1 Department of Cardiology, Heart Center, Amsterdam UMC, University of Amsterdam, Amsterdam Cardiovascular Sciences, 1105 AZ Amsterdam, The Netherlands
†These authors contributed equally.
Academic Editors: Ceolotto Giulio and Teruo Inoue
Abstract
Acute coronary syndrome mostly arises from rupture or erosion of a vulnerable plaque. Vulnerable plaques typically appear as lipid-rich plaques with a thin cap, called thin-cap fibroatheromas. Various intracoronary imaging techniques can be used to detect vulnerable plaques, such as intravascular ultrasound (IVUS), optical coherence tomography (OCT) and near-infrared spectroscopy (NIRS), each visualizing different high-risk plaque characteristics. IVUS and its post-processing techniques, such as virtual histology IVUS, can primarily be used to identify calcified and soft plaques, while OCT is also able to quantitatively measure the cap thickness. The addition of NIRS allows the exact measurement of lipid content in the plaque. Non-invasive imaging techniques to identify vulnerable plaques, such as computed tomography, are less often used but are evolving and may be of additional diagnostic use, especially when prophylactic treatments for vulnerable plaques are further established. Pharmacological treatment with lipid-lowering or anti-inflammatory medication leads to plaque stabilization and reduction of cardiovascular events. Moreover, the implantation of a stent or scaffold for the local treatment of vulnerable plaques has been found to be safe and to stabilize high-risk plaque features. The use of drug-coated balloons to treat vulnerable plaques is the subject of ongoing research. Future studies should focus on non-invasive imaging techniques to adequately identify vulnerable plaques and further randomized clinical studies are necessary to find the most appropriate treatment strategy for vulnerable plaques.
Keywords
- Vulnerable plaque
- Atherosclerosis
- Acute coronary syndrome
- Intracoronary imaging
- Non-invasive imaging
Since the introduction of percutaneous coronary intervention (PCI) in the 1970s, the mortality rates of chronic coronary syndrome (CCS) and acute coronary syndrome (ACS) have steadily decreased [1, 2]. However, ischemic heart disease is still a major cause of death and disability and it accounts for approximately one-third of all deaths in people older than 35 years [3]. The American Heart Association (AHA) estimated that ischemic heart disease, and specifically ACS, accounts for around $150 billion health costs in the United States each year [4]. Even patients with prior PCI for ACS who are on guideline-directed secondary preventive therapy, have a significant residual risk for repeat coronary events. In the first year, this risk is mainly driven by target-lesion related events (e.g., stent-related), while in the years succeeding the residual risk primarily arises from lesions in other coronary segments, which were often not considered rupture-prone during the initial PCI [5]. Therefore, early identification of these lesions responsible for (recurrent) coronary events could be of clinical significance and preventive treatment of these lesions might reduce disease burden and related health costs.
In 1989, Muller et al. [6] introduced the concept “vulnerable plaque”
for—often hemodynamically insignificant—coronary plaques that were at
increased risk for rupture. It was observed that in most cases of ACS, the
stenosis grade of the culprit was mild (i.e.,
The term “vulnerable plaque” is typically used for plaques that are prone to
cause a coronary event, either by rupture or erosion causing acute thrombosis, or
by rapid plaque progression leading to significant stenosis and subsequent flow
limitation [9]. The highest disease and mortality burden in cardiovascular
disease is caused by ACS, which in the majority of cases results from (sub-)total
occlusion of the coronary artery due to thrombotic obstruction [12]. The
formation of an intraluminal thrombus is usually precipitated by plaque rupture,
which causes the release of thrombogenic factors leading to platelet aggregation
and thrombin formation [13]. It is therefore of clinical importance to detect
these rupture-prone plaques in an early stage. Accordingly, several studies
retrospectively reviewed previous coronary angiography images of patients that
presented with myocardial infarction (MI) to understand the morphology of the
ruptured plaques causing the event [14, 15, 16]. It was found that those lesions
causing a repeat event were often non-obstructive with
Fig. 1.Schematic overview of vulnerable plaque features. Schematic
representation of a vulnerable coronary plaque. The lipid-rich necrotic core is
centered in the plaque and separated from the lumen by a thin fibrous cap (
The AHA proposed a scheme to classify advanced atherosclerotic plaques according to plaque type [25, 26]. This classification scheme ranges from the initial fatty streak, as found in children and adolescents (Type I) to more advanced lesions with lipid-rich, confluent and necrotic cores (Type IV), lesions with calcifications or large fibrous caps (Type V) or complicated lesions (Type VI). However, the classification implies that plaque evolution occurs following a linear pattern, which is often not the case. Therefore, Virmani et al. [24] suggested an alteration classification where the more advanced (Type IV–VI) lesions are described according to a more histopathological approach. According to the authors, a TCFA corresponds with a type IV atherosclerotic plaque according to the AHA classification schema [24, 26]. Fig. 2 displays a schematic overview of the different plaque types.
Fig. 2.Classification of coronary atherosclerosis. Integrated coronary plaque classification based on the American Heart Association [26] and Virmani schemes [24]. * Total occlusion as resulting from prior thrombi.
Naghavi et al. [9, 10] wrote a consensus document to uniformly define
vulnerable plaques. The authors advice to use the term “vulnerable plaque” for
“all thrombosis-prone plaques and plaques with a high probability of undergoing
rapid progression, thus becoming culprit plaques”. Five major criteria for a
vulnerable plaque have been identified: (1) the presence of a thin cap with large
lipid core; (2) the presence of active inflammation (i.e., infiltration of
macrophages); (3) endothelial denudation with superficial platelet aggregation
(i.e., erosion); (4) a fissured plaque (mostly indicating recent rupture) and (5)
stenosis
The first prospective natural history study to correlate plaque characteristics
to subsequent cardiovascular events was the PROSPECT study, conducted between
2004 and 2006 [27]. This study included almost 700 patients treated with PCI for
ACS who underwent additional 3-vessel angiography and intravascular
ultrasonography (IVUS). Major adverse cardiovascular events (MACE), consisting of
cardiac death, cardiac arrest, MI or rehospitalization for unstable or
progressive angina, were adjudicated to be either related to the initial culprit
lesion, or to an additional non-culprit lesion. The PROSPECT investigators found
that approximately 20% of patients experienced follow-up events, equally
attributable to culprit and non-culprit lesions, in the 3 years following
successful PCI. The majority of non-culprit events was a result of angiographic
mild lesions with a mean diameter stenosis of 32% and one-third of the lesions
with a diameter stenosis of
These findings were confirmed in the recently published PROSPECT II study [28].
This was a prospective natural history study using 3-vessel IVUS with
co-registration of near-infrared spectroscopy (NIRS) in almost 900 patients with
recent myocardial infarction. Patients were clinically followed-up for 4 years
and again a large plaque burden of
The identification of lesions causing non-culprit events might become even more important, as the risk of culprit events by in-stent restenosis and (very) late stent thrombosis has declined considerably since the advent of newer generation drug-eluting stents (DES).
Assessment of plain angiography images may inform the operator about lesion specifics such as the presence of calcifications, thrombosis, or the extent of luminal obstruction as expressed in percentage of diameter stenosis. However, morphological characteristics of plaques cannot be distinguished without the use of intracoronary imaging. Several techniques exist to characterize plaques. Here we describe the most commonly used intracoronary imaging techniques: IVUS, optical coherence tomography (OCT) and NIRS, which are also summarized in Table 1 (Ref. [29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54]).
| Invasive imaging modalities | Non-invasive imaging modalities | ||||||
| Intravascular ultrasound (IVUS) | Optical coherence tomography (OCT) | Near-infrared spectroscopy (NIRS) | Coronary angiography computed tomography (CTCA) | Cardiovascular magnetic resonance imaging (CMR) | Nuclear imaging | ||
| Plaque features | |||||||
| Cap thickness | – | ++ [29] | – | – | – | – | |
| Lipid core | + [30, 31] | + [32] | ++ [33, 34, 35, 36] | –/+ | + [37] | – | |
| Inflammation | – | ++ [38] | – | – | – | ++ [39, 40] | |
| Plaque erosion/rupture | + [41, 42] | ++ [43] | – | – | – | – | |
| Microcalcifications | ++ [30, 31] | + [44] | – | – | + [37] | + [45] | |
| Plaque burden | ++ [46] | + [47] | – | + [48, 49] | – | – | |
| Vessel remodeling | ++ [50] | – | – | ++ [51, 52] | – | – | |
| Technical features | |||||||
| Image source | Ultrasound | Near-infrared light | Near-infrared light | CT | MRI | CT | |
| Guide catheter size, Fr | 5 | 5/6 | 5 | N/A | N/A | N/A | |
| Penetration depth, mm | 4–8 [53, 54] | 1–2 [53, 54] | 1–2 [53, 54] | N/A | N/A | N/A | |
| Spatial resolution | 40–100 mm [53, 54] | 10–20 mm [53, 54] | N/A | 0.35 mm | 2 mm | 4–5 mm | |
| Temporal resolution | N/A | N/A | N/A | 80 ms | 25–50 ms | 90 ms | |
| Iodine-based contrast tracer | – | + | – | + | – | – | |
| Radionuclide tracer | – | – | – | – | – | + | |
| Radiation exposure | –/+ * | + | –/+ * | + | – | ++ | |
| CT, computed tomography; Fr, French; mm, millimeter; | |||||||
IVUS is an invasive imaging technique that uses ultrasound to visualize the
inside of the coronary artery walls [55]. The technique is built on the
principles of ultrasonography, where high-energy sound waves are radiated into
the tissue, and the reflection is returned to the transducer and converted into
images. Echogenic components with acoustic shadowing indicate the presence of
calcium, while echolucent components may indicate “soft plaque” [30, 31]. IVUS
has a high tissue penetration (4–8 mm), enabling the evaluation of the entire
coronary artery structure (including the external elastic membrane), but it
traditionally had a limited resolution (axial 100–150
Conventional grayscale IVUS can be used for the assessment of luminal dimensions
and plaque morphology and to evaluate stent deployment. With grayscale IVUS, the
plaque burden can be measured using the following formula:
OCT uses coherent near infrared light to generate images by measuring the
intensity of light returning from the vessel wall. Due to its high resolution
(10–20
Fig. 3.Fibrous cap measurement on optical coherence tomography. A
cross-section of the coronary artery with OCT demonstrates a plaque with
overlying bright structure corresponding with the fibrous cap. The high
resolution of OCT allows measurement of the fibrous cap, which in this case
measures less than 65
NIRS is a relatively new catheter-based imaging modality developed to detect lipid-rich plaques [36], Fig. 4. The NIRS system provides a spatial map of lipid distribution in the coronary artery wall, a chemogram, and produces a quantification of the amount of lipid, called the lipid core burden index (LCBI). To combine the chemogram with morphological imaging of the coronary vessel and plaque structure, NIRS is usually combined in an integrated catheter with either IVUS (IVUS-NIRS) or, less commonly, with OCT (OCT-NIRS) [64, 65, 66].
Fig. 4.Lipid-rich plaque on intravascular ultrasound with near-infrared
spectroscopy. (A) demonstrates the chemogram as obtained with NIRS pullback.
This is a chemical map of the coronary artery, with the most distal part of the
pullback on the right and the proximal part on the left. All pixels that
demonstrate a probability of
In 2013, Madder et al. [34] demonstrated that a maximum LCBI per 4 mm
segment (maxLCBI
Accordingly, a prospective study by Madder et al. [67] in 121 patients confirmed that
the presence of lipid-rich plaques with maxLCBI
Apart from these aforementioned intracoronary imaging techniques, several non-invasive imaging techniques exist that could identify vulnerable plaque characteristics.
A widely available non-invasive imaging technique to visualize coronary artery
disease (CAD) is computed tomography coronary angiography (CTCA). CTCA has a very
high diagnostic accuracy to detect coronary stenosis in patients without
previously known CAD with a sensitivity of 95–99% and a specificity of 64–83%
[68, 69]. Moreover, CTCA may be used to assess plaque morphology to visualize
non-stenotic coronary plaques [48, 49]. The plaque density as assessed on CTCA
with Hounsfield Units (HU) has been found to correspond well with echogenicity on
IVUS, enabling CTCA to differentiate between the different plaque types [70],
Fig. 5. Plaques that are scored as soft plaques with necrotic cores based on
echogenicity of IVUS typically appear with low attenuation on CTCA (HU
Fig. 5.Vulnerable plaque on computed tomography coronary angiography. (A) demonstrates the left anterior descending artery on CTCA. A non-calcified lipid plaque in the mid-section of the artery, around the origin of the first diagonal branch, is indicated by the asterisk. In (B) the corresponding cross-section of the left anterior descending artery and side branch on IVUS-NIRS is displayed. The non-calcified plaque appears echolucent on IVUS (indicated by the asterisk) and the yellow NIRS signal (the surrounding circle) indicates that the plaque is lipid-rich.
Other lesion features apart from plaque morphology that can be visualized with CTCA include vessel remodeling. IVUS-based studies found that high-risk plaques that cause ACS often show positive, i.e., outward, remodeling of the coronary artery at the lesion site [50]. This IVUS feature can also be visualized with CTCA and the finding has been associated with ACS [51, 52]. Additionally, perivascular adipose tissue can be visualized using CTCA, which can be used as a biomarker for coronary inflammation and thus identify inflamed, vulnerable atherosclerotic plaques [74].
Cardiovascular magnetic resonance (CMR) imaging is often used in cardiovascular medicine to evaluate structural heart disease. CMR is not frequently used in coronary plaque analysis, but it has been used to classify atherosclerotic plaques in the carotid arteries [75]. Therefore, studies have explored the utilization of CMR as a diagnostic tool to identify vulnerable coronary plaques. Károlyi et al. [37] analyzed 28 plaques of donor hearts with CMR with proven CAD. The authors classified lipid-rich plaques as those that appear hypointense on the T2-weighted CMR images, calcified plaques as those with hypointense areas on T1-weighted images, but not on the ultrashort echo time images, and fibrotic plaques as isointense regions on all sequences. This classification system was adapted from that of the carotid artery classification. These CMR classified plaques were then correlated with histopathological findings and it was demonstrated that CMR could adequately distinguish calcified plaques (sensitivity 100% and specificity 90%) and lipid-rich plaques (sensitivity 90% and specificity 75%), suggesting that CMR could be an additional diagnostic tool for coronary plaque analysis.
On a larger scale, Noguchi et al. [76] examined a total of almost 600
patients that had suspected or known CAD who underwent CMR (without contrast) to
investigate whether T1-weighted imaging could identify high-risk coronary plaques
that cause future events. The plaque-to-myocardium signal intensity was
identified as the most important predictor for future coronary events. This
signal intensity ratio itself is incrementally associated with high-risk plaque
morphology [77]. Noguchi et al. [76] used a cut-off value of
Nuclear imaging using radioactive tracers containing a
Another nuclear imaging modality is single positron emission computed tomography (SPECT). There has been a report of the use of SPECT to identify vulnerable plaques with TCFA-like features, mostly focusing on the detection of neovascularization, but evidence for a diagnostic value of SPECT in the vulnerable plaque analysis is limited [81].
Current guidelines recommend lipid-lowering treatment in patients with established coronary artery disease irrespective of low-density lipoprotein (LDL) cholesterol [82]. The abovementioned technological advances in coronary imaging, including the ability to quantify plaque burden, have enabled evaluation of the recommended lipid-lowering treatment. The ASTEROID investigators demonstrated that two years of statin treatment did not only reduced LDL cholesterol, but also led to regression of plaque burden measured by quantitative coronary angiography [83]. Multiple studies using serial IVUS imaging have later reaffirmed that statin therapy can slow disease progression and even promotes plaque regression in a dose-response manner [84, 85, 86].
Novel imaging modalities have also sparked interest in the effects of lipid-lowering treatment on plaque composition, looking beyond mere plaque burden or size to the role of macrophage infiltration (inflammation) and fibrous cap thickness. In the early 2000’s, Crisby et al. [87] demonstrated that statin therapy effects plaque composition. Carotid plaques obtained during endarterectomy from statin-treated patients showed a lower lipid burden and less inflammatory material compared to carotid plaques from non-statin-treated patients, suggesting a plaque stabilizing effect of statin treatment. Other studies have later reiterated that the anti-inflammatory properties of statin therapy can positively impact plaque stability [88, 89]. Multiple studies have also demonstrated that statin treatment can thicken and harden (by calcification) the fibrous cap of lipid-rich plaques, making these plaques less prone for rupture [90, 91, 92, 93, 94].
In patients who do not reach their treatment goal with the maximum tolerated
dose of statin, a cholesterol absorption inhibitor (ezetimibe) or a proprotein
convertase subtilisin kexin type 9 (PCSK9) inhibitor on top of statin treatment
should be considered [82]. Clinical trials have shown the positive effect of
ezetimibe on cardiovascular outcomes in certain subgroups, but data on the effect
of ezetimibe on lipid-rich plaques is limited [95, 96]. PCSK9 inhibitors have also
demonstrated to effectively decrease LDL cholesterol levels and prevent adverse
cardiovascular events in clinical trial and real-world populations [97, 98, 99]. In
statin-treated patients, additional use of PCKS9 inhibitors induced plaque
regression measured by IVUS-imaging in a greater percentage of patients compared
to placebo [100]. Until recently, it remained unclear if administration of PCSK9
inhibitors also effects plaque composition in statin-treated patients [101].
During the ESC Congress 2021 the first results of the HUYGENS study
(ClinicalTrials.gov, identifier NCT03570697) were presented. HUYGENS assessed
whether intensified lipid lowering treatment with PCSK9 inhibitors on top of the
maximally tolerated statins effected the high-risk features of lipid-rich plaques
in 161 patients with non-ST-segment elevation ACS [102]. In total, 135 patients
completed repeated OCT imaging after 12 months of treatment with either a PCSK9
inhibitor (evolocumab) or placebo. More intensive lipid-lowering using a PCKS9
inhibitor resulted in an increase of the minimum fibrous cap thickness and a
decrease in the maximum lipid arc. At 12 months, only one in eight patients
treated with a PCSK9 inhibitor in addition to the maximally tolerated statin dose
had a fibrous cap thickness of
Accumulation of cholesterol within the vessel wall induces inflammation by
activating the innate immune response and is associated with plaque instability
[103]. Therefore, systemic treatment with anti-inflammatory agents might be
beneficiary in patients with coronary artery disease. In recent years especially
the use of colchicine, an anti-inflammatory agent previously only used for
conditions such as pericarditis and gout, has received considerable interest
[104, 105]. Observational studies had already demonstrated that the use of
colchicine was associated with a lower prevalence of MI in patients receiving
colchicine for inflammatory conditions [106, 107, 108]. The open-label LoDoCo trial was
the first randomized controlled trial evaluating the effect of low-dose
colchicine (0.5 mg once daily) in addition to standard secondary prevention
therapies on a composite endpoint of ACS, out-of-hospital cardiac arrest and
ischemic stroke in patients with CCS (n = 532) [104]. Colchicine use drastically
reduced the primary outcome (hazard ratio 0.33; 95% CI 0.18–0.59; p
Despite these aforementioned effects of systemic treatment on stabilization of lipid-rich plaques, it appears that solely a strict systemic lipid-lowering regime and even adding an anti-inflammatory agent might not be enough. Patients on intensive statin therapy, according to treatment allocation in the PROVE IT TIMI 22 trial, had a residual risk for cardiovascular events of roughly 20% during 2 years follow-up [114]. This stresses the need for an additional, more local treatment of vulnerable plaques.
The recently published PROSPECT ABSORB trial explored local treatment of
vulnerable plaques by stenting with a bioresorbable vascular scaffold (BVS) [64].
The rationale of this study was based on a previous study where OCT images were
assessed after BVS or bare-metal stent implantation of TCFAs and a potential
beneficial effect on plaque stabilization was suggested since neo-intimal tissue
development was observed after short- and mid-term follow-up [115]. The idea was
that this would lead to thickening of the fibrous cap overlying the lipid pool
and a decrease of wall shear stress, resulting in a reduction of plaque rupture
or erosion. BVS was considered to be able to obtain similar neointimal response
and shear stress reduction as DES [116, 117]. It was preferred over DES since it
was observed that the neointimal response caused by BVS led to smaller compromise
of the coronary lumen than with bare-metal stent, plus it would overcome the
placement of a permanent stent [115]. The PROSPECT II study, as discussed above,
enrolled almost 900 patients with ACS to perform 3-vessel IVUS-NIRS after
treatment of every flow-limiting stenosis [28]. All patients that had
non-obstructive plaques with a plaque burden greater than 65% on IVUS, the study
definition for vulnerable plaque, in the PROSPECT II study were included in the
PROSPECT ABSORB trial and randomized to medical therapy or BVS treatment of the
identified vulnerable plaque [64]. Randomized patients underwent follow-up
angiography after 25 months with repeat IVUS-NIRS and it was found that the
minimum luminal area was greater in patients treated with BVS (7 mm
A major concern of local treatment of a lipid-rich plaque is the risk for distal embolization of the lipid pool and potential periprocedural MI [119, 120]. However, no procedural MI occurred in the entire PROSPECT ABSORB trial, and the primary safety endpoint of target-lesion failure (consisting of cardiac death, target-vessel related MI or target-lesion revascularization) was equal between randomization groups.
Still, implantation of a stent or scaffold in non-flow-limiting, thus
non-ischemic, plaques could introduce potential harms of a new, stent-related
“disease” such as stent thrombosis or in-stent restenosis that would otherwise
not occur. Therefore, the DEBuT-LRP study (ClinicalTrials.gov, identifier
NCT04765956) is currently investigating the safety and efficacy of treatment of
lipid-rich plaques with a drug-coated balloon (DCB). An animal study demonstrated
that in cholesterol-fed rabbits with balloon-injury-induced lesions in the aorta,
angioplasty with a paclitaxel-coated balloon led to a higher reduction of
inflammation and plaque burden than plain balloon angioplasty [121]. Human
studies confirmed that DCB treatment led to plaque burden reduction and even an
increase of the fibrous cap thickness [122, 123]. Thus DCBs are a proven
alternative to stenting for several indications, but could now also play a role
in the treatment of lipid-rich plaques [124]. The DEBuT-LRP study aims to enroll
40 patients with NSTE-ACS that will subsequently undergo 3-vessel IVUS-NIRS and a
lipid-rich plaque (i.e., maxLCBI
| Systemic treatment | Local treatment | ||||
| Lipid-lowering drugs | Anti-inflammatory drugs | Bioresorbable vascular scaffold | Drug-eluting stent | Drug-coated balloon | |
| Plaque features* | ↑ Fibrous cap thickness [90, 91, 92, 93, 94] | ↓ Inflammation [125] | ↑ Fibrous cap thickness [115] | ↑ MLA [117] | ↑ Fibrous cap thickness [122, 123] |
| ↓ Plaque burden [83, 84, 85, 86] | ↑ MLA [116, 117] | ↓ Plaque burden [121, 122, 123] | |||
| ↓ Inflammation [88, 89] | ↓ Inflammation [121] | ||||
| Clinical endpoints | ↓ MACE [95, 96, 97, 98, 99, 126] | ↓ MACE [104, 105, 110] | - | - | - |
| MACE, major adverse cardiovascular events; MLA, minimum luminal area. * Effect on (vulnerable) plaque features based on imaging studies. | |||||
ACS mostly arises from rupture or erosion of a vulnerable plaque. Vulnerable plaques typically appear as lipid-rich plaques with a thin cap, called TCFA. These vulnerable plaques can be detected using intracoronary imaging and possibly also with non-invasive imaging techniques. Currently, the implantation of a stent or scaffold for the treatment of vulnerable plaques has been found to be safe and to stabilize high-risk plaque features. Future studies should focus on optimizing imaging techniques and evaluating the effectiveness of vulnerable plaque stabilization on clinical endpoints.
AvV and NMRvdS wrote the manuscript with support from JPSH and BEPMC. All authors read and approved the final manuscript.
Not applicable.
Thanks to all the peer reviewers for their opinions and suggestions.
This research received no external funding.
The authors declare no conflict of interest.