Coronary artery calcification (CAC) remains one of the greatest challenges in percutaneous coronary interventions (PCI). CAC adversely affects not only procedural success due to difficulty crossing and dilating resistant calcific plaques, but also clinical outcomes due to higher risk of complications and suboptimal stent implantation.1,2 With an ageing population and rising prevalence of comorbidities associated with CAC, there has been an increasing trend in the number of PCI performed for patients with heavy CAC.2
Factors affecting adverse outcomes of PCI for CAC are limited ability of angiography to detect and evaluate CAC and associated features relevant to the PCI outcomes, and insufficient lesion preparation leading to suboptimal stent implantation. Compared with angiography, intravascular imaging (IVI) can significantly improve the diagnostic accuracy of CAC and its features, which help determine the need for advanced lesion preparation and optimise stent implantation.2 With growing evidence of benefits of IVI-guided PCI, guidelines and consensus statements acknowledge the pivotal role of IVI in the management of complex coronary artery disease, including heavily calcified lesions.2–4 Here we review how to use and interpret IVI in the diagnosis and management of CAC during PCI.
Coronary Artery Calcification on Invasive Angiography
CAC can be detected by fluoroscopy as radiopaque densities in the coronary arterial wall, and one-third of patients with chronic coronary artery disease exhibit angiographic evidence of CAC.5,6 Moderate CAC is defined as calcium visualised during cardiac motion on one side of the vessel prior to contrast injection, whereas severe calcification – found in 10–20% of all cases – is defined as calcium seen without cardiac motion on both sides of the arterial lumen (Figure 1).5–7 Angiographically moderate-to-severe CAC is associated with adverse procedural outcomes, such as suboptimal stent expansion and an increased risk of complications, including flow-limiting stent edge dissection.2,8 Furthermore, even after adjusting for clinical and anatomical factors, moderate-to-severe CAC is independently associated with an elevated risk of major adverse cardiovascular events.5–7,9
However, angiography has limited accuracy and inter- and intra-observer reproducibility to detect CAC and its associated features.2,10 The overall sensitivity of coronary angiography to detect CAC is only modest (~50%), which depends on the arc, length, thickness and distribution of calcium.8,10 Although the sensitivity increases as the severity of CAC increases, it is still ~60% and 85% for the detection of three-quadrant and four-quadrant CAC, respectively.10 Furthermore, angiography alone has suboptimal resolution to assess the severity and types of CAC, such as calcified nodules, which may affect procedural planning and clinical outcomes.4,10,11
Intravascular Imaging and Coronary Artery Calcification
Compared with angiography, IVI, such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT), has superior resolution and accuracy for evaluation of CAC. IVI more frequently detects CAC than angiography, and provides quantitative and morphological information on CAC (Figures 2 and 3).2,8,10 Also, IVI can be used to assess calcium fracture to determine the adequacy of calcium modification prior to stent implantation, and stent expansion to optimise the implanted stent and enhance clinical outcomes. In this regard, it is highly valuable to be able to interpret and use IVI during PCI of calcified lesions.
Coronary Artery Calcification on Intravascular Ultrasound
Ultrasound has limited penetration through calcium. As a result, CAC is manifested as a highly echogenic area (bright) with acoustic shadowing of deeper structures (dark) on IVUS (Figure 2).2,12 CAC can be found at the media, closer to the adventitia than to the lumen (deep calcium; Figure 2A1), or at the intimal–lumen interface, closer to the lumen than to the adventitia (superficial calcium; Figure 2B1).12 Although IVUS is highly sensitive for the detection of CAC, it cannot accurately measure the thickness of CAC due to attenuation of ultrasound signal beyond the leading edge of the calcium.12 It may be possible to predict the calcium thickness using assessment of reverberations or multiple reflections. Due to the oscillation of the ultrasound signal between the transducer and the calcium, CAC can cause reverberations, which are seen as concentric arcs at reproducible distances on images.12 If IVUS detects CAC with a smooth surface and reverberations, it is likely thinner calcium (Figure 2C1). In contrast, thicker calcium tends to have an irregular surface without reverberations on IVUS (Figure 2D1).2,12 A calcified nodule manifests as a nodular calcification that protrudes into the lumen (Figure 2E1).
IVUS enables assessment of morphological features of CAC that are associated with stent underexpansion. A 4-point IVUS-based scoring system has been developed, giving 1 point for each feature: superficial calcium angle >270° longer than 5 mm, 360° of superficial calcium, calcified nodule and vessel diameter (media-to-media) <3.5 mm (Figure 3).13 Since the lesions with the calcium score of =2 showed better stent expansion with atherectomy compared with routine lesion preparation with balloon angioplasty, upfront advanced calcium modification therapies are recommended for those lesions.13
Coronary Artery Calcification on Optical Coherence Tomography
Intracoronary OCT provides greater axial resolution than IVUS, since it uses near-infrared light, which has a shorter wavelength than ultrasound.14 In OCT, CAC is manifested as a low-intensity (low attenuation) area with clear delineation (Figure 2). Although IVUS can delineate the arc of calcium, but not its thickness, OCT allows evaluation of both calcium arc and thickness in the majority of cases. This is because tissue penetration of the light is less attenuated by the calcium compared with the sound wave (Figure 2C2 and Figure 2D2).2,14 Thus, the volume of CAC (determined by arc, thickness and length) is better quantified by OCT than IVUS. Due to its lower penetration depth, however, it should also be noted that OCT is limited in its ability to visualise the far side of the lesions with very thick calcium and deep calcium, especially in the presence of highly attenuating structures, such as red thrombus or lipid.2,14
Similar to IVUS, an OCT-based calcium scoring system has been developed.15 The OCT-based calcium score reflecting volumetric measurements of calcium included maximum calcium angle >180° (2 points), maximum calcium angle 90–180° (1 point), maximum calcium thickness >0.5 mm (1 point) and calcium length >5 mm (1 point), for a total calcium score of 0–4 points (Figure 3).15 The OCT-based calcium score was associated with stent expansion: 99% (interquartile range [IQR] 93–108) in score 0, 85% (IQR 78–93) in score 1, 86% (IQR 77–100) in score 2, 80% (IQR 73–85) in score 3 and 78% (IQR 70–86) in score 4 (p<0.01). Therefore, an OCT-based calcium score of =4 may indicate the need for advanced calcium modification (rule of “5”: arc >50% of circumference, thickness >0.5 mm and length >5 mm).
Intravascular Imaging and Calcium Modification
Evaluation of CAC using IVI and validated scoring systems help determine the need for advanced calcium modification, such as specialty balloons, rotational (RA) or orbital atherectomy (OA), or intravascular lithotripsy (IVL). The goal of the advanced calcium modification therapy is to induce calcium fracture prior to the stent implantation, which is associated with enhanced stent expansion.16 Calcium fracture can be seen in IVI as a new disruption or discontinuity in the calcium sheet (Figure 4; white arrowheads). However, it should also be noted that microfractures, which are not visible by IVI, but seen on micro-CT and histology, can facilitate stent expansion, suggesting that the absence of visible calcium fracture on IVI does not always indicate insufficient lesion preparation.17,18 An alternative way to assess the adequacy of lesion preparation by the advanced calcium modification therapies is to ensure full expansion of non-compliant (NC) balloon in two orthogonal views on fluoroscopy. This can be further supported by the use of advanced fluoroscopic tools, such as StentBoost (Philips), SyncVision Device Detection (Philips), StentViz (GE Healthcare) and CLEARstent (Siemens). Once adequate lesion preparation is confirmed by IVI or advanced fluoroscopic tools, stents are implanted and further optimised using IVI.
Cutting or Scoring Balloon
Cutting balloons (Wolverine™; Boston Scientific) are equipped with blades designed to create radially directed, longitudinal cuts, facilitating vessel expansion while limiting uncontrolled dissection.19 Whereas scoring balloons (AngioSculpt®, Philips; NSE Alpha™, B Braun; ScoreFlex™, OrbusNeich) are equipped with nitinol wires on the surface of either semi-compliant or NC balloons designed to reduce balloon slippage and facilitate plaque disruption.20 In patients with severe CAC on IVUS, cutting balloons before stent implantation resulted in a larger minimal stent area compared with standard balloons.19 Among angiographically severe calcified lesions prepped using a scoring balloon, the calcium thickness cut-off value for complete calcium fracture was 0.57 mm.20 These results suggest that speciality balloons may be helpful for the treatment of calcified coronary lesions, especially when the calcium is not very thick on IVI (e.g. thickness <0.5 mm on OCT).
Rotational or Orbital Atherectomy
RA and OA treat CAC using the ‘differential cutting’ mechanism, which selectively ablates the rigid calcium while minimising trauma to the soft non-calcified tissue.21 On IVI, calcium modification induced by atherectomy manifests as a cylinder-shaped, sharply delineated groove that follows the course of the guidewire or guidewire bias (Figures 4A and 4B).22,23 The ablated calcium area in severely calcified lesions was small and similar between RA and OA on OCT, and greater calcium ablation occurred in the lesions with smaller lumen diameters.23.24 The maximum reverberation angle in IVUS, which reflects a polished calcium surface, significantly increased after RA without changes in the calcium arc.24 Calcium fractures can also occur following atherectomy, but mainly after stenting and high-pressure balloon dilatation. A recent study demonstrated that calcium fractures on OCT were more frequent after atherectomy than the conventional balloon-based strategy.25
Although there was no significant difference in clinical outcomes between RA- and conventional balloon-based strategies in randomised trials, the RA-based strategy resulted in a significantly higher procedural success rate with 14% crossover due to balloon uncrossable and undilatable lesions.21,26,27 The ongoing Eclipse Trial (NCT03108456) will compare minimal stent area and 1-year target vessel failure between OA- and balloon-based strategies in severely calcified coronary lesions.28
Laser Atherectomy
Excimer laser coronary atherectomy (ELCA) uses ultraviolet light to ablate plaque via three mechanisms of action: photochemical, photothermal and photomechanical.29 The rapid expansion and implosion of vapour bubbles generated by ELCA disrupts the plaque and obstructive intravascular materials, and increases the compliance of vessel.29 Although ablative effects of ELCA on severe coronary calcium are unpredictable, ELCA can be used for the treatment of uncrossable calcified lesions or in-stent restenosis (ISR) or underexpanded stent due to fibrocalcific plaques. Furthermore, since any 0.014-inch guidewire can be used for ELCA, it can be useful when it is difficult to exchange the 0.014-inch guidewire to dedicated wires for OA or RA.
Intravascular Lithotripsy
Coronary IVL is a novel therapy for the treatment of heavily calcified lesions, which uses acoustic shock waves in a balloon-based system.30 IVL can safely and effectively modify severely calcified coronary lesions, facilitating stent implantation.17 Differential propagation of acoustic shock waves within the calcium and adjacent soft tissue creates compressive circumferential forces to fracture the calcium, which is the major mechanism of action of IVL.31 Therefore, compared with atherectomy, which selectively ablates calcium due to guidewire bias, IVL induces circumferential calcium modification, as evidenced by multiple calcium fractures in single cross-sections of OCT images (Figure 4C).32 In addition, compared with NC or specialty balloons, which work better in the lesions with thinner calcium, the frequency and magnitude of calcium fracture by IVL are proportional to the burden of CAC, including in eccentric calcium.30,32,33 OCT-defined calcium fracture was identified in ~40% of all lesions after IVL, which increased to ~80% among the most severely calcified lesions according to calcium volume index.32 These lead to consistent improvements in luminal gain and stent expansion after IVL for both concentric and eccentric CAC.33
Along with its efficacy, IVL is increasingly used due to its safety and ease of use. In a pooled analysis of Disrupt CAD I–IV studies, the procedure was successful in 92.4% of cases with no IVL-related perforations, abrupt vessel closure or no reflow.34 The 30-day major adverse cardiovascular events were 7.3%, which was largely attributed to in-hospital non-Q wave MI.34
Calcification in In-stent Restenosis and Intravascular Imaging
IVI enables identification of the underlying mechanism of ISR: mechanical (underexpansion and stent fracture), biological (neointimal hyperplasia, and calcified and non-calcified neoatherosclerosis) and combined.35 For example, IVI can differentiate stent underexpansion due to heavy calcium behind the stent struts from a previously placed undersized stent (Figure 5A1). IVI can also detect neointimal calcium, which is found in ~15–20% of late ISR after drug-eluting stents implantation (Figure 5B1).36,37
Since treatment of ISR heavily depends on its mechanism, IVI has a crucial role in the management of ISR. Treatment of stent underexpansion due to heavy calcium behind the stent struts has been challenging, since the metallic framework of the stent can interfere with calcium modification therapies, such as atherectomy or specialty balloons. A super high-pressure NC balloon (OPN NC®; SIS-Medical-AG), ELCA or IVL can be considered (Figure 5).38,39 As a bailout for underexpanded and undilatable ISR, RA can be considered to debulk old stent (‘stentablation’), although the operator should be cautious about burr entrapment.40 If the predominant mechanism of ISR is stent underexpansion, implanting another layer of stent without resolving the underlying problem should be avoided. For the treatment of ISR predominantly due to calcified neoatherosclerosis, a similar approach to the one used for de novo calcified coronary lesions can be undertaken. Whether to place a new stent or not would depend on the number of layers of old stents and availability of alternative options, such as a drug-coated balloon.35
Conclusion
Compared with angiography, IVI not only increases diagnostic accuracy to detect CAC, but also enables assessment of morphological features of CAC, which help determine the need for advanced calcium modification therapy to induce calcium fracture and facilitate stent expansion. IVI can also be used to determine the adequacy of lesion preparation prior to stent implantation and optimise the implanted stent. Finally, IVI is critical to understand the mechanism of calcific ISR and determine the most appropriate treatment strategy. Therefore, IVI should routinely be considered in the diagnosis and management of de novo calcified coronary lesions and calcific ISR.