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Epidemiology, Pathophysiology, and Management Guidelines of Aortic Insufficiency Eric M. Isselbacher, MD, MSc Associate Director, MGH Heart Center Co-Director, MGH Thoracic Aortic Center Associate Professor of Medicine, Harvard Medical School 1st North American Aortic Valve Repair Symposium, May 14, 2015
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Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

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Page 1: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Epidemiology, Pathophysiology, and Management Guidelines of Aortic Insufficiency

Eric M. Isselbacher, MD, MSc

Associate Director, MGH Heart CenterCo-Director, MGH Thoracic Aortic Center Associate Professor of Medicine, Harvard Medical School

1st North American Aortic Valve Repair Symposium, May 14, 2015

Page 2: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Presenter Disclosure Information

• No relationships to disclose

Page 3: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Prevalence of AI by Age and Gender:Framingham Offspring Study

Singh JP, et al. Am J Cardiol 1999;83:897–902 Bekeredjian R, et al. Circulation 2005;112:125-134

Age (years) 20-39 40-49 50-59 60-69 70-83

MaleMild 0 1.4% 3.7% 12.1% 12.2%

Moderate 0 0.3% 0.5% 0.6% 2.2%

Female

Mild 0 0.7% 1.9% 6.0% 14.6%

Moderate 0 0 0.2% 0.8% 2.3%

Page 4: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Etiology of Chronic Aortic Insufficiency

• Bicuspid aortic valve • Aortic aneurysm

– Aortic root• Marfan syndrome

– Ascending aorta• Calcific changes

– Mixed AS/AI• Infectious endocarditis• Marantic endocarditis• Rheumatic valve disease• Aortitis

– Takayasu, GCA, Behcet’s– Syphilis

• Subvalvular membrane• Supracristal (subvalvular) VSD

– Aortic cusp prolapse• Anorectic drugs • Prosthetic valve dysfunction

– Bioprosthetic leaflet failure– Mechanical valve thrombosis – Paravalvular leaks

• TAVR paravalvular leaks• LVAD – especially continuous

flow devices

Page 5: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Most Common Etiologies of Chronic AI

Etiology Percent

Bicuspid aortic valve 13-28

Dilated root or ascending aorta 19-26

Degenerative 7-40

Rheumatic 6-12

Endocarditis 3-10

Other/Uncertain 4-35

Page 6: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Pathophysiology of Chronic Severe AI: Early to Mid Compensated

• Volume of regurgitation increases gradually – LV cavity progressively dilates– LV hypertrophy

• Increased volume eccentric LVH = addition of new sarcomeres (preload at sarcomere level relatively unchanged)

• Increased afterload concentric LVH – LV end-diastolic volume increases– Stroke volume increases

• Net cardiac output maintained• Pattern progresses slowly

– Patients can tolerate even severe AI for years.

Page 7: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Pathophysiology of Chronic Severe AI: Late Decompensated

• After significant dilatation, myocardial dysfunction follows– Ejection fraction falls

• Cardiac output falls– LA pressure rises

• Patient develops heart failure• Myocardial oxygen demand rises, supply falls

– Mismatch leads to ischemia, angina, ventricular arrhythmias.

Page 8: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Survival of Patients with Chronic Severe AI: by LV End-Systolic Diameter (LVESD)

DuJardin KS, et al. Circulation 1999;99:1851-1857 Bekeredjian R, et al. Circulation 2005;112:125-134

55 mm

> 55 mm

Page 9: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Survival of Patients with Chronic Severe AI: by Symptoms (NYHA class)

DuJardin KS, et al. Circulation 1999;99:1851-1857 Bekeredjian R, et al. Circulation 2005;112:125-134

NYHA I

NYHA II

NYHA III-IV

Page 10: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Evaluation

Page 11: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Grading of AI by Echocardiography

• Primary goal is to distinguish severe from moderate – Jet height / LVOT diameter > 0.6

• May not be true if the jet is eccentric– Pressure half-time < 250 msec – Regurgitant volume > 60 ml– Regurgitant fraction > 55%– Early termination of the mitral inflow (due to increase in

LV pressure due to the AI)– Holodiastolic flow reversal in the descending aorta.

Page 12: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Grading of AI Severity by TTE in a Sample of 20 Cases by 20 Expert Readers

Dahiya A, et al. Am J Cardiol 2012;110:709-714

Page 13: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Quantification of AR with direct measurement of the vena contracta area using 3D TTE

Ewe SH, et al. Am J Cardiol 2013;112:560-566

Comparison between 2D and 3D TTE for AR quantification, using 3D 3-directional velocity-encoded MRI (VE-MRI) as reference method

Page 14: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

MRI: Advantages

• Unlimited imaging planes• Comprehensive and quantitative • Integrated quantitative flow assessment

– Accurate measure of regurgitant fraction

Page 15: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Survival without surgery for conventional indictions vs. MRI regurgitant fraction ≥ 37%

Myerson SG, et al. J Cardiovasc Magnet Res 2011; 13(Suppl 1):099

Page 16: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Echo remains the modality most often used

Page 17: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Management

Page 18: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Medical Management

• Vasodilators have long been used in cases when AI is moderate or severe – Nifedipine – ACE inhibitors

• 2 key studies, conflicting data– Scognamiglio et al. in 1994 – Evangelista et al. in 2005

Scognamiglio R, et al. N Engl J Med 1994;331:689-69 Evangelista A, et al. N Engl J Med 2005;353:1342-1349

Page 19: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

N.B.: there was no placebo control group

Scognamiglio R, et al. N Engl J Med 1994;331:689-69

Probability of AVR in Patients with Severe AI Treated with Nifedipine (20 mg bid) vs. Digoxin

P < 0.001at 6 years

Page 20: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Vasodilator Therapy

• The 1998 ACC/AHA guidelines gave a class I recommendation for the use of long-term vasodilator therapy in patients with chronic, severe AI

Page 21: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Evangelista A et al. N Engl J Med 2005;353:1342-1349

Probability of AVR in Patients with Severe AI Treated with Nifedipine, Enalapril, or Placebo

P = 0.29at 7 years

Page 22: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Efficacy of Vasodilators in Severe AI:A Controlled Animal Model

• Eric Plante and colleagues, Université Laval, Quebec • 60 rats had severe AR (confirmed by echo) induced by

retrograde puncture of the AV leaflets • Randomly divided into 5 groups:

– Normal sham-operated animals– AR untreated– AR treated with nifedipine– AR treated with captopril – AR treated with losartan

• Drug treatments were started 2 weeks after surgical procedure and continued thereafter for 6 months

• Echos at 6 months.

Plant E, et al. Circ Heart Fail 2009; 2: 25-32

Page 23: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Echo Data After 6 Months of Treatment

Parameter Sham (n=11)

Placebo (n=11)

Captopril (n=10)

Losartan (n=10)

Nifedipine (n=9)

AR, % NA 63 ± 4 64 ± 4 61 ± 3 60 ± 4

EDD, mm 8.5 ± 0.2* 11.6 ± 0.3 10.8 ± 0.3 10.9 ± 0.2 11.8 ± 0.3

ESD, mm 4.3 ± 0.3* 7.7 ± 0.3 6.5 ± 0.4† 6.5 ± 0.2† 8.1 ± 0.4

EF, % 74 ± 2* 55 ± 2 63 ± 3† 64 ± 2† 53 ± 3

Plant E, et al. Circ Heart Fail 2009; 2: 25-32

* = p < 0.01 compared with placebo; † = p < 0.05 compared with placebo

Page 24: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Efficacy of captopril in rat model of pure AI: Showed for the first time a survival benefit

Arsenault M, et al. Circ Heart Fail 2013;6:1021-1028

Page 25: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,
Page 26: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Retrospective Analysis of 2266 Pts with Mod or Severe AI: Benefits of ACEI/ARB use

Elder DHJ, et al. J Am Coll Cardiol 2011;58:2084–91

Freedom from CV events (CV hospitalization or death)

Users

Non-users

Page 27: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

2014 ACC/AHA Guidelines

• Treatment of hypertension (SBP >140 mmHg) is recommended in patients with chronic AR, preferably with dihydropyridine Ca++ channel blockers or ACEIs/ARBs

• I see no good reason to choose nifedipine if patient can tolerate ACEIs or ARBs

Nishimura RA, et al. JACC 2014.02.536

Page 28: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Use of Beta-blockers in Severe AI?

Page 29: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Sampat U, et al. J Am Coll Cardiol 2009;54:452-457

Effect of Beta-Blockers on Survival in Patients with Severe AR: A Cohort of 756

Page 30: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

The Timing of Surgery

Page 31: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Surgical Indications Are Based on Symptoms and on LV Size and Function

Page 32: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Indications for Surgery in AI:2014 ACC/AHA guidelines

Class Indication

Nishimura RA, et al. JACC 2014.02.536

Page 33: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Indications for Surgery in AI:2014 ACC/AHA guidelines

Class IndicationI • Any pt with symptomatic severe AI, regardless of LV EF

• Asymptomatic pt with severe AI and LV EF < 50% at rest• Asymptomatic pt with severe AI undergoing cardiac

surgery for other indications

Nishimura RA, et al. JACC 2014.02.536

Page 34: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Indications for Surgery in AI:2014 ACC/AHA guidelines

Class IndicationI • Any pt with symptomatic severe AI, regardless of LV EF

• Asymptomatic pt with severe AI and LV EF < 50% at rest• Asymptomatic pt with severe AI undergoing cardiac

surgery for other indications

IIa • Asymptomatic pt with severe AI and normal LV function but severe LV dilatation (LVESD > 50 mm or > 25 mm/m2)

Nishimura RA, et al. JACC 2014.02.536

Page 35: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Indications for Surgery in AI:2014 ACC/AHA guidelines

Class IndicationI • Any pt with symptomatic severe AI, regardless of LV EF

• Asymptomatic pt with severe AI and LV EF < 50% at rest• Asymptomatic pt with severe AI undergoing cardiac

surgery for other indications

IIa • Asymptomatic pt with severe AI and normal LV function but severe LV dilatation (LVESD > 50 mm or > 25 mm/m2)

IIa • Asymptomatic pt with moderate AI undergoing ascending aortic surgery, mitral valve surgery, or CABG

Nishimura RA, et al. JACC 2014.02.536

Page 36: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Indications for Surgery in AI:2014 ACC/AHA guidelines

Class IndicationI • Any pt with symptomatic severe AI, regardless of LV EF

• Asymptomatic pt with severe AI and LV EF < 50% at rest• Asymptomatic pt with severe AI undergoing cardiac

surgery for other indications

IIa • Asymptomatic pt with severe AI and normal LV function but severe LV dilatation (LVESD > 50 mm or > 25 mm/m2)

IIa • Asymptomatic pt with moderate AI undergoing ascending aortic surgery, mitral valve surgery, or CABG

IIb • Asymptomatic pt with severe AI and normal LV function (LV EF ≥ 50%) but with progressive severe LV dilatation(LVEDD > 65 mm) if surgical risk is low

Nishimura RA, et al. JACC 2014.02.536

Page 37: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Refining Risk Stratification: Biomarkers

Page 38: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

BNP to Risk Stratify Patients with Asymptomatic Severe AI and Normal LV Function

Months

Event-free Survival (LV systolic dysfunction, symptoms, or death)

Pizarro R, et al. JACC 2011;58:1705-14

Page 39: Epidemiology, Pathophysiology, and Management Guidelines ... · Epidemiology, Pathophysiology, and Management Guidelines of Aortic ... 1st North American Aortic Valve Repair Symposium,

Epidemiology, Pathophysiology, and Management Guidelines of Aortic Insufficiency

Eric M. Isselbacher, MD, MSc

Associate Director, MGH Heart CenterCo-Director, MGH Thoracic Aortic Center Associate Professor of Medicine, Harvard Medical School

1st North American Aortic Valve Repair Symposium, May 14, 2015