Anne Langsted1, Børge G Nordestgaard1, Marianne Benn1, Anne Tybjærg-Hansen1, Pia R Kamstrup1. 1. Department of Clinical Biochemistry (A.L., B.G.N., M.B., P.R.K.) and The Copenhagen General Population Study (A.L., B.G.N., M.B., A.T.-H., P.R.K.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark; The Copenhagen City Heart Study (B.G.N., M.B., A.T.-H.), Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Department of Clinical Biochemistry (A.T.-H.), Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences (A.L., B.G.N., A.T.-H., P.R.K.), University of Copenhagen, Copenhagen, Denmark.
Abstract
CONTEXT: Novel, low-density lipoprotein (LDL) cholesterol-lowering proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors also lower lipoprotein(a) levels, but the effect on aortic valve stenosis and myocardial infarction is unknown. OBJECTIVE: We tested the hypothesis that the PCSK9 R46L loss-of-function mutation is associated with lower levels of lipoprotein(a) and with reduced risk of aortic valve stenosis and myocardial infarction. DESIGN: We used two prospective cohort studies of the general population and one patient-based cohort. SETTING:Cohort studies selected at random individuals of Danish descent. PARTICIPANTS: We studied 103 083 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease Study. MAIN OUTCOME MEASURES: Lipoprotein(a), LDL cholesterol, and PCSK9 R46L genotype and diagnoses of aortic valve stenosis and myocardial infarction from national registries; lipoprotein(a) was measured from 49,617 individuals. RESULTS:Median (interquartile range) lipoprotein(a) levels were 10 (5-30) mg/dl for PCSK9 R46L noncarriers, 9 (4-32) mg/dl for heterozygotes, and 8 (4-42) mg/dl for homozygotes (trend P = .02). The corresponding values for LDL cholesterol levels were 124 (101-147) mg/dl, 104 (85-132) mg/dl, and 97 (85-128) mg/dl, respectively (trend P = 2 × 10(-52)). PCSK9 R46L carriers vs noncarriers had an age- and sex-adjusted odds ratio of 0.64 (95% confidence interval, 0.44-0.95) for aortic valve stenosis, 0.77 (0.65-0.92) for myocardial infarction, and 0.76 (0.64-0.89) for aortic valve stenosis or myocardial infarction. CONCLUSIONS:PCSK9 R46L carriers have lower levels of lipoprotein(a) and LDL cholesterol as well as reduced risk of aortic valve stenosis and myocardial infarction. This indirectly suggests that PCSK9 inhibitors may have a role in patients with aortic valve stenosis.
RCT Entities:
CONTEXT: Novel, low-density lipoprotein (LDL) cholesterol-lowering proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors also lower lipoprotein(a) levels, but the effect on aortic valve stenosis and myocardial infarction is unknown. OBJECTIVE: We tested the hypothesis that the PCSK9R46L loss-of-function mutation is associated with lower levels of lipoprotein(a) and with reduced risk of aortic valve stenosis and myocardial infarction. DESIGN: We used two prospective cohort studies of the general population and one patient-based cohort. SETTING: Cohort studies selected at random individuals of Danish descent. PARTICIPANTS: We studied 103 083 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease Study. MAIN OUTCOME MEASURES: Lipoprotein(a), LDL cholesterol, and PCSK9R46L genotype and diagnoses of aortic valve stenosis and myocardial infarction from national registries; lipoprotein(a) was measured from 49,617 individuals. RESULTS: Median (interquartile range) lipoprotein(a) levels were 10 (5-30) mg/dl for PCSK9R46L noncarriers, 9 (4-32) mg/dl for heterozygotes, and 8 (4-42) mg/dl for homozygotes (trend P = .02). The corresponding values for LDL cholesterol levels were 124 (101-147) mg/dl, 104 (85-132) mg/dl, and 97 (85-128) mg/dl, respectively (trend P = 2 × 10(-52)). PCSK9R46L carriers vs noncarriers had an age- and sex-adjusted odds ratio of 0.64 (95% confidence interval, 0.44-0.95) for aortic valve stenosis, 0.77 (0.65-0.92) for myocardial infarction, and 0.76 (0.64-0.89) for aortic valve stenosis or myocardial infarction. CONCLUSIONS:PCSK9R46L carriers have lower levels of lipoprotein(a) and LDL cholesterol as well as reduced risk of aortic valve stenosis and myocardial infarction. This indirectly suggests that PCSK9 inhibitors may have a role in patients with aortic valve stenosis.
Authors: Anastasia Diamantopoulou; Ziyi Sun; Jun Mukai; Bin Xu; Karine Fenelon; Maria Karayiorgou; Joseph A Gogos Journal: Proc Natl Acad Sci U S A Date: 2017-07-10 Impact factor: 11.205
Authors: Sotirios Tsimikas; Sergio Fazio; Keith C Ferdinand; Henry N Ginsberg; Marlys L Koschinsky; Santica M Marcovina; Patrick M Moriarty; Daniel J Rader; Alan T Remaley; Gissette Reyes-Soffer; Raul D Santos; George Thanassoulis; Joseph L Witztum; Simhan Danthi; Michelle Olive; Lijuan Liu Journal: J Am Coll Cardiol Date: 2018-01-16 Impact factor: 24.094
Authors: Matthew T Mefford; Santica M Marcovina; Vera Bittner; Mary Cushman; Todd M Brown; Michael E Farkouh; Sotirios Tsimikas; Keri L Monda; J Antonio G López; Paul Muntner; Robert S Rosenson Journal: J Lipid Res Date: 2019-09-11 Impact factor: 5.922
Authors: Teresa Trenkwalder; Christopher P Nelson; Muntaser D Musameh; Ify R Mordi; Thorsten Kessler; Costanza Pellegrini; Radoslaw Debiec; Tobias Rheude; Viktor Lazovic; Lingyao Zeng; Andreas Martinsson; J Gustav Smith; Jesper R Gådin; Anders Franco-Cereceda; Per Eriksson; Jonas B Nielsen; Sarah E Graham; Cristen J Willer; Kristian Hveem; Adnan Kastrati; Peter S Braund; Colin N A Palmer; Amparo Aracil; Oliver Husser; Wolfgang Koenig; Heribert Schunkert; Chim C Lang; Christian Hengstenberg; Nilesh J Samani Journal: Int J Cardiol Date: 2018-11-17 Impact factor: 4.164
Authors: Brian A Bergmark; Michelle L O'Donoghue; Sabina A Murphy; Julia F Kuder; Marat V Ezhov; Richard Ceška; Ioanna Gouni-Berthold; Henrik K Jensen; S Lale Tokgozoglu; François Mach; Kurt Huber; Zbigniew Gaciong; Basil S Lewis; Francois Schiele; J Wouter Jukema; Terje R Pedersen; Robert P Giugliano; Marc S Sabatine Journal: JAMA Cardiol Date: 2020-06-01 Impact factor: 14.676