High-Sensitivity C-Reactive Protein Is Within Normal Levels at the Very Onset of First ST-Segment Elevation Acute Myocardial Infarction in 41% of Cases

A Multiethnic Case-Control Study

Methods

Study population

In the FAMI (First Acute Myocardial Infarction) study, participants were recruited from urban areas of Italy, Scotland, and China (a total of 32 centers participated) (Online Appendix). These 3 countries were chosen based on data from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) registry (8), which showed extreme differences in coronary artery event rates, with Scotland having 4 times higher incidence rate of myocardial infarction than China and Italy did in an intermediate position. All patients, irrespective of age, who arrived in hospital via the emergency room or admitted to the coronary care unit within 6 h of symptom onset of STEMI, were screened. Patients were eligible if they had electrocardiographic evidence of STEMI, no previous history of coronary artery disease, and reported symptom onset of <6 h. A blood sample was obtained before any reperfusion procedures.

One control subject matched for age (up to 5 years older or younger), sex, and environment (enrolled from the same city) was recruited for each index case. Inclusion criteria for control subjects included no previous diagnosis of coronary disease or history of exertional chest pain.

A total of 1,206 cases and 984 control subjects were enrolled between October 2002 and April 2007. Of these, 887 patients and 887 control subjects who met all entry and matching criteria were finally analyzed in this paper: Figure 1 shows the consort flow diagram, and Table 1 shows the distribution per country.

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Figure 1

Consort Flow Diagram of Enrollment

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Table 1

Enrollment Numbers and Age and Sex Distribution for the Overall Population and for Individual Ethnic Groups

Results

A total of 887 patients with acute myocardial infarction occurring as their first manifestation of coronary artery disease and 887 matched control subjects were included in the study (Fig. 1). Overall, 76% of patients in the total population were men, and their mean age at presentation was 9 years lower than that of women (68 ± 11.9 years vs. 59 ± 11.7 years) across all 3 ethnic groups (Table 1). There was a very low percentage of patients on cardiovascular drugs, as we eliminated those with a previous history of cardiovascular disease (Table 2). The diagnosis of infarction was documented unequivocally in all by the presence of ST-segment elevation on presentation and by the subsequent peak creatine phosphokinase: median 1,606 (interquartile range [IQR]: 770 to 3,037) U/l. In addition, 795 (89.6%) patients underwent emergency coronary reperfusion therapy. Overall, 34.4% of STEMI patients had 1 or more episodes of angina in the 48 h preceding admission prior to the incident that brought them to hospital admission.

In these patients with a definite STEMI, the interval between symptom onset and blood sampling was short enough not to have increased appreciably pre-existing hsCRP levels, as troponin I in the admission blood sample was ≤0.2 ng/ml in 52% of patients and was only slightly elevated in the remaining patients: median 2.09 (IQR: 0.32 to 14.03) ng/ml. Indeed, there was no difference in hsCRP levels in patients sampled ≤2, 2 to 4, or ≥4 to 6 h from the onset of symptoms. Moreover, hsCRP levels were similar in patients with troponin I ≤0.2 and >0.2 ng/ml. Thus, these hsCRP values are likely to closely reflect those preceding the acute event.

Although these patients had an unequivocally documented acute STEMI, 40.9% had admission hsCRP values lower than the cutoff value of 2 mg/l; conversely, 37.0% of control subjects had values ≥ 2 mg/l, with distribution of values similar across the 3 ethnic groups.

Median hsCRP levels in the admission blood sample in the whole study group were significantly higher than those of control subjects: median 2.49 (IQR: 1.18 to 5.55) mg/l versus median 1.32 (IQR: 0.58 to 3.10) mg/l, respectively (p < 0.0001), but with a very large overlap (Fig. 1). Indeed, 27.0% of STEMI patients had hsCRP values lower than the median value for control subjects and, conversely, 31.1% of control subjects had values higher than the median value for STEMI patients. Thus, the calculated sensitivity, specificity, and overall accuracy for identifying the presence of STEMI with a 2 mg/l cutoff were 66%, 64%, and 65%, respectively.

There were no significant differences in hsCRP levels between patients with (34.4% of the cases) and without (65.6%) episodes of angina in the 48 h preceding admission: median 2.65 (IQR: 1.13 to 5.82) versus median 2.39 (IQR: 1.16 to 5.37), respectively, p = NS.

Interleukin 6 levels were also significantly higher in patients than in control subjects, with a large overlap: median 5.08 (IQR: 2.88 to 9.89) pg/ml versus median 1.38 (IQR: 0.71 to 2.67) pg/ml (p < 0.0001), respectively, and in each ethnic group, about 20% of patients had values above 10 pg/ml (Fig. 2). There was no correlation between hsCRP and IL-6 levels. Also, levels of IL-6 were not statistically different in patients sampled <2 h, 2 to 4 h, or 4 to 6 h from onset of symptoms, but levels of IL-6 were slightly elevated in patients who had troponin I >0.2 pg/ml: median 5.7 (IQR: 3.3 to 10.8) pg/ml versus median 4.4 (IQR: 2.5 to 8) pg/ml (p = 0.0025).

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Figure 2

hs-CRP and IL-6 Levels

Scatter plot distribution of patients and control subjects of high-sensitivity C-reactive protein (hsCRP) admission levels for the total population (A) and for each country (B). Scatter plot of patients and control subjects for interleukin (IL)-6 admission levels for the total population (C) and for each country (D). Note the scale change on the y axis for IL-6. For both markers in all graphs, patients versus control subjects: p < 0.0001. IQR = interquartile range.

Both Scottish patients and their control subjects had slightly higher admission values of hsCRP than the Italians and Chinese did (p = 0.001), but the absolute difference between patients and control subjects was similar in all 3 ethnic groups. The levels of IL-6 were not different across the 3 groups.

Overall, there was a significant association between hsCRP levels ≥2 mg/l and first myocardial infarction for the entire population and for all 3 ethnic groups. In the overall population adjusted for age, sex, smoking, dyslipidemia, diabetes, hypertension, and body mass index, the odds ratio was 2.24 (95% confidence interval [CI]: 1.42 to 3.28) for hsCRP (Fig. 3), which is comparable to that reported in previous primary prevention studies (14) and an odds ratio (OR) of 5.89 (95% CI: 4.37 to 7.96) for IL-6. The high predictive value of IL-6 levels suggests that, in spite of the early time of sampling after the onset of symptoms, IL-6, but not hsCRP levels, reflected an acute myocardial infarction–related component, as indicated by the higher IL-6 values observed in patients with elevated troponin I.

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Figure 3

Prevalence of Traditional RF and Elevated hsCRP

Prevalence of traditional risk factors (RF) and elevated high-sensitivity C-reactive protein (hsCRP) for the overall population and for each ethnic group and association of the RF with ST-segment elevation myocardial infarction (STEMI) for the overall population. Odds ratios are adjusted for age, sex, smoking, dyslipidemia, diabetes, hypertension, and body mass index. Cutoff for CRP is 2 mg/l.

The overall prevalence of the 4 major modifiable cardiovascular RF (smoking habit, dyslipidemia, hypertension, and diabetes) was significantly higher in patients than in control subjects (p < 0.0001). Each of them was found to have a significant predictive value for STEMI in the whole study group after adjustment for age, sex, and for the remaining RF (Fig. 3). There were no significant interactions with the ethnic groups in the multivariate analysis. The risk of STEMI associated with multiple RF was: 1 RF: OR: 1.21 (95% CI: 0.79 to 1.87); 2 RFs: OR: 2.64 (95% CI: 1.68 to 4.15); 3 RFs: OR: 6.41 (95% CI: 2.64 to 15.55); 4 RFs: OR: 10.12 (95% CI: 2.88 to 32.66). However, the majority of patients presenting with their first acute myocardial infarction had only 1 or 2 of the major RF, whereas the number of patients with 3 or 4 RF was rather small, which is consistent with previous reports (15). A similar trend was observed in all 3 ethnic groups.

The presence of hsCRP ≥2 mg/l had an incremental predictive value for STEMI in patients with 1 or more RF with an OR of 2.12 (95% CI: 1.63 to 2.75) (p < 0.0001) (Fig. 4). The incremental predictive value of hsCRP did not differ when only patients with troponin I <0.2 ng/ml were considered: OR: 2.09 (95% CI: 1.42- to 2.92). There were no significant differences in the number of cardiovascular RF among patients with hsCRP <2 mg/l and those with hsCRP ≥2 mg/l (Table 3).

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Figure 4

Increased Risk Associated With Elevated hsCRP

Odds ratios for STEMI associated with exposure to multiple RF (smoking, dyslipidemia, diabetes, and hypertension) for each group of 0, 1, 2, 3, and ≥4 RF and incremental odds ratio associated with the presence of hsCRP ≥2 mg/l. Abbreviations as in Figure 3.

Discussion

Our findings indicate that in over 40% of 887 patients admitted within 6 h from symptoms onset for an unequivocally documented STEMI, before emergency reperfusion strategies were performed in 89.6% of the cases, hsCRP serum levels were below 2 mg/l. The percentage of low baseline levels might have been even larger if, in some patients, the baseline hsCRP value became elevated above baseline just before the sampling time because of the acute infarction process. This possibility appears unlikely for myocardial necrosis because of the early sampling, but it cannot be excluded for potential inflammatory triggers of infarction.

At any rate, a substantial percentage of patients appears to develop acute STEMI in spite of baseline levels of hsCRP <2 mg/l and, hence, would not be eligible for preventive strategies now under consideration (16).

The median values and interquartile ranges of hsCRP in our patients and control subjects were similar to those reported in previous preventive studies (14), which however were only focused on median values and did not give appropriate consideration to the wide dispersion of values, largely overlapping with those of control subjects, and to its practical implications.

Indeed a very wide dispersion of values of hsCRP was reported in the control subjects of PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22) study (14) and found to be unrelated to the low-density lipoprotein cholesterol levels. Our findings also demonstrated that patients with unequivocally documented very acute STEMI exhibit a very wide dispersion of values and a broad overlap with control subjects (Fig. 2). The wide dispersion of hsCRP values was observed in spite of the selection of a phenotypically homogeneous group by restricting the inclusion criteria to patients with STEMI within 6 h from onset of symptoms occurring as their very first manifestation of coronary disease, very few of whom were on cardiovascular drugs. Previous reports from our group indicated that hsCRP was higher in patients in whom infarction was preceded by “severe unstable angina” (17), but the findings were not confirmed in the present report based on a much larger number of patients, in any of the 3 ethnic groups, possibly because of less stringent definition of “unstable angina.”

The intriguing observation of markedly elevated levels of IL-6 above 10 pg/ml in about 20% of patients in each ethnic group (Fig. 2) and the lack of correlation with hsCRP levels suggested the investigation of the inflammatory components of STEMI at the 2 extreme ends of the spectrum in matched patients with either markedly elevated or very low IL-6 levels. The biological and genetic characterization of these 2 extreme groups are currently in progress using some of the multiple samples stored in the central biological bank, but conclusive results are not yet available. Such differences are not related to commonly considered variables, because these 2 extreme groups had similar incidence of pre-infarction angina, similar estimated infarct size, similar levels of hsCRP, and similar RF profile. Among those patients with hsCRP <2 mg/l, more than 80% had ≤2 traditional RF, a proportion not significantly different from that observed in patients with hsCRP ≥2 mg/l (Table 3). Current work includes the study of a set of 48 single nucleotide polymorphisms potentially involved in multiple biological pathways.

At present, we have no plausible explanation for the finding of hsCRP levels <2 mg/l in 41% of the cases in all 3 ethnic groups considered.

Conclusions

We found that 41% of patients in 3 different ethnic groups develop an acute STEMI as the very first manifestation of coronary disease despite having hsCRP levels below 2 mg/l. This observation indicates that the current reductionist (“one size fits all”) approach based on statistically significant differences in median values might have limitations when the dispersion of values about the median is very wide and overlaps with control subjects (18,19). In such a large fraction of patients, it appears mandatory to search for new pathophysiological mechanisms in order to identify specific markers of risk and novel therapeutic targets for effective preventive strategies.