Update on the Diagnosis & Update on the Diagnosis & Management of Acute Aortic Dissection Management of Acute Aortic Dissection

Kim A. Eagle, MDKim A. Eagle, MDDirectorDirector

University of MichiganUniversity of MichiganCardiovascular CenterCardiovascular Center

Kim A. Eagle, MD, FACCDirector University of Michigan Cardiovascular Center

Grants: Hewlett Foundation, Mardigian Foundation, Varbedian Fund, GORE

Consultant: NIH NHLBI

““Acute Aortic SyndromesAcute Aortic Syndromes””

•• Classic Aortic Classic Aortic

DissectionDissection

•• Intramural Intramural

HematomaHematoma

•• Penetrating Penetrating

Aortic UlcerAortic Ulcer

AorticAorticDissectionDissection

IMHIMH

PAU

“Atypical" Aortic Dissection(Intramural Hematoma)

“Atypical" Aortic Dissection(Intramural Hematoma)

TL

FL

Typical = Dissection flap and false lumen"Atypical" = No dissection flap; Medial hematoma

IRAD Classification SystemIRAD Classification SystemType A DissectionType A Dissection

IRAD Investigators

5649423528211470

Days From Symptom Onset

Prob

abili

ty o

f Sur

viva

l

0.0

0.2

0.8

1.0

Surgical Management

Medical Management

Log Rank p<0.001(Between Managements)

8-21 Days(Subacute)

>21 Days(Chronic)

2-7 Days(Acute)

0-24 Hours(Hyperacute)

0.4

0.6

IRAD Classification SystemIRAD Classification SystemType B DissectionType B Dissection

5649423528211470Days From Symptom Onset

Prob

abili

ty o

f Sur

viva

l

0.7

0.8

0.9

1.0

Surgical Management

Medical Management

Endovascular Management

Log Rank p<0.001(Between Managements)

8-21 Days(Subacute)

>21 Days(Chronic)

2-7 Days(Acute)

0-24 Hours(Hyperacute)

IRAD Investigators

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% NSHTN 75.2% 72.0% 80.7% <0.001Marfan 4.3% 4.5% 3.8% NS

Prior Heart 16.9% 15.3% 19.8% 0.002Surgery

Iatrogenic 3.3% 3.8% 2.6% 0.09

Demographics and Past HistoryDemographics and Past History

IRAD Investigators

GeneticGeneticSyndromeSyndrome

CommonCommonClinicalClinical

FeaturesFeaturesGeneticGeneticDefectDefect

DiagnosticDiagnosticTestTest

MarfanMarfanSyndromeSyndrome

Skeletal featuresSkeletal featuresEctopic lentleEctopic lentle

FBN1FBN1mutations*mutations*

Ghent diagnosticGhent diagnosticCriteria, DNA for Criteria, DNA for sequencingsequencing

LoeysLoeys--DietzDietzSyndromeSyndrome

Bifid uvula or cleft Bifid uvula or cleft palatepalateArterial tortuosityArterial tortuosityHypertelorismHypertelorism

TGFBR2TGFBR2 ororTGFBR1TGFBR1mutationsmutations

DNA forDNA forsequencingsequencing

EhlersEhlers--DaniosDaniosSyndromeSyndrome

Thin, translucent Thin, translucent skin GI ruptureskin GI ruptureRupture of gravid Rupture of gravid uterusuterusRupture of medium Rupture of medium to large arteriesto large arteries

COL3A1COL3A1mutationsmutations

DNA for sequencingDNA for sequencingDermal fibroblasts Dermal fibroblasts for analysis of type for analysis of type 3 collagen3 collagen

TurnerTurnerSyndromeSyndrome

Short statureShort staturePrimary amenorheaPrimary amenorheaBAVBAVAortic coarctationAortic coarctation

45 X45 Xkaryotypekaryotype

Cells for karyotype Cells for karyotype analysisanalysis

Genetic Disorders:Genetic Disorders:Thoracic Aortic DiseaseThoracic Aortic Disease

*The defective gene at a second locus for MFS is TGFBR2 but the clinical phenotype as MFS is debated.

Genetics of Familial ThoracicGenetics of Familial Thoracic(n = 454 Families)(n = 454 Families)

Defective GeneDefective GeneLeading to Leading to

FamilialFamilialTAADTAAD

Frequency inFrequency inFamilial TAADFamilial TAAD

AssociatedAssociatedClinicalClinical

FeaturesFeatures

Comments onComments onAortic DiseaseAortic DiseaseManagementManagement

TGFBR2 TGFBR2 mutationmutation(R460)(R460)

4%4%

Thin translucent Thin translucent skinskinArterial tortuosity Arterial tortuosity is more common is more common in older in older individualsindividualsAneurysms of Aneurysms of arteriesarteries

Multiple aortic Multiple aortic dissections dissections documented at documented at aortic diameters aortic diameters <5.0cm<5.0cm

MYH11 MYH11 mutationsmutations 1%1% PDAPDA

Patient with Patient with document document dissection at dissection at 4.5cm4.5cm

ACTA2 ACTA2 mutationsmutations 14%14% Livedo reticularisLivedo reticularis

Iris flocculiIris flocculi

2 of 13 patients 2 of 13 patients with documented with documented dissections dissections <5.0cm<5.0cm

TAD Guidelines: Genetic ConditionsTAD Guidelines: Genetic ConditionsConditionMarfan Syndrome

Recommendation• Echo at Dx and 6

months• Echo annually if stable• Echo more often if Ao.

Diam. increasing or >4.5cm

• Prophyllactic surgery at 4.5-5.0cm

• Prophyllactic surgery in women planning pregnancy at 4.0cm

Evid. LevelΙ

ΙΙ

ΙΙa

ΙΙa

Hiratzka LF, et al. JACC 2010;55:1509-44.

TAD Guidelines: Genetic ConditionsTAD Guidelines: Genetic ConditionsConditionLoeys-Dietz or

TGFBR 1 or 2

Turner Syndrome

Loeys-Dietz orTGFBR 1 or 2

Recommendation• Complete aortic

imaging at Dx and 6 months

• Annual complete aortic MRI: Brain to pelvis

• Heart and aortic imaging at Dx

• If abnormal → annual• If normal → aortic

imaging 5-10 years

• Aortic repair:4.2cm by TEE4.4-4.6cm by CT

Evid. Level

Ι

Ι

ΙΙ

ΙΙa

Hiratzka LF, et al. JACC 2010;55:1509-44.

ConditionBiCuspid

AorticValve

Documentedgenetic aortic conditions (FBNI, TGFBR 1 & 2, COL3AI, ACTA2, MYH

II)

TAD Guidelines: Genetic ConditionsTAD Guidelines: Genetic ConditionsRecommendation• Aortic root/Asc. aorta

imaged• Aortic imaging of

1st degree relatives• First degree relatives

undergo counselingat testing;

• Genetic positivesundergo aortic imaging

Evid. LevelΙ

Ι

Hiratzka LF, et al. JACC 2010;55:1509-44.

p-value<0.001

0.06<0.001

<0.001

<0.001

<0.001

0.004

<0.001

IRADIRADPresenting SymptomsPresenting Symptoms

Variable• Pain

AbruptAnterior

Back

Abdominal

Sharp

Tearing

• Syncope

All94.0%

84.0%71.9%

53.1%

31.2%

62.8%

47.1%

12.6%

Type A92.6%

82.9%78.0%

42.8%

25.5%

58.4%

44.0%

18.3%

Type B96.5%

85.7%61.1%

70.5%

40.8%

69.4%

52.0%

2.9%

IRAD Investigators(n=2807)

IRADIRADPhysical ExamPhysical Exam

(n=2820)(n=2820)

VariableHigh BP

Low BP

Shock/Tamponade

Murmur AI

Pulse Deficit

Stroke

All43.3%

11.4%

8.0%

27.6%

25.7%

6.5%

Type A30.3%

16.0%

12.0%

38.3%

30.5%

9.1%

Type B65.3%

3.5%

1.3%

10.7%

18.1%

2.2%

p-value<0.001

<0.001

<0.001

<0.001

<0.001

<0.001

IRAD Investigators

Variable• CXR

Normal Wide Mediast.or Aorta

PL. Effusion• EKG

NormalNSST-T ’sIschemiaNew MI

IRADIRADEKG & CXREKG & CXR

(n=2353)

All

22.4%

67.6%14.4%

32.2%40.7%14.3%

5.5%

Type A

20.2%

69.5%12.5%

29.9%41.2%17.1%

7.4%

Type B

25.9%

64.5%17.3%

36.2%39.8%

9.6%2.1%

p-value

0.001

0.0120.002

0.001NS

<0.001<0.001

IRAD Investigators

DD--Dimer Levels in Aortic DissectionDimer Levels in Aortic Dissection

Suzuki T, et al. Circulation 2009;119:2702-07.

0

1000

2000

3000

4000

5000

D-D

imer

(ng/

ml)

AD+(A)n=19

AD+(B)n=4

MIn=9

Anginan=14

PEn=2

Time after onset (0-6h)

AD+(A)n=26

AD+(B)n=7

MIn=14

Anginan=5

PE

Time after onset (6-12h)

AD+(A)n=19

AD+(B)n=12

MIn=23

Anginan=18

PEn=3

Time after onset (12-24h)

Sensitivity of the First Imaging Study to Sensitivity of the First Imaging Study to Detect AoD and Intramural HematomaDetect AoD and Intramural Hematoma

IRAD Investigators

85.5%85.5%97.3%97.3% 96.9%96.9%

87.3%87.3%559559654654

1880188019331933

31313232 6262

7171

(n=2690)

Who are You Measuring?Who are You Measuring?Aortic Diameter at Sinuses of Valsalva by Aortic Diameter at Sinuses of Valsalva by

Gender (Adjusted for BSA)Gender (Adjusted for BSA)NS p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 p=0.002

Men Women

Dia

met

er (c

m)

Devereux et al. J Am Coll Cardiol 2010;55:A87. [Epub on DVD].

Proportion of U.S. Citizens withDilated Ascending Aortas

Proportion of U.S. Citizens withDilated Ascending Aortas

4.2 - 4.4cm 3,800,000+

4.5 – 4.9cm 1,600,000+

≥ 5.0cm 200,000+

+20% caused by genetic condition.

R. Devereux. Aortic Summit. Sept 22, 2009.

Aortic Aneurysms:Aortic Aneurysms:Yearly Risk of ComplicationsYearly Risk of Complications

Scientific American, August: 2005.

Ave

rage

Yea

rly R

ate

of C

ompl

icat

ions

(%)

Rupture Dissection Rupture orDissection

Diameter ofDiameter ofAneurysm (cm)Aneurysm (cm)

4.0 to 4.94.0 to 4.9

5.0 to 5.95.0 to 5.9

6.0 or greater6.0 or greater

Maximum Aorta Diameter:Maximum Aorta Diameter:Type A DissectionType A Dissection

Pape et al. AHA 2005.

(59% < 5.5 cm)

Descending Aortic Diameter Descending Aortic Diameter ≥≥ 6.0cm: A 6.0cm: A Poor Predictor of Type B Aortic DissectionPoor Predictor of Type B Aortic Dissection

Cou

nt

Trimarchi S, et al. J Am Coll Cardiol 2009;53: A452.Descending Diameter

Descending Diameter (categorical)

• Medical Therapy for all, for life

• Surgery if possible….esp A1>A2>A3

• Consider fenestration if surgery not

possible, especially if malperfusion

occurs

Type A DissectionType A Dissection

InIn--hospital Survival hospital Survival in TAin TA--AADAAD

Sinha S, presented ACC 2011.

Follow-up Survival in TA-AAD

• Uncomplicated - No false lumen: Medical

• Uncomplicated - False channel +/- aneurysm - consider stent

• Complicated - stent +/- surgery

Type B DissectionType B Dissection

Nienaber CA, et al. Circulation 2003;108:628-635.Nienaber CA, et al. Circulation 2003;108:772-778.

Comparison of Medical Therapy to Endovascular Treatment in Type B

Dissection:Long Term Follow-Up

Comparison of Medical Therapy to Endovascular Treatment in Type B

Dissection:Long Term Follow-Up

Fattori R, et al. Circulation 2010.

Endovascular

Year of Follow-up0 1 2 3 4 5

1.0

0

0.2

0.4

0.6

0.8

Surv

ival

log rank p=0.05

Medical

(n=89)

(n=320)

• Evidence of leakage or subacute rupture

• Extensive false channel despite excellent

medical Rx

• Extensive aneurysm

• Progressive morbidity despite medical Rx

Stent Graft TherapyStent Graft TherapyIndications in Acute DissectionIndications in Acute Dissection

Nienaber CA, et al. Circulation 2003;108:628-635.Nienaber CA, et al. Circulation 2003;108:772-778.

1. Beta-blockers

2. Ca++ blockers

3. ACE/ARB

4. Statins

FollowFollow--up Treatment?up Treatment?

Medical ManagementMedical ManagementCITATION STUDY DESIGN RESULTS

Genoni et al. Eur J CardioThorac Surg. 2001; 5:606-10.

Retrospective: 78/130 pts with chronic dissection on medical therapy only

Dissection Related Surgery51/71 B-blocker → 10 (19%)20/71 other → 9 (45%)

Aortic ExpansionBB 6/51 (12%)

Other 8/20 (40%)Shores, et al. NEJM 1994;330:1335.

Randomized Trial inAortic Root Disease(propranolol 212±68 mg)

Aortic Dilation RatePropranolol 0.023 cm/yrNot on BB 0.084 cm/yr

Ladoceur et al. Am J Cardiol 2007; 99:406.

Retrospective; Ao Dilation in children withMarfan Syndrome

Dilation slowed by 0.2mm/yr

Beta Adrenergic Blockade Slows Beta Adrenergic Blockade Slows Aorta Growth in MarfanAorta Growth in Marfan’’ss

Shores, J. NEJM 1994; 330:1335-1341.

Randomized trial of propranolol in 70 adolescent and adultpatients with classic Marfan's syndrome

BetaBeta--Blockers Lower RiskBlockers Lower Riskin Ehlerin Ehler--DanosDanos

Kaplan-Meier curves of event-free survival in 53 patients with vascular Ehlers-Danlos Primary endpoint (A). Primary and secondary endpoints (B).

Kim-Thanh Ong et al. www.thelancet.com 2010:376;1476-84.

Medical Management: ACE & ARBsMedical Management: ACE & ARBs

CITATION STUDY DESIGN RESULTSHackam et al.

Lancet2006;368:659.

Retrospective, Case control, Population Based

ACE inhibition prior to admission:Decr. likelihood of ruptureAneurysm OR 0.82 (0.74-0.90)

Mochizuki et al. Lancet 2007; 369:

1431.

Randomized with HTN, CAD or CHF to Valsartan (40-160mg) or other.

Valsartan decreased:Composite CV outcome- OR 0.61 (0.47-0.79)Aortic Dissection- OR 0.18 (0.04-0.88)

Jikei Heart StudyJikei Heart Study

Mochizuki S, et al. Lancet 2007;369:1431-39.

Non-ARBAll Patients Valsartan Group Treatment Group

Calcium-channel blocker 2052 (67%) 1041 (68%) 1011 (66%)ACE inhibitor 1073 (35%) 548 (36%) 525 (34%)

Blocker 988 (32%) 486 (32%) 502 (33%)Blocker 167 (5%) 74 (5%) 93 (6%)

Thiazide 68 (2%) 29 (2%) 39 (3%)Antialdosterone agent 116 (4%) 52 (3%) 64 (4%)Other diuretics 243 (8%) 117 (8%) 126 (8%)Statin 951 (31%) 461 (30%) 490 (32%)Fibrate 79 (3%) 42 (3%) 37 (2%)Dissection 12 (0.7%) 2 (0.1%) 10 (0.6%)

α

β

LongLong--TermTerm

• B-Blockers: HR <60BPM

• Control Blood Pressure: <120/80 -Prefer ARB’s or ACE’s

• Statins for atherosclerosis

• “Watch” for aneurysm formation: 1, 3, 6, 12 months to start

• Educate the patient: a lifelong disease; sx, activity, meds, f/up

Where is the Future?Where is the Future?

Clinical DataClinical DataTreatmentsTreatmentsFamily HistoryFamily HistoryDemographicsDemographicsEnvironmentalEnvironmental

ImagingImaging

Gene Expression ProfilesGene Expression Profiles

Genomic DataGenomic DataSNPSNP’’ssGenomeGenome--scale sequencescale sequence

Metabolic DataMetabolic DataProteomic DataProteomic Data

??

Predictions:Predictions:RiskRisk

Individualized Prognosis & DiagnosisIndividualized Prognosis & DiagnosisDrug ResponseDrug Response

Environment (e.g. Diet) ResponseEnvironment (e.g. Diet) Response

PatternsPatternsIntegrationIntegration

ModelsModels