Diseases of The Aorta 2016 Understanding & Approachmediquest.in/data/session7/The Dilated Thoracic...

Diseases of The Aorta 2016

Understanding & Approach

TAA, TAD, AAA, AAR

ACC - Mumbai, Jan. 24, 2016 No Disclosures

Understanding - TAA, TAD, AAA, AAR - 2016

• Definition, Mortality, Imaging, ECM (4)

• Types, Demographics (TAA,TAD,AAA,AAR) (5)

• Etiology, Pathogenesis (TAA,TAD,AAA,AAR)

Dysfunctional Structure (5)

Hemodynamics (3)

Approach to Hemodynamics (2)

Approach to Dysfunctional Structure (1)

• Interventional (TAA,TAD,AAA,AAR) (4)

TAA: Th.Ao.An. –TAD: Th.Ao.Dis. – AAA: Abd.Ao.An – AAR: Abd,Ao.Rupt.

JZ Goldfinger, V Fuster et al., JACC 2014;64:1725

1). Classification of Thoracic Aortic Dissection

(6 people per 100.000 per year)

VS Ramanath et. al. Mayo Clin Proc. 2009;84:465.

CA Nienaber et. al. Circulation 2003;108:628.

2) A 14-day Mortality In 645 Pts From IRAD Stratified

By Medical And Surgical Treatment In TAD Type A & B

IRAD (TT Tsai et. al.) Eur J Vasc Endov Surg 2009;37:149-Av 9h to Surgery

PG Hagan et. al. JAMA 2000;283:897

TA Mort

1% q.2h

4 Days

TA. S

TB. S

TB. M

A Evangelista et. al. Nat. Rev. Cardiol. 2013;10:477 – End Doing Both

3) Imaging Modalities In The Diagnosis Of AAS

4D Phase Contrast MRI From A Patient

With Aortic Dissection

RE Clough et. al. Nat. Rev. Cardiol. 2015;12:103

4) Pathophysiological Features of Marfan’s & Bicuspid Aortopathy

S Verma et. al. N Engl J Med 2014;370:1920






Hemodynamics (3)





1).TAA, 2).TAD, 3). AAA, 4). AAR

2. TAA 1. TAA-Marfan’s 3. AAA,

Prevalence 1.25% 1 in 10,000 5%

Genetic Genetic Genetic Risk Factors Predisposition Predisposition Predisposition a. Bicuspid Valve Age, Male b. Hypertension Hypertension c. Atherosclerosis Smoking Cystic medial Cystic medial Inflammatory Histology Necrosis Necrosis Infiltrate, VSMC Apoptosis Rupt./ Disect. + +++ ++

SL Liao, V Fuster et al. Nat. Rev. Card. 2012



• Types, Demographics (TAA,TAD,AAA, AAR) (5)



Hemodynamics (3)




TAA: Thor. Aort. Aneur. –TAD: Thor. Aort. Dissect. – AAA: Abd. Aort. Aneur.

Junquiera LC, Carneiro J:

Basic Histology Text and Atlas, 11th ed. McGraw-Hill Access Medicine. 2005.

STRUCTURE NORMAL AORTA FUNCTION

ELASTIN

Fibrillin

TGF-b

MMPs

SMC

COLLAGEN

VASA

VASORUM

DISTENSION

ACTIVITY

> Mucoid

RESISTANCE

NUTRITION

1). Mutant Fibrillin 1 in the Regulation

of Aorta Homeostasis

I El-Hamamsy et. al. Nat Rev Cardiol. 2009;6:771.

?

Junquiera LC, Carneiro J:

Basic Histology Text and Atlas, 11th ed. McGraw-Hill Access Medicine. 2005.

STRUCTURE 1) AORTIC ANEURYSM - MFS DYSFUNCTION

< Fibrillin

> TGF

> MMPs

< ELASTIN

>SMC

< SMC

< COLLAGEN

< VASA

VASORUM

< DISTENSION

> ACTIVITY

> Mucoid

< RESISTANCE

< NUTRITION

1,2a?) TAA/TAD – MARFAN’S / BIC. – 2bc) HYPERT. / ATHER

FBN1

Mutation

↓ Fibrillin

↑TGF-β

↑MMP ↓ TIMP

Rupture

↓ Collagen

Aneurysm

Formation

CMD

↑Stiffness

↓ Elastin

↑ Collagen

Degenerative

Diseases

VSMC

↑ Proteases

↑ dp/dt

↑ Aortic diameter

↑ BP

SL Liao, V Fuster et al. Nat. Rev. Cardiol. 2012

1). Marfan’s Type of Syndromes

DIAGNOSTIC CRITERIA FOR

Ghent Nosology

FBN1/TGFBR2 MUTATIONS

LOEYS-DIETZ

TYPE I

MARFAN

SYNDROME

Visceral rupture, bruising,

Thin translucent skin,

Characteristic facial

appearance

Consider other diseases

MRA, Biochemical diagnosis, Genetic

LOEYS-DIETZ

TYPE II

EHLERS-DANLOS

TYPE IV

FAAD†

First-degree relat.

with aortic aneur. or

Dissect.or aneury.

in other localizat.

Aortic An. arterial

Tort., hypertelorism,

cleft pal, bifid uvula

Normal synthesis

Type III procollag.

Abn. synthesis of

type III procollag.

TAAD1, TAAD2 and

FAA MUTATIONS

TGFBR1 and TGFBR2

MUTATIONS

COLA31 MUTATIONS

+

V Canadas, I Vilacosta, I Bruna, V Fuster. Nat Card Rev 2012

1Group -2a?) Fibrillin?,TGF-b

E Gillis et. al. Circ Res. 2013;113:327

CA Nienaber et. al. Lancet 2015; 385: 800

1Group -2a?) Monogenic Disorders

of Aortic Dissection by Site and Gene

2a) Bicuspid Aortic Valve - Morphology Features

That Influence the Pattern of Aortopathy

S Verma et. al. N Engl J Med 2014;370:1920 – Types 1,2,3

R Mahadevia et. al. Circulation. 2014;129:673

Bicuspid Aortic Cusp Fusion Alters Aortic

3D flow Patterns, Wall Shear Stress & Aortopathy

J Swedenborg et. al. Arterioscler Thromb Vasc Biol. 2011;31:73

T Duellman et al. Circ Cardiov. Genet 2012; 5:529 (Marshfield, WI) – MMP 9 M Nahrendorf, Rweissleder et. al. ATVB. 2011;31:750 A Klink, V Fuster, ZA Fayad et. al. J Am Coll Cardiol 2011;58:2522

3) MRI Imaging Aortic Aneurysm

Mouse Model and Nanoparticle PET-CT

Circulating Biomarkers & AAA Incidence

Six biomarkers - white blood cell count, fibrinogen, D-

dimer, troponin T, N-terminal pro-brain natriuetic

peptide, and high-sensitivity C-reactive protein - were

strongly associated positively with AAA incidence.

Compared with having none of the 6 biomarkers in the

highest quartile, the hazard ratios of AAA for those

with 1, 2, 3, or 4 to 6 biomarkers in the highest quartile

were 2.2, 3.3, 4.0, and 9.9, respectively (P for trend <

0.0001) after adjustment for other risk factors.

ARIC (AR Folsom et al.) Circ 2015; 132:578






Hemodynamics (3)





dp / dtmax

BP

3

2

1.Arterial

Diameter

1) Hemodynamic Frs - Dilatation To Dissection

1 - EK Prokop, RF Palmer, MW Wheat. Circ Res 1970; 27:121 –TURKEY DISSECTION






Hemodynamics (3)





TAD - J Sanz, A Einstein, V Fuster. In Acute Aortic Disease. Ed. J Elefteriades - 2010

Time

Baseline

2) Vasodilator

(i.e., Nitroprusside)

(3) Beta blockade

2) TAD – Hemodynamic Approach

3) MFS - IMPACT OF BLOCKERS

ON AORTIC ROOT DIAMETER

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Age (y.o.)

Ao

rtic

Dia

mete

r (m

m)

10

15

20

25

30

35

40

45

Control Group: slope = 1.15±0.08

Treatment Group: slope = 1.04±0.05

M Ladouceur et al., AJC 2007; 99:406 (Paris)






Hemodynamics (3)





COMPARE: evaluated the effect of losartan on aortic dilatation rate in

adults with Marfan syndrome (MFS). Patients with MFS have an increased

risk of life-threatening aortic complications, mostly preceded by aortic

dilatation. A total of 233 patients (47% female) underwent randomization

to losartan 50-100mg/d (n=116) or no additional treatment (n=117). Follow-

up was 3.1 ± 0.4 years.

End Points Losartan Control p

1. Aortic-root enlargement (mm) 0.77 1.35 0.014

No aortic-root growth (%) 50 31 0.022

2. Previous root replacem.: significant lower aortic arch expaansion

MARFAN SARTAN: 300 patients, 1ary EP-root diameter, 2ary EP-clinical

M Groenink et al., EHJ 2013; Aug 21 - Netherlands

1a) TAA in Marfan’s (and Other?) - ARBs Look Promising

1b) Atenolol vs Losartan in Children and Young Adults

with Marfan’s Syndrome

We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfan’s syndrome. The primary outcome was the rate of aortic-root enlargement, over a 3-year period. Secondary outcomes included the rate of change in the absolute diameter of the aortic root; the rate of change in aortic regurgitation; the time to aortic dissection, aortic-root surgery, or death; somatic growth; and the incidence of adverse events. A total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean [±SD] 11.5±6 years. We found no significant difference in the rate of aortic-root dilatation between the two treatment groups over a 3-year period.

RV Lacro et al., NEJM 2014; 371:2061 – American Study

1c). Marfan Sartan: A Randomized, Double-Blind,

Placebo-Controlled Trial

A double-blind, randomized, multi-centre, placebo-controlled,

add on trial comparing Losartan (50 mg when < 50 kg, 100 mg

otherwise) vs. placebo in patients with MFS according to Ghent

criteria, age > 10 years old, and receiving standard therapy.

303 patients, mean age 29.9 years old, were randomized. The

two groups were similar at baseline, 86% receiving -blocker

therapy. The median follow-up was 3.5 years. Losartan was

able to decrease blood pressure in patients with MFS but not to

limit aortic dilatation during a 3-year period in patients > 10

years old. -blocker therapy alone should therefore remain the

standard first line therapy in these patients.

O Milleron et al., Eur Heart J 2015; 36:2160 – French Study

O Milleron et. al. Eur Heart J. 2015;36:2160 – French Study

Marfan Sartan: A Randomized, Double-blind, Placebo-controlled

Trial - Aortic Root Dilatation






Hemodynamics (3)





1) TAA - Indications For Surgery

• 40 mm with indication for elective AVR (BAV etc)

• 45 mm in MFS

• 50 mm in BAV (?)

• 55 mm for an ascending aortic aneurysm,

• 60 mm for a descending aortic aneurysm;

• 70 mm in high-risk comorbidities;

• Growth rate 10 mm per year in <55 mm diameter

• Recurrent symptoms, Evidence of proximal dissect.

L Cozijnsen et al., Circ 2011; 123:924

Ince, CA Nienaber. Nature CV Med 2007; 4:418

1a) Children With Marfan’s Or Loeys-dietz’s (N=35)

Freedom From Reoperation And Actual Survival

0 12 24 36 48 60 72 84 0

10

20

30

40

50

60

70

80

90

100

Months

Survival

Reoperation

Eve

nt-

Fre

e S

urv

iva

l (%

)

valve-sparing root replacement , and mitral valve repair have low reoperative risk

MD Everett, AT Yetman et al., JTCS 2009; 137:1327 (Salt Lake City, Denver)

J Coselli, DC Miller et al., JTCS 2014;147:1758 (Marfa Patients Study Group)

1b). Risk of Aortic Surgery After Definite

Bicuspid Aortic Valve Diagnosis (n=416)

HI Michelena et. al. JAMA 2011;306:1104.

M Gaudino et. al. J Thorac Cardiovasc Surg 2015;150:1120

1c) Temporal Trends In The Overall Number Of Aortic

Root Procedures And By Type Of Operation

Predictors of Early and Medium-Term Outcome

of 200 Consecutive Aortic Valve and Root Repairs

Between 2003 and 2013, 200 consecutive patients (149 men,

51 women; mean age, 52.1 years) with significant aortic

regurgitation and aortic root enlargement underwent aortic

valve repair and associated root reconstruction. Root

management consisted of either root remodeling or

reimplantation with Dacron prostheses. Early mortality was

2%, and early repair failure was 3%. Survival at a mean

follow-up of 48.6 ± 34.3 months was 94%, with a freedom from

reoperation of 91%. Repair failure and reoperation were

associated with bicuspid valve and complex leaflet repair.

MJ Jasinski et al., J Thorac Cardiovasc Surg 2015; 149:123 (Poland)

TE David. J Thorac Cardiovasc Surg. 2015;149:408

Aortic Valve Reimplantation

With Creation Of Neo–aortic Sinuses

2a) Contained Acute Aortic Syndrome

RE Clough et. al. Nat. Rev. Cardiol. 2015;12:103 RR Baliga et. al. J Am Coll Cardiol Img 2014;7:406

6-15% - CT / MR Diameter 16 mm, Rupture within 10 days

Early & Late Outcomes of Acute Type A

Aortic Dissection With Intramural Hematoma

Between 2000 and 2013, we performed 418 repairs for acute

type A aortic dissection: 64 patients or 15% had type A IMH

and 354 patients 85% with typical dissection. With IMH, the

time from presentation to repair was, by strategy, longer

(median, 67 vs 6 hours), but no mortality occurred within 3

days of presentation. Mortality with IMH did not differ from

typical dissection (10.9% vs 14.7%). Although expectant repair

within 3 days may be applied, the purposeful delay imparted

little advantage.

AL Estrera et al., J Thorac Cardiovasc Surg 2015; 149:137 (Houston)

Acute Type A Intramural Hematoma

Analysis of Current Management Strategy

AL Estrera et al., J Thorac Cardiovasc Surg 2015; 149:137 (Houston)

No mortality occurred within 3 days of presentation. Mortality with IMH

did not differ from typical dissection (10.9% vs 14.7%).

Best cutoff to Predict Events: 16 mm (Hematoma) - Often Type A

Early And Late Outcomes Of Acute Type A

Aortic Dissection With Intramural Hematoma

AL Estrera et. al. J Thorac Cardiovasc Surg 2015;149:137

2b) Acute Type A Aortic Dissection:

Comparing Bicuspid vs Tricuspid Valve

Between 1995 and 2011, 460 consecutive patients had

acute type A aortic dissection - 91.6% with TAV and

8.4% with BAV. Patients with BAV have a distinctive

dissection pattern with the entry tear frequently

located in the aortic root and—despite their younger

age—are subject to substantial hospital mortality. For

BAV patients, composite root replacement yields an

outcome equal to an age- and gender-matched normal

population.

CD Etz et al., Eur J Cardio-Thoracic Surg 2015; 48:142

H Nagamine et al., EJCTS. 2015;48:671 – Type A D. Ant. or Bilat. False Lumen (65%) JM Zhu et. al. J Thorac Cardiovasc Surg. 2015;150: 101

Neoaortic Arch From The Inside

Circulation. 2014;129:1610

Endovascular Repair of the Ascending Aorta

in Patients at High Risk for Open Repair

From 2007 to 2013, 6 patients (aged 16-90 years) underwent

endovascular repair (pseudoaneurysm, n=4; acute type A

aortic dissection, n=2). All patients had extensive

comorbidities or anatomic features making an open surgical

approach high risk. Three cases were done on an emergency

basis (aortic dissection, n=2; ruptured pseudoaneurysm,

n=1). Ascending aortic access was obtained through

transapical (n=4), transfemoral (n=1), and left common carotid

artery (n=1) approaches. 30-day mortalities were zero.

P Vallabhajosyula et al., JTCS 2015; 149:S144

P Vallabhajosyula et. al. JTCS 2015;149:S144

Endovascular Repair Of The Asc Aorta

In Pts At High Risk For Open Repair

3) Irad – Type B Dissection – Survival Curve (N=300)

100

75

50

25

0

Su

rviv

al

rate

(%

)

300 600 900 1200

Log rank P =.61

Surgical (11%)

Endovascular (11%)

Medical (18%)

29%

10%

10%

Hospital Mortality

IRAD (Tsai TT et al.) Circulation 2006; 114:2226

IRAD (S Trimarchi et al.) Circulation 2010; 122:1283

Worst Prognosis: Hypotension, Pleural Effusion, Renal Failure

Refractory Pain & Hypertension

Days

RO Afifi et. al. Circulation 2015;132:748

Outcomes of Patients With Acute Type B

Aortic Dissection

RP Cambria. Advances at Mass General. 2015

Site of TEVAR Implementation

M Lachat et. al. Eur Heart J. 2015;36:585

Developments In The Treatment

Of Aortic Aneurysms In 2014

4a). Annual Risk of Rupture of AAA

K Craig Kent. N Engl J Med 2014;371:2101

Screening for AAA: U.S. Preventive Services

Task Force Recommendation Statement

• The USPSTF recommends 1-time screening for AAA with

ultrasonography in men aged 65 to 75 years who have ever smoked. (B

recommendation)

• The USPSTF recommends that clinicians selectively offer screening

for AAA in men aged 65 to 75 years who have never smoked (C

recommendation)

• The USPSTF concludes that the current evidence is insufficient to

assess the balance of benefits and harms of screening for AAA in

women aged 65 to 75 years who have ever smoked. (1 statement)

• The USPSTF recommends against routine screening for AAA in women

who have never smoked. (D recommendation)

ML LeFevre et al., Ann Intern Med 2014; 161:281

Aneurysm Global Epidemiology Study

Health Measures Can Reduce AAA Mortality

Nineteen World Health Organization member states were

included (Europe, 14; Australia, 2; North America, 2; Asia, 1).

AAA mortality has not declined globally, and differences

between nations can be explained by variations in traditional

CV risk factors. Declines in smoking prevalence correlate

most closely with declines in AAA mortality, and a novel

obesity paradox has been identified that requires further

investigation. Public health measures could therefore further

reduce global AAA mortality, with greatest benefit in the

younger age group.

D Sidloff et al., Circ 2014; 129:747

Growth Rate for Small AAA – Meta-Analysis

Small AAAs of 3.0 cm – 5.4 cm in diameter are monitored by ultrasound

surveillance. The intervals between surveillance scans should be

chosen to detect an expanding aneurysm prior to rupture. Studies were

identified for inclusion through a systematic literature search through

December 2010. Study authors were contacted, which yielded 18 data

sets providing repeated ultrasound measurements of AAA diameter over

time in 15,471 patients. Predictions of the risk of exceeding 5.5-cm

diameter and of rupture within given time intervals were estimated.

Growth rates increased on average by 0.59 mm per year. In contrast to

the commonly adopted surveillance intervals in current AAA screening

programs, surveillance intervals of several years may be clinically

acceptable for the majority of patients with small AAA.

The RESCAN. JAMA 2013; 309:806 – JL Duncan BMJ 2012; 344:e2958 > 25 mm LT Risk

JM Guirguis-Blake et al., Ann Intern Med 2014; 160:321 – Validated Prospectively

DB Buck et. al. Nat. Rev. Cardiol. 2014;11:112

Endovascular Treatment

Of Abdominal Aortic Aneurysms

Annual Proportion of Elective

Endovascular & Open Repairs for AAA in the US

K Craig Kent. N Engl J Med 2014;371:2101

ML Schermerhorn et. al. NEJM 2015;373:328

Long-Term Outcomes of Abdominal Aortic Aneurysm

in the Medicare Population

4b) Endovascular Or Open Repair

For Ruptured AAA One-year Outcomes

This pragmatic multicentre (29 UK and 1 Canada) trial

randomized 613 patients with a clinical diagnosis of ruptured aneurysm; 316 to an endovascular first strategy and 297 to open repair. The principal 1-year outcome was mortality; secondary outcomes were re-interventions, hospital discharge, health-related quality-of-life (Qol) (EQ-5D), costs. An endovascular first strategy does not offer a survival benefit over 1 year but offers patients faster discharge with better Qol and is cost-effective.

IMPROVE Trial (R Grieve et. al.) Eur Heart J. 2015;36:2061

Diseases of The Aorta 2016

Understanding & Approach

TAA, TAD, AAA, AAR

ACC - Mumbai, Jan. 24, 2016 No Disclosures

R Fattori et. al. J Am Coll Cardiol 2013;61:1661 Medical Rx 1548, Surgical Rx 1706, TEVAR 3457

Interdisciplinary Expert Consensus Document on Management of TAD Type B - Complications

Role of Mechanotransduction in Vascular Biology

Focus on Thoracic Aortic Aneurysms and Dissections

TAA and dissections are associated with poorly

controlled hypertension and mutations in genes for

extracellular matrix constituents, membrane

receptors, contractile proteins, and associated

signaling molecules. This grouping of factors

suggests that these thoracic diseases result, in part,

from dysfunctional mechanosensing and

mechanoregulation of the extracellular matrix by the

intramural cells, which leads to a compromised

structural integrity of the wall.

JD Humphrey et al., Circ Res 2015; 116:1448

How Does the Ascending Aorta

Geometry Change When It Dissects?

Six tertiary centers of 2 continents reviewed their acute aortic

dissection type A databases, which contained 1,821 patients.

Included were all non-Marfan patients with nonbicuspid aortic

valves who had undergone computed tomography

angiography <2 years before and within 12 h after aortic

dissection onset. Aortic geometry before and after dissection

onset were compared. Geometry of the thoracic aorta is

affected by aortic dissection, leading to an increase in

diameter that is most pronounced in the ascending aorta.

Both spontaneous and retrograde dissection result in similar

aortic geometry changes.

B Rylski et al., JACC 2014; 63:1311

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