Inflammation, heart failure, and mortality in survivors of acute myocardial infarction

Obtaining the C-reactive protein (CRP) level has become an easy method for assessing low-level systemic inflammation that may predict coronary events in both healthy patients and those who have experienced a recent coronary event.¹ Among healthy patients, the CRP level may indicate chronic vascular inflammation causing destabilization of vulnerable plaques. In acute myocardial infarction (MI), however, this level most likely reflects the reaction to myocardial necrosis.^2,3 By serving as a marker for this process, CRP level may predict the risk of heart failure and mortality in the period immediately following MI.⁴

Subjects and methods

We prospectively studied 1044 patients who presented with acute MI and survived the index event. C-reactive protein levels were obtained within 12 to 24 hours of symptom onset. All-cause mortality and the development of heart failure (defined as hospital readmission for heart failure treatment) were the primary end points. Patients were followed-up for 6 to 42 months (median, 23 months). Cox proportional hazard analyses were performed to establish the association between the primary end points and quartiles of CRP, adjusting for clinical variables and ejection fraction.

Results

During follow-up, 112 patients (10.7%) were admitted for the treatment of heart failure. As shown in the

, heart failure increased in a graded fashion with increasing quartiles of CRP, based on Kaplan-Meier analysis. Unadjusted and adjusted Cox proportional hazards models for heart failure admission, according to quartiles of CRP, are shown in the

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. Assessment of the CRP level provided additional predictive data greater than that supplied by recognized predictors of postinfarction heart failure and ejection fraction prior to discharge (Table). Additional important factors that predicted heart failure were recurrent MI (hazard ratio [HR] = 2.5; 95% confidence interval [CI], 1.3-4.8; = .008), peak creatine kinase level (HR = 1.3 per quartile; 95% CI, 1.1-1.6; = .003), reduced left ventricular ejection fraction (HR = 2.4; 95% CI, 1.5-3.7; < .001), admission Killip class > 1 (HR = 2.0; 95% CI, 1.3-3.0; = .002), and age (HR = 1.4 per 10 years; 95% CI, 1.2-1.7; < .001).

FigureTable

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Recurrent MI was not predicted by CRP level (16 recurrent infarctions occurred in the first quartile, 21 in the second quartile, 20 in the third quartile, and 20 in the fourth quartile; = .84). The mortality rate during follow-up was 10.8% (n = 113). Increasing CRP quartiles independently portended mortality after discharge from the hospital, after adjustment for ejection fraction and other clinical predictors of death, using a mutivariable Cox proportional hazards model. The adjusted HRs for mortality were 1.4 (95% CI, 0.6-2.9), 2.3 (95% CI, 1.2-4.6), 3.0 (95% CI, 1.5-5.7) in the second, third, and fourth CRP quartiles, respectively, compared with patients in the first quartile.

Discussion

A significant, graded correlation between progress to heart failure and death after acute MI and CRP values taken 12 to 24 hours after symptoms began was shown in this study. Even after adjusting for multiple clinical variables, left ventricular ejection fraction, and the occurrence of recurrent MI during follow-up, the correlation between heart failure and CRP level was preserved.

In patients with acute coronary syndromes, the time of measurement and the clinical setting affect the predictive value of CRP levels for different outcomes, as well as the mechanism of CRP increase. Many studies have shown that future coronary events in seemingly healthy people are correlated with the low-grade increase in CRP occurring in the chronic stage of atherosclerosis. Because of extensive vascular inflammation in patients with acute coronary syndromes,⁵ CRP levels may rise further and correlate with recurrent MI and clinical instability.⁶ In patients with acute coronary syndromes, however, increased CRP levels and other inflammation biomarkers, such as interleukin-6, occur nearly entirely in patients with signs of myocardial necrosis.³

Release of CRP appears to be triggered by myocardial necrosis in the presence of low-grade vascular-mediated inflammation.^2,3 Because the extent of CRP elevation in patients with MI results from the inflammatory response to myocardial injury, not vascular inflammation, an increase in CRP correlates with increased death but not recurrent MIs.^4,7,8

The idea that CRP levels indicate continuing myocardial inflammation immediately following acute MI is supported by our finding that development of heart failure can be predicted by increased CRP levels. Our study confirms earlier studies, which showed that complications such as the development of ventricular aneurysms and cardiac rupture are associated with the increased CRP levels occurring in patients with acute MI.⁸

C-reactive protein levels increase within a few hours after acute MI and reach peak levels within 2 to 4 days.^2,3,8 The association between mortality or heart failure and the increase in CRP levels can only be shown if CRP values are taken shortly after acute MI.^2,3 This is because CRP levels return to their baseline values within 4 to 6 weeks following acute MI, as the inflammatory response to myocardial necrosis decreases.^3,8 At this time, elevated CRP levels again reflect the degree of vascular inflammation and are predictive of future coronary events.¹

In patients who survived an episode of MI, the later development of heart failure portends a grave prognosis. Patients who develop heart failure following acute MI have been shown to have a mortality risk 10 times greater than those who do not progress to heart failure.⁹ Our data indicate that inflammatory markers may be useful in identifying patients at high risk for HF in spite of apparent clinical stability.

The later progression to heart failure after acute MI is a complex process, influenced by multiple actions, such as recurrent MI and progressive remodeling.¹⁰ In the present study, the association between increased CRP levels and heart failure persisted after we eliminated patients with recurrent MI who later progressed to heart failure. Along with previous studies,^8,11 our results indicate that the severe inflammation that plays a role in progressive ventricular modeling may be reflected by the higher CRP levels immediately following acute MI. C-reactive protein levels seem to be more than just a biomarker for inflammation. Increased CRP levels also seem to contribute significantly to damage to the myocardium through local complement activation.¹²

How increased CRP is related to future heart failure is unclear. However, it appears that primarily cytokine-mediated reaction to inflammation is a major factor in repair and remodeling following acute MI. Cell fibrosis, repair, migration, and growth are regulated by cytokines, which are released by interstitial, vascular, and immune tissue during acute MI.¹³

Experimental studies of MI have shown that in the immediate period following acute MI and for up to 1 day afterward, upregulation of intramyocardial cytokine production occurs. In the region of infarct, a 50-fold increase in the release of such cytokines as tumor necrosis factor-α, interleukin-6, and interleukin-1β also occurs. Cytokines are also upregulated in the myocytes of the portion of the myocardium not affected by the infarction. Evidence from animal studies has led to the theory that ventricular function and remodeling may be affected over time by early inflammatory response after MI.¹³

The increased CRP levels seen after acute MI result from cytokines derived from the myocardium or infiltrating inflammatory cells, especially interleukin-6, which is the main stimulator of CRP in the liver.^4,11 C-reactive protein, therefore, may be a basic biomarker for the potency of the inflammatory response in the myocardium.

Conclusions

We showed that progression to heart failure and long-term mortality could be predicted by CRP levels taken soon after the occurrence of acute MI. In addition, we provided additional evidence showing that the extent of the immediate inflammatory response influences later outcome.