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Arterial Tortuosity andCardiovascular Outcomesin Thoracic AorticDiseaseDisease

Shaine A Morris MD MPH

Pediatric Cardiology

Texas Children’s Hospital

Baylor College of Medicine

Background

• Patients with genetically-mediated aortic disease likeMarfan syndrome (MFS) andMarfan syndrome (MFS) andLoeys-Dietz syndrome (LDS)are at high risk of adversecardiovascular outcomes

• Valve dysfunction

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• Aortic aneurysm

• Aortic dissection

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Background

• No good predictors of aortic dissection

• Current prophylactic surgery guidelines focus on• Current prophylactic surgery guidelines focus ona combination of genetic diagnosis with aorticdimensions:

• Marfan syndrome: 5.0 cm

• Loeys-Dietz syndrome: 4.2 cm

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Hiratzkaetal,Circulation2010

M arfansyndrom e

Aortic dimensions at Type A dissectionin MFS and LDS

L oeys-Dietzsyndrom e

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Kim etal.JCT VS 2014,T uraetal.Heart2016;W illiam setal,AnnT horS urg2015;L oeysetal,N EJM 2006,Ibaetal,AnnT horS urg2012,M orrisetal,Circ2011;W illiam setal,AnnT horS urg2007

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Arterial tortuosity

• Arterial tortuosity is a common featurewith TGFBR1/2 mutations1

• Arterial tortuosity has since been

T GFBR 2

• Arterial tortuosity has since beendescribed with many other genemutations associated with dissection:

• FBN1 2

• SMAD3 3

• TGFB2 4

FBN 1X O

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• TGFB2

• PRKG1 5

and

• Turner syndrome 6

1. Loeys BL, et al. N Engl J Med 20062. Morris et al. Circulation 20113. Vad de Laar et al. Nature Genetics 2011

4. Lindsay et al. Nat Genetics 20125. Guo et al. Am J Hum Genetics 20136. Morris et al. J Cardiovasc Magn Reson 2014

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Circulation2011

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Univariatep

Multivariatep

VTI (continuous) <0.001 0.003

Max Root z-score(continuous)

0.014 0.631

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Circulation2011

Diagnosis(LDS vs. MS)

0.952

Arterial tortuosity-etiology

• Overarching hypothesis: there is abnormallengthening of the arteries in a fixed space, resultingin forced curving and bending of the vesselsin forced curving and bending of the vessels

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Arterial tortuosity- theories

• Vessel has maladaptation to axial stress,lengthens as an intrinsic effort to reduce stressalong the vessel1.along the vessel1.

• Increased TGFb activity has also been postulatedto affect the degree of arterial tortuosity3

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1.Hum phrey Jetal.JBiom ech20092.Jacksonetal.ArteriosclerT hrom bVascBiol2005

3.Frankenetal.IntJCard2015

New Study

Study populations: Marfan, TGFBR1, TGFBR2

• National Registry of Genetically Triggered ThoracicAortic Aneurysms and Cardiovascular ConditionsAortic Aneurysms and Cardiovascular Conditions(GenTAC)

• Texas Children’s Hospital patients, followedbetween 1980 and May 30, 2016

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Methods• Predictor variable: VTI

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• Primary outcomes• Stanford type A aortic dissection• Stanford type B aortic dissection

Results: Study population

153

51

153

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Patient characteristics

Characteristic AllN=204

MFSN=153

LDSN=51

p

Male sex 114 (56%) 92 (60%) 22 (43%) 0.034Male sex 114 (56%) 92 (60%) 22 (43%) 0.034

BAV 7 (3%) 2 (1%) 5 (10%) 0.004

Median age at lastclinical follow-up

25.4 (16.0,40.0)

30.0 (18.9,41.1)

15.4 (9.9, 26.1) <0.001

Median first rootdimension

3.99 (2.98,4.73)

4.20 (3.20,4.87)

3.23 (2.63,4.26)

0.003

Median first root z- 4.05 (2.73, 4.17 (2.82, 3.60 (2.43,4.97) 0.186

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Median first root z-score

4.05 (2.73,5.36)

4.17 (2.82,5.39)

3.60 (2.43,4.97) 0.186

Patient outcomes

Outcome AllN=204

Type A aortic dissection, n (%) 27 (13%)Type A aortic dissection, n (%) 27 (13%)

Type B aortic dissection, n (%) 32 (16%)

Any aortic dissection, n (%) 47 (23%)

Any aortic surgery, n (%) 123 (60%)

Prophylactic root/ascending/arch surgery, n (%) 97 (47%)

Mitral valve surgery, n (%) 23 (11%)

Death, n (%) 5 (2%)

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Death, n (%)SuicideEncephalopathyUnknown

5 (2%)212

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VTI by gene mutation

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Freedom from Type A dissection

P =0.304

DiagnosisM arfanL oeys-Dietz

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Freedom from Type A dissection

P =0.007< 50≥ 50

VT I

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Comparison HR (95%CI) p

VTI ≥ 50 2.77 (1.28-5.97) 0.010

VTI ≥ 50, adj. for diagnosis 2.71 (1.20-6.11) 0.016

Freedom from Type B dissection

P =0.205DiagnosisM arfanL oeys-Dietz

< 50≥ 50

VT IP =0.041

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Comparison HR (95%CI) p

VTI ≥ 50 2.04 (1.02-4.11) 0.045

VTI ≥ 50, adj. for diagnosis 2.39 (1.18-4.86) 0.016

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What about root size?

• Of the 27 Type A aortic dissections, only 7patients had pre-dissection aortic imaging

• 2 LDS (both TGFBR2)• 2 LDS (both TGFBR2)

• 5 MFS (4 FBN1 +, other no testing but +EL)

• 6/7 dissected at root diameter <5.0 cm

• 3/7 had a prior aortic event (2 type B dissections, 1

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• 3/7 had a prior aortic event (2 type B dissections, 1prophylactic root replacement)

What about root size?

Model 1: Type A dissection HR (95%CI) p

VTI ≥ 50 7.41 (1.06-51.61) 0.043

Root z-score at first study 1.08 (0.65-1.80) 0.759Root z-score at first study 1.08 (0.65-1.80) 0.759

Model 2: Type A dissection HR (95%CI) p

VTI ≥ 50 5.33 (1.01-28.10) 0.048

Maximum root dimension 0.58 (0.17-2.04) 0.396

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Model 3: Type A dissection HR (95%CI) p

VTI ≥ 50 8.07 (1.22-53.32) 0.030

Maximum root z-score 1.08 (0.69-1.70) 0.744

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Summary

• Arterial tortuosity, as assessed by VTI is present inmany conditions associated with aortic dissection

• A VTI ≥ 50 is independently associated with earlier adverse cardiovascular outcomes, and has greaterprognostic value than genetic diagnosis

• VTI should be taken into account when counselingand managing patients with MFS and LDS

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and managing patients with MFS and LDS

Thank you!

Fundingby N HL BIR 21HL 121630,K23HL 127266,HHS N 268200648199C and

HHS N 26821000048CHHS N 26821000048C

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Secondary Outcomes

Any aortic dissection HR (95%CI) p

VTI ≥ 50 2.10 (1.17-3.74) 0.012VTI ≥ 50 2.10 (1.17-3.74) 0.012

VTI ≥ 50, adj. for diagnosis 2.24 (1.23-4.08) 0.008

Any aortic surgery HR (95%CI) p

VTI ≥ 50 1.91 (1.31-2.77) 0.001

VTI ≥ 50, adj. for diagnosis 1.76 (1.18-2.62) 0.005

Prophylactic root/ascending/arch surgery HR (95%CI) p

VTI ≥ 50 1.75 (1.14-2.67) 0.010

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VTI ≥ 50 1.75 (1.14-2.67) 0.010

VTI ≥ 50, adj. for diagnosis 1.60 (1.02-2.51) 0.043

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Patient characteristics

Characteristic MFSN=153

LDSN=51

Ectopia lentis (EL) 74 (48%)Ectopia lentis (EL)FBN1 mutationEL or FBN1

74 (48%)61 (40%)

104 (68%)

TGFBR1 mutationTGFBR2 mutation

9 (18%)42 (82%)

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Freedom from dissection, by aorticroot dimension

P =0.225P =0.225P <0.001

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Freedom from Type A Dissection by risk

P =0.007

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Freedom from Type A Dissection by VTI-a

P =0.008

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Comparison HR (95%CI) p

From birth, censor for surg 4.60 (2.01-10.55) <0.001

From birth, no censor 3.36 (1.50-7.53) 0.003

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Freedom from Type A Dissection by VTI-a

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Comparison MFS HR (95%CI) MFS p LDS HR (95%CI) LDS p

From birth, censor for surg 4.71 (1.90-11.66) 0.001 2.10 (0.21-20.63) 0.524

From birth, no censor 3.46 (1.44-8.34) 0.006 1.90 (0.90-18.31) 0.580

Multivariable analysis

Model 1 HR (95%CI) pModel 1 HR (95%CI) p

VTI-adjusted>58

4.98 (2.08-11.96)

<0.001

LDS vs. MFS 1.11 (0.40-3.10) 0.844

Male vs Female 1.54 (0.69-3.46) 0.294

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Age =25 y Root = 4 cm (mild) Desc aorta=2.2cm (upper nl)

Supports waiting for surgery

Given:

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No surgery If surgery now

Median survival in years 46.5 (95%CI 43-50) years 35 (95%CI 30-45)years

Median survival without Type Adissection

24 (95%CI 21-30) years 44.5 (95%CI 39-50)years

Mean Quality-adjusted life years(estimated)

40.7 ± 13.6 years 28.6 ± 16.6 years

P <0.0001P =0.116

A ge=25y R oot= 4 cm (m ild) Descaorta=2.2 cm(uppernl)

S upportsw aitingforsurgery

Given:

N osurgery Ifsurgery now

M ediansurvivalinyears 46.5 (95% CI43-50)years 35 (95% CI30-45)years

M ediansurvivalw ithoutT ypeA dissection 24 (95% CI21-30)years 44.5 (95% CI39-50)years

M eanQ uality-adjustedlifeyears(estim ated) 40.7± 13.6 years 28.6 ± 16.6 years

P <0.0001P =0.116

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M orrisetal,AHA S cientificS essions2015

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M orrisetal,AHA S cientificS essions2015

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Filamin A mutations (FLNA)

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N orm al FL N A FL N A

VTI over time

• Mean decrease: 1.5 units per year duringadolescence

• VTI-adjusted: VTI + (minimum of age at VTI or• VTI-adjusted: VTI + (minimum of age at VTI or18) * 1.5

• Evaluated Type A dissection:

• 5/53 LDS

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• 5/53 LDS

• 22/160 MFS

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ROC: VTI-a and Type B Aortic dissection

VT I-a= 29

VT I-a= 53

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AU C=0.690,p=0.001

Extra Slides

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Extra Slides

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Aortic tortuosity and outcomes

• Franken et al.

• Secondary analysis of Dutch RCT

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Frankenetal.IntJCardiology,2015

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Aortic tortuosity and outcomes

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Future directions

• Ultimate goals:

• Create an open source risk calculator to help guide imaging,medical therapy, and prophylactic aortic surgerymedical therapy, and prophylactic aortic surgery

• Contribute towards standardization of treatment in this population

• Reduce imaging and surgical costs in low risk patients

• Reduce adverse events in all patients

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Concept of Static and Dynamic predictors

• Static predictors-Do not change with age• Gene affected

• Mutation• Mutation

• Sex

• Aortic z-score (usually)

• Dynamic (time-dependent) predictors- Changewith age

• Aortic dimension

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• Aortic dimension

• Aortic surgery history

• Aortic dissection history

Aortic dimension/z-score

Dynamic Static

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Tierney et al. J Peds 2007

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Family history

• Maybe certain mutations are “more dangerous”

M ildaorticrootdilation:4.2 cm atage52yN oeventsS am eT GFBR 2 m utation

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S evereandrapidaorticrootdilationAorticdissectionage16 yT GFBR 2 m utation

60sAortic

603.2 cm

35yAortic

dissection

Aorticdissectionat

age40y

3.2 cmN oevents

433.8cmN oevents

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dissection

33.0 cm -severedilation

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Arterial tortuosity

• Arterial tortuosity is a common featurewith TGFBR1/2 mutations1

• Arterial tortuosity has since been

T GFBR 2

• Arterial tortuosity has since beendescribed with many other genemutations associated with dissection:

• FBN1 2

• SMAD3 3

• ACTA2 4

FBN 1X O

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• ACTA2

• PRKG1 5

and

• Turner syndrome 6

1. Loeys BL, et al. N Engl J Med 20062. Morris et al. Circulation 20113. Vad de Laar et al. Nature Genetics 2011

4. Munot et al. Brain 20125. Guo et al. Am J Hum Genetics 20136. Morris et al. J Cardiovasc Magn Reson 2014

Root Dilation/VTI and Surgery

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Arterial tortuosity-etiology

• Overarching hypothesis: there is abnormallengthening of the arteries in a fixed space, resultingin forced curving and bending of the vesselsin forced curving and bending of the vessels

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ROC: VTI-a and Type A Aortic dissection

VT I-a= 32

VT I-a= 58

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AU C=0.679,p=0.003

Gene as a predictor• Some conditions seem to have a higher risk of

dissection at smaller dimensions

• TGFBR1/TGFBR2• TGFBR1/TGFBR2

• ACTA2“ Clinicaloutcom esappearsim ilarbetw eentreatedpatientsw ith T GFBR 2 m utationsandindividualsw ith

FBN 1 m utations.P rognosisdependsonclinicaldiseaseexpressionandtreatm entratherthansim ply the

presenceofaT GFBR 2 genem utation.”

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presenceofaT GFBR 2 genem utation.”

Attiasetal.Circulation2009

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Thank youBaylor College of Medicine• Pediatric Cardiology

• Daniel J Penny MD PhD• Pediatric Clinical CV Research Core

• Carol Looney

• Jon E. Tyson MD MPH• Claudia Pedroza PhD• Siddarth Prakash MD PhD• Stephanie Wallace CGC

GenTAC Consortium

Fundingby N HL BIR 21HL 121630 andK23HL 127266

• Carol Looney• Shelley Andreas• Melissa Challman• William Payne

• Pediatric Cardiac MR/CT Team• Rajesh Krishnamurthy MD• Shiraz Maskatia MD• Cory Noel MD• Prakash Masand MD

GenTAC Consortium• Federico Asch MD• Seitaro Oda MD• Kim Eagle MD• Kalyan Kancherla MD

RTI International• Barbara Kroner PhD• Lilliana Preiss

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• Prakash Masand MD• Siddarth Jadhav MD• Ram Krishnamurthy PhD• Tobias Shlingmann MD• Alex Dodd

• Cardiothoracic Surgery• Scott LeMaire MD

UT Health Science Center Houston

• Lilliana Preiss

Boston Children’s Hospital• Ronald V. Lacro MD

NIH/NHLBI• Eser Tolunay PhD