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Scratching the surface of atherosclerosis: Distinguishing phenotypes of plaque erosion

      Keywords

      Seminal vascular biology studies have elucidated that the majority of acute ischaemic events are precipitated by rupture of an atherosclerotic plaque, with breakdown of its fibrous cap and exposure of highly thrombogenic plaque contents to circulating blood. This concept of the vulnerable plaque phenotype has stimulated efforts to develop novel imaging modalities to detect these plaques and targeted therapies to passivate the disease in both the primary and secondary prevention settings. Increasing evidence has highlighted the role of intensive lipid lowering in promoting plaque stabilisation on imaging, contributing to its role in reducing cardiovascular risk [
      • Nicholls S.J.
      • Kataoka Y.
      • Nissen S.E.
      • et al.
      Effect of Evolocumab on Coronary Plaque Phenotype and Burden in Statin-Treated Patients Following Myocardial Infarction.
      ,
      • Raber L.
      • Ueki Y.
      • Otsuka T.
      • et al.
      Effect of alirocumab added to high-intensity statin therapy on coronary Atherosclerosis in patients with acute myocardial infarction: the PACMAN-AMI randomized clinical trial.
      ].
      However, emerging evidence suggests that acute ischemia can occur in the setting of several atheroma phenotypes. In fact, some plaques undergo erosion of the overlying endothelium and thrombus formation, with an intact fibrous cap. The importance of plaque erosion has been confirmed by both pathology and imaging studies, being more prevalent in women and smokers. Initial characterisation of these lesions suggested that erosion occurs in fibrous plaques, while rupture occurs in lipid rich plaques [
      • Partida R.A.
      • Libby P.
      • Crea F.
      • et al.
      Plaque erosion: a new in vivo diagnosis and a potential major shift in the management of patients with acute coronary syndromes.
      ]. More recent studies suggest that erosion can complicate a range of plaque phenotypes [
      • Dai J.
      • Fang C.
      • Zhang S.
      • et al.
      Not all plaque erosions are equal: novel insights from 1,660 patients with STEMI: a clinical, angiographic, and intravascular OCT study.
      ]. The impact of conventional cardiometabolic risk factors and these different plaque features remains to be elucidated.
      In this issue of Atherosclerosis, Sekimoto and colleagues have investigated differences between patients with either plaque rupture or erosion in the setting of an acute coronary syndrome [
      • Sekimoto T.
      • Mori H.
      • Koba S.
      • et al.
      Clinical features and lipid profiles of plaque erosion over lipid-rich plaque versus fibrous plaque in patients with acute coronary syndrome.
      ]. They employed optical coherence tomography (OCT), a light based intravascular imaging modality, to characterise the biology of the culprit lesion. OCT generates high resolution imaging, with the ability to visualise superficial features within atheroma, including the fibrous cap and collections of both lipid and macrophages. As a result, OCT can determine the presence of plaque rupture or erosion, in addition to other pathologies, underlying acute ischemic syndromes. This permitted the investigators to directly compare patients with evidence of plaque rupture or erosion, in the presence of a lipidic or fibrous atheroma phenotype. The study provides important insights with evidence of similarity of clinical characteristics and plaque features in patients with plaque rupture and those with erosion overlying a lipidic plaque. More than two thirds of patients with plaque erosion had evidence of a lipid rich, rather than fibrous atheroma, providing increasing evidence that erosion can occur in a range of plaque phenotypes. Erosion of a lipid rich plaque was comparable to plaque rupture in its association with ST elevation myocardial infarction, to a greater degree than observed in patients with more fibrous plaques. Levels of atherogenic lipid parameters, including apolipoprotein B, non-HDL cholesterol and small dense LDL cholesterol, were all lowest in patients with erosion overlying a fibrous plaque. Similarly, the presence of fibrous plaque erosion associated with the least amount of lipid and macrophages within the artery wall.
      These findings are important, as they provide further understanding of the various forms of plaque biology underscoring acute coronary syndromes. Not only does it reinforce the concept that erosion can occur in a range of plaque phenotypes, it also suggests that erosion of a lipid rich plaque behaves similarly to the traditional setting of plaque rupture. In this state, exposure of circulating blood to lipid rich plaque contents establishes a highly thrombogenic state, leading to rapid arterial occlusion. What is clear is that the presence of atherogenic dyslipidaemia plays an important role in determining this phenotype, and is likely to influence clinical outcomes accordingly. These findings provide additional mechanistic data, providing a biological rationale underscoring the association between atherogenic dyslipidaemia and cardiovascular risk.
      Why is elucidating the natural history of plaque erosion of clinical importance? A number of clinical studies have established that erosion underscores at least one third of acute coronary syndromes, representing a common factor involved in the progression of atherosclerotic disease. The ability to develop new biomarkers, that will accurately predict the presence of erosion, may lead to better prevention approaches. Furthermore, in the patient who has already experienced a clinical event, the demonstration of erosion may lead to implementation of a different therapeutic strategy than patients with plaque rupture. This may particularly be the case for the ability to distinguish erosion that occurs in the setting of either lipidic or fibrotic atherosclerosis. The current finding of atherogenic dyslipidaemia in erosion lipid rich plaque erosion suggests these patients may more likely benefit from more intensive lipid lowering, than patients with fibrotic plaque erosion. While serial OCT studies have demonstrated the benefits of intensive lipid lowering, with the combination of statins and PCSK9 inhibitors [
      • Nicholls S.J.
      • Kataoka Y.
      • Nissen S.E.
      • et al.
      Effect of Evolocumab on Coronary Plaque Phenotype and Burden in Statin-Treated Patients Following Myocardial Infarction.
      ,
      • Raber L.
      • Ueki Y.
      • Otsuka T.
      • et al.
      Effect of alirocumab added to high-intensity statin therapy on coronary Atherosclerosis in patients with acute myocardial infarction: the PACMAN-AMI randomized clinical trial.
      ], this has not been investigated in the setting of plaque erosion. Given that plaque erosion is more prevalent in women, the relative contribution of these plaque phenotypes to their cardiovascular risk remains to be determined.
      Additional studies are required in this field. While early studies have established potential biological pathways implicated in plaque erosion, the relative contribution of cardiometabolic risk factors remains to be determined. The natural history of plaque erosion in these different settings is unknown. It also remains to be determined whether identifying the presence of erosion with different plaque phenotypes will influence the subsequent use of established preventive therapies or emerging interventions, with the potential to directly influence the specific factors that promote erosion. Further work is required to understand the vascular biology and its interaction with clinical factors. Ultimately, new clinical trials will need to demonstrate whether erosion targeted therapies impact cardiovascular risk.
      The vulnerable plaque paradigm has promoted major efforts to develop novel approaches to risk prediction and mitigation. Advances in plaque imaging have identified multiple biological pathways that can lead to acute ischemia. How this will influence the ability to tailor personalized approaches to cardiovascular prevention remains to be determined. The presence of plaque erosion as a major factor in atherosclerotic cardiovascular disease suggests we are only just beginning to scratch the surface, in our efforts to achieve the most optimal approach to the prevention of cardiovascular disease.

      Declaration of competing interest

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:SJN has received research support from AstraZeneca , New Amsterdam Pharma , Amgen , Anthera , Eli Lilly , Esperion , Novartis , Cerenis , The Medicines Company , Resverlogix , InfraReDx , Roche , Sanofi- Regeneron and LipoScience and is a consultant for AstraZeneca , Amarin , Akcea , Eli Lilly , Anthera , Omthera , Merck , Takeda , Resverlogix , Sanofi- Regeneron , CSL Behring , Esperion , Boehringer Ingelheim , Vaxxinity and Sequiris .

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