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Acute Aortic Syndromes:
What Keeps Me Awake at Night
Kim A. Eagle, MD
Albion Walter Hewlett Professor of Internal Medicine
Director Samuel and Jean Frankel Cardiovascular Center
University of Michigan, Ann Arbor, MI
Acute Aortic Syndromes:
What Keeps Me Awake at Night
Kim A. Eagle, MD
Disclosures
Registry
IRAD
Research Grants
•  Gore (Major Sponsor) •  Terumo
International Registry of Aortic Conditions•  Mardigian Foundation •  Varbedian Fund
Role: Founder
•  Hewlett Foundation
GenTAC
•  Medtronic
Genetically Triggered
•  Robert & Anne Aikens
Aortic Conditions
Role: Study Chair
•  University of
Michigan
(Founding Sponsor)
•  National Heart, Lung & Blood Institute
•  National Institute of Arthritis & Musculoskeletal
& Skin Diseases
Lecture Outline
§ 
Where have we been?
§ 
§ 
§ 
§ 
§ 
Epidemiology
Classification
Clinical Presentation/ECG/Chest X-Ray
Static Imaging
Treatments
§ 
§ 
Medical
Non-Medical
•  Where are we headed?
• 
• 
• 
• 
Genetics
Acute Biomarkers
Chronic Biomarkers
Dynamic Imaging
•  Reflections on the Theme
Understanding Acute Aortic Syndromes...
Where Have We Been?
Clinical Presentation
Predisposing
Conditions
Static Imaging
Results
Chest X-Ray
Diagnosis
using
all inputs
Physical Findings
↓
Medical Rx-All
ECG Results
Intervention?
(some)
Routine
Laboratory
Tests
↓
Long Term Follow-Up,
Treatment, & Surveillance
Epidemiology: Incidence and Outcomes
of Aortic Dissection
§ 
§ 
§ 
9 General practice sites – UK: 2002-12
52 incident dissections (6/100,000/yr)
Risk Factors
§ 
§ 
§ 
§ 
§ 
HTN- 67%
Smoking- 62%
BP poorly controlled pre-AoD
56% BP’s > 140/90:
33/52 died, 18 (>50%) at home
Hospital survivors: 5yr. Survival
§  Type A- 86%
§  Type B- 83%
“Acute Aortic Syndromes”
¨ 
Classic Aortic
Dissection
¨ 
Intramural
Aortic
Dissection
Hematoma
¨ 
Penetrating
Aortic Ulcer
IMH
PAU
Intimal Medial
Hemorrhage
Classic
Intimal Tear
Intima
Media
Adventitia
Cystic Medial
Necrosis
Intimal
Tear
Cystic
Medial
Necrosis
Medial
Hemorrhag
e
Current Classification by Time From
Symptom Onset - Outdated
Acute AoD
•  Presentation within 14 days of onset
Stanford Type A
Stanford Type B
Involves the ascending aorta
with or without
descending aorta
Confined to descending aorta
Treasure T, et al. J Heart Valve Dis 1996;5:623-29.
Aortic Dissection:
Mortality vs. Time from Symptom Onset
100
95
90
85
Percent dead
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
0
6 12 18 24
Hours
2
3
4
5
6
7
8
9
Days
10 11 12 13 14
4
6
8 10
Weeks
12
6
9
12 15 18 21
Months
2
3
4
5
6
7
8
9
Years
Mortality rate ….425 Cases
Hirst, Johns, and Kime; Medicine 1958; 37:217-279.
Survival Curve – Type A Dissection
Hyperacute Acute
Subacute
Chronic
Booher AM, et al. Am J Med 2013;26:e19-24.
Demographics and Past History
Variable
All
Type A Type B p-value
(n=3037) (n=1924)
(n=1113)
Age (yrs)
61.9
61.3
63.0
0.003
Male
67.1%
67.2%
67.1%
NS
HTN
75.2%
72.0%
80.7%
Marfan
4.3%
4.5%
3.8%
NS
19.8%
0.002
Prior Heart
16.9%
15.3%
<0.001
Surgery
Iatrogenic
3.3%
3.8%
2.6%
0.09
IRAD Investigators
How Common is Aortic Dissection in ED
Patients with Thoracic Pain?
41,495
2,426
38,819
(5.8%)
Not suspicious
for Aortic
Dissection
(93%)
Other Disease
128
(0.3%)
Aortic
Dissection
250
(0.6%)
Suspicious
122
(0.3%)
No Aortic
Dissection
Von Kodolitsch et al., Arch Intern Med. 2000;160:2977-2982.
Pain attending the splitting of the aortic wall
is usually excruciating and extensive,
radiating from midthorax front or back
through the chest, down the back, and even
into the thighs or up into the neck. The pain
in the thorax or back comes suddenly at its
maximum and is often prostrating, inducing a
state of shock or even death.
- Paul Dudley White, 1944
IRAD
Presenting Symptoms
Variable
All
Type A
Type B
p-value
•  Pain
94.0%
92.6%
96.5%
<0.001
Abrupt
84.0%
82.9%
85.7%
0.06
Anterior
71.9%
78.0%
61.1%
<0.001
Back
53.1%
42.8%
70.5%
<0.001
31.2%
25.5%
40.8%
<0.001
Sharp
62.8%
58.4%
69.4%
<0.001
Tearing
47.1%
44.0%
52.0%
0.004
•  Syncope
12.6%
18.3%
2.9%
<0.001
Abdominal
(n=2807)
IRAD Investigators
IRAD
Physical Exam
Variable
All
High BP
43.3%
30.3%
65.3%
<0.001
Low BP
11.4%
16.0%
3.5%
<0.001
Shock/Tamponade
8.0%
12.0%
1.3%
<0.001
Murmur AI
Type A Type B p-value
27.6% 38.3%
10.7%
<0.001
Pulse Deficit 25.7% 30.5%
18.1%
<0.001
2.2%
<0.001
Stroke
6.5%
9.1%
(n=2820)
IRAD Investigators
Sensitivity of ACC/AHA Guidelines for Acute
Aortic Dissection
2538 (100%)
High Risk Conditions
Marfan Syndrome
Family History Aortic Disease
Known Aortic Valve Disease
Recent Aortic Manipulation
Known Thoracic Aortic Aneurysm
713 (28.1%)
High Risk Pain Features
Chest, back, or abdominal pain
described as any of the following:
• Abrupt onset
• Severe intensity
• Ripping or tearing
2220 (87.5%)
Add Risk Score
Score = 0
108 (4.3%)
Yes – Widened
Mediastinum
35 (48.6%)
Score = 1
927 (36.5%)
No – Widened
Mediastinum
37 (51.4%)
High Risk Exam Features
Evidence of Perfusion Deficit
• Pulse Deficit
• Systolic BP differential
• Focal Neurologic Deficit
(in conjunction with pain)
Murmur of Aortic Insufficiency
(new and with pain)
Hypotension or Shock state
1294 (51%)
Score = 2 or 3
1503 (59.2%)
Chest X-Ray No Chest X-Ray
72
36
Rogers AM, et al. Circulation2011;123:2213-18.
IRAD
EKG & CXR
Variable
•  CXR
Normal
Wide Mediast.
or Aorta
PL. Effusion
•  EKG
Normal
NSST-T ’s
Ischemia
New MI
Type A Type B p-value
All
22.4%
20.2%
25.9%
0.001
67.6%
14.4%
69.5%
12.5%
64.5%
17.3%
0.012
0.002
32.2%
40.7%
14.3%
5.5%
29.9%
41.2%
17.1%
7.4%
36.2%
39.8%
9.6%
2.1%
0.001
NS
<0.001
<0.001
(n=2353)
IRAD Investigators
IRAD Diagnostic Tests
Imaging test 1.8/case (60% > 1)
First Modality
AG
MRI
4%
2%
TEE
33 %
CT
61%
Moore AG, et al. Am J Cardiol 2002;89:1235-1238.
Sensitivity of the First Imaging Study to
Detect AoD and Intramural Hematoma
100.0%
Sensitivity (%)
90.0%
80.0%
88.8%
70.0%
935
1053
60.0%
97.6%
97.8%
2625
2690
44
45
89.8%
88
98
50.0%
40.0%
30.0%
20.0%
10.0%
0.0%
TEE
CT
MRI
(n=3886)
Cath
IRAD Investigators
What is the Size
of a Normal Aorta?
• How Measured?
• Where Measured?
• In Who?
Where to
Measure?
Who are You Measuring?
Aortic Diameter at Sinuses of Valsalva by Gender
(Adjusted for BSA)
NS
p<0.001
15-24 Y
25-34 Y
p<0.001
p<0.001
p<0.001
p<0.001
p=0.002
4
Diameter (cm)
3.5
3
2.5
2
1.5
35-44 Y
Men
45-54 Y
55-64 Y
>64 Y
Women
Devereux et al. J Am Coll Cardiol 2010;55:A87. [Epub on DVD].
How Are You Measuring?
Oblique Imaging Can Cause Over-Estimation
of Aortic Diameter: A GenTAC Substudy
FRONTAL
DOUBLE OBLIQUE
AXIAL
PLANIMETRY
Weinsaft et al. J Am Coll Cardiol 2010;55:A162. [Epub on DVD].
How Are You Measuring?
Patients
Meeting
Surgical
Criteria (%)
50
p = 0.002
40
30
20
10
0
Segments
Meeting Surgical
Criteria (%)
All Segments
All Segments
Axial Method
Double Oblique Method
50
40
p = 0.03
p < 0.001
30
20
p = 1.0
10
0
Sinuses of Valsalva
Sinotubular Junction
Mid Ascending Aorta
Weinsaft et al. JACC, 2010.
Maximum Aorta Diameter:
Type A Dissection
(59% < 5.5 cm)
Pape LA, et al. Circulation 2007;116:1120-27.
Treatment: Type A Dissection
•  Medical Therapy for all, for life
•  Surgery if possible
•  Consider fenestration if surgery not
possible, especially if malperfusion
occurs
Percentage of Nonoperative TA-AAD
Patients Over Time
100
81.6
Percentage of In-hospital
Mortality of All TA-AAD
Patients Over Time
30
88 91.4
25
Type A
Operativ
e
Patients
(p <
0.001)
60
40
20
18.4
12
8.6
0
27.1
21.2
20
Percent
Percent
80
29.3
15
Inhospital
Mortality
(p =
10
5
0
Years (in tertiles)
Years (in tertiles)
Sinha S, presented ACC 2011.
Type B Dissection
•  Uncomplicated - No false
lumen: Medical
•  Uncomplicated - False channel
+/- aneurysm - consider stent
•  Complicated - stent +/- surgery
Nienaber CA, et al. Circulation 2003;108:628-635.
Nienaber CA, et al. Circulation 2003;108:772-778.
Stable Type B Dissection
“Instead” 1 – Yr. Mortality
#Mortality
Medical Treatment663%
Stent Graft
7010%
Nienaber C, et al. Circulation 2009;120:2519-28.
INSTEAD XL – Trial: Kaplan-Meier Estimates of
Aortic Progression and Adverse Events
OMT
OMT +
TEVAR
Nienaber C, et al. Circ Cardiovasc Interv 2013:6;407-416.
INSTEAD XL – Trial Results
OMT
OMT + TEVAR
(n=68)
(n=72)
5 year follow-up
Maximum aortic diameter
56.4±6.8
44.5±11.5
<0.0001
True lumen diameter at level A18.7±6.7
32.6±5.5<0.0001
False lumen diameter at level A
37.1±9.1 10.4±13.2
<0.0001
True lumen diameter at level B16.9±7.2
28.6±6.4<0.0001
Nienaber C, et al. Circ Cardiovasc Interv 2013:6;407-416.
False lumen
diameter at level B
31.2±11.9
Endovascular Treatment
•  TEVAR when feasible is preferred
for complicated Acute Type B
•  Uncomplicated → medical therapy
•  F/up Imaging: Admission, 7-days, 6
weeks, then annually
•  Late indications for TEVAR/Surgery:
-  Aortic instability - Malperfusion
-  Hemorrhage
-  Hemodynamic
compromise
- Expansion to >55 mm
or annual increase
>4 mm
Fattori R, et al. J Am Coll Cardiol 2013;61:1661-1678.
How to Follow?
1. Treatment
2. Surveillance
3. Patient Education
Medical Therapy of Thoracic Aortic
Aneurysms: Are We there Yet?
AR
B
ACEI
βblocker
↑ Angiotensin II
Fibrillin
1 mutation
AT1
Statin
↑ NADH/NADPH
Tetracycline
s/
Macrolides
↑ ROS
↑ TGF beta
Shear stress
↑ Cyclophilin A
↑ MMP
↑ psmad2
Inflammatory
reaction
Cystic medial
necrosis
Cellular proliferation
Matrix degradation
Aneurysm
formation
Danyi P, et al. Circulation 2011;124:1469-1476.
Freedom from Reoperation After Repair of Type A
AoD vs. Postoperative β-blocker Therapy
Zierer A, et al. Ann Thorac Surg 2007;84:479-87.
Long-Term
•  B-Blockers: HR <60BPM
•  Control Blood Pressure: <120/80 - Prefer
ARB’s in Marfan or Loeys-Dietz
•  Statins for atherosclerosis
•  Anticoagulants?
•  “Watch” for aneurysm formation: 1, 3, 6, 12
months to start
•  Educate the patient: a lifelong disease; sx,
activity, meds, f/up
Understanding Acute Aortic Syndromes:
Where Are We Headed?
Clinical Presentation
Pre-Existing
Conditions
Genetic Predisposition
Static Imaging Result
Dynamic Imaging
Result
Clinical Evaluation
Static Imaging Result
Dynamic Imaging
Result
•  Initial Diagnosis
•  Initial
Prognostication
•  Initial Treatment
– Medical
– Surgical
– Intervention
– Combination
•  Response to Initial
Therapy
•  Individualized
Long Term
Therapy
•  Targeted Family
Screenings
Physical Findings
ECG Testing
Routine Laboratory
Tests
Acute Biomarkers
GeneticPredisposition
Chronic Biomarkers
Genetics of Aortic Diseases:
An Emerging Science
Effect Size
50.0
High
Mendelian Families
(Single Gene Disorders)
Missing Heritability
3.0
Intermediate
Modest
Low
1.5
1.1
Intermediate Frequency,
Moderate Effects
(Rare Variants, CNV’s)
Hard to
Identify:
Rare Variants with
Small Effects
Rare
GWAS loci e.g.
(Common Variants;
SNP’s)
0.5%
5%
Low Frequency
Common
Allele Frequency
(Adapted from) Magnani JW, et al. Circulation 2011;124:1982-93.
Indexed Aortic Root Dimensions
of 3 Study Groups
BAVs (53% Abnormal)
Indexed Aortic Dimensions (cm/m)
3.5
FDRs (32% Abnormal)
Controls (0% Abnormal)
3.0
2.5
p < 0.001
p = 0.14
BAVs (n=54)
FDRs (n=48)
Controls (n= 45)
p < 0.001
p < 0.001
2.0
1.5
1.0
Annulus
Valsalva
Junction
Ascending
Aorta
Biner, et al. JACC 2009;53:2288-95.
Indications for Aortic Root Repair in
Bicuspid Aortic Valve are:
1.  Maximal diameter of > 5.5cm (Class I).
2.  Maximal diameter of > 5cm with family history
of aortic dissection or annual increase in size
of > 0.5cm (Class IIa).
3.  Maximal diameter of 4.5cm if patient
undergoing surgery for aortic stenosis or
regurgitation (Class IIa).
It is a Class IIa indication to recommend AVR in the presence
of moderate or greater aortic insufficiency when undergoing
other open heart surgery (in this case aortic root repair)).
ACC/AHA Guidelines 2014 on management of valvular heart disease: Online release March 2014.
Biomarkers “Targets” in Acute and
Chronic Thoracic Aortic Disease
Regulatory Proteins (TGFB)
Clotting
Factors
(D-Dimer)
Diagnosis
and/or
Risk Prediction
Elastic Fibers
(Fibrillin Fragments)
Smooth Muscle
Cells
(Myosin Heavy
Chain)
Inflammation
(CRP)
D-Dimer in Acute Aortic Dissection
Author/Year
# Cases A/B
Sx
# Ctrl Onset Sens
Spec
Weber 2003
24
12/12
30
24
100%
69
Eggebrecht 2004
16
6/10
48
16
100%
81%
Hazui 2005
29
29/0
-
4
93%
-
Akutsu 2005
30
12/18
48
4.5
100%
54%
Ohlman 2006
94
67/27
94
29
99%
34%
Weigand 2007
25
-
-
-
88%
-
218
97% 34-81%
Bio – IRAD:
D-Dimer Levels in Aortic Dissection
D-Dimer (ng/ml)
5000
4000
3000
2000
1000
0
Time after onset
(0-6h)
Suzuki T, et al. Circulation 2009;119:2702-07.
Time after onset
(6-12h)
Time after onset
(12-24h)
Fibrillin Fragments in
Thoracic Aortic Disease
Marshall LM, et al. Circ Res 2013:113:1159-68.
Partial Thrombosis of False Lumen in Acute
Type B Dissection
x
x
Tsai TT, et. Al. N Engl J Med 2007;357:349-359., Tsai TT, et al. J Vasc Surg 2008;47:844-51.
Dynamic Imaging: A Key Concept for
Personalized Treatment and Follow-Up?
Helicity Quantification
Clough RE, et al. J Vasc Surg. 2012; 55:914-23.
A, Aortic valve images (shown at every 3 times steps starting from left
ventricular contraction) were (B) coregistered with the 4D flow data for
3D flow visualization of a normal subject with a tricuspid aortic valve
Barker A J et al. Circ Cardiovasc Imaging 2012;5:457-466.
A–C, Coregistered steady-state free precession images
provide anatomic landmarks to locate (D and E) the
direction and propagation of a systolic flow jet
Barker A J et al. Circ Cardiovasc Imaging 2012;5:457-466.
Helicity
Clough RE, et al. J Vasc Surg. 2012; 55:914-23
Disease is very old, and nothing
about it has changed.
It is we who change
as we learn to recognize
what was formerly
imperceptible.
- Charcot
IRAD Hospitals
Founding “Fathers”
•  Kim Eagle
•  Eric Isselbacher
•  Christoph Nienaber
Bio-IRAD
USA
¤ 
¤ 
¤ 
¤ 
¤ 
¤ 
¤ 
¤ 
¤ 
New York Methodist
Cornell University
Beth Israel, Boston
Henry Ford, Detroit
Cedars Sinai
Sentara Norfolk General
University of Michigan
SUNY-Stony Brook
University of Pennsylvania
Spain
§  Barcelona
Italy
¨ 
¨ 
¨ 
¨ 
¨ 
¨ 
¨ 
¨ 
¨ 
¨ 
¨ 
¨ 
¨ 
Rome
Catania
Salerno
Lecce
Avellino
Venosa
Varese
Catanzaro
Brindisi
Brescia
Bari
Taranto
Milan
GenTAC Org Chart
Eagle KA, et al. Am Heart J 2009;157:319-26.
University of Michigan Collaborators
IRAD Core
Jim Froehlich
Eva Kline-Rogers
Dan Montgomery
Anna Booher
Elise Woznicki
UM Aortic Program
G. Michael Deeb
Jon Eliason
David Williams
Himanshu Patel
UM Aortic Program
James C. Stanley
Santhi Ganesh
Kristen Willer
Stan Chetcuti
Bill Armstrong
David Bach
Ralph Stern
Mike Shea
Rob Brook
Troy LaBounty
Bo Yang
“There is no disease more
conducive to clinical humility
than aneurysm of the aorta”
- Sir William Osler
Acknowledgements
Mentorship
¨ 
Dr. Larry Cohen – Joy of
Cardiology & Professionalism
¨ 
Dr. Roman DeSanctis – My
“Medical” Father
¨ 
Dr. George Thibault – Outcomes &
Guidelines
¨ 
Dr. Valentin Fuster – Think Global –
Anything possible!
Support
•  Mr. & Mrs. Walter Eagle – Value
of hard work, honesty & family
•  Mr. Donald S. Hopkins – Invested
in my career
•  Mrs. Darlene Farrell Eagle –
Lifelong companion
•  Mr. Taylor Eagle – My greatest
legacy?
•  Countless others: Colleagues,
students, patients, and family
members
Faith, family, friends, colleagues…These are the “things” that matter…
Thank you