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Coronary Interventions
Optical Coherence Tomographic Evaluation of
Transplant Coronary Artery Vasculopathy With
Correlation to Cellular Rejection
Liang Dong, MD; Akiko Maehara, MD; Tamim M. Nazif, MD; Ari T. Pollack, MD;
Shigeo Saito, MD; LeRoy E. Rabbani, MD; Mark A. Apfelbaum, MD; Kate Dalton, MS, RD;
Jeffrey W. Moses, MD; Ulrich P. Jorde, MD; Ke Xu, PhD; Gary S. Mintz, MD;
Donna M. Mancini, MD; Giora Weisz, MD
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Background—Cardiac allograft vasculopathy is an accelerated fibroproliferative process that affects the coronary arteries
of transplanted hearts. Intracoronary imaging with optical coherence tomography enables detection of subangiographic
cardiac allograft vasculopathy.
Methods and Results—At the time of routine surveillance coronary angiography, 48 consecutive heart transplant recipients
underwent optical coherence tomographic imaging of 1 coronary artery. Imaging findings were compared per rejection
history that was graded according to the International Society of Heart and Lung Transplantation classification as none/
mild (International Society of Heart and Lung Transplantation 0, 1A/1B, or 2) or high-grade rejection (≥3A). Compared
with the none/mild rejection group (37 patients) using Mann–Whitney U test, patients in the high-grade rejection group
(11 patients) had a thicker intima in all coronary segments (distal: 0.22 mm [0.09–0.41] versus 0.09 mm [0.06–0.17],
P=0.02; middle: 0.35 mm [0.00–0.45] versus 0.14 mm [0.08–0.24], P=0.002; and proximal: 0.34 mm [0.21–0.44] versus
0.15 mm [0.11–0.21], P=0.005) and a higher prevalence of foamy macrophages (distal: 55% versus 9%, P=0.003; middle:
55% versus 22%, P=0.004; and proximal: 44% versus 13%, P=0.05) using χ2 statistics. Side branches in the high-grade
rejection group had smaller lumen diameters and a higher prevalence of intimal thickening (54% versus 36%; P=0.01).
Intimal microvessels were also more prevalent in the high-grade rejection group versus the none/mild rejection group
(46% versus 11%; P=0.02).
Conclusions—Coronary optical coherence tomographic evaluation revealed that patients with a history of high-grade cellular
rejection, compared with those with none/mild rejection, had more coronary artery intimal thickening with macrophage
infiltration, involving all coronary segments and side branches.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01403142. (Circ Cardiovasc Interv. 2014;7:00-00.)
Key Words: heart transplantation ◼ tomography, optical coherence
C
symptoms, early diagnosis and surveillance of CAV remain
important clinical challenges.2 Optical coherence tomography (OCT) provides high-resolution (10–20 μm) intravascular
imaging in vivo and has been used to visualize and characterize coronary atherosclerotic plaque composition.3 The current
study used OCT to identify CAV disease patterns and to investigate the relationship to prior acute cellular rejection.
ardiac allograft vasculopathy (CAV) is a unique form of
accelerated coronary artery disease that is a major cause
of morbidity and mortality in heart transplant recipients, especially those who survive beyond the first year after transplantation.1,2 The pathophysiology of CAV involves immunologic
and nonimmunologic factors that cause localized inflammation with persistent vascular injury and endothelial dysfunction. Despite improvements in immunotherapy, the incidence
of angiographically detected CAV has not changed appreciably
during the past 2 decades, and limited progress has been made
in characterizing this disease process. Emerging evidence now
suggests that alterations in medical therapy may interrupt the
progression of CAV. Because of the absence of typical ischemic
Methods
Study Population
The analysis included 48 consecutive heart transplant recipients
who underwent routine surveillance coronary angiography between February 2011 to December 2012. These patients underwent
Received July 11, 2013; accepted March 6, 2014.
From the NewYork Presbyterian Hospital, Columbia University Medical Center, New York, NY (L.D., A.M., T.M.N., A.T.P., S.S., L.E.R., M.A.A., K.D.,
J.W.M., U.P.J., D.M.M., G.W.); the Cardiovascular Research Foundation, New York, NY (L.D., A.M., S.S., J.W.M., K.X., G.S.M., G.W.); The Second
Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China (L.D.); and Shaare Zedek Medical Center, Jerusalem, Israel (G.W.).
Correspondence to Giora Weisz, MD, Department of Cardiology, Shaare Zedek Medical Center, 12 Shmuel (Hans) Beyth St, Jerusalem 91031, Israel.
E-mail [email protected]
© 2014 American Heart Association, Inc.
Circ Cardiovasc Interv is available at http://circinterventions.ahajournals.org
1
DOI: 10.1161/CIRCINTERVENTIONS.113.000949
2 Circ Cardiovasc Interv April 2014
Table 1. Rejection Grade and Groups
What Is Known
• Pathological
reports showed that cardiac allograft
vasculopathy is a diffuse, accelerated fibroproliferative process that affects the coronary arteries of
transplanted hearts.
• Previous intravascular ultrasound studies of cardiac
allograft vasculopathy showed intimal thickening
with advanced morphological changes.
What the Study Adds
• Intracoronary
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imaging with optical coherence tomography enables detection of cardiac allograft
vasculopathy more clearly both quantitatively and
qualitatively.
• Coronary optical coherence tomography revealed
that patients with a history of high-grade cellular rejection, compared with those with no/mild rejection,
had more coronary artery intimal thickening with
macrophage infiltration involving all coronary segments, as well as side branches.
orthotopic cardiac transplantation at Columbia University Medical
Center (New York, NY) between January 1996 and August 2011 and
were followed for acute cellular rejection by serial right ventricular
endomyocardial biopsies. The study was approved by the institutional
review board, and all patients gave written informed consent.
Classification of Transplant Cellar Rejection
All patients underwent serial right ventricular endomyocardial biopsies according to institutional protocol and clinical needs. The
presence of acute cellular rejection was graded according to the
International Society of Heart and Lung Transplantation (ISHLT)
classification proposed in 1990: grade 1A, focal, mild acute rejection;
grade 1B, diffuse, mild acute rejection; grade 2, focal, moderate acute
rejection; grade 3A, multifocal, moderate rejection; grade 3B, diffuse,
borderline severe acute rejection; and grade 4, severe acute rejection.
In consideration of the updated classification proposed in 2005, we
categorized tissue as showing none/mild rejection (ISHLT 0, 1A/1B,
or 2) or high-grade rejection (≥3A; Table 1).4 Rejection grade was
chosen as the worst grade per patient recorded since transplantation.
Quantitative Coronary Angiographic Analysis
Angiographic analysis was done using QAngio XA version 7.2.34.0
(Medis Medical Imaging Systems, Leiden, The Netherlands) blinded
to the OCT findings. After guiding catheter calibration, proximal,
mid, and distal coronary artery segments were identified that corresponded to the areas of OCT analysis, and the minimal lumen diameter in each segment was measured. Qualitative analysis included
side branch narrowing, lumen irregularity, and calcium.5
OCT Imaging, Definitions, and Analysis
After diagnostic coronary angiography, patients received intravenous
coronary heparin and nitroglycerin (100 μg). A 2.7F OCT imaging
catheter (C7 Dragonfly, St Jude Medical, St Paul, MN) was advanced
over an angioplasty guidewire into a target vessel. The target vessel
was either (1) the vessel showing the most severe disease or irregularities on angiography or (2) the left anterior descending (LAD) when
all 3 vessels looked the same or appeared to be normal. OCT images
were obtained using the LightLab C7-XR Frequency Domain OCT
system during continuous contrast injection (4 mL/s, 14–18 mL total)
Group
None/mild rejection
(n=37)
ISHLT 1990
ISHLT 2004
0
0
1A
4
21
1R
1B
2
High-grade rejection
(n=11)
No. of Cases
7
5
3A
2R
3B
3R
4
11
0
0
ISHLT indicates International Society of Heart and Lung Transplantation; and
N/A, not applicable.
with a motorized pullback speed of 20 mm/s, a frame rate of 100/s,
and a maximum scan length of 54 mm.
OCT images were analyzed off-line by 2 independent investigators (L.D. and A.M.) using LightLab ORW software (version C.0.4).
Each OCT pullback was separated into 3 segments (proximal, middle, and distal) corresponding with the coronary angiogram. After
coregistration of OCT and angiographic studies and assessment of
the angiograms based on the American Heart Association classification of proximal, middle, and distal segments, the OCT image was
divided into (1) 3 equal segments if all 3 (proximal, middle, and distal) angiographic segments had been visualized by OCT or (2) 2 equal
segments if only 2 angiographic segments (proximal and middle or
middle and distal) had been visualized by OCT.6 Calibration was
done for each segment, and every frame was evaluated.
For interpretation of the OCT images, the internal elastic lamina
(IEL) and external elastic lamina (EEL) were identified as high backscattering bands (≈20 μm). The intima is a thickening inside of the
IEL, the media is a low backscattering layer between the IEL and
EEL, and the adventitia is a high backscattering and heterogeneous
layer outside the EEL. Plaque with attenuation has fast signal drop-off
indicates lipidic plaque or macrophages; attenuation behind surface
high backscattering with a narrow trailing shadow that changes frame
by frame is considered to represent foamy macrophages rather than
lipidic plaque.7,8 Thrombi are graded as (1) red blood cell–rich thrombus that has strong backscattering with a high degree of attenuation,
(2) platelet-rich thrombus that has less backscattering with a lower
degree of attenuation, or (3) mixed thrombus.9,10 Organized thrombus
shows low backscattering with little attenuation.7 Microvessels within
the intima appear as signal-poor voids that are sharply delineated and
can usually be followed in multiple contiguous frames. Calcium is a
signal-poor region with sharply delineated borders. Ruptured plaques
show features of intimal tearing, disruption, or dissection of the cap.
A visible abnormal branch structure (VABS) was defined as the
presence of intimal thickening inside of a side branch in which both
the lumen and the media of the side branch connected to the main vessel (Figure 1). For every visible side branch, the lumen diameter was
measured as the largest of the minimum diameters among consecutive frames to avoid overestimation because of angulation.
For quantitative analysis, we chose the frame with minimum lumen
area and the maximum plaque thickness in each segment to measure
EEL, IEL, and lumen area. Percent media/EEL area, intima/EEL
area, and intima/IEL area11 were calculated as:
%
%
Media
EEL
Intima
EEL
Intima
area=
area=
EEL area − IEL area
EEL area
× 100;
IEL area − lumen area
EEL area
IEL area − lumen area
× 100;
× 100.
EEL
IEL area
When the EEL was not visible over a circumference of >60°, we reviewed cross-sections proximal or distal to the minimal lumen area
%
area=
Dong et al OCT Evaluation of Transplant Vasculopathy 3
B
A
Figure 1. Visible abnormal branch structure.
A, Consecutive frames showing intima thickening (white arrows) in a side branch from a patient
with in a high-grade rejection case. B, Consecutive
frames showing no intima thickening (white arrows)
in a side branch from a patient with none/mild
rejection.
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slice. We only contoured the EEL if this helped to fill in the missing
arc of EEL. In this cohort, 89% of attenuation had the appearance of
trailing attenuation with narrow shadow. Therefore, even with attenuation, in most (90%) of the slices the EEL was analyzable.
Statistical Methods
Statistical analysis was performed with SAS software, version 9.1
(SAS Institute Inc, Cary, NC). For patient level data, categorical
variables are presented as frequencies and compared between groups
with χ2 statistics or Fisher exact test (if there was an expected cell value <5), and continuous variables are presented as median and first to
third quartiles and compared between groups using Mann–Whitney
U test. The correlation between mean intimal thickness versus IEL
area was analyzed using Pearson correlation. Intraobserver and interobserver variability for the qualitative analysis was measured by κ
test of concordance. For side branch data, a model with the generalized estimating equations approach was used to compensate for any
potential cluster effect of multiple side branches in the same patient
and is presented as least square means with 95% confidence intervals.
To identify independent predictors of lumen dimensions, clinical
variables with P<0.2 were entered into the multiple linear regression
model. A P<0.05 was considered statistically significant.
Results
The age of donor at heart transplantation was 31±11 years
(high rejection group versus none/mild rejection group: 29±8
years versus 32±12 years; P=0.42). Among them, 58% were
men (high rejection group versus none/mild rejection group:
40% versus 63%; P>0.99); and 46% of donors were cytomegalovirus positive (high rejection group versus none/mild
rejection group: 11% versus 57%; P=0.02).
Patient characteristics are summarized in Table 2. There
were no significant clinical differences between the none/mild
versus high-grade rejection groups except for the time from
heart transplant that was longer in the high-grade rejection
group. Sirolimus and clopidogrel were more often prescribed
in patients with high-grade rejection, but there were no other
significant differences in medical treatment between groups
(Table 3).
Angiographic Findings
Angiographic findings are shown in Table 4. Comparing
patients with high-grade rejection to those with none/mild
rejection, there were no significant differences in minimal
lumen diameter in the proximal or mid segments, but the
Clinical Characteristics
The coronary arteries that were imaged included 44 LAD
arteries, 3 left circumflex arteries, and 1 right coronary artery.
OCT imaging of all 3 segments (proximal, mid, and distal)
was successful in 38 cases, whereas imaging of either the distal or proximal segment was incomplete in 10 cases.
Patient age at heart transplantation was 56±14 years (median,
61 years), and 77% were men. The median duration from
transplantation to OCT imaging was 5.6 years: 8.2 years in
the h­ igh-grade rejection group and 4.9 years in the low-grade
rejection group (P=0.03). Among the 37 low-grade rejection
patients, there were 19 patients (51%) who were >4 years after
transplantation, whereas among the 11 high-grade rejection
patients, there were 10 patients (91%) who were >4 years after
transplantation. In 11 high-grade rejection patients, the median
time of rejection from the transplantation was 4.2 years.
About half of the transplant recipients were whites (26
of 48). The none/mild rejection group included 37 patients
(ISHLT 0 in 4 cases, ISHLT 1A in 21 cases, ISHLT 1B in
7 cases, and ISHLT 2 in 5 cases), whereas the high-grade
rejection group included 11 patients (ISHLT 3A in all cases;
Table 1). There were no patients with ISHLT grade 3B or
grade 4 rejection.
Table 2. Patient Characteristics
None/Mild
Rejection (n=37)
Age, y
60 (53–65)
High-Grade
Rejection (n=11)
64 (32–66)
P Value
0.81
Male sex
76% (28)
82% (9)
1.0
Height, cm
175 (170–180)
175 (167–183)
1.0
Weight, kg
88 (69–104)
86 (75–103)
1.0
Body mass index, kg/m2
26.8 (23.8–32.3)
27.5 (26.4–30.6)
0.6
HTx indication for ICM
35% (13)
46% (5)
0.72
Duration post HTx, y
4.9 (1.0–9.0)
8.2 (7.0–11.8)
0.03
Humoral rejection
8% (3)
9% (1)
1.0
Hypertension
38% (14)
27% (3)
0.72
Dyslipidemia
38% (14)
36% (4)
1.0
Diabetes mellitus
30% (11)
36% (4)
0.72
Smoking
30% (11)
36% (4)
0.72
Prior coronary artery
disease
41% (15)
46% (5)
1.0
5% (2)
9% (1)
0.55
Prior peripheral vessel
disease
HTx indicates heart transplantation; and ICM, ischemic cardiomyopathy.
4 Circ Cardiovasc Interv April 2014
Table 3. Medical Treatment
Table 5. Optical Coherence Tomographic Finding
None/Mild Rejection High-Grade Rejection
(n=37)
(n=11)
P Value
Aspirin
None/Mild Rejection
(n=37)
High-Grade Rejection
(n=11)
P Value
87% (32)
82% (9)
0.65
Distal segment
0% (0)
18% (2)
0.05
EEL area, mm2
8.07 (6.24–11.30)
6.50 (5.07–7.46)
0.15
Statin
76% (28)
64% (7)
0.46
IEL area, mm
7.30 (5.16–9.73)
5.67 (4.64–6.60)
0.13
β-Blocker
19% (7)
18% (2)
1
Lumen area, mm2
6.14 (3.57–8.40)
4.31 (2.79–5.36)
0.01
ACE-I/ARB
30% (11)
27% (3)
1
0.09 (0.06–0.17)
0.22 (0.09–0.41)
0.02
CCB
46% (17)
46% (5)
0.98
Mean intima
thickness, mm
Steroid
76% (28)
73% (8)
1
%media/EEL area
10.3 (7.9–13.1)
11.5 (8.8–15.4)
0.27
11.7 (7.2–17.7)
35.7 (10.9–45.2)
0.009
13.1 (7.7–20.0)
39.0 (12.9–50.3)
0.007
55% (6)
0.003
Clopidogrel
Tacrolimus
2
57% (21)
55% (6)
1
%intima/EEL area
8% (3)
36% (4)
0.04
%intima/IEL area
Mycophenolate mofetil
68% (25)
46% (5)
0.29
Mycophenolic acid
16% (6)
9% (1)
1
Prevalence of
attenuation
Cyclosporine
38% (14)
36% (4)
1
Sirolimus
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ACE-I indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin II
receptor blockers; and CCB, calcium channel blockers.
minimal lumen diameter in the distal segment was significantly smaller in high-grade rejection patients. Qualitative
parameters were not different between the 2 groups.
Quantitative OCT Findings
OCT findings are shown in Table 5 and Figures 2 through 4.
There were no significant differences in EEL areas, IEL areas,
or %media/EEL between the 2 groups. However, the mean
intimal thickness, %intima/EEL area, and %intima/IEL area
were all significantly greater in the high-grade rejection group,
resulting in smaller lumen areas. Comparing proximal versus
middle versus distal segments in the 2 groups separately, mean
intimal thickness was not significantly different between any
adjacent segment, including (1) distal versus middle, P=0.14,
and middle versus proximal, P=0.90, in the high-grade rejection group and (2) distal versus middle, P=0.43, and middle
versus proximal, P=0.10, in the none/mild rejection group.
By regression analysis, mean intimal thickness did not correlate with IEL area in the high-grade rejection group (P=0.76),
although there was a moderate correlation between mean intimal thickness and IEL area (R=0.38; P=0.0004) in the none/
mild rejection group.
Table 4. Angiographic Findings
None/Mild
Rejection (n=37)
High-Grade
Rejection (n=11)
P Value
2.04 (1.64–2.37)
1.70 (1.19–1.96)
0.009
Mid segment MLD, 2.37 (2.12–2.67)
mm
2.29 (1.83–2.53)
0.25
Proximal segment
MLD, mm
2.35 (2.09–3.29)
0.5
Distal segment
MLD, mm
2.57 (2.24–2.94)
Lumen irregularity
0% (0)
0% (0)
N/A
Branch orifice
narrowing
3% (1)
0% (0)
1
Calcification
0% (0)
0% (0)
N/A
MLD indicates minimum lumen diameter; and N/A, not applicable.
9% (3)
Middle segment
EEL area, mm2
12.54 (8.54–15.37)
9.8 (7.63–13.79)
0.25
IEL area, mm2
11.40 (7.48–13.31)
9.10 (7.05–12.41)
0.26
Lumen area, mm2
9.43 (6.68–11.05)
6.46 (3.74–7.64)
0.03
Mean intima
thickness, mm
0.14 (0.08–0.24)
0.35 (0.22–0.45)
0.002
%media/EEL area
9.7 (8.3–11.2)
9.9 (7.6–11.8)
0.67
%intima/EEL area
13.0 (8.7–18.2)
30.4 (22.8–43.0)
0.0007
%intima/IEL area
14.5 (9.5–20.7)
34.5 (24.5–46.5)
0.0006
Prevalence of
attenuation
22% (8)
55% (6)
0.004
Proximal segment
EEL area, mm2
17.77 (12.46–22.45)
12.36 (10.79–17.89)
0.19
IEL area, mm2
15.69 (11.28–20.45)
11.23 (9.65–15.24)
0.16
13.06 (9.11–16.08)
8.13 (6.55–12.47)
0.06
0.15 (0.11–0.21)
0.34 (0.21–0.44)
0.005
Lumen area, mm
2
Mean intima
thickness, mm
%media/EEL area
9.6 (8.5–11.4)
11.3 (9.1–11.7)
0.4
%intima/EEL area
11.2 (9.1–14.3)
20.9 (15.5–35.9)
0.002
%intima/IEL area
12.5 (10.4–16.5)
23.8 (18.2–39.6)
0.003
Prevalence of
attenuation
13% (4)
44% (4)
0.05
EEL indicates external elastic lamina; and IEL, internal elastic lamina.
In the high-grade rejection group, there were 5 patients
who had 2 episodes of high-grade rejection and 6 patients
who had a single episode of high-grade rejection (none had
>2 episodes). Patients with 2 episodes of high-grade rejection
trended toward a smaller IEL area compared with patients
with a single episode of high-grade rejection (4.6 [3.2–6.4]
versus 6.2 [5.7–6.6] mm2; P=0.13).
Only 4 patients (3 in the none/mild rejection group and one
in the high-grade rejection group) had a history of humoral
rejection. Percent intimal/IEL area trended toward larger in
the patients with a history of humoral rejection compared with
those without a history of humoral rejection (26.1% [18.3%–
43.9%] versus 13.6% [8.8%–24.7%]; P=0.09).
Qualitative OCT Findings
Intraobserver and interobserver variability yielded good concordance for the diagnosis of trailing attenuation with narrow
Dong et al OCT Evaluation of Transplant Vasculopathy 5
None/Mild Rejection
(mm)
0.9
0.6
Mean Intima Thickness
P=0.005
P=0.002
(mm2)
21
(%)
60
40
% Intima/IEL
P=0.003
P=0.007
20
Proxmial
Middle
Distal
Minimum Lumen Area
0
(%)
90
Proxmial
14
Middle
Distal
Plaque with Attenuation
Figure 2. Optical coherence tomographic findings.
Mean intima thickness, %intima/internal elastic
lamina (IEL) area, and prevalence of plaque with
attenuation were greater in the high-grade rejection
group, which resulted in smaller minimum lumen
areas in high-grade rejection group.
P=0.004
P=0.06
60
P=0.03
P=0.01
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7
0
P=0.0006
P=0.02
0.3
0
High Grade Rejection
P=0.003
P=0.054
30
Proximal
Middle
Distal
0
Proximal
Middle
shadow (κ=0.90 and κ=0.90), microvessels (κ=0.95 and
κ=0.84), thrombus (κ=0.89 and κ=0.89), and VABS (к=0.84
and к=0.80). Qualitative analysis showed that patients in the
high-grade rejection group had significantly greater prevalence of plaque with attenuation than the none/mild rejection
group in all 3 segments: proximal, middle, and distal. The
majority of attenuation had the appearance of trailing with
narrow shadow, suggesting macrophages; this finding was
present in 89% of plaque with attenuation in the none/mild
rejection group and in all plaque with attenuation in the highgrade rejection group.
Mural thrombus was found in 3 of 48 patients (6%), including 1 in the none/mild rejection group (involving <1 quadrant and 1.6 mm in length) and 2 in the high-grade rejection
group. In the patient in the none/mild rejection group, a mixed
thrombus was observed in the middle segment of the LAD
artery. One of the patients from the high-grade rejection group
had multiple mixed thrombi in both the middle and proximal
segment (Figure 5A), involving 4 quadrants and a total length
of 11 mm, whereas the other had an organized thrombus in
the proximal segment of the LAD (Figure 5A′), involving 2
quadrants and a total length of 9 mm. One plaque rupture with
no associated thrombus was found in a single patient in the
high-grade rejection group.
Intimal microvessels were visualized in 9 patients (19%):
5 patients with high-grade rejection and 4 patients with none/
mild rejection (46% versus 11%; P=0.02). Multiple segment involvement was observed in 4 patients and single segment involvement in 5 patients. Overall, microvessels were
observed in 8 distal segments, 6 middle segments, and 8 proximal segments. In 55% (12 of 22) of the microvessels, the distribution pattern was mainly localized parallel to the lumen of
the main vessel and with >3 microvessels circumferentially in
one image frame (Figure 5B).
Eight patients (3 with high-grade rejection and 5 with none/
mild rejection cases) had intimal calcification in ≥1 coronary
artery segment (17%), and 3 patients had it in >1 segment.
Overall, calcification was found in 16 segments, including 2
distal, 7 middle, and 7 proximal. In 3 patients, the calcium
Distal
was found in >1 coronary artery segment, and in 5 patients,
the calcium was found in only 1 segment. Calcification was
crescent-shaped, thin (maximum thickness <0.3 mm), and
superficial in 10 instances (63%; Figure 5C).
Other than the greater prevalence of plaque with attenuation
and intimal microvessels in the high-grade rejection group,
none of the other qualitative findings were different between
the 2 groups.
Side Branch OCT Analysis
The analysis included 332 side branches from 44 LAD arteries. Side branch diameter was smaller in the high-grade rejection group compared with the none/mild rejection group (1.01
[0.80–1.21] versus 1.23 [1.10–1.36] mm; P=0.06). The prevalence of small side branches (<0.5 mm in lumen diameter)
in the high-grade rejection group was greater compared with
the none/mild rejection group (34.2% versus 23.0%; P=0.05).
The prevalence of VABS was also significantly greater in the
A
B
Figure 3. Representative none/mild rejection grade case. In the
angiogram (A), the vessel looks normal from the distal to the
proximal segments. In the corresponding optical coherence
tomographic images (B), 3 layers of normal arterial structures are
seen without any abnormal intimal thickness or attenuation.
6 Circ Cardiovasc Interv April 2014
−2.93 [−5.41, −0.45], P=0.03; lumen area at distal segment,
−2.66 [−5.03, −0.29], P=0.03; average diameter of side branch
per patient, −0.33 [−0.68, 0.02], P=0.07). Conversely, duration after transplant or other clinical factors including age,
transplant indication for ischemic heart disease, and diabetes
mellitus were not predictors. When %intima/IEL area at distal
or middle segment was used as the dependent variable, both
high-grade rejection group (versus none/mild rejection) and
duration post transplant were independent predictors. When
%intima/IEL area at proximal segment was used as the dependent variable, only high-grade rejection group was an independent variable.
B
A
Discussion
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Figure 4. Representative high-grade rejection case. In the angiogram (A), the middle and distal left anterior descending segments
look smaller than expected from vessel tapering alone. The optical coherence tomographic image (B) shows the 3 layers of the
arterial structure with proximal, middle, and distal segments having significant intimal thickening with trailing attenuation (white
arrow) in the middle and distal segments.
high-grade rejection group than in the none/mild rejection
group (54% [47/87] versus 36% [98/272]; P=0.01).
Within the none/mild group, the 12 patients with either
ISHLT grade 1B or 2 rejection had a higher prevalence of
VABS compared with the 25 patients with either ISHLT grade
0 or 1A rejection (57.3% versus 23.8%; P=0.0003). However,
the 12 patients with either ISHLT grade 1B or 2 rejection had
similar mean intimal thickness and a similar prevalence of
plaque with attenuation compared with the 25 patients with
either ISHLT 0 or 1A rejection grade.
Predictors of OCT Findings
Using multivariate linear regression, only high-grade rejection
(versus none/mild rejection) was an independent predictor of
lumen area at distal segment, lumen area at middle segment,
lumen area at proximal segment, and the average diameter of
side branch per patient (regression coefficient [95% confidence interval] and P value: lumen area at proximal segment,
−3.61 [−7.28, 0.06], P=0.06; lumen area at middle segment,
A
A’
B
B’
The principal findings of the present study are that (1) OCT
demonstrated greater intimal thickening and findings suggestive of a higher prevalence of foamy macrophages in all
coronary segments in patients with prior high-grade cellular
rejection than those with none/mild rejection, and (2) OCT
demonstrated more intimal thickening within side branches
and VABS as a part of the more diffuse involvement in patients
with prior high-grade rejection.
The pathophysiology of CAV involves immunologic and
nonimmunologic factors that cause localized inflammation
with persistent vascular injury and endothelial dysfunction.12.13
As such, CAV may be conceived of as a form of chronic rejection,14 and the prevalence of CAV increases with time: 20% at
3 years, 30% at 5 years, and 45% at 8 years after transplantation.15 Histologically, there is subendothelial accumulation of
lymphocytes (primarily T cells), myointimal proliferation of
smooth muscles cells, development of l­ipid-laden foam cells,
and perivascular fibrosis. Concentric intimal hyperplasia leads
to progressive luminal compromise and typically results in a
diffuse obliterative process of the intramural and epicardial
coronary arteries.16
The early diagnosis of CAV is essential to facilitate treatment of CAV before progression to the point of requiring revascularization. However, ischemic symptoms are
frequently absent or atypical because of allograft denervation.
Multiple noninvasive modalities, including dobutamine stress
echocardiography, pharmacological radionuclide myocardial
C
C’
Figure 5. Representative qualitative optical coherence tomographic findings. A and A′, Mural thrombus (white arrows) from 2 patients with International
Society of Heart and Lung Transplantation (ISHLT)
3A grade rejection. A, mixed thrombus; A′, low scattering area without attenuation, indicating organized
thrombus. B and B′, Intimal microvessels (white
arrows). B, From an ISHLT 2 grade rejection patient;
and B′, from an ISHLT 1A grade rejection patient. In
both patients, the multiple microvessels were located
parallel to the lumen border. C and C′, Superficial
calcium (white arrows) from 2 patients with ISHLT 3A
grade rejection. In both patients, there was a similar
pattern of superficial broadly thin calcification parallel to the intimal surface.
Dong et al OCT Evaluation of Transplant Vasculopathy 7
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perfusion imaging, computerized tomographic angiography,
and MRI, are available, but none has replaced angiography
that remains the gold standard for diagnosing CAV.17 Routine
coronary angiography is, therefore, performed on a periodic
basis at many cardiac transplant centers.2
On angiography, CAV usually seems diffuse and concentric,18 similar to the pathology findings,19 and differs from the
lesions of typical atherosclerotic disease that tend to be more
proximal, focal, and eccentric. The angiographic diagnosis of
CAV provides important prognostic information. In one study,
absence of angiographic disease was a significant predictor
of cardiac event-free survival in heart transplant recipients.20
However, coronary angiography frequently underestimates
the extent and severity of the disease. The positive predictive
power of coronary angiography (compared with intravascular ultrasound [IVUS]) is only 44%,21 and IVUS detects a
5× greater number of CAV lesions than can be found angiographically in the same patients.22 The process of lumen loss
can also be studied using serial IVUS. In one report of 38
cases studied annually for 5 years,23 the investigators found
that early lumen loss was primarily caused by intimal thickening and that late lumen loss was caused primarily by vessel constriction (negative remodeling). Furthermore, intimal
thickening determined using IVUS showed a poor prognosis
in heart transplant recipients, even in the presence of normal
angiography.24–27 Radiofrequency (virtual histology)-IVUS of
plaque composition in CAV has extended these findings to
show increasing amounts necrotic core and calcium over time
that are associated with greater rejection.28–30
Because of its higher resolution compared with IVUS,
OCT may be more suitable for the assessment of vessel
intima and small structures3 and provides greater information about plaque components.7–10 For example, in 15 patients
who were studied a mean of 2.8 years after cardiac transplant,
half of the patients had lipid-rich or calcified atherosclerotic
plaques.31 Another OCT evaluation of 53 heart transplant
patients showed that the prevalence of thin-cap fibroatheroma,
macrophages, and microchannels increased in relation to the
duration from the transplant.32 In the current analysis, trailing
attenuation with narrow shadow likely caused by macrophage
accumulation was seen in the majority of patients, even those
with none/mild rejection.
In the current study, intimal microvessel formation, thrombus, calcification, and plaque rupture were found in ≈15% of
patients and were located within middle or proximal segments
except microvessels, which were located equally from the distal to the proximal segments. Previous OCT studies in atherosclerotic coronary artery disease in nontransplant patients
suggested that intimal microvessels were related to plaque
vulnerability such as thin-cap fibroatheroma or plaque rupture
along with serum high sensitivity C-reactive protein and were
a potential predictor of subsequent progression of nonsignificant coronary plaques, as well as of intraluminal thrombi.33,34
CAV is a diffuse process that involves not only distal arterial
segments but also side branches. Because of limited resolution,
previous IVUS or virtual histology-IVUS studies were unable
to evaluate changes in side branches that can be detected by
OCT. The effect of intimal proliferation on the luminal area of
side branches may explain the significantly higher prevalence
of small side branches (diameter <0.5 mm) in the high-grade
rejection group in the current study. In addition, VABS was
present even in some patients with none/mild rejection and
before intimal thickening in the main vessel; this suggests that
side branch involvement may appear earlier than the main vessel disease and may be used as a predictor of early rejection.
Limitations
This study included only 48 patients with only 11 patients having a history of high-grade rejection, and OCT imaging was
limited to 1 coronary artery. This may have affected the statistical analysis because of the 3:1 ratio of low-to-high–grade rejection patients. The distribution of years after transplantation is
skewed, especially in the high-grade rejection group who were
assessed significantly later than the none/mild rejection group;
this may confound the relationship between the rejection grade
and the OCT findings. Many patients died from the first to the
12th year in both groups such that sampling was incomplete
in both groups. None of the patients in this analysis had grade
3B or 4 (3R) rejection, so conclusions cannot be drawn about
the effect of severe rejection of CAV. Correlation of OCT findings with histopathologic finding is not available. Because there
was no OCT evaluation at the time of the transplant, we cannot eliminate the possibility that intimal hyperplasia already
existed in the donor hearts. Despite the good reproducibility for
the assessment of VABS in the current study, this diagnosis may
be difficult because the side branch is located in the farfield.
Finally, type I statistical error may have occurred, given the
number of patients and the number of statistical tests; therefore,
this analysis should be considered hypothesis generating.
Conclusions
In patients after cardiac allograft transplantation, OCT imaging demonstrated greater intimal thickening in patients with a
history of high-grade rejection than those with mild or without
rejection. Involvement was diffuse and included distal, middle, and proximal segments, as well as side branches. OCT
may have the potential for early detection of CAV in heart
transplantation patients.
Acknowledgments
We thank Khady N. Fall, MD, for her assistance in acquiring optical
coherence tomographic data.
Disclosures
Dr Dong received grant support from Boston Scientific. Dr Mintz
is a consultant for Volcano Corporation (research grant) and Boston
Scientific (grant support). Dr Maehara received grant support (institutional) from Boston Scientific and honoraria from Boston Scientific.
Dr Weisz is a consultant for InfraReDx. The other authors report no
conflicts. The study has no external funding.
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Optical Coherence Tomographic Evaluation of Transplant Coronary Artery Vasculopathy
With Correlation to Cellular Rejection
Liang Dong, Akiko Maehara, Tamim M. Nazif, Ari T. Pollack, Shigeo Saito, LeRoy E. Rabbani,
Mark A. Apfelbaum, Kate Dalton, Jeffrey W. Moses, Ulrich P. Jorde, Ke Xu, Gary S. Mintz,
Donna M. Mancini and Giora Weisz
Circ Cardiovasc Interv. published online April 8, 2014;
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