The role of non-invasive imaging in the diagnosis of cardiac allograft vasculopathy

Miller; Non-invasive assessment of cardiac allograft vasculopathy

Christopher A Miller, MBChB1; Saqib Chowdhary, PhD1; Simon G Ray, MD1; Jaydeep

Sarma, PhD1; Simon G Williams, MD1; Nizar Yonan, MD1; Tarun K Mittal, MD2; Matthias

Schmitt, MD, PhD1.

1. North West Regional Heart Centre and Heart and Lung Transplant Unit, University

Hospital of South Manchester, Wythenshawe, Manchester, UK.

2. Harefield Hospital, Royal Brompton & Harefield NHS Trust, Middlesex, London, UK.

Correspondence to; Dr Christopher Miller, North West Regional Cardiac Centre, University

Hospital of South Manchester, Wythenshawe, Manchester, UK. Tel: +441612914940. Fax:

+441612914940. Email: chrismiller@doctors.org.uk

Manuscript ID number: CIRCCVIM/2010/961425 – Version 3

Word count: 6180

Subject codes: [29]Coronary imaging, [30]CT and MRI, [31]Echocardiography, [32]Nuclear

cardiology and PET, [37]CV surgery.

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Introduction

Cardiac allograft vasculopathy (CAV) is common, with a prevalence of 52% at 10-years post-

transplantation, and represents a leading cause of death beyond the first year, responsible

for approximately 15% of deaths annually.1 It is characterised by diffuse and concentric

intimal proliferation, typically involving the intramural, as well as epicardial coronary arteries.

Its diagnosis is difficult to establish clinically due to denervation of the transplanted heart.

Consequently it presents late with silent myocardial infarction, progressive heart failure or

arrhythmic sudden death.2 Screening is therefore required for its early detection.

Whilst coronary intravascular ultrasound (IVUS) is considered the ‘gold-standard’ technique

for detecting the anatomical features of CAV (Table 1), its broad clinical use in this context is

limited by cost and lack of widespread expertise, and its evaluation is limited to epicardial

vessels.3 Coronary angiography, performed annually or biannually, remains the most

common clinical screening method.4 However due to the diffuse nature of CAV with a lack of

‘normal reference’ segments and the relatively late occurring luminal narrowing, the

sensitivity of angiography is as low as 30% when compared to IVUS (Figure 1).5 As a result,

complications frequently occur before disease is evident angiographically.6 Furthermore,

angiography is associated with significant, albeit uncommon complications (overall

complication rate 7.4/1000 procedures, including rates of 0.65/1000, 1.6/1000 and 0.72/1000

for cerebrovascular accidents, vascular complications and death respectively), is disliked by

transplant recipients, is costly and repeated studies are associated with an important

cumulative radiation dose.7

Non-invasive screening would conceivably be safer, more tolerable and cheaper and as

such is highly desirable. Echocardiography and single photon emission computed

tomography (SPECT) are the most extensively investigated, but neither has become widely

3  

 

accepted as an alternative to invasive screening. Preliminary data regarding positron

emission tomography (PET), cardiovascular magnetic resonance (CMR) and coronary

computed tomography angiography (CTA) suggests these modalities may prove to be more

effective.

The evaluation of imaging modalities faces two particular challenges. First, invasive coronary

physiological assessment demonstrates that the functional significance of CAV represents a

complex interplay between epicardial and microvascular coronary compartments.8 Both must

be taken into account for accurate diagnosis. Second, as described, the clinical standard for

detecting CAV (i.e. angiography) has limited sensitivity. Therefore studies using this as the

sole comparator are inherently limited in the information they provide. Furthermore

angiographic coronary stenoses of 50% or 70%, often used as the significance threshold in

such studies, represent advanced disease. Adverse events frequently occur well before this

degree of luminal narrowing is reached.

The pathophysiology, invasive diagnostic assessment and treatment of CAV have been

extensively reviewed in a recent article by Schmauss at al.4 This review will focus on the

non-invasive imaging approaches for the diagnosis of CAV.

Echocardiography

The sensitivity of resting left ventricular ejection fraction and regional wall motion for

detecting CAV is low at less than 50% across multiple studies, although the specificity of

regional dysfunction is much higher (more than 80%) and should prompt further

investigation.9 Tissue Doppler imaging may improve sensitivity, indeed a study using pulsed-

wave tissue Doppler obtained at the basal left ventricular inferolateral wall in nearly 300

transplant recipients found a peak systolic wall motion velocity <10cm/s had a 97% positive

4  

 

predictive value for CAV, whereas a value of >11cm/s had a 90% negative predictive

value.10 The comparator was angiography and IVUS (those without angiographic evidence of

CAV also underwent IVUS) (Figure 2).

Stress echocardiography is the most widely investigated functional imaging technique for

detecting CAV, although published studies are relatively small with heterogeneous design

and varying results (Table 2). Dobutamine-stress appears more sensitive than exercise,

most likely because allograft denervation results in a blunted heart-rate response to

exercise. The largest study, which included 109 patients, found Dobutamine stress

echocardiography (DSE) to have a sensitivity and specificity of 72% and 88% respectively

for the diagnosis of CAV, defined as approximately Stanford Class III or IV on IVUS (Table

1) or any luminal irregularities on angiography.11

Quantitative DSE analysis using regional deformation parameters may improve sensitivity. In

a study of 42 patients undergoing DSE with colour myocardial Doppler imaging, a peak

systolic longitudinal strain rate of <0.5/second had a sensitivity of 88% for detecting any

angiographic abnormalites including minor diffuse irregularities, compared to 63% for

conventional DSE analysis.12 Mitral annular systolic, early diastolic and late diastolic

velocities at peak Dobutamine-stress are also reduced in transplant recipients despite no

demonstrable abnormality in regional systolic function.13

The value of myocardial contrast echocardiography (MCE) to assess myocardial perfusion

remains to be established in CAV. In a study of 33 patients undergoing Dobutamine-stress,

semi-quantitative MCE (ratio of stress and rest myocardial signal-intensity upslopes) had a

sensitivity and specificity of only 58% and 67% respectively for detecting significant CAV,

defined as a combination of >50% stenosis on angiography or significant wall irregularities

on IVUS and an associated reversible perfusion defect on SPECT.14 However when MCE

5  

 

analysis was combined with conventional DSE analysis, sensitivity and specificity improved

to 86% and 91% respectively, compared to 71% and 83% respectively for conventional DSE

analysis alone. In another study, qualitative Dobutamine-stress MCE performed in 35

patients had a sensitivity and specificity of 70% and 96% respectively for detecting

angiographic stenoses >50%. Correlation with coronary territory was poor except for the left

anterior descending artery (LAD), and it failed identify disease extent.15

Direct measurement of coronary blood flow velocity at rest and during adenosine-stress in

the distal LAD using contrast-enhanced transthoracic Doppler echocardiography to calculate

coronary flow reserve (CFR) has also been used to assess for CAV. In a study of 22

patients, a CFR of less than 2.9 had sensitivity, specificity and negative predictive value of

80%, 100% and 89% respectively for detecting a maximal intimal thickness of >0.5mm on

IVUS.16

Both resting and stress echocardiography provide useful prognostic information with DSE in

particular having a high negative predictive value for adverse cardiac events.11, 17 In the

largest prognostic study, 1 of 159 normal DSEs (0.6%) were followed by an adverse cardiac

event during a mean 2.5-year follow-up.11

Nuclear imaging

As with the DSE literature, there is considerable variation in methodology and results of

studies assessing the accuracy of SPECT for detecting CAV. Of note, SPECT has only been

assessed in relation to angiography, most commonly using luminal narrowing of >50%

(Table 3). In the largest study, Dipyridamole-stress Sestamibi SPECT had a sensitivity and

specificity of 92% and 86% respectively when compared to luminal narrowing of >50%, but a

6  

 

sensitivity of only 56% when compared to any angiographic abnormalities including minor

luminal irregularities.18

Like DSE, Dobutamine-stress SPECT provides important prognostic information. In two

studies of 77 and 166 patients followed-up for 22- and 30-months respectively, 12-month

negative predictive values for major cardiac events were 98% and 95%.19, 20 The prognostic

value of Dipyridamole-stress SPECT may be lower (negative predictive value of 86% in a

study of 78 patients), although this has only been assessed in a single study with a

substantially longer follow-up (mean 78-months).18

The ability of positron emission tomography (PET) to readily quantify myocardial blood flow

(MBF) has provided insight into coronary artery function in CAV, indeed there is data, albeit

limited at present, to suggest that this ability may allow PET to be more sensitive for

detecting CAV than other non-invasive techniques.

Studies using PET have shown that resting MBF is higher in transplant recipients than in

healthy controls, thought to be due to the increased resting heart rate secondary to allograft

vagal denervation.21-23 PET has also been used to demonstrate impaired endothelial function

in CAV, with an abnormal MBF response to cold-pressor testing due to impairment of

vasodilatory capacity.22, 23 Furthermore, PET data has shown that MBF is homogeneous

across coronary territories, in keeping with the diffuse nature of the CAV.21 This finding may

explain in part the limited sensitivity of conventional functional imaging techniques that rely

on the development heterogeneity in myocardial blood flow or contractility (Figure 3).

In 2 studies using 13N-ammonia PET, myocardial perfusion ratio (MPR, ratio of absolute

MBF during stress and rest) correlated significantly with IVUS measures of CAV severity,

albeit with modest correlation coefficients. In the first study, using adenosine-stress in 27

7  

 

patients with normal angiographic appearances, MPR showed a significant inverse

correlation with plaque volume index, defined as total plaque volume divided by total vessel

volume x100 (r=-0.40; p<0.05).21 In the second study using Dipyridamole-stress in 32

patients, MPR showed a significant inverse correlation with mean maximal intimal thickness

and intimal index, defined as intimal area divided by intimal plus luminal area (r=-0.61;

p<0.005 and r=-0.52; p<0.05 respectively).22 Further highlighting the advantage of absolute

MBF, 20% of subjects regarded as normal by semi-quantitative PET analysis (summed

stress and rest scores) had a significantly abnormal MPR. In another study in which

Dipyridamole-stress 13N-ammonia PET and IVUS were performed in 17 patients at 18-

months post-transplant, MPR predicted the changes in total vessel area and luminal

diameter seen on repeat IVUS 15-months later.23

A limitation of nuclear imaging as a screening tool is the associated radiation dose,

particularly with serial studies. PET also remains expensive with limited availability.

CMR

The versatility and safety profile of CMR make it attractive as a screening modality for CAV

but evidence is limited at present.

In a study of 69 transplant recipients with no evidence of acute rejection, mean diastolic

strain rate (mean strain rate from peak systole to 50% of diastole) measured using CMR

‘tagging’ at 1.5Tesla, was significantly reduced in patients with ‘severe’ CAV (angiographic

luminal narrowing >50%) and with ‘minor’ CAV (lumen irregularities or focal stenoses <50%),

compared to age-matched healthy controls.24 Mean diastolic strain rate also allowed

differentiation between transplant recipients with ‘severe’ CAV, ‘minor’ CAV and normal

angiographic appearances. Systolic parameters were less sensitive (Figure 4).

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The prevalence of infarct-typical late-gadolinium enhancement (LGE) and mean infarct mass

per-patient on CMR imaging in a study of 53 transplant recipients, correlated significantly

with the degree of CAV visible at angiography.25 The majority of infarcts were found in the

mid and apical segments, with no correlation to coronary territory. Interestingly, nearly a

quarter of patients with ‘mild’ angiographic CAV (minor irregularities causing <30% stenosis)

had infarct-typical LGE. The authors suggested this was due to ‘silent’ myocardial infarction

occurring in the presence of non-significant angiographic disease and may provide further

evidence of prognostically significant CAV occurring in the absence of significant

angiographic changes. However patients were not scanned at baseline (i.e. shortly after

transplant) and therefore unrecognised infarct in the donor heart or peri-operative infarction

could not be excluded as the cause. The study also described the presence of infarct-

atypical LGE patterns unrelated to angiographic severity, the cause and significance of

which are not clear.

In a study of 69 transplant recipients undergoing adenosine-stress perfusion CMR, semi-

quantitative MPR (ratio of stress and rest signal intensity upslopes) was significantly reduced

in transplant recipients with ‘severe’ CAV (angiographic luminal narrowing >50%), ‘minor’

CAV (irregularities causing <50% stenosis) and even those with angiographically normal

arteries compared with aged-matched healthy volunteers.24 MPR also allowed differentiation

between grades of CAV. In another study that included 27 patients, those with ‘severe’ CAV

(angiographic stenoses >50% in all major epicardial vessels) had a significantly lower MPR

(ratio of stress and rest maximum signal intensity) and resting endocardial:epicardial

maximal signal intensity ratio than patients without angiographically-evident disease.26

Interestingly in a subgroup of patients with normal angiographic appearances but with

significantly reduced coronary flow reserve on invasive Doppler assessment, MPR and

resting endocardial:epicardial ratio were significantly reduced. In a further study of 17

9  

 

patients, resting absolute endocardial blood flow and resting endocardial:epicardial blood

flow ratio were significantly lower in patients with ‘severe’ CAV (>50% stenosis in all major

epicardial vessels and an invasive coronary flow reserve of <2.5) than in patients with a

normal invasive parameters (Figure 5).27

Non-contrast, respiratory-navigated, 3-dimensional steady-state free precession CMR

coronary angiography performed at 1.5Tesla in 16 patients, had a sensitivity and specificity

of 60% and 100% respectively for detecting CAV, defined as any irregularities on

conventional angiography (‘per-segment’ analysis).28 Vessels with a diameter of less than

1.5mm were excluded from analysis.

There is presently no published data on the prognostic value of CMR in CAV, although work

is underway.

Nephrogenic systemic fibrosis (NSF) is an extremely rare but serious complication of

Gadolinium contrast administration that causes fibrosis of the skin and other organs and can

result in significant functional impairment and reduced life expectancy. It is particularly

associated with advanced chronic kidney disease or severe acute renal failure. As renal

dysfunction is common post-transplant, with approximately 4% and 10% of patients having

an estimated glomerular filtration rate (eGFR) of less than 30milliliters/minute/1.73m2 at 5-

and 10-years following transplant respectively, NSF may limit the role of CMR in CAV

screening.29 In one of the largest registries, overall incidence of NSF following a Gadolinium

contrast-enhanced magnetic resonance examination was 0.02%.30 All cases occurred in

patients with an eGFR of less than 30milliters/minute/1.73m2, particularly in those with an

acute deterioration in renal function. Haemodialysis, especially when performed on the same

day as imaging, was associated with a significant reduction in NSF incidence. Other risk

factors for NSF include Gadolinium dose administration of greater than 0.1mmol/Kg, severe

10  

 

liver failure or liver transplant and pro-inflammatory events such as tissue injury secondary to

surgical procedures.

Cardiac devices e.g. pacemakers, implantable cardioverter-defibrillators and retained wires

also represent a potential limitation to CMR, although increasingly CMR-compatible devices

are being manufactured.

CTA

The potential combination of non-invasive luminal and vessel wall assessment makes CTA

attractive for CAV screening.

Sixty-four detector CTA has been assessed in a small number of studies (Table 4). Two

studies have compared CTA with IVUS, both defining CAV as intimal thickening >0.5mm. In

the first, which included 20 patients, sensitivity and specificity of CTA was 70% and 92%

respectively (analysis performed ‘per-segment’).31 B-blockers were administered when

resting heart-rate was above 65 beats-per-minute (bpm). Whilst this sensitivity may initially

appear disappointing, the sensitivity of conventional angiography was only 11%. The

considerably higher sensitivity of CTA was because it was able to visualise vessel wall

changes and coronary plaque. Indeed other studies have found 30–50% of coronary

segments classified as normal by conventional angiography have wall thickening visible on

CTA (Figure 6, 7).32, 33 In the second study, which included 30 patients, dual-source 64-

detector CTA had a sensitivity and specificity of 85% and 84% respectively, including correct

identification of all 17 patients with CAV.34 Heart-rate limiting medication was not used. The

authors suggested the greater sensitivity of CTA in this study was due to the higher temporal

resolution afforded by dual-source technology.

11  

 

Temporal resolution remains a weakness of CTA, indeed motion artefact accounted for the

majority of the 20-30% non-analysable coronary segments in the available studies. As such,

the high resting heart-rate of transplant recipients (typically 80-110bpm) together with a

delayed and variable B-blocker response (mean heart-rate in the available studies was 77–

86bpm following pre-scan B-blocker and 79–87bpm without) represent particular challenges.

Newer technology may lead to significant improvements, indeed only 4% of segments were

non-analysable in the described study utilising dual-source CTA, despite a mean heart-rate

of 80bpm.34 No studies have reported the use of If channel blockers.

CTA also has limited ability to assess smaller vessels, particularly important given the nature

of CAV. Many of the available studies excluded vessels <1.5mm from analysis, including the

study using dual-source CTA.35

Another drawback of CTA as a potential screening technique is the associated radiation

dose. Average dose per CTA in the available studies was 9.5–21.4millisieverts compared to

2.0–6.0millisieverts for conventional angiography. The latest CTA technology used in

experienced centres for assessing native coronary artery disease is reported to be

associated with much lower doses, although such technology often requires controlled heart-

rates.

Furthermore, patients at risk of CAV are also at increased risk of contrast-induced

nephropathy (CIN). High iodine-concentration contrast is usually required for CTA in similar

or greater volumes than for conventional angiography. Mean eGFR in patients 5-years post-

transplant is approximately 55milliliters/minute/1.73m2 and the incidence of CIN is known to

increase when eGFR is <60milliliters/minute/1.73m2.29 Indeed up to a quarter of potential

patients were excluded from the available studies due to renal impairment.

12  

 

Coronary calcium scoring is of limited value in CAV as calcification is often absent even in

severe disease.36 There is no prognostic data for CTA in the context of CAV yet.

Adenosine supersensitivity

Enhanced sensitivity of the denervated sinus and atrioventricular nodes to adenosine is well

recognised in transplant recipients and therefore high vigilance is required for any functional

imaging technique using this stressor agent.37 In a study of 102 transplant recipients

undergoing SPECT, adenosine infusion at a dose of 140 micrograms/kilogram/minute over

6-minutes was associated with significantly higher rates of sinus pauses (4.9% vs. 0%),

second (11.8% vs. 4.9%) and third degree (2.9% vs. 0%) atrioventricular block compared to

age and sex-matched non-transplant patients, resulting in early termination of 1.9% of

studies although there were no significant immediate or long-term sequelae.38

Guidelines

The 2010 International Society of Heart and Lung Transplantation Guidelines for the Care of

Heart Transplant Recipients assign DSE and SPECT a Class IIa recommendation, Level of

Evidence B; stating that they “may be useful for the detection of CAV in transplant recipients

unable to undergo invasive evaluation”.39 CTA is assigned a Class IIb recommendation,

Level of Evidence C; with the description “ CTA shows promise in the evaluation of CAV

although higher resting heart rates in these patients limit the technical quality”. PET and

CMR are not included in the guidelines. Annual or biannual invasive coronary angiography is

given a Class I recommendation, Level of Evidence C. CAV screening is not included in the

respective Appropriate Use Criteria for the imaging techniques described.

Conclusions

13  

 

The development of accurate non-invasive imaging techniques for CAV screening is

important given the impact of the disease and the significant limitations of the current clinical

surveillance technique. Echocardiography and SPECT are the most extensively investigated

however most published studies are small with markedly differing methodologies and often

discrepant results and as such, neither technique as found widespread acceptance for CAV

screening. Newer techniques allowing quantification of myocardial deformation, visualisation

of myocardial injury, absolute MBF quantification and arterial wall imaging hold potentially

greater promise however supporting data is limited at present. Further investigation is

needed in appropriately powered studies with evaluation against ‘gold-standard’ methods for

characterising the anatomical and physiological manifestations of CAV.

Acknowledgements

None

Funding Sources

Christopher Miller is supported by a Fellowship from the National Institute for Health

Research, UK. Christopher Miller, Simon Williams, Nizar Yonan, and Matthias Schmitt have

received research funding from New Start Transplant Charity.

Disclosures

None

14  

 

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22  

 

Figure legends

Figure 1. Invasive assessment of CAV in a patient with severe disease, highlighting the

limited sensitivity of conventional coronary angiography. Whilst no LAD flow-limiting

stenoses are seen on angiography (A), IVUS (B) shows significant intimal thickening,

measuring up to 0.9mm (dashed line) and fractional flow reserve (FFR, C) is markedly

reduced at 0.61 indicating significant epicardial disease. No discrete ‘step-down’ is seen on

FFR pull-back along the LAD (D) in keeping with the diffuse nature of CAV. In this case,

index of microcirculatory function (IMR, C) was 11.6 indicting normal microvascular function.

Figure 2. Mid-ventricular radial strain derived from 2-dimensional speckle tracking

echocardiography in 2 transplant recipients at rest. In the first patient (A-C) with minimal

CAV seen at IVUS (C, intimal thickness 0.2mm (dashed line)), global peak systolic strain

was 51% (A, B). In the second patient (D-F) with severe CAV (F, intimal thickness 0.9mm),

global peak systolic strain was reduced at 10% and peak strain was seen to occur following

aortic valve closure (AVC). In both patients, left ventricular ejection fraction was normal.

Figure 3. Adenosine-stress Rubidium-82 PET in a patient 20-years post-transplant.

Screening angiography was not possible due to lack of vascular access. Relative perfusion

analysis was normal (A, mid-ventricular short-axis; B, vertical long-axis; C, horizontal long-

axis stress images with corresponding rest images, B, D, F respectively). However given the

high likelihood of significant disease at this late stage post-transplant and the modest

sensitivity of semi-quantitative perfusion analysis in CAV, it was unclear whether this result

was correct or whether there was homogenous reduction in perfusion secondary to diffuse

disease which semi-quantitative analysis was unable to detect. Quantitative perfusion

analysis (G, stress; H, rest; I, reserve; J, myocardial blood flow values) confirmed normal

myocardial blood flow in all three coronary territories.

23  

 

Figure 4. Mid-ventricular short-axis circumferential strain and strain rate derived from

‘tagged’ CMR images in patients in minimal (A-D) and severe (E-H) CAV. Strain maps (B

and F), derived from tagged CMR images (A and E respectively), use colour to display

degree of strain. Strain and strain rate (peak systolic and diastolic) were reduced in the

patient with severe disease (G and H) compared to the patient with minimal disease (C and

D). Left ventricular ejection fraction was normal in both patients.

Figure 5. Quantitative adenosine-stress perfusion CMR in 2 transplant recipients; one with

minimal (A-H) and one with severe CAV (I-P). Absolute MBF is calculated from arterial input

function (AIF) and myocardial time-signal intensity curves (B and J) through a process of

model-independent deconvolution and displayed as perfusion maps (C-H and K-P), where

pixel colour corresponds to blood flow in milliliters/gram/minute. The patient with minimal

disease (intimal thickness 0.2mm on IVUS, A) showed normal stress (C, basal; D, mid-

ventricular; E, apical short axis; global median MBF 2.92milliliters/gram/minute) and rest

perfusion (F-H; MBF 1.30milliliters/gram/minute) and normal perfusion reserve (2.2). In the

patient with severe disease (intimal thickness 0.9mm, I) stress perfusion was reduced (K-M;

MBF 1.44milliliters/gram/minute) and rest perfusion was normal (N-P; MBF

1.34milliliters/gram/minute) resulting in a reduced perfusion reserve (1.1). In both patients

blood flow was homogeneous across coronary territories.

Figure 6. CTA of a patient 5-years post-transplant showing diffuse concentric thickening of

the wall of the mid-LAD (A, arrows) best seen in curved multi-planar reformatted (B, arrows)

and short axis images (C, arrow heads) but difficult to appreciate on invasive angiography

(D, arrows).

24  

 

Figure 7. CTA of a patient 12-years post-transplant showing mixed plaque in the LAD after

the second diagonal (A, arrow) causing greater than 50% luminal stenosis, confirmed with

invasive angiography (B, arrow). However, mixed plaque seen more proximally on CTA

(arrow heads) is difficult to appreciate on invasive angiography.

25  

 

Table 1. Stanford Classification of CAV severity on IVUS

Reproduced with permission from Wolters Kluwer Health via Rightslink.

Class I Class II Class III Class IV

Severity Minimal Mild Moderate Severe

Intimal thickness

or

<0.3 mm

<0.3mm

0.3–0.5mm

or

>1.0mm

or

Extent of plaque <180 >180 >0.5mm, <180 >0.5mm, >180

26  

 

Table 2. Studies evaluating the accuracy of stress echocardiography for the diagnosis

of CAV

Study Patients

(n)

Stress CAV diagnosis Sensitivity

(%)

Specificity

(%)

Collings et al.,199440 51 Exercise Angiography* 25 86

Collings et al.,199440 35 Exercise IVUS† 15 83

Cohn et al.,199641 51 Exercise IVUS† 15 85

Ciliberto et al.,199342 80 Dipyridamole Angiography‡ 32 100

Ciliberto et al.,199342 80 Dipyridamole Angiography§ 87 100

Akosah et al.,199443 41 Dobutamine Angiography‡ 95 55

Herregods et al.,199444 28 Dobutamine Angiography‡ 0 100

Akosah et al.,199545 45 Dobutamine Angiography‡ 96 53

Derumeaux et al.,199546 41 Dobutamine Angiography‡ 86 91

Spes et al.,199647 46 Dobutamine IVUS| | 79 83

Derumeaux et al.,199848 37 Dobutamine Angiography§ 65 95

Spes et al.,199911 109 Dobutamine Angiography/IVUS# 72 88

Bacal et al.,200417 39 Dobutamine Angiography§ 64 91

Eroglu et al.,200812 42 Dobutamine Angiography‡ 63**

88††

88**

85††

Weighted average 53 88

*Coronary stenosis>40%, †Stanford classification>Grade III, ‡any angiographic

abnormalities including luminal irregularities, §coronary stenosis>50%, | |approximating to

Stanford classification grade III-IV, #angiographic luminal irregularities or IVUS severity

approximating to Stanford classification grade III-IV, **conventional regional wall motion

analysis, ††regional peak systolic strain rate analysis.

27  

 

Table 3. Studies evaluating the accuracy of SPECT for the diagnosis of CAV

*discrete stenoses or diffuse concentric coronary narrowing, †coronary stenosis>50%, ‡any

angiographic abnormalities including luminal irregularities.

Study Patients

(n)

Tracer Stress CAV diagnosis Sensitivity

(%)

Specificity

(%)

Ciliberto et al.,199349 50 Thallium-201 Exercise Angiography* 67 100

Rodney et al.,199450 25 Thallium-201 Exercise Angiography† 77 100

Bacal et al.,200417 39 Thallium-201 Exercise Angiography† 40 96

Smart et al.,199151 73 Thallium-201 Dipyridamole Angiography† 21 88

Carlsen et al.,200052 67 99mTc

sestamibi or

99mTc

tetrofosmin

Dipyridamole Angiography† 80 92

Ciliberto et al.,200118 78 99mTc

sestamibi

Dipyridamole Angiography†

Angiography‡

92

56

86

89

Elhendy et al.,200053 50 99mTc

tetrofosmin

Dobutamine Angiography† 90 55

Hacker et al.,200519 63 99mTc

sestamibi

Dobutamine Angiography† 82 87

Wu et al.,200554 47 Thallium-201 Dobutamine Angiography† 89 71

Weighted average 68 87

28  

 

Table 4. Studies evaluating the accuracy of 64-detector CTA for the diagnosis of CAV

*intimal thickness>0.5mm, †coronary stenosis<50% or minor luminal irregularities, ‡coronary

stenosis>70%, § coronary stenosis>50%, | |any angiographic abnormalities including luminal

irregularities, **analysis by coronary segment.

Study Patients (n) CAV diagnosis Sensitivity (%) Specificity (%)

Gregory et al.,200631 20 IVUS* 70** 92**

Iyengar et al.,200633 19 Angiography† 100 67

Pichler et al.,200835 60 Angiography‡ 88 97

Von Ziegler et al.,200855 26 Angiography§ 100 81

Schepis et al.,200934 30 IVUS* 85** 84**

Nunoda et al.,201028 10 Angiography| | 90** 98**

Weighted average 81 91

29  

 

30  

 

31  

 

32  

 

33  

 

34  

 

35