Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.

Review

Expectations and limitations of contemporary intravascular imaging: lessons learned from pathology Expert Rev. Cardiovasc. Ther. 12(5), 601–611 (2014)

Oscar D Sanchez, Kenichi Sakakura, Fumiyuki Otsuka, Kazuyuki Yahagi, Renu Virmani and Michael Joner* CVPath, 19 Firstfield road, Gaithersburg, MD 20878, USA *Author for correspondence: [email protected]

Acute coronary syndrome is the leading cause of death worldwide and plaque rupture is the most common underlying mechanism of coronary thrombosis. During the last 2 decades the understanding of atherosclerotic plaque progression advanced dramatically and pathology studies provided fundamental insights of underlying plaque morphology, which paved the way for invasive imaging modalities, which bring a new area of atherosclerotic plaque characterization in vivo. The development of intravascular ultrasound (IVUS) allowed the field to evaluate the principles of vascular anatomy, which is often underestimated by coronary angiography. Furthermore, IVUS image technologies were developed to obtain improved characterization of plaque composition. However, since spatial resolution of IVUS is insufficient to distinguish details of plaque morphology, a broad adoption of this technology in clinical practice was missing. Optical coherence tomography is a light-based imaging modality with higher spatial resolution compared to IVUS, which enables the assessment of vascular anatomy with great detail. KEYWORDS: atherosclerosis • fibroatheroma • IVUS • OCT • pathologic intimal thickening • pathology • thin-cap fibroatheroma • vulnerable plaque

Atherosclerotic coronary disease is the leading cause of death worldwide, and plaque rupture, which is the most common underlying mechanism of coronary thrombosis, most often results in a sudden onset of acute coronary syndrome (ACS) [1,2]. The most important pathological factors for the formation of atherosclerotic coronary lesions are endothelial dysfunction, deposition of oxidized lipoproteins, inflammation and cellular apoptosis [3]. The pathologies of coronary atherosclerotic lesions, such as pathologic intimal thickening (PIT), fibroatheroma, thin-cap fibroatheroma (TCFA) (vulnerable plaque), plaque rupture, erosion and calcified nodule, are fundamental for the interpretation of vascular imaging. The development of intravascular ultrasound (IVUS) enabled us to evaluate arterial remodeling, plaque area and volume as well as vessel wall morphology [4,5]. Based on the principles of ultrasound-derived radiofrequency signals, virtual histology (VH-IVUS) informahealthcare.com

10.1586/14779072.2014.902749

and integrated backscattered (IB-IVUS) were the first attempts to characterize plaque composition and quantify plaque component area or volume [6,7]. However, owing to the limited resolution of IVUS, a reliable assessment of plaque composition could not be achieved, to date [7]. With the introduction of optical coherence tomography (OCT), which generates images from backscattered signals of emitted near-infrared light, a novel technology was introduced that produces high-resolution tomographic images, allowing a detailed assessment of vascular morphology [8]. The current review provides an overview of atherosclerotic plaque progression with emphasis on findings from intravascular imaging. Pathology of coronary artery disease

The development of vulnerable atherosclerotic lesions is an evolving process including clearly defined stages of disease burden to be described in the following (FIGURE 1).

 2014 Informa UK Ltd

ISSN 1477-9072

601

Review

Sanchez, Sakakura, Otsuka, Yahagi, Virmani & Joner

Progression of human coronary atherosclerosis Intimal thickening

Pathologic intimal thickening

Intimal xanthoma

Fibrous cap atheroma

Thin-cap fibroatheroma NC

NC

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.

EL

Erosion

Rupture

Calcified nodule Nodule

NC Th

FC

Th

NC

Th

Healed rupture

Th FC Ca2+

Th Th

Th

Th

consensus classification of atherosclerotic coronary lesions [1,11]. This lesion is characterized by the presence of a lipid-rich necrotic core encapsulated by surrounding fibrous tissue. Histologically, it separates into early- and late-stage fibroatheroma. The early phase is characterized by the infiltration of macrophages into the lipid pool, together with the focal loss of proteoglycan and/or collagen. The late fibroatheroma can produce significant luminal stenosis from episodes of hemorrhage and healing with or without calcification, and eventually, with the presence of increase in vasa vasorum within the intimal plaque. However, it is important to stress that maturation of fibroatheroma is a continuous process with variable intermediate stages. TCFA (vulnerable plaque)

Figure 1. Histopathology of human coronary plaque progression. Descriptions begin at top, from left to right. Intimal thickening is normal in all age groups and is characterized by smooth muscle cell accumulation within the intima. Intimal xanthoma or so-called fatty streak corresponds to the accumulation of predominant macrophages within the intima. These lesions have been shown to also regress in later adult life. Pathological intimal thickening marks the first of the progressive lesions and denotes the accumulation of extracellular lipid in the absence of apparent necrosis. Fibrous cap atheroma indicates the presence of an encapsulated necrotic core, which may eventually become thinned (thin-cap atheroma). Thin-cap fibroatheroma may rupture, which often results in activation of coagulation causing a luminal thrombosis. On the other hand, the thrombus of plaque erosion occurs in the absence of rupture and may overlie a substrate of pathological intimal thickening (left) or fibrous cap atheroma (right). Eruptive calcified nodules represent a rare form of coronary thrombus. Acute rupture may progress to healing (healed plaque rupture) with resolution of the luminal occlusion. Ca2+: Calcification; EL: Extracellular lipid; FC: Fibrous cap; NC: Necrotic core; Th: Thrombus. Reproduced with permission from [1].

TCFA is characterized by a large necrotic core (representing >25% of plaque area) harbored by a thin fibrous cap pathologically defined as 40% narrowed, contribute to a significant increase in plaque burden and luminal narrowing. A characteristic histopathological phenomenon of healed plaque rupture pertains to the layered appearance of tissue secondary to disrupted fibrous cap with surrounding repair phenomena [16]. Intravascular ultrasound Physical principles & coronary anatomy

Ultrasound images are produced by passing an electrical current through a piezoelectric crystalline material that expands and contracts to produce sound waves. Those waves are reflected from the tissue and returned to the transducer, which produces an electrical impulse that is converted into an image [17]. The normal coronary artery has a three-layered structure, the innermost representing the intima, which has greater echogenicity compared with the lumen and media [17]. The internal elastic membrane (IEM) separates the tunica media from intima and is composed of elastic fibers. The second layer is the media, which is usually less echogenic than the intima, which results from the predominance of SMCs, and sometimes even generates an echolucent image [17]. A discrete interface between the media and the adventitia is the external elastic membrane (EEM) [17]. The third and outer layer consists of the adventitia, which is rich in collagen, and therefore, generates an echoreflective image [18]. Lesion morphology

Lipid-rich necrotic plaque is seen as a ‘soft’ (echolucent) plaque by IVUS, as a result of the lipid content in it [17]. Fibrous plaques, which represent the majority of atherosclerotic lesions, have an intermediate echogenicity relative to fibroatheroma and calcified plaques [17]. Calcification appears as a bright echoreflective image by IVUS and has a discriminatory dorsal shadowing like in most other applications of ultrasound technology. informahealthcare.com

Review

Vulnerable plaque

The low resolution of IVUS does not allow to precisely define TCFA; however, plaque burden can reliably be measured as previously described [17]. Thrombus can be appreciated as intraluminal mass that may have a variable gray scale [18]. IVUS cannot identify plaques prone to rupture, to date [18–20]. A plaque rupture site can be seen by IVUS as a tear in a fibrous cap with or without overlying thrombus [17]. A signature of plaque ulceration can be seen in representative notches of the intima inner border [17]. Attenuated plaque defined as intense ultrasound signal attenuation in the absence of calcification has been suggested to reflect the presence of lipid-rich plaque and therefore been associated with ACS and no-reflow phenomenon following stent implantation [21,22]. Lee et al. reported that the prevalence of attenuated plaque in ST Elevation Myocardial Infarction and Non-ST Elevation Myocardial Infarction patients was as high as 25.6 and 17.6%, respectively (p < 0.001). The authors evaluated patients presenting with ACS and compared the angiographic characteristics in those with or without attenuated plaque; they found that no reflow phenomenon was more frequently observed in patients with attenuated plaque compared with those without (26.7 vs 4.6%; p < 0.001). They also evaluated coronary blood flow after percutaneous coronary intervention (PCI) and found that it was more frequently deteriorated in those patients with attenuated plaque (8.0 vs 2.8%; p = 0.001). Finally, the authors also reviewed 100 patients with stable angina undergoing PCI and found no attenuated plaque by IVUS evaluation [21]. Calcified nodule can sometimes be reliably visualized by IVUS as a nodular bright echoreflective zone beneath the fibrous plaque with continuity to luminal thrombosis [23]. Virtual histology-IVUS & integrated backscattered-IVUS

The color-coded maps of VH-IVUS include four major components: fibrous (green), fibrofatty (light-green), necrotic core (red) and dense calcification (white). Compared with histological specimens of human coronary arteries, VH-IVUS has a sensitivity, specificity and predictive accuracy ranging from 80 to 92% in identifying the four plaque components aforementioned [6]. IB-IVUS uses a 40 MHz single rotational transducer with a fast Fourier transformation that can construct colorcoded tissue maps, which comprise fibrous (green), dense fibrosis (yellow), lipid pool (blue) and calcify tissue (red) [24]. When compared with the histological results, the sensitivity of IBIVUS for calcified, fibrotic and lipid-rich plaques has been reported as 90, 84 and 90%, respectively [25]. The correlation of plaque characterization between IB-IVUS, VH-IVUS and histology within the same coronary arterial cross-section was evaluated by Okubo et al. [19]. A total of 152 pairs of coronary arteries were compared by IB-IVUS, VH-IVUS and histology. The overall agreement between histological and IB-IVUS assessment was higher (k = 0.81; 95% CI: 0.74–0.89) than histological and VH-IVUS agreement (k = 0.66; 95% CI: 0.56– 0.75). However, the authors report some discrepancies between 603

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.

Review

Sanchez, Sakakura, Otsuka, Yahagi, Virmani & Joner

There are two types of OCT systems: the earlier version time domain OCT and the more recent fourier domain OCT systems, also known as frequency Media domain OCT, swept source OCT or optical frequency domain imaging (OFDI). The main difference between Image time-domain OCT and OFDI systems is wire that OFDI systems are capable of obtaining A-lines (multiple axial scans) at much higher imaging speed, facilitating rapid pullback imaging during the administration of a nonocclusive flush; using transparent media such as lactated ringer or radiocontrast [32]. Since OCT measures Figure 2. Optical coherence tomography shows the three-layer appearance of normal vessel wall, with the muscular media being revealed as a low signal the intensity of light returning from tislayer comprised between internal and external lamina. sues, those that have greater signal intenReproduced with permission from [33]. sity, like calcium and elastic fibers, show stronger optical scattering and therefore a IB-IVUS and histological findings, like small areas of lipid stronger OCT signal [32]. accumulations that could be misinterpreted as dense fibrous [19]. The penetration depth of near-infrared light is limited Some limitations of IVUS technology remain unsolved, such as almost entirely by basic tissue optical properties, tissues like low spatial resolution, which ranges from 150 to 250 mm. For elastic fibers and calcium can variably be penetrated by OCT that reason, IVUS is incapable to identify plaques prone to light; however, the major attenuators of OCT light are macrorupture or distinguish lipid pool from true necrotic core [26]. phages and lipids; therefore, OCT is not suited to study vessel The biggest value of performing IVUS is likely to be seen in remodeling in contrast to IVUS [33,34]. In fact, in the presence the fact that vascular remodeling can reliably be judged with this of a large plaque burden, OCT does not penetrate sufficiently imaging modality owing to its capability to view the entire vascu- to allow visualization of the media. As a second limitation, lar wall. As adaptive vascular remodeling represents a major sign OCT cannot produce an image through blood, necessitating of atherosclerotic plaque progression [27], IVUS can be used to dis- clearing or flushing blood from the lumen during image tinguish less from more advanced lesion types and therefore acquisition. remains a useful tool for the assessment of plaque progression over Nonatherosclerotic coronary artery wall appears as a threetime [28]. The PROSPECT study, was a prospective study which layered structure in OCT images (FIGURE 2). Imaging of the endoenrolled 697 patients with ACS who underwent VH-IVUS after thelial monolayer is beyond the resolution of OCT, to PCI [29]. At a median follow-up of 3.4 years, atherosclerotic pla- date [32]. The media, which ranges from 125–350 mm in thickques were investigated by VH-IVUS in a longitudinal dimension ness, can be seen as a layer of low-backscattering signal delimand major adverse cardiovascular events (MACE), caused by ited by the IEM and EEM [35]. Histologically, the IEM and either the originally treated (culprit) or the nonuntreated (noncul- EEM are constituted of a thin layer of elastic fibers (

Expectations and limitations of contemporary intravascular imaging: lessons learned from pathology.

Acute coronary syndrome is the leading cause of death worldwide and plaque rupture is the most common underlying mechanism of coronary thrombosis. Dur...
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