Arterial Tortuosity and Cardiovascular Outcomes in Thoracic Aortic

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Dwain Mitchell
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Pediatric Cardiology Texas Children s Hospital

with geneticallymediated aortic disease like

(LDS) are at high risk of adverse cardiovascular

1 Arterial Tortuosity and Cardiovascular Outcomes in Thoracic Aortic Disease Shaine A Morris MD MPH Pediatric Cardiology Texas Children s Hospital Baylor College of Medicine Background Patients with geneticallymediated aortic disease like Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS) are at high risk of adverse cardiovascular outcomes Valve dysfunction Aortic aneurysm Aortic dissection 1

Background No good predictors of aortic dissection Current prophylactic surgery guidelines focus on a combination of genetic diagnosis with aortic dimensions: Marfan syndrome: 5.

2 Background No good predictors of aortic dissection Current prophylactic surgery guidelines focus on a combination of genetic diagnosis with aortic dimensions: Marfan syndrome: 5.0 cm Loeys-Dietz syndrome: 4.2 cm Hiratzkaetal,Circulation2010 Aortic dimensions at Type A dissection in MFS and LDS M arfansyndrom e L oeys-dietzsyndrom e Kim etal.jct VS 2014,T uraetal.heart2016;w iliam setal,annt hors urg2015; L oeysetal,n EJM 2006,Ibaetal,AnnT hors urg2012,m orrisetal,circ2011; W iliam setal,annt hors urg2007 2

Arterial tortuosity Arterial tortuosity is a common feature with

described with many other gene mutations associated with

X O T GFBR 2 FBN 1 1. Loeys BL, et al. N Engl J Med 2006 2.

Nature Genetics 2011 4. Lindsay et al. Nat Genetics 2012 5.

3 Arterial tortuosity Arterial tortuosity is a common feature with TGFBR1/2 mutations 1 Arterial tortuosity has since been described with many other gene mutations associated with dissection: FBN1 2 SMAD3 3 TGFB2 4 PRKG1 5 and Turner syndrome 6 X O T GFBR 2 FBN 1 1. Loeys BL, et al. N Engl J Med Morris et al. Circulation Vad de Laar et al. Nature Genetics Lindsay et al. Nat Genetics Guo et al. Am J Hum Genetics Morris et al. J Cardiovasc Magn Reson 2014 Circulation2011 3

4 Univariate p Multivariate p VTI (continuous) < Max Root z-score (continuous) Diagnosis (LDS vs. MS) Circulation2011 Arterial tortuosity-etiology Overarching hypothesis: there is abnormal lengthening of the arteries in a fixed space, resulting in forced curving and bending of the vessels 4

5 Arterial tortuosity- theories Vessel has maladaptation to axial stress, lengthens as an intrinsic effort to reduce stress along the vessel 1. Increased TGFb activity has also been postulated to affect the degree of arterial tortuosity 3 1.Hum phrey Jetal.JBiom ech Jacksonetal.ArteriosclerT hrom bvascbiol Frankenetal.IntJCard2015 New Study Study populations: Marfan, TGFBR1, TGFBR2 National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) Texas Children s Hospital patients, followed between 1980 and May 30,

6 Methods Predictor variable: VTI Primary outcomes Stanford type A aortic dissection Stanford type B aortic dissection Results: Study population

7 Patient characteristics Characteristic All N=204 MFS N=153 LDS N=51 Male sex 114 (56%) 92 (60%) 22 (43%) BAV 7 (3%) 2 (1%) 5 (10%) Median age at last clinical follow-up Median first root dimension 25.4 (16.0, 40.0) 3.99 (2.98, 4.73) 30.0 (18.9, 41.1) 4.20 (3.20, 4.87) p 15.4 (9.9, 26.1) < (2.63, 4.26) Median first root z (2.73, 4.17 (2.82, 3.60 (2.43,4.97) score 5.36) 5.39) Patient outcomes Outcome All N=204 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%) Suicide 2 Encephalopathy 1 Unknown 2 7

8 VTI by gene mutation Freedom from Type A dissection P =0.304 Diagnosis M arfan L oeys-dietz 8

Freedom from Type A dissection P =0.007 VT I < 50 50 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.

9 Freedom from Type A dissection P =0.007 VT I < Comparison HR (95%CI) p VTI ( ) VTI 50, adj. for diagnosis 2.71 ( ) Freedom from Type B dissection Diagnosis M arfan L oeys-dietz P =0.205 VT I < P =0.041 Comparison HR (95%CI) p VTI ( ) VTI 50, adj. for diagnosis 2.39 ( )

10 What about root size? Of the 27 Type A aortic dissections, only 7 patients had pre-dissection aortic imaging 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 prophylactic root replacement) What about root size? Model 1: Type A dissection HR (95%CI) VTI ( ) Root z-score at first study 1.08 ( ) Model 2: Type A dissection HR (95%CI) VTI ( ) Maximum root dimension 0.58 ( ) Model 3: Type A dissection HR (95%CI) VTI ( ) Maximum root z-score 1.08 ( ) p p p 1 0

11 Summary Arterial tortuosity, as assessed by VTI is present in many conditions associated with aortic dissection A VTI 50 is independently associated with earlier adverse cardiovascular outcomes, and has greater prognostic value than genetic diagnosis VTI should be taken into account when counseling and managing patients with MFS and LDS Thank you! Fundingby N HL BIR 21HL , K23HL ,HHS N C and HHS N C 1 1

12 Secondary Outcomes Any aortic dissection HR (95%CI) p VTI ( ) VTI 50, adj. for diagnosis 2.24 ( ) Any aortic surgery HR (95%CI) p VTI ( ) VTI 50, adj. for diagnosis 1.76 ( ) Prophylactic root/ascending/arch surgery HR (95%CI) p VTI ( ) VTI 50, adj. for diagnosis 1.60 ( )

13 Patient characteristics Characteristic MFS N=153 Ectopia lentis (EL) 74 (48%) FBN1 mutation 61 (40%) EL or FBN1 104 (68%) TGFBR1 mutation TGFBR2 mutation LDS N=51 9 (18%) 42 (82%) Freedom from dissection, by aortic root dimension P =0.225 P <

14 Freedom from Type A Dissection by risk P =0.007 Freedom from Type A Dissection by VTI-a P =0.008 Comparison HR (95%CI) p From birth, censor for surg 4.60 ( ) <0.001 From birth, no censor 3.36 ( )

15 Freedom from Type A Dissection by VTI-a Comparison MFS HR (95%CI) MFS p LDS HR (95%CI) LDS p From birth, censor for surg 4.71 ( ) ( ) From birth, no censor 3.46 ( ) ( ) Multivariable analysis Model 1 HR (95%CI) p VTI-adjusted > ( ) < LDS vs. MFS 1.11 ( ) Male vs Female 1.54 ( )

16 2 /2 5 / Given: Age =25 y Root = 4 cm (mild) Desc aorta=2.2 cm (upper nl) Supports waiting for surgery P =0.116 Median survival in years No surgery Median survival without Type A dissection 24 (95%CI 21-30) years 44.5 (95%CI 39-50) years 40.7 ± 13.6 years 28.6 ± 16.6 years 46.5 (95%CI 43-50) years Mean Quality-adjusted life years (estimated) If 0001 surgery now P <0. 35 (95%CI 30-45) years Given: A ge=25 y R oot= 4 cm (m ild) Descaorta=2.2 cm (uppernl) S upportsw aitingforsurgery P =0.116 P < N osurgery M ediansurvivalinyears Ifsurgery now 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 16

17 2 /2 5 / M orrisetal,aha S cientifics essions2015 M orrisetal,aha S cientifics essions

2 /2 5 /2 0 17 Filamin A mutations (FLNA) N orm al FL N A

18 2 /2 5 / Filamin A mutations (FLNA) N orm al FL N A FL N A VTI over time Mean decrease: 1.5 units per year during adolescence VTI-adjusted: VTI + (minimum of age at VTI or 18) * 1.5 Evaluated Type A dissection: 5/53 LDS 22/160 MFS 18

2 /2 5 /2 0 17 ROC: VTI-a and Type B Aortic dissection

19 2 /2 5 / ROC: VTI-a and Type B Aortic dissection VT I-a= 29 VT I-a= 53 AU C=0.690,p=0.001 Extra Slides 19

20 2 /2 5 / Extra Slides Aortic tortuosity and outcomes Franken et al. Secondary analysis of Dutch RCT Frankenetal.IntJCardiology,

21 2 /2 5 / Aortic tortuosity and outcomes Future directions Ultimate goals: Create an open source risk calculator to help guide imaging, medical 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 21

22 2 /2 5 / Concept of Static and Dynamic predictors Static predictors-do not change with age Gene affected Mutation Sex Aortic z-score (usually) Dynamic (time-dependent) predictors- Change with age Aortic dimension Aortic surgery history Aortic dissection history Aortic dimension/z-score Dynamic Static Tierney et al. J Peds

23 2 /2 5 / Family history Maybe certain mutations are more dangerous M ild aorticrootdilation:4.2 cm atage52y N oevents S am et GFBR 2 m utation S evereand rapid aorticrootdilation Aorticdissectionage16 y T GFBR 2 m utation 60 60s 3.2 cm Aortic N oevents dissectionat age40y cm N oevents 35y Aortic dissection cm -severedilation 23

24 2 /2 5 / T GFBR 2 Arterial tortuosity Arterial tortuosity is a common feature with TGFBR1/2 mutations1 Arterial tortuosity has since been described with many other gene mutations associated with dissection: 2 FBN1 SMAD3 3 ACTA2 4 PRKG1 5 XO FBN 1 and Turner syndrome 6 1. Loeys BL, et al. N Engl J Med Morris et al. Circulation Vad de Laar et al. Nature Genetics Munot et al. Brain Guo et al. Am J Hum Genetics 2013 xxx00.#####.ppt 2/25/2017 PM 6. Morris et al.9:26:33 J Cardiovasc Magn Reson 2014 Root Dilation/VTI and Surgery 24

25 2 /2 5 / Arterial tortuosity-etiology Overarching hypothesis: there is abnormal lengthening of the arteries in a fixed space, resulting in forced curving and bending of the vessels 25

26 2 /2 5 /

2 /2 5 /2 0 17 ROC: VTI-a and Type A Aortic dissection VT

003 Gene as a predictor Some conditions seem to have a

TGFBR1/TGFBR2 inicaloutcom esappearsim ilarbetw eentreated

27 2 /2 5 / ROC: VTI-a and Type A Aortic dissection VT I-a= 32 VT I-a= 58 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 inicaloutcom esappearsim ilarbetw eentreated Cl ACTA2 patientsw itht GFBR 2 m utationsand individualsw ith FBN 1 m utations.p rognosisdependsonclinicaldisease expressionand treatm entratherthansim ply the presenceofat GFBR 2 genem utation. Attiasetal.Circulation

2 /2 5 /2 0 17 Thank you Fundingby N HL BIR 21HL 121630 andk23hl 127266 Baylor College of Medicine Pediatric Cardiology Daniel J Penny MD PhD Pediatric Clinical CV Research Core Carol Looney

Tobias Shlingmann MD Alex Dodd Cardiothoracic Surgery Scott LeMaire MD Jon E.

28 2 /2 5 / Thank you Fundingby N HL BIR 21HL andk23hl Baylor College of Medicine Pediatric Cardiology Daniel J Penny MD PhD Pediatric Clinical CV Research Core 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 Siddarth Jadhav MD Ram Krishnamurthy PhD Tobias Shlingmann MD Alex Dodd Cardiothoracic Surgery Scott LeMaire MD Jon E. Tyson MD MPH Claudia Pedroza PhD Siddarth Prakash MD PhD Stephanie Wallace CGC GenTAC Consortium Federico Asch MD Seitaro Oda MD Kim Eagle MD Kalyan Kancherla MD RTI International Barbara Kroner PhD Lilliana Preiss Boston Children s Hospital Ronald V. Lacro MD NIH/NHLBI Eser Tolunay PhD UT Health Science Center Houston 28

HTAD PATIENT PATHWAY

HTAD PATIENT PATHWAY Strategy for Diagnosis and Initial Management of patients and families with (suspected) Heritable Thoracic Aortic Disease (HTAD) DISCLAIMER This document is an opinion statement reflecting