Download Thorax/abdomen

Online Appendix for the following JACC article
TITLE: Aggressive Cardiovascular Phenotype of Aneurysms-Osteoarthritis Syndrome
Caused by Pathogenic SMAD3 Variants
AUTHORS: Denise van der Linde, MSc, Ingrid M. B. H. van de Laar, MD, Aida M. BertoliAvella, MD, PHD, Rogier A. Oldenburg, MD, PHD, Jos A. Bekkers, MD, Francesco U. S.
Mattace-Raso, MD, PHD, Anton H. van den Meiracker, MD, PHD, Adriaan Moelker, MD,
PHD, Fop van Kooten, MD, PHD, Ingrid M. E. Frohn-Mulder, MD, Janneke Timmermans,
MD, Els Moltzer, PHD, Jan M. Cobben, MD, PHD, Lut van Laer, PHD, Bart Loeys, MD, PHD,
Julie De Backer, MD, PHD, Paul J. Coucke, PHD, Anne De Paepe, MD, PHD, Yvonne
Hilhorst-Hofstee, MD, Marja W. Wessels, MD, PHD, Jolien W. Roos-Hesselink, MD, PHD
APPENDIX
ONLINE METHODS
Transthoracic echocardiography (TTE)
Aortic root dimensions were measured at the level of the aortic annulus, Valsalva sinus, sinotubular
junction, and proximal ascending aorta. Aortic dilatation was considered when normalized diameters
for gender and body surface area (BSA) were greater than the mean + 2 standard deviations (27). Left
ventricular mass was calculated using the Devereux-modified formula (28). Left ventricular
hypertrophy (LVH) was defined by a BSA-indexed threshold of >134 g/m 2 for men and >110 g/m2 for
women (29). Mitral valve regurgitation was quantified into 4 grades: trace, mild, moderate and severe
(30). Mitral valve prolapse was defined by a coaptation occurring 2 mm behind the mitral annulus in
the parasternal long-axis view (31).
Computed tomography angiography (CTA)
Presence of aneurysms, dissections and arterial tortuosity throughout the body was systematically
evaluated by an experienced cardiovascular radiologist. Aortic root dimensions were measured at the
level of the aortic annulus, Valsalva sinus, sinotubular junction, proximal ascending aorta, aortic arch,
thoracic descending aorta and abdominal aorta. We considered the aorta dilated if the Z-score was ≥2
according to gender and BSA (25). Tortuosity was defined as a severe (pigtail-like) curve or multiple
curves in an artery. A trained neuroradiologist and neurologist evaluated presence, location, type and
diameter of intracranial aneurysms, dissections or tortuosity.
Cardiovascular risk factor assessment
Information on cardiovascular risk factors was collected during the outpatient clinic visit at the
Department of Cardiology. Smoking was classified as never, former, or current smoking. Height and
weight were measured and body mass index was calculated (kg/m 2). Sitting blood pressure was
measured during 30 minutes at 5-minute intervals using an automated device (Dynamap, Critikon Inc,
model 8101) in a private room.
Biochemical measurements
Blood samples for laboratory measurements were obtained intravenously after a 30-minute rest
period. Plasma renin concentration was measured by an immunoradiometric assay (Cisbio),
aldosterone by radioimmunoassay (Coat-A-Count, Siemens), endothelin-1 by achemiluminescent
ELISA (QuantiGlo, R&D Systems), and N-terminal probrain natriuretic peptide (NT-proBNP) by a
radioimmunoassay (Phoenix Pharmaceuticals, Inc).
Aortic pulse wave velocity (aPWV)
Measurements of aortic stiffness were carried out in a controlled environment at 22±1 ºC after subjects
had reclined at rest for 15 minutes. The aPWV was assessed by ECG-gated applanation tonometry
(SphygmoCor® system, ArtCor, Sydney, Australia) with patients in supine position (32). Time delay
between the rapid upstroke of the feet of recorded pulse waves in the carotid and femoral arteries was
measured. The distance between the carotid artery and groin was measured with calipers. The aPWV
was calculated as the ratio between the distance and foot-to-foot time delay and was expressed in
meters per second.
Carotid distensibility
Carotid diameters and intima-media thickness (IMT) were measured on the distal wall of the right
common carotid artery, 1 to 2 cm beneath the bifurcation, with a high-precision echo-tracking device
(Wall Track System, Pie-medical Esaote) (33). End-diastolic diameter (D) and absolute stroke change
in diameter during systole (ΔD) were computed as the mean of 5 cardiac cycles of 3 successive
recordings. Cross-sectional arterial wall distensibility coefficient was calculated according to the
following equation: distensibility coefficient (DC) = 2ΔD/(D*central pulse pressure) (10-3/kPa) (34). Wall
cross-sectional area and Young’s elastic modulus were calculated according to previously described
formulas (35).
ONLINE TABLES
Online Table 1 Cardiovascular abnormalities for each individual patient
Vascular abnormalities in thorax/abdomen
Age
(years)
at baseline
Gend
er
Aortic
root
aneur
ysm
Aneurysms in
other arteries
Dissection
Tortuosity
Intracranial and
brachiocephalic vascular
abnormalities
Aneurysm
Tortuosity
Intracardiac abnormalities
Mortality
Congen
ital
heart
defects
Mitral
valve
abnorm
alities
AF
LVH
72
F
--
--
--
--
--
--
no
yes
yes
yes
74
F
no
no
no
--
--
--
no
yes
yes
yes
67
F
yes
no
Type A
yes
--
--
no
no
no
yes
69, aortic
dissection
45
M
yes
no
Type A
--
--
--
no
--
--
--
63
F
no
abdominal aorta,
common and
external iliac artery
no
no
yes
yes
no
no
no
--
47, aortic
dissection
no
62
M
yes
no
no
no
no
yes
no
yes
no
no
no
57
F
yes
no
no
no
--
--
no
no
no
no
no
30
F
yes
no
no
--
--
--
no
yes
no
no
no
34
M
--
--
--
--
--
--
--
--
--
--
--
46
F
yes
Type A and
B
yes
--
--
PDA
and
ASD
yes
yes
yes
OA knee,
spine
c.859C>T
(p.Arg287Trp)
56
F
no
descending aorta,
brachiocephalic,
iliac and superior
mesenteric artery
no
35,
sudden
cardiac
death, no
autopsy*
52, aortic
dissection
no
yes
yes
yes
no
yes
yes
no
no
OA feet,
c.859C>T
No / yes,
age
(years)
and
cause
77, heart
failure *
78, heart
failure
Major
osteoartic
ular traits
Pathogenic
SMAD3
variants
--
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
OA feet,
hands,
knees, hip,
spine
OA feet,
hands,
knee,
spine
OA knee,
OCD
OA feet,
hands,
knee,
spine,
OCD knee
OA feet,
hands,
knee
OA,
hands,
knees, hip,
spine
OA
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
hands,
knee
--
31
M
yes
no
no
yes
yes
yes
no
no
no
no
no
44
F
no
Type B
yes
yes
yes
no
yes
no
no
no
OA hands,
spine
20
M
yes
common, internal
and external iliac,
splenic and celiac
artery
no
no
yes
--
--
no
yes
no
no
no
37
F
yes
no
Type A
--
--
--
--
--
--
--
39
M
yes
splenic and
hepatic artery
yes
no
no
no
yes
yes
yes
13
M
no
no
Proximal left
anterior
descending
coronary
artery
no
39, aortic
dissection
no
OA knee,
hip, OCD
knee
--
--
--
--
no
yes
--
no
no
--
41
F
no
no
no
no
no
no
no
no
no
no
no
16
M
yes
no
no
no
no
no
no
yes
no
no
no
OA knee,
spine
--
39
F
no
no
no
no
no
no
no
no
no
no
no
34
F
yes
no
no
no
no
no
no
no
no
no
no
33
F
yes
no
no
--
no
no
no
no
no
no
no
30
M
yes
no
no
no
yes
no
yes
no
yes
no
29
M
yes
pulmonary, celiac
and superior
mesenteric artery
no
no
no
yes
yes
no
no
no
no
no
26
M
no
no
no
yes
no
PS and
PDA
yes
yes
no
no
26
M
yes
pulmonary artery,
PDA, superior
mesenteric,
common iliac
artery and
vertebral artery
no
no
yes
no
no
no
yes
no
no
no
OA hands
and knee,
OCD knee
OA feet,
knee,
spine,
OCD knee
OA knee,
spine,
OCD knee
OA spine,
OCD knee
OA hands,
OCD knee
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
OA hands,
OCD
scoliosis
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
OA feet,
hands,
spine,
OCD
c.859C>T
(p.Arg287Trp)
58
F
yes
--
no
--
--
--
no
yes
no
no
no
OA feet,
hands,
knee, hip,
spine
--
42
M
yes
no
Type A
yes
--
--
no
no
no
--
42, aortic
dissection
44
F
yes
no
no
yes
no
yes
no
yes
no
no
no
OA knee,
spine,
OCD knee
35
F
yes
no
Type A
--
--
--
--
--
--
--
36, aortic
dissection
--
60
M
--
abdominal aorta,
iliac arteries
Type B
--
--
--
--
--
--
--
62, aortic
dissection
--
54
M
yes
--
--
--
no
yes
no
yes
--
--
--
no
yes
no
no
54, aortic
dissection
no
OCD hip
F
Type A and
B
no
no
15
abdominal aorta,
pulmonary artery
no
17
M
no
no
no
--
--
--
no
no
no
no
no
13
M
no
no
no
--
--
--
no
yes
no
no
no
9
F
no
no
no
--
--
--
no
no
no
no
no
OA hands,
spine
OA, OCD
knee
--
55
M
--
--
--
--
--
--
--
--
--
--
68
M
--
--
--
--
--
--
--
--
--
--
62
F
--
--
--
--
--
--
--
--
--
--
54
M
yes
no
Type A
--
--
--
no
no
--
--
55,
sudden
cardiac
death, no
autopsy*
68, bowel
rupture, no
autopsy*
62,
sudden
cardiac
death, no
autopsy*
no
--
c.859C>T
(p.Arg287Trp)
c.741742delAT
(p.Thr247fsX6
1)
c.741742delAT
(p.Thr247fsX6
1)
c.741742delAT
(p.Thr247fsX6
1)
c.741742delAT
(p.Thr247fsX6
1)
c.782C>T
(p.Thr261Ile)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
c.859C>T
(p.Arg287Trp)
OA
c.859C>T
(p.Arg287Trp)
--
c.859C>T
(p.Arg287Trp)
OA
c.859C>T
(p.Arg287Trp)
--
c.313delG
48
M
yes
no
Type A
yes
--
--
no
no
no
no
no
--
56
M
yes
no
Type A
--
--
--
no
no
--
--
no
--
41
M
yes
no
no
no
--
--
no
no
--
no
no
34
M
yes
no
Type A
--
--
--
--
--
--
--
OA, OCD
knee
--
34, aortic
dissection
-- indicates there data were not available; LVH, left ventricular hypertrophy; AF, atrial fibrillation; ASD, atrial septal defect; PDA, persistent ductus arteriosus; PS, pulmonary stenosis; OA,
osteoarthritis; OCD, osteochondritis dissecans. * These patients were obligate carriers.
(p.Ala105Profs
X11)
c.1080dupT
(p.Glu361X)
c.788C>T
(p.Pro263Leu)
c.1045G>C
(p.Ala349Pro)
c.1045G>C
(p.Ala349Pro)
Online Table 2 Detailed information about 9 AOS patients with brachiocephalic and intracranial vascular abnormalities.
Gender
Age
(years)
Aneurysm
Aneurysm
location(s)
Diameter
(mm)
Anterior
or
posterior
Post
Intra- or
extracranial
Tortuosity
Tortuosity
location(s)
4.5
Fusiform
or
saccular
Fus
Female
44
Yes, *
Basilar artery
(bilateral)
Female
63
Yes, one
Female
56
Yes, two
Male
29
Male
Anterior
or
posterior
Ant
Intra- or
extracranial
Intra
Yes
Left arteria
communicans
anterior A2
origo
1: Top of
basilar artery
2: Origo of
basilar artery
3
Fus
Ant
Intra
Yes
Internal carotid
arteries
(bilateral)
Origo vertebral
arteries
(bilateral)
Post
Extra
1: 7
2: 5.5
1: Fus
2: Fus
1: Post
2: Post
1: Intra
2: Intra
Yes
1: Origo right
vertebral artery
2:
Vertebrobasilar
system
Internal carotid
artery, and
arteria cerebri
anterior and
media
(bilateral)
Left vertebral
artery
1: Post
2 : Post
1: Extra
2: Intra
Yes, two
1: Basilar
artery
2: Right
ophthalmic
artery
1: 5
2: 4
1: Fus
2: Sac
1: Post
2: Ant
1: Intra
2: Intra
Yes
Ant
Extra and
intra
31
Yes, two
1: 5
2: 5
1: Sac
2: Sac
1: Ant
2: Ant
1: Extra
2: Intra
Yes
Male
26
Yes, two
1: Right
carotid
siphon
2: Left carotid
siphon
1: Top of
basilar artery
2: Proximal
vertebral
artery
Post
Intra
1: 5
2: 11
1: Fus
2: Fus
1: Post
2: Post
1: Intra
2: Extra
No
Male
34
No
Yes
1: Internal
carotid
(bilateral)
2:
Vertebrobasilar
1:Internal
1: Ant
2: Post
1: Extra
2: Intra
Male
62
No
Yes
1: Ant
1: Extra
Extra
carotid
(bilateral)
2:
Vertebrobasilar
system
Female 44
No
Yes
Vertebral
arteries
(bilateral)
Abbreviations: ant = anterior; post = posterior; intra = intracranial; extra = extracranial; fus = fusiform; sac = saccular.
* In addition, multiple caliber changes intracranial and extracranial anterior and posterior were found.
2: Post
2: Intra
Post
Intra
Online Table 3 Aortic stiffness and biochemical measurements in AOS patients and controls.
Variable
Reference
Values
AOS patients
(n=21)
38.6 ± 14.8
9 (43)
Control group
(n=21)
38.8 ± 10.4
9 (43)
pvalue
0.975
1.000
0.347
Age, years
Male, n (%)
Smoker, n (%)
Never
16 (76)
18 (86)
Current
2 (10)
0 (0)
Former
3 (14)
3 (14)
Heart rate, bpm
65.8 ± 15.6
68.4 ± 10.0
0.555
Pulse wave velocity, m/s *
9.2 ± 2.2
7.8 ± 1.8
0.076
Transit time, msec
169 ± 61
154 ± 29
0.383
Augmentation index @HR75, %
23 ± 18
18 ± 17
0.220
Systolic blood pressure, mmHg
Brachial
127 ± 15
128 ± 12
0.790
Central
116 ± 14
112 ± 15
0.386
Diastolic blood pressure, mmHg
Brachial
74 ± 9
74 ± 8
0.968
Central
75 ± 9
74 ± 6
0.883
Mean arterial pressure, mmHg
Brachial
92 ± 11
93 ± 8
0.669
Central
92 ± 11
87 ± 8
0.076
Pulse pressure, mmHg
Brachial
53 ± 7
54 ± 11
0.735
Central
41 ± 8
37 ± 10
0.129
Carotid intima-media thickness, µm
621 ± 193
620 ± 149
0.981
Carotid end-diastolic diameter, mm
6.8 ± 1.3
6.7 ± 0.7
0.774
Carotid stroke change, µm
383 ± 142
444 ± 214
0.325
Wall cross-sectional area, mm2
5.8 ± 2.2
6.8 ± 2.1
0.184
Distensibility coefficient, 10-3/kPa
26.2 ± 9.9
29.3 ± 13.4
0.438
Young’s elastic modulus, kPa x 103
0.18 ± 0.11
0.22 ± 0.10
0.351
NT-proBNP, pg/ml
<115
94.1 (52.5 – 172.9)
12.7 (8.5 – 55.1)
<0.001
Renin, pg/ml
6 – 30
6.8 (4.0 – 16.2)
9.2 (5.9 – 10.6)
0.917
Aldosterone, pg/ml
50 – 200
56.5 (36.0 – 70.0)
50.5 (33.5 – 71.0)
0.598
ET-1, pg/ml
<2.5
1.7 (1.5 – 2.0)
0.7 (0.6 – 1.0)
<0.001
AOS indicates aneurysms-osteoarthritis syndrome; NT-proBNP, N-terminal Pro Brain Natriuretic Peptide; ET-1, endothelin-1. * Pulse wave velocity
measurements could only be obtained in 19 AOS patients.
Online Table 4 Comparison of cardiovascular findings in different disorders affecting the aorta.
Cardiovascular features
Aneurysmsosteoarthritis
syndrome5
Marfan
syndrome2,10,20,36-
SMAD3
FBN1
Thoracic aortic aneurysm
Main location of aortic
dilatation
71%
Sinus of Valsalva
Aneurysms of other arteries
in abdomen/thorax
Arterial
tortuosity
abdomen/thorax
Intracranial aneurysms
Intracranial tortuosity
Mitral valve abnormalities
Atrial fibrillation
Congenital heart disease *
Left ventricular mass
Median survival (years)
Genetic defect or mutation
Loeys-Dietz
syndrome3,8,9,39,40
Vascular EhlersDanlos
syndrome39,41-43
Turner
syndrome44-46
Bicuspid aortic
valve4,21,47-49
COL3A1
45,X0
77%
Sinus of Valsalva
TGFBR1 /
TGFBR2
98-100%
Sinus of Valsalva
20-30%
Sinotubular
junction
18%
7%
52-73%
25-50%
Descending
thoracic and
abdominal aorta
48-63%
Multiple, among
which NOTCH1
15-45%
Ascending aorta
4-29%
None
48%
40%
67-84%
NR
NR
NR
38%
50%
51%
22%
6%
Increased in 19%
62 †
6.5%
NR
60-80%
8%
1%
Increased in 2.9%
70 †
32%
67-84%
29%
NR
22-35%
NR
37
25-33%
NR
6%
NR
0%
NR
48
5%
NR
2%
1%
16-49%
Increased
70
10%
NR
NR
NR
15%
Increased
Comparable to
population
estimates
NR
Increased
NR
NR
40
NT-proBNP
Elevated
Elevated
NR
NR
Normal
Pulse wave velocity
Increased
Increased
NR
Normal
Increased
Intima-media thickness
Normal
Normal
NR
Decreased
Increased
Carotid distensibility
Normal
Decreased
NR
Increased
NR
NR indicates not reported; NT-proBNP, N-terminal Pro Brain Natriuretic Peptide.
* Including: atrial septal defect, persistent ductus arteriosus, pulmonary stenosis, coarctation of the aorta, partial anomalous pulmonary venous return.
† With elective interventions.
ONLINE FIGURES: Full-size figures of images in Figure 1.
Online Figure 1. Aneurysm of the aortic root (54 mm) in 31-year-old male.
Online Figure 2. Stanford type A aortic dissection at a maximal aortic diameter of 40 mm in a 50-yearold female, with in addition tortuosity of the abdominal great arteries.
Online Figure 3. Aortic dissection with dissection flap extending from distal abdominal aorta into the
left common iliac artery (true lumen in internal iliac artery and false lumen in external iliac artery) and
aneurysm in the right common iliac artery (27 mm) and right external iliac artery (16 mm) in 45-yearold female.
Online Figure 4. Tortuosity and aneurysm in left splenic artery (21 mm) in same 45-year-old female.
Online Figure 5. Two saccular aneurysms in the left and right carotid siphon in a 31-year-old male.
Online Figure 6. Fusiform aneurysm of the top of the basilar artery in a 26-year-old male.
Online Figure 7. Tortuosity of the internal carotid arteries in a 34-year-old male.
ONLINE VIDEO LEGENDS
Online Video 1. Aneurysm of the aortic root (54 mm) in 31-year-old male.
Online Video 2. Extensive tortuosity of the splenic arteries in a 39-year-old male.
Online Video 3. Distal abdominal aortic dissection with dissection flap extending into the left common
iliac artery (true lumen in internal iliac artery and false lumen in external iliac artery) and aneurysm in
the right common iliac artery (27 mm) and right external iliac artery (16 mm) in 45-year-old female.
Online Video 4. Tortuosity of the internal carotid arteries in a 34-year-old male.
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