Work

Inflammation and features of the vulnerable plaque: from mechanisms and imaging to outcomes

Year: 2020

Type: article

Abstract: For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. The understanding of atherosclerosis has been markedly expanded in the last two decades with insights into inflammation as a major component of plaque development, erosion, and rupture. Although there is an overlap between cholesterol and inflammation, both are contributors to atherosclerosis in their own right.1 While atherosclerosis is a chronic inflammation induced by cholesterol, as the late Rudolf Virchow stated, inflammation alters endothelial function and contributes to the disease process also independently of lipids as documented by experimental2 and clinical studies.3–5 Inflammation importantly contributes to the vulnerability of plaques which are the substrate of acute coronary occlusion.6 A novel mechanism of plaque vulnerability, i.e. the glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) an immune checkpoint protein regulating T cells, is presented in the article ‘Glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) drives atherosclerosis in mice and is associated with an unstable plaque phenotype and cerebrovascular events in humans’ by Esther Lutgens and colleagues from the University of Amsterdam in the Netherlands.7 In patients with cerebrovascular events, GITR expression was elevated in carotid endarterectomy specimens compared with asymptomatic patients and correlated with parameters of plaque vulnerability such as an increased content of plaque macrophage, lipid, glycophorin A, interleukin-6 (IL-6) and IL-12, and C-C-chemokine ligand-2. Furthermore, soluble GITR levels were elevated in plasma from cardiovascular (CV) patients compared with healthy controls. The molecular mechanisms were assessed in Gitr–/–/Apoe–/– double knockout mice in which plaques were reduced and contained fewer macrophages, a smaller necrotic core, and thicker fibrous caps. RNA-sequencing of Gitr–/–/Apoe–/– and Apoe–/– monocytes and macrophages revealed altered pathways of cell migration, activation, and mitochondrial function, with decreased integrin levels, reduced recruitment to endothelium, and fewer reactive oxygen species. Likewise, GITR-deficient macrophages produced fewer cytokines and had a reduced migratory capacity. Thus, the immune checkpoint GITR drives myeloid cell recruitment and activation in atherosclerosis, thereby inducing plaque growth and vulnerability in mice and human plaques. GITR has the potential to become a novel therapeutic target in atherosclerosis (Figure 1), a conclusion that is further discussed in a educational Editorial by Michael Joner and colleagues from the Deutsches Herzzentrum Munchen in Germany.8 Our data reveal a novel role for the immune checkpoint GITR in driving myeloid cell recruitment and activation in atherosclerosis, thereby inducing plaque growth and vulnerability in mice. In humans, elevated GITR expression in carotid plaques is associated with a vulnerable plaque phenotype and adverse cerebrovascular events. (This figure was created in part using templates modified from Servier Medical Art (Mountain View, CA, USA, www.servier.com, licensed under a Creative Commons Attribution 3.0 Unported Licence) (from Shami A, Atzler D, Bosmans LA, Winkels H, Meiler S, Lacy M, van Tiel C, Ta Megens R, Nitz K, Baardman J, Kusters P, Seijkens T, Buerger C, Janjic A, Riccardi C, Edsfeldt A, Monaco C, Daemen M, de Winther MPJ, Nilsson J, Weber C, Gerdes N, Gonçalves I, Lutgens E. Glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) drives atherosclerosis in mice and is associated with an unstable plaque phenotype and cerebrovascular events in humans. See pages 2938–2948). Our data reveal a novel role for the immune checkpoint GITR in driving myeloid cell recruitment and activation in atherosclerosis, thereby inducing plaque growth and vulnerability in mice. In humans, elevated GITR expression in carotid plaques is associated with a vulnerable plaque phenotype and adverse cerebrovascular events. (This figure was created in part using templates modified from Servier Medical Art (Mountain View, CA, USA, www.servier.com, licensed under a Creative Commons Attribution 3.0 Unported Licence) (from Shami A, Atzler D, Bosmans LA, Winkels H, Meiler S, Lacy M, van Tiel C, Ta Megens R, Nitz K, Baardman J, Kusters P, Seijkens T, Buerger C, Janjic A, Riccardi C, Edsfeldt A, Monaco C, Daemen M, de Winther MPJ, Nilsson J, Weber C, Gerdes N, Gonçalves I, Lutgens E. Glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) drives atherosclerosis in mice and is associated with an unstable plaque phenotype and cerebrovascular events in humans. See pages 2938–2948). Age-related dysbiosis enhances inflamm-ageing eventually accelerating atherogenesis. Age-related dysbiosis enhances inflamm-ageing eventually accelerating atherogenesis. With ageing several endogenous and exogenous changes (included in the upper boxes), foster a less healthy oral and gut microbiota (left and right boxes, respectively). These alterations impair the homoeostatic symbiosis between the intestinal flora and the host. Total bacterial load increases, while microbiota diversity falls allowing pathobionts to establish a condition of chronic local inflammation known as dysbiosis (central box). Together with local consequences, dysbiosis also causes systemic effects (lower box) including increased circulating bacteria, danger-associated molecular pathways as well as trimethylamine N-oxide and other microbiota-derived metabolites eventually causing the systemic activation of inflammatory pathways, promoting age-related cardiovascular and cerebrovascular disease (bottom of the figure) (from Liberale L, Montecucco F, Tardif J-C, Libby P, Camici GG. Inflamm-ageing: the role of inflammation in age-dependent cardiovascular disease. See pages 2974–2982). Age-related dysbiosis enhances inflamm-ageing eventually accelerating atherogenesis. Age-related dysbiosis enhances inflamm-ageing eventually accelerating atherogenesis. With ageing several endogenous and exogenous changes (included in the upper boxes), foster a less healthy oral and gut microbiota (left and right boxes, respectively). These alterations impair the homoeostatic symbiosis between the intestinal flora and the host. Total bacterial load increases, while microbiota diversity falls allowing pathobionts to establish a condition of chronic local inflammation known as dysbiosis (central box). Together with local consequences, dysbiosis also causes systemic effects (lower box) including increased circulating bacteria, danger-associated molecular pathways as well as trimethylamine N-oxide and other microbiota-derived metabolites eventually causing the systemic activation of inflammatory pathways, promoting age-related cardiovascular and cerebrovascular disease (bottom of the figure) (from Liberale L, Montecucco F, Tardif J-C, Libby P, Camici GG. Inflamm-ageing: the role of inflammation in age-dependent cardiovascular disease. See pages 2974–2982). Early epidemiological studies have demonstrated that IL-69 and high-sensitivity C-reactive protein (CRP10) independently predict future major cardiovascular events (MACE) comparable with LDL cholesterol (LDL-C). However, whether aggressive contemporary lipid lowering has altered these relationships is unknown. In their article ‘Comparison of interleukin-6, C-reactive protein, and low-density lipoprotein cholesterol as biomarkers of residual risk in contemporary practice: secondary analyses from the Cardiovascular Inflammation Reduction Trial’11 Paul Ridker and colleagues from the Brigham and Women’s Hospital in Boston, Massachusetts, USA measured IL-6, CRP, and LDL-C in 4168 North American patients of the CIRS Trial with prior myocardial infarction or multivessel coronary disease, diabetes, or metabolic syndrome, and assessed MACE up to 5 years. Randomized use of 15 mg/day methotrexate had no effect on MACE or plasma levels of IL-6, CRP, or LDL-C; however, baseline levels of these markers were all predictive of MACE. Effect estimates were not statistically different in these analyses for comparisons between IL-6, CRP, or LDL-C, although IL-6 was the strongest predictor of all-cause mortality. The highest absolute risks were observed among those with elevated levels of both LDL-C and markers of inflammation, with a hazard ratio of 6.4. Thus, despite aggressive contemporary secondary prevention, the relationships between inflammation, cholesterol, and CV risk are largely unchanged from those described two decades ago. As such, the reduction of the remaining CV risk may require a combination of anti-inflammation and cholesterol reduction, as stressed in a thought-provoking Editorial by Wolfgang Koenig from the Deutsches Herzzentrum Muenchen in Germany.12 Intravascular ultrasound (IVUS) imaging visualizes vulnerable plaque features including plaque attenuation and echolucency.13 While IVUS-derived vulnerable plaque features associate with microvascular obstruction during percutaneous coronary intervention (PCI), the relationship between these features and clinical outcomes has not been established. In their manuscript entitled ‘Progression of ultrasound plaque attenuation and low echogenicity associates with major adverse cardiovascular events’, Stephen Nicholls and colleagues from Monash Health in Clayton, Australia addressed this question in 1497 patients.14 Attenuation and echolucency were measured to allow for calculation of an attenuation index and echolucency volume. Attenuation or echolucency were identified in 19% at baseline, and 11% developed an increase in attenuation or echolucency at follow-up. The incidence of MACE was 8.2% in patients with baseline attenuation and echolucency, and 3.9% in those without. Patients with progression of attenuation and echolucency were more likely to have a history of infarction and greater baseline percentage atheroma volume than those without. On multivariable analysis, attenuation and echolucency progression was more strongly associated with MACE. Thus, attenuation and echolucency progression on IVUS is associated with a higher prevalence of MACE, supporting a potential role for the identification of high-risk vulnerable plaques in patients with coronary artery disease. The ongoing worldwide increase in life expectancy portends a rising prevalence of age-related CV disease such as myocardial infarction and stroke in the coming decades.15 Thus, the understanding the molecular mechanisms of CV ageing may be essential for a deeper understanding of these disease and provide future therapeutic targets, as outlined in the review ‘Inflamm-ageing: the role of inflammation in age-dependent cardiovascular disease’ by Giovanni Camici and colleagues from the University of Zurich, Switzerland.16 Of note, a state of chronic sterile low-grade inflammation, also known as inflamm-ageing, characterizes older organisms and importantly contributes to the development of frailty, disability, and most chronic degenerative CV diseases. Due to chronic activation of inflammasomes and reduced anti-inflammatory mechanisms, inflamm-ageing contributes to the activation of leucocytes, and endothelial and vascular smooth muscle cells, thereby accelerating CV ageing and atherosclerosis and stroke.17 Furthermore, inflamm-ageing promotes athero-thrombotic complications by enhancing platelet reactivity and predisposing to plaque rupture and erosion. Thus, inflamm-ageing and its contributors or molecular mediators might furnish targets for novel therapeutic strategies that could promote healthy ageing and conserve resources for healthcare systems worldwide. This subject is further pursued in another review entitled ‘Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis’ by Thomas Thum and colleagues from the Hannover Medical School in Germany.18 They note that while anti-inflammatory treatment has recently been shown to prevent MACE, there are concerns about systemic immunosuppression. Targeting the main source of inflammation and of plaque-destabilizing factors, rather than the specific elements of the inflammatory pathway, may provide a more selective treatment option. Of note, senescent cells are a source of proinflammatory and proatherogenic molecules. Targeting molecular ageing processes holds the potential to interfere with, or even reset, vascular ageing, thus preventing vascular inflammation, atherosclerosis progression, and CV disease. Recently, novel antisenescence treatment options with translational potential have emerged, counteracting inflammatory signalling. However, several questions and open challenges need to be addressed before these novel treatment approaches may enter the clinical setting, as outlined in this insightful review. Finally, Patrick Serruys and colleagues from the Imperial College in London, UK remind us that despite advanced understanding of the biology of atherosclerosis, coronary heart disease remains the leading cause of death worldwide.15 In their Current Opinion article ‘Vulnerable plaques and patients: state-of-the-art’,19 they note that half of individuals succumbing to sudden cardiac death do not experience premonitory symptoms. Further, non-obstructing plaques can trigger cardiac events, yet the majority of ruptured or eroded plaques remain clinically silent. Since the term ‘vulnerable plaque’ was introduced, there have been major advances in its understanding, shifting from ‘plaque vulnerability’ to identifying the ‘vulnerable patient’. Moreover, acute coronary syndromes are not only caused by thin-capped, lipid-rich plaques that rupture, but also by plaque erosion as well as calcified nodule or functional coronary alterations. Whilst there have been advances in preventive strategies and in pharmacotherapy, events continue to occur even in patients receiving optimal medical treatment, suggesting that the broad spectrum of coronary pathologies are optimally considered. Although, currently, the predictive value of imaging of culprit plaques and their inflammatory features, as recently developed using computed tomography (CT),20 is too low for clinical use, improving coronary plaque imaging may be instrumental in guiding pharmacotherapy intensity and optimal allocation of novel and costly treatment strategies. Recent technical and diagnostic advances justify continuation of interdisciplinary research efforts to improve cardiovascular prognosis by both systemic and ‘local’ diagnostics and therapies. This issue also contains the ‘2019 vs. 2016 ESC/EAS statin guidelines for primary prevention of atherosclerotic cardiovascular disease’ by Børge Grønne Nordestgaard and Martin Bødtker Mortensen from the Copenhagen University Hospital in Herlev, Denmark.21 The 201922 compared with 2016 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) dyslipidaemia guidelines23 contains new recommendations for primary prevention with statins; however, the potential impact of these changes is unclear. The authors compared the 2019 and 2016 guidelines regarding statin eligibility and potential impact on prevention of atherosclerotic cardiovascular disease (ASCVD) in the general population. Finally, the issue is complemented by a Discussion Forum contribution. In a contribution entitled ‘Mast cell tryptase level should be checked in all patients with suspected Kounis syndrome’ Sujoy Khan from the Hull University Teaching Hospitals NHS Trust in Cottingham, Hull, UK discusses the recent publication ‘Intravascular ultrasound-confirmed plaque rupture following multiple bee stings’ by Tomoki Sakaue and colleagues from the Kitaishikai Hospital in Ozu, Japan.24,25 The editors hope that readers of this issue of the European Heart Journal will find it of iinterest. With thanks to Amelia Meier-Batschelet for help with compilation of this article.

Source: European Heart Journal

DOI: 10.1093/eurheartj/ehaa686

Author: Thomas F Lüscher