C-REACTIVE PROTEIN and HEART DISEASE
Abstract: CRP or C-reactive protein is a test that identifies a measure of inflammation of body tissue that appears independently related to risk of coronary heart disease. Values of CRP also are related to most other risk factors for heart disease and thus are difficult to separate. But CRP does appear to increase the effect of serum cholesterol in producing coronary disease. Although CRP is not now provided in usual blood tests, a measurement can be provided on a doctor's request. Life Ahead includes a valuation of an added risk indicated by high values of CRP that can provide an added caution to those interested.
What it is and Does: The health risk factor of C-reactive protein (CRP) has been given unusual publicity during the past few years. Higher values of CRP are associated with higher risks of heart disease. Although this blood test is not provided as a part of usual physical exams, and thus would not normally be included in Life Ahead, the test can be ordered by the doctor. Because of publicity and claims such as “CRP can be more important than cholesterol” it was felt desirable to include a valuation of CRP in Life Ahead for those interested.
CRP is a marker for what is termed inflammation. Any disturbance of body tissue tends to promote a combating reaction from the immune system. A chemical or physical disturbance of artery walls at a specific location can promote faster than usual development of atherosclerosis at this site. This commonly is observed following balloon type angioplasty that pushes back atherosclerosis plaques. There also may be a variety of chemical mechanisms that produce inflammation.
Many well known risk factors for heart disease produce inflammation and raise values of CRP. In fact a key problem is that nearly all known risk factors are involved.. Increased values of unfavorable factors as total cholesterol, blood pressures, smoking, body weight, and body fat increase CRP. Increased values of favorable factors as HDL cholesterol, exercise, and cardiofitness decrease CRP. Because the total actual effects of all of these factors on coronary heart disease are well verified from more extensive direct research, it has been difficult to identify the contribution of lifestyle to risk from a CRP measurement that is not already included in the risk valuation of these other factors.
CRP appears to be an Independent Factor of Risk: The fact that CRP is an additional and independent factor affecting disease has been shown more recently by various papers of Dr. RP Ridker and others, especially (N Engl J Med 1997, 336:973). They found that when controlling for values of cholesterol, risks associated with an increase from about 0.4 to 3 mg/l of CRP increased risk of coronary disease by 2.3 times. A similar study on women (N Engl J Med 2002,347:1557) showed a similar result. This is not “More important than cholesterol.” Remarkable correlations (JD Neaton, Arch Intern Med 1992, 152:56) have shown cholesterol to increase risk 7 times for a doubling from 150 to 300+ mg/dl, and cholesterol can produce differences in risk to 20 times when including differences in HDL. But a previously unidentified risk of 2 ½ times still is an important disclosure. Raw unadjusted values of CRP can indicate risks to 5 times or more by bringing in its associations with other known risk factors, and a random sample of people could find differences in risk related to CRP larger than their risks related to differences in cholesterol
There are two key problems with use of CRP. First, the risks measured to date are not adequately adjusted for all other factors such as exercise and fitness, blood pressures, body weight, etc. Because of extensive inter-correlation with these other factors, the true independent effect of the factor may be less than the above 2.3 times. Second, there is no clear message about what we can do about elevated CRP values beyond what already is now well known. For example, CRP is reduced by exercise, by maintaining proper body weight, by not smoking, etc. If we do observe these proper health habits that are valued in Life Ahead more completely by much other research, any elevated CRP that remains becomes similar a to a non-actionable family related risk. It is something we should be warned about as an added need for adopting prudent habits.
CRP Appears to Enhance Cholesterol Produced Atherosclerosis: A key finding in the above noted research was that the effect of CRP depends on cholesterol level. Risks of heart disease for a CRP change of from 0.5 to 2 mg/l were to up 2 to 3 times at average and high levels of cholesterol. But at a low cholesterol of about 175 this change in CRP increased risk only 10-20%. Similarly a risk only of 1.3 times was noted at favorable levels of HDL and high values of CRP. The risks for CRP increased substantially as level of cholesterol was increased. This suggests that the inflammation factor enhances the effect of cholesterol on coronary risk, perhaps by producing more atherosclerosis or thrombosis.
Another interesting finding was that the effect on risk of unadjusted CRP was reduced by more than half in the presence of a regular 325 mg per day pill of aspirin. This suggests that high CRP produces thrombosis that can be partly offset by aspirin. In fact, the reduction in risk of CRP from aspirin found was actually larger than the total reduction in risk of coronary disease measured in most aspirin trials. A question now becomes “Is reduction in risk of CRP the key role of aspirin in reducing risk of heart disease?” Another question becomes “How frequently was aspirin used by the individuals that produced the other risk values of CRP now measured? This could affect the presently measured risks of CRP.
Effects of Life Style Factors on CRP: Several reports showed that increased exercise reduced values of CRP. A valuation from the Cooper Institute (Arterioscler Thromb Vasc Biol 2002, 22:1869) showed that their most cardiofit group averaged a CRP of 0.70 mg/l and that the least fit group averaged a CRP of 1.64 mg/l. An expected difference in coronary risk ratio of 1.4 times would be expected from this difference in level of CRP. But it should be observed that the actual overall difference in coronary disease risks measured for these specific Cooper Institute groups that were of low and exceptionally high cardiofitness was about 7 times (Blair, SM, 1989, JAMA 262:2395). Thus the CRP contribution to risk from cardiofitness was only a fraction of the total change in coronary risk measured.
Another study showed interesting findings about exercise and CRP values (Dufaux, Int J Sports Med 1984, 5:102). 356 men and 103 women trained 4 or more times per week. A control group was measured for CRP at 502 ng/ml. Men swimmers obtained 102 and swimming women had 110 CRP. Middle runners obtained 315, men and 250, women. Racing cyclists and soccer player men obtained CRP of 620 and 660 ng/ml. Swimming that puts the least stress on the body achieved a very large reduction in CRP. But exercise that caused the most body stress did not reduce but actually increased CRP levels. Perhaps exercise that produces much body stress increases inflammation, and this may be a significant factor affecting the overall benefits to health of various kinds of exercise. Much more research on this appears needed.
Most other relationships reported between CRP and factors such as weight, diet, etc were insufficiently quantified for valuing similarly their contribution to total factor risk. .
The CRP Model used in Life Ahead: An equation set was developed based on the values provided in above listed Ridkin paper for the risk associated with CRP at various levels of Total Cholesterol. These risks then were normalized to the values of the average Life Ahead populations of men and women at age 50 as is done for all other factors. An average population value of 1.15 mg/l is taken for CRP, and the usually measured effect of Total Cholesterol is assumed at this level of CRP. The effect of cholesterol then is further modified for values of CRP above and below the 1.15 value depending on Total Cholesterol level as per the example values of CRP in mg/l in the table following. A maximum CRP risk value of 3.0 and a minimum value of 0.3 is accepted based on data available.
C-Reactive Protein
mg/dl 0.30 1.0 1.15 1.5 2.0 3.0 Ratio, 3.0 / 0.3)
Total Cholesterol:
175 0.86 0.97 1.00 1.05 1.15 1.23 1.4
213 0.68 0.94 1.00 1.13 1.30 1.55 2.3
250 0.55 0.71 1.00 1.21 1.52 2.00 3.0
An implication of the relationship with total cholesterol is that a high value and risk of CRP will increase further the risk of a diet high in cholesterol producing saturated fat or one deficient in fiber. Life Ahead thus now recognizes this probable relationship of CRP with diet. A more complete model would include aspirin use here if the role of aspirin can be confirmed further. The present Life Ahead method now includes risk of aspirin as a separate factor.
CRP and Well-Days: Life Ahead suggests that differences in CRP values can have a significant effect on Well-Days of life. Starting from an average diet and serum cholesterol, near average health habits and an average CRP of 1.15 mg/l, a computation found that a man of age 50 should enjoy about 9000 future Well-Days. A quite low CRP of 0.5 at the same other conditions would increase Well-Days to 9250 for a 0.7 added year of life. An increase to CRP to 3.0 would reduce Well-Days to 8500, a loss of 500 or 1.4 years of life. Thus the span of CRP likely in a group of 50 year old people having similar health habits and other risks would produce differences of about 2 years of average healthy expected life. It might be worthwhile to include this measure in the standard blood test but inclusion of this now is controversial. But health-interested persons can ask their doctor to obtain a test. A high value of CRP will indicate a need for more serious action to improve other coronary risks.
The above computed differences in Well-Days for differences in CRP would larger for those having less healthy diets, for those younger, or for individuals unfit. They would be smaller for those with quite healthy diets, those older, and those quite fit.