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Impact of inflammation-mediated response on pan-coronary plaque vulnerability, myocardial viability and ventricular remodeling in the postinfarction period - the VIABILITY study : Protocol for a non-randomized prospective clinical study
research-article
Author(s):
Mirabela Morariu , MD
a ,
Roxana Hodas , MD
a
,
∗ ,
Theodora Benedek , MD, PhD
a ,
Imre Benedek , MD, PhD
a ,
Diana Opincariu , MD
a ,
Andras Mester , MD
a
,
b ,
Monica Chitu , MD, PhD
a ,
Istvan Kovacs , MD, PhD
a ,
Ciprian Rezus , MD, PhD
c ,
Dan Pasaroiu , MD
b ,
Noemi Mitra , MD
b ,
Sándor M. Szilágyi , PhD
b
,
d ,
Dan Georgescu , MD, PhD
e ,
Elena Rezus , MD, PhD
c
Publication date (Electronic):
26 April 2019
Journal:
Medicine
Publisher:
Wolters Kluwer Health
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Abstract
Introduction:
While the role of inflammation in acute coronary events is well established, the impact of inflammatory-mediated vulnerability of coronary plaques from the entire coronary tree, on the extension of ventricular remodeling and scaring, has not been clarified yet.
Materials and methods:
The present manuscript describes the procedures of the VIABILITY trial, a descriptive prospective single-center cohort study. The main purpose of this trial is to assess the link between systemic inflammation, pan-coronary plaque vulnerability (referring to the plaque vulnerability within the entire coronary tree), myocardial viability and ventricular remodeling in patients who had suffered a recent ST-segment elevation acute myocardial infarction (STEMI). One hundred patients with STEMI who underwent successful revascularization of the culprit lesion in the first 12 hours after the onset of symptoms will be enrolled in the study. The level of systemic inflammation will be evaluated based on the serum biomarker levels (hs-CRP, matrix metalloproteinases, interleukin-6) in the acute phase of the myocardial infarction (MI) and at 1 month. Pan-coronary plaque vulnerability will be assessed based on serum biomarkers known to be associated with increased plaque vulnerability (V-CAM or I-CAM) and at 1 month after infarction, based on computed tomographic angiography analysis of vulnerability features of all coronary plaques. Myocardial viability and remodeling will be assessed based on 3D speckle tracking echocardiography associated with dobutamine infusion and LGE-CMR associated with post-processing imaging methods. The study population will be categorized in 2 subgroups: subgroup 1 - subjects with STEMI and increased inflammatory response at 7 days after the acute event (hs-CRP ≥ 3 mg/dl), and subgroup 2 - subjects with STEMI and no increased inflammatory response at 7 days (hs-CRP < 3 mg/dl). Study outcomes will consist in the rate of post-infarction heart failure development and the major adverse events (MACE) rate.
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Most cited references20
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The inflammatory response in myocardial injury, repair, and remodelling.
Nikolaos G Frangogiannis (2014)
Myocardial infarction triggers an intense inflammatory response that is essential for cardiac repair, but which is also implicated in the pathogenesis of postinfarction remodelling and heart failure. Signals in the infarcted myocardium activate toll-like receptor signalling, while complement activation and generation of reactive oxygen species induce cytokine and chemokine upregulation. Leukocytes recruited to the infarcted area, remove dead cells and matrix debris by phagocytosis, while preparing the area for scar formation. Timely repression of the inflammatory response is critical for effective healing, and is followed by activation of myofibroblasts that secrete matrix proteins in the infarcted area. Members of the transforming growth factor β family are critically involved in suppression of inflammation and activation of a profibrotic programme. Translation of these concepts to the clinic requires an understanding of the pathophysiological complexity and heterogeneity of postinfarction remodelling in patients with myocardial infarction. Individuals with an overactive and prolonged postinfarction inflammatory response might exhibit left ventricular dilatation and systolic dysfunction and might benefit from targeted anti-IL-1 or anti-chemokine therapies, whereas patients with an exaggerated fibrogenic reaction can develop heart failure with preserved ejection fraction and might require inhibition of the Smad3 (mothers against decapentaplegic homolog 3) cascade. Biomarker-based approaches are needed to identify patients with distinct pathophysiologic responses and to rationally implement inflammation-modulating strategies.
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Inflammation and its resolution as determinants of acute coronary syndromes.
Peter Libby, Ira Tabas, Gabrielle Fredman … (2014)
Inflammation contributes to many of the characteristics of plaques implicated in the pathogenesis of acute coronary syndromes. Moreover, inflammatory pathways not only regulate the properties of plaques that precipitate acute coronary syndromes but also modulate the clinical consequences of the thrombotic complications of atherosclerosis. This synthesis will provide an update on the fundamental mechanisms of inflammatory responses that govern acute coronary syndromes and also highlight the ongoing balance between proinflammatory mechanisms and endogenous pathways that can promote the resolution of inflammation. An appreciation of the countervailing mechanisms that modulate inflammation in relation to acute coronary syndromes enriches our fundamental understanding of the pathophysiology of this important manifestation of atherosclerosis. In addition, these insights provide glimpses into potential novel therapeutic interventions to forestall this ultimate complication of the disease. © 2014 American Heart Association, Inc.
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Coronary Atherosclerotic Vulnerable Plaque: Current Perspectives
Introduction Atherosclerosis is the most common form of vascular disease and constitutes the major cause of death, with 17.5 million related deaths annually (31% of global mortality).1 Atherosclerotic plaque represents the hallmark lesion of atherosclerosis. Most, but not all,2, 3 acute cardiac events occur in the context of plaque‐related thrombus formation, with the remainder associated with primary cardiomyopathy or arrhythmogenesis (primary myocardial electrical instability or ischemia related). Given that advances in technology allow for imaging, access, and localized treatment of atherosclerotic plaques, enormous efforts have been devoted to recognizing “vulnerable plaques,” defined as rupture‐prone (or, more teleologically relevant, event‐prone) plaques and, subsequently, treating them.4 Despite the above, results of vulnerable plaque‐oriented approaches, in terms of both personalized risk assessment and guided treatment effects, have generally been poor, thus raising doubts regarding the validity and usefulness of the vulnerable plaque concept.5, 6, 7, 8 In the present review, processes associated with decreased stability and related to the vulnerable plaque hypothesis, along with current and experimental methods for detecting vulnerable plaques, are discussed. Finally, potential alternative strategies, representing an amalgamation of differing views of atherosclerosis, will be explored. On the Genesis of Atherosclerotic Plaque Disruption of the endothelial cell‐mediated vessel lumen‐wall barrier is considered the earliest prodrome lesion of atherosclerosis. The molecular basis of the barrier lies in intercellular (tight and adherens junctions) and cell/extracellular matrix (ECM) adhesion, both being necessary for its integrity. Both structures are linked to the cytoskeleton, thus allowing for cellular adaptation to applied stresses.9 In fact, these stresses and consequent induced strains (deformations) are sine qua non stimuli for barrier maintenance, acting through mechanosensor‐mediated signal transduction pathways (involving actin and integrins).10 Furthermore, endothelial cells lose their polarized structure and assume a spindle‐like conformation, expressing leukocyte adhesion molecules.11 Consequently, areas of the vasculature with inherently low transmural and shear stresses (cause) and strains (effect), such as bifurcation points and the inner wall of curved vessels (such as the right coronary artery), may begin developing barrier defects early in life.12 Lipid‐Driven Mechanisms These breaches of vascular barrier integrity allow for lipoprotein infiltration and deposition in the intima.13 Uptake by both locally present and recruited macrophages attempts to prevent their accumulation by means of reverse cholesterol transport. However, cholesterol does have deleterious cellular effects, causing apoptosis, initiating inflammation and thus preventing its removal.14 Upon further material accumulation, an amorphous lipid core (hence the component “athero,” from the Greek ἀθήρα, meaning gruel) is formed—the infamous necrotic core. Lipid particles residing in the core undergo enzymatic modifications, becoming oxidized, and trigger the release of proinflammatory mediators.15 Additionally, oxidized low‐density lipoprotein (LDL) has been found to trigger necroptosis,16 an alternate form of programmed cell death, originally a defensive infection mechanism, whereupon cells do not quietly implode, but rather release particles and messengers inducing proinflammatory activation of adjacent cells.17 Thus, lipid accumulation and modification strongly enhances both quantitative and qualitative plaque progression. Activated macrophages and apo‐/necroptotic cells within the necrotic core produce tissue factor (factor III), a major component of 1 coagulation pathway, significantly enhancing its thrombogenicity. Lipoprotein(a) (Lp(a)) is a specialized molecule thought to have arisen recently in evolutionary history, either in the context of infection control (given its ability to amass oxidized lipids and draw inflammatory cells to injured vessel walls—normally caused by infectious agents, not atherosclerosis) or as a surrogate for ascorbic acid in vascular wall repair.18 However, in the context of atherosclerosis, it assumes 4‐fold deleterious/destabilizing effects by promoting thrombosis, inflammation, cholesterol delivery to atheromas, and smooth muscle cell (SMC) proliferation. Studies' findings have, foreseeably, associated Lp(a) levels with vulnerable plaque phenotype.19 Inflammatory‐Immune Mechanisms Inflammation is also a major event in atherosclerosis natural history and plaque progression, usually related to decreased structural stability. Both components of immunity, innate and adaptive, have been found to be activated in atherosclerosis‐related inflammation. Postulated infectious mechanisms (Chlamydia pneumoniae) also act through this pathway, although the process soon becomes self‐sustained regardless of pathogen presence.20 Increased local thermal activity has been considered a direct effect of inflammation, stemming from presence of metabolically highly active immune cells, energy production uncoupling attributed to ischemia, and exothermic chemical reactions (such as oxidation, H2O2 dissociation).21 Moreover, given results of theoretical calculations, blood‐wall friction as well as turbulent flow at the maximal stenosis area also contribute to localized heating. Increased temperature is not only a potentially measurable result of atherosclerotic plaque presence, but has also been related to higher blood viscosity and red cell aggregation. Finally, neovascularization of advanced plaques might also play a role, on the premise of heating the metabolically more‐inert abluminal area and core of the plaque, although a cooling effect of blood‐flow–related convection should be considered.22 The Role of ECM A second dynamic equilibrium is established regarding ECM production and degradation,2 giving rise to vessel remodeling, that is, the response of the ever changing plaque to alterations in mechanical factors.23 ECM, comprised of both cellular and acellular (usually in the form of proteoglycans) components constitutes the initial, theoretically temporary, container of the necrotic core, preventing its contact with the bloodstream. Furthermore, the mechanical strength of its luminal part (cap) determines plaque resistance to stress. SMCs and myofibroblasts are the main producers and maintainers of ECM, with inflammatory cells and necrotic core stimulating its degradation. ECM degradation is not limited to the luminal side of the plaque; rather, abluminal layer involvement is evident, especially in plaques with larger necrotic cores (and, consequently, more macrophages and inflammation), providing a mechanistic link and interpretation of the well‐known association between positive remodeling, plaque necrotic core size, and instability.24, 25 Furthermore, direct deleterious effects of the necrotic core have been documented, in the form of cholesterol crystals that expand upon formation and with changes in temperature and pH, rupturing container (foam) cells and straining the plaque from within (not unlike ice), and pierce the fibrous cap, weakening it and providing a thrombogenic substrate to circulating coagulation components. In fact, the relationship between cap thinning and plaque propensity to rupture is not linear, given that significant increases in deformation and tensile stress, for the same load, are noted past a certain point (Young's modulus reduction >60%).26 Neoangiogenesis Neoangiogenesis is a feature of advanced atherosclerosis, appearing late in the natural history of plaques. The main stimulus for neovessel formation comes in the form of hypoxia‐inducible factors secreted by hypoxic macrophages deep in the lesion's necrotic core27 and involves endothelial cells losing polarity and sprouting tube‐like forms as precursors to fully fledged neovessels. In fact, the anoxemia theory of atherosclerosis postulates that it is the depletion of ATP in macrophages, attributed to the extremely high rates of energy taxing cholesterol uptake, which leads to apoptosis, formation of a necrotic core, and angiogenetic stimuli. The neovessel wall lacks proper structure, in terms of elastic laminae and smooth muscle cell support, and thus they are leaky, prone to rupture, and provide the plaque with elements crucial for its continued progression,28 in the form of cholesterol (both lipoprotein and red blood cell membrane derived), cytokines, and leukocytes, straight to the necrotic core, thus establishing a vicious positive feedback loop favoring destabilization and, ultimately, rupture.29 Plaque hemorrhage may thus underlie episodes of accelerated plaque growth.30 The Many Faces of Mineralization The final act in the course of atherosclerosis as a chronic unresolved inflammatory process lies in the permanent and secure encasement of its source area in a highly calcified structure (mineralization), replacing the temporary fibrotic “seal” produced by chemokine‐attracted intima invading SMCs. The process of vascular mineralization is now considered active, highly regulated, and akin to bone formation.31, 32 Notably, vascular calcification, as opposed to bone formation, appears to be triggered, not inhibited by, inflammation.33 However, in a process reminiscent of myocardial wall rupture risk following infarction, initial phases of calcification with formation of calcified specs and nodules (microcalcification) will actually reduce plaque mechanical strength34 by introducing contact areas between materials (calcified nodules and fibrous cap components) with different elastic moduli, different behavior under stress, and thus prone to stress‐induced debonding or caveolation.35 This effect is particularly prominent in cases of adjacent specs, interpreting central plaque rupture and high peak stresses in theoretically nonvulnerable (cap thickness >65 μm, or even >100 μm) plaques.36 The above could help explain the often contradictory findings regarding calcification effects on plaque stability,2 given that older imaging modalities could not reliably discern between spotty/nodular calcification and fused, reinforced calcified structures. The Divergent Course of Erosion Plaque erosion mechanisms underlie almost one quarter of all acute coronary syndrome (ACS) events,37 with rising prevalence, yet they remain largely unresolved.38 Eroded plaques tend to lack features associated with rupture prone structure, exhibiting thicker caps, large numbers of SMCs, and smaller necrotic cores, while being quiescent in terms of inflammation.39 However, significant divergence has been documented in terms of ECM properties. Both a shift toward collagen III (as opposed to collagen I usually dominating plaque ECM) and hyaluronan (a proteoglycan subtype) production has been found—in fact, hyaluronan is almost absent even at rupture sites. Given that collagen III has more‐elastic properties, compared to its type I counterpart, and that endothelial cell adhesion to hyaluronan is reduced (especially in larger‐vessel–derived endothelial cells),40 detachment of cells from their basal membrane becomes possible, even at lower stresses—or in cases of coronary spasm41 (increased membrane mobility and weaker attachment). Furthermore, not only is hyaluronan more susceptible to neutrophil‐derived protease cleavage, but also increased numbers of neutrophils have been detected near erosion‐prone plaques as well and have been shown to induce endothelial apoptosis.42 Finally, hyaluronan itself has been associated with reduced proliferation and survival of endothelial cells in cultures and possesses prothrombotic properties (increased platelet adhesion and accelerated fibrin polymerization).43 Given preponderance of women, smokers, diabetics, and the elderly among patients suffering plaque erosion, it could be inferred that certain idiosyncratic features or noxious (metabolic or exogenous) stimuli alter the usual course of events during atherosclerosis progression, leading to formation of a less‐ruptured (increased elasticity?), yet more thrombosis‐prone plaque. The lack of need for structural support with exogenous scaffolding and increased thrombogenicity may interpret the findings of the recent Effective Antithrombotic Therapy Without Stenting: Intravascular Optical Coherence Tomography‐Based Management in Plaque Erosion (EROSION) study, where antithrombotic therapy was a viable option, compared to stenting, in nonocclusive stenoses causing erosion‐related acute events.37 The enhanced role of neutrophils in plaque erosion—analogous to that of macrophages in rupture—is thought to be mediated by released strands of DNA, called neutrophil extracellular traps (NETs), originally sequestering pathogens and disarming them by means of DNA‐drawn enzymes.44 However, in the framework of plaque erosion, the process, aptly termed NETosis, leads to a prothrombotic state, by enhancing platelet aggregation and coagulation and inhibiting fibrinolysis (fibrin mesh constituting another putative pathogen trap). Indeed, myeloperoxidase‐positive cells have been found in larger quantities in the blood of patients with eroded plaques and in the overlying thrombi.45 Effects of Plaque Environment—External Stresses Effects of abnormal exogenous stresses continue in late stages of atherosclerosis.46 Normal laminar flow causes relatively stable transverse and shear stresses, with limited oscillatory variations.11 Moreover, in addition to cell reorientation, exogenous stress leads to collagen laminae reorientation, introducing anisotropy of the fibrous cap and rendering it more prone to rupture.47 Mechanical factors may also, through mechanoreceptors, lead to a multitude of effects on other cellular processes, such as increased reactive oxygen species (ROS) production and inflammation.11 In fact, plaque tendency to rupture at the shoulders, as well as cases of fissuring in other areas of the fibrous cap, may be interpreted by integrating mechanical factors' effects on biology. As blood flow is diverged toward the remaining lumen by the upstream plaque edge, a low‐stress area occurs, prone to loss of cellular architecture and increased lipoprotein and leukocyte permeability, thus continuously providing fuel for plaque growth and inflammation. At the shoulder area, however, stresses increase considerably attributed to blood incompressibility. Thus, not only are ROS production and inflammation stimulated in the underlying tissue (as a result of high, rather than low, stresses in this area), but an abrupt transition between mildly and highly stressed areas occurs, favoring plaque rupture and neovessel formation and rupture.48 Similarly, at the downstream shoulder, flow turbulence leads to decrease of transmural pressure attributed to vortex‐formation–related energy dissipation, mirroring the events of the upstream region. Presence of a large necrotic core exaggerates this unfavorable altering of stress distribution, further straining the shoulder area.49 At intermediate plaque areas, between shoulders, highly oscillatory stresses may occur attributed to the Bernoulli effect. Similarly, this mechanism of blood acceleration through the stenotic lumen and reduction of transmural pressure exerts detrimental effects on the vasa vasorum with blood content oscillations, causing plaque expansion and dilation at every cardiac cycle, stressing and building up fatigue in the fibrous scaffold of the plaque, and potentially causing the structurally defective vasa vasorum to rupture. High shear stresses could conceivably play an analogous role in enhancing endothelial cell denudation in plaque erosion. Based on the above, it is evident that all types of abnormal stress patterns, if sustained, have discrete adverse effects on atherosclerotic lesions: Low stresses are involved in initial stages, whereas high and oscillatory stresses come into play later on in disease progression. Vulnerable Plaque Hypothesis Ultimately, plaque destabilization (a general term for complication related changes) is a biomechanical phenomenon that can be thought of as depending on a complex interplay between applied stresses, structural features, and biological processes that determine mechanical strength.50, 51, 52, 53, 54, 55, 56 This approach, although not conclusive, is useful as a framework for pursuing ways to prevent, predict, and avert rupture/erosion. Obviously, focusing solely on plaque characteristics will ignore the effects that exogenous forces exert on stability. On the other hand, focusing on luminal stenosis will only assess the applied forces and disregard plaque contribution, explaining the oft‐cited finding of far greater prevalence of nonstenotic lesions in cases of destabilized (ruptured) plaques.57 Furthermore, not all cases of destabilization will lead to clinical events, given that vessel occlusion, leading to peripheral necrosis with mechanical or electrical instability, is associated with blood thrombogenicity and the ability of counter‐regulatory mechanisms to contain its sequelae—prevalence of silent ruptures in stable coronary artery disease patients has been reported to reach 58%.58 Plaque rupture is the most common form of plaque destabilization,50, 59, 60 accounting for two thirds of fatal myocardial infarctions (MIs) and sudden cardiac deaths and refers to transmural fissuring of the fibrous cap, leading to exposal of the thrombogenic and proinflammatory underlying necrotic core to circulating blood. The affected plaque usually has the features of a thin cap fibroatheroma, as described previously61 (Table 1). On the other hand, plaque erosion denotes a histologically seen thrombus superimposed on a cell‐denuded endothelial layer of a nonruptured plaque71 with different structural features, as observed in the alternative course of plaque progression. Finally, calcified nodules have been found in cases of culprit lesions, as expected by their inherent disruptive effects on plaque integrity, constituting another rupture‐prone structure, alternative to thin cap fibroatheroma.50, 59, 60 Table 1 Thin Cap Fibroatheroma Features Histology61 Cap thickness 90 degrees), suggesting increased lipid content. Lipid arc is defined the widest arc demarcating a signal poor region with diffuse borders65, 67 Necrotic lipid pools presence (signal‐poor regions poorly delineated, underlying a signal rich cap), quantified based on number of quadrants occupied Superficial microcalcifications (subtending a 100 μm).63 Most prospective studies regarding ability of vulnerable plaques to predict events used IVUS‐based approaches in their definition of vulnerability.77, 78, 79, 80 Optical coherence tomography (OCT) is the second major coronary plaque invasive imaging modality that uses near‐infrared light (1.3 μm in wavelength) in a manner analogous to sonography. Light reflected form plaque structures provides image data whereas the background effect of scattered light is negated through use of interferometric techniques. Bright or dark areas occur as a result of constructive or destructive interference between reflected and reference beams. Given the much smaller wavelength of light in comparison to ultrasound, OCT resolution is 1 order of magnitude higher (≈10 μm), allowing for proper visualization of fibrous caps, collagen content (polarization‐sensitive OCT), macrophages (related to inflammation),81 neovessels (appearing as microchannels), ruptures, and thrombi. OCT performance, with regard to microcalcifications at the lower end of the spectrum ( 1.5 mm in diameter,96 where the majority of plaques are located99). Its accuracy in detecting lesion presence is noninferior to IVUS,100 and, consequently, it exhibits an excellent rule‐out ability with a negative prognostic value approaching 100%, even in prolonged follow‐up.101, 102 Furthermore, although unable to quantify cap thickness, it is nevertheless able to detect presence of thin cap fibroatheromas, comparing favorably with OCT. Regarding vulnerable plaques, CTCA can reliably assess the presence, size, and thickness of the necrotic core, by grading tissue in Hounsfield units (HU; plaques with large cores will cause less attenuation and thus have lower unit values).103 Specific high‐risk plaque criteria have been developed, such as positive remodeling (remodeling index [RI], ≥1.1, also a surrogate for plaque composition104), (very) low (given that the threshold for a ≥10% necrotic core is 41 HU) attenuation plaque (LAP; 10 000) elementary components with homogeneous properties,52 and fluid‐structure interaction simulations, also integrating rheological effects on plaque structural stress. They are the only means able to actually assess true vulnerability by integrating the plaque structure with its surroundings; however, all of them are critically dependent on an accurate imaging technique to provide vessel geometry and plaque structural data as input.23 Intrinsic parameters classically associated with vulnerability (cap thickness, necrotic core size, vessel anisotropy, and all forms of calcification) are combined with the anticipated effects of applied stresses, fatigue attributed to vessel motion during the cardiac cycle, and blood pressure/flow effects to yield meaningful results regarding conditions leading to rupture/erosion. Should more parameters be available as inputs and not need to be inferred (such as stain by use of Brillouin microscopy), results will accordingly be more precise. A major limitation of current computational models lies in the perceived difference of structural properties between plaque components in vivo and purified materials used to determine inserted parameters.119 Despite the above, advances in algorithms have led to reduction of necessary time to construct the model and obtain convergent solutions (ie, functions describing plaque behavior) from weeks (!) to less than 2 hours.51 The latter is comparable to offline time needed for 3‐dimensional reconstruction of IVUS and OCT data; thus, it may herald active application of models to clinical practice in the near future so as to evaluate the atherosclerotic plaque not as an isolated structure, but as part of a living vessel. Although relatively scarce, some clinical data exist advocating the added prognostic value of integrating computational models in clinical practice. More specifically, even in the negative Prediction of Progression of Coronary Artery Disease and Clinical Outcome Using Vascular Profiling of Shear Stress and Wall Morphology (PREDICTION) study, wall shear stress was found predictive of a future decrease in luminal area and clinically significant obstruction,80 whereas balloon‐induced rupture was noted to occur at the site of the maximal structural stress in a 2001 study using IVUS to generate a finite‐element model.53 More important, in patients presenting with ACSs, increased stress values were noted in high‐risk areas, suggesting a potential cause‐and‐effect relation.54 Obviously, large, well‐designed prospective studies and, subsequently, randomized, clinical trials are currently lacking and sorely needed to verify or refute the validity of the above integrative approach. Questioning the Vulnerable Plaque Hypothesis Considerable issues are currently being raised with regard to the vulnerable plaque hypothesis context, especially its clinical significance.6, 7, 120 Despite vulnerable plaque features presence having high sensitivity in cases of acute events, prospective studies, such as Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT),79 VH‐IVUS in Vulnerable Atherosclerosis (VIVA),77 and the European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis (ATHEROREMO‐IVUS),78 have consistently shown that their positive predictive value is low, implying low prognostic value on an individual basis, used in addition to classical risk‐stratification factors. In the same framework, the PREDICTION study only demonstrated an ability for IVUS and shear stress features to predict plaque enlargement and lumen narrowing, not acute events.80 Failure of a shear‐stress inclusive approach to define plaque vulnerability may be related to IVUS resolution, considerably inferior to that of OCT. Moreover, in the recently presented 2‐year follow‐up of the COLOR registry,93 NIRS‐determined culprit plaque vulnerable phenotype was not associated with a difference in major adverse cardiovascular events occurrence (5.4% vs 6.3% in the nonvulnerable plaques; P=0.41), suggesting that a stented lesion has the same possibility to cause a new clinical event regardless of its type. In fact, adverse events during follow‐up were more commonly related to nonculprit lesions; however, outcomes for the NIRS‐defined vulnerable nonculprit plaques have not yet been analyzed. In conjunction, the full results from the COLOR and LRP studies (NCT02033694)92 are expected to definitely answer whether NIRS fares any better in identifying plaques prone to causing future events. Recent findings appear to suggest that the notion of nonstenotic plaques underlying ACSs is a misconception, given that, when having been assessed close to the episode of which they were the culprit, plaques appear severely stenotic, having undergone a period of accelerated growth.79, 121 Although vulnerable plaques may carry high lipid burdens, masked by their expansive remodeling, 1 of the major tenets of the vulnerable plaque hypothesis is that stenosis degree has little impact on the plaque's fate, compared to its structural features (although nothing actually precludes it from being severely stenotic).2 However, this controversy can be reconciled by considering that plaques with accelerated progression are, in fact, vulnerable plaques, fueled by repeated episodes of hemorrhage and subclinical (healed) rupture and erosion.122 Studies suggesting plaques may alternate between vulnerable and nonvulnerable phenotypes123 cast doubt on the significance of diagnosing plaque vulnerability and, conversely, suggest that nonvulnerable plaques may transition into an unstable morphology and suffer rupture or erosion. The stochastic (by current knowledge), rather than determinate, nature of plaque progression is indirectly supported by the finding that extensive nonobstructive atherosclerosis confers similar risk for MI and sudden death as obstructive, but less‐extensive, disease.124 Additionally, occurrence of clinical events heavily depends on blood and myocardial features (Figure 2); thus, significance of treating rupture prone plaques becomes unclear. However, it is not inconceivable that plaque interdependence may extend well beyond an observed domino‐like effect (a destabilized plaque releasing mediators knocking others—even in remote vascular beds—out of balance).125 More specifically, flow alterations following a silent event or even a successful coronary intervention could inevitably, and currently unpredictably, alter the course of even distant lesions. Finally, the number of nonculprit, asymptomatic, potentially type‐switching plaques may be such, especially in cases of high atherosclerotic burden5 that renders, in combination with the above, all efforts at localized “vulnerability‐guided” treatment, without the ability to accurately assess implications futile, if not dangerous.126 Figure 2 Projected natural course of atherosclerotic plaques based on their intrinsic and extrinsic features. This figure depicts potential evolution of plaques based on an integrative assessment, including external and internal factors, and underlies the necessary paradigm shift in the vulnerable plaque definition. Size and thickness of arrows implies relative probability for a course between the 2 listed in every step. Obviously, the default state, that is, maintenance of the status quo with plaques remaining quiescent, is far more likely in all cases—no arrow denotes certainty for an event. As seen in the diagram, even stable, by all accounts, plaques can rupture/erode. This can be attributed to a phenotype/external stressor shift, an erroneous assessment, or simply an unlikely event given that plaque behavior is, as everything in medicine, the sum of probabilistic, not determinate, events. Additional levels of uncertainty are inserted through the, currently unpredictable, blood and myocardium response to a destabilizing event. Nonvulnerable blood and plaque destabilization combination may also lead to events, albeit rarely. “Silent” events are considered, for the purposes of this figure, both those resolving previous to thrombus formation and those with thrombosis yet remaining clinically undetected. “High” and “low” risk structural features can only be defined relatively, that is, how would the plaque behave in cases of applied loads that can be considered moderate. Obviously, further research is necessary to elucidate these parameters. Color coding: blue—initial definition; red—current perception; green—integrative approach. Double‐headed arrows denote bidirectional processes. ACS indicates acute coronary syndrome. Despite the above, the apparent shortcomings of the vulnerable plaque hypothesis are not attributed to it having been superseded by our ability to prevent, diagnose, and treat coronary atherosclerosis. Rather, current widespread interpretation and focus on imaging and still‐frame structural features have significantly diverged from the original concept, with regard to which we have only covered half the necessary path.46 More specifically, renewed focus on extrinsic effects on plaques and development of accurate and usable computational models127 will allow for improved assessment of plaques prone to destabilization of any form. Large, prospective, clinical trials will be mandated to acquire relevant data to be used in the development of appropriate vulnerability criteria. Although this will only apply to plaque destabilization, not hard clinical event prognosis, an accurate model incorporating all additional blood, myocardium, and patient‐related parameters (indeed replacing the plaque vulnerability concept) is not expected to be available in the foreseeable future. Regarding treatment options, it is true that numerous vulnerable plaques usually coexist in patients at risk for cardiovascular events.128 This, in combination with the domino effect during an ACS, potential for plaque morphology alteration with regression of the vulnerable phenotype and presence of further determinants of clinical outcome (vulnerable blood—vulnerable myocardium) argue against isolating and locally treating vulnerable plaques, and in favor for implementing systemic atherosclerosis treatment approaches,129, 130, 131 interpreting presence of these plaques to signify the degree of its progression in terms of natural history. Exceptions to the above may arise in cases of nonculprit destabilized plaque detection during an acute event (potential for domino effect, as suggested by findings of the CvLPRIT [Complete versus Lesion‐only Primary PCI trial] trial132), presence of accelerated plaque progression with increasing stenosis (nonetheless requiring close patient follow‐up), and establishment of clinically applicable criteria for imminent plaque destabilization.114 Thus, in this aspect, more judicious use of targeted localized therapies is warranted, as indeed suggested by vulnerable plaque skeptics. Current and Future Perspectives In addition to the classical armamentarium, several newer conceptual and systemic treatment approaches for reducing atherosclerosis burden and preventing its progression are now being actively pursued. Autophagy is a cellular process affecting both lipid accumulation and inflammation. In its kernel, autophagy describes the process through which cells are able to digest some of their components (ranging in size from signal molecules and lipids to organelles),133 and reclaim usable core materials, such as aminoacids.134 The biological role of autophagy, somewhat counterintuitive, appears to lie not only in ensuring recycling of damaged or degraded molecules, especially long‐lasting ones, but also in allowing cells to regulate processes, such as inflammation, by degrading triggering stimuli, thus ending their effects.135, 136 Master regulators of autophagy include the mammalian target of rapamycin complex and AMP‐activated protein kinase.137 Additional autophagy activating stimuli include endoplasmic reticulum stress (caused by misfolded proteins), ROS, and modified lipids, such as oxidized LDL.138, 139 Reliance of cellular protein renewal on autophagy and inhibitory effects of energy and nutrient abundance on the latter have given rise to the hypothesis that autophagy status plays a crucial role in determining vascular age (vessels being under continuous stress and in need of replacing worn components). Research findings have confirmed the above and consequently provided a plausible basis for the well‐known adage relating reduced caloric intake to longevity. On the other hand, overstimulation of autophagy ultimately leads to cell death and plaque destabilization attributed to destruction of necessary structures to ensure survival.140 In the context of atherosclerosis, dysregulation of autophagy has been described to affect endothelial cells, SMCs, and macrophages.135 More specifically, endothelial cells depend critically on autophagy for maintenance of proper function, and the nitric oxide (NO) system has been shown to rely on presence of normal autophagy levels (increases in endothelial NO synthase).141 Contact of endothelial cells with components of the ECM induces autophagy, and the latter may inhibit neoangiogenesis.142 Effects of autophagy on smooth muscle include inhibition of cell death following exposure to lipid peroxides, thus stabilizing lesions.138 The most significant effects of autophagy on atherosclerosis, however, are related to macrophages. In addition to the established cytoplasmic cholesterol efflux, formation of autophagosomes encircling lipid droplets allows for a second pathway contributing to the removal of lipid material from plaques.143 Interestingly, inflammatory and lipid mediators (interleukin‐6 and oxidized LDL), have been shown to inhibit macrophage autophagy in a vicious circle.144 Indeed, autophagy inhibition and stimulation, often in tandem with apoptosis stimulation and inhibition, have been shown to promote and arrest, respectively, atherosclerotic plaque progression.145 microRNAs (miRNAs) are small, noncoding RNA molecules that act as post‐transcriptional regulators of gene expression.146 In atherosclerotic plaques, alterations in miRNA signatures have been found in all major involved cell types, with macrophage and endothelial‐cell–derived miRNAs promoting plaque destabilization (through promotion of inflammation and angiogenesis, respectively).147 Conversely, SMC miRNA profile may be modulated to increase plaque cap integrity, and thus stability, by either switching them to a less‐synthetic, more‐contractile phenotype, improving plaque mechanical strength, or inducing increased production of collagen to increase fibrous cap thickness.148 Modulation involves both upregulation (by administration of miRNA mimics) and downregulation (through use of antagomirs and miRNA sponges). Notable, the miRNA approach is the only one able to address all aspects of plaque destabilization attributed to miRNA involvement in all phases of atherosclerosis, efficiency of the miRNA gene expression control mechanism, and the potential to include multiple miRNAs in a single vector. Finally, yet other miRNAs have been shown to act by affecting autophagy149 and be upregulated in areas of increased endothelial shear stress. Despite several more‐promising in vitro and animal studies,150 clinical application of miRNA manipulation is currently impeded by lack of adequate vectors and off‐target effects. The notion of cell senescence is also being strongly implicated in atherosclerosis in current studies. In principle, senescence is a ubiquitous biological process underlying not only biological ageing and tissue degeneration, but tissue remodeling as well (removal of differentiated cells with limited functional potential and replacement by other from the progenitor cell pool).151 Thus, the established fact of (biological) age being the strongest predictor and risk factor for vascular disease is put into perspective. Broadly, cell senescence can be classified as replicative (associated with telomere shortening), stress‐induced premature senescence (not associated with telomeres per se, but exhibiting the same biochemical changes arresting cell‐cycle progression), and oncogene induced, with only the former 2 involved in atherosclerosis progression. In addition to changes in telomeres, chromatin structure (switch to heterochromatin—transcriptionally quiescent), and inhibition of cell‐cycle completion promoting proteins (mainly cyclin‐dependent kinases), senescent cells display a characteristic secretory profile, including specific cytokines.152, 153 Although, in principle, a method to promote senescent cell clearance by phagocytosis (efferocytosis) and replacement, long‐term persistence of this secretory phenotype leads to disproportional proliferation, angiogenesis, endothelial dysfunction, and inflammatory cell recruitment.151 In general, the role of senescence in atherosclerosis and plaque vulnerability appears to be related to both exhaustion of replicative potential of cells attributed to constant need for replenishment of disease‐related losses and premature induction of functional handicaps (cell‐cycle arrest) not only precluding self‐renewal (autophagy and synthesis of components), but also inducing a noxious secretory phenotype. Senescence has been found to occur in both SMCs and endothelial cells, rendering them dysfunctional. Verily, presence of senescent SMCs has been linked to atherogenesis and presence of unstable plaque features, such as large necrotic core and thinner fibrous cap (potentially mediated by senescence‐related cytokines),154 whereas senescent endothelial cells are characterized by both NO synthase uncoupling and over‐response to inflammatory stimuli.155 Significant advances in the understanding of inflammation have led to the notion that inflammation abatement is an active, rather than passive, process.156 Specialized proresolving mediators (SPMs) are a group of structurally related signaling molecules derived from polyunsaturated fatty acids acted upon by 1 or a combination of lipoxygenase, cyclooxygenase, and cytochrome P450 monooxygenase enzymes (thus nonselective inhibition of lipoxygenase may not always be beneficial). Main subclasses are resolvins, maresins, protectins, and lipoxins. More broadly, they are considered autacoids (αὑτός+ἀκω, “self‐heal”), hormones produced, acting, and catabolized locally. It appears that they constitute the second part of a negative feedback loop, being produced by inflammatory cells and acting on them and other cells in the tissue vicinity to promote healing, including efferocytosis stimulation,157 and quench proinflammatory stimuli. Moreover, SPMs initiate a positive feedback loop for the firm induction and progression of the reparatory process. In atherosclerotic plaques, in accord with the concept of chronic inflammatory activation, plaque progression and assumption of a vulnerable phenotype are both related to increased levels of proinflammatory lipid mediators (such as leukotriene B4) and decreased levels of SPMs,158 evidencing that, in chronicity, inflammation has gone awry. Thus, inflammation control should involve not only suppression of promoting pathways, as is the current treatment paradigm in atherosclerosis, by means of medications (eg, statins), but also reinforcement of those promoting healing and dampening of inflammatory responses. Recent research has established that exogenous administration of a cocktail of SPMs does indeed lead to plaque stabilization by halting further engorgement of the necrotic core, leading to increases in the numbers of SMCs and cap thickness and altering macrophage phenotype to a reparatory one (M2).158 Further pathways of interest for research and putative significance for the natural history of atherosclerosis have been identified. Pyroptosis is among them and refers to a form of proinflammatory cell death of immune cells, following detection of foreign antigens within, whereupon cells commit suicide while releasing immune‐stimulatory molecules.159 Differences from apoptosis include dependence on caspase 1 activation and formation of the inflammasome (as opposed to caspases 8 and 9 and apoptosome, respectively). The difference from necroptosis lies in the occurrence in immune (as opposed to tissue) cells. Studies have shown that intracellular oxidized LDL may act as an inductor of macrophage pyroptosis, through a mitochondrial‐DNA–dependent pathway. Although apoptosis, necroptosis, and autophagy have been reported in atherosclerosis, it is entirely possible that pyroptosis of immune cells is also involved (and thus apoptotic foam cells are, at least in part, actually pyroptotic cells), more dynamically contributing to plaque destabilization.160 On more‐conventional grounds, generalized immunosuppressive treatment has been implemented with favorable results whereas therapies targeted to specific components (eg, inhibition of MMPs) have yielded encouraging results. Conclusions The concept of vulnerable plaque was developed with the intent of formally defining and describing atherosclerotic plaques having caused acute clinical events (a posteriori). Need for clinical applicability led to definition shifting toward plaques prone to causing events and by extension prone to destabilization (rupture, erosion). Most subsequent clinical studies further narrowed the scope by focusing on intrinsic (structural) determinants of instability, such as quantitative and qualitative composition and remodeling. Attributed to the neglect accorded to effects of extrinsic stressors (eg, dynamic pressure/pressure head, turbulent/laminar flow; see Figure 1), and the routine use of a single imaging modality in plaque assessment, this led to plaques considered nonvulnerable, under the current concept, to be found causing events. Despite the above, the vulnerable plaque concept has led to tremendous advances in our understanding of pathogenesis and treatment of atherosclerosis, along with substantial improvement of the relevant technological armamentarium. Results from newer studies and trials appear to suggest that a change of approach to the vulnerable plaque concept is mandated to further improve patient diagnosis and treatment. However, a return to the fundamentals of the vulnerable plaque hypothesis appears more appropriate (Table 3). Table 3 Vulnerable Plaque Conundrum What it originally meant A plaque that is the culprit lesion for an acute coronary event What it should mean A plaque that is prone to rupture when all intrinsic and extrinsic effects are taken into account (regardless of structure) How it is currently interpreted in the majority of literature A plaque with specific morphological features—usually referring exclusively to thin cap fibroatheromas This table attempts to summarize the different connotations inherent in the term “vulnerable plaque.” It can be appreciated that a teleological approach has shifted toward a utilitarian one, allowing for easier classification of plaques as “vulnerable” or not, yet depriving this characterization of prognostic implications. In particular, improvement in the assessment of the complex interplay between intrinsic and extrinsic factors mentioned above (Figure 1) by use of advanced computational models is crucial in more accurately determining which plaques are truly vulnerable161 and thus allow for a more‐accurate estimate of their “natural future” (Figure 2). Their detection should be interpreted as a marker of advanced atherosclerosis progression, in the context of such systemic alterations as deranged autophagy, SPM and noncoding RNA regulation, and treated both aggressively and systematically. The fundamental question whether and under what circumstances localized treatment of plaques should be pursued is further complicated by two factors: The ability of plaques to alternate between different structural phenotypes (thus changing their location in the Figure 1 curve) and plaque interdependence, as described above. It could be safely said, based on large trials' evidence, that treating current (nonculprit) vulnerable plaques does not affect disease progression and patient course. However, whether this will hold true in the future, with integrative approaches, incorporating advanced computational models, and changing the working definition of vulnerability, cannot be at present determined, pending development of such tools and related prospective trials. The vulnerable blood and vulnerable myocardium concepts should be brought back into focus to allow for assessment of the vulnerable patient by determining which plaque‐blood‐myocardium combinations are prone to leading to catastrophic events (that may actually be arrhythmic rather than ischemic). On the other hand, not all silent events are innocent: It is conceivable that they might alter, by mechanisms discussed previously, the course of other plaques, in the long term—although at present this is merely conjectural and hypothesis generating. In conclusion, although the vulnerable plaque is a valid concept in principle, holding great promise for future research, current interpretation of (incomplete) data for vulnerability assessment has rendered it inaccurate. Resources could be more effectively redirected toward large‐scale efforts to reduce the epidemiological atherosclerosis burden, for which there is solid evidence for improving life expectancy and quality, and also toward developing more‐sophisticated models for an integrative approach to plaque assessment. In any case, it should be kept in mind that “preventing is better than treating.” Thus, guided localized treatment of plaques, rather than systemic approach to patients, is, in the great majority of cases and given lack of reliable simulation models, not advisable at present for reasons of effectiveness and safety. Disclosures None.
Author and article information
Journal
Journal ID (nlm-ta): Medicine (Baltimore)
Journal ID (iso-abbrev): Medicine (Baltimore)
Journal ID (publisher-id): MEDI
Title:
Medicine
Publisher:
Wolters Kluwer Health
ISSN
(Print):
0025-7974
ISSN
(Electronic):
1536-5964
Publication date Collection:
April
2019
Publication date
(Electronic):
26
April
2019
Volume: 98
Issue: 17
Electronic Location Identifier: e15194
Affiliations
Author notes
[∗
]Correspondence: Roxana Hodas, Clinic of Cardiology, University of Medicine, Pharmacy,
Sciences and Technology of Targu-Mures, Romania (e-mail:
roxana.hodas@
123456yahoo.ro
).
Article
Publisher ID: MD-D-19-02091 Accession ID: 15194DOI: 10.1097/MD.0000000000015194
PMC ID: 6831282
PubMed ID: 31027064
SO-VID: e42b93b1-c17d-470f-aad3-61084769aab9
Copyright © Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.
License:
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0
History
Date
received
: 16
March
2019
Date
accepted
: 18
March
2019
Categories
Subject:
3400
Subject:
Research Article
Subject:
Study Protocol Clinical Trial
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