The American Journal of Medicine
Volume 115, Issue 9 , Pages 735-737, 15 December 2003

Should C-reactive protein be measured routinely during acute myocardial infarction?

  • James S. Zebrack, MD

      Affiliations

    • The Heart Center, Salt Lake City, Utah, USA (JSZ)
    • University of Utah, Salt Lake City, Utah, USA (JSZ, JLA)
    • Corresponding Author InformationRequests for reprints should be addressed to James S. Zebrack, MD, The Heart Center, 1160 East 3900 South, Suite 2000, Salt Lake City, Utah, USA 84124
    • ,
  • Jeffrey L. Anderson, MD

      Affiliations

    • University of Utah, Salt Lake City, Utah, USA (JSZ, JLA)
    • LDS Hospitals (JLA), Salt Lake City, Utah, USA

Article Outline

 

Acute myocardial infarction is the primary discharge diagnosis for 750,000 patients in the United States each year. Despite large randomized trials showing decreased mortality with angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and statins, use of these medications remains suboptimal (1). Suboptimal use likely relates in part to a perception that a patient is at low risk of future events. New risk markers may be useful in identifying higher-risk patients who might benefit from more aggressive medical therapy.

In addition to the traditional risk factors of age, lipid levels, diabetes, hypertension, and smoking, a number of risk markers are now available for improving the evaluation of the post–myocardial infarction patient. These include left ventricular function, angiographic findings, peak creatine kinase or troponin levels, and B-type natriuretic peptide. C-reactive protein is an emerging risk marker that is recommended to complement the assessment of patients at primary cardiovascular risk and, to a more limited extent, stable patients at secondary risk. However, utility of this marker in evaluating patients with acute myocardial infarction is uncertain (2).

C-reactive protein is a highly conserved protein used to defend against bacterial infections. It was originally described as a protein binding to the cell wall of pneumococci. It is now believed that C-reactive protein recognizes and binds to the phosphorylcholine molecule on microorganisms but also oxidized low-density lipoproteins (LDL) and apoptotic cells. It interacts with complement to form the membrane attack complex and triggers proinflammatory signals to activate the immune system, which is helpful in the setting of bacterial infections, but may be maladaptive in the presence of excess oxidized LDL or tissue damage. High levels in the presence of oxidized LDL accelerate atherosclerosis (promoting uptake of LDL by macrophages and facilitating foam cell formation) and augment inflammation within plaque, often leading to rupture and thrombotic vascular occlusion. Several trials have demonstrated the strong predictive value of C-reactive protein in stable and unstable angina, independent of troponin (3) and the burden of atherosclerosis (4).

In the setting of acute myocardial infarction, its predictive value is less well defined, in part due to its associated acute phase reaction. After myocardial infarction, C-reactive protein levels begin to rise within a few hours, peak in 2 to 4 days, and return to baseline levels after a few weeks (5). Thus, if levels are measured at random times after acute myocardial infarction, values are elevated at varying levels above baseline, and the strong predictive value for long-term prognosis is lost (6). If levels are measured in the early hours of acute myocardial infarction (7), at peak levels 8, 9, 10, or after several weeks (11), C-reactive protein appears to provide predictive value for short-term prognosis (weeks to several months). The study by Suleiman et al in this issue of The American Journal of Medicine supports this association (12).

Several studies have shown a weak correlation between C-reactive protein and peak creatine kinase levels; however, C-reactive protein provides strong independent predictive value beyond that of total creatine kinase or creatine kinase–MB isoform 7, 8, 9. The highly dynamic acute phase response shown by C-reactive protein in the setting of acute myocardial infarction raises several issues about timing of measurements, the pathophysiologic mechanism, and predictive value. Indeed, total circulating C-reactive protein levels in the setting of acute myocardial infarction likely represents a marker of the composite of levels representing chronic vascular inflammation as well as (and likely dominated by) the inflammatory response to acute myocardial injury, which is dependent on infarct size and host (immune) response factors.

In the setting of myocardial infarction, C-reactive protein might also have direct harmful effects. After coronary ligation in rats, injection of C-reactive protein increased infarct size by 40% by a complement-dependent mechanism (13). Peak levels also have been associated with ventricular and papillary muscle rupture, independent of total creatine kinase levels (14). After myocardial infarction, C-reactive protein and complement are found to colocalize only in areas of myocardial necrosis, increasing in concentration after 12 hours (15). C-reactive protein also reduces the production of nitric oxide, which in turn inhibits angiogenesis (16). Also, patients with high levels have enhanced red blood cell aggregation (17), and C-reactive protein is a predictor of left ventricular thrombus after myocardial infarction (18). Thus, there is increasing evidence that C-reactive protein might be a perpetrator of, as well as a risk marker for, events in the early period after acute myocardial infarction.

Suleiman et al present important data to help clarify the question of utility of C-reactive protein testing in patients presenting with acute myocardial infarction, defined as chest pain lasting >20 minutes associated with elevated cardiac marker levels (12). In contrast to previous cross-sectional studies, the trial was prospective and had a moderately large sample (N = 448). Also, C-reactive protein levels were consistently measured within 12 to 24 hours of the onset of symptoms. Most patients (76%) had ST-elevation infarction, of whom 43% received reperfusion therapy. C-reactive protein level proved to be strongly predictive of mortality at 30 days (P<0.0001). Mortality was much lower (3%) in patients with C-reactive protein levels <6.9 mg/L (tertile 1) than in those with levels between 6.9 and 22.3 mg/L (10%; tertile 2) and levels >22.3 mg/L (22%; tertile 3). In fact, C-reactive protein levels approximated the actual 30-day mortality rates. In addition, tertiles were predictive of the development of heart failure, with rates of 18% in tertile 1, 19% in tertile 2, and 44% in tertile 3. C-reactive protein level did not correlate with the risk of reinfarction or the need for revascularization, but it correlated strongly with infarct size (regional wall motion score) as measured by echocardiography. Its predictive value was reduced but not eliminated in multivariable modeling.

These observations indicate that patients with higher C-reactive protein levels (due to early acute phase reaction and, possibly, higher chronic levels) have larger infarcts and greater left ventricular dysfunction and mortality in the 30 days after acute myocardial infarction. They also are consistent with, but do not prove, the hypothesis that C-reactive protein itself might promote additional myocardial damage. The lack of correlation with reinfarction, unstable angina, or need for revascularization suggests that C-reactive protein levels early after acute myocardial infarction mark the extent of and reaction to myocardial injury, and not chronic atherosclerotic plaque instability. Hence, its prognostic value is short term and related to the specific myocardial infarction, and not related to the ongoing atherosclerotic process.

C-reactive protein values have been correlated with age, diabetes, renal insufficiency, and heart failure (2). Trends toward higher levels in the absence of reperfusion or the use of statins have also been noted. Because time from onset of chest pain to admission was not reported, it is uncertain to what extent higher levels and the associated increased mortality represent patients presenting later in the course of myocardial infarction and thus not qualifying for reperfusion therapy.

The study by Suleiman et al has noteworthy limitations. Only a single C-reactive protein level was measured during one time interval (12 to 24 hours after symptom onset) and the precise time of draw was not reported. It is unknown whether an earlier or later measurement, or one that takes place after symptom onset or admission, would be more prognostic of 30-day mortality, or whether serial measurements to determine C-reactive protein peak and integral would provide improved predictive information. Also, the study falls short of determining the true independent, incremental predictive value of C-reactive protein after acute myocardial infarction. The multivariable modeling reduced the size and statistical significance of the predictive value for mortality and heart failure. However, the authors did not report analyses with forced adjustment for creatine kinase peak and ejection fraction (or wall motion score); for example, measurements of infarct size that are routinely obtained and are highly prognostic.

Consequently, it should be considered if routine C-reactive protein testing is warranted in the setting of acute myocardial infarction. As pointed out, a number of cardiac risk factors also correlate with higher levels, and although C-reactive protein was confirmed by Suleiman et al to be a strong independent predictor of 30-day mortality, its true incremental value, when creatine kinase peak, ejection fraction, and other prognostic factors are first considered, remains uncertain. Thus, it is difficult to recommend routine testing at this time for all patients presenting with acute myocardial infarction. However, given that testing for C-reactive protein is increasingly available and relatively inexpensive, and that it provides a parallel and complementary, if not clearly incremental, assessment of early post-infarction risk, we believe it can be recommended for use at the discretion of the physician in patients in whom an additional measure of risk is desirable. In contrast, when testing is used for the purpose of long-term secondary cardiovascular risk assessment (2), it should be delayed for at least 4 to 6 weeks after myocardial infarction to allow resolution of the acute phase reaction and a return to chronic “baseline” levels.

Finally, we should consider what, if any, are the therapeutic implications of a high C-reactive protein level in the setting of acute myocardial infarction. To date, no trials have demonstrated that treatment causing reductions in this marker are beneficial independent of other biologic effects, especially in the acute setting. Indeed, it would be difficult to design a trial that shows the benefit of C-reactive protein lowering, independent of the other effects that currently available medications (which are reported to reduce C-reactive protein levels) also exert (e.g., lipid lowering; improved glucose tolerance; antiplatelet, antihypertensive, and antiadrenergic effects). One such trial of a compound related to probucol is ongoing, although results are several years away. Aspirin, beta-blockers, ACE inhibitors, and statins likely have greater absolute benefit in myocardial infarction patients with high C-reactive protein levels, but should still be prescribed in such patients with low levels. Hence, we believe that the therapeutic implication of high C-reactive protein levels in association with acute myocardial infarction is to ensure aggressive use of established secondary preventive strategies, which are still consistently underutilized 1, 19, 20.

Back to Article Outline

References 

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PII: S0002-9343(03)00637-5

doi:10.1016/j.amjmed.2003.10.006

The American Journal of Medicine
Volume 115, Issue 9 , Pages 735-737, 15 December 2003

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