Lipoprotein(a) and calcification in aortic valve stenosis EAS - - PowerPoint PPT Presentation

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Lipoprotein(a) and calcification in aortic valve stenosis EAS - - PowerPoint PPT Presentation

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Lipoprotein(a) and calcification in aortic valve stenosis EAS Satellite Meeting 24 th of May 2019 Kang H. Zheng, MD Faculty Disclosure Declaration of financial interests For the last 3 years and the subsequent 12 months: I I have received a

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Lipoprotein(a) and calcification in aortic valve stenosis

EAS Satellite Meeting 24th of May 2019 Kang H. Zheng, MD

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Faculty Disclosure

I I have received a research grant(s)/ in kind support

A From current sponsor(s) YES NO B From any institution YES NO

II I have been a speaker or participant in accredited CME/CPD

A From current sponsor(s) YES NO B From any institution YES NO

III I have been a consultant/strategic advisor etc

A For current sponsor(s) YES NO B For any institution YES NO

IV I am a holder of (a) patent/shares/stock ownerships

A Related to presentation YES NO B Not related to presentation YES NO Declaration of financial interests For the last 3 years and the subsequent 12 months:

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Faculty Disclosure

Declaration of non-financial interests:

  • None
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Inflammation Calcification

Otto – NEJM 2014

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Pawade – JACC 2015

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Why is aortic stenosis important?

  • Aortic stenosis is highly prevalent in

the elderly

  • Set to become major healthcare burden

with an ageing population

  • Effective medical therapies to slow

disease progression are lacking

  • Untreated symptomatic aortic stenosis

has a yearly mortality rate >25%!

  • Only treatment is surgical or

transcatheter valve replacement, but

  • ptimal timing is not established

Eveborn - Heart 2013

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Why is aortic stenosis important?

  • Aortic stenosis is highly prevalent in the

elderly

  • Set to become major healthcare

burden with an ageing population

  • We lack effective medical therapies to

slow disease progression

  • Untreated symptomatic aortic stenosis

has a yearly mortality rate >25%!

  • Only treatment is surgical or

transcatheter valve replacement, but

  • ptimal timing is not established

Danielsen – Int J Car 2014 Eurostat 2010

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Why is aortic stenosis important?

  • Aortic stenosis is highly prevalent in the

elderly

  • Set to become major healthcare burden

with an ageing population

  • We lack effective medical therapies to

slow disease progression

  • Untreated symptomatic aortic stenosis

has a yearly mortality rate >25%!

  • Only treatment is surgical or

transcatheter valve replacement, but

  • ptimal timing is not established

Stewart – JACC 1997

Cardiovascular Health Study (n=5201)

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Why is aortic stenosis important?

  • Aortic stenosis is highly prevalent in the

elderly

  • Set to become major healthcare burden

with an ageing population

  • We lack effective medical therapies to

slow disease progression

  • Untreated symptomatic aortic stenosis

has a yearly mortality rate >25%!

  • Only treatment is surgical or

transcatheter valve replacement, but

  • ptimal timing is not established
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Why is aortic stenosis important?

  • Aortic stenosis is highly prevalent in the

elderly

  • Set to become major healthcare burden

with an ageing population

  • We lack effective medical therapies to

slow disease progression

  • Untreated symptomatic aortic stenosis

has a yearly mortality rate >25%!

  • Only treatment is surgical or

transcatheter valve replacement, but

  • ptimal timing is not established

Carabello – Lancet 2009

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Why is aortic stenosis important?

  • Aortic stenosis is highly prevalent in the

elderly

  • Set to become major healthcare burden

with an ageing population

  • We lack effective medical therapies to

slow disease progression

  • Untreated symptomatic aortic stenosis

has a yearly mortality rate >25%!

  • Only treatment is surgical or

transcatheter valve replacement, but

  • ptimal timing is not established

Everett – Heart 2018

There is an unmet need for novel therapies to slow or halt aortic stenosis progression!

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Early studies recognized ↑Lp(a) was associated with aortic valve disease

Gotoh – Am J Cardiol 1995

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1990 1995 2000 2005 2010 2015 2020 5 10 15 20 25

Pubmed aortic valve AND "lipoprotein(a)"

Year Articles

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Thanassoulis - NEJM 2013 LPA rs10455872 Risk for incident aortic stenosis: HR per allele, 1.68 (95% CI, 1.32 to 2.15) Risk for aortic-valve replacement: HR per allele, 1.54 (95% CI, 1.05 to 2.27)

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Lp(a) levels and LPA polymorphisms associate with incident aortic stenosis across cohorts

EPIC-Norfolk (n=17.5K); Arsenault – Circ 2014 Copenhagen (n=77.6K); Kamstrup – JACC 2014 GERA cohort (Northern California); Chen – JAMA Cardio 2018 Meta-analysis; Helgadottir – Nature Comm 2018

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Tsimikas – JACC 2017

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Oxidized phospholipids may explain the association with AS

Kamstrup – ATVB 2017

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Autotaxin generates lysoPA to promote aortic valve calcification via a NFkB-IL6-BMP2 signaling pathway

Bouchareb – Circulation 2015

Nsaibia – J Intern Med 2016

Plasma autotaxin associated with risk

  • f AS in patients with CAD
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Purified Lp(a) induces calcification in valve interstitial cells

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Blocking OxPL in LDLR deficient mice attenuates aortic valve calcification

Que – Nature 2018

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Lessons learned from targeting LDL-C in aortic stenosis

↑ LDL-C ↑ Lp(a) Epidemiology

✓ ✓

Genetics

✓ ✓

Experimental models

✓ ✓

Mechanism

✓ ✓

Intervention

✕ ?

  • 1. LDL-C associates with AS incidence, but not disease progression
  • 2. Disease drivers for initation phase may be different from the propagation phase

↑ LDL-C ↑ Lp(a) ↑ LDL-C ↑ Lp(a) ? Aikawa – Circulation 2012

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Lp(a) and OxPL associate with faster disease progression in mild-moderate AS

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Lp(a) and OxPL associate with faster disease progression in mild-moderate AS

  • More prospective longitudinal studies are needed
  • Are these findings relevant for the elderly patient encountered

in daily practice?

  • Relationship of Lp(a) and OxPL with sensitive imaging markers
  • f calcification has not been well defined
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We analyzed a pooled cohort of 2 prospective studies

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Baseline characteristics were similar across Lp(a) and OxPL-apoB tertiles

Lp(a) distribution Baseline CT Ca-score Baseline peak aortic jet velocity

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Lp(a) associates with increased calcification activity and faster disease progression

Follow-up (1-3 yrs) 18F-NaF PET/CT

  • Detects active microcalcification
  • Predicts disease progression

18F-NaF uptake Change in CT Ca-score Change in peak aortic jet velocity

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Higher event rate in patients with ↑Lp(a) and ↑OxPL-apoB

Multivariate Cox regression Event free survival

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Lp(a) induces osteogenic differentiation in VICs through OxPL

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18F-NaF uptake is increased in ↑Lp(a) subjects without established calcification

Despres – CJC Open, in press

Participant with a high Lp(a) level (256.9 nmol/L) Participant with a low Lp(a) level (7.8 nmol/L) Computed tomography Computed tomography 18F-NaF PET/CT 18F-NaF PET/CT

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18F-NaF uptake is increased in first degree relatives

Perrot – JAMA Cardio, in press

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Circ Res 2019

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Acknowledgements