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Recognition of the association between inflammation and atherosclerosis in general or acute myocardial infarction (AMI) in particular is considered one of the most important advances in our understanding of cardiovascular disease in the last 20 years. Basic as well as clinical research has revealed that inflammatory processes are involved in all phases of the atherothrombotic process including plaque development, progression, instability/vulnerability and rupture, and thrombosis [1–3].

These insights have led to the inflammatory hypothesis of atherosclerosis and provided hope that inflammatory processes may provide diagnostic and therapeutic targets. This possibility is currently being investigated in at least two large studies of proven anti-inflammatory drugs, which have no confounding effects on cholesterol or platelet function, as cardiovascular therapeutic agents [1]. The aim of the first of these studies is to evaluate whether interleukin-1β inhibition as compared to placebo can reduce the rates of recurrent myocardial infarction, stroke and cardiovascular death amongst 17 200 stable patients with coronary artery disease who remain at high risk of cardiovascular events [3]. The second one is randomly allocating stable patients with postAMI, who are receiving complete standard medication including high-dose statins, to either low-dose methotrexate (10–15 mg per week) or placebo [1]. Unfortunately, recent studies to evaluate the diagnostic utility of inflammatory biomarkers have been rather disappointing [4–6].

AMI is a major cause of death and disability worldwide. Identifying those patients with acute chest pain who are suffering from AMI and those at high risk of death remains a clinical challenge. Delayed ‘rule-in’ diagnosis of AMI or inappropriate patient discharge increases morbidity and mortality [7–9]. Delayed ‘rule-out’ prolongs the time spent in hospital, thus increasing patients’ anxiety and causing substantial cost to the healthcare system [7–9].

Evidence from recent large prospective studies suggests that currently available inflammatory markers may not have a role as clinical tools in the early diagnosis of AMI. In these diagnostic studies, the underlying hypothesis was that plaque instability and plaque rupture are very early events in the pathophysiology of AMI and that biomarkers reflecting these inflammatory processes could therefore complement markers of cardiomyocyte necrosis (a much later phenomenon) in the early diagnosis of AMI. Multiple inflammatory markers including myeloperoxidase, myeloid-related protein 8/14, pregnancy-associated plasma protein-A, matrix metalloproteinase 9 and C-reactive protein thought to be associated with plaque instability and rupture failed the test of clinical utility [4–6]. In studies enroling consecutive patients presenting with acute chest pain to the emergency department, the diagnostic accuracy as quantified by the area under the receiver operating characteristics curve was 0.50–0.65 (compared with about 0.85–0.90 for conventional cardiac troponin assays). Moreover, none of these markers added diagnostic information when used in combination with standard or sensitive cardiac troponin assays. Possible reasons for this failure include: insufficient release from coronary plaques; substantial systemic noise; a higher than expected percentage of AMI occurring without preceding plaque rupture; plaque rupture preceding thrombosis and embolization and, therefore, the onset of acute chest pain after a prolonged interval; and increased levels of these markers associated with other inflammatory disorders (e.g. pneumonia and pleuritis) that form the differential diagnosis of patients with acute chest pain.

Results from recent prognostic studies of large cohorts with acute coronary syndrome reported as a secondary analysis suggested that current inflammatory biomarkers also lose prognostic significance after a sensitive cardiac troponin and a natriuretic peptide are added to the model [7].

In a fascinating pilot study reported in this issue of the Journal [10], Vuilleumier and colleagues extend their previous pioneering work on auto-antibodies for cardiovascular risk stratification [11–13] and explore the diagnostic accuracies of anti-apolipoproteinA-1 (anti-ApoA-1) IgG and anti-phosphorylcholine (anti-PC) IgM alone, expressed as a ratio (anti-ApoA-1 IgG/anti-PC IgM) and combined with the NSTEMI-TIMI score. In their single-centre prospective study in 138 patients with acute chest pain, the combination of anti-ApoA-1 IgG, anti-PC IgM and the NSTEMI-TIMI score provided high diagnostic accuracy for NSTEMI with an area under the curve of 0.88. As in any pilot study, this one has important limitations, most of which are appropriately acknowledged by the authors. One additional key limitation is the lack of a suitable contemporary comparator, such as a sensitive cardiac troponin assay. It is clear that the hypothesis-generating findings of Vuilleumier and colleagues now need to be confirmed (or rejected) in a large prospective multicentre study of consecutive patients with acute chest pain.

Could auto-antibodies eventually prove to be clinically useful? Two arguments suggest that this could be possible. First, as Vuilleumier and co-workers discuss, auto-antibody levels are expected to be relatively stable over time. Thus, auto-antibody levels may be less dependent on the time interval between plaque rupture and the onset of AMI compared with previously examined inflammatory biomarkers. If this is the case, auto-antibodies may even ultimately evolve as markers of vulnerable patients and allow the targeted initiation of preventive measures even before the onset of AMI. Second, the association between these auto-antibodies and both atherosclerosis and plaque vulnerability seems to be strong, as anti-ApoA-1 IgG has been shown to promote inflammation, atherosclerosis development and plaque vulnerability in vitro and in vivo, whereas anti-PC IgM reduces atherosclerosis [10–13]. However, there are two arguments against the potential clinical utility of auto-antibodies: First, the competitor is strong. Sensitive cardiac troponin assays have significantly improved the early diagnosis of AMI, particularly in patients with recent onset of chest pain [9]. Although we are just beginning to learn how best to use sensitive cardiac troponin assays [9, 14, 15], there is now less room for improvement by adding an additional biomarker. Second, turn-around time is critical in the emergency department setting. It is unclear whether assays for auto-antibodies could be redesigned to be widely available and achieve a turn-around time of 1 h or less.

In conclusion, Vuilleumier and colleagues should be congratulated for this novel concept of how to use auto-antibodies clinically in the early diagnosis of AMI.

Conflict of interest statement

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No conflict of interest was declared.

References

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  2. Conflict of interest statement
  3. References