Role of MCRP in the clinical management and the pathophysiology of the acute coronary syndromes

Austin, Catrin Rebeca (2018) Role of MCRP in the clinical management and the pathophysiology of the acute coronary syndromes. Doctoral thesis (PhD), Manchester Metropolitan University.

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Abstract

Introduction: The rise in emergency department admissions for chest pain necessitates a quicker and more specific test for the different acute coronary syndromes. For a non-ST elevated myocardial infarction (NSTEMI) diagnosis, the current Gold Standard requires at least one cTn (cTn) value above the 99th percentile of a reference population across 12h of serial testing. Current research suggests serum levels of monomeric C-reactive protein (mCRP) and ultra-high-sensitive cTn assays may rule out NSTEMI more rapidly. Aims: To develop a novel immunoassay for mCRP for use on clinical samples to assess its diagnostic accuracy for NSTEMI. The Singulex Clarity and the Abbott iSTAT point of care hs-cTnI assays were assessed against the standard laboratory assay from Roche® Diagnostics hs-cTnT assay for NSTEMI diagnosis using non-kinetic (0h, 3h and max values) and kinetic (Δabsolute, %Δbaseline and %Δmean) values and in combination with H-FABP and ECG ischaemia. Methods: A competitive immunoassay for mCRP was optimised, which became an ELISA with a commercial anti-CRP detection antibody. Diagnostic tests calculated the clinical sensitivity, specificity, positive predictive value and negative predictive value for non-kinetic and kinetic values with the aim of creating the highest clinical sensitivity possible for NSTEMI rule out. Patients were grouped into 3 risk groups and cut-offs were optimised for each group. Predictor composites of 0h cTn, cTn deltas, ECG ischaemia and H-FABP were used for NSTEMI diagnosis and prediction of 3 different composite outcomes at 30 days. Cox regression assessed the assays’ and risk factors’ utility in 30-day MACE prediction. Results: The mCRP immunoassay was not sensitive enough for physiological mCRP concentrations (LoD 2 μg/ml) and the inter-assay imprecision was too great to be clinically useful. The Roche and Singulex assays showed 100% sensitivity and NPV for kinetic values in intermediate risk groups and predictor composites. The Singulex assay had 100% sensitivity for non-kinetic values also but the iSTAT assay did not perform well as a rule out diagnosis tool. Singulex Δabsolute and prior angina were independent predictors for 30-day MACE. Discussion: The mCRP immunoassay had problems because the antibody was not commercially produced, had to be used at high concentrations and therefore is not suitable for a competitive immunoassay. The Singulex assay could be used for early rule out but its variability could limit its clinical utility. The iSTAT assay is a useful tool for identifying high-risk patients quickly and all assays performed better when patients were split into risk groups by 0h cTn levels. Multi-faceted diagnostic tools are becoming more prominent for NSTEMI diagnosis and rule out.