Lipoprotein(a) and calcification in aortic valve stenosis

EAS Satellite Meeting

24th of May 2019

Kang H. Zheng, MD

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:

Faculty Disclosure

Declaration of non-financial interests:

• None

Inflammation

Calcification

Otto – NEJM 2014

Pawade – JACC 2015

Why is aortic stenosis important?

• Aortic stenosis is highly prevalent in the elderly

• Set to become major healthcare burdenwith an ageing population

• Effective medical therapies to slow disease progression are lacking

• Untreated symptomatic aortic stenosishas a yearly mortality rate >25%!

• Only treatment is surgical or transcatheter valve replacement, but optimal timing is not established

Eveborn - Heart 2013

Why is aortic stenosis important?

• Aortic stenosis is highly prevalent in theelderly

• Set to become major healthcareburden with an ageing population

• We lack effective medical therapies toslow disease progression

• Untreated symptomatic aortic stenosishas a yearly mortality rate >25%!

• Only treatment is surgical or transcatheter valve replacement, but optimal timing is not established

Danielsen – Int J Car 2014

Eurostat 2010

Why is aortic stenosis important?

• Aortic stenosis is highly prevalent in theelderly

• Set to become major healthcare burdenwith an ageing population

• We lack effective medical therapies toslow disease progression

• Untreated symptomatic aortic stenosishas a yearly mortality rate >25%!

• Only treatment is surgical or transcatheter valve replacement, but optimal timing is not established

Stewart – JACC 1997

Cardiovascular Health Study (n=5201)

Why is aortic stenosis important?

• Aortic stenosis is highly prevalent in theelderly

• Set to become major healthcare burdenwith an ageing population

• We lack effective medical therapies toslow disease progression

• Untreated symptomatic aortic stenosishas a yearly mortality rate >25%!

• Only treatment is surgical or transcatheter valve replacement, but optimal timing is not established

Why is aortic stenosis important?

• Aortic stenosis is highly prevalent in theelderly

• Set to become major healthcare burdenwith an ageing population

• We lack effective medical therapies toslow disease progression

• Untreated symptomatic aortic stenosishas a yearly mortality rate >25%!

• Only treatment is surgical or transcatheter valve replacement, but optimal timing is not established

Carabello – Lancet 2009

Why is aortic stenosis important?

• Aortic stenosis is highly prevalent in theelderly

• Set to become major healthcare burdenwith an ageing population

• We lack effective medical therapies toslow disease progression

• Untreated symptomatic aortic stenosishas a yearly mortality rate >25%!

• Only treatment is surgical or transcatheter valve replacement, but optimal timing is not established

Everett – Heart 2018

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

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

Gotoh – Am J Cardiol 1995

1990 1995 2000 2005 2010 2015 2020

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Pubmedaortic valve AND "lipoprotein(a)"

Year

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s

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)

Lp(a) levels and LPA polymorphisms associatewith 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

Tsimikas – JACC 2017

Oxidized phospholipids may explain theassociation with AS

Kamstrup – ATVB 2017

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

Bouchareb – Circulation 2015

Nsaibia – J Intern Med 2016

Plasma autotaxin associated with risk of AS in patients with CAD

Purified Lp(a) induces calcification in valve

interstitial cells

Blocking OxPL in LDLR deficient mice attenuates aortic valve calcification

Que – Nature 2018

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

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

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 of calcification has not been well defined

We analyzed a pooled cohort of 2 prospective studies

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

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

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

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

Multivariate Cox regressionEvent free survival

Lp(a) induces osteogenic differentiation in VICs through OxPL

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

18F-NaF uptake is increased in first degree relatives

Perrot – JAMA Cardio, in press

Circ Res 2019

Acknowledgements