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 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
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 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 optimal timing is not established Eveborn - Heart 2013
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 Eurostat 2010 • Untreated symptomatic aortic stenosis has a yearly mortality rate >25%! • Only treatment is surgical or transcatheter valve replacement, but optimal timing is not established Danielsen – Int J Car 2014
Why is aortic stenosis important? Cardiovascular Health Study (n=5201) • 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 optimal timing is not established Stewart – JACC 1997
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 optimal timing is not established
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 Carabello – Lancet 2009 transcatheter valve replacement, but optimal timing is not established
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 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 associated with aortic valve disease Gotoh – Am J Cardiol 1995
Pubmed aortic valve AND "lipoprotein(a)" 25 20 Articles 15 10 5 0 1990 1995 2000 2005 2010 2015 2020 Year
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) Thanassoulis - NEJM 2013
Lp(a) levels and LPA polymorphisms associate with incident aortic stenosis across cohorts Copenhagen (n=77.6K); Kamstrup – JACC 2014 GERA cohort (Northern California); Chen – JAMA Cardio 2018 Meta-analysis; Helgadottir – Nature Comm 2018 EPIC-Norfolk (n=17.5K); Arsenault – Circ 2014
Tsimikas – JACC 2017
Oxidized phospholipids may explain the association with AS Kamstrup – ATVB 2017
Autotaxin generates lysoPA to promote aortic valve Plasma autotaxin associated with risk calcification via a NFkB-IL6-BMP2 signaling pathway of AS in patients with CAD Nsaibia – J Intern Med 2016 Bouchareb – Circulation 2015
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 ↑ LDL-C ↑ LDL-C ↑ Lp(a) ↑ Lp(a) ? ✓ ✓ Mechanism ✕ Intervention ? Aikawa – Circulation 2012 1. LDL-C associates with AS incidence, but not disease progression 2. Disease drivers for initation phase may be different from the propagation phase
Lp(a) and OxPL associate with faster disease progression 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 across Lp(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 Change in CT Ca-score progression 18F-NaF uptake Follow-up (1-3 yrs) Change in peak aortic jet velocity 18F-NaF PET/CT - Detects active microcalcification - Predicts disease progression
Higher event rate in patients with ↑ Lp(a) and ↑ OxPL-apoB Event free survival Multivariate Cox regression
Lp(a) induces osteogenic differentiation in VICs through OxPL
18F-NaF uptake is increased in ↑ Lp(a) subjects without established calcification Participant with a low Lp(a) level Participant with a high Lp(a) level (7.8 nmol/L) (256.9 nmol/L) Computed tomography Computed tomography 18F-NaF PET/CT 18F-NaF PET/CT Despres – CJC Open, in press
18F-NaF uptake is increased in first degree relatives Perrot – JAMA Cardio, in press
Circ Res 2019
Acknowledgements
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