Lipoprotein(a) Particle Production as a Determinant of Plasma Lipoprotein(a) Concentration Across Varying Apolipoprotein(a) Isoform Sizes and Background Cholesterol-Lowering Therapy

Dick C. Chan, Gerald F. Watts, Blai Coll, Scott M. Wasserman, Santica M. Marcovina, P. Hugh R. Barrett

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Abstract

Background Elevated lipoprotein(a) (Lp(a)), a low-density lipoprotein-like particle bound to the polymorphic apolipoprotein(a) (apo(a)), may be causal for cardiovascular disease. However, the metabolism of Lp(a) in humans is poorly understood. Methods and Results We investigated the kinetics of Lp(a)-apo(a) and low-density lipoprotein-apoB-100 in 63 normolipidemic men. The fractional catabolic rate ( FCR ) and production rate PR ) were studied. Plasma apo(a) concentration was significantly and inversely associated with apo(a) isoform size ( r=-0.536, P<0.001) and apo(a) FCR ( r=-0.363, P<0.01), and positively with apo(a) PR ( r=0.877, P<0.001). There were no significant associations between the FCR s of apo(a) and low-density lipoprotein-apoB-100. Subjects with smaller apo(a) isoform sizes (≤22 kringle IV repeats) had significantly higher apo(a) PR ( P<0.05) and lower apo(a) FCR ( P<0.01) than those with larger sizes. Plasma apo(a) concentration was significantly associated with apo(a) PR ( r=0.930, P<0.001), but not with FCR ( r=-0.012, P>0.05) in subjects with smaller apo(a) isoform size. In contrast, both apo(a) PR and FCR were significantly associated with plasma apo(a) concentrations ( r=0.744 and -0.389, respectively, P<0.05) in subjects with larger isoforms. In multiple regression analysis, apo(a) PR and apo(a) isoform size were significant predictors of plasma apo(a) concentration independent of low-density lipoprotein-apoB-100 FCR and background therapy with atorvastatin and evolocumab. Conclusions In normolipidemic men, the plasma Lp(a) concentration is predominantly determined by the rate of production of Lp(a) particles, irrespective of apo(a) isoform size and background therapy with a statin and a proprotein convertase subtilisin-kexin type 9 inhibitor. Our findings underscore the importance of therapeutic targeting of the hepatic synthesis and secretion of Lp(a) particles. Lp(a) particle catabolism may only play a modest role in determining Lp(a) concentration in subjects with larger apo(a) isoform size. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 02189837.

Original languageEnglish
Pages (from-to)e011781
JournalJournal of the American Heart Association
Volume8
Issue number7
DOIs
Publication statusPublished - 2 Apr 2019

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Apoprotein(a)
Lipoprotein(a)
Protein Isoforms
Cholesterol
Therapeutics
LDL Lipoproteins
Apolipoprotein B-100
Hydroxymethylglutaryl-CoA Reductase Inhibitors

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@article{6c34dcd4a52e4eed82f943c5a60c1540,
title = "Lipoprotein(a) Particle Production as a Determinant of Plasma Lipoprotein(a) Concentration Across Varying Apolipoprotein(a) Isoform Sizes and Background Cholesterol-Lowering Therapy",
abstract = "Background Elevated lipoprotein(a) (Lp(a)), a low-density lipoprotein-like particle bound to the polymorphic apolipoprotein(a) (apo(a)), may be causal for cardiovascular disease. However, the metabolism of Lp(a) in humans is poorly understood. Methods and Results We investigated the kinetics of Lp(a)-apo(a) and low-density lipoprotein-apoB-100 in 63 normolipidemic men. The fractional catabolic rate ( FCR ) and production rate PR ) were studied. Plasma apo(a) concentration was significantly and inversely associated with apo(a) isoform size ( r=-0.536, P<0.001) and apo(a) FCR ( r=-0.363, P<0.01), and positively with apo(a) PR ( r=0.877, P<0.001). There were no significant associations between the FCR s of apo(a) and low-density lipoprotein-apoB-100. Subjects with smaller apo(a) isoform sizes (≤22 kringle IV repeats) had significantly higher apo(a) PR ( P<0.05) and lower apo(a) FCR ( P<0.01) than those with larger sizes. Plasma apo(a) concentration was significantly associated with apo(a) PR ( r=0.930, P<0.001), but not with FCR ( r=-0.012, P>0.05) in subjects with smaller apo(a) isoform size. In contrast, both apo(a) PR and FCR were significantly associated with plasma apo(a) concentrations ( r=0.744 and -0.389, respectively, P<0.05) in subjects with larger isoforms. In multiple regression analysis, apo(a) PR and apo(a) isoform size were significant predictors of plasma apo(a) concentration independent of low-density lipoprotein-apoB-100 FCR and background therapy with atorvastatin and evolocumab. Conclusions In normolipidemic men, the plasma Lp(a) concentration is predominantly determined by the rate of production of Lp(a) particles, irrespective of apo(a) isoform size and background therapy with a statin and a proprotein convertase subtilisin-kexin type 9 inhibitor. Our findings underscore the importance of therapeutic targeting of the hepatic synthesis and secretion of Lp(a) particles. Lp(a) particle catabolism may only play a modest role in determining Lp(a) concentration in subjects with larger apo(a) isoform size. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 02189837.",
keywords = "apolipoprotein, cardiovascular disease risk factors, cholesterol‐lowering drugs, lipids and lipoprotein metabolism, low‐density lipoprotein",
author = "Chan, {Dick C.} and Watts, {Gerald F.} and Blai Coll and Wasserman, {Scott M.} and Marcovina, {Santica M.} and Barrett, {P. Hugh R.}",
year = "2019",
month = "4",
day = "2",
doi = "10.1161/JAHA.118.011781",
language = "English",
volume = "8",
pages = "e011781",
journal = "Journal of the American Heart Association",
issn = "2047-9980",
publisher = "John Wiley & Sons",
number = "7",

}

TY - JOUR

T1 - Lipoprotein(a) Particle Production as a Determinant of Plasma Lipoprotein(a) Concentration Across Varying Apolipoprotein(a) Isoform Sizes and Background Cholesterol-Lowering Therapy

AU - Chan, Dick C.

AU - Watts, Gerald F.

AU - Coll, Blai

AU - Wasserman, Scott M.

AU - Marcovina, Santica M.

AU - Barrett, P. Hugh R.

PY - 2019/4/2

Y1 - 2019/4/2

N2 - Background Elevated lipoprotein(a) (Lp(a)), a low-density lipoprotein-like particle bound to the polymorphic apolipoprotein(a) (apo(a)), may be causal for cardiovascular disease. However, the metabolism of Lp(a) in humans is poorly understood. Methods and Results We investigated the kinetics of Lp(a)-apo(a) and low-density lipoprotein-apoB-100 in 63 normolipidemic men. The fractional catabolic rate ( FCR ) and production rate PR ) were studied. Plasma apo(a) concentration was significantly and inversely associated with apo(a) isoform size ( r=-0.536, P<0.001) and apo(a) FCR ( r=-0.363, P<0.01), and positively with apo(a) PR ( r=0.877, P<0.001). There were no significant associations between the FCR s of apo(a) and low-density lipoprotein-apoB-100. Subjects with smaller apo(a) isoform sizes (≤22 kringle IV repeats) had significantly higher apo(a) PR ( P<0.05) and lower apo(a) FCR ( P<0.01) than those with larger sizes. Plasma apo(a) concentration was significantly associated with apo(a) PR ( r=0.930, P<0.001), but not with FCR ( r=-0.012, P>0.05) in subjects with smaller apo(a) isoform size. In contrast, both apo(a) PR and FCR were significantly associated with plasma apo(a) concentrations ( r=0.744 and -0.389, respectively, P<0.05) in subjects with larger isoforms. In multiple regression analysis, apo(a) PR and apo(a) isoform size were significant predictors of plasma apo(a) concentration independent of low-density lipoprotein-apoB-100 FCR and background therapy with atorvastatin and evolocumab. Conclusions In normolipidemic men, the plasma Lp(a) concentration is predominantly determined by the rate of production of Lp(a) particles, irrespective of apo(a) isoform size and background therapy with a statin and a proprotein convertase subtilisin-kexin type 9 inhibitor. Our findings underscore the importance of therapeutic targeting of the hepatic synthesis and secretion of Lp(a) particles. Lp(a) particle catabolism may only play a modest role in determining Lp(a) concentration in subjects with larger apo(a) isoform size. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 02189837.

AB - Background Elevated lipoprotein(a) (Lp(a)), a low-density lipoprotein-like particle bound to the polymorphic apolipoprotein(a) (apo(a)), may be causal for cardiovascular disease. However, the metabolism of Lp(a) in humans is poorly understood. Methods and Results We investigated the kinetics of Lp(a)-apo(a) and low-density lipoprotein-apoB-100 in 63 normolipidemic men. The fractional catabolic rate ( FCR ) and production rate PR ) were studied. Plasma apo(a) concentration was significantly and inversely associated with apo(a) isoform size ( r=-0.536, P<0.001) and apo(a) FCR ( r=-0.363, P<0.01), and positively with apo(a) PR ( r=0.877, P<0.001). There were no significant associations between the FCR s of apo(a) and low-density lipoprotein-apoB-100. Subjects with smaller apo(a) isoform sizes (≤22 kringle IV repeats) had significantly higher apo(a) PR ( P<0.05) and lower apo(a) FCR ( P<0.01) than those with larger sizes. Plasma apo(a) concentration was significantly associated with apo(a) PR ( r=0.930, P<0.001), but not with FCR ( r=-0.012, P>0.05) in subjects with smaller apo(a) isoform size. In contrast, both apo(a) PR and FCR were significantly associated with plasma apo(a) concentrations ( r=0.744 and -0.389, respectively, P<0.05) in subjects with larger isoforms. In multiple regression analysis, apo(a) PR and apo(a) isoform size were significant predictors of plasma apo(a) concentration independent of low-density lipoprotein-apoB-100 FCR and background therapy with atorvastatin and evolocumab. Conclusions In normolipidemic men, the plasma Lp(a) concentration is predominantly determined by the rate of production of Lp(a) particles, irrespective of apo(a) isoform size and background therapy with a statin and a proprotein convertase subtilisin-kexin type 9 inhibitor. Our findings underscore the importance of therapeutic targeting of the hepatic synthesis and secretion of Lp(a) particles. Lp(a) particle catabolism may only play a modest role in determining Lp(a) concentration in subjects with larger apo(a) isoform size. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 02189837.

KW - apolipoprotein

KW - cardiovascular disease risk factors

KW - cholesterol‐lowering drugs

KW - lipids and lipoprotein metabolism

KW - low‐density lipoprotein

UR - http://www.scopus.com/inward/record.url?scp=85063623114&partnerID=8YFLogxK

U2 - 10.1161/JAHA.118.011781

DO - 10.1161/JAHA.118.011781

M3 - Article

VL - 8

SP - e011781

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

IS - 7

ER -