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Molecular (M), Clinical (C) and Population (P)Bases of Cardiovascular Disease and Health

16 and 17 July 2018 / 16 y 17 de julio de 2018Cardona (Barcelona, Spain) – Auditori Valentí Fuster

Challenges of Thoracic & Abdominal Aortic Diseases

MCP BASES OF ATHEROTHROMBOTIC DISEASE, 2019

2. MCP Bases of Atherothrombotic Disease

5. Challenges of ACS STEMI & NSTEMI

6. Challenges of Stable CAD & Microcirculation

7. Challenges of Acute Stroke & Chronic Carotid Disease

8. Challenges of Thoracic & Abdominal Aortic Diseases

Cardona, July 15, 2019 No Disclosures

Molecular (M), Clinical (C), Population (P)Bases of Cardiovascular Disease and Health, 2019

Diseases of The Aorta 2019Understanding & Approach – TAA-D, AAA-R

1. Types / Diagn., Pathology / Genetics, Classes (3)

2. Pathogenesis of the 3 Etiologies (3)

3. Optimal Medical Therapy of the 3 Etiologies (3)

4. Surgical Approach of TAA TAD Type A (3)

5. Interventional Approach of TAD Type B (3)

6. Interventional Approach of AAA & AAR (3)

1). Types 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.

Acute Aortic Dissection With Primary Entry TearIn The Arch A Group1 and Arch B Group 2.

S Trimarchi et. al. J Thorac Cardiovasc Surg 2019;157:66

A Evangelista et. al. Nat. Rev. Cardiol. 2013;10:477

Diagnosis by Imaging Modalities of TAD

2. Pathogenesis: Gross, Molecular, Genetics

S Verma et. al. N Engl J Med 2014;370:1920 - Marfan’s etc

Aortic Dissection Samples From Degenerative & Mixed Cases

O Leone et. al. J Thorac Cardiovasc Surg 2018;156:1776 (Bologna, Italy)

Degenerative

Degenerative Atherosclerotic

O Leone et. al. J Thorac Cardiovasc Surg 2018;156:1776 (Bologna, Italy)

Although degenerative lesions of the medial layer were present in all specimens -intralamellar mucoid-, substantial atherosclerosis with risk factor profile coexisted in approximately one quarter of cases. Patients with mixed degenerative-atherosclerotic abnormalities had a coherent clinical risk profile, a clinical presentation frequently mimicking acute coronary syndrome, and a higher incidence of non aorta-related events during follow-up.

Clinical Validity of Genes for Heritable ThoracicAortic Aneurysms and Dissections (HTAAD)

M Renard et. al. J Am Coll Cardiol 2018;72:605

J Am Coll Cardiol 2018;72:605

Up to 25% of individuals with TAD harbor an underlying Mendelian pathogenic variant. Using the Clinical Genome Resource or ClinGenframework.(NIH 2013), genes were classified based on the strength of association with HTAAD into 5 categories: definitive (n=9), strong(n=2), moderate (n=4), limited (n=15), and no reported evidence (n=23). Eleven genes in the definitive and strong groups were designated as “HTAAD genes” or category A. Eight genes were classified as unlikely to be progressive or category B, and 4 as low risk or category C.

2. TAA-BHA 1. TAA-Marfan’s/NSTAA 3. AAA,

Prevalence 1.25% 1 in 10,000 5%

Genetic Genetic GeneticPathogenesis Predisposition Predisposition Predisposition

Bicuspid Valve Male Hypertension HypertensionAtherosclerosis Smoking

Cystic medial Cystic medial InflammatoryHistology Necrosis Necrosis Infiltrate, VSMC

Apoptosis

Rupt./ Disect. + +++ ++

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

3). Classification - Diseases of The Aorta

1). MARFAN’S / NSTAA & BHAFBN1

Mutation

↓ Fibrillin

↑TGF-β

↑MMP↓ TIMP

Rupture

↓ Collagen

AneurysmFormation

CMD

↑Stiffness

↓ Elastin↑ Collagen

DegenerativeDiseases

VSMC

↑ Proteases

↑ dp/dt↑ Aortic diameter↑ BP

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

Genotype Impacts Survival In Marfan’s

R Franken et. al. Eur Heart J. 2016;37:3285

Nonsyndromic Thoracic Aortic Aneurysm Dissectionvs Marfan’s vs. Bicuspid Aortic Valve Aneurysm

Genetic aortopathy (GA) underlies thoracic aortic aneurysms (TAA) in younger adults. Diagnosis of TAA was made for 760 patients (NS-TAA, n=311; MFS, n=221; BAV, n=228). The 687 patients surviving > 30 days after presentation were followed for a median of 7 years. Clinical outcomes for MFS and NS-TAA are similar but worse than BAV. Independent predictors of mortality, including family history of aortic dissection and age. Management of NS-TAA, including surgical intervention, should be similar to that of MFS.AG Sherrah et al., J Am Coll Cardiol 2016; 67:618 (Sydney)

AG Sherrah et. al. J Am Coll Cardiol 2016;67:618

Nonsyndromic Thoracic Aortic Aneurysm and Dissection Outcomes vs Marfan Syndrome vs Bicuspid Aortic Valve

2). MARFAN’S / NSTAA & BHAFBN1

Mutation

↓ Fibrillin

↑TGF-β

↑MMP↓ TIMP

Rupture

↓ Collagen

AneurysmFormation

CMD

↑Stiffness

↓ Elastin↑ Collagen

DegenerativeDiseases

VSMC

↑ Proteases

↑ dp/dt↑ Aortic diameter↑ BP

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

Bicuspid Aortic Valve - Morphology Features That Influence the Pattern of Aortopathy

S Verma et. al. N Engl J Med 2014;370:1920 – Types 1,2,3R Mahadevia et. al. Circulation. 2014;129:673 - Detail

J Swedenborg et. al. Arterioscler Thromb Vasc Biol. 2011;31:73T Duellman et al. Circ Cardiov. Genet 2012; 5:529 (Marshfield, WI) – MMP 9M Nahrendorf, Rweissleder et. al. ATVB. 2011;31:750A Klink, V Fuster, ZA Fayad et. al. J Am Coll Cardiol 2011;58:2522

3a). MRI Imaging – AAA InflammationMouse Model and Nanoparticle PET-CT

b) MRI-USPIO – AAA Inflammation PredictsExpansion, Rupture, and Need for Surgical Repair

Ultrasmall superparamagnetic particles of iron oxide or USPIO, detect cellular inflammation (macrophages) on MRI. In a prospective multicenter open-label cohort study, 342 patients with AAA (diameter ≥40 mm) were classified by the presence of USPIO enhancement and were monitored with serial ultrasound and clinical follow-up for ≥2 years. The primary end point was the composite of aneurysm rupture or repair. USPIO-enhanced MRI predicts the rate of aneurysm growth and clinical outcome. However, it does not provide further information recognized by clinical risk factors.MARS Study Investigators (D Newby et. al) Circulation. 2017;136:787

T2* Map (Blue) Demonstrating Enhancement Of The Posterior Aneurysm Wall With USPIO (Red) By MRI

MARS Study Investigators (D Newby et. al) Circulation. 2017;136:787

c) Nanotherapy Prevention of AAA Expansion Targeting of Rapamycin in Rats

W-H Zimmermann. J Am Coll Cardiol 2018;72:2606

1a). MFS - IMPACT OF β BLOCKERS & ARBsON 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.)

Aort

ic D

iam

eter

(mm

)

10

15

20

25

30

35

40

45

Control Group: slope = 1.15±0.08

Treatment Group: slope = 1.04±0.05

M Groenink et al., EHJ 2013; Aug 21 – Netherlands - ARB ?RV Lacro et al., NEJM 2014; 371:2061 – American Study – ARB Negative

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

1b) Losartan vs Atenolol to Prevent Aortic Dilation in Marfan Syndrome

Beta-blockers (BB) are the standard treatment in MFS. A total of 128 patients included in the previous LOAT clinical trial, 64 in the atenolol and 64 in the losartan group, were followed up to >5 years. There were no differences in aortic dilation rate or presence of clinical events between treatment groups. Therefore, losartan might be a useful, low-risk alternative to BB in the long-term management

LOAT (G Teixido-Tura et al.,) J Am Coll Cardiol 2018; 72:1613

Losartan & Irbersantan in Marfan Syndrome

LOAT (G Teixido-Tura et. Al). J Am Coll Cardiol 2018;72:1613M Mullen. ESC 2018 - n=192 , Irbesartan 150-300 & Plac., 3 yrs: 0.53 vs 0.74 mm yr

J Am Coll Cardiol 2018;72:1369

1c) A total of 1,213 hospitalized AA/AD patients were identified between 2001 and 2011. In the main case crossover analysis, exposure to fluoroquinolone was more frequent during the hazard periods (60 days prior) than during the referent periods (60 to 180 days). Exposure to fluoroquinolone was substantially associated with AA/AD.

Fluoroquinolones and the Risk of Aortic Aneurysm/Aortic Dissection Within 60 Days

CC Lee et. al. J Am Coll Cardiol 2018;72:1369

2). CD31 Signaling Favors the Switch From the Proinflammatory M1 to the Reparative M2 Phenotype

F Andreata et. al. J Am Coll Cardiol 2018;72:45

Treatment With A Drug-suitable CD31 Agonist May Facilitate The Clinical Management Of ADIM

J Thorac Cardiovasc Surg 2017;153:537

Targeted inhibition of MT1-MMP may have therapeutic relevance as an approach to attenuating the TAA development.

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

Time

Baseline1) Vasodilator

(i.e., Nitroprusside)2) Beta blockade

3) TAD – Hemodynamic Approach

BP1,2.

2.

Surgical / Interventional Approach To TAA-D and AAA-R

1. TAA AA – Surgical Indications 2. TAD Type A – Surgical Approaches 3. TAD Type A – Endovascular Approach

1. TAA DA - Surgical / Intervent. Indications 2. TAD Type B – Surgical Approach3. TAD Type B – Endovascular Approach

1. AAA Surgical / Interventional Indications2. AAA Endovascular Approach3. AAR Surgical Interventional Approach

1). TAA - Indications For Surgery• ≥ 45 mm with indication for elective AVR • ≥ 45 mm in MFS, NSTAA • ≥ 50 mm in BAV• ≥ 55 mm for an ascending aortic aneurysm (Earlier?) • ≥ 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.

L Cozijnsen et al.Circ 2011; 123:924 - ACC/AHA Circ.2016;133:680

a). In Patients with AortopathyRecommendations For Earlier Operation

MA Borger et. al. J Thorac Cardiovasc Surg 2018;156:473

JB Kim et. al. J Am Coll Cardiol 2016;68:1209

Aortic Dissection and/or Rupture, and Composite of Event & Surgery Within 5 Years

b). A 14-day Mortality In 645 Pts From IRAD StratifiedBy 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 SurgeryPG Hagan et. al. JAMA 2000;283:897

TA Mort1% q.2h4 Days

TA. STB. S

TB. M

c) Type A Dissection - Survival Stratified Based on The Different Surgical Techniques

H-H Sievers et. al. J Thorac Cardiovasc Surg 2018;156:2076

JB Kim et. al. J Am Coll Cardiol 2016;68:1209

Dissection in Ascending Aortic Aneurysms: Risk Threshold - Age

Survival For All Patients Aged >80 Years Who Underwent AA Surgery vs The US Expected.

KM Wanamaker et.al. J Thorac Cardiovasc Surg 2019;157:53

Survival For Elderly Patients Who Underwent

AA Surgery


About 415 patients aged 70 years or older who underwent ascending aortic surgery, 285 were age 70-79 years and 130 were age ≥80 years. Surgical indications included aortic aneurysm (63.1%), calcified aorta with need for other cardiac procedure (26.4%), and type A dissection (10.5%). Advanced age alone should not be a contraindication for ascending aortic surgery.

d) Staged Aorta Repair in Marfan Syndrome

Between October 1999 and December 2017, 82 patients with Marfansyndrome underwent 118 aortic repairs. We divided the aorta into 4 segments for categorization: (1) the aortic root, (2) aortic arch, (3) descending thoracic, and (4) abdominal aorta. Staged repair was defined as a subsequent operation on a different segment of the aorta after initial repair (n=111. 94.1%), and reoperation was defined as an operation on the same segment (n=7, 5.9%).The mean age at initial operation was 41.7 ± 14.9 years. Staged repairs included aortic root replacement (n=42, 36%), total arch replacement (n=11, 9.3%), combined aortic root and total arch replacement (n=13, 11%), thoracoabdominal aortic repair (n=36, 31%). Operative mortality was 0.8% (1/118). Stroke occurred in 1.7% (2/118), and spinal cord injury occurred in 1.7% (2/117). Overall survival was 95.8 ± 2.4% at 10-years. Twenty-four patients underwent replacement of the whole aorta.

Y Ikeno, Y Okita et al. J Thorac Cardiovasc Surg. 2019; 157:2138., (Kobe Japan),

Replacement of The Whole Segment of The Aorta

Y Ikeno, Y Okita et. al. J Thorac Cardiovasc Surg 2019;157:2138 (Kobe, Japan)

Outcomes of Aortic Root Repair & Replacement In Acute Type A Aortic Dissection: 21 year Experience

B Yang, GM Deeb et. al. J Thorac Cardiovasc Surg 2019;157:2125 (Ann Arbor, MI)

2) Contained Acute Aortic Syndrome

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

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

Acute Type A Intramural HematomaAnalysis 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

3) Endovascular Valve–carrying Conduits Location of The Entry Tears

M Kreibich et. al. J Thorac Cardiovasc Surg 2019;157:26


Two Thirds Of All Patients Who Present With Type A Dissections Are Potential Candidates For Treatment With

Endovascular Valve–carrying Conduits.

1). TAA - Indications For Surgery• ≥ 45 mm with indication for elective AVR • ≥ 45 mm in MFS, NSTAA • ≥ 50 mm in BAV• ≥ 55 mm for an ascending aortic aneurysm (Earlier?) • ≥ 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.

L Cozijnsen et al.Circ 2011;123:924 - ACC/AHA Circ.2016;133:680



1. TAA DA - Surgical / Intervent. Indications2. TAD Type B – Surgical Approach3. TAD Type B – Endovascular Approach


2). Type B Dissection – Survival Curve (N=300)

100

75

50

25

0

Surv

ival

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 FailureRefractory Pain & Hypertension

Days

RP Cambria. Advances at Mass General. 2015

3) Site of TEVAR Implementation

1). Screening for AAA: U.S. Preventive ServicesTask 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

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

Annual Risk of Rupture of AAA

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

A Karthikesalingam et. al. N Engl J Med 2016;375:2051 - > Death

Diameter of AAA at the Time of Repairin England in 2014 and in the United States in 2013

2). Annual Proportion of Elective Endovascular & Open Repairs for AAA in the US

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

EVAR Trial Investigators (R Patel et. al.) Lancet 2016; 388: 2366 - UK

Time To First Re-intervention In The EVAR Open Repair Groups During 15 Years (5.5 cm)

Open And Endovascular Repair Showing Survival After Intact AAA Repair

MT Laine et. al. Circulation. 2017;136:1726 - Finland

3). 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


1. Types / Diagnosis, Pathogenesis, Classes (3)






2. MCP Bases of Atherothrombotic Disease

5. Challenges of ACS STEMI & NSTEMI

6. Challenges of Stable CAD & Microcirculation

7. Challenges of Acute Stroke & Chronic Carotid Disease

8. Challenges of Thoracic & Abdominal Aortic Diseases

Cardona, July 15, 2019 No Disclosures

Molecular (M), Clinical (C), Population (P)Bases of Cardiovascular Disease and Health, 2019

Challenges of Thoracic & Abdominal Aortic Diseasesvfustercourse.com/assets/pdfs/ponencia7.pdf ·...

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