Journal of the American College of Cardiology Vol. 63, No. 17, 2014� 2014 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2014.01.017

STATE-OF-THE-ART PAPER

Coronary Artery Calcification

Pathogenesis and Prognostic Implications

Mahesh V. Madhavan, BA,* Madhusudhan Tarigopula, MD, MPH,y Gary S. Mintz, MD,yAkiko Maehara, MD,*y Gregg W. Stone, MD,*y Philippe Généreux, MD*yzNew York, New York; and Montréal, Quebec, Canada

C

From the *New Y

Center, New York

New York; and th

Montréal, Quebec

Duke Charitable

fellowship. Dr. Mi

from Volcano and

from Boston Scien

a consultant to Bo

and Volcano. Dr.

vascular Systems, I

Dr. Tarigopula ha

this paper to disclo

Manuscript rece

2014, accepted Jan

oronary artery calcification (CAC) is a risk factor for adverse outcomes in the general population and in patientswith coronary artery disease. The pathogenesis of CAC and bone formation share common pathways, and riskfactors have been identified that contribute to the initiation and progression of CAC. Efforts to control CAC withmedical therapy have not been successful. Event-free survival is also reduced in patients with coronary calcificationafter both percutaneous coronary intervention (PCI) and bypass graft surgery. Although drug-eluting stents anddevices for plaque modification have modestly improved outcomes in calcified vessels, adverse event rates are stillhigh. Innovative pharmacologic and device-based approaches are needed to improve the poor prognosis of patientswith CAC. (J Am Coll Cardiol 2014;63:1703–14) ª 2014 by the American College of Cardiology Foundation

Coronary artery calcification (CAC) results in reducedvascular compliance, abnormal vasomotor responses, andimpaired myocardial perfusion (1,2). The presence of CACis associated with worse outcomes in the general populationand in patients undergoing revascularization (3,4). Thepresent paper will review the pathogenesis of CAC and itsimpact on the prognosis and treatment of patients withcoronary artery disease (CAD).

Pathophysiology and Risk Factors

Calcium regulatory mechanisms that affect bone formationand growth also influence CAC. Alkaline phosphatase iscentral to early calcium deposition and has been proposed asa molecular marker of vascular calcification (5,6). Vascularsmooth muscle cells (VSMCs) produce matrix vesicles,which regulate mineralization in the vascular intima andmedia (5,7). Other cell types (e.g., microvascular pericytesand adventitial myofibroblasts) have the potential togenerate mineralized matrix and undergo osteoblastic dif-ferentiation, resulting in calcified deposits (5).

ork-Presbyterian Hospital and the Columbia University Medical

, New York; yCardiovascular Research Foundation, New York,

e zHôpital du Sacré-Coeur de Montréal, Université de Montréal,

, Canada. Mr. Madhavan was supported by a grant from the Doris

Foundation to Columbia University to fund a clinical research

ntz has received grant support from Volcano; has received honoraria

Infraredx; and has received fellowship support and speaker fees

tific. Dr. Maehara has received grant support from and has served as

ston Scientific; and has received lecture fees from St. Jude Medical

Stone has served as a consultant to Boston Scientific and Cardio-

nc. Dr. Généreux has received speaker fees from Abbott Vascular.

s reported that he has no relationships relevant to the contents of

se.

ived September 10, 2013; revised manuscript received January 13,

uary 14, 2014.

Two recognized types of CAC are atherosclerotic andmedial artery calcification. Atherosclerotic calcificationchiefly occurs in the intima (5). Inflammatory mediators andelevated lipid content within atherosclerotic lesions induceosteogenic differentiation of VSMCs (7). Conversely, CACin the media is associated with advanced age, diabetes, andchronic kidney disease (CKD) (6). Previously thought to bea benign process, medial calcification contributes to arterialstiffness, which increases risk for adverse cardiovascularevents (2).

The extent of CAC correlates with plaque burden (8).Microcalcifications in the fibrous cap might promotecavitation-induced plaque rupture (9). Additionally, calcificnodules might disrupt the fibrous cap, leading to thrombosis(10). Recurrent plaque rupture and hemorrhage with subse-quent healing might result in the development of obstructivefibrocalcific lesions and are frequently found in patients withstable angina and sudden coronary death (10,11).

A number of risk factors contribute to the developmentof CAC (Table 1). CAC might be inherited through bothcommon allelic variants (e.g., chromosome 9p21) and raremutations in phosphate metabolism that have also beenassociated with myocardial infarction (MI) (12–14). Certainmicroribonucleic acids have also been implicated in CACdevelopment (15), and their dysregulation has been associ-ated with VSMC transition to an osteoblast-like phenotype(15).

Patients with CKD have greater cardiovascular morbidityand mortality, largely due to the presence of CAC andaccelerated atherosclerosis. Hypercalcemia and hyper-phosphatemia promote CAC. In addition to affecting thecalcium-phosphate solubility equilibrium, phosphate canstimulate osteochondrogenic transformation of VSMCs

Table 1 Risk Factors for Coronary Calcification

Risk Factor Intimal Calcification Medial Calcification

Advanced age Yes Yes

Diabetes mellitus Yes Yes

Dyslipidemia Yes No

Hypertension Yes No

Male Yes No

Cigarette smoking Yes No

Renal etiology

Dysfunction (YGFR) No Yes

Hypercalcemia No Yes

Hyperphosphatemia Yes Yes

PTH abnormalities No No

Duration of dialysis No Yes

Modified with permission from Goodman et al. (123).GFR ¼ glomerular filtration rate; PTH ¼ parathyroid hormone.

Abbreviationsand Acronyms

BMS = bare-metal stent(s)

CABG = coronary artery

bypass graft surgery

CAC = coronary artery

calcification

CBA = cutting balloon

atherotomy

CKD = chronic kidney

disease

CT = computed tomography

DES = drug-eluting stent(s)

HU = Hounsfield units

LCA = laser coronary

atherectomy

MACE = major adverse

cardiovascular event(s)

MI = myocardial infarction

OA = orbital atherectomy

PES = paclitaxel-eluting

stent(s)

RA = rotational atherectomy

VSMC = vascular smooth

muscle cell

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(6,16). Secondary hyperparathy-roidism in CKD is also a riskfactor for CAC (5), and dialysisin younger individuals is associ-ated with similar calcium levels aswith advanced age (17). Addi-tionally, the renin-angiotensin-aldosterone system might play arole in medial artery calcification,because angiotensin II type-1receptor blockers abolishedCAC development in a pre-clinicalmodel (18).

In diabetic individuals, advancedglycation end-products mightpromote mineralization of micro-vascular pericytes, and tight gly-cemic control might slow CACin type 1 (but not type 2) diabetes(7,19). Moreover, the transcrip-tion factor proliferator-activatedreceptor gamma might deter cal-cification by inhibiting Wnt5a-dependent signaling in VSMCs(20,21).

The receptor activator of nu-

clear factor-kappaB ligand/osteoprotegerin pathway hasemerged as a potential link between osteoporosis and CAC(5). Osteoprotegerin acts as a decoy receptor, which coun-teracts the pro-osteoclastic and bone resorptive effects of thereceptor activator of nuclear factor-kappa pathway (5). Micedeficient in osteoprotegerin experience increased calcifica-tion and plaque progression (22). However, human epide-miologic data suggest that higher osteoprotegerin levels areassociated with CAC and cardiovascular events (23). Furtherstudy is required to elucidate the role of this pathway inCAC pathogenesis.

Interestingly, ingestion of a high-calcium diet has notbeen associated with CAC (24), and no relationship hasbeen observed between dietary calcium intake and CAD(25). These data suggest that CAC is the result of aberrantregulatory mechanisms rather than simple calcium overload.Enhanced understanding of the pathways that contributeto CAC is needed if more effective therapies are to bedeveloped.

Prevalence, Detection, and Prognosis

The prevalence of CAC is age- and sex-dependent, occur-ring in �90% of men and �67% of women older than70 years of age (26,27). Additionally, CAC is most frequentin Caucasians (28). The extent of CAC strongly correlateswith the degree of atherosclerosis and the rate of futurecardiac events (29–31).

Computed tomography (CT) is the only noninvasive testwith high sensitivity and specificity for calcium detection

and is capable of quantifying calcification (32). In large-scaleobservational studies, CT-scan–based calcium scoresadded prognostic value for predicting cardiac death andMI, especially in patients at intermediate risk for events(Fig. 1) (29,33–35). As a result, the most recent AmericanCollege of Cardiology/American Heart Association guide-lines note that noninvasive measurement of CAC score isreasonable for cardiovascular risk assessment in asymptom-atic patients at intermediate risk (those with a 10% to 20%rate of coronary events over 10 years; class IIa, Level ofEvidence: B) (36). Interpretation and utility of CAC scoresis dependent on the underlying risk profiles of patients forCAD (37).

As the CAC score increases, it loses sensitivity and gainsspecificity for predicting CAD (38,39). A CAC score of>0 Hounsfield units (HU) suggests some underlying athero-sclerosis, whereas scores �100 and �400 HU should promptrisk factor modification and further diagnostic evaluation,respectively (40). Asymptomatic persons without traditionalrisk factors but with a documented CAC score �400 HUmight have a worse cardiovascular prognosis than thosewith �3 risk factors but no CT-detected CAC (41).

Coronary angiography has low-moderate sensitivitycompared with grayscale intravascular ultrasound (IVUS)and CT for detection of CAC but is very specific (highpositive predictive value) (38,42,43). Angiographic CACis often classified into 3 groups: none/mild, moderate, andsevere. Severe calcification is most commonly defined asradiopacities seen without cardiac motion before contrastinjection, usually affecting both sides of the arterial lumen(Fig. 2), and moderate calcification as radiopacities notedonly during the cardiac cycle before contrast injection (44).

Intravascular ultrasound is substantially more accuratethan cineangiography for CAC detection, with sensitivityof 90% to 100% and specificity of 99% to 100% (45,46).The signature of calcified plaque on grayscale IVUS is abright echo with acoustic shadowing (47), and the extentof calcification can be graded by several metrics. The arcof calcium is classified as none, 1 quadrant (0� to 90�),

Figure 1 Select Studies Demonstrating Improved Risk Stratification of CHD Events With Use of CAC Scores

(A) With data from the MESA (Multi-Ethnic Study of Atherosclerosis) (35), a demonstration that the addition of the coronary artery calcification (CAC) score to Framingham risk

factors (age, sex, smoking, systolic blood pressure, use of antihypertensive medications, and lipid status) led to an improvement in prediction of coronary heart disease (CHD)

events. Specifically, there was a significant shift in the number of patients reclassified from intermediate (3% to 10% risk of CHD events in 5 years) to high risk (>10% risk of

CHD events in 5 years). (B) Similar findings are presented from the Rotterdam study (33). With the addition of CAC scores to a refitted Framingham model, 52% of men and

women from the intermediate-risk group were reclassified to a different risk category.

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2 quadrants (91� to 180�), 3 quadrants (181� to 270�), or4 quadrants (271� to 360�). Calcium location is defined assuperficial if present in the intimal-luminal interface, deep

Figure 2 Example of Severe Coronary Artery Calcification as Assess

Example of severe coronary artery calcification as assessed by angiography before (A) a

coronary artery, visible on the still image of A (arrows).

if within the medial-adventitial border or closer to theadventitia than the lumen, or both superficial and deep.Deposits can be assessed relative to the thickest plaque

ed by Angiography

nd after (B) contrast injection. Note the presence of calcium on both sides of the

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accumulation as concordant (center of calcium arc �45� ofthickest plaque accumulation), perpendicular (center of cal-cium arc 45� to 135� from thickest plaque accumulation),or opposite (center of arc of calcium �135� from thickestplaque accumulation). Finally, the calcium length can bemeasured (Fig. 3) (42,48). However, because ultrasounddoes not penetrate calcium, calcium thickness cannot bedetermined, and volume cannot be calculated.

Radiofrequency analysis of the IVUS signal allows forin vivo characterization of coronary plaque components,including fibrotic plaque, fibrofatty plaque, necrotic core, anddense calcium (49). In the PROSPECT (Providing RegionalObservations to Study Predictors of Events in the CoronaryTree) study in which 3-vessel coronary radiofrequency IVUSwas performed, patients with the highest dense calcium vol-umes were more likely to have high-risk atherosclerotic fea-tures and had the highest 3-year rates of major adversecardiovascular events (MACE), although not necessarilyarising from the calcified plaque itself (50–52).

Optimal coherence tomography (OCT) provides higher-resolution imaging (10 to 20 mm) than grayscale IVUS(150 to 200 mm). Optimal coherence tomography detectscalcium as low-intensity, low-attenuation areas with sharpborders (Fig. 3) (53). The sensitivity (95% to 100%) andspecificity (97% to 100%) of OCT for CAC rival that ofIVUS (46,53). Moreover, because light penetrates calcium,OCT can in many cases assess calcium thickness and mea-sure calcium volume (54).

Integrating anatomical and functional information willlikely improve upon the prognostic utility of establishedimaging techniques. In a recent study that combinedsingle-photon emission computed tomography myocardialperfusion imaging with CAC scoring, overlapping regionswith both calcification and poor perfusion strongly pre-dicted MACE (55). Dweck et al. (56) have employedradiolabeled 18F-sodium fluoride to visualize regions ofactive inflammation and calcification on positron emissiontomography, offering the promise to detect pre-clinicalCAC to facilitate earlier diagnosis, risk factor modification,and/or treatment.

Therapies for CAC

Medical therapy. Several studies have examined whethermedical therapy can halt or even reverse CAC progression(Table 2). In the St. Francis Heart Study, 1,005 patientswith calcium scores �80th percentile for age and sex wererandomized to atorvastatin 20 mg daily or placebo (57).Atorvastatin resulted in reduced low-density lipoproteinlevels and a nonsignificant decline in MACE with no effect,however, on CAC progression. Although selective renin-angiotensin-aldosterone system inhibition does not seemto significantly reduce CAC (58), no studies have investi-gated whether modulating the receptor activator of nuclearfactor-kappaB or proliferator-activated receptor gammapathways influences CAC in humans.

Calcium-channel blockers (59), hormonal therapy (60),phosphate binders (61,62), and most recently medicinalsupplements (63,64) have all been suggested to reduce CACprogression in small randomized trials and prospectivestudies. Larger prospective trials are required to definitivelyevaluate these approaches before they can be recommended.Percutaneous coronary intervention 1: balloon angioplastyand stents. CAC increases the likelihood of proceduralfailure and complications after balloon angioplasty (65,66).Noncompliant calcified plaques often require high-pressuredilation, increasing the risk for coronary dissection andthrombosis (66–68). Moreover, the force (tension) appliedfrom the balloon to the vessel wall might not be uniformacross the length of the lesion, due to varying amounts ofcalcification, further increasing the risk for dissection andacute vessel closure, MI, restenosis, and MACE (69–72).Extensive calcification in severely obstructive lesions impedesdevice delivery and increases the risk of procedural failure(73–75). As such, angiographic measures of proceduralsuccess, such as acute gain and diameter stenosis, are oftenworse in calcified lesions (66,68,76). Calcified lesions arealso associated with particulate embolization, resulting inincreased rates of peri-procedural myonecrosis (77,78).

Although implantation of bare-metal stents (BMS)compared with balloon angioplasty improves acute and long-term event-free survival in both calcified and noncalcifiedlesions, stent underexpansion, asymmetric expansion, andmalapposition are frequently observed in heavily calcifiedlesions (4,68,77). Eccentric compared with concentriccalcification is associated with less acute gain and noncircularstent geometry (68). Stent underexpansion in particular in-creases the risk for complications, including restenosis andstent thrombosis (4,79,80).

Several studies have shown that drug-eluting stents(DES) are more effective than BMS in calcified lesions(Table 3). Less neointimal hyperplasia in calcified (andnoncalcified) lesions after DES compared with BMS re-duces angiographic late loss, restenosis, and repeat revascu-larization (81–85). Moreover, multiple studies have reportedsimilar rates of stent thrombosis with DES and BMS incalcified lesions, with comparable rates of death and MI(74,81–84).

The extent to which CAC contributes to poor outcomesafter DES is controversial. Most studies have reportedcomparable rates of stent thrombosis, MI, and death afterpercutaneous coronary intervention (PCI) with DES incalcified and noncalcified coronary arteries (76,81,86,87).However, data with regard to the absolute efficacy of DES incalcified lesions are conflicting. Small-scale studies havesuggested that the degree of neointimal hyperplasia is similarin calcified and noncalcified lesions (85,88), suggesting thatthe potency of antiproliferative agents might be independentof CAC. Consistent with these studies are reports showingsimilar rates of angiographic restenosis and target lesionrevascularization in DES-treated calcified and noncalcifiedlesions (74,86,87). Conversely, other studies have reported

Figure 3 Intravascular Ultrasound Images of Mild, Moderate, and Severe Calcification

(A to C) Intravascular ultrasound images of mild, moderate, and severe calcification, visualized as superficial hyperechoic tissue with acoustic shadowing, delimited by the arc

of calcification relative to the center of the lumen (white arrows). (D to F) Corresponding slices obtained by optimal coherence tomography (OCT). Calcification by OCT is

visualized as a signal-poor or heterogenous region with sharply delineated borders. Because light (but not sound) can penetrate calcified tissue, the thickness of calcification

may be evaluated by OCT but not by intravascular ultrasound (white arrow in F).

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greater rates of restenosis and repeat revascularization inDES-treated calcified compared with noncalcified lesions(76,89). Potential risk factors for restenosis and repeatrevascularization include stent underexpansion, damage ofDES polymer coats by calcified lesions, or adjunctive use ofother devices (e.g., rotational atherectomy [RA]) that mightdirectly promote neointimal hyperplasia (76,90).PCI 2: devices to improve vessel compliance. CUTTING

AND SCORING BALLOONS. Cutting and scoring balloons do

not remove calcium. They improve vessel compliance bycreating discrete incisions in the atherosclerotic plaque,enabling greater lesion expansion and reducing recoil whilepreventing uncontrolled dissections (91). Studies evaluatingthe use of cutting balloon atherotomy (CBA) in calcifiedlesions are shown in Table 4. A meta-analysis of 4 ran-domized CBA versus balloon angioplasty trials (before theroutine stent era) in calcified and noncalcified lesions sug-gested that CBA is associated with similar rates of restenosis

Table 2 Studies of Medical Therapies for Targeting CAC Progression

First Author (Ref. #) Year N Design Intervention Outcomes

Motro and Shemesh (59) 2001 201 RCT Nifedipine vs. HCTZ/amiloride Nifedipine was associated with significantly reducedcoronary calcium progression at 3 years inhypertensive patients.

Chertow et al. (61) 2002 200 RCT Sevelamer vs. calcium-basedphosphate binder

Sevelamer was associated with significantly lower CACscore progression in hemodialysis patients at 52 weeks.

Arad et al. (57) 2005 1,005 RCT Atorvastatin vs. vitamin C vs.vitamin E vs. placebo

Treatment arms did not have a significant effect on CACprogression.

Houslay et al. (124) 2006 102 RCT Atorvastatin vs. placebo Statins had no significant effect on rate of CAC progression.

Manson et al. (60) 2007 1,064 RCT Estrogen vs. placebo Women treated with estrogen had significantly lowercalcified plaque burden.

Maahs et al. (58) 2007 478 CS ACEi/ARB vs. otherantihypertensives

Diabetics with albuminuria had nonsignificant reduction inCAC progression with ACEi/ARB treatment.

Qunibi et al. (62) 2008 203 RCT Calcium acetate/atorvastatinvs. sevelamer/atorvastatin

Calcium acetate and sevelamer groups had comparablerates of CAC progression in hemodialysis patientsat 1 year.

Budoff et al. (63) 2009 65 RCT AGE/vitamins B12 and B6/folic acid/L-arginine vs. placebo

Treatment group experienced significantly lower rates ofCAC progression at 1 year.

Zeb et al. (64) 2012 65 RCT AGE/CoQ10 vs. placebo AGE/CoQ10 was associated with significantly lower ratesof CAC progression at 1 year.

ACEi ¼ angiotensin-converting enzyme inhibitor; AGE ¼ aged garlic extract; ARB ¼ angiotensin receptor blocker; CAC ¼ coronary artery calcification; Co ¼ coenzyme; CS ¼ case series; HCTZ ¼ hydro-chlorothiazide; HRT ¼ hormonal replacement therapy; RCT ¼ randomized controlled trial.

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(odds ratio: 1.01, 95% confidence interval: 0.85 to 1.21)and MACE (odds ratio: 0.94, 95% confidence interval:0.78 to 1.14) compared with balloon angioplasty alone.However, MI and vessel perforation were more commonwith CBA (92).

Vaquerizo et al. (93) have more recently reported similaracute and intermediate-term outcomes (at 15 � 11 months)in calcified lesions pre-treated with CBA compared withRA before DES implantation. Whether these results applyto the most heavily calcified lesions is uncertain. Finally,

Table 3 Outcomes of Studies Comparing DES and BMS in Calcified L

First Author (Ref. #) InterventionFollow-Up(Months)

Resten(%

Moussa et al. (74) PES 12 7.5

BMS 18.3

p value 0.1

Seo et al. (82) SES 6–9 8.8

BMS 33.3

p value <0.0

Khattab et al. (83)* DES 9 7.4

BMS 52.7

p value 0.0

Rathore et al. (84)* DES 6–9 11.0

BMS 28.1

p value <0.0

Bangalore et al. (81)* DES 12 d

BMS d

p value d

Schwartz et al. (125)* DES d

BMS In-hospital d

PTCA d

p value d

*Used rotational atherectomy.BMS ¼ bare-metal stent(s); DES ¼ drug-eluting stent(s); MACE ¼major adverse cardiovascular event(s)

coronary angioplasty; SES ¼ sirolimus-eluting stent(s); TLR ¼ target lesion revascularization.

pre-dilation with a scoring balloon has been demonstrated toenhance DES expansion (94). This device might be a usefuladjunct to PCI in calcified lesions (95).

ROTATIONAL ATHERECTOMY. In contrast to cutting andscoring balloons, high-speed RA ablates coronary calcium.The RA device employs a diamond-coated elliptical burr,which can reach rotational speeds as high as 200,000 rpm,abrading hard tissue into smaller particles (<10 mm) whiledeflecting off softer elastic tissue (96). This principle ofdifferential cutting was confirmed by early IVUS-based

esions

osis)

TLR(%)

MI(%)

Death(%)

MACE(%)

5.1 4.1 2.5 11.8

11.9 3.2 0.8 16.8

0 0.09 0.68 0.29 0.27

7.9 0.0 0.0 7.9

19.5 0.0 2.4 24.4

5 NS NS NS <0.05

7.4 0.0 0.0 7.4

35.2 2.9 2.9 38.2

008 0.006 0.4 0.4 0.004

10.6 d d d

25.0 d d d

01 0.001 d d d

d 5.6 3.9 d

d 5.8 4.9 d

d 0.90 0.35 d

d 2.7 0.9 3.6

d 0.0 5.3 5.3

d 0.0 11.1 14.8

d 1.0 0.0246 0.047

; MI ¼myocardial infarction(s); PES ¼ paclitaxel-eluting stent(s); PTCA ¼ percutaneous transluminal

Table 4 Studies of Cutting and Scoring Balloons in Calcified Coronary Lesions

First Author (Ref. #) Year N Design Intervention Outcomes

Okura et al. (126) 2002 224 RCT CBA vs. PTCA CBA was associated with significantly greater lumencross-sectional area gain than PTCA in calcified lesions.Dissections were more common with CBA.

de Ribamar Costa et al. (94) 2007 299 CS DES vs. SBA/DES vs.semi-compliant balloon/DES

SBA was associated with greater stent expansion comparedwith direct stenting or stenting with pre-dilation withconventional balloons.

Grenadier et al. (95) 2008 521 CS SBA þ PTCA SBA was associated with high rates of procedural success(97.9%), with low rates of short- and long-term adverseoutcomes.

Vaquerizo et al. (93) 2010 145 CS RA � CBA þ DES Low rates of TLR and ST were observed with CBA alone andRAþCBA in patients receiving DES at 15 � 11 months.

Only studies with �100 patients were included.CBA ¼ cutting balloon atherotomy; RA ¼ rotational atherectomy; SBA ¼ scoring balloon angioplasty; ST ¼ stent thrombosis; other abbreviations as in Table 2 and 3.

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studies (97,98), which demonstrated that RA preferentiallyablates calcium deposits.

Studies assessing high-speed RA are summarized inTable 5. In the pre-stent era, use of RA alone was associatedwith increased neointimal hyperplasia, restenosis, and repeatrevascularization, most likely due to platelet activation andthermal injury (99–101). Moreover, patients with calcifiedlesions undergoing RA are at increased risk for thrombusformation and slow or no reflow, with increased rates ofperiprocedural MI (78). Although slow, deliberate passeswith or without glycoprotein IIb/IIIa inhibitors can reducethe burden of microparticle embolization, the risk of vesselperforation after RA in complex calcified lesions is alsoincreased (102).

BMS implantation after RA in calcified lesions facilitatesgreater acute lumen gains, although restenosis ratesremained high (68,103,104). DES use after RA has beenassociated with better long-term outcomes (83,84), although

Table 5 Studies of High-Speed RA in Calcified Coronary Lesions

First Author (Ref. #) Year N Design Intervention

Ellis et al. (99) 1994 316 MR RA and PTCA

Warth et al. (100) 1994 709 MR RA � PTCA

MacIsaac et al. (101) 1995 2,161 MR RA and PTCA

Hoffmann et al. (68) 1998 323 CS RA and BMS

Kobayashi et al. (104) 1999 126 CS RA and BMS

Dill et al. (127) 2000 502 RCT RA and PTCA

Whitlow et al. (128) 2001 500 RCT RA � PTCA

Clavijo et al. (105) 2006 150 CS RA and DES

Mezilis et al. (106) 2010 150 CS RA and DES

Rathore et al. (84) 2010 516 CS RA andDES vs. BMS

Schwartz et al. (125) 2011 158 CS RA andBMS or DES

Benezet et al. (107) 2011 102 CS RA and DES

Naito et al. (129) 2012 233 CS RA and DES

Abdel-Wahab et al. (75) 2013 240 RCT RA and DES

Only studies with �100 patients were included.MR ¼ multicenter registry; other abbreviations as in Tables 2 to 4.

case series reported inconsistent results (105–107). Recently,the prospective, randomized ROTAXUS (RotationalAtherectomy Prior to Taxus Stent Treatment for ComplexNative Coronary Artery Disease) trial was performed todetermine whether lesion preparation with RA beforepaclitaxel-eluting stent (PES) implantation provides benefitscompared with PES with balloon pre-dilation alone incalcified lesions (75). Among 240 patients with complexcalcified lesions randomized to RA or standard therapyfollowed by PES, strategy success was higher with RA pre-treatment (92.5% vs. 83.3%; p ¼ 0.03). However, despite anearly acute lumen gain advantage with RA, 9-monthangiographic follow-up revealed higher late loss in the RAgroup. Rates of restenosis, target lesion revascularization,definite stent thrombosis, and MACE were not significantlydifferent between the groups.

Thus, RA cannot routinely be recommended in calcifiedlesions if full balloon expansion is anticipated before DES

Outcomes

Greater procedural success compared with reports with PTCA alone.

Comparable success rates between RA and adjunctive PTCA.

No difference in procedural success or adverse outcome rates betweencalcified and noncalcified lesions with RA and adjunctive PTCA.

Greater acute lumen gain and final residual stenosis with adjunctive RA.

Lower restenosis rates with aggressive compared with less aggressive RA.

RA/PTCA vs. PTCA showed comparable rates of procedural success andadverse outcomes.

Aggressive RA with minimal ballooning offers no advantage over standard burrsizing followed by PTCA.

No difference in 6-month outcomes.

RA and DES showed low rates of adverse outcomes in heavily calcified lesionsup to 6 years.

RA with DES showed significantly lower rates of restenosis and TLR comparedwith BMS.

Procedural success with RA/stent placement higher than RA alone.

RA with DES has high procedural success and low rates of adverse outcomes.

No difference in TLR, all-cause or cardiac death, or MACE between PES and SES.

Greater acute gain but no difference in 9-month outcomes.

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implantation. The latest PCI guidelines state that RA is areasonable strategy in calcified lesions that are not crossableby a balloon catheter or adequately dilated before stentimplantation (Class IIa, Level of Evidence: C) (108). Lesionpreparation with RA before PCI is currently performedin approximately 8% of cases with calcified lesions in theUnited States (81). Additional studies are required todetermine the extent of calcification that necessitates RAbefore stenting.

LASER CORONARY ATHERECTOMY. Pulsed excimer or holmi-um laser energy generates transient high-pressure waves,which can dilate resistant lesions through a photoacousticmechanism (109–111). Studies evaluating laser coronaryatherectomy (LCA) in calcified and noncalcified lesions(Table 6) show inconsistent results and the potential forprocedural complications such as vessel dissection (especiallywith superficial calcium) and perforation and higher rates ofrestenosis (112,113). Furthermore, IVUS has not shownqualitative or quantitative evidence of substantial calciumablation by LCA (114). Nonetheless, LCA has a role incalcified lesions to shatter calcium behind previously-implanted stent struts in cases of marked stent under-expansion (115).

ORBITAL ATHERECTOMY. Similar to RA, orbital atherectomy(OA) exerts a differential ablative effect on hard and softsurfaces, producing particles <2 mm in size. This recentlyU.S. Food and Drug Administration-approved systemconsists of a diamond-coated crown, which orbits over theatherectomy guidewire in an elliptical path, exerting a cen-trifugal force on the vessel wall (116). In contrast to RA, theablative element is located laterally on the coil, which con-sists of 3 helically-wound wires that can be compressed withthe application of pressure like a spring. The device allowsthe physician to control ablation depth, with increasingrotational speed (ranging from 60,000 to 120,000 rpm)

Table 6 Studies of Laser Coronary Angioplasty in Calcified Coronary

First Author (Ref. #) Year N Design Intervention

Ghazzal al. (130) 1992 200 MR ELCA and PTCA

Bittl et al. (113) 1992 764 MR ELCA and PTCA

Bittl and Sanborn (131) 1992 200 MR ELCA and PTCA

Baumbach et al. (132) 1994 470 MR ELCA and PTCA

Mintz et al. (114) 1995 190 CS ELCA andPTCA or DCA

Reifart et al. (133) 1997 685 RCT ELCA, RA, or PTCA

Stone et al. (134) 1997 215 RCT HLCA and PTCA

Appelman et al. (135) 1998 308 RCT ELCA and PTCA

Badr et al. (136) 2013 119 CS ELCA � PTCA

Only studies with �100 patients were included.DCA ¼ directional coronary atherectomy; ELCA ¼ excimer laser coronary angioplasty; HLCA ¼ holmiu

translating to a larger orbit of rotation. In addition, orbitalmotion might allow for greater blood flow with less heatgeneration and thermal injury during the procedure (116).Like RA, OA might improve the compliance of calcifiedlesions to reduce procedural complications and facilitatestent placement.

After the ORBIT I (Safety and Feasibility of OrbitalAtherectomy for the Treatment of Calcified Coronary Le-sions) pilot study (116), 443 patients with severely calcifiedcoronary lesions were enrolled in the prospective, single-armORBIT II study (Pivotal Trial to Evaluate the Safety andEfficacy of the Diamondback 360� Orbital AtherectomySystem in Treating De Novo, Severely Calcified CoronaryLesions) (117). The in-hospital mortality rate after OA of0.2% compares favorably with the 1.7% rate after RA in theROTAXUS trial (75). The 89.8% primary safety endpointof 30-day freedom from MACE and 89.1% proceduralsuccess rate both exceeded performance goals. Future ran-domized studies are planned to evaluate the optimal tech-nique for OA use and to determine whether routine use ofOA before current-generation DES improves outcomes inhigh-risk patients with CAC.Coronary artery bypass graft surgery. Calcified vesselspose a technical challenge for the surgeon. Severely calcifiedlesions have been associated with atheroembolic complica-tions and incomplete revascularization after coronary arterybypass graft surgery (CABG), resulting in worse outcomesin high-risk patients (118,119). Additionally, patients withCAC are more likely to develop calcified saphenous veingrafts, a strong predictor of early and late graft failure (120).Among 755 patients with non–ST-segment acute coronarysyndromes undergoing CABG in the prospective ACUITY(Acute Catheterization and Urgent Intervention TriagestrategY) trial, severe CAC was independently associatedwith the occurrence of death or MI and MACE at 1 year(121). Thus, CAC impairs the results of both PCI and

Lesions

Outcomes

No difference in outcomes in calcified lesions treated with ELCA before PTCA.

High rate of restenosis (43%) in calcified lesions at 6 months. Significant increasein rate of complications in calcified vs. noncalcified lesions at 6 months.

Nonsignificant reduction in procedural success in calcified lesions.

No difference in rates of complications in calcified vs. noncalcified lesions treatedwith ELCA before PTCA.

Increase in lumen cross-sectional area without calcium ablation and with high rateof dissection (39%).

Greatest procedural success in RA group. Higher TLR with ELCA and RA.

Comparable rates of procedural success and long-term outcomes but greater ratesof in-hospital complications, MI, and MACE in those treated with HLCA beforePTCA than PTCA alone.

ELCA with adjunctive PTCA demonstrated no difference in 6-month outcomescompared with PTCA alone in calcified lesions.

Lower rates of angiographic success in calcified lesions compared with otherlesion types.

m laser coronary angioplasty; other abbreviations as in Tables 2 to 5.

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CABG. Additional studies are required to guide optimalrevascularization strategies and improve outcomes in pa-tients with severe CAC.

Conclusions and Future Directions

Patients with CAC are at high risk for the development ofsymptomatic CAD and MACE. Statins have not beenshown to halt the progression or affect the natural history ofCAC. Further studies are needed to determine whethernovel systemic therapies benefit patients with CAC. Amongpatients undergoing PCI, calcification proximal to and at thetarget lesion site directly contributes to suboptimal proce-dural results and worsened long-term outcomes. Althoughthe advent of DES has led to improved outcomes after PCIof CAC, long-term MACE rates remain high. Currently,adjunctive devices to improve lesion compliance, debulkplaque, and otherwise prepare the lesion for stenting arereserved for heavily calcified lesions and for those in whichstent delivery or expansion is otherwise anticipated to be orfound to be difficult. As such, many patients with heavyCAC are referred to CABG, especially if the distal coronaryanastomotic target segments are not heavily diseased orcalcified. Nevertheless, severe CAC poses technical chal-lenges to the surgeon as well, and results are suboptimal.

Further advances are needed in the early diagnosis, pre-vention, and treatment of CAC. Deeper understanding ofthe fundamental mechanisms underlying the pathogenesisand progression of CAC and its relationship with advancedatherosclerosis is necessary. Standardized screening in thegeneral population with improved calcium detection mightimprove outcomes if effective preventative therapies aredeveloped. At a minimum, the presence of CAC on CTimaging should prompt aggressive risk factor and lifestylemodification. In patients undergoing PCI of heavily calcifiedlesions, optimized methods of lesion preparation and cal-cium ablation are needed, as are safer and more effectiveantiproliferative therapies. In this regard, it has already beensuggested that bioresorbable vascular scaffolds might beuseful for calcified lesions (122), although optimal lesionpreparation will be essential, given their greater profile andpropensity to recoil. In the future, the societal impact ofCAC is likely to increase with an aging population, placinga premium on developing effective therapeutic strategiesfor this pandemic condition.

Reprint requests and correspondence: Dr. Philippe Généreux,Columbia University Medical Center and The CardiovascularResearch Foundation, 111 East 59th Street, 12th Floor, New York,New York 10022. E-mail: pg2295@columbia.edu.

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Key Words: coronary artery calcification - coronary artery disease - PCI.