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REVIEW TOPIC OF THE WEEK

Allograft VasculopathyThe Achilles’ Heel of Heart Transplantation

Sharon Chih, MBBS, PHD,a Aun Yeong Chong, MBBS, MD,b Lisa M. Mielniczuk, MD, MSC,a

Deepak L. Bhatt, MD, MPH,c Rob S.B. Beanlands, MDd

ABSTRACT

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Cardiac allograft vasculopathy (CAV) remains the Achilles’ heel of long-term survival after heart transplantation. Almost

one-third of patients develop CAV by 5 years post-transplant and 1 in 8 deaths beyond a year are due to CAV. Abnormal

vascular fibroproliferation in CAV occurs as a result of coronary endothelial inflammation, injury, and dysfunction trig-

gered by immune and nonimmune insults. Surveillance methods for CAV have significant limitations, particularly for

detecting early disease. Areas of investigation include myocardial and coronary blood flow quantification, and intra-

coronary imaging to detect early changes in the vessel wall and high-risk plaques. Treatment approaches continue to

evolve, but prevention remains the focus. Newer mammalian target of rapamycin inhibitors can significantly delay the

progression of CAV; however, their optimal use remains to be established. Further investigation is needed to understand

the complex pathophysiology of CAV, improve surveillance techniques, and develop therapies to prevent and slow

disease progression. (J Am Coll Cardiol 2016;68:80–91) © 2016 by the American College of Cardiology Foundation.

M ore than 5,000 heart transplants are per-formed annually worldwide, improvingthe survival of patients with advanced

heart disease (1). Cardiac allograft vasculopathy(CAV) has been a major impediment to successful

m aHeart Failure and Transplantation, Division of Cardiology, Departmen

tawa, Ontario, Canada; bInterventional Cardiology, Division of Cardiology,

titute, Ottawa, Ontario, Canada; cBrigham andWomen’s Hospital Heart &

ssachusetts; and dCardiac Imaging, Division of Cardiology, Department

tawa, Ontario, Canada. Dr. Bhatt has served on the advisory board for Car

rdiology, and Regado Biosciences; has served on the board of directors f

vascular Patient Care; has served as the chair of the American Heart Asso

ta monitoring committees for the Duke Clinical Research Institute, Ha

pulation Health Research Institute; has received honoraria from the Ame

nical Trials and News, ACC.org), Belvoir Publications (Editor-in-Chief, Ha

inical trial steering committees), Harvard Clinical Research Institute (clini

itor-in-Chief, Journal of Invasive Cardiology), Journal of the American C

pulation Health Research Institute (clinical trial steering committee), Slac

y’s Intervention), Society of Cardiovascular Patient Care (secretary/treas

ved as the deputy editor for Clinical Cardiology; has served as the vice-cha

s served as the chair of the VA CART Research and Publications Comm

traZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Isc

dicines Company; has received royalties from Elsevier (editor, Cardiovasc

ease); has served as a site coinvestigator for Biotronik, Boston Scientific

erican College of Cardiology; and has conducted unfunded research for F

ved as a consultant for and received grant support from Jubilant DraxIma

d has received research grant support from GE Healthcare, Lantheus Med

rs have reported that they have no relationships relevant to the content

nuscript received February 2, 2016; revised manuscript received March 3

long-term outcomes in heart transplantation. Regis-try data show a high incidence of CAV and minimalreduction over the past 2 decades, from 32% to 29%and 46% to 40% at 5 and 8 years post-transplant,respectively (1). Over the same period, 5-year survival

t of Medicine, University of Ottawa Heart Institute,

Department of Medicine, University of Ottawa Heart

Vascular Center and Harvard Medical School, Boston,

of Medicine, University of Ottawa Heart Institute,

dax, Elsevier Practice Update Cardiology, Medscape

or Boston VA Research Institute and Society of Car-

ciation Quality Oversight Committee; has served on

rvard Clinical Research Institute, Mayo Clinic, and

rican College of Cardiology (senior associate editor,

rvard Heart Letter), Duke Clinical Research Institute

cal trial steering committee), HMP Communications

ollege of Cardiology (guest editor, associate editor),

k Publications (chief medical editor, Cardiology To-

urer), and WebMD (CME steering committees); has

ir of the NCDR-ACTION Registry Steering Committee;

ittee; has received research funding from Amarin,

hemix, Medtronic, Pfizer, Roche, Sanofi, and The

ular Intervention: A Companion to Braunwald’s Heart

, and St. Jude Medical; has served as a trustee for

lowCo, PLx Pharma, and Takeda. Dr. Beanlands has

ge, Lantheus Medical Imaging, and General Electric;

ical Imaging, and Jubilant DraxImage. All other au-

s of this paper to disclose.

0, 2016, accepted April 5, 2016.

AB BR E V I A T I O N S

AND ACRONYM S

CAV = cardiac allograft

vasculopathy

CFR = coronary flow reserve

DSE = dobutamine stress

echocardiography

HLA = human leukocyte

antigen

IVUS = intravascular

ultrasound

MIT = maximal intimal

thickness

mTORi = mammalian target of

rapamycin inhibitor

OCT = optical coherence

tomography

PET = positron emission

tomography

SPECT = single-photon

emission computed

tomography

J A C C V O L . 6 8 , N O . 1 , 2 0 1 6 Chih et al.J U L Y 5 , 2 0 1 6 : 8 0 – 9 1 Cardiac Allograft Vasculopathy

81

for CAV detected within 3 years of transplant hasimproved marginally, from 71% to 76%, but remainslower than the 82% survival for patients withoutCAV (1). Notably, CAV is a leading cause of long-term mortality, accounting for up to 1 in 8 deathsbeyond a year post-transplant (1). Evolving defini-tions for CAV (Table 1) and changing trends in clin-ical practice, including the use of statins andmammalian target of rapamycin inhibitors (mTORi),have modified the natural history of disease (2).Furthermore, the recognition of early CAV as anadverse prognostic indicator has emphasized theimportance of early detection. Unfortunately, CAVsurveillance remains challenging, particularly fordetecting early disease by noninvasive imaging. Inlight of these ongoing challenges and developments,we shall review: 1) current understanding of CAVpathophysiology; 2) screening strategies, focusingon emerging imaging techniques that target assess-ment of coronary physiology and the arterial wall;and 3) therapeutic approaches, particularly the roleof mTORi.

PATHOGENESIS

CAV is an accelerated fibroproliferative diseaseaffecting the vasculature of the transplanted heart.Pathologically, smooth muscle proliferation, accu-mulation of inflammatory cells, and lipid depositioncause circumferential intimal thickening. In contrastto the focal, eccentric, proximal epicardial lesions inatherosclerosis, CAV is diffuse and affects epicardialand intramural vessels. Intravascular imaging hasshown disease occurs within the first year of trans-plant, and has a biphasic response, involving initialintimal thickening with expansion of the externalelastic membrane and relative preservation ofluminal area, followed by constrictive remodelingand luminal narrowing (3). Plaque compositionchanges from early fibrous and fibrofatty tissue to lateatheromatous necrotic core and calcification.

ENDOTHELIAL INJURY

CAV pathophysiology involves complex interplaybetween immune and nonimmune factors causingvascular inflammation, which triggers a final commonpathway of endothelial injury and fibroproliferativecellular responses (Central Illustration) (4). Theendothelium maintains vascular homeostasis throughregulation of vessel tone, inhibition of platelet acti-vation, thrombosis, leukocyte adhesion, and vascularsmooth muscle cell proliferation. In CAV, endothelialinjury initiates and drives a cascade of excessive

tissue repair mechanisms involving vascularcell proliferation, fibrosis, and remodeling.

IMMUNE FACTORS

Allograft endothelial cells express “foreign”human leukocyte antigens (HLA) that arerecognized by recipient T-lymphocytes.Activated T-lymphocytes secrete cytokines(interleukins 2, 4, 5, and 6; interferon-gamma;tumor necrosis factor-alpha), stimulatingT-lymphocyte proliferation and up-regulationof endothelial adhesion molecules (intercel-lular and vascular cell adhesion molecule-1,P-selectin), resulting in endothelial cell acti-vation and recruitment of inflammatory cells(5). Macrophages recruited to the intimasecrete cytokines (interleukin-1 and -6, tumornecrosis factor-alpha) and growth factors(platelet-derived growth factor, insulin-likegrowth factor-I, transforming growth factor-alpha and -beta) that cause smooth muscle

cell migration to the intima, proliferation, and extra-cellular matrix deposition. In vitro studies also show arole of the humoral response with high-titer class IHLA antibodies stimulating endothelial and smoothmuscle cellular proliferation through activation of themammalian target of rapamycin (mTOR)/S6 kinase/S6RP pathway, as well as redistribution of intracel-lular fibroblast growth factor receptors to the plasmamembrane (6,7). Circulating HLA antibodies havebeen associated with increased rejection and devel-opment of CAV (8).

NONIMMUNE FACTORS

Nonimmune insults predisposing to CAV includevascular risk factors (in both donors and recipients ofolder age, male sex, obesity, hyperglycemia, hyper-lipidemia), ischemic heart disease etiology, braindeath, organ preservation, and ischemia-reperfusioninjury. These share in common inflammatory injurycausing endothelial dysfunction. Cytomegalovirus(CMV) infection is associated with the developmentof CAV (9). CMV generates a proatherogenic milieuthrough production of inflammatory cytokines,expression of adhesion molecules, mononuclearactivation, and smooth muscle cell proliferation (10).CMV also impairs endothelial nitric oxide synthase–mediated coronary vasodilatation through increasedproduction of the nitric oxide synthase inhibitorasymmetric dimethylarginine (11). There is also evi-dence for CMV molecular mimicry of endothelial cellsurface molecules and subsequent immune-mediatedendothelial injury (12).

TABLE 1 ISHLT Recommended Nomenclature for CAV

Classification Severity Definition

CAV0 Nonsignificant No detectable angiographic lesion

CAV1 Mild Angiographic LM <50% orPrimary vessel with maximum lesion <70% orBranch stenosis <70%

CAV2 Moderate Angiographic LM <50%,Single primary vessel $70% orIsolated branch stenosis in 2 systems $70%

CAV3 Severe Angiographic LM $50% or$2 primary vessel $70% orIsolated branch stenosis in all 3 systems $70% orCAV1 or CAV2 with allograft dysfunction

(LVEF #45%) or evidence of significantrestrictive physiology

A “primary vessel” denotes the proximal and middle third of the left anterior descending artery,left circumflex, the ramus, and the dominant or codominant right coronary artery. A “secondarybranch vessel” includes the distal third of the primary vessels or any segment within a large septalperforator, diagonals, and obtuse marginal branch or nondominant right coronary artery.Restrictive cardiac allograft physiology is defined as symptomatic heart failure with echocardio-graphic E/A velocity ratio >2, isovolumetric relaxation time <60 ms, deceleration time <150 ms,or restrictive hemodynamics (right atrial pressure >12 mm Hg, pulmonary capillary wedge pres-sure >25 mm Hg, cardiac index <2 l/min/m2). Reprinted with permission from Mehra et al. (2).

CAV ¼ cardiac allograft vasculopathy; ISHLT ¼ International Society for Heart & Lung Trans-plantation; LM ¼ left main coronary artery; LVEF ¼ left ventricular ejection fraction.

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DIAGNOSIS AND PROGNOSTICATION

Routine surveillance is essential for early CAV diag-nosis, as patients are frequently asymptomatic.Classic symptoms of myocardial ischemia are usuallyabsent due to allograft denervation. Consequently,patients often present with atypical symptoms or lateafter the development of graft dysfunction with heartfailure, arrhythmia, or sudden death. Detection ofearly CAV is particularly challenging. Many noninva-sive modalities have been evaluated against coronaryangiography using references that representadvanced disease, such as coronary stenosis >50%.Additionally, angiography is a relatively insensitivemethod for diagnosing CAV (discussed subsequently).Invasive screening remains the accepted standard ofcare, with interest in newer techniques that enabledetailed imaging of the vessel wall, plaque charac-terization, and assessment of both coronary macro-and microvasculature.

NONINVASIVE IMAGING

Several noninvasive imaging modalities are used forCAV evaluation. Although acceptable results havebeen demonstrated as “rule out” tests for obstructiveCAV, none are ideal for detecting early disease(Table 2) (13).

STRESS ECHOCARDIOGRAPHY. Dobutamine stressechocardiography (DSE) is commonly used for CAVscreening. Sensitivity, specificity, positive predictivevalue (PPV), and negative predictive value (NPV)

compared with IVUS are 72%, 83%, 88%, and 62%,respectively (14). A normal DSE, however, has a high(92% to 100%) NPV for subsequent cardiac events,indicating prognostic value (14,15). A recent largeretrospective analysis (N ¼ 497) of 1,243 DSEs per-formed for CAV surveillance at a median of 8.7 yearspost-transplant reported a low 2% prevalence ofpositive DSE (79% negative, 11% nondiagnostic) and apoor (7%) sensitivity for angiographic CAV (16).Ischemia on DSE did not predict cardiovascular out-comes. Small studies suggest improved performancewhen DSE is combined with speckle tracking orcontrast echocardiography (17,18). In a Dopplercontrast echocardiography study (N ¼ 105), coronaryflow reserve (CFR) calculated from flow velocity inthe distal left anterior descending artery was lower inpatients who subsequently developed angiographicCAV: 2.4 � 0.6 versus 3.2 � 0.7 (18). A CFR# 2.5 wasindependently associated with a higher probability ofnew angiographic CAV and death.

MYOCARDIAL PERFUSION IMAGING. Single-photonemission computed tomography (SPECT) myocardialperfusion imaging (MPI) has been extensively inves-tigated in CAV. Similar to DSE, studies have shownprognostic value, but moderate diagnostic accuracy,likely related to a limited ability to detect balancedischemia, as may be expected with the typical diffusedisease of CAV (19,20). In the largest series (N ¼ 110),SPECT had 63% to 84% sensitivity and 70% to 78%specificity for detecting minor to severe ($50% ste-nosis) CAV (20).

Positron emission tomography (PET) MPI has su-perior diagnostic accuracy to SPECT for evaluation ofcoronary artery disease (21). The prognostic value ofPET perfusion and flow quantification is also welldemonstrated (22,23). Flow quantification using PETholds the most potential for early CAV diagnosis bydetecting homogenous reductions in flow that mayoccur with diffuse disease. This is in contrast to mo-dalities that identify disease on the basis of hetero-geneity in perfusion (or contractility), which rely ondifferences relative to a zone presumed to be normal.Such techniques define only the territory supplied bythe most severe stenosis, which underestimates dis-ease if it is diffuse with no normal reference region.Hence, flow quantification is better able to detectmicrovascular or diffuse disease (22). Small studies of19 to 27 patients have shown moderate inverse cor-relation between PET flow reserve and IVUS indexesof CAV (24,25). Prognostic value was also reported ina retrospective study (N ¼ 140) for PET parameters,including reduced stress myocardial blood flow andflow reserve (26). Prospective studies are needed.

CENTRAL ILLUSTRATION CAV Surveillance and Management

Intimal Hyperplasia

Myocardial Ischemia

Myocardial Fibrosis

Allograft Dysfunction

Macrovascular/Epicardial disease

Donor organ managementStatinAspirin

Cytomegalovirus prophylaxisImmunosuppression:

mycophenolic acid, mTORiTreat metabolic disorders,

rejection, infection

Vasodilators (CCB, ACEI)Endothelial protection*

(L-arginine, antioxidants)

InflammationLymphocyte and macrophage activation

Cytokine release

Endothelial Injury & DysfunctionVasomotor dysfunction

Thrombus formationLeukocyte adhesion

Smooth muscle cell proliferation

Risk FactorsNonimmune:Brain death

Organ preservation injuryIschemic reperfusion injury

Metabolic disordersCytomegalovirus infection

Immune:Rejection

HLA mismatchHLA antibodies

Microvasculardisease

PATHOPHYSIOLOGY MANAGEMENT

Coronary angiographyIntravascular ultrasound

Optical coherence tomography*CT coronary angiography*

EVALUATION

Biomarkers*Gene expression profiling*

Biomarkers*Gene expression profiling*

Coronary angiographyIntravascular ultrasound

Optical coherence tomography*Invasive coronary flow*

CT coronary angiography*

Stress echocardiographyMyocardial perfusion imaging

Myocardial flow quantification*

Cardiac magnetic resonance imaging*

EchocardiographyCardiac magnetic resonance imaging

mTORi

Percutaneous coronary intervention

Retransplantation

Chih, S. et al. J Am Coll Cardiol. 2016;68(1):80–91.

Immune and nonimmune factors cause endothelial inflammation and injury, triggering vascular fibroproliferation of the coronary vasculature and allograft dysfunction.

Cardiac allograft vasculopathy (CAV) pathogenesis targets for established and investigational (bold italics) evaluation methods and treatments are shown.

*Investigational. ACEI ¼ angiotensin-converting enzyme inhibitor; CCB ¼ calcium-channel blockers; CT ¼ computed tomography; HLA ¼ human leukocyte antigen;

mTORi ¼ mammalian target of rapamycin inhibitor.

J A C C V O L . 6 8 , N O . 1 , 2 0 1 6 Chih et al.J U L Y 5 , 2 0 1 6 : 8 0 – 9 1 Cardiac Allograft Vasculopathy

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TABLE 2 Imaging Techniques for CAV

ModalitySurveillance

Recommendations* Information Strengths Limitations

Noninvasive

Stressechocardiography

Class IIa for DSE Cardiac structure and functionRegional wall motionMyocardial deformationMyocardial perfusionCoronary flow reserve

AvailabilityPrognostic

Dependent on acoustic windows

SPECT Class IIa Myocardial perfusionVentricular function

AvailabilityPrognostic

Radiation exposure

PET Not included Myocardial perfusionMyocardial flow quantificationVentricular function

Quantify global/regionalmyocardial blood flow

Quantify global/regionalmyocardial flow reserve

Some prognostic dataLess radiation versus

angiography and SPECTRapid sequential rest-stress

testing with Rb-82On-site cyclotron not

required for Rb-82

Limited availabilityRadiation exposure

CMR imaging Not included Cardiac structure and functionMyocardial perfusionLate gadolinium enhancement

SafetyComprehensive cardiac

evaluation

High resting heart rates post-transplant

Cardiac devices contraindicatedChallenging perfusion

quantification softwareNephrogenic systemic fibrosis in

renal failure

CTCA Class IIb Coronary stenosisCoronary calcification

Evaluation of arteriallumen and wall

High resting heart rates post-transplant

Radiation exposureContrast-induced nephropathyLimited ability to assess smaller

vessels

Invasive

Coronaryangiography

Class I Coronary stenosisMyocardial blush

Prognostic Evaluation limited to epicardialvessels

Insensitive for detection of earlydisease

Insensitive for detection ofdiffuse disease

Radiation exposureContrast nephropathy

IVUS Class IIa Arterial wallArterial lumenPlaque volumePlaque characterization

High tissue penetrationHighly prognostic

Evaluation limited to epicardialvessels

CostLimited availability

OCT Not included Arterial wallArterial lumenPlaque volumePlaque characterization

High spatialresolution (10 mm)

Evaluation limited to epicardialvessels

Reduced tissue penetration(compared with IVUS)

CostLimited availability

Coronary flow Not included Fractional flow reserveCoronary flow reserveIndex of microcirculatory

resistance

Functional evaluationof epicardial vesselsand microvasculature

Risk of enhanced sensitivity toadenosine

CostLimited availability

*International Society of Heart & Lung Transplantation (13).

CAV ¼ cardiac allograft vasculopathy; CMR ¼ cardiac magnetic resonance; CTCA ¼ computed tomography coronary angiography; DSE ¼ dobutamine stress echocardiogram;IVUS ¼ intravascular ultrasound; OCT ¼ optical coherence tomography; PET ¼ positron emission tomography; Rb ¼ rubidium; SPECT ¼ single-photon emission computedtomography; Tc ¼ technetium.

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Small studies have evaluated cardiac magneticresonance (CMR) MPI for detecting CAV. An earlystudy showed good correlation between myocardialperfusion reserve and invasive CFR, as well as highaccuracy for detecting angiographic CAV (27). In

another study, myocardial perfusion reserve was anindependent predictor of CAV and had high diag-nostic performance for moderate CAV disease (areaunder the curve: 0.89) (28). Both typical and atypicalinfarct patterns of delayed gadolinium enhancement

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have been observed in patients with absent or mildangiographic disease, suggesting possible early CAV(29). Important limitations for clinical application inthe transplant population include high resting heartrates from denervation posing difficulties for imageacquisition, pacemakers contraindicating CMR, andthe risk of nephrogenic systemic fibrosis with severerenal impairment.COMPUTED TOMOGRAPHY CORONARY ANGIOGRAPHY.

New-generation multislice multidetectors and dual-source technology have improved spatial and tem-poral resolution of computed tomography coronaryangiography (CTCA). A meta-analysis of prospectivetrials in CAV (N ¼ 615) reported 94% sensitivity, 92%specificity, 99% NPV, and 67% PPV for stenosis $50%on invasive angiography (30). As expected, sensitivity(81%) and NPV (50%) were lower when CTCA wascompared with IVUS. Radiation dose (3 to 18 mSv) andcontrast (60 to 115 ml) were not insignificant. Impor-tant limitations for CAV include poor visualizationof the distal coronary arteries and high restingheart rates.

INVASIVE IMAGING

CORONARY ANGIOGRAPHY. Coronary angiographyis the accepted clinical standard for CAV diagnosis onthe basis of clinical availability and prognostic sig-nificance (13). Large multi-institutional analysesshow an approximate 19% likelihood of progression tosevere CAV within 5 years once disease is evident onangiography (31). Severe angiographic CAV (>70%stenosis left main, $2 primary vessels, or 3 coronarysystems) is associated with a 5-year 50% likelihood ofdeath or retransplantation (31). These findings wereintegrated into 2010 society recommendations forCAV nomenclature (Table 1) (2). Despite its prognosticutility, angiography is an insensitive tool for detect-ing CAV, due to inability to visualize beyond thearterial lumen and larger epicardial vessels. These aresignificant limitations, as the diffuse, concentric, andlongitudinal nature of CAV disease, as well asexpansive vascular remodeling, cause absence or lateluminal obstruction (Figure 1A).

INTRAVASCULAR ULTRASOUND. IVUS is a usefuladjunct to angiography, providing cross-sectionalimaging of the lumen and vessel wall that improvesdetection of angiographic occult CAV (Figure 1B)(32,33). The prognostic value of IVUS in CAV is welldemonstrated. Rickenbacher et al. showed that pa-tients with maximal intimal thickness (MIT) >0.3 mmat 1 year post-transplant had a 3-fold increased risk ofdeveloping angiographic CAV and reduced 4-yearsurvival (73% vs. 96%) (34). In another study, severe

intimal thickening (average MIT 0.9 � 0.3 mm) wasassociated with a 10-fold increased risk of major car-diovascular events (32). Rapidly progressive CAV,defined as an increase in MIT $0.5 mm within 1 yearof transplant has also been shown to predict thedevelopment of angiographic CAV (65% vs. 33%),death/graft loss (21% vs. 6%), and cardiovascularevents at 5 years (33). Recently, prognostic relevancewas demonstrated for an increase in MIT $0.35 mmon IVUS performed later, at 1 and 5 years post-transplant (35). Plaque components can also beexamined on IVUS by virtual histology. Using thistechnique, Raichlin et al. (36) observed an associationbetween rejection and inflammatory plaques (pres-ence of necrotic core and dense calcium $30%), andsubsequent CAV progression.

OPTICAL COHERENCE TOMOGRAPHY. Optical coherencetomography (OCT) provides high (10 to 20 mm) reso-lution (10-fold greater than IVUS) intravascular im-aging that is ideally suited for assessing the vesselintima and plaque morphology (Figure 2). OCT-measured intimal thickness and plaque characteris-tics have been validated against histology and IVUS.Preliminary OCT studies have added insight on CAVpathogenesis. Increased atherosclerotic and vulner-able plaque characteristics are observed with greatertime from transplantation (37). Suggesting a potentialrole for neovascularization in CAV, Ichibori et al. (38)reported increased microchannels in patients morethan a year post-transplant, which also correlatedwith intimal volume and coronary risks. In support ofrejection as a CAV risk factor, Dong et al. (39) showedthat high-grade cellular rejection was associated withthicker intima and macrophage infiltration. Limita-tions of OCT include cost, contrast requirements, andlower tissue penetration that limits assessment ofdeep plaque features. Prospective studies are neededto determine whether OCT-derived measurementscorrelate with clinical outcomes.

INVASIVE CORONARY FLOW STUDIES. CAV affectsboth epicardial and microcirculatory compartments,causing complex changes in coronary physiology.Invasive coronary sensor “pressure” and “flow” wiresallow independent assessment of the epicardial ar-teries and microvasculature by measuring fractionalflow reserve (FFR) and index of microcirculatoryresistance (IMR), respectively. Coronary flow acrossboth macrovascular and microvascular compartmentsis measured by CFR. Discordant normal FFR andreduced CFR have been reported after heart trans-plantation, representing diffuse epicardial or micro-vascular CAV (Figure 1C) (40). Similarly, for a givenepicardial plaque burden, FFR has been observed to

FIGURE 1 Invasive Coronary Evaluation of CAV

(A) Angiogram demonstrating diffuse left anterior descending artery (LAD) disease without focal stenosis. (B) Intravascular ultrasound

demonstrating LAD intimal thickening (maximal intimal thickness ¼ 1.3 mm). (C) Intracoronary flow studies demonstrating normal fractional

flow reserve (0.91) and reduced coronary flow reserve (1.2). CAV ¼ cardiac allograft vasculopathy.

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increase, whereas IMR deteriorated (41). Bothscenarios likely reflect the reduced physiologicalimpact of epicardial disease in the presence ofmicrovascular dysfunction and increased micro-vascular resistance as the maximal achievable coro-nary flow is diminished (Online Figure 1). Theseobservations highlight the importance of evaluatingboth epicardial arteries and microvasculature in CAV,as both are affected and changes in one may affectassessment in the other. Furthermore, the microvas-culature is affected early, and small studies haveshown that microvascular dysfunction, as measuredby reduced CFR, increased IMR, or abnormal vaso-constrictor response to acetylcholine, predicts thedevelopment of intimal thickening and angiographicCAV (42,43).

MANAGEMENT

Management of CAV is focused on primary preven-tion, imaging surveillance, and early treatment.Figure 3 shows a proposed algorithm for CAV sur-veillance and management.

MEDICATIONS

ASPIRIN. Antiplatelet therapy has not been wellexamined in heart transplantation. Aspirin is usedempirically, on the basis of presumed microthrombiformation at sites of immune injury in the coronaryendothelium. Interestingly, an ex vivo platelet func-tion study showed marked platelet aggregation inresponse to adenosine diphosphate and aspirin

FIGURE 2 Optical Coherence Tomography

(A) Minimal eccentric intimal thickening. (B) Eccentric fibrofatty plaque.

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resistance in heart transplant patients compared withnative coronary disease and healthy controls (44). Alower response to platelet stimulation was demon-strated in a small subset of transplant patientsreceiving 500 mg aspirin.

STATINS. Statins are standard care post-transplant.In addition to reduction in cholesterol, statins alsoinhibit inflammatory and immune responses,including inhibition of natural killer cell cytotoxicity(45). In a landmark trial (N ¼ 97), pravastatin initiated2 weeks post-transplant improved lipid profiles, andreduced severe rejection, CAV, and mortality (46). Ameta-analysis of 3 randomized trials showed statinsreduced 1-year mortality from 17% to 5% (47).

VASODILATORS. Small studies of calcium-channelblockers and angiotensin-converting enzyme in-hibitors suggest improved microvascular functionand delayed development of CAV (48,49). A placebo-controlled randomized trial showed diltiazem,commenced 2 to 4 weeks after transplant, decreasedreduction in angiographic coronary diameter andincreased 5-year freedom from graft loss or angio-graphic disease (56% vs. 30%) (48). A combination ofan angiotensin-converting enzyme inhibitor and acalcium-channel blocker was shown to be superior toeither medication alone for reducing the develop-ment of CAV (49).

IMMUNOSUPPRESSION. Mycophenolic acid reducesprogression of intimal thickening compared withazathioprine and is the preferred antimetabolite in

over 80% of patients (1). The mTORis sirolimus andeverolimus inhibit vascular smooth muscle andfibroblast proliferation. Summarized in Table 3 arerandomized controlled studies of mTORis in de novoheart transplant recipients, demonstrating reducedCAV incidence and progression (50–53). Traditionally,calcineurin inhibitors (CNI) have formed the foun-dation of maintenance immunosuppression, signifi-cantly reducing rejection and improving survival. Incontrast to the CNI-reduced strategy in many of thede novo mTORi studies, the SCHEDULE (SCandina-vian HEart transplant everolimus De novo stUdy withearLy calcineurin inhibitors avoidancE) trial adopteda CNI-free regimen involving cyclosporine with-drawal by 7 to 11 weeks post-transplant (52).Grade $2R rejection was increased with the CNI-freeapproach (Table 3). The effect of mTORi on CAV hasalso been examined in maintenance heart transplantpatients. Mancini et al. (54) randomized patients withsevere CAV at 4.3 � 2.3 years post-transplant toconversion from mycophenolate/azathioprine tosirolimus (n ¼ 22) or usual immunosuppression(n ¼ 24). Sirolimus slowed CAV progression by asemiquantitative catheterization score, but no differ-ence was observed on IVUS. Additional studiesincluded patients with and without CAV. Topilskyet al. (55) demonstrated attenuation of CAV on IVUS inpatients converted to sirolimus with CNI withdrawal(n ¼ 45) at 1.2 years post-transplant compared withpatients continued on usual immunosuppression(n ¼ 58). In another study (N ¼ 29, 3.8 � 3.4 years

FIGURE 3 Proposed Algorithm for CAV Surveillance

and Management

Post-transplant cardiac allograftvasculopathy (CAV) prevention

Vascular risk factor managementAvoidance of rejection

Cytomegalovirus prophylaxisAspirin Statin

De novo mTORi

Early post-transplant CAV surveillance

Does patient have CAV?*

Coronary angiography ± intravascular ultrasoundat 6 weeks and 12 months

Continue CAV prevention

Annual CAV surveillanceCoronary angiography +/- intravascular ultrasound

for ≤5 years post-transplantNon-invasive imaging for ≥6 years

Therapeutic considerations:• Conversion to mTORi early

post-transplant• Percutaneous coronary

intervention for obstructive focal disease

• Retransplantation for severe ISHLT grade 3 CAV with allograft dysfunction

Preventive measures early post-transplant include consideration

of de novo mammalian target of rapamycin inhibitor (mTORi).

Surveillance in the first year and annually, up to 3 to 5 years post-

transplant, is by invasive angiography and, if available, intra-

vascular ultrasound (IVUS). Beyond 5 years, noninvasive imaging

(dobutamine stress echocardiography, myocardial perfusion

imaging, or computed tomography coronary angiography) could

guide the need for invasive testing. Treatment options include

conversion to mTORi (particularly if early post-transplant);

percutaneous coronary intervention for focal obstructive disease;

and retransplantation in selected patients with severe CAV and

associated allograft systolic dysfunction. *International Society

for Heart & Lung Transplantation (ISHLT) cardiac allograft vas-

culopathy (CAV) grade 1 to 3 or $0.5 mm increase in maximal

intimal thickness on serial IVUS.

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post-transplant), CNI substitution with sirolimusslowed CAV progression on IVUS, but there was nodifference in the subgroup of patients more than 2years post-transplant (56). Similarly, the random-ized NOCTET (Nordic Everolimus [Certican] Trial inHeart and Lung Transplantation) substudy (N ¼ 111)demonstrated no effect on CAV progression in pa-tients converted to everolimus at an average of 5.8years post-transplant (57). Hence, late conversion tomTORi appears ineffective, likely related todiffering plaque composition at various stages ofCAV development. An IVUS study showed signifi-cantly less plaque volume progression and greaterreduction in the fibrous plaque component in pa-tients converted to sirolimus #2 years, but not laterpost-transplant (58). On the basis of these studies,many programs consider early conversion to mTORiif there is evidence of CAV. Importantly, the po-tential benefits of mTORi need to be balancedagainst significant intolerance, with the need formedication cessation in up to a third of patients.Adverse effects when mTORis are used in theearly post-operative period include pericardial ef-fusions, wound healing problems, and bacterial in-fections. It is unclear whether adverse effects arerelated to dosing and whether tolerability can beimproved by delaying introduction up to 3 monthspost-transplant, after operative recovery and woundhealing.

REVASCULARIZATION

Revascularization for CAV is limited by diffuse coro-nary disease and high mortality with surgical inter-vention. Percutaneous coronary intervention is oftenundertaken for focal disease, despite the lack of evi-dence for any survival advantage over medical ther-apy. A single-center study (N ¼ 105) showed a high31% stent restenosis rate associated with lowerfreedom from a composite endpoint of death,myocardial infarction, or retransplantation at 7 yearsfollow-up (28% vs. 63%), driven primarily by lowersurvival (39% vs. 84%) (59). A systematic review (N ¼312) found that drug-eluting stents reduced the long-term risk of stent restenosis compared with bare-metal stents, but without any difference in clinicalendpoints, including survival (60).

RETRANSPLANTATION

Current consensus recommendations reserve re-transplantation for selected patients with advancedCAV (61). Retransplantation is controversial becauseof organ shortages, lower survival, and increased CAV

TABLE 3 Randomized Trials of De Novo mTORi in Heart Transplantation

First Author (Ref. #)Year

Study Name Immunosuppression NumberFollow-Up(months) Intravascular Ultrasound Rejection Findings

Arora et al. (52)2015SCHEDULEMulticenter

(Scandinavia)

RAD þ MMF (n ¼ 47)versusCsA þ MMF (n ¼ 48)

CsA withdrawnweek 7–11for RAD group

95 of 115(83%)

12 MIT $0.5 mm*– RAD: 51%– CsA: 65%MIT change*– RAD: 0.03 � 0.06 mm– CsA: 0.08 � 0.12 mmAtheroma volume change*– RAD: 1.3 � 2.3%– CsA: 4.2 � 5.0%Atheroma volume change*– RAD: 1.1 � 19.2 mm3

– CsA: 13.8 � 28.0 mm3

BPAR, p ¼ NS– RAD: 77%– CsA: 63%$2R grade*– RAD: 43%– CsA: 15%

Allograft function NSInfection– Less CMV for RAD: 5%

versus 31%*– Bacterial NSImmune markers– Decline in sTNF-1 for RAD– Others NS: CRP, VEGF,

VCAM-1, vWF, IL-8

Kobashigawa et al. (50)2014RAD A2310 substudyMulticenter (Europe,

America, Australia,New Zealand,Taiwan)

RAD 1.5 mg þ CsA (n ¼ 88)versusMMF þ CsA (n ¼ 101)

RAD 3.0 mg groupterminated earlydue to increasedmortality

189 of 553(34%)

12 MIT change $0.5 mm*– RAD: 13%– MMF: 27%MIT change*– RAD: 0.03 � 0.05 mm– MMF: 0.07 � 0.11 mmIntimal volume*– RAD: 2.04 � 7.00 mm3

– MMF: 7.74 � 12.93 mm3

$2R grade, p ¼ NS– RAD: 22%– MMF: 25%

Graft loss/retransplant/deathNS

Serious adverse event*– RAD: 71%– MMF: 58%Pericardial effusion*– RAD: 43%– MMF: 28%Infection*– Less CMV for RAD: 8%

versus 21%– More bacterial for RAD: 30%

versus 22%

Keogh et al. (51)2004Multicenter (Australia,

New Zealand)

SRL þ CsA (n ¼ 92)versusAZA þ CsA (n ¼ 44)

136 24 MIT*– SRL: 0.5 � 0.3 mm– AZA: 0.9 � 0.3 mmAtheroma volume*– SRL: 18.3 � 11.3%– AZA: 28.7 � 15.3%Atheroma volume*– SRL: 5.7 � 4.1 mm3

– AZA: 7.1 � 4.7 mm3

$2R grade 6 months*– SRL 3 mg/day: 32%– SRL 5 mg/day: 33%– AZA: 57%

12-month survival NS

Eisen et al. (53)2003RAD B253Multicenter (Europe,

America)

RAD 1.5 mg þ CsA (n ¼ 209)versusRAD 3 mg þ CsA (n ¼ 211)versusAZA þ CsA (n ¼ 214)

634 12 MIT change $0.5 mm*– RAD 1.5: 36%– RAD 3: 30%– AZA: 53%MIT change*– RAD 1.5: 0.04 mm– RAD 3: 0.03 mm– AZA: 0.10 mm

$2R grade*– RAD 1.5: 31%– RAD 3: 21%– AZA: 46%

Infection*– Less CMV for RAD: 8%

versus 22%– More bacterial for RAD:

33%–38% versus 25%

*p < 0.05.

AZA ¼ azathioprine; BPAR ¼ biopsy-proven acute rejection; CMV ¼ cytomegalovirus; CRP ¼ C-reactive protein; CsA ¼ cyclosporine; IL-8 ¼ interleukin-8; MIT ¼ maximal intimal thickness; MMF ¼mycophenolic acid; mTORi ¼ mammalian target of rapamycin inhibitor; NS ¼ nonsignificant; RAD ¼ everolimus; SRL ¼ sirolimus; sTNF-1 ¼ soluble tumor necrosis factor-1; VCAM-1 ¼ vascular cellularadhesion molecule-1; VEGF ¼ vascular endothelial growth factor; vWF ¼ von Willebrand factor.

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compared with de novo transplantation (1). A recentregistry analysis reported comparable 9-year survivalamong patients with CAV retransplanted (n ¼ 65) ormedically managed (n ¼ 4,530): 55% versus 51% (62).Subgroup analysis suggested a survival benefit forretransplantation with associated allograft systolicdysfunction. This finding is supported by earlierstudies showing lower 5-year survival in patientswith CAV and either allograft systolic dysfunction orrestrictive cardiac physiology (63).

CONCLUSIONS

CAV is a leading cause of death after heart trans-plantation. Early rapid intimal thickening predicts the

development of angiographic disease and adversecardiac outcomes, including reduced survival.Accordingly, prevention strategies must be imple-mented early, and surveillance techniques targetingdetection of early disease are essential. It is likely thatan invasive approach will best identify early CAV,combining high-resolution examination of the vesselintima by IVUS or OCT and coronary physiologystudies to assess the coronary macro- and microvas-culature. Furthermore, invasive assessments willlikely aid our understanding of CAV pathophysiologyand provide insight into potential noninvasive ap-proaches. Investigation in noninvasive imaging isongoing and will most likely have highest utility inmedium- to long-term follow-up and reduce the need

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for invasive testing. Current management is focusedon prevention strategies directed at modifiable im-mune and nonimmune targets. The mTORis havebeen a significant advance in slowing progression ofCAV, but their optimal use needs to be establishedwith further randomized studies.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Sharon Chih, Heart Failure and Transplantation,University of Ottawa Heart Institute, 40 RuskinStreet, Ottawa, Ontario K1Y 4W7, Canada. E-mail:schih@ottawaheart.ca.

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KEY WORDS coronary and myocardial flowreserve, endothelial injury, heart transplant,intimal hyperplasia, intravascularultrasound, mammalian target of rapamycininhibitors

APPENDIX For a supplemental figure, pleasesee the online version of this article.