Tabla 1. Current studies using various intravascular imaging modalities to identify vulnerable plaq...

Tabla 2. interventional randomized controlled studies to assess vulnerable plaque/lesions. Sample ...

Introduction

Nearly 50 years ago, pathologists convened at a National Institutes of Health workshop along with cardiologists, researchers and hematologists and agreed in consensus that coronary thrombosis was the primary cause of transmural myocardial infarction (MI) and most cases of sudden cardiac death [1]. Pathologically, it had been shown that a tear in a lipid-rich atherosclerotic plaque was the main cause for thrombus formation and these plaques became known as thin-capped fibroatheromas or TCFAs for short [2,3]. Additional data based on pathologic analysis at autopsy indicated that the TCFA, a combination of a large lipid-rich necrotic core covered by a thin fibrous cap (< 65 μm) infiltrated with macrophages and lymphocytes, was the culprit in most cases of fatal MIs described above while another mechanism called plaque erosion could be seen in up to 1/3 of cases [4,5]. While pathologists had reached consensus, it took until 1980 for De Wood et al. to conclusively show that thrombus caused acute transmural MI in living patients [6]. The terminology for MI has, of course, changed since then but clinicians routinely are confronted with ST-elevation MI (STEMI) and Type 1 non ST-elevation MI (NSTEMI) caused by atherothrombosis [7]. But what type of plaque was responsible in-vivo for the MI? Prior to the utilization of intravascular imaging, there was only speculation but no definitive answer. The TCFA was suspected based on the pathological data, but unproven.

In 1989, Muller et al introduced the concept of a vulnerable plaque (VP) as one prone to disruption and thrombosis [8]. A later definition for a VP or high risk plaque (HRP) which were considered equivalent terms indicated that not every intracoronary thrombus caused by plaque disruption necessarily led to a symptomatic event but to plaque progression [9]. A VP was originally coined by Muller et al. to explain why certain plaques in patients led to acute coronary syndromes. Why was MI more prevalent in the early morning hours or after some type of stress? Furthermore, patients experiencing fatal or non-fatal myocardial infarction were not just those at high risk as defined by the presence of conventional risk factors [10]. Other investigators showed that MIs often evolved on angiography from plaques that were non-obstructive prior to the event [11,12]. What was the angiogram hiding?

Traditionally, cardiologists were more concerned with significant obstructive rather than non-obstructive disease on angiography as in early angiographic studies, prognosis was related to the number of diseased vessels with significant, angiographic luminal disease [13]. Yet treating significant disease even with revascularization in some randomized trials reduced angina and improve quality of life but did not always decrease subsequent death or infarction [14,15]. This article discusses the in vivo identification of these thrombosis-prone, vulnerable atherosclerotic plaques as well as the potential therapies/strategies that are available or might be available in the future to prevent subsequent acute coronary events.

Intravascular Imaging

While coronary angiography continues to be the usual method for the invasive detection of coronary anatomy, it cannot detect VP given its inability to define the anatomical vessel wall being only a “lumenogram” of the coronary artery. The in-vivo identification of TCFAs as potential VPs has been possible and greatly facilitated by intracoronary, catheter-based imaging as well as by non-invasive coronary CT imaging which will be covered in the next section. All established invasive techniques have been validated experimentally to define certain aspects of plaque anatomy. A brief discussion of each device is contained in the following section.

Angioscopy was the first technique miniaturized and able to define the internal surface of the coronary artery. Light emitted by a flexible fiber bundle endoscope, passed over an angioplasty wire (as are all devices) could interrogate the surface anatomy of the coronary artery when the catheter was flushed with saline and temporary proximal balloon occlusion of the lumen carried out. Yellow plaques and particularly glistening yellow plaques were representative of TCFAs [16].

Intravascular ultrasound (IVUS) provided a cross section of the coronary artery and did not require a blood free field of view. It defined plaque burden, vessel size, positive/negative remodeling and vessel wall calcification [17]. Its resolution of 100 to 150 μm and negative signal with a lipid core make it incapable of defining TCFA lipid and a thin cap. The IVUS signal was modified and VH (virtual histology) IVUS was developed and utilized in the PROSPECT study to identify TCFAs [18]. This technique has been subsequently criticized as inaccurate for TCFA identification and is no longer utilized for this purpose [19].

Optical coherence tomography (OCT) uses infrared light to define plaque anatomy with a higher resolution (10 to 15 μm) than IVUS but lower penetration to define vessel size in larger arteries. While it requires contrast flush to visualize plaque structures, it can accurately identify intracoronary thrombus, plaque rupture versus plaque erosion, fibrous cap thickness and presumably plaque lipid and inflammation [20].

Near Infrared Spectroscopy (NIRS) is the most accurate for defining plaque lipid by detecting the chemical signal of cholesterol and its esters [21]. NIRS cannot generate a 3 dimensional image so it has been co-registered with IVUS in a combined catheter which has been used in natural history studies [22]. Lipid-rich plaques are defined by a maximum lipid-core burden image. While IVUS-NIRS is the only Federal Food and Drug Administration approved intracoronary imaging technique for detecting VPs, it cannot accurately measure cap thickness. An investigational combination catheter of OCT and NIRS is in development. There are other concept catheters in various stages of development including micro OCT and near infrared fluorescence [23].

Non-Invasive Imaging

The advent of newer, sophisticated non-invasive technology has led to the early identification of coronary artery disease (CAD) and coronary ischemia before adverse events occur. Coronary computerized tomographic angiography (CCTA) has been at this forefront by providing rapid, accurate anatomical assessment in patients with suspected CAD. In addition to its ability to detect the degree of coronary artery stenosis, several high-risk CCTA plaque features have been associated with adverse outcomes, independent of the degree of anatomic obstruction. These features include low attenuation plaque (LAP), positive remodeling (PR), ‘napkin ring’ sign, and/or the presence of spotty calcifications [24,25]. We describe several studies that demonstrate this relationship.

Motoyama et al. examined the relationship of HRP on CCTA with the incidence of acute coronary syndrome (ACS), both with and without significant coronary artery stenosis [26]. Over a mean period of 3.9 years, a 2.8% overall ACS event occurred. Those with high-risk CCTA features were more likely to have an ACS event (16.3% vs 1.4%). Furthermore, when stratified to patients with high risk CCTA features and no significant coronary artery stenosis (< 70%), ACS occurred in 14.9% of patients versus 0.6% without any high risk features or significant stenosis (adjusted hazard ration [HR] 13.13; 95% CI: 3.80-82.66). Nested observational data from over 4,415 patients in the PROMISE trial via core lab adjudication looked specifically at HRP features on CCTA, as described above [27]. Patients with high risk features had significantly higher major adverse cardiovascular events (MACE) on follow-up, 6.4% vs 2.4% with HR 2.73. This was still present despite controlling for atherosclerotic cardiovascular disease (ASCVD) risk scoring and the presence of significant coronary artery stenosis, HR 1.72 (95% CI: 1.13-2.62). High risk CCTA characteristics also were a significant strong predictor of worse outcomes in women and younger individuals. It is worth noting that overall event rates were low in data from the PROMISE trial, totaling to 3% or just 131 events over the study media time period of 25 months. More recently, the SCOT-HEART trial compared the use of CCTA to the usual standard of care in the low to intermediate risk population with chest pain [28]. Post-hoc analysis of this trial with 1,769 patients followed for a median length of 4.7 years demonstrated LAP as the strongest predictor for MI with HR of 1.60 [29]. This was irrespective of ASCVD risk score, coronary calcium score, or coronary artery stenosis. Patients with a > 4% LAP burden had almost five times increased risk of MI, HR 4.65 (95% CI: 2.06-10.5).

The uptake of CT fractional flow reserve (FFR) has been observed in the last few years as a hemodynamic alternative to traditional invasive assessment in the cardiac catheterization lab. Sub-analysis from the 3V FFR FRIENDS study [30] examined 772 vessels by CCTA, CT-FFR and invasive FFR. A subsequent analysis compared HRP features and their relationship to adverse outcomes [31]. These researchers found that when revascularization was deferred, due to invasive FFR > 0.80, if three or more HRP features were seen on CCTA, a fourfold significant increase in composite adverse outcomes was observed at 5 years (odds ratio 4; 95% CI: 1.464-10.920). These subsequent outcomes were patient-related and primarily ischemic revascularization rather than MI or cardiac death.

While HRP on CCTA identifies vulnerable patients i.e. those at high risk for a subsequent acute event, can CCTA identify the actual plaque at high risk of the thrombotic event? There are only limited data to address this question. The ICONIC study, a nested case control study with a cohort of over 25000 patients undergoing CCTA with a follow up period of 3.4 years identified 234 patients with a subsequent ACS [32]. These were propensity matched 1:1 for several risk factors and CCTA obstructive disease. More than 65% of patients with ACS had non obstructive disease at baseline and 52% had high risk plaque. However, of 129 culprit lesion precursors of ACS identified by comparing the location of the ACS event on subsequent angiography to the CCTA lesion site at baseline, three-fourths were non obstructive on CCTA but only 31% exhibited a baseline HRP. More data are needed in this area as this will be critical in the identification of the actual vulnerable plaque if a local approach could ever be contemplated.

Another aspect of CT technology that has been adapted into clinical practice is the ability to quantify overall coronary artery calcium (CAC) score, typically in Agaston units (AU). The presence of CAC itself, even in relatively younger, asymptomatic patients can portend an increased risk for ACS and sudden cardiac death [33]. In a prospective observational study where CAC scoring was added to the Framingham Risk Score (FRS) to estimate a patient’s risk for ASCVD, CAC > 300 was predictive for a significant increased risk of adverse outcomes in patients across all ASCVD risk levels > 10%, when using the FRS algorithm [34]. Some of our largest data on CAC and its implication for cardiovascular events in asymptomatic patients comes from the Multi-Ethnic Study of Atherosclerosis (MESA). 10 year follow up data from this population based, prospective cohort study shows an incremental increase in adverse events (cerebrovascular accident, cardiovascular death, or non-fatal MI) with higher amounts of CAC [35]. At 10 years, CAC ≥ 100 and CAC > 300 were associated with approximately 7.5% and 13.1-25.6% risk for these adverse outcomes.

On the other hand, almost all patients with CAC = 0 had < 5% risk for these events [34]. Thus, giving way to the ‘power of zero’ concept. This is mirrored in another 10 year follow up study from the MESA cohort where CAC of 0 was the strongest ‘negative risk factor’ when compared to other potential favorable characteristics for ASCVD [36]. These favorable characteristics included an absence of carotid plaque, low carotid intima-media thickness, normal ankle-brachial index, and normal serum biomarkers associated with ASCVD. Therefore, cardiac CT demonstrating a CAC score of 0 can play a powerful role in primary prevention and identify those at the lowest risk for cardiovascular events. However, there are still patients with CAC of 0 who incur cardiovascular events where the presence of traditional risk factors such as weight loss, activity, and tobacco cessation should be aggressively managed to mitigate subsequent risk [37].

CCTA will likely continue to evolve and play an important role in further identifying at risk patients before adverse cardiovascular events occur. This modality can highlight the importance of plaque morphology, composition, and extra-luminal findings that are not appreciated using traditional angiography without intravascular imaging. Therefore, CCTA data support the concept of the vulnerable plaque, which is prone to subsequent adverse events even in a non-obstructive disease. Other imaging techniques have been utilized in the hunt for high risk coronary plaques including cardiac magnetic resonance imaging (CMR) and positron emission tomography (PET), but the data are limited and particularly with CMR, its sensitivity for detection is inferior to that of CCTA imaging [38].

Local vs. Systemic Therapy

for Vulnerable Plaque

There has been great interest in the literature concerning the best treatment for VPs or vulnerable patients to prevent future significant adverse coronary events. As mentioned in the introduction, how should one best prevent thrombotic events? Should one either just promote life-style modifications in primary or primordial prevention, combine this with medications such as statins administered as per guidelines or prescribed earlier in the natural history of coronary disease? In certain patients primarily in secondary prevention, could there be a hybrid interventional/medication approach?

Interventional Approach

to Vulnerable Plaque

The interventional approach is based on the presumption that local or regional therapy with modern stent platforms or some other technology to a vulnerable plaque could potentially prevent subsequent thrombotic events. But this hypothesis demanded randomized trial data. In 2008, Ambrose proposed prerequisites for this approach. This needed three requirements: 1) define a VP based on its natural history, 2) prove that an interventional approach reduced subsequent events better that optimal medical management alone, and 3) define the number needed to treat to indicate that his approach was reasonable and cost effective [39].

Prior to considering an interventional approach to VP, there have been multiple natural history studies published over the last several years in which non culprit invasive interrogation of one or more coronary arteries was attempted during percutaneous intervention of a culprit lesion [16,18,22,40-42]. In each case, interrogation was performed with different intravascular imaging techniques and the patients followed up (Table 1 for plaque-related events). Plaque and patient-related events were recorded. Plaque-related events (adverse event at the lesion site) required repeat angiographic analysis. End points were not exclusively thrombotic events and varied between trials but could include progressive or unstable angina. The type of MI was not always categorized (STEMI vs. NSTEMI, or even which type of NSTEMI 1 to 5). Medical management varied in the trials with higher events noted in trials with less attention to optimal lipid levels on follow up. Follow up also varied from 1 year in CLIMA and Uchida et al. to about 6 years in Kubo et al. (Table 1).

The following conclusions can be drawn from these trials:

1. In patients not optimally managed post procedure by present standards, a VP will often cause myocardial infarction at the lesion site on follow up. This was seen in both Uchida et al. and Kubo et al. trials.
2. In other trials, thrombotic events (MI or cardiac death) at VP sites were documented in only a very small percentage of the total number of VPs (< 5%) but may be slightly higher when plaque burden or lipid arc was large or minimal lumen area small. In CLIMA, the thrombotic event rate at the lesion site on 1 year follow-up was 19.4% (7 of 36) when all 4 high risk OCT criteria were present but the specific criteria required were seen in only 3.7% of the total population.
3. In general, the presence of a VP anywhere, similar to what has been reported with CT angiography, increased the number of patient-related events on follow up.

   New interventional trials are presently on-going [44-46] and include PREVENT, COMBINE-INTERVENE and INTERCLIMA to assess if stenting and optimal medical therapy vs. optimal medical therapy alone will reduce subsequent events (Table 2). Even drug eluting balloons are being assessed as a no stent option to treat vulnerable lesions [47]. Already, a pilot study has randomized a small number of patients to an interventional vs. conservative management strategy. In a sub study of PROSPECT 2 called PROSPECT ABSORB, 182 patients with VPs and a high plaque burden (≥65%) but non obstructive on angiography were randomized to a bioabsorbable vascular scaffold and guideline-directed medical therapy vs medical therapy alone and restudied at 2 years with imaging [48]. The scaffold was associated with neointimal thickening and reduced lipid plaque content on imaging follow-up. There was also a >50% reduction in adverse events at the 4 year follow-up with the scaffold (4.3% vs. 10.7%) vs. medical management alone although not statistically significant.

   One would hope that all future trials or natural history studies would be large enough, have long term (several years) follow up for events and similar end points. We believe that the end points should be primarily either STEMI, Type 1 NSTEMI or cardiovascular death (all presumed thrombotic events) in order to convince the cardiology community that an interventional approach might be warranted on non-culprit, VPs that are non-obstructive and require invasive imaging to diagnose. It is debatable whether a Type 2 NSTEMI without documented evidence of lesion progression should be an appropriate end point for a VP trial as Type 2 infarcts can be seen even without significant coronary artery disease [49].

   Finally, can a local or regional interventional strategy be a first line approach to prevent subsequent serious events? The answer is likely no. Even if the on-going interventional approaches are positive with reduced events in the interventional arm, there are several reasons why we believe its use would be limited. These include the following:

   The initial presentation of CAD if often STEMI or sudden death [50]. Presently, there is nothing to support an interventional approach in primary prevention.

   Given the overall number of TCFAs, based on the published natural history studies with optimum medical management on follow-up, the number needed to treat will likely be too high (only a small percentage will manifest a symptomatic thrombotic event) to routinely intervene on all such plaques [39].

   Plaque erosions are responsible for at least 1/3 of STEMI and Type 1 NSTEMI patients and the underlying plaque type is not a TCFA [50]. Thus, finding a subsequent plaque erosion will be challenging and not presently possible.

   Convincing interventionalists to routinely perform and interpret imaging of non-culprit vessels for TCFA identification during percutaneous coronary intervention of an index culprit lesion is, in our opinion, a significant challenge based on imaging reimbursement issues, fear of imaging complications, duration of index procedure etc.

   The development and use of better non-invasive techniques and medical strategies for vulnerable plaque detection/therapy will limit the interventional approach.

   Systemic Therapy for Vulnerable

   Plaques

   Can systemic therapy alone stabilize a VP or prevent a VP from forming? There are several studies which have shown that lipid lowering with high dose statins and/or PCSK-9 inhibition can increase fibrous cap thickness and possibly even reduce lipid content of plaques considered vulnerable [51]. However, are we treating patients too late in the natural history of coronary artery disease to make a difference [52]? Even PCSK-9 trials indicated no more than a 15% reduction in events on follow up [53]. The answer may be in the timing of our interventions. Trials and guidelines encourage an optimum life style but consider lipid lowering only at age ≥40 unless baseline LDL is ≥190 mgs/dl [54]. However, asymptomatic atherosclerosis precedes by decades the symptomatic manifestations of disease. Perhaps, non-invasive imaging with coronary artery calcium scores or some other non-invasive technique could be used as a simple screening test to identify sub clinical disease in patients < 40 years of age in those deemed at high risk. It has been suggested in a large cohort of young patients in the CAC Consortium, 30 to 50 years of age undergoing non contrast CT with or without risk factors that the ideal age for detecting a CAC>0 in men with risk factors was about 37 years of age and in women with diabetes at age 50 [55]. Lipid lowering would be considered if scores were >0. Of course, this is only hypothesis generating and a score of 0 might still under estimate coronary artery disease burden. Such a proposal would require a large randomized trial with long term follow up to assess a reduction in adverse events.

   Conclusions

   The recent data support the concept that VPs are an important cause of subsequent symptomatic thrombotic events. While on-going trials are exploring a localized or regional approach, it is more likely that a non-invasive approach will be more efficacious in most patients. This non- invasive approach is yet to be precisely defined but should include early diagnosis (perhaps imaging) and appropriate medical and lifestyle management. However, a limited role for a localized strategy is still possible pending trial results. With the current interest in this subject, the next several years should provide greater insight and hopefully more evidence-based solutions.

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