High plasma concentrations of C-reactive protein (CRP), which are predictive of a poor prognosis in patients with acute coronary syndromes,1 might reflect an inflammatory pathogenetic component. It is well known, however, that short periods of ischaemia are powerful inflammatory stimuli sufficient to induce the synthesis of acute phase reactants.2 Therefore, the acute phase response in acute coronary syndrome may simply reflect the extent and severity of myocardial ischaemia. To establish whether myocardial ischaemia is an adequate stimulus to induce an increase in CRP, its plasma concentrations were evaluated in a group of patients with chronic stable angina and normal baseline values of CRP in whom myocardial ischaemia was induced by exercise.

Fifteen patients (10 men, mean (SD) age 60 (9) years) with chronic stable angina and reproducible positive exercise testing for myocardial ischaemia participated in this study. No patient had suffered a previous myocardial infarction and mean left ventricular ejection fraction was 62 (5)%. All patients had at least one critical stenosis in the proximal two thirds of one major epicardial coronary artery. The control group consisted of nine healthy subjects (six men, mean age 61 (9) years) without evidence of ischaemic heart disease and normal physical examination, rest ECG, and echocardiogram. After pharmacological washout, treadmill exercise testing was performed following the modified Bruce protocol. The level of the ST segment, 80 ms after the J point, was calculated after signal averaging by means of a computer assisted system in all 12 leads.

For CRP, venous blood samples were obtained immediately before (T₀), at the end of the exercise test (T₁), and 6 (T₂), 24 (T₃), and 48 (T₄) hours after the exercise test. CRP concentration was immunologically determined by immunoturbidimetric method (Roche Unimate 3 CRP, Milan, Italy). The normal upper reference value for CRP with this method is up to 5 mg/l. Data on CRP are expressed as median values and interquartile ranges and were analysed by using two way analysis of variance (ANOVA) for repeated measures. Differences between groups were considered to be significant at a probability value of p < 0.05.

All patients with chronic stable angina had positive exercise tests and reached ST segment depression > 2.0 mm with a mean (SD) value of 2.9 (0.3) mm at 80 (13)% of the predicted heart rate. Ten patients complained of typical chest pain during exercise testing. All controls had negative exercise test and none experienced chest pain. The mean value of ST segment depression was 0.53 (0.18) at 96 (3)% of the predicted heart rate.

Baseline values of CRP were similar in patients and controls (table 1). At the end of exercise testing and 6, 24, and 48 hours after the testing the values of CRP did not change significantly in both groups.

CRP is an acute phase reactant and represents a sensitive marker for underlying systemic inflammation.3 Recently, its prognostic role in a variety of cardiovascular conditions has been repeatedly emphasised. Baseline concentrations of CRP in apparently healthy persons, in subjects with cardiovascular risk factors, and in patients with stable angina represent an independent risk factor for future cardiovascular events. Furthermore, high concentrations of CRP in patients with unstable angina and myocardial infarction are associated with a worse prognosis independently of the extent and severity of myocardial ischaemia or cell injury. Finally, persistently raised plasma concentrations of CRP after coronary surgery have been shown to be predictive of postoperative complications, and in patients with coronary artery disease undergoing successful coronary artery angioplasty or stent implantation, pre- and postprocedural higher plasma concentrations of CRP are independent predictors of cardiac events at follow up.4

On the basis of this clinical evidence it is assumed that the increase in CRP is not secondary to the extent and severity of myocardial ischaemia, but it may be an independent marker of the inflammatory component involved in the pathogenesis of acute coronary syndromes. Many experimental studies, however, have shown that short periods of ischaemia and reperfusion are powerful proinflammatory stimuli capable of inducing leucocyte and complement activation, cytokine production, and acute phase protein synthesis.2 The increase in acute phase reactant may therefore simply be the biochemical marker of recurrent myocardial ischaemia–reperfusion episodes. Yet, in this study, carried out in patients with chronic stable angina and normal plasma concentrations of CRP, severe exercise induced myocardial ischaemia failed to affect CRP serum concentrations, thus indicating that myocardial ischaemia “per se” is not an adequate stimulus to cause an increase in CRP. Thus, the increase of CRP serum concentrations observed in patients with acute coronary syndromes is unlikely be caused by myocardial ischaemia, but it is more likely to represent a marker of the inflammatory process involved in the pathogenesis of myocardial ischaemia.

A potential flaw of our study is that the duration and severity of transient exercise induced myocardial ischaemia might not have been sufficient to produce an adequate stimulus to induce the production of CRP. Yet, in a previous study, no increase in CRP plasma concentrations was observed in patients with variant angina despite the longer duration of the single ischaemic episodes (> 10 minutes) and total ischaemic burden (> 40 minutes).5 Furthermore, although the number of patients and controls was small, the statistical power of the study in the assessment of CRP changes within and between groups was sufficiently high (> 80% for pairwise comparisons); thus it is unlikely that significant changes in CRP were not detected.

In conclusion, the results of the present study, showing that exercise induced severe myocardial ischaemia does not induce an increase in CRP, support the concept that myocardial ischaemia “per se” is not an adequate stimulus to cause an increase in CRP serum concentrations, and that the increase observed in patients with acute coronary syndromes is unlikely to be related to myocardial ischaemia but is rather a marker of an underlying inflammatory process which may contribute to the pathogenesis of myocardial ischaemia.