生物谷報道：C反應(yīng)蛋白（CRP）是一種重要的炎癥反應(yīng)因子,，但近來也做為心臟疾病,，尤其是心肌梗死等重大心臟疾病的重要標(biāo)志檢測物。但有關(guān)它在心血管疾病中的重要作用,，以及檢測,，篩選，預(yù)防有何重要影響,？本文全面綜述2005年以來有關(guān)CRP在心血管疾病中的研究,，提示檢測CRP有助于篩選早期的心肌梗死以及無癥狀性心肌損傷病。
 
Abstract:

Acute coronary events strike nearly 1.4 million Americans annually. This includes an estimated 700,000 new coronary events, 500,000 recurrent events, and 175,000 silent first events each year.1

Adding to the clinical challenge is the fact that while conventional risk factors remain an important means of predicting who is at risk of developing coronary heart disease (CHD), it?s unwise to rely on conventional risk factors alone for estimating patient risk. A 2003 evaluation of 122,458 patients enrolled in 14 international trials was meant to underscore that conventional risk factors are still important, yet one in five men with CHD in these trials (n=87,869) had none of the four conventional risk factors analyzed: smoking, hypertension, diabetes, and hyperlipidemia (Slide 1).2
 
Citation:
Khot UN, Khot MB, Bajzer CT, et al. Prevalence of conventional risk factors in patients with coronary heart disease. JAMA 2003;290:898-904.

Another challenge: Despite the overwhelming effectiveness of HMG-CoA reductase inhibitors in lipid lowering, 60% to 70% of cardiovascular events continue to occur despite statin therapy. This is in stark contrast to a 1996 prediction that statin therapy might eliminate heart attacks by the year 2000.3

It should be noted that in the large review of international trials mentioned above, only 34.1% of men with CHD had hyperlipidemia. If the lipid hypothesis of atherosclerosis is still correct, why do so few CHD patients have hyperlipidemia and why are so many events still occurring in patients on statin therapy?

The seemingly anomalous data have led investigators to question whether the accepted target levels for low-density lipoprotein (LDL) cholesterol are low enough. Recent trials, including REVERSAL4 and PROVE IT/TIMI-22,5 have shown that lower target LDL levels, particularly in high-risk patients, are effective in further reducing cardiovascular events. (The implications of these studies were discussed in a 2004 update of clinical guidelines.) Yet, even intensive statin therapy is not the complete answer. In the PROVE-IT TIMI-22 study, for example, high-dose statin therapy still was associated with a 25% recurrent event rate at 2.5 years.
 

Should CRP Join LDL as a Target of Therapy?
In an effort to improve the prediction of future coronary events, a number of plasma-based biomarkers have been studied (Slide 2), with C-reactive protein (CRP) having the greatest amount of supportive data and the strongest evidence that it is additive to other measures of risk prediction. In this interview, Paul Ridker, MD, FACC, argues that CRP should join LDL as a treatment target.
 
Citation:
Reproduced with permission from Stampfer MJ, Ridker PM, Dzau VJ. Risk factor criteria. Circulation 2004;109(25 Suppl 1):IV3-5.

There are several key factors supporting the importance of targeting CRP:
Ridker, et al., have shown that CRP is a strong predictor of future cardiac events at all levels of LDL cholesterol, at all levels of the Framingham Risk Score, and at all levels of the metabolic syndrome.
In prior collaborations with the CARE and AFCAPS/TexCAPS investigators, Ridker, et al., also have shown that statin therapy lowers CRP in a manner largely independent of LDL cholesterol and that statins result in greater clinical benefit when levels of CRP are elevated.
More than just a marker, a growing body of evidence suggests that CRP plays a direct role in atherothrombosis (Slide 3).
In addition to being potent lipid-lowering agents, statins appear to have anti-inflammatory properties that are important for prognosis and treatment.
These findings, along with basic laboratory evidence, have lead to the hypothesis that the level of CRP achieved after treatment with statin therapy might have clinical relevance in a manner analogous to that of achieved LDL cholesterol. Moreover, as hsCRP and lipid levels are largely independent and reflect different pathophysiologies, combined screening approaches using both LDL and hsCRP appear to be superior to use of either alone.
A new analysis of PROVE-IT TIMI-22 illustrates some of these points. The original study compared the relative efficacy of pravastatin 40 mg and atorvastatin 80 mg for reducing events in 3,745 acute coronary syndrome patients. Individuals who achieved the dual goals of LDL <70 mg/dl and hsCRP <2 mg/l benefited the most in terms of risk reduction (Slide 4).6 Interestingly, in a paper published in the New England Journal of Medicine, Ridker, et al. reported that it didn't matter whether the patient was on high-dose or standard-dose statin therapy. While patients assigned to atorvastatin daily were significantly more likely than those receiving standard-dose pravastatin to have a decrease in the levels of both biomarkers to target values (Slide 5), once those target levels were met there was little evidence of a differential outcome according to the specific allocation to either ?aggressive? or ?moderate? statin therapy.7

Description:
Cumulative incidence of recurrent myocardial infarction or coronary death in the PROVE-IT TIMI-22 trial among those who did and did not achieve the dual goals of low-density lipoprotein cholesterol (LDL-C) <70 mg/dl and high-sensitivity C-reactive protein (hsCRP) <2 mg/l. Cumulative incidence for those who achieved LDL-C <70 and the even lower hsCRP goal of <1 mg/l is also shown (dotted line).
Citation:
Reproduced with permission from Ridker PM, Morrow DM, Rose LM, et al. Relative efficacy of atorvastatin 80 mg and pravastatin 40 mg in achieving the dual goals of low-density lipoprotein cholesterol <70 mg/dl and C-reactive protein <2 mg/l. An analysis of the PROVE-IT TIMI-22 Trial. J Am Coll Cardiol. 2005;45:1644-8. Copyright of the American College of Cardiology Foundation.
 

Citation:
Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352:20-8.

In a follow-up paper published May 17, 2005, in JACC, Ridker, et al., again concentrated on the 3,745 acute coronary syndrome patients randomized in the PROVE-IT TIMI-22 trial who were alive and free of recurrent events at 30 days. Of these patients, 1,018 (27%) achieved these dual goals after initiation of statin therapy. Overall, those who achieved both goals had a 35% lower risk of recurrent events (p=0.007). After full adjustment of age, gender, smoking status, diabetes, hypertension, and body mass index, those who achieved dual goals had a 29% lower risk of recurrent cardiovascular events (p=0.04).

Looking at the relative risks of recurrent coronary events in patients on statin therapy in PROVE-IT TIMI-22, the NEJM paper showed a very similar risk-predicting value to achieved CRP as there was to achieved LDL (Slide 6). And the predictive value was not attenuated when adjusted for variables such as Framingham risk, diabetes, and body mass index. However, the magnitude of LDL reduction does not predict the magnitude of CRP reduction. In other words, just because LDL is lowered to goal does not mean the patient is no longer at risk; if CRP remains elevated, so does the risk of recurrent events.
 

Citation:
Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352:20-8.

In this interview, Dr. Ridker addresses these new data and discusses what the body of evidence suggests in terms of clinical practice.

Dr. Block:
I'm with Dr. Paul Ridker, who is well known as one of the leading investigators in the world on the subject of C-reactive protein (CRP). Even though it?s only been a few months since our last conversation, things have moved ahead rather quickly in terms of the clinical use of CRP.

Let's begin with CRP as a predictor of coronary events. Is it useful now clinically to measure this marker? Should we just start moving that strategy?

Dr. Ridker:
In just the last 18 months we've seen very consistent results from several very large studies. All of them show that measuring high-sensitivity CRP (hsCRP) increases your ability to predict risk at all levels of cholesterol, all levels of Framingham Risk Score, and at all levels of metabolic syndrome.

Yes, I think the time has come to add the measurement of hsCRP for a very large number of patients where we're struggling with how high is someone's risk and what can we do to motivate the patient to reduce this risk.

Dr. Block:
If it?s time to start assessing hsCRP, let's talk about the levels of this marker: what is a good level? What is a bad level? Are there borderline levels? And how high is really high?

Dr. Ridker:
In 2002 we decided to use a cut point system of values of less than 1 mg/l as lower risk, 1 to 3 mg/l as moderate, and greater than 3 mg/l as higher risk. That has held up very well in studies of women as well as men, in different ethnic groups, and around the world. So, an hsCRP value >3 mg/l, and in particular one that's 5 mg/l to 8 mg/l, these are very high-risk patients and, importantly, patients can have high values of hsCRP in the absence of high cholesterol.

That's the key to this whole field of research: If half of all heart attacks and strokes continue to occur among people with essentially normal LDL cholesterol, we can do a much better job of predicting risk and that's where hsCRP really fits in for primary prevention.

Dr. Block:
If a patient comes in and their CRP is at very high levels, how do we treat this? Is statin therapy an effective way to lower CRP? Or are there other ways to do this?

Dr. Ridker:
Well, the first thing is to recognize that diet, exercise, and smoking cessation, all proven methods for lowering vascular risk, all lower CRP. Statins are very important, too, for lowering CRP levels. They do so in a manner quite independent of lowering LDL cholesterol.

We've learned from some very large studies that the relationship between how low your cholesterol gets and how low your CRP gets cannot be judged without measuring the CRP. You can?t just assume that if you successfully lower LDL cholesterol that hsCRP levels will be reduced, too. Yet it's very clear from both primary and secondary prevention studies that our patients do better when their CRPs are lower, even when the LDL cholesterol levels are low, medium, or high.

That's most prominently described in secondary prevention trials. As a cardiologist I've argued that most of the CRP story, until now, has been a subject for the general internist and the primary care physician. That was the assumption because as cardiologists our patients have coronary artery disease so we're always very aggressive.

That has changed, based on two papers published in January 2005 in The New England Journal of Medicine, one from our group7 and the other from the Cleveland Clinic.8 Both papers are very important to understand because we looked at very high-risk ACS patients. Our paper was based on the results of the PROVE IT Trial and Steve Nissen, MD, FACC, reported the results of the REVERSAL Study.

Both studies found overwhelming evidence of improved long-term survival with lower CRP. To be specific, in PROVE IT we found that even if LDL was reduced to below 70 mg/dl, the best outcomes occurred if CRP also dropped to less than 2 mg/l. The same was true in the REVERSAL trial. Moreover, the REVERSAL data showed that to actually see disease regression required that both LDL and CRP levels had to be reduced.

It is no longer enough just to lower LDL cholesterol aggressively with statins. We have to begin a new era where we both measure and monitor CRP levels in much the same way we measure and monitor LDL cholesterol. And that's a real change in how we manage this disease.

Dr. Block:
What do we do about the patient who has a normal or low LDL, who may or may not have atherosclerosis, but has a high inflammatory state with a CRP of 8?

Dr. Ridker:
Well, if that patient has had a prior event, the PROVE IT and REVERSAL data tell us we have to get their CRP levels down. For primary prevention you're asking the critical question: What do we do with patients without identifiable atherosclerosis and a low LDL ? which means they don't qualify for statin therapy for primary prevention ? but an elevated CRP level?

We can?t answer that question yet, but those patients would qualify for entry in the JUPITER Trial. JUPITER is a large primary prevention trial looking to enroll about 15,000 patients with LDL <130 mg/dl and a moderate-to-high CRP level; specifically, all patients have a CRP level of 2 or higher. We have about 3,000 patients randomized already in the United States and Canada and almost 40% have metabolic syndrome. So, this trial may teach us not only about the high CRP patient, but it may also teach us about what metabolic syndrome really means.

Metabolic syndrome, as currently defined, is the presence of at least 3 of 5 specific characteristics, but the definition does not really get at the core issue of hypofibrinolysis and this low-grade inflammatory response. Our endocrine colleagues are very close to adding a CRP criterion to metabolic syndrome. I think that's a good idea because it emphasizes that metabolic syndrome is more than just a patient that is overweight with lipid abnormalities. Adding the CRP criterion would suggest that their inflammatory response is unusual, too. That?s what we may find out in the JUPITER Trial when we analyze the data for the metabolic syndrome patients.

Dr. Block:
We are used to thinking of elevated CRP as being 3 mg/l or above, but we do see patients occasionally with a CRP in the 20s or higher. What does this mean?

Dr. Ridker:
When you see a really high CRP value, you should repeat the test to make sure they?re not in the acute phase response. Also, don?t average the two measurements together; take the lower of the two levels as the patient?s CRP level.

If the hsCRP is chronically 10 mg/l or higher, we now have evidence that these patients are not false positives, which was the prior concern, but they?re actually very high-risk patients for getting vascular disease. Yes, it?s possible that they have some underlying inflammatory condition that has been missed, such as inflammatory bowel disease. But whatever the reason for the chronic inflammation that is driving CRP levels into that high of a range, the increased vascular risk remains. Again: these patients are not false positives and they would be a group of patients in whom I would be particularly aggressive in terms of risk reduction and perhaps pharmacologic therapies.

What?s almost as interesting, Peter, is the very low CRPs at the far other end of the spectrum. It turns out some of us are lucky enough to have extremely low levels, not just below a value of 1, but below 0.3 or 0.5. That?s a group who seem to almost never get atherosclerosis regardless of their Framingham score and regardless of their calcium scores.

Dr. Block:
So, a CRP of 3 mg/l or higher is the dividing line that separates high risk from lower risk. What percentage of patients have such high levels of CRP?

Dr. Ridker:
About 25% of the population will have a CRP level of 3 or higher. These very high CRP levels we?re talking about ? greater than 10 ? are rare and usually will be seen in far less than 1% of patients, but they are very high-risk patients.

Guidelines:

The third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). NIH Pub. No. 02-5215. Bethesda, MD: National Heart, Lung, and Blood Institute, 2002;279 pages. Adult Treatment Panel III

Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004;44:720-32. Full text