earlier treatment if the hs-CRP is elevated.
In patients who have already been found to have a high hs-CRP, a Coronary Calcium Score may help to differentiate those who need more aggressive treatment. If no detectable plaque is present then simple lifestyle changes, such as improved diet and exercise along with Omega 3 supplementation, should help to lower the levels of inflammation which may alter the long-term risk of eventually developing atheroscolerosis.