CARDIOVASCULAR MAGNETIC RESONANCE
IN TURNER SYNDROME :
JUST AN EXPENSIVE GADGET OR
USEFUL CLINICAL TOOL ?
Claus H. Gravholt
Department of Endocrinology and Internal Medicine
Department of Molecular Medicine
Aarhus University Hospital, Denmark
Kristian H. Mortensen, PhD
Department of Radiology
Papworth and Addenbrookes Hospitals
Cambridge University Hospitals NHS Foundation Trust, UK
3-FOLD INCREASED RISK OF EARLY DEATH :
HALF ATTRIBUTED TO CARDIOVASCULAR DISEASE
ACQUIRED
CONGENITAL
Accounts for 41% of all-cause
excess mortality
Accounts for 8% of all-cause
excess mortality
Price [1986]; Schoemaker [2008]; Gravholt [1998]; Stochholm [2006]
CLEARY ABNORMAL PHENOTYPE :
DOES THIS KNOWLEDGE HELP PATIENTS ?
Intima media thickness
Arterial diameter
Augmentation index
Ambulatory arterial stiffness index
Arterial distensibility
QT-interval
Exercise capacity
VO2 max
Left ventricular function
Left ventricular mass
Left atrial size
Blood pressure
Heart rate
Serum Cholesterol
Inflammatory markers
Sympathovagal balance
…
NO OUTCOME STUDIES :
NO VALIDATED MARKERS :
FEW PROSPECTIVE STUDIES
NECESSARY BULDING STONES TO
IMPROVE UNDERSTANDING OF DISEASE
PROCESSES IN TS, .. But how to
TRANSLATE INTO CLINICAL ?
Baguet [2005]; Landin-Wilhelmsen [2001]; Nathwani [2000]; Andersen [2008]; Bondy [2006]; Pirgon [2008]; Ostberg [2005]
DIGGING DEEPER : PREVENTING AORTIC EVENTS ?
AORTIC DISSECTION
TS = INDEPENDENT MARKER : WITHIN TURNER SYNDROME ?
FREQUENT OCCURENCES >< INFREQUENT OVERALL
2:100
≈ 100-fold increased risk
2/3 Ascending // 1/3 Descending
Aortic dilation
Aortic coarctation, Bicuspid aortic valves
Hypertension, karyotype, pregnancy
> 10% : not predicted
Lopez [2007]; Gravholt [2006]; Carlson [2009]; Carlson [2012]
WHO, WHEN, WHAT, HOW TO MONITOR AND INTERVENE ?
‘Patients with Turner syndrome should undergo imaging of the heart and aorta for evidence of
bicuspid aortic valve, coarctation of the aorta, or dilatation of the ascending thoracic aorta. If initial
imaging is normal and there are no risk factors for aortic dissection, repeat imaging should be
performed every 5 to 10 years or if otherwise clinically indicated. If abnormalities exist, annual
imaging or follow-up imaging should be done. (Level of Evidence: C)’
Although TTE is noninvasive, its failure to visualize consistently and measure accurately the
tubular portion of the ascending thoracic aorta is problematic. It is not typically used to follow
aneurysms in that aortic segment. However, because TTE does accurately visualize the aortic
root, its primary role as an imaging method for serial follow-up is in patients with aortic
disease limited to the root, particularly those with Marfan syndrome. It is also used, often in
conjunction with CT or MR, to observe patients with concomitant structural heart disease, such as
bicuspid aortic valve, mitral valve prolapse, cardiomegaly, or cardiomyopathy.
2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines
Hiratzka [2010]
THE EASY ANSWER .. HOW TO OPTIMALLY IMAGE ?
MRI
RADIATION FREE
SENSITIVE + SPECIFIC
REPEATABLE
NON-INVASIVE
ECHO
CXR
AORTOGRAPHY
MDCT
The same patient with ascending aortic dilation (arrows) secondary to severe aortic valve stenosis.
THE GOLD STANDARD : ESCAPING ANATOMICAL PLANES
THE GOLD STANDARD : ADAPTABLE TO PATIENT
NONCONTRAST
3D
3D
2D
2D
FUNCTIONAL DATA
CONTRAST ENHANCED IMAGING
THE GOLD STANDARD : IS A DIAMETER A DIAMETER ?
3D Multiplaner Imaging
THE HARDER QUESTION …
DEFINING DISEASE THAT TENDS TO BE CLINICALLY SILENT
ANUERYSM: SURGICAL MORTALITY
MORTALITY WITH AORTIC DISSECTION
Elective surgery: 9.0 %
22% pre-hospital mortality
34% 30-day in-hospital mortality
Aortic diameter : only validated risk marker
Good positive predictive value (incremental risk with size)
poor negative predictive value (cut off work poorly)
Turner syndrome : irrespective of BSA correction or not : same issues
Olsson [2010].
THE HARDER QUESTION … DEFINING DISEASE
COMPARISON WITH HEALTHY FEMALES
Aortic dissection strikes at diameters that are ‘normal’ even after BSA correction
Patterns of disease and samples of tissue: not just accelerated ageing
Poor discriminator ≈ 50% will have an aortic diameter that would be defined as dilated
Highly abnormal phenotype : hazardous to deduct
COMPARISON WITHIN TURNER SYNDROME
But, … no normal data and what is the true risk of aortic events in relation to this?
Proposed threshold : 2.5 cm/m2 : 3 events (44, 47 and 57 years of age) with 486 years at risk
Supported by retrospective volunteer registry study of 20 aortic dissections
More systematic, prospective studies are pivotal
Gravholt [2006]; Matura [2007]; Carlson [2012]
AWAITING HARD ENDPOINT STUDY :
OPTIMISING CLINICAL DATA USAGE
‘Patients with a growth rate of more than 0.5 cm/year in an aorta that is less than 5.5 cm in diameter
should be considered for operation. (Level of Evidence: C)’
2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines
CROSS-SECTIONAL + PROSPECTIVE REGISTRATION : ISSUES
>50% will have aortic dilatation
at one or more points
Accelerated growth rates comparable to
bicuspid aortic valve and at least double of
background population
>2.5cm/m2 threshold
0.1 - 0.4 mm/year
What are we triaging for … surgery ? … medicine ? … more follow-up (for what again) ?
Lanzarini [2007], Mortensen [2011]; Hiratzka [2010]
CAN WE APPROACH THE NORMATIVE MRI DATA IN A
WAY THAT MAY BETTER THE TELL US ABOUT HOW AN
INDIVIDUAL ENCOUNTERED IN CLINICAL PRACTICE
MAY COMPARE WITH THEIR PEERS WITH TURNER
SYNDROME ?
AORTIC MRI: PROSPECTIVE KNOWLEDGE
NON-CONTRAST 3D MRI
102 included at baseline
 Post-operative death: aortic aneurism repair [1]
 Sudden unexplained death [2]
 Stanford type A dissection [1]
 Severe Aortic valve stenosis for valve replacement [1]
89% for follow-up
 Death of gastric cancer [1]
 Severe mitral vale regurgitation for surgery [1]
82% for end-of-study
Study of aortic diameter at 9 positions
from aortic sinuses to diaphragmatic
aorta
10 minute study
Free breathing
Well-tolerated (100%)
Olsson [2010].
AORTIC MRI: MODELLING AORTIC DIAMETER
>2000 MEASUREMENTS
>280 MRI STUDIES
4.8 ± 0.5 YEARS FOLLOW-UP ON AVERAGE
CURRENT + FUTURE DIAMETER
Mortensen et al, J Cardiovasc Magn Res, 14
PERCIEVED LOW RISK
CROSS-SECTIONAL
PROSPECTIVE
Dots = actual
Line = predicted
26-year old / 45,X
Tricuspid aortic valve + no aortic coarctation
No antihypertensive treatment
ABP 104/66 mm Hg
BSA 1.46 m2
Mortensen et al, J Cardiovasc Magn Res, 15:47, 2013
Dots = actual at 4 years
Line = predicted at 4 years
Line = predicted at 8 years
PERCIEVED HIGH RISK
CROSS-SECTIONAL
Dots = actual
Line = predicted
49 years old / 45,X/46,X,r(X)
bicuspid valves + aortic coarctation
On antihypertensive treatment
ABP 124/67 mm Hg
BSA 1.60 m2
Mortensen et al, J Cardiovasc Magn Res, 15:47, 2013
PROSPECTIVE
Dots = actual at 4 years
Line = predicted at 4 years
Line = predicted at 8 years
SIGNIFICANCE : ABOVE NORM ± DEVIATING
CROSS-SECTIONAL
PROSPECTIVE
Dots = actual
Line = predicted
43 years old / 45,X
bicuspid aortic valve / no coarcation
Antihypertensive treatments
ABP 143/90 mm Hg
BSA 1.47 m2
Mortensen et al, J Cardiovasc Magn Res, 15:47, 2013
Dots = actual at 4 years
Line = predicted at 4 years
Line = predicted at 8 years
Case
• Turner syndrome mosaic
• Bicuspid aortic valve – operated at the age of 4
month due to stenosis
• Just referred to us – followed at another
department during childhood
• Normotensive
• Echo: moderate stenosis (gradient 30 mmHg).
Aortic ecatsia in ascending aorta (4 cm), no
coarctation – the rest of the aorta is normal
MR
• Aortic ectasia with a maximum of 4.5 cm
(Position 4)
• Somewhat ectatic truncus brachiocephalicus
• H: 154, W: 76, BSA 1,74
• Indexed aortic size: 2.58 cm/m2
In our model she grossly exceeds the range
40.0
35.0
30.0
25.0
20.0
15.0
10.0
5.0
0.0
1
2
3
4
5
6
7
Mortensen et al. J Cardiovasc Magn Reson. 2013 Jun 6;15(1):47.
8
9
FURTHER STUDY OF THE IMPACT OF RISK FACTOR :
% INFLUENCE IN AORTIC DIAMTER
Variable
Aortic coarctation
Age
BITRI
Antihypertensive treatment
Aortic sinus
4.42
0.30
10.39
-4.02
Sinotubular junction
-1.54
0.31
13.76
-0.74
Mid-ascending aorta
-5.81
0.60
19.03
-0.99
Distal ascending aorta
-3.10
0.45
8.12
0.31
Proximal aortic arch
-6.73
0.34
8.39
-1.15
Mid aortic arch
-5.66
0.09
0.80
-0.77
Distal transverse aortic arch
-1.70
0.26
2.41
0.55
Proximal descending
23.40
0.07
5.19
-1.39
Distal descending aorta
14.43
0.34
4.77
1.00
P value
<0.0001
<0.0001
0.0004
0.005
Position
First indication that antihypertensive treatment works, ..
Mortensen et al, J Cardiovasc Magn Res, 15:47, 2013
BUT (!) IT’S NOT ALL ABOUT DIAMETER
ESSENTIAL TO COMBINE QUALITATIVE + QUANTITATIVE
All-in-one package with MRI?
Exploring old and developing new areas, ..
FLOW PATTERNS AND WALL PROPERTIES : CAUSE OR EFFECT
Wall shear stress
and oscillatory
sheer stress are
altered in dilated
aortas compared
with normal
Altered flow
patterns in
dilated or
obstructive
aortopathy :
vortices and
helices
Wall shear stress?
Pulse wave velocity?
Oscillatory shear stress?
Changing flow patterns over time?
Unpublished
Quantitative measures?
Burk [2012]
AORTOPATHY GUIDELINES 2010
BASELINE screening
All
Beyond dissection ..
ANNUAL screening
Bicuspid aortic valve
Aortic coarctation
Aortic dilation
Dilation and aneurism??
Aortic growth??
Indication for medical prophylaxis??
Indication for surgical prophylaxis??
Risk of surgery?
5-10 YEARS screening
Other
BEYOND AORTA: LEFT VENTRICULAR CARDIOMYOPATHY
T1 MAPPING – NON-CONTRAST : MYOCARDIAL FIBROSIS
Left ventricular function –
diastolic dysfunction and
perturbed myocardial metabolism
?
RED = ABNORMAL (HIGH T1)
GREEN = NORMAL
Underlying processes in TS, ..
ischemia, increased afterload,
insulin resistance, growth
hormone deficiency, thyroid ??
T1 values are closely associated with not only left ventricular systolic and diastolic function but also metabolism in
early diabetics, and predicts mortality in aortic stenosis.
Jellis [2011]; Dweck [2011]
Thank you