C-reactive protein and cardiovascular disease: a review of risk prediction and interventions

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Abstract

Background: Coronary vascular disease (CVD) has a high prevalence in the United States, yet 40–50% of those with that diagnosis have normal or mildly increased cholesterol levels. Increased C-reactive protein (CRP) has been associated with CVD, in those presenting after an acute coronary event, and also in apparently healthy individuals. Methods: We reviewed the literature on this association, and on the relationship between CRP and traditional CVD risk factors including smoking, hypertension, cholesterol and obesity. Also examined is the effect of various medications used in patients with CVD on CRP concentrations. Results: CRP correlates with risk of CVD in patients who have a history of acute coronary disease, stable angina, and in those who have never been diagnosed with CVD. CRP imparts risk that is independent of hyperlipidemia. Conclusion: Once commercially available CRP assays are shown to be reliable, CRP may help predict short- and long-term cardiovascular outcomes and may have a role in CVD screening analogous to that of lipid. In the future CRP may modify treatment and preventive therapies.

Introduction

The prevalence of coronary vascular disease (CVD) in the United States is high by all measures. The Third National Health and Nutrition Examination Survey found the age-adjusted prevalence of CVD among Americans age 40 y and older to be 11.8% [1], a figure that underestimates the full burden of the disease because it does not capture those who died of myocardial infarction (MI). CVD has been thought of as a disease of lipid deposition and cholesterol testing has been used as a tool to identify those at high risk. Yet half of those who suffer an MI do not have significantly increased cholesterol concentrations. Only 50% of those in the Framingham Heart Study cohort who sustained a MI had increased total cholesterol (TC) concentrations [2]. Supporting these findings, Rubins et al. [3] found only 40% of 8500 Veterans with coronary artery disease had increased TC that would warrant pharmacological treatment. Similarly, the Euroaspire study showed only 44% of known cardiac patients from major European hospitals had TC >5.5 mmol/l [4]. As a result of efforts to understand these findings, researchers currently view CVD as more than a disease of lipid deposition, and as a process involving multiple elements in which chronic inflammation seems to play a significant role. Many inflammatory proteins and molecules have been investigated; a significant body of evidence has linked C-reactive protein (CRP) to CVD. That evidence is presented here, along with a brief review of several proposed mechanisms of action and interventions that modify this risk factor.

Section snippets

CRP

CRP is an acute phase reactant, a marker of inflammation with a half-life of ~19 h. It is synthesized primarily in hepatocytes and regulated by interleukin 6 (IL-6), interleukin 1 (IL-1), tumor necrosis factor-alpha (TNF-alpha) and other cytokines. CRP has a normal range of <2 mg/l in populations without evidence of acute illness; with illnesses such as rheumatoid arthritis or sepsis, concentrations can increase to 300 mg/l [5], [6]. The exact function of CRP is unclear, however it is thought

Measurement of CRP

When CRP is used primarily for measuring states of extremely active inflammation, such as sepsis or arthritis, values of 50–100 mg/l are most relevant. The development of high sensitivity methods with lower detection limits of 0.2 mg/l allowed differentiation of low-level states of inflammation that are important in CVD risk, as will be reviewed below. Early research used an ELISA based assay, which was shown to correlate well with a commercially available latex method in the PHS data set [16].

Predicting outcomes of acute coronary syndromes

Clinicians first associated CRP to CVD by noting the increased concentration of this marker following an acute MI. If CRP was synthesized in response to an MI, perhaps it could be used to assess infarction size and predict short-term outcomes. One of the earliest studies from 1982 showed peak CRP concentrations correlated with peak CK MB (r=0.441, P<0.001) and those with a complicated MI course had a prolonged increase in CRP [22]. Another early study, published in 1978, found peak CRP values

Short term outcomes in unstable angina

Some data show that patients presenting with acute onset cardiac chest pain, who have no myocardial ischemia by electrocardiogram or CK MB but progress to MI, have increased CRP. However other studies have contradicted this finding. A small study found unstable angina patients with admission CRP >3 mg/l had more in-hospital ischemic episodes, and no patient with CRP <3 mg/l went on to have an MI [26]. A slightly larger study showed CRP values at admission did not predict in-hospital outcome;

Predicting outcomes long after acute coronary events

Other research has examined whether CRP can predict long-term outcome after coronary events, over months or even years. In one study, both admission and discharge CRP values correlated with adverse cardiac outcomes at 3 months (hazard ratio 1.9, 95% CI 1.2–8.3, P<0.005); discharge CRP >15 mg/l predicted endpoints better than ST segment depression on admission EKG or silent ischemia as detected by 24 h Holter (hazard ratio 3.16, 95% CI 2.0–5.2, P=0.0001) [27]. Another 3-month study of unstable

Predicting clinical course in stable angina

Much less research has been done on the predictive ability of CRP in patients with stable angina. Liuzzo et al. [30] found 87% of patients with stable angina had CRP values <3.0 mg/l, and found that having a CRP >3.0 mg/l was not a negative prognostic indicator for the next 6 months (though there were only 4 patients in this category). Another small study showed that in patients with stable angina, admission CRP concentrations were significantly lower than in those with unstable angina. Here,

Using CRP to predict a coronary event in men without CVD

Several studies have examined the ability of CRP to predict future coronary events in apparently healthy individuals (Fig. 1). In an epidemiological study of British middle-aged men, the prevalence of CVD was 1.5 times higher with each doubling in baseline CRP [41]. The Multiple Risk Factor Interventional Trial (MRFIT) showed increased CRP predicted increased risk of CVD in middle aged men, but that the relationship was statistically significant only for smokers [42]. However, in the

Predicting CVD in healthy women

Most of the studies previously described on CRP in healthy individuals included men only or primarily, leading researchers to question whether CRP is useful in predicting CVD risk in women. Early epidemiologic studies that included elderly women with sub-clinical CVD, such as the Cardiovascular Health Study and the Rural Health Study, found women with higher CRP had more coronary events (P≤0.05) [50]. The Women's Health Study (WHS) showed that those in the highest quartile of CRP had a relative

CRP and other cardiovascular risk factors

The relationship of CRP to CVD raises the question of how other risk factors relate to this marker. Those with well-known risk factors for cardiac events, including the elderly, smokers, obese and those with hyperlipidemia may have an even greater risk of CVD if their CRP is increased.

Cholesterol

Several studies have shown that the risk of increased CRP is independent of lipid levels both in those with known CVD and in healthy individuals. In those with known CVD, such as unstable angina patients, high TC and CRP predicted re-admission when compared to high TC and low CRP values [19]. The ECAT study also found the risk of coronary events in angina patients with high TC was low if their CRP was low, while a CRP >3.6 mg/l put a patient with increased TC at greater risk for a coronary

Age

CRP increases with age and is associated with a greater risk of CVD. A survey of CRP concentrations in 5748 patients of all ages from the MONICA trial showed median levels double from the second to the sixth or seventh decade of life [61]. The ECAT Angina trial showed that for patients 45–69 years old, CRP concentrations were 2.0% higher for each year older [39]. Several trials showed that increased CRP in the elderly is also associated with increased risk, with a relative risk similar to that

Hypertension

Hypertension is a risk factor for CVD that does not have a clearly understood pathophysiology. Some have speculated that risk may be mediated through vessel inflammation, perhaps related to the renin–angiotensin system [62]. One small study found CRP concentrations in patients with essential hypertension are significantly increased compared to healthy controls (P<0.001) [63]. It is unknown whether CRP values correlate with renin or angiotensin II levels in patients with hypertension, and

Smoking

CRP is increased in smokers, and increased CRP in smokers confers extra cardiac risk. Das [64] showed CRP values were increased in smokers; unfortunately CVD status was not recorded in the study. However, it is known that smoking increases IL-6, which stimulates CRP production. Many trials have documented CRP concentrations are increased in smokers, including the ECAT trial [39], and the MONICA study where CRP concentrations were twice as high in smokers as non-smokers [44]. The MRFIT study of

Obesity

CRP is increased in patients with a higher body mass index as shown in several of the large trials described above [39]. The MONICA study showed CRP was twice as high in those with an increased body mass index (BMI) as in those with a normal BMI [40]. In trials focused particularly on this issue, CRP is associated with measures of central obesity, the form previously connected with high CVD risk. A study of healthy non-diabetics patients demonstrated this same relationship [66], as did a small

CRP and other forms of arteriosclerosis

Given the relationship found between CVD and CRP, it is logical to postulate that increased CRP could put someone at risk for other types of vascular disease. A nested case control study of healthy men from the PHS showed CRP was slightly though significantly increased in those who developed peripheral artery disease (PAD), (1.34 vs. 0.99 mg/l for controls). Those who required surgery for their disease were more likely to be in the highest CRP quartile, with a relative risk of 4.1 [71]. A study

Using CRP to predict risk in the individual patient

Though the data are not yet comprehensive, it is possible to make some useful recommendations for the individual patient (Table 1). For those who already carry a diagnosis of CVD, CRP can be used to predict risk of adverse event in the short- and long-term. A higher peak CRP in a patient acutely presenting with a MI likely indicates a larger infarct. A continued rise in CRP in those who have undergone a procedure, such as PCTA or CABG, is a poor prognostic indicator. In a patient presenting

Interventions

The findings described above raise the question of whether the CVD risk associated with increased CRP is modifiable. Researchers have investigated the effects of medications already in use in CVD prevention or treatment that have anti-inflammatory effects, such as aspirin and HMG CoA reductase inhibitors. Other interventions, such as dietary changes, weight loss and exercise also warrant attention. Some interventions have been shown to modify CRP concentrations with a concurrent fall in

Aspirin

Aspirin has long been known to decrease risk of future CVD events due to anti-platelet effects. In the PHS, 325 mg of aspirin every other day produced a 44% decrease in risk of MI. Notably, those with the highest CRP had greatest decrease in risk, 55.7% vs. 13.9% in those with lowest CRP [43]. A randomized double blind crossover trial found patients with stable angina and normal cardiac function who took 300 mg aspirin daily for 3 weeks had lower CRP by 29% [77]. The doses used in these two

HMG CoA reductase inhibitors

HMG CoA reductase inhibitors decrease the risk of MI in patients with high lipid levels [78]. Several trials found HMG CoA reductase inhibitors produced reductions in mortality and morbidity. In hypercholesterolemic patients pravastatin produced a 30% reduction in cardiac events [79]. The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial found a 24% reduction in mortality due to CVD with pravastatin treatment for men and women with normal to moderately increased TC [80].

Conclusions

CRP is useful in predicting risk for future cardiovascular events. It correlates with risk of CVD in patients who have a history of acute coronary disease, stable angina, and in those who have never been diagnosed with CVD. Measurement of CRP appears to be useful in predicting, independently from troponin, short- and long-term outcomes. There is likely an important clinical role for CRP in CVD screening analogous to that of lipid screening. In a population where CVD is so prevalent, and yet in

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