From vulnerable plaque to vulnerable patient: the search for biomarkers of plaque destabilization

There is a strong need for biomarkers to identify patients at risk for future cardiovascular events related with progressive atherosclerotic disease. Ideally, increasing knowledge of the mechanisms of atherosclerotic plaque destabilization should be translated in clinical practice. Currently, the following commonly followed strategies can be identified with the objective to detect either the local vulnerable plaque that is prone to rupture and gives rise to a thrombotic occlusion, or the systemic vulnerable patient, who has a high probability to suffer from an adverse clinical event. On the one hand, studies are ongoing to determine local atherosclerotic plaque characteristics to predict future local plaque rupture and subsequent vascular thrombosis. Newly developed imaging modalities are being developed and validated to detect these plaques in vivo. On the other hand, systemic approaches are pursued to discover serum biomarkers that are applicable to define patients at risk for future cardiovascular events. We propose a third original approach that is optional but yet unexplored, that is, to use local plaque characteristics as a biomarker not just for local plaque destabilization but for future cardiovascular events due to plaque progression in any vascular system. This review aims to provide an overview of the current standings of the identification of the vulnerable plaque and the vulnerable patient.     

Identifying the vulnerable plaque: A review of invasive and non-invasive imaging modalities

Atherosclerotic cardiovascular disease is the current leading cause of death in industrialized countries. The vast majority of acute cardiovascular events (50-70%) are ascribed to thrombosis following rupture of a vulnerable plaque. Therefore there is an urgent need to discern vulnerable, unstable plaques from stable plaques. A variety of imaging modalities, both invasive and non-invasive, have been developed for the assessment of visualization and quantification of atherosclerosis. In this review, we discuss the advantages and limitations of the available imaging techniques, and their clinical potential for assessment of plaque vulnerability.     

Detecting the vulnerable plaque in patients

Atherosclerosis is a systemic condition that eventually evolves into vulnerable plaques and cardiovascular events. Pathology studies reveal that rupture‐prone atherosclerotic plaques have a distinct morphology, namely a thin, inflamed fibrous cap covering a large lipidic and necrotic core. With the fast development of imaging techniques in the last decades, detecting vulnerable plaques thereby identifying individuals at high risk for cardiovascular events has become of major interest. Yet, in current clinical practice, there is no routine use of any vascular imaging modality to assess plaque characteristics as each unique technique has its pros and cons. This review describes the techniques that may evolve into screening tool for the detection of the vulnerable plaque. Finally, it seems that plaque morphology has been changing in the last decades leading to a higher prevalence of ‘stable’ atherosclerotic plaques, possibly due to the implementation of primary prevention strategies or other approaches. Therefore, the nomenclature of vulnerable plaque lesions should be very carefully defined in all studies.     

Radionuclide imaging: a molecular key to the atherosclerotic plaque

Despite primary and secondary prevention, serious cardiovascular events such as unstable angina or myocardial infarction still account for one-third of all deaths worldwide. Therefore, identifying individual patients with vulnerable plaques at high risk for plaque rupture is a central challenge in cardiovascular medicine. Several noninvasive techniques, such as magnetic resonance imaging, multislice computed tomography, and electron beam tomography are currently being tested for their ability to identify such patients by morphological criteria. In contrast, molecular imaging techniques use radiolabeled molecules to detect functional aspects in atherosclerotic plaques by visualizing their biological activity. Based upon the knowledge about the pathophysiology of atherosclerosis, various studies in vitro and in vivo and the first clinical trials have used different tracers for plaque imaging studies, including radioactive-labeled lipoproteins, components of the coagulation system, cytokines, mediators of the metalloproteinase system, cell adhesion receptors, and even whole cells. This review gives an update on the relevant noninvasive plaque imaging approaches using nuclear imaging techniques to detect atherosclerotic vascular lesions.     

Noninvasive imaging of the vulnerable atherosclerotic plaque

Atherosclerosis is an inflammatory disease, complicated by progressively increasing atherosclerotic plaques that eventually may rupture. Plaque rupture is a major cause of cardiovascular events, such as unstable angina, myocardial infarction, and stroke. A number of noninvasive imaging techniques have been developed to evaluate the vascular wall in an attempt to identify so-called vulnerable atherosclerotic plaques that are prone to rupture. The purpose of the present review is to systematically investigate the accuracy of noninvasive imaging techniques in the identification of plaque components and morphologic characteristics associated with plaque vulnerability, assessing their clinical and diagnostic value.     

冠状动脉易损斑块形成机制研究进展

心血管疾病已经成为全世界致死率最高的疾病。急性冠脉综合征作为危害性极大的心血管事件之一,多由斑块破裂后继发血栓形成所致。深入了解易损斑块形成机制和影响因素,对急性心血管事件的预防和治疗具有非常重要的临床意义。本文将结合近年来有关易损斑块的研究结果,就易损斑块的概念、基本特征、病理生理机制的研究进展作一综述。     

中国人群脂蛋白a与冠状动脉易损斑块相关性的Meta分析

目的：系统评价脂蛋白a[Lipoprotein a, Lp （a）]对冠状动脉易损斑块的预测价值。方法：以脂蛋白a、易损斑块、不稳定斑块、冠状动脉、冠心病、Lipoprotein a、Lipoprotein (a)、vulnerable plaque、unstable plaque、coronary vessel、coronary artery、coronary heart disease、coronary disease等为检索词,检索PubMed,Embase,Cochrane Library,CNKI,CBM以及万方平台从建库到2020年7月的关于Lp （a）与冠脉易损斑块相关性的临床试验研究,。采用NOS质量评分量表对文献进行质量评价,应用RevMan 5.3软件及Stata 12.0软件对纳入的文献进行Meta分析。结果：经筛选后最终纳入文献11篇,1351名患者,易损斑块组717人,稳定斑块组634人。Meta分析结果显示：易损斑块组中患者血清Lp （a）水平较稳定斑块组明显升高（SMD=1.27,95%CI：0.77,1.77）。结论：人血清中Lp （a）可能是冠状动脉易损斑块形成的重要危险因素,其含量的升高可能具有预测急性心血管事件发生的能力。     

Current status of vulnerable plaque detection

Critical coronary stenoses have been shown to contribute to only a minority of acute coronary syndromes (ACS) and sudden cardiac death. Autopsy studies have identified a subgroup of high‐risk patients with disrupted vulnerable plaque and modest stenosis. Consequently, a clinical need exists to develop methods to identify these plaques prospectively before disruption and clinical expression of disease. Recent advances in invasive and noninvasive imaging techniques have shown the potential to identify these high‐risk plaques. The anatomical characteristics of the vulnerable plaque such as thin cap fibroatheroma and lipid pool can be identified with angioscopy, high frequency intravascular ultrasound, intravascular MRI, and optical coherence tomography. Efforts have also been made to recognize active inflammation in high‐risk plaques using intravascular thermography. Plaque chemical composition by measuring electromagnetic radiation using spectroscopy is also an emerging technology to detect vulnerable plaques. Noninvasive imaging with MRI, CT, and PET also holds the potential to differentiate between low and high‐risk plaques. However, at present none of these imaging modalities are able to detect vulnerable plaque neither has been shown to definitively predict outcome. Nevertheless in contrast, there has been a parallel development in the physiological assessment of advanced atherosclerotic coronary artery disease. Thus recent trials using fractional flow reserve in patients with modest non flow‐limiting stenoses have shown that deferral of PCI with optimal medical therapy in these patients is superior to coronary intervention. Further trials are needed to provide more information regarding the natural history of high‐risk but non flow‐limiting plaque to establish patient‐specific targeted therapy and to refine plaque stabilizing strategies in the future. © 2009 Wiley‐Liss, Inc.     

Lp-PLA<Subscript>2</Subscript>: A New Target for Statin Therapy

Inflammation plays an important role in atherogenesis and plaque vulnerability. Inflammatory-type markers have been evaluated for their association with atherosclerotic vascular disease and their ability to improve cardiovascular disease (CVD) risk stratification. Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is a vascular-specific inflammatory enzyme that increases the risk of CVD events and stroke approximately twofold. A consensus panel recently recommended the measurement of Lp-PLA₂ in moderate-risk and high-risk patients for improved risk stratification and modification of low-density lipoprotein target levels. Lipid-lowering agents, particularly statins, lower Lp-PLA₂ mass and activity; therefore, Lp-PLA₂ may represent an important target of lipid-lowering therapy for reducing the inflammatory nature of atherosclerosis and plaque vulnerability. It is unknown whether lowering inflammatory markers such as Lp-PLA₂ will have a direct benefit on CVD events and mortality. A large morbidity and mortality trial was recently initiated to evaluate the long-term safety and efficacy of darapladib, an Lp-PLA₂ antagonist, in patients with high-risk coronary heart disease.     

Detecting vulnerable plaque using peripheral blood: inflammatory and cellular markers

The concept of the vulnerable patient has arrived. Enhanced diagnostic methods will eventually permit accurately finding and treating these patients and their disease. Clinical Cardiologists now recognize that coronary atherosclerosis is two pathophysiologically distinct syndromes: stable and unstable. Stable coronary syndromes result from fixed, severe stenoses limiting blood flow and causing secondary myocardial ischemia. The unstable acute coronary syndromes are frequently catastrophic and are pathophysiologically distinct. They result from different cell subsets causing vascular inflammatory syndromes rather than gradual lumen constriction by plaque. Though pathophysiologically distinct, they may show common pathophysiology when a ruptured plaque heals and progressively becomes a critical stenosis. For the present hs-CRP measurement is the strongest correlative factor for future clinical events due to arterial inflammation: myocardial infarction, unstable angina, stroke, and peripheral vascular disease in both diseased and apparently healthy, asymptomatic patients. The CRP plasma level also is the best risk assessment in patients with either stable or unstable angina, long term after myocardial infarction, and in patients undergoing revascularization therapies. One study showed the only independent cardiovascular risk indicators using multivariate, age adjusted and traditional risk analysis were CRP and Total/HDL cholesterol ratio. If CRP, IL-6, and ICAM-1 levels are added to lipid levels, risk assessment can be improved over lipids alone. The prevalence of high-risk subjects in the general population is low, amplifying diagnostic problems for vulnerable plaque. Since no test yet has high sensitivity or specificity, diagnostic errors are high, with many false positives and negatives. Sensitivity or specificity must be increased by developing a risk marker panel, or by simultaneously finding other markers that themselves are highly sensitive and specific for vulnerable plaque.     

Pharmacological modulation of plaque instability

Atherosclerotic plaque rupture is promoted by metalloproteinase (MMP)-2 and MMP-9, enzymes that degrade the fibrous cap leading to plaque erosion. MMP biosynthesis is mediated by prostaglandin (PG)E2, the product of cyclooxygenase (COX)-2/inducible PGE synthase (mPGES) activity. We have recently reported the overexpression of COX-2/mPGES-1 in vulnerable plaques as a basis of MMP-mediated plaque instability. Hypercholesterolemia and hypertension are two important risk factors for atherosclerosis. Recent trial showed that statins and AT1 receptor blockers significantly reduce the incidence of cardiovascular events in humans. Since anti-inflammatory effects have been reported in association to therapy with statins or AT1 receptor blockers, in two different studies we hypothesized that these drugs can stabilize atherosclerotic plaques through modulation of COX-2/mPGES-1-dependent MMP biosynthesis. Our data demonstrated the stabilizing effect of atherosclerotic plaques by simvastatin or irbesartan, that is due, at least in part, to the reduction of inflammatory burden and suppression of PGE2-dependent metalloproteinases release.     

<Superscript>18</Superscript>F-Fluorodeoxyglucose PET Imaging of Coronary Atherosclerosis and Plaque Inflammation

The emphasis of current cardiovascular imaging modalities is on the anatomic detection of coronary artery luminal narrowing. However, in the clinical setting, vulnerable plaques that are not flow limiting may account for the majority of cardiovascular events. Thus, the pursuit for developing noninvasive imaging techniques that target vulnerable plaques is a laudable goal. Recent studies have demonstrated the clinical feasibility of direct visualization and characterization of coronary and carotid artery plaques with ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography imaging. In experimental studies, the intensity of FDG uptake has been shown to correlate with macrophage density and inflammatory state of plaques. Vascular plaque FDG uptake has been linked to cardiovascular events such as myocardial infarction and stroke. Anti-inflammatory drugs and statins have been shown to attenuate FDG uptake in plaques. Thus, the identification of FDG uptake in vascular plaques may have important clinical implications for predicting and preventing future cardiovascular events.     

Imaging of the vulnerable plaque: noninvasive and invasive techniques

In a large proportion of previously asymptomatic individuals, sudden coronary death or acute myocardial infarction occurs as the first manifestation of coronary atherosclerosis. Imaging of coronary atheromatous plaques has traditionally centered on assessing the degree of luminal stenosis. The angiographic techniques that are routinely used to identify stenotic atherosclerotic lesions are unable to identify high-risk plaques; plaques prone to rupture and cause a cardiovascular event. This is partly due to the fact that the majority of culprit lesions that produce acute cardiovascular syndromes are not severely stenotic, possibly due to significant positive remodeling and reduced protective collateral circulation as well as because the risk of plaque rupture is more closely related to plaque content than plaque size. Recently, the focus of new imaging techniques is to identify the high risk plaques; the "vulnerable plaques." In this review, we will refer to the noninvasive and invasive techniques that can detect the vulnerable plaque.     

Carotid plaque compared with intima-media thickness as a predictor of coronary and cerebrovascular disease

Atherosclerosis is the underlying cause of most myocardial infarction (MI) and ischemic strokes. B-mode ultrasound of carotid arteries provides measures of intima-media thickness (IMT) and plaques, both widely used as surrogate measures of cardiovascular disease. Although IMT and plaques are highly inter-correlated, IMT’s role as a marker of atherosclerosis has been questioned, especially when measurements include the common carotid artery (CCA) only. Plaque and intima-media thickening may reflect different biological aspects of atherogenesis with distinctive relations to clinical vascular disease. Plaque measured in the carotid bulb or internal carotid artery is stronger related to hyperlipidemia and smoking and is a stronger predictor for MI, whereas CCA-IMT is stronger related to hypertension and ischemic stroke. Echolucent plaque morphology (ie, lipid-rich plaques) seems to increase the risk for MI and stroke. New evidence suggests that total plaque area is the most strongly predictive of cardiovascular risk of the ultrasound phenotypes.     

微观结构在易损斑块进展中的作用

急性冠状动脉综合征常常导致严重的心血管事件,而冠状动脉粥样硬化斑块破裂是绝大多数急性冠状动脉综合征发生的原因,因此检测高破裂风险的易损斑块,对筛选和干预急性冠状动脉综合征具有重要意义。随着研究的不断进展,易损斑块内的一些微观结构如斑块内新生血管、微小钙化、胆固醇结晶,在易损斑块的进展中起到重要的作用。因此,本文以易损斑块内最常见的3种微观结构为重点,综述斑块内微观结构在易损斑块进展中的作用。     

Biomarkers of Plaque Instability

Atherosclerosis is the proximate cause of arterial thrombosis, leading to acute occlusive cardiovascular syndromes. Thrombosis in atherosclerosis usually results from rupture of the fibrous cap of atherosclerotic plaques with a smaller proportion resulting from superficial endothelial erosion. Ruptured plaques are often associated with intimal and adventitial inflammation, increased size of lipid-rich necrotic core with thinned out collagen-depleted fibrous cap, outward remodeling, increased plaque neovascularity, intraplaque hemorrhage, and microcalcification. By inference, non-ruptured plaques with similar compositional features are considered to be at risk for rupture and hence are labeled vulnerable plaques or high-risk plaques. Identification of vulnerable plaques may help in predicting the risk of acute occlusive syndromes and may also allow targeting for aggressive systemic and possibly local therapies. Plaque rupture is believed to result from extracellular matrix (which comprises the protective fibrous cap) dysregulation due to excessive proteolysis in the context of diminished matrix synthesis. Inflammation is believed to play a key role by providing matrix-degrading metalloproteinases and also by inducing death of matrix-synthesizing smooth muscle cells. Systemic markers of inflammation are thus the most logical forms of potential biomarkers which may predict the presence of vulnerable or high-risk plaques. Several studies have suggested the potential prognostic value of a variety of systemic markers, but regrettably, their overall clinical predictive value is modestly incremental at best, especially for individual subjects compared to groups of patients. Nevertheless, continued investigation of reliable, cost-effective biomarkers that predict the presence of a high-risk plaque and future athero-thrombotic cardiovascular events with greater sensitivity and specificity is warranted.     

The vulnerable plaque: a necessary concept in the management of atherothrombosis

The advance of cardiology has improved the prognosis of atherothrombosis through direct diagnosis and early management, but the global incidence of atherothrombotic events has been modified only slightly. Currently, although the stenosing effect of atherosclerosis is well known and if treated hardly poses a problem, the unpredictable risk of arterial thrombosis continues to cause the seriousness of the disease in as much as it is not linked to the degree of stenosis. The initiation of thrombosis progresses via destabilisation phenomena of atherosclerotic plaques with rupture or erosion of the capsule. The identification of plaques "at risk" of instability, so-called "vulnerable" plaques, is thus now a fundamental concept. Thanks to anatomo-pathology, certain morphological and functional criteria of these vulnerable plaques are better understood and are starting to find a clinical resonance. An inflammatory syndrome scenario, thin capsule, and a large lipidic heart associated with an as yet quiescent atherosclerotic plaque are predictive elements of acute coronary syndrome. These elements show promise and an already combined biological and morphological approach will certainly be at the heart of clinical research for years to come.     

Ceramidas Plasmáticas na Estratificação de Risco das Doenças Cardiovasculares

Ceramide production takes place throughout the body and plays a key role in the maintenance of normal physiology. However, ceramide levels are altered during disease states, particularly considering the development of diabetes and dyslipidemia. Ceramide production is also associated with atherosclerotic plaque instability. Recent studies revealed that patients with unstable coronary artery disease (CAD) presented increased plasma ceramide levels (especially C16, C18, and C24:1). These molecules are currently considered emerging biomarkers of cardiovascular diseases (CVD), being used for predicting atherosclerotic plaque instability and adverse cardiovascular events independently from traditional risk factors. With the aim of describing and discussing the role of ceramides in the stratification of cardiovascular diseases, this narrative review contextualizes the importance of this biomarker in the present cardiology scenario.     

Exploring the role of extracellular matrix proteins to develop biomarkers of plaque vulnerability and outcome

Cardiovascular disease (CVD) is the most common cause of death in industrialized countries. One underlying cause is atherosclerosis, which is a systemic disease characterized by plaques of retained lipids, inflammatory cells, apoptotic cells, calcium and extracellular matrix (ECM) proteins in the arterial wall. The biologic composition of an atherosclerotic plaque determines whether the plaque is more or less vulnerable, that is prone to rupture or erosion. Here, the ECM and tissue repair play an important role in plaque stability, vulnerability and progression. This review will focus on ECM remodelling in atherosclerotic plaques, with focus on how ECM biomarkers might predict plaque vulnerability and outcome.     

Molecular imaging of vulnerable plaque by cardiac magnetic resonance imaging

Coronary atherosclerosis is known to be the major cause for morbidity and mortality in the industrial world. In Europe, every year approximately 600,000 persons die from coronary artery disease, a majority of them without any prior symptoms. Plaque rupture, mostly of noncalcified vulnerable plaques, is supposed to play a major role in this setting, and noninvasive techniques are mandatory to stratify the individual risk for experiencing an acute coronary event. During the last decade, magnetic resonance imaging has gained importance as a noninvasive imaging technique in cardiology. Continuous technical improvements enabled a rapidly expanding field of application, and recently noninvasive imaging of plaques has been introduced. In addition to morphological characterization, functional imaging of plaques has gained interest for a more specific risk assessment. This article summarizes pathophysiological aspects of the concept of vulnerable plaque, technical requirements for noninvasive plaque imaging, and characterization with magnetic resonance imaging.