update on the pathophysiology of aortic...

Update on the Pathophysiology of Aortic Stenosis

Philippe Pibarot, DVM, PhD, FACC, FAHA, FESC, FASEResearch Group in Valvular Heart Diseases

Canada Research Chair in Valvular Heart Diseases

UniversitéLAVAL

Institut Universitaire de Cardiologieet de Pneumologie de Québec / Québec Heart & Lung Institute

DisclosurePhilippe Pibarot

Financial relationship with industry:

Edwards Lifesciences: Echo CoreLab - SAPIEN 3

V-Wave: Echo CoreLab

Cardiac Phoenix: Research Grant for Echo CoreLab

Ionis Pharmaceuticals

Other financial disclosure:

Research Grants from Canadian Institutes of Health

Research and Heart & Stroke Foundation of Quebec

Aortic Stenosis:Most frequent CVD after CAD and Hypertension

0.2%0.2%1%2%3%

Prevalence in PopulationAge 18-45Age 46-55Age 56-65Age 66-75 Age >75

2%2%10%20%30%

AORTICSCLEROSIS

NORMAL AORTIC STENOSIS

0

20

40

60

80

100

Asymptomatic period(increasing obstruction,

myocardial overload)

Age (year)0 40 50 60 70 80

Average deathage (male)

Onset of severe symptoms

0 2 4 6Average survival (yr)

AnginaSyncopeFailure

Symptomatic severe AS : indication of AVR (class I)

The Natural History of Aortic Stenosis

The Burden of Aortic Stenosis Afflicts about 1 million people in North

America Prevalence increases with age:

In population >65 y.o: 25% sclerosis and 3% stenosis

No medical therapy to reduce AS progression!

Severe symptomatic AS: SAVR or TAVR AS responsible for 20,000 deaths and

80,000 AVRs per year in North America

Presenter

Presentation Notes

[Aortic Valve Stenosis is the most frequent valvular disease in the western world]. It is also the most frequent cardiovascular disease after coronary artery disease and hypertension. The prevalence of this disease is indeed quite high with 25% of the subjects over 65 years old having an aortic valve sclerosis and 3 % having an aortic valve stenosis. Moreover, this prevalence is expected to double by 2020 due to population aging. This disease is directly responsible for approximately 20,000 deaths and 100,000 aortic valve replacements per year in North America only and the cost of a valve replacement surgery in the US is approximately 120,000 $. So, if you do a simple calculation, you realize that this disease is associated with a huge health and socio-economic burden. [And, for a long time, (calcific) aortic stenosis has been considered as a “degenerative” disease because it was thought to be the result of aging and “wear and tear” of the aortic valve].

MG < 40 mmHg AVA > 1 cm2

C StageAsymptomatic Severe AS

2014 ACC-AHA Guidelines: Progression Stages

3.6 m/s

HIGH GRADIENTASYMPTOMATIC

LOW LVEFC2 Stage

AVR, Class I

BICUSPID VALVEAORTIC SCLEROSIS

A Stage

HIGH GRADIENTASYMPTOMATIC

NORMAL LVEFC1 Stage

AVR, Class IIa/IIb

MG≥ 40 mmHgLVEF ≥ 50%

MG≥ 40 mmHgLVEF < 50%

B StageMild to Moderate AS

A StageAt Risk of AS

1.8 m/s

MG < 15 mmHg AVA > 2 cm2

MILD / MODERATE ASB Stage

AVR, Class III

MG≥ 40 mmHg MG < 40 mmHg AVA ≤ 1 cm2

LVEF < 50%

MG < 40 mmHg AVA ≤ 1 cm2

LVEF ≥ 50%SVI < 35 mL/m2

2014 ACC-AHA Guidelines: Progression Stages

3.6 m/s

«CLASSICAL»LOW-FLOW

LOW-GRADIENTD2 Stage

AVR, Class IIa

HIGH GRADIENTSYMPTOMATIC

D1 StageAVR, Class I

3.6 m/s3.6 m/s

«PARADOXICAL»LOW-FLOW

LOW-GRADIENTD3 Stage

AVR, Class IIa

NORMAL -FLOWLOW-GRADIENT

Stage ?AVR ?

MG < 40 mmHg AVA ≤ 1 cm2

LVEF ≥ 50% SVI > 35 mL/m2

D StageSymptomatic Severe AS

The Changing Face of Aortic Stenosis “Degenerative” process as a result of wear and tear?

AS shares many cellular similarities with vascular atherosclerosis

AS has been linked to several traditional risk factors for coronary artery disease

AS: an atherosclerotic disease?

Is there a hope for pharmacotherapy in AS?

Presenter

Presentation Notes

For a long time, (calcific) aortic stenosis has been considered as a “degenerative” disease because it was thought to be the result of aging and “wear and tear” of the aortic valve. This perception [The perception of AS being a degenerative disease] has changed over the years with the publication of several studies showing that the aortic valve sclerosis shares many cellular (and histological) similarities with vascular atherosclerosis. Furthermore, AS has been linked to several traditional risk factors for coronary artery disease[ including: age, male gender, hypercholesterolemia, diabetes, hypertension, smoking, obesity So, there is now a growing body of evidence supporting the concept that AS is active diseases related to an atherosclerotic process. So AS is an atherosclerotic disease. And of course, this raises the possibility that AS might be a modifiable disease. If we find a drug that is able to substantially slow the progression of AS, this would have a huge clinical implications. Such a therapy could avoid thousands of valve replacements and save thousands of lives every year.

Pharmacological Therapy for AS?

Rossebo NEJM, 359:1343-56, 2008

Cowell, NEJM, 352:2389-97,2005

The Failure of Statins in Aortic StenosisSALTIRE SEAS

ASTRONOMER

Chan Circulation121:306-314, 2010

Dweck et al . JACC 2012

Calcific AS has some similarities but also some dissimilarities with atherosclerosis

Presenter

Presentation Notes

Summary of the Pathological Processes Occurring Within the Valve During Aortic Stenosis Mechanical stress results in endothelial damage that allows infiltration of lipid and inflammatory cells into the valve. Lipid oxidization further increases inflammatory activity within these lesions and the secretion of proinflammatory and profibrotic cytokines. The latter drives the differentiation of fibroblasts into myofibroblasts that secrete increased collagen under the influence of angiotensin. In combination with the action of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), disorganized fibrous tissue accumulates within the valve. This leads to thickening and increased stiffness of the valve and in the latter stages the development of myxoid fibrous degeneration. Microcalcification begins early in the disease, driven by microvesicle secretion by macrophages. However, calcification accelerates in a proportion of patients because of the differentiation of myofibroblasts into osteoblasts. This occurs under the influence of several procalcific pathways, including osteoprotegerin (OPG)/receptor activator of nuclear factor kappa B (RANK)/RANK ligand (RANKL), Runx 2-cbfal 2, Wnt3-Lrp5-b catenin, and tumor necrosis factor (TNF)-. Osteoblasts subsequently coordinate calcification of the valve as part of a highly regulated process akin to skeletal bone formation, with expression of many of the same mediators, such as osteocalcin, alkaline phosphatase (Alk P), and bone morphogenic protein (BMP)-2. With time, maturation of valvular calcification occurs so that by the end stages of the disease, lamellar bone, microfractures, and hemopoeitic tissue can all be observed within the valve. These pathogenic processes are sustained by angioneogenesis, with new vessels localizing, in particular, to regions of inflammation surrounding calcific deposits. Hemorrhage in relation to these vessels has also been demonstrated in severe disease and may have a role in accelerating disease progression. IL-1 interleukin-1–beta; LDL low-density lipoprotein; TGF transforming growth factor. Dweck et al. 2012.

57 y.o. man with mild calcific AS

Case #1: Patient with Mild AS and Rapid Progression during FU (B Stage)

VPeak: 2.3 m/s Peak/mean gradients: 22/12 mmHg AVA: 1.36 cm2

Calcium score: 901 AU

Baseline 2.5 years later

VPeak: 4.4 m/s (progression 0.8 m/s/yr) Peak/mean gradients: 77/44 mmHg AVA: 0.88 cm2

Calcium score: 2007 AU

Lipoprotein (a) level: 147 mg/dl

Association between LPA and Aortic Valve Calcification

Thanassoulis G et al. N Engl J Med 2013;368:503-512

rs10455872

Genomewide significance prespecified = P<5.0×10−8

Presenter

Presentation Notes

Figure 1 Associations between Each Single-Nucleotide Polymorphism (SNP) and Aortic-Valve Calcium or Mitral Annular Calcium, According to Chromosomal Position. Manhattan plots show that a single SNP on chromosome 6 (rs10455872) has genomewide significance for aortic-valve calcium (P=9.0×10−10) (Panel A) and that two SNPs on chromosome 2 (rs17659543 and rs13415097) have genomewide significance for mitral annular calcium (P=1.5×10−8 and P=1.8×10−8, respectively) (Panel B). The X on the x axis in each panel indicates the X sex chromosome.

CB

D E

Lipoprotein(a) and AS Progression: Astronomer Trial

Capoulade et al. J Am Coll Cardiol 2015;66:1236–46

Lipoprotein(a) and Progression of Calcific AS

There is now a strong body of evidence to support the hypothesis that Lp(a) and its associated OxPL are involved in AS progression

About 20% of the general population (65 Million people in North America) have elevated Lp(a)

Lp(a) circulating levels are determined genetically and currently available drugs only achieve modest reduction in Lp(a) and have significant side effects

Recent Phase I and II trials report that oligonucleotide antisense directed to Apo(a), reduces Lp(a) levels by >75% with minimal side effects

Rationale for Lipoprotein(a) Lowering in AS

Lipid DepositionLipid RetentionLipid OxidationInflammation

Renin-Angiotensin SystemValve fibrosis

Myocyte ApoptosisMyocardial fibrosis

LV hypertrophy

CalcificationOsteoblastsRunX2, BMP

RANK/OPGMatrix Gla Prot

EctonucleotidasesFetuin AAORTIC

STENOSIS

OSTEOBLASTIC DISEASE

/ OSTEOPOROSISATHEROSCLEROSIS

HYPERTENSION

ACE InhibitorsARBs

Lp(a) loweringPCSK9 inhib.

(statins)

BisphosphonatesRANK Antibodies

Adapted from Dweck et al. JACC 2012

Congenital Bicuspid Aortic ValveMost frequent congenital

CV disease: 0.5-1 % of the population

More frequent in males

Life-time risk of AVR for AS is about 50%

Develop AS 10 years earlier compared to subjects with tricuspid valve

Correlation Between AoV Calcification andAS Hemodynamic Severity in Patients with a

Bicuspid Aortic ValvePatients > 50 y.o. Patients < 50 y.o.

Shen et al. Heart 2016

Case #2: 62 y.o. Patient withBicuspid AS (C1 Stage)

Gradients: 63 / 45 mmHgAVA (EOA): 0.89 cm2

AVA (AOA): 0.97 cm2

AVC Score: 5313 AU

62 y.o. manAsymptomatic

Case #3: Young Patient with Bicuspid AS and High Gradient (C1 Stage)

Gradients: 63 / 45 mmHgAVA (EOA): 0.71 cm2

AVA (AOA/GOA): 1.2 cm2

AVC Score: 0 AU

36 y.o. womanAsymptomatic

Role of Jet Eccentricity in Generating Disproportionately Elevated Transvalvular

Gradients in Bicuspid ASCentric Jet Eccentric Jet

↓ Contraction coefficient(EOA/AOA)

↓ EOA↑ Gradient

Abbas et al. Echocardiography2014

In patients with Tricuspid AS: Calcium is the main culprit lesion

AoV Calcification by EchoPredicts Outcomes in AS

Rosenhek et al N Engl J Med 2000; 343:611-7

Valve Calcification(≥3/4)

Case #1: Severe AoV Calcification

Quantification of Valvular Calcification by CT

Messika-Zeitoun, JACC, 2004;110:356-362

None Mild

Moderate Severe

Correlation between AoVCalcification by CTand Hemodynamic / Clinical Outcomes in AS

AVC Correlates withhemodynamic severity

Severe AVC:- Predicts hemodynamically severe AS- Predicts rapid AS progression- Predicts mortality

Aggarwal et al. Circ Img 2012Clavel et al. JACC 2013Clavel et al. JACC 2014

Differences in Women vs. Men in the Anatomic vs. Hemodynamic Severity of AS

Clavel et al. JACC 2013

Fig. 4 AoV Ca Scor by CT to Differentiate Hemodynamically Severe vs. Non- Severe Stenosis

Pseudo-Severe True-Severe

AVC score: 1034 AU AVC density: 220 AU/cm2

AVC score: 3682 AUAVC density: 980 AU/cm2

AVC Score: >2000AU in ♂ AVC Density: >500 AU/cm2 in ♂>1200 AU in ♀ >300 AU/cm2 in ♀

Clavel et al. JACC 2013

Women have less AoV calcification but more fibrosis compared to men

Naoum et al. JACC CV Imaging 2015

30-80% of patients with calcific AS have hypertensionHypertension doubles mortality in AS

Patients with Calcific AS often have Concomitant Hypertension

Kadem et al. Heart 2005; 91:354-361

Impact of Hypertension on LV Systolic Wall Stress in Presence of AS: Animal StudyCatheter Gradient

Doppler Gradient

Peak Systolic Wall Stress

Presenter

Presentation Notes

In contrast to what was observed for transvalvular pressure gradients, the peak systolic LV wall stress, which reflects the load imposed on the left ventricle, increased markedly during hypertension. So this is highly insidious because although the stenosis apparently looks less severe in presence of concomitant hypertension, the burden imposed on the LV ventricle is much higher. And this may lead of course to the development of LV dysfunction and the occurrence of adverse outcomes. 30s

Impact of Hypertension and Anti-Hypertensive Medications on AS Progression and Outcomes

Capoulade et al. Eur Heart J Clin Invest. 2013.

AS Progression AVR or Death

Impact of Systolic Hypertension on Progression of AS

Pathophysiology of AS: Take Home Messages

Pathophysiology of AS differs in: Younger vs. older patients: lipid-mediated inflammation vs. phospho-

calcic dysmetabolism Women versus men: less calcification but more fibrosis Bicuspid versus tricuspid valve

Next milestones in the management of AS: Tailor management according to age, sex, and valve phenotype

Better identify and treat hypertension in AS

RCT of ARB in patients with mild-to-moderate AS

RCT of Lp(a) lowering in younger patients with mild AS

update on the pathophysiology of aortic...

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