Abstract
BackgroundAtherosclerotic plaque rupture is the culprit event which underpins most acute vascular syndromes such as acute myocardial infarction. Novel biomarkers of plaque rupture could improve biological understanding and clinical management of patients presenting with possible acute vascular syndromes but such biomarker(s) remain elusive. Investigation of biomarkers in the context of de novo plaque rupture in humans is confounded by the inability to attribute the plaque rupture as the source of biomarker release, as plaque ruptures are typically associated with prompt down-stream events of myocardial necrosis and systemic inflammation.MethodsWe developed a novel approach to identify potential biomarkers of plaque rupture by integrating plaque imaging, using optical coherence tomography, with both plaque and plasma proteomic analysis in a human model of angioplasty-induced plaque disruption.ResultsWe compared two pairs of coronary plaque debris, captured by a FilterWire Device, and their corresponding control samples and found matrix metalloproteinase 9 (MMP9) to be significantly enriched in plaque. Plaque contents, as defined by optical coherence tomography, affect the systemic changes of MMP9. Disruption of lipid-rich plaque led to prompt elevation of plasma MMP9, whereas disruption of non-lipid-rich plaque resulted in delayed elevation of plasma MMP9. Systemic MMP9 elevation is independent of the associated myocardial necrosis and systemic inflammation (measured by Troponin I and C-reactive protein, respectively). This information guided the selection of a subset of subjects of for further label free proteomics analysis by liquid chromatography tandem mass spectrometry (LC–MS/MS). We discovered five novel, plaque-enriched proteins (lipopolysaccharide binding protein, Annexin A5, eukaryotic translocation initiation factor, syntaxin 11, cytochrome B5 reductase 3) to be significantly elevated in systemic circulation at 5 min after plaque disruption.ConclusionThis novel approach for biomarker discovery in human coronary artery plaque disruption can identify new biomarkers related to human coronary artery plaque composition and disruption.
Highlights
Atherosclerotic plaque rupture is the culprit event which underpins most acute vascular syndromes such as acute myocardial infarction
Even in such controlled settings, characterisation of biomarker of plaque disruption are further complicated by the presence of downstream effects such as myocardial necrosis and systemic inflammation after percutaneous coronary intervention (PCI) [7, 10, 11], as these downstream events lead to changes in cardiac enzymes and c-reactive protein (CRP) and can confound the identification of other circulating biomarkers that are associated with plaque disruption
We imaged coronary artery plaques, using optical coherence tomography (OCT) prior to plaque disruption, in 36 patients undergoing percutaneous coronary intervention (PCI). These plaques were classified as either lipidrich (n = 23) or non-lipid-rich (n = 13) plaques based on OCT characteristics
Summary
Atherosclerotic plaque rupture is the culprit event which underpins most acute vascular syndromes such as acute myocardial infarction. Novel biomarkers of plaque rupture could improve biological understanding and clinical management of patients presenting with possible acute vascular syndromes but such biomarker(s) remain elusive. Intraarterial imaging of plaque in vivo using optical coherence tomography (OCT) can define plaque composition, providing additional information to improve the specificity of biomarker discovery [6,7,8,9] Even in such controlled settings, characterisation of biomarker of plaque disruption are further complicated by the presence of downstream effects such as myocardial necrosis and systemic inflammation after PCI [7, 10, 11], as these downstream events lead to changes in cardiac enzymes (cTnI) and c-reactive protein (CRP) and can confound the identification of other circulating biomarkers that are associated with plaque disruption
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