INTRODUCTION
Heavy coronary artery calcium (CAC) poses an authentic challenge for successful percutaneous coronary intervention (PCI). Treatment of such calcified lesions is confronted with augmented procedural complications,[1] with higher rates of target lesion revascularization, restenosis, and major adverse cardiac events.[2345] Heavily calcified lesions are prone to stent underexpansion and malapposition, which increase the rates of stent thrombosis and in-stent restenosis.[67] Several strategies and technologies have been crafted to treat CAC with the aim of optimal lesion preparation followed by successful stent implantation. Advances include balloon-based (cutting and scoring balloon, super high-pressure balloon, and lithoplasty balloon) and atherectomy (rotational, laser, and orbital) techniques. Here, the author highlights the utility of such modalities in contemporary practice.
PATHOPHYSIOLOGY OF CORONARY ARTERY CALCIUM
CAC is an active process that reflects a wider systemic inflammatory status, typically visually examined in patients with metabolic syndrome, diabetes mellitus, or chronic kidney disease.[89] It is more prevalent in men older than 70 years of age (>90% in men vs. 67% in women).[10] The incidence of CAC varies according to the imaging modality utilized. The moderate-to-severe CAC can be encountered in up to one-third of coronary lesions in coronary angiography (CAG).[11] Atherosclerotic CAC is dysmorphic calcium precipitation engendered by chondrocyte-like cells and linked to the expression of inflammatory factors, such as cytokines relinquished by tissue macrophages and foam cells. It is likely that inflammation precedes calcification and plays a paramount role in its progression, with the two processes, namely coexisting and promoting each other.[12] CAC is commonly associated with larger plaque burden, multivessel disease, and a more preponderant degree of lesion complexity, including involvement of coronary bifurcation or chronic total occlusion.[11] Moreover, specific patterns of CAC, such as calcified nodules and coronary microcalcifications, are associated with plaque instability and vulnerability.[13] Typically, these lesions pose significant challenges to cross with standard devices and are less liable to respond to conventional balloon dilatation. Inevitably, inadequate lesion preparation before stenting increases the risk of stent loss, stent underexpansion/fracture, and the rate of intraprocedural complications, such as no reflow, coronary dissection, or perforation.[11] Interestingly, the passage of the drug-eluting stent (DES) through areas of cumbersomely heavy CAC has additionally been linked to polymer damage with consequent impairment of drug elution.
IMAGING TECHNIQUES
Coronary computed tomographic angiography
Coronary computed tomographic angiography (CCTA) is the most important noninvasive imaging tool utilized to detect CAC. CAC is depicted as an area of hyperattenuation, defined as an area of at least 1 mm2 with >130 Hounsfield units or ≥3 adjacent pixels utilizing the Agatston method.[14] A CAC score is calculated utilizing a weighted value assigned to the highest density of calcification in each coronary segment multiplied by the area and summed finally for all arteries to give a total coronary calcium score correlated with the patient outcomes.[15] This score carries a vigorous prognostic factor for clinical events in the mid to long term in asymptomatic population. CCTA may unearth spotty calcification, which is designated one of the denouements of plaque vulnerability. This imaging technique meticulously allows identification and localization of calcium along coronary arteries, thereby improving PCI procedural success.
Coronary angiography
CAG is often limited by underestimating calcium, erroneous grading, and inability to assess calcium depth within the plaque. CAC is relegated as none or mild, moderate, or severe. The radiopacity observed only during the cardiac cycle before injection of contrast medium defines moderate CAC. Severe CAC is delineated as radiopacity observed without cardiac motion, visible on both sides of the arterial lumen as a double track.[11] The calcium content inclines to appear as hazy areas with inhomogeneous contrast staining, and hence, the differentiation from thrombus is difficult utilizing CAG only. CAG can determine CAC only in 38% of cases, and the identification seems to be dependent on the degree of the arch of calcification (60% for moderate and 85% for rigorous CAC) as demonstrated by Mintz et al.[16]
Intravascular ultrasound
The hallmark of CAC on intravascular ultrasound (IVUS) is an echodense plaque that is brighter than reference adventitia with acoustic shadowing. One of the demerits of IVUS is that dense fibrous tissue may additionally cast a shadow akin to CAC. CAC establishes reverberations in contrast to dense fibrous tissue. IVUS enhances the sensitivity to detect CAC significantly compared with CAG (73% of cases vs. 38%; P < 0.001).[16] Quantitatively (the arc of the lesion), CAC has been relegated into four classes on IVUS: Class I, 0°–90° calcification; Class II, 91°–180° calcification; Class III, 181°–270° calcification; and Class IV, >270° calcification.[17] Semiquantitative grading relegates CAC as absent or subtending 1, 2, 3, or 4 quadrants. IVUS determines abluminal calcified deposits within the deeper layers (media or adventitia) of the vessel wall. It allows only the definition of the calcific arch without offering insights into precise thickness of calcium because of acoustic shadowing. Maximum circumferential extension of calcium >180° is linked to possible stent underexpansion. An IVUS CAC score [Figure 1] of ≥2 (2 points for calcium length >270° >5 mm, 1 point each for calcium nodule, smaller vessel diameter (<3.5 mm), and reverberation <90°) emerges as a relevant predictor for stent underexpansion, warranting adjunctive plaque modification devices.[18]
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Figure 1: Intravascular ultrasound depicting indicators calcium score (calcium length, angle, nodule, and vessel diameter). Ca: Calcium
Optical coherence tomography
Optical coherence tomography (OCT) designates CAC as a signal-poor or heterogeneous region with sharply delineated borders. Unlike IVUS, where CAC is most often confused with dense fibrous tissue, OCT-detected CAC very often simulates lipid or necrotic core; however, the signal-poor regions of CAC are sharply delineated, whereas the signal-poor regions of lipid or a necrotic core have poorly defined or diffuse borders.[19] OCT can quantify CAC thickness better due to higher resolution but may miss deep calcifications because of decreased penetration. OCT can quantify CAC thickness, area, and volume automatically [Table 1].[20] A lesion with CAC score of 4 (2 points for CAC angle >1800, 1 point for CAC thickness >0.5 mm, and 1 point for CAC length >5 mm) in OCT has emerged as a reliable predictor for stent underexpansion (stent expansion <70%) as proposed by Fujino et al.[21]
Table 1: Comparison of imaging techniques in for the detection of coronary artery calcium
TREATMENT MODALITIES
A key concept in approaching heavy CAC involves facilitating lesion crossing and plaque modification. The support wires, buddy wires, guide extensions, lesion predilatation, and anchoring of the guide catheter with inflation of a second balloon in a side branch or distal vessel are possible means for lesion crossing. The underlying calcified plaque gets modified using the dedicated balloon-based [Table 2] and/or ablation devices.
Table 2: Balloon based plaque modification strategies
Balloon-based strategies
High- and super high-pressure noncomplaint balloons
A noncomplaint (NC) balloon may be the initial choice in mild-to-moderate calcified stenosis with restricted calcium arc (<90°). However, the risk of eccentric balloon expansion because of the incremented hoop stress conferred by heavy CAC is not fully mitigated by NC balloon. The focal points of resistance within a lesion result in nonuniform balloon expansion and “dog boning” with hyperexpansion in the more compliant segments of the vessel without fracturing the calcium.
Super high-pressure balloon technology incorporates a rapid-exchange NC balloon (OPN, SIS Medical, Frauenfeld, Switzerland) with a twin-layer structure allowing inflation pressure up to 35–40 atm without bursting of the balloon [Table 2]. This is considered as not only efficacious but also a safe approach when experiencing heavy calcified lesions undilatable by conventional high-pressure NC balloon. Albeit this balloon can be used both before and after stent implantation, most evidence corroborates safety and efficacy during poststenting dilation. The unique twin-layer technology ascertains uniform balloon expansion over a wide range of pressures, abbreviating the risk of balloon rupture, vessel damage, and coronary perforation.[21] The main limitations of the OPN NC balloon are its relatively rigid profile which, together with the stiffness of the twin-layer technology, undermines any endeavor to recross when inflated. Guide extension catheter may avail prosperous distribution of such balloon.[22]
Cutting and scoring balloons
The cutting balloon (Flextome™, Boston Scientific, Natick, MA, USA) is a semicompliant monorail over-the-wire (OTW) balloon with 3 or 4 microtomes mounted on its body, designed to cut the continuity of fibrocalcific plaque creating fissures on the plaque. The cutting balloon ascertains a more controlled lesion predilation, with less adjacent vessel wall trauma and less risk of dissection. The presence of cutting elements on the surface of the balloon allows efficacious dilation with a lower inflation pressure [Figure 2]. The microblades additionally avert the balloon slippage. One randomized tribulation failed to show a preponderation of cutting balloon for type A/B lesions compared with standard balloons.[23] An IVUS-predicated study[24] denoted that cutting balloon achieves larger luminal gain compared to conventional balloon. It is constrained by high profile obstructing its passage through tortuous and calcified vessels. With its most recent iteration (Wolverine), the atherotome's support thickness has been reduced, without affecting the functional height of the blade, resulting in an overall smaller crossing profile with improved crossability.
Figure 2: Depiction of the effects of cutting balloon on heavy coronary calcium by OCT. (a-f) Baseline lesion in LAD. (b-f) Baseline lesion in left circumflex. (m-r) Final result following modification of calcified plaque by cutting balloon and left main bifurcation stenting. *Calcification. (a, g, m) Angiographic images, (b-f, h-l, n-r) OCT images. OCT: Optical coherence tomography, LAD: Left anterior descending, Arrow (a, g) indicates calcium *(b, d, e, f, i, l) indicates calcium
The principle of using a “buddy wire” to fracture calcified plaque promoted the development of the scoring balloon: a low-profile semicompliant balloon with a scoring element on the surface (AngioSculpt, Biotronik, Berlin Germany; Scoreflex OrbusNeich, Hong Kong, China; NSA Alpha B. Braun, Melsungen, Germany).[25] During inflation, the radial force is mainly exerted on the scoring element, and this is transmitted to the vessel wall causing plaque fissuration [Table 2]. The embedded nitinol element ensures anchoring of the balloon with a lower risk of “melon-seeding” effects and a lower risk of dissection and perforation. It is likely that prolonged inflation might improve the device navigation with a “creep phenomenon:” a sustained tensile load ensuring microcrack formation and propagation, leading to a phasic tissue elongation.[26] Scoring balloons have been considered as an alternative to cutting balloons in moderate calcification and, in recent years, have been preferred due to superior flexibility and deliverability, although no specific randomized control trials exist in the literature so far.
Constrained semicompliant balloon (chocolate balloon)
The chocolate balloon (TriReme Medical, Pleasanton, CA, USA) is an OTW balloon with a mounted nitinol constraining structure categorically aimed at uniform, controlled inflation and an expeditious deflation ascertaining an atraumatic dilatation obviating the need for cutting or scoring balloons [Table 2]. The nitinol constraining structure generates balloon segments or “pillows” that make contact with the vessel and functions to minimize local forces. The “grooves” promote plaque modification. The distinctive pillows and grooves reduce vessel trauma and the rate of dissection.[22]
Intravascular lithotripsy
Intravascular lithotripsy (IVL) is the most recent armamentarium for the treatment of lesions with heavy CAC. It delivers localized pulsatile sonic pressure waves, modifying preferentially calcific plaque without chasing the soft tissue and subsequently promoting stent delivery and optimization.[27] The balloon catheter with multiple lithotripsy emitters is negotiated over a guidewire to the target lesion. The balloon is annexed to the external pulse engenderer. With balloon inflation at low pressure (4 atm), a burst of 10 pulses of high energy is delivered over 10 s followed by further balloon inflation at 6 atm for 15–20 s before deflation. This process can be repeated to a total of 8 cycles per balloon (80 pulses). The balloon sizing is predicated on the desired stent size for that target lesion (i.e., 1:1 for the reference vessel diameter) and is often guided by intracoronary imaging.[28] The IVL balloons are all 12-mm long with diameters ranging from 2.5 to 4.0 mm. Guide catheter extenders and buddy wire support may assist deliverability and position of this large profile device.
By inducing calcium fractures (as assessed with IVUS or OCT).[293031] the IVL therapy achieves optimal stent expansion in undilatable lesions refractory to specialty balloons and rotational atherectomy (RA). The navigation of IVL balloon could be impacted by rigorous tortuosity or angulation, critical lumen reduction, and plaque indentation into the lumen and a small vessel and multiple stent layers. Up to 46% of the lesions might also require dedicated lesion pre- and/or post-dilatation with NC balloons or could benefit from other adjunctive devices such as cutting or scoring balloons or atherectomy to either facilitate balloon delivery or increase calcium compliance after IVL therapy.[3032] IVL avoids guidewire bias by targeting CAC circumferentially. Reduced learning curve, apparent lack of embolization, and perforation are all very attractive attributes of IVL compared to atherectomy [Table 3].[22] Furthermore, IVL is possible following stenting. Unlike RA, IVL can be utilized with more than one guidewire to forefend side branches in bifurcation lesions. Because of the presumed ability to pass across a second balloon, IVL can be utilized with the kissing balloon technique.
This modality can cause vessel complications albeit balloon rupture is uncommon. The sudden balloon burst has been described with arterial dissection during IVL. Recently, there is a case report of perforation following this therapy.[33] Furthermore, vessels with a diameter >4 mm (maximum shockwave balloon size) or important plaque eccentricity preclude appropriate IVL balloon apposition to the vessel wall and may abbreviate the efficacy of the therapy. IVL could be safely performed with high procedural success, minimal complications with substantial calcific plaque fracture in most lesions in a prospective multicenter Disrupt CAD II study.[34]
Table 3: Advantages and disadvantages of intravascular lithotripsy
Atherectomy or ablative devices
A strategy of debulking [Table 4] calcified lesions as a component of bail-out technique to address cumbersomely heavy CAC has evolved into a primary lesion preparation approach called primary atherectomy in contemporary practice. Compared to bail-out strategy, the primary atherectomy is associated with decreased procedural and fluoroscopy times, contrast volume, and number of predilatation balloon catheters used.[35] This alters plaque morphology, inflicts fractures in CAC, and improves lesion compliance, to increase the likelihood of improved and consummate with complete minimum lumen diameter and consummate stent expansion.
Table 4: Comparison of various ablative techniques
Rotational atherectomy
RA (Boston Scientific, Marlborough, MA, USA) system is composed of a high-speed rotating diamond-coated burr that is aimed to act as an abrasive rotatory surface against calcific plaque. The elliptic-shaped metallic burr is available in different sizes (from 1.25 to 2.5 mm) and is mounted over an advancer (RotaLink) drive-shaft connected to a motor that converts compressed gas into rotational energy. The burr is advanced over a RotaWire (dedicated 0.009-inch 325 cm long wire) designed to maximize flexibility and to minimize wire bias. The recently introduced RotaPro (Boston Scientific) represents an updated iteration, and it offers a better user interface and controls integrated on the advancer. Applying the principle of “differential cutting” RA acts preferentially on the fibrocalcific plaque tissue while sparing elastic tissue [Figure 3]. The ablated tissue is pulverized in 5–10 mm debris, which is released into the distal coronary microcirculation. This is the likely mechanism underlying the potential for transient slow/no reflow following RA.[36] The wiring technique has been facilitated by the utilization of a customary workhorse wire or hydrophilic wire subsequently exchanged over microcatheters or OTW balloons with the RotaWire. CAC eccentricity, vessel luminal area, burr size, and wire bias degree impact the RA results substantially.[37] An optimal scenario for RA in terms of prognostically luminal gain is a lesion with concentric circumferential calcium (cross-section >270° of CAC) and a minimal lumen area smaller than the burr size. Complications of RA include burr entrapment, coronary dissection, and perforation, but their occurrence can be usually minimized by optimal technique. Fundamental elements of contemporary optimal technique include utilization of a single burr (1.5 mm) with burr-to-artery ratio of 0.6, rotational speed of about 140,000–180,000 rpm, gradual burr advancement utilizing a pecking motion, short ablative runs (15–20 s), and avoidance of decelerations >5000 rpm. However, in lesions not crossable with a 1.5-mm burr or in very long tortuous segments, a 1.25-mm burr with stepwise escalation may be needed.[38]
Figure 3: IVUS depiction of the effects of RA on heavy coronary calcium. (a-f) Baseline lesion in LAD, (g-l) Baseline lesion in LCX. (m-r) Final result after RA followed by left main bifurcation stenting. (s-x) Final result after RA followed by left main bifurcation stenting. (a, g, m, s) Angiographic images. (b-f, h-l, n-r, t-x) IVUS imaging, IVUS: Intravascular ultrasound, RA: Rotational atherectomy, LAD: Left anterior descending, LCX: left circumflex, Arrow (a.g) indicates calcium Arrow heads (b, c, d, e, j) depicts calcium
RA Prior To Taxus Stent Treatment For Intricate Native Coronary Artery Disease[39] trial failed to demonstrate a superiority of RA versus conventional balloon dilatation before DES implantation in heavy CAC. Upfront high-speed RA is feasible in almost all patients and improves the success of DES deployment compared with modified cutting or scoring balloons, according to the results of the contemporary Comparison of Strategies to PREPARE Astringently CALCIFIED Coronary Lesions trial. Albeit both strategies ascertain equal safety and efficacy, the utilization of RA is no longer associated with excessive late lumen loss in the modern era.[40]
Orbital atherectomy
Orbital atherectomy (OA) is another novel treatment modality for heavy CAC.[31] It consists of an eccentrically mounted diamond-coated 1.25-mm crown, connected to a drive shaft and to a controller powered by a pneumatic console (CSI Diamond 360° Coronary OA System, St. Paul, Minnesota, USA). The crown of OA with diamond chips both on front and back enables bidirectional atheroablation [Table 4] compared with the Rotaburr which only allows antegrade ablation. The crown entrapment is less likely compared to burr entrapment due to retrograde ablation. The crown is advanced over a dedicated (ViperWire Advance, St. Paul, Minnesota, USA) a 0.014-inchwire, with superior maneuverability compared with the 0.009-inch RotaWire. Utilizing the controller, the operator can move the crown forward and backward and can regulate the speed of the crown orbit (80,000–120,000 rpm). OA incorporates centrifugal forces which pushes and compresses the crown against the plaque with a “sanding” action of the calcified component. OA might have a selective action on the rigid calcified component, whereas healthy elastic tissue may be spared. While the RA burr is moved forward in a gradual, pecking motion to allow intermittent ablation, the OA crown is advanced with a gradual, continuous motion, even interrupting in a region of interest to allow more time for ablation. Eminently, by incrementing its orbit as rotational speed increases, OA allows ablation of CAC utilizing the same device (1.25-mm crown) in vessels up to 3.5-mm diameter. Other advantages of OA include the 6-F guiding catheter compatibility, smaller size of particles released during ablation (2 vs. 5–10 mm in RA), no interruption in blood flow during crown orbiting, and less vascular heating. The OA system in treating de novo, calcified coronary lesions (ORBIT I), a prospective, single-arm study demonstrated device success in 98% (defined a residual stenosis <50% after OA) and procedural prosperity (defined as residual stenosis <20% after stenting) in 94% of patients with de novo calcified plaque. It showed dissections without sequelae in 12% of cases but did not reveal any case of slow/no reflow following OA.[41] The ORBIT II study[42] further corroborated the preliminary results of the ORBIT I in a larger cohort of patients, demonstrating device success of 98.6% and procedural prosperity of 91.4%, with 2.3% rate of severe coronary dissections. The ongoing, randomized Evaluation of Treatment Strategies for Severe Calcific Coronary Arteries: OA vs. Conventional Angioplasty Technique Prior to Implantation of DESs: The ECLIPSE Tribulation (ECLIPSE) (NCT03108456, CLN-0011-P) is further likely to evaluate OA compared to conventional balloon angioplasty for the treatment of severe calcified lesions before DES implantation.
Excimer laser coronary atherectomy
Utilizing photochemical, photothermal, and photomechanical mechanisms, excimer laser coronary atherectomy (ELCA) ablates heavy CAC. The microparticles released (<10 μm) avoid microvascular obstruction as they are absorbed by the reticulo-endothelial system.[43] The CVX-300 system (Spectranetics, Colorado Springs, CO, USA) emits pulses of ultraviolet light at 308 nm wavelengths; the generated ultraviolet pulses only penetrate tissue depths of 50 um and consequently lead to relatively pure plaque disintegration without inflicting injuries at the deeper medial or adventitial layers. ELCA catheters are available in four diameters, which are compatible with 6, 7 and 8 Fr catheters; 6 Fr: 0.9 and 1.4 mm, 7 Fr: 1.7 mm, and 8 Fr: 2.0 mm, predicated on a catheter: vessel diameter ratio of 0.5:0.6, and are compatible with a 0.014 inch guidewire. In the context of CAC, the utilization of ELCA is limited to that of a “bail-out” strategy in lesions uncrossable for dedicated balloons or for the RotaWire or ViperWire. The feasibility and efficacy of amalgamating laser to facilitate RA have been described and referred as the RASER technique.[44] This technique has been applied mainly in the treatment of calcific undilatable in-stent restenosis, with positive results reported in a recent OCT study.[45]
CONCLUSION
The ominous quandary of heavy CAC is likely to increase in near future because of an aging population and increased rates of diabetes and chronic renal disease. This may further impose clinical and technical complexity to PCI. In contemporary practice, the optimal therapy for significant CAC is multi-adjunctive and requires the availability of several modalities including intracoronary imaging in the catheterization laboratory [Figure 4]. For moderate degree of CAC, the lesion preparation could be achieved with balloon-predicated approaches. Conversely, higher degree of CAC may require more aggressive ablative approaches, such as ELCA, RA, or OA. Because of its ease of use, shorter learning curve, and unique action on both superficial and deep CAC, IVL has the potential of more widespread adoption. The authors feel that there would be a surge in a hybrid approach involving drill (RA or OA) and shock (IVL) in near future. Despite the growing data for different modalities, additional randomized controlled trials are warranted to further demystify the preponderation of one modality over another.
Figure 4: Proposed algorithm for treatment of calcified coronary lesions, CAC: Coronary artery calcium, ELCA: Excimer laser coronary atherectomy, IVL; Intravascular lithotripsy, IVUS: Intravascular ultrasound, NC: Noncompliant, OA: Orbital atherectomy, OCT: Optical coherence tomography. CAC score of 4 in OCT or ≥2 in IVUS is a reliable indicator of stent underexpansion
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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