Inflammatory Differences in Plaque Erosion and Rupture in Patients With ST‐Segment Elevation Myocardial Infarction

Chandran, Sudhakar; Watkins, Johnathan; Abdul‐Aziz, Amina; Shafat, Manar S.; Calvert, Patrick A.; Bowles, Kristian M.; Flather, Marcus; Rushworth, Stuart A.; Ryding, Alisdair

doi:10.1161/jaha.117.005868

Cited by 41 publications

(20 citation statements)

References 31 publications

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“…Proteomic strategies applied to coronary arterial blood samples suggest distinct patterns of protein release in patients with ACS due to erosion versus rupture. 70 Beyond anti-platelet therapy, individuals with markers indicating substantive NETosis with ACS could undergo treatment with deoxyribonuclease (DNase) or inhibitors of PAD4. While these notions remain highly conjectural, they merit consideration as we strive to a more targeted treatment of individual segments of patients with ACS and have achieved success with current management strategies for ACS, rendering it unlikely that further intensification of management of traditional risk factors will yield increasing inroads into residual risk.…”

Section: Therapeutic and Clinical Implications Of Superficial Erosionmentioning

confidence: 99%

Reassessing the Mechanisms of Acute Coronary Syndromes

Libby

Pasterkamp

Crea

et al. 2019

Circulation Research

350

221

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The mechanisms that underlie superficial erosion, a cause of coronary thrombosis quite distinct from plaque rupture, have garnered recent interest. In an era of improved control of traditional risk factors such as low-density lipoprotein, plaque erosion may assume greater clinical importance. Plaques complicated by erosion tend to be matrix-rich, lipid-poor, and usually lack prominent macrophage collections, unlike plaques that rupture, which characteristically have thin fibrous caps, large lipid pools, and abundant foam cells. Thrombi that complicate superficial erosion appear more platelet-rich than the fibrinous clots precipitated by plaque rupture. The pathogenesis of plaque rupture probably does not pertain to superficial erosion, a process heretofore little understood mechanistically. We review here data that support a substantial shift in the mechanisms of the thrombotic complications of atherosclerosis. We further consider pathophysiologic processes recently implicated in the mechanisms of erosion. Multiple mechanisms likely predispose plaques to superficial erosion including experiencing disturbed flow, basement membrane breakdown, endothelial cell death, and detachment potentiated by innate immune activation mediated through pattern-recognition receptors and endothelial-to-mesenchymal transition. Monocytes/macrophages predominate in the pathogenesis of plaque rupture and consequent thrombosis, but polymorphonuclear leukocytes likely promote endothelial damage during superficial erosion. The formation of neutrophil extracellular traps (NETs) probably perpetuate and propagate intimal injury and potentiate thrombosis due to superficial erosion. These considerations have profound clinical implications. Acute coronary syndromes (ACS) due to erosion may not require immediate invasive therapy. Understanding the biological bases of erosion points to novel therapies for ACS due to erosion. Future research should probe further the mechanisms of superficial erosion, and develop point-of-care tests to distinguish ACS due to erosion vs. rupture that may direct more precision management. Future clinical investigations should evaluate intervening on the targets that have emerged from experimental studies and the management strategies that they inform.

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Section: Therapeutic and Clinical Implications Of Superficial Erosionmentioning

confidence: 99%

Reassessing the Mechanisms of Acute Coronary Syndromes

Libby

Pasterkamp

Crea

et al. 2019

Circulation Research

350

221

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“…Another potential thrombogenic fate of an atherosclerotic plaque is that of plaque erosion, in which a thrombus is formed in the absence of rupture, often with a disrupted endothelium and an enhanced proliferation of VSMCs (Virmani et al, 1999 ; Braunwald, 2013 ). Although less common than plaque rupture, plaque erosion has been shown to be more common in women and the elderly, while the underlying mechanisms of plaque erosion are only beginning to be elucidated and still incompletely understood (Libby and Pasterkamp, 2015 ; Chandran et al, 2017 ). Regardless of the etiology of the plaque source, the resulting thrombus formed by these processes may also embolize and travel to a secondary vessel causing ischemia, myocardial infarction, or sudden coronary death (Davies, 2000 ; Bentzon et al, 2014 ).…”

Section: Formation Of the Atherosclerotic Plaque: Local And Distant (mentioning

confidence: 99%

The Aging Risk and Atherosclerosis: A Fresh Look at Arterial Homeostasis

2017

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A considerable volume of research over the last decade has focused on understanding the fundamental mechanisms for the progression of atherosclerosis—the underlying cause for the vast majority of all cardiovascular (CVD)-related complications. Aging is the dominant risk factor for clinically significant atherosclerotic lesion formation, yet the heightened impact of aging on the disease is not accounted for by changes in traditional risk factors, such as lack of physical activity, smoking, hypertension, hyperlipidemia, or diabetes mellitus. This review will examine the pathological and biochemical processes of atherosclerotic plaque formation and growth, with particular focus on the aging risk vis-a-vis arterial homeostasis. Particular focus will be placed on the impact of a number of important contributors to arterial homeostasis including bone marrow (BM)-derived vascular progenitor cells, differential monocyte subpopulations, and the role of cellular senescence. Finally, this review will explore many critical observations in the way the disease process has been reassessed both by clinicians and researchers, and will highlight recent advances in this field that have provided a greater understanding of this aging-driven disease.

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“…Yet, the need for OCT to discriminate between plaque rupture and erosion mandates a similar approach to their management in routine clinical practice. Further development of less invasive diagnostic biomarkers could advance the ability to distinguish these two aetiologies of ACS to guide more individualized treatment strategies [46].…”

Section: Discussionmentioning

confidence: 99%

A pivotal role for Nrf2 in endothelial detachment- implications for endothelial erosion of stenotic plaques

Satta

McElroy

Langford-Smith

et al. 2019

Preprint

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Endothelial erosion of atherosclerotic plaques and resulting thrombosis causes approximately 30% of acute coronary syndromes (ACS). As changes in the haemodynamic environment strongly influence endothelial function and contribute to plaque development, we reconstructed the coronary artery geometries of plaques with thrombi overlying intact fibrous caps from 17 ACS patients and performed computational fluid dynamic analysis. The results demonstrated that erosions frequently occur within areas of stenosis exposed to elevated flow. We recapitulated this flow environment in vitro, exposing human coronary artery endothelial cells to elevated flow and modelled smoking (a risk factor for erosion) by exposure to a combination of aqueous cigarette smoke extract and TNFα. This treatment induced endothelial detachment, which increased with pharmacological activation of the antioxidant system controlled by transcription factor Nrf2 (encoded by NFE2L2). The expression of Oxidative Stress Growth INhibitor genes OSGIN1 and OSGIN2 increased under these conditions and also in the aortas of mice exposed to cigarette smoke. Sustained high level expression of OSGIN1+2 resulted in cell cycle arrest, induction of senescence, loss of focal adhesions and actin stress fibres, and dysregulation of autophagy. Overexpression of either Nrf2 or OSGIN1+2 induced cell detachment, which did not depend on apoptosis, and could be partially rescued by inhibition of HSP70 using VER-155008, or AMP kinase activation using metformin. These findings demonstrate that under elevated flow, smokinginduced hyperactivation of Nrf2 can trigger endothelial cell detachment, highlighting a novel mechanism that could contribute to ACS involving endothelial erosion overlying stenotic plaques.

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Inflammatory Differences in Plaque Erosion and Rupture in Patients With ST‐Segment Elevation Myocardial Infarction

Cited by 41 publications

References 31 publications

Reassessing the Mechanisms of Acute Coronary Syndromes

Reassessing the Mechanisms of Acute Coronary Syndromes

The Aging Risk and Atherosclerosis: A Fresh Look at Arterial Homeostasis

A pivotal role for Nrf2 in endothelial detachment- implications for endothelial erosion of stenotic plaques

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