Update on acute coronary syndromes: the pathologists' view

Clinical features and lipid profiles of plaque erosion over lipid-rich plaque versus fibrous plaque in patients with acute coronary syndrome

Plaque disruption generally occurs in the setting of a thin cap fibroatheroma morphology, characterized by a large necrotic lipid core, intense macrophage infiltration, microcalcifications, and a thin fibrous cap,1 but it has recently become clear that characterization of plaque risk based on anatomy alone is necessary but not sufficient to predict those high-risk plaques likely to destabilize and cause a new clinical event. Using the baseline anatomic plaque characteristics of large plaque burden, small minimal lumen area, and thin cap fibroatheroma morphology, the major long-term natural history follow-up studies have generally demonstrated a major adverse cardiac event (MACE) rate ≤20% over 1 to 3 years of follow-up.2–6 The low positive predictive accuracy of these ostensibly high-risk plaques for subsequent adverse clinical events based on plaque anatomy alone is likely related to inadequate assessment of the true vulnerability of an individual plaque by current imaging modalities utilizing intravascular ultrasound (IVUS), optical coherence tomography, or near-infrared spectroscopy and the fact that the majority of high-risk plaques continue to evolve over time and become quiescent,7,8 so that an imaging snapshot at a single point in time does not adequately represent the natural history path of that particular plaque. See Article by Brown et al A variety of innovative in vivo approaches are being actively pursued to go beyond assessment of plaque anatomy alone to identify which apparent high-risk plaques based on anatomy will actually progress to cause a new MACE in follow-up. Candidate in vivo approaches include assessment of active inflammation within plaques by identifying ongoing local …

Objective: Culprit plaque morphology in young acute coronary syndrome (ACS) patients differs from that of elder patients. The underlying mechanisms responsible for ACS in younger compared to elder patients are yet to be explored with optical coherence tomography. Methods: This was a prospective, single-center, investigational study. Patients were divided into groups according to age, ≤35 (N=43) and >35 years (N=50) and further subdivided according to the underlying mechanism i.e. plaque rupture (PR) and plaque erosion (PE). Results: A total of 93 patients were included in this analysis. Thin-cap fibroatheroma (TCFA) was significantly higher among elder than younger patients for both PR (80.0% vs. 31.8%, p=0.002) and PE (66.7% vs. 6.3%, p<0.001) groups. Microchannels were also significantly more prevalent among elder than younger patients for both PR (65.0% vs. 18.2%, p=0.004) and PE groups (55.6% vs.12.5%, p=0.013). Macrophages were significantly higher in elder than younger patients for both PR (25.0% vs. 0%, p=0.018) and PE (44.4% vs. 0%, p=0.003) groups. In contrast, fibrous cap thickness was greater in younger than elder patients for both PR (105.71±48.02 μm vs. 58.00±15.76 μm, p<0.001) and PE (126.67±48.22 μm vs. 54.38±24.21 μm, p<0.001) groups. Intimal thickness was greater in elder than younger patients for both PR (728.00±313.92 mm 2 vs. 342.27±142.02 mm 2 , p<0.001) and PE (672.78±334.57 mm 2 vs. 295.00±99.60 mm 2 , p<0.001) groups. Plaque type, thrombus formation, and minimal luminal diameter did not differ significantly according to age. Conclusion: We conclude that the high resolution of OCT is able to define the detailed microstructure of the culprit lesion and allows a greater understanding of the mechanisms of coronary artery disease. The frequency of TCFA, microchannels, macrophages, and intimal thickness was significantly higher in elder ACS patients compared to younger patients. However, fibrous cap thickness was significantly greater in younger ACS patients compared to elder patients.

We used optical coherent tomography (OCT) and virtual histology intravascular ultrasound (VH-IVUS) to assess culprit lesions in 146 Korean pts with acute coronary syndrome (ACS). Methods: Culprit lesion plaque rupture (PR) or plaque erosion (PE) was diagnosed with OCT; and IVUS was used to determine arterial remodeling. PE (n=56) was the presence of intracoronary thrombus attached to the luminal surface with no detectable signs of fibrous cap rupture that was seen in 90 ACS pts with PR. Positive remodeling was a remodeling index (lesion/reference EEM [external elastic membrane] area) >1.05. Results: Pt age was 60±12 yrs in PR and 62±11 yrs in PE; 19% of PR vs 18% of PE were females. Overall, 25% (14/56) of PE had non-ST elevation myocardial infarction (NSTEMI) and 34% (19/56) had STEMI; conversely, 14.4% (13/90) of PR had NSTEMI and 71% (64/90) had STEMI (p<0.0001). Vessel size, minimal lumen area, and lumen area at the PR or PE site were similar; however, lesion length was longer in PR. Plaque area was smaller with negative remodeling in PE while PR showed positive remodeling with a larger necrotic core area by VH-IVUS (Table). By OCT, PE were fibrotic in 50% (28/56), fibrocalcific in 16% (9/56), and lipidic in 32.1% (18/56, all but one of which was a thick cap fibroatheroma). Conclusion: Multimodality intravascular imaging with OCT and VH-IVUS showed fundamentally different pathoanatomic substrates underlying plaque rupture and erosion in Asian pts.

The most common cause of acute coronary syndrome (ACS) is rupture of an atherosclerotic lesion containing a large necrotic core and a thin fibrous cap followed by acute luminal thrombosis because the rupture of the thin fibrous cap allows contact of the platelets with the highly thrombogenic necrotic core. Pathologic studies have suggested that the precursor of the ruptured plaque is the so-called thin cap fibroatheroma (TCFA). Unfortunately, true natural history studies of TCFAs and their transition to ruptured plaques are rare. Most of the data and concepts have been inferred from studies performed at a single point in time. Intravascular ultrasound (IVUS) studies have shown ruptured plaques in approximately two thirds of ACS culprit lesions and occur in predictable locations. The features that differentiate secondary, nonculprit plaque ruptures from those that cause ACS events appear to be superimposed thrombosis and lumen compromise, either from the thrombus or from the underlying lesion. Secondary plaque ruptures appear to heal with optimal medical therapy. In vivo definitions of TCFAs have been derived from pathology study to include positive remodeling, a fibrous cap less than 100 microm (and perhaps <65 microm) at its minimum thickness, macrophage infiltration especially in the thin fibrous cap, a large lipid/necrotic core often containing hemorrhage and/or speckled or diffuse calcification (not enough to increase plaque stability although the absence of any calcium is also rare in rupture-prone plaques), and abundant intraplaque vasa vasorum and/or hemorrhage. Early data from in vivo imaging have substantiated the pathologic observations, but have also suggested that spontaneous stabilization of TCFAs with medical therapy alone is possible.

Despite the significant decline in cardiovascular mortality in women over the past several decades, sex differences in the underlying pathology of acute coronary syndromes remain poorly understood. Previous postmortem studies have demonstrated sex differences in coronary plaque morphology with a higher prevalence of plaque erosion in young women and more plaque rupture in older women after menopause, whereas men showed no increase in prevalence of plaque rupture with age. However, in vivo data are limited. This study included patients who presented with acute coronary syndrome and underwent preintervention optical coherence tomography imaging of the culprit lesion. The culprit plaque was categorized as plaque rupture, plaque erosion or culprit plaque with calcification, and stratified by age. Features of plaque vulnerability at culprit lesion were also analyzed. In 1368 patients (women=286), women and men had a similar distribution of culprit plaque morphology (plaque rupture versus plaque erosion). However, significant sex differences were found in the underlying mechanisms of acute coronary syndrome among different age groups: women showed a significant ascending trend with age in plaque rupture (P<0.001) and the features of plaque vulnerability such as lipid plaque (P<0.001), thin-cap fibroatheroma (P=0.005), and microstructures including macrophages, cholesterol crystals, and calcification (P=0.026). No trend was observed in men. Age related sex differences in culprit plaque morphology and vulnerability were identified in patients with acute coronary syndrome: prevalence of plaque rupture and vulnerability increased with age in women but not in men. URL: https://www. gov; Unique identifier: NCT01110538 and NCT03479723.

Pancoronary plaque vulnerability in patients with acute coronary syndrome and ruptured culprit plaque: A 3-vessel optical coherence tomography study

Background and ObjectivesWe assessed plaque erosion of culprit lesions in patients with acute coronary syndrome in real world practice.Subjects and MethodsCulprit lesion plaque rupture or plaque erosion was diagnosed with optical coherence tomography (OCT). Intravascular ultrasound (IVUS) was used to determine arterial remodeling. Positive remodeling was defined as a remodeling index (lesion/reference EEM [external elastic membrane area) >1.05.ResultsA total of 90 patients who had plaque rupture showing fibrous-cap discontinuity and ruptured cavity were enrolled. 36 patients showed definite OCT-plaque erosion, while 7 patients had probable OCT-plaque erosion. Overall, 26% (11/43) of definite/probable plaque erosion had non-ST elevation myocardial infarction (NSTEMI) while 35% (15/43) had ST elevation myocardial infarction (STEMI). Conversely, 14.5% (13/90) of plaque rupture had NSTEMI while 71% (64/90) had STEMI (p<0.0001). Among plaque erosion, white thrombus was seen in 55.8% (24/43) of patients and red thrombus in 27.9% (12/43) of patients. Compared to plaque erosion, plaque rupture more often showed positive remodeling (p=0.003) with a larger necrotic core area examined by virtual histology (VH)-IVUS, while negative remodeling was prominent in plaque erosion. Overall, 65% 28/43 of plaque erosions were located in the proximal 30 mm of a culprit vessel-similar to plaque ruptures (72%, 65/90, p=0.29).ConclusionAlthough most of plaque erosions show nearly normal coronary angiogram, modest plaque burden with negative remodeling and an uncommon fibroatheroma might be the nature of plaque erosion. Multimodality intravascular imaging with OCT and VH-IVUS showed fundamentally different pathoanatomic substrates underlying plaque rupture and erosion.

Once atherosclerosis develops, stenosis (or occlusion) may occur in the lumen of various arteries of the living body. This can lead to a range of conditions, including myocardial infarction, cerebral infarction, aortic aneurysm and peripheral artery disease. The acronym 'ATIS' (AtheroThrombosIS) is a collective term for diseases characterized by a common course of development based on atherosclerosis. This article reviews pathological findings in atherothrombotic lesions of human coronary, carotid, and vertebrobasilar arteries as well as leg arteries and veins. Histologically, atheromatous plaques of coronary arteries can broadly be typed as fibrous and lipid-rich (atheromatous). Macroscopically, fibrous plaque has a whitish appearance and is composed of smooth muscle cells and collagen fibres. Lipid-rich (atheromatous) plaque, on the other hand, appears yellow macroscopically, with the superficial layer (closer to the lumen) having a white fibrous cap which covers the atheroma. This fibrous cap is quite thin and is likely to rupture. Typical pathological features of such atherothrombosis are narrowing of the vascular lumen due to lipid-rich (atheromatous) plaque, and thrombus formation due to a broken fibrous cap. Such plaque rupture is the underlying cause of acute myocardial infarction in about 70% of patients, while acute myocardial infarction in the remaining patients (30%) results from plaque erosion. In cases of plaque erosion, atheroma is seldom seen, and atherosclerosis manifests in a full-circumferential manner, resulting in thrombus formation due to endothelial cell injury and eventually leading to obstructive thrombi. Thus, thrombus formation associated with myocardial infarction is attributable to plaque rupture if the lesion contains a lipid-rich (atheromatous) plaque. In cases where plaques cause particularly intense injury of endothelial cells, plaque erosion is likely to occur, resulting in formation of obstructive thrombi within the vascular lumen. Primary factors involved in the evolution of ATIS are injury of vascular endothelial cells, inflammation of a vulnerable plaque and intra-plaque haemorrhage. ATIS in other vascular systems has similar pathological features. The continued increase in the aged population and the morbidity of lifestyle-related diseases will make more cases of ATIS intractable. It will be of paramount importance to prevent intractable ATIS in the future.

Characterizing silent plaque ruptures in non-infarct related vessels of patients with AMI: a pooled, multimodality, serial intracoronary imaging study

Antiplatelet agents and statin therapies are widely used in patients with known cardiovascular disease. Plaque rupture (PR) and plaque erosion (PE) are the most frequent underlying mechanisms of acute coronary syndromes (ACS). The conditions and medications that are associated with ST-segment elevation myocardial infarction (STEMI) following PR or PE have not been systematically studied. A total of 838 ACS patients (494 with STEMI, 344 with NSTE-ACS) who were diagnosed with PR or PE by optical coherence tomography were included. The patients were categorized into two groups based on underlying pathology, and the baseline characteristics and culprit plaque morphology associated with STEMI were investigated within each group. Among 838 patients, 467 (55.7%) had PR, and 371 (44.3%) were diagnosed with PE. Among patients with PR, older age, hyperlipidemia, no antiplatelet therapy, higher level of low-density lipoprotein cholesterol, and greater lipid burden and macrophage infiltration were associated with increased probability of STEMI. Among patients with PE, no dual antiplatelet therapy and no statin therapy were associated with increased probability of STEMI. The incidence of STEMI caused by PR was significantly lower on antiplatelet therapy (P < 0.001), and the incidence of STEMI caused by PE was significantly lower on antiplatelet therapy (P < 0.001) or on statin therapy (P < 0.001). Antiplatelet therapy is associated with lower probability of STEMI, regardless of underlying pathology, and statin therapy is associated with lower probability of STEMI in PE as clinical presentation of ACS. Statin therapy prior to the onset of acute coronary syndromes (ACS) may reduce the probability of plaque rupture. Antiplatelet therapy prior to the onset of ACS is associated with reduced probability of ST-segment elevation myocardial infarction (STEMI) following both plaque rupture and plaque erosion, and dual antiplatelet therapy offers additional protection compared to a single antiplatelet agent in plaque erosion. The combination of statin and antiplatelet therapy may have an additive effect on reducing the probability of STEMI caused by plaque erosion. Yellow: lipid pool(necrotic core); red: fibrin-rich thrombus; gray; platelet-rich thrombus.

To investigate local haemodynamics in the setting of acute coronary plaque rupture and erosion. Intracoronary optical coherence tomography performed in 37 patients with acute coronary syndromes caused by plaque rupture (n = 19) or plaque erosion (n = 18) was used for three-dimensional reconstruction and computational fluid dynamics simulation. Endothelial shear stress (ESS), spatial ESS gradient (ESSG), and oscillatory shear index (OSI) were compared between plaque rupture and erosion through mixed-effects logistic regression. Lipid, calcium, macrophages, layered plaque, and cholesterol crystals were also analysed. By multivariable analysis, only high ESSG [odds ratio (OR) 5.29, 95% confidence interval (CI) 2.57-10.89, P < 0.001], lipid (OR 12.98, 95% CI 6.57-25.67, P < 0.001), and layered plaque (OR 3.17, 95% CI 1.82-5.50, P < 0.001) were independently associated with plaque rupture. High ESSG (OR 13.28, 95% CI 6.88-25.64, P < 0.001), ESS (OR 2.70, 95% CI 1.34-5.42, P = 0.005), and OSI (OR 2.18, 95% CI 1.33-3.54, P = 0.002) independently associated with plaque erosion. ESSG was higher at rupture sites than erosion sites [median (interquartile range): 5.78 (2.47-21.15) vs. 2.62 (1.44-6.18) Pa/mm, P = 0.009], OSI was higher at erosion sites than rupture sites [1.04 × 10-2 (2.3 × 10-3-4.74 × 10-2) vs. 1.29 × 10-3 (9.39 × 10-5-3.0 × 10-2), P < 0.001], but ESS was similar (P = 0.29). High ESSG is independently associated with plaque rupture while high ESSG, ESS, and OSI associate with plaque erosion. While ESSG is higher at rupture sites than erosion sites, OSI is higher at erosion sites and ESS was similar. These results suggest that ESSG and OSI may play critical roles in acute plaque rupture and erosion, respectively.

Background: Distinct plaque morphologies underlie the major causes of acute coronary syndrome (ACS) and sudden coronary death. We used polygenic risk scores (PRSs) for hypercholesterolemia and hypertriglyceridemia, two major risk factors for coronary artery disease (CAD), to evaluate the relative contributions of these risk factors to specific plaque morphologies that underly ACS. Hypothesis: Lipid-related PRS is associated with plaque rupture and/or plaque erosion. Methods: We extracted DNA from formalin-fixed paraffin-embedded heart tissues and genotyped 954 subjects from our sudden death autopsy registry, each of whom cause of death was determined by autopsy. Low-density lipoprotein (LDL)-specific and triglyceride (TG)-specific PRSs were constructed based on the Global Lipids Genetics Consortium genome-wide association study results, excluding single nucleotide polymorphisms with overlapping associations ( P &lt;0.05) for both lipid traits. Results: Subjects in the highest quintile of LDL-specific PRS had significantly more plaque rupture, ≥75% lumen narrowing, thrombotic CAD, and CAD-related death compared to those in the lowest quintile. Even after adjusting for traditional risk factors, LDL-specific PRS remained significantly associated with rupture (odds ratio [OR]: 1.22 per standard deviation, 95%CI: 1.04–1.43, P =0.017), ≥75% lumen narrowing (OR: 1.33, 95%CI: 1.13–1.57, P &lt;0.001), thrombotic CAD (OR: 1.21, 95%CI: 1.04–1.41, P =0.016), and CAD-related death (OR: 1.31, 95%CI: 1.13–1.52, P &lt;0.001). In contrast, subjects within the highest TG-specific PRS had significantly higher prevalence of thrombotic CAD, and TG-specific PRS remained significantly associated with thrombotic CAD after adjustment (OR: 1.20, 95%CI: 1.03–1.40, P =0.020). No association was observed between LDL-/TG-specific PRS and plaque erosion. Conclusions: This is the first study to associate lipid PRSs with specific plaque morphologies, revealing distinct pathogenic mechanisms underlying plaque rupture and erosion. Early genetic risk stratification and subsequent lipid-lowering interventions may provide substantial clinical benefits in mitigating cardiovascular risk and preventing sudden coronary death, especially in relation to plaque rupture. Our data raises questions about the effectiveness of such strategies in preventing plaque erosion, suggesting the need for further investigation to better understand the pathogenesis of plaque erosion.

Significant stenosis without thrombus may be the third most common etiology of acute coronary syndrome

A novel PET tracer for targeted imaging of atherosclerosis