Calcified Plaques in the Human Coronary Artery ― Each Calcified Plaque Is Never the Same ―
Article ID: CJ-21-0473
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Article ID: CJ-21-0473
Since the introduction of percutaneous coronary intervention (PCI) into the clinical arena, the presence of coronary artery calcification (CAC) has been repeatedly reported as an important risk factor for periprocedural complications, procedural failure, revascularization, and stent thrombosis. As society is aging, the frequency of PCI for severe calcified lesions is increasing, but despite the advent of drug-eluting stents (DES), CAC has remained an unresolved issue in the field of PCI.
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Several imaging modalities have been used to evaluate CAC severity. Coronary angiography has a high positive predictive value for CAC, but the sensitivity is not high. Intravascular ultrasound (IVUS) is more accurate than coronary angiography in detecting CAC, with 90–100% sensitivity and 99–100% specificity.1 Additionally, it can provide direct information on the circumferential, diametrical, and longitudinal distribution of CAC. However, IVUS cannot accurately measure the thickness and volume of CAC owing to its limited ability to penetrate CAC. Moreover, the image resolution of IVUS is insufficient to differentiate the various CAC types observed in the pathological assessment of the human coronary artery. Therefore, few studies have examined the qualitative differences between calcified lesions and their effect on clinical outcomes.
The recent advent of optical coherence tomography (OCT) technology has allowed the in vivo classification of CAC and investigations of clinical significance. In a recent postmortem study, Saita et al classified CAC into 4 types: (1) superficial dense calcified plates, (2) deep intimal calcification, (3) scattered microcalcification, and (4) calcified nodule (CN).2 They validated the histological examination using OCT findings. Notably, OCT accurately distinguished CNs from other entities as high-backscattering protruding masses with an irregular surface and low-intensity areas with diffuse borders.
The concept of CN was first introduced in a postmortem study by Virmani et al.3 Described as a dense, eruptive, calcified mass with an irregular surface, it is characterized by an underlying heavily calcified plaque with a distinct nodular mass of calcium that protrudes into the lumen and causes dysfunction or loss of the overlying endothelial cells.3,4 The nodules are surrounded by fibrin with a non-occlusive platelet-rich “white” thrombus on top. CN is the most infrequent cause of intracoronary thrombus formation resulting in the culprit lesions of acute and chronic coronary syndromes. On OCT, a CN is sometimes indistinguishable from protruding intracoronary thrombus.
Although the mechanism of CN development is unknown, it is frequently observed on the fractured underlying calcified plate. Thus, a potential hypothetical mechanism involves mechanical stress that fragments the calcium sheet, resulting in small nodules surrounded by fibrin that may eventually erupt through the plaque surface. Indeed, CNs occur in highly calcified tortuous arteries and are frequently detected in the middle right coronary and left anterior descending coronary arteries, where the torsion stress is maximal.3,5 Intraplaque hemorrhage from surrounding leaky capillaries is also likely involved because intraplaque fibrin deposition is frequently observed without direct communication with the intracoronary lumen. The etiology of CN remains unidentified, but studies have consistently associated it with chronic renal failure, hemodialysis, peripheral artery disease, and older patients.5,6
In this issue of the Journal, Iwai et al7 retrospectively examine the long-term prognostic impact of CNs in 251 moderate to severe CAC patients who underwent DES implantation. They report that major adverse cardiac events (MACE) (a composite of cardiac death, myocardial infarction (MI), and target lesion revascularization) occurred more frequently in CN patients than in those with calcified protrusion (CP) or superficial calcific sheet (SC) during a median follow-up of 728 days after PCI. This difference was primarily driven by a higher incidence of TLR and MI among CN patients. In an OCT study targeting patients with acute coronary syndrome (ACS), Kobayashi et al reported that the minimum stent area (MSA) was smaller in culprit lesions with a CN than in those with plaque rupture and erosion, which were associated with a significantly higher incidence of TLR in CN lesions.8 In a large-scale retrospective registry of 436 ACS patients who underwent OCT-guided emergency PCI, we also reported that the presence of a CN in ACS culprit lesions was independently associated with a higher incidence of adverse events after the onset of ACS. However, the comparisons were made between ACS culprit lesions with a CN and without calcification, such as plaque rupture and erosion. Considering the differences in lesion and patient characteristics between CN and non-calcified lesions, CNs were associated with a poorer long-term prognosis due to suboptimal stent expansion and a higher incidence of comorbidities. The present study extends earlier findings by demonstrating worse clinical outcomes with CNs than with other types of CAC, such as SC and CP. Under the same category of moderate to severely calcified plaque on angiography, high-risk features such as CNs were identified using OCT.
Although their data proved that MACE occurred more frequently in CN patients than in CP or SC patients and that CNs were an independent predictor of MACE, the underlying mechanisms of the higher incidence of TLR and MI were not identified. TLR occurred more frequently in CN patients despite their greater post-PCI MSA. CN was associated with a higher incidence of stent edge dissection (SED) and incomplete stent apposition (ISA), but the incidence of these findings was higher than that of TLR. SED occurred in 30% of lesions, ISA occurred in 91%, and the incidence of TLR was 7%. There was no significant difference in MSA, SED incidence, stent under-expansion, and ISA between lesions with and without MACE in each calcified plaque subtype. These data suggested that the occurrence of TLR in CN lesions was not caused by known TLR mechanisms for general lesions. Instead, unique mechanisms might influence the CN lesions. Iwai et al did not evaluate OCT imaging at the time of TLR. However, we sometimes experience cases of TLR due to progressive CN regrowth at the exact location where the CN was observed during the index PCI (Figure). Because the nodules are surrounded by fibrin with platelet-rich white thrombus on top, DES is likely insufficient to protect against restenosis in this type of lesion. Thus, their data7 showing a higher incidence of TLR in CN lesions make sense. Delayed reendothelialization seen after DES implantation may enhance additional thrombus attachment at the site of the original CN segment, resulting in in-stent restenosis or stent thrombosis. Mori et al reported 2 cases wherein CN resulted in stent thrombosis and in-stent chronic total occlusion.9 In this scenario, it is reasonable to have no significant difference between MACE and non-MACE in terms of post-PCI OCT findings, because these phenomena could occur regardless of the extent of stent optimization. A detailed assessment of OCT images at the time of TLR in CN lesions is needed to confirm this hypothesis.
Case of target lesion revascularization due to regrowth of a calcified nodule (white arrowheads). PCI, percutaneous coronary intervention.
Nevertheless, Iwai et al provide important information about the potential ability of OCT to detect high-risk morphological features among various types of calcified lesions. Further studies are required to obtain additional insights on the effective treatment strategy for this least frequent, but extremely high-risk entity of CAC.
H.O. received research funds from Abbott Vascular Japan. T.H. declares no conflicts of interest.
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