Blood measurements of hs-CRP are often performed to assess the risk of future heart disease. It has also been suggested that hs-CRP can be used to target therapy and tailor risk modification to prevent cardiovascular disease (CVD).
Therefore it is important to understand when and why these measurements should be done, and how they should be interpreted.
It has been known for ages that inflammation plays a major role in the development of heart disease. Although the idea initially emerged in the late 1800’s, it was sidelined for decades in favor of the so-called cholesterol hypothesis.
However, recently the “inflammation hypothesis” has resurfaced and many scientists believe inflammation is a primary causative factor in many chronic diseases of today, such as diabetes, heart disease, cancer and degenerative brain disease.
A standard lipid profile is commonly used to assess the risk of heart disease. Blood levels of LDL-cholesterol (LDL-C) are traditionally used for risk assessment. LDL-C is often used as a therapeutic target as well, and dietary recommendations and drug therapy often primarily aim at lowering LDL-C.
CRP and hsCRP
C-reactive protein (CRP) is produced by the liver. This protein was discovered in 1930 by William Tillett and Thomas Francis, investigators at the Rockefeller University. They found it could be isolated from the blood of patients with a particular type of pneumonia. Later it was discovered that elevated CRP-levels could be measured in blood in response to inflammation.
The difference between CRP and hs-CRP is contained in the “hs” abbreviation; “high sensitivity.”
CRP is traditionally measured down to concentrations of 3-5 mg/L, whereas hs-CRP measures down to levels around 0.3 mg/L. This improved sensitivity allows hs-CRP to be used to detect low-grade inflammation.
The Predictive Value of hs-CRP
In 1943 Gunnar Lofstrom, a Swedish scientist described elevated blood levels of CRP in patients with heart attack (acute myocardial infarction).
Studies in the 1990’s further confirmed the association between CRP and atherosclerotic coronary artery disease and acute cardiovascular events such as heart attacks and stroke.
However, although CRP-levels were found to be raised in patients with these disorders, the question remained whether CRP levels among healthy individuals could predict future cardiovascular events.
With the publication of the Physician’s Health Study (PHS) in 1997, there was a paradigm change in the use of hs-CRP as a marker of cardiovascular risk.
The study was a prospective evaluation of 22.000 initially healthy men. Baseline levels of hs-CRP were significantly higher among those who subsequently went on to have a heart attack or stroke compared to those who did not. The results indicated that the predictive value of hs-CRP was independent of other risk factors such as blood cholesterol and smoking. The results also suggested that hs-CRP was a better predictor of cardiovascular events than several other inflammatory biomarkers.
In the WHS (Women’s Health Study), LDL-C was compared with hs-CRP in almost 28.000 healthy women who were followed for eight years. After correction for other risk factors, hs-CRP was found to be a stronger predictor of cardiovascular events than LDL-C. Women in the high hs-CRP and low LDL-C group were at greater absolute risk than the subgroup with low hs-CRP and high LDL-C levels. However, screening for both biological markers provided a better predictive value than either test alone.
What Is the Ideal Level of hs-CRP?
Large scale clinical trials have used a hs-CRP cut point of 2 mg/ml for defining an increased risk of CVD.
This would imply that those who have hs-CRP above 2 mg/ml are at increased risk.
However, a desirable value is probably less than 1 mg/ml. An hs-CRP level higher than 3 mg/ml is associated with increased risk in most studies.
- Low risk: less than 1.0 mg/L
- Average risk: 1.0 to 3.0 mg/L
- High risk: above 3.0 mg/L
- Above 10 mg/mL usually indicates acute inflammation
Can hs-CRP Be Used to Target Therapy?
It has been suggested that hs-CRP may be used to select patients who may benefit from treatment with statin drugs or to tailor the intensity of risk modification in general.
The JUPITER trial randomized 17.800 middle-aged to elderly individuals at intermediate or low-risk to treatment with rosuvastatin (a cholesterol lowering drug) or placebo. Patients selected for the study had to have hs-CRP > 2mg/l, and LDL-C < 130 mg/dl (3.37 mmol/l). Rosuvastatin significantly lowered both hs-CRP and LDL-C. There were significantly fewer cardiovascular events on rosuvastatin compared with placebo (44% relative risk reduction).
The results of the JUPITER trial may indicate that hs-CRP levels can be helpful for selecting individuals who may benefit from statin therapy.
The Limitations of Measuring hs-CRP
It is important to remember that both CRP and hs-CRP become elevated in a wide range of acute and chronic inflammatory conditions such as infections, rheumatic arthritis, many other inflammatory diseases, and many cancers. These conditions cause release of interleukin-6 and other cytokines that trigger the synthesis of CRP by the liver.
Because there are many disparate conditions that can increase CRP and hs-CRP, an elevated CRP level does not indicate a specific disease.
Due to its poor sensitivity and low negative predictive value, measurements of hsCRP can not be used to rule out disease.
Most clinical guidelines have emphasized that data from experimental research, epidemiological studies, and large clinical trials do not provide conclusive evidence for the routine use of hsCRP measurements for risk prediction.
At this time, there is insufficient evidence to recommend widespread use of hs-CRP in clinical practice.