Accepted Manuscript Changes in ultracentrifugally separated plasma lipoprotein subfractions in patients with polygenic hypercholesterolemia, familial combined hyperlipoproteinemia, and familial hypercholesterolemia following treatment with atorvastatin Koichiro Homma, Yasuhiko Homma, Tadashi Yoshida, Hideki Ozawa, Yutaka Shiina, Shu Wakino, Koichi Hayashi, Hiroshi Itoh, Shingo Hori PII:
S1933-2874(14)00419-X
DOI:
10.1016/j.jacl.2014.12.007
Reference:
JACL 718
To appear in:
Journal of Clinical Lipidology
Received Date: 7 June 2014 Revised Date:
6 December 2014
Accepted Date: 9 December 2014
Please cite this article as: Homma K, Homma Y, Yoshida T, Ozawa H, Shiina Y, Wakino S, Hayashi K, Itoh H, Hori S, Changes in ultracentrifugally separated plasma lipoprotein subfractions in patients with polygenic hypercholesterolemia, familial combined hyperlipoproteinemia, and familial hypercholesterolemia following treatment with atorvastatin, Journal of Clinical Lipidology (2015), doi: 10.1016/j.jacl.2014.12.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Changes in ultracentrifugally separated plasma lipoprotein subfractions in patients with polygenic hypercholesterolemia, familial combined hyperlipoproteinemia, and familial
RI PT
hypercholesterolemia following treatment with atorvastatin
Koichiro Hommaa,b, Yasuhiko Hommad, Tadashi Yoshidac, Hideki Ozawae, Yutaka Shiinad, Shu
SC
Wakinoa, Koichi Hayashia, Hiroshi Itoha, Shingo Horib
M AN U
Departments of aInternal Medicine, bEmergency Medicine, and cApheresis and Dialysis Center, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan Departments of dClinical Health Science and eInternal Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, Japan
TE D
Short title: Atorvastatin and lipoprotein subfractions
EP
Correspondence: Koichiro Homma, M.D., Ph.D. Department of Internal Medicine, School of Medicine, Keio University
AC C
35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan Tel.: 81-3-5363-3796 Fax: 81-3-3359-2745
E-mail: [email protected]
1
ACCEPTED MANUSCRIPT
Highlights
•
Statins reduce plasma LDL by stimulating hepatic LDL uptake via
•
RI PT
LDL-receptors. It is unclear whether statins equally stimulate uptake of all subfractions via LDL-receptors.
LDL-receptor activity and the decrease in plasma LDL subfractions was studied.
•
Atorvastatin treatment reduced plasma levels of the 3 LDL subfractions.
•
LDL-receptor activity was negatively correlated only with md-LDL decreases.
AC C
EP
TE D
M AN U
SC
•
2
ACCEPTED MANUSCRIPT
Abstract
Background
RI PT
Plasma levels of low-density lipoproteins (LDLs) are decreased through stimulation of their hepatic uptake by statins via an LDL-receptor. However, it is unclear whether statins equally stimulate the hepatic uptake of all LDL subfractions.
SC
Objective
We compared the effects of atorvastatin on 3 LDL subfractions, and their associations with
M AN U
LDL-receptor activities, in Japanese patients with polygenic hypercholesterolemia (PHC), familial combined hyperlipoproteinemia (FCHL), and familial hypercholesterolemia (FH). Materials and Methods
Atorvastatin was administered to patients with PHC (n = 11), FCHL (n = 16), and FH (n = 13). We measured plasma levels of lipids, remnant-like particle cholesterol, apoproteins, and
TE D
cholesterol in lipoprotein fractions. Sequential ultracentrifugation was performed to subfractionate the plasma lipoproteins, and lymphocyte LDL-receptor activities were estimated using flow cytometry.
EP
Results
The average daily dosage of atorvastatin was 10 mg, 27 mg, and 40 mg in patients with PHC,
AC C
FCHL, and FH, respectively; after 12 months of atorvastatin treatment, LDL-cholesterol (LDL-C) plasma levels decreased by 44%, 50%, and 53%, respectively (all, p < 0.0001). Atorvastatin reduced low-density LDL-C plasma levels in patients with PHC (48% reduction), FCHL (53%), and FH (46%) (all, p < 0.0001). Plasma levels of medium-density (md)- and high-density LDL-C were also significantly reduced in the 3 patient groups (all, p ≤ 0.0147). LDL-receptor activity was negatively correlated with baseline levels of md-LDL-C and with the decreases in plasma md-LDL-C levels. Conclusion 3
ACCEPTED MANUSCRIPT
Atorvastatin decreased the levels of the 3 LDL fractions. The md-LDL decrease appeared to be mainly due to stimulation of LDL-receptor activity.
RI PT
Key words: Atorvastatin, Lipoprotein subfractions, LDL-receptor activity, polygenic hypercholesterolemia, hypercholesterolemia, Familial combined hyperlipoproteinemia, Familial
Abbreviations:
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LDL: low-density lipoprotein
M AN U
SC
hypercholesterolemia
FCHL: familial combined hyperlipoproteinemia FH: familial hypercholesterolemia
C: cholesterol
AC C
ld: low density
EP
PHC: polygenic hypercholesterolemia
md: medium density hd: high density
RPL-C: remnant-like particle cholesterol VLDL: very low-density lipoprotein IDL: intermediate density lipoprotein NMR: nuclear magnetic resonance TG: triglyceride 4
ACCEPTED MANUSCRIPT
d: density HDL: high density lipoprotein SD: standard deviation
AC C
EP
TE D
M AN U
SC
RI PT
DM; diabetes mellitus
5
ACCEPTED MANUSCRIPT
Introduction
Numerous large-scale, double-blind, placebo-controlled studies have shown that statins are
RI PT
effective for the primary and secondary prevention of coronary artery and cerebrovascular diseases, primarily by decreasing plasma low-density lipoprotein (LDL) cholesterol (LDL-C) levels. LDL consists of several subfractions (1-7); the levels of the large, less-dense LDLs are elevated in patients with familial hypercholesterolemia (FH), and the small, more-dense LDL
SC
levels are elevated in patients with familial combined hyperlipoproteinemia (FCHL) (8, 9).
M AN U
Small, dense LDLs have also been reported to be more susceptible to oxidation as compared to large, less-dense LDLs (10, 11). The main mechanism of statin-mediated lowering of plasma LDL-C levels involves the stimulation of hepatic LDL uptake by increasing LDL-receptor activity (12, 13). Large, less-dense LDL molecules are reported to have a higher affinity for the
TE D
LDL-receptors as compared to the small, dense LDL molecules (14, 15).
The statin-induced decreases in plasma levels of cholesterol in LDL subfractions are controversial (16-20), and the effects of atorvastatin are not always consistent (16, 19, 20). In
EP
particular, atorvastatin has been reported to decrease the plasma levels of cholesterol in less-dense LDLs (20); cholesterol in the small, dense LDLs (19); and cholesterol in all LDL
AC C
subfractions (16). Ultracentrifugation was the first reported method for separating plasma lipoproteins (21), and in the present study, we used sequential ultracentrifugation to separate the 3 plasma LDL subfractions. In this study, we aimed to compare the effect of atorvastatin on each LDL subfraction in Japanese patients with polygenic hypercholesterolemia (PHC), FCHL, and FH. In addition, we examined the correlation between atorvastatin and lymphocyte LDL-receptor activity.
6
ACCEPTED MANUSCRIPT
Materials and Methods This study was approved by the Ethics Committee of Tokai University Hospital and was started
RI PT
after informed consent was obtained from all the participants.
Patients
Forty Japanese patients were divided into 3 groups, according to their type of dyslipidemia: PHC (n = 11), FCHL (n = 16), and FH (n = 13). Those with PHC had plasma LDL-cholesterol
SC
(C) levels of ≥160 mg/dL and triglyceride (TG) levels of
S1933-2874(14)00419-X
DOI:
10.1016/j.jacl.2014.12.007
Reference:
JACL 718
To appear in:
Journal of Clinical Lipidology
Received Date: 7 June 2014 Revised Date:
6 December 2014
Accepted Date: 9 December 2014
Please cite this article as: Homma K, Homma Y, Yoshida T, Ozawa H, Shiina Y, Wakino S, Hayashi K, Itoh H, Hori S, Changes in ultracentrifugally separated plasma lipoprotein subfractions in patients with polygenic hypercholesterolemia, familial combined hyperlipoproteinemia, and familial hypercholesterolemia following treatment with atorvastatin, Journal of Clinical Lipidology (2015), doi: 10.1016/j.jacl.2014.12.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Changes in ultracentrifugally separated plasma lipoprotein subfractions in patients with polygenic hypercholesterolemia, familial combined hyperlipoproteinemia, and familial
RI PT
hypercholesterolemia following treatment with atorvastatin
Koichiro Hommaa,b, Yasuhiko Hommad, Tadashi Yoshidac, Hideki Ozawae, Yutaka Shiinad, Shu
SC
Wakinoa, Koichi Hayashia, Hiroshi Itoha, Shingo Horib
M AN U
Departments of aInternal Medicine, bEmergency Medicine, and cApheresis and Dialysis Center, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan Departments of dClinical Health Science and eInternal Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, Japan
TE D
Short title: Atorvastatin and lipoprotein subfractions
EP
Correspondence: Koichiro Homma, M.D., Ph.D. Department of Internal Medicine, School of Medicine, Keio University
AC C
35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan Tel.: 81-3-5363-3796 Fax: 81-3-3359-2745
E-mail: [email protected]
1
ACCEPTED MANUSCRIPT
Highlights
•
Statins reduce plasma LDL by stimulating hepatic LDL uptake via
•
RI PT
LDL-receptors. It is unclear whether statins equally stimulate uptake of all subfractions via LDL-receptors.
LDL-receptor activity and the decrease in plasma LDL subfractions was studied.
•
Atorvastatin treatment reduced plasma levels of the 3 LDL subfractions.
•
LDL-receptor activity was negatively correlated only with md-LDL decreases.
AC C
EP
TE D
M AN U
SC
•
2
ACCEPTED MANUSCRIPT
Abstract
Background
RI PT
Plasma levels of low-density lipoproteins (LDLs) are decreased through stimulation of their hepatic uptake by statins via an LDL-receptor. However, it is unclear whether statins equally stimulate the hepatic uptake of all LDL subfractions.
SC
Objective
We compared the effects of atorvastatin on 3 LDL subfractions, and their associations with
M AN U
LDL-receptor activities, in Japanese patients with polygenic hypercholesterolemia (PHC), familial combined hyperlipoproteinemia (FCHL), and familial hypercholesterolemia (FH). Materials and Methods
Atorvastatin was administered to patients with PHC (n = 11), FCHL (n = 16), and FH (n = 13). We measured plasma levels of lipids, remnant-like particle cholesterol, apoproteins, and
TE D
cholesterol in lipoprotein fractions. Sequential ultracentrifugation was performed to subfractionate the plasma lipoproteins, and lymphocyte LDL-receptor activities were estimated using flow cytometry.
EP
Results
The average daily dosage of atorvastatin was 10 mg, 27 mg, and 40 mg in patients with PHC,
AC C
FCHL, and FH, respectively; after 12 months of atorvastatin treatment, LDL-cholesterol (LDL-C) plasma levels decreased by 44%, 50%, and 53%, respectively (all, p < 0.0001). Atorvastatin reduced low-density LDL-C plasma levels in patients with PHC (48% reduction), FCHL (53%), and FH (46%) (all, p < 0.0001). Plasma levels of medium-density (md)- and high-density LDL-C were also significantly reduced in the 3 patient groups (all, p ≤ 0.0147). LDL-receptor activity was negatively correlated with baseline levels of md-LDL-C and with the decreases in plasma md-LDL-C levels. Conclusion 3
ACCEPTED MANUSCRIPT
Atorvastatin decreased the levels of the 3 LDL fractions. The md-LDL decrease appeared to be mainly due to stimulation of LDL-receptor activity.
RI PT
Key words: Atorvastatin, Lipoprotein subfractions, LDL-receptor activity, polygenic hypercholesterolemia, hypercholesterolemia, Familial combined hyperlipoproteinemia, Familial
Abbreviations:
TE D
LDL: low-density lipoprotein
M AN U
SC
hypercholesterolemia
FCHL: familial combined hyperlipoproteinemia FH: familial hypercholesterolemia
C: cholesterol
AC C
ld: low density
EP
PHC: polygenic hypercholesterolemia
md: medium density hd: high density
RPL-C: remnant-like particle cholesterol VLDL: very low-density lipoprotein IDL: intermediate density lipoprotein NMR: nuclear magnetic resonance TG: triglyceride 4
ACCEPTED MANUSCRIPT
d: density HDL: high density lipoprotein SD: standard deviation
AC C
EP
TE D
M AN U
SC
RI PT
DM; diabetes mellitus
5
ACCEPTED MANUSCRIPT
Introduction
Numerous large-scale, double-blind, placebo-controlled studies have shown that statins are
RI PT
effective for the primary and secondary prevention of coronary artery and cerebrovascular diseases, primarily by decreasing plasma low-density lipoprotein (LDL) cholesterol (LDL-C) levels. LDL consists of several subfractions (1-7); the levels of the large, less-dense LDLs are elevated in patients with familial hypercholesterolemia (FH), and the small, more-dense LDL
SC
levels are elevated in patients with familial combined hyperlipoproteinemia (FCHL) (8, 9).
M AN U
Small, dense LDLs have also been reported to be more susceptible to oxidation as compared to large, less-dense LDLs (10, 11). The main mechanism of statin-mediated lowering of plasma LDL-C levels involves the stimulation of hepatic LDL uptake by increasing LDL-receptor activity (12, 13). Large, less-dense LDL molecules are reported to have a higher affinity for the
TE D
LDL-receptors as compared to the small, dense LDL molecules (14, 15).
The statin-induced decreases in plasma levels of cholesterol in LDL subfractions are controversial (16-20), and the effects of atorvastatin are not always consistent (16, 19, 20). In
EP
particular, atorvastatin has been reported to decrease the plasma levels of cholesterol in less-dense LDLs (20); cholesterol in the small, dense LDLs (19); and cholesterol in all LDL
AC C
subfractions (16). Ultracentrifugation was the first reported method for separating plasma lipoproteins (21), and in the present study, we used sequential ultracentrifugation to separate the 3 plasma LDL subfractions. In this study, we aimed to compare the effect of atorvastatin on each LDL subfraction in Japanese patients with polygenic hypercholesterolemia (PHC), FCHL, and FH. In addition, we examined the correlation between atorvastatin and lymphocyte LDL-receptor activity.
6
ACCEPTED MANUSCRIPT
Materials and Methods This study was approved by the Ethics Committee of Tokai University Hospital and was started
RI PT
after informed consent was obtained from all the participants.
Patients
Forty Japanese patients were divided into 3 groups, according to their type of dyslipidemia: PHC (n = 11), FCHL (n = 16), and FH (n = 13). Those with PHC had plasma LDL-cholesterol
SC
(C) levels of ≥160 mg/dL and triglyceride (TG) levels of
