TY - JOUR
T1 - Small dense low-density lipoprotein cholesterol is the most atherogenic lipoprotein parameter in the prospective framingham offspring study
AU - Ikezaki, Hiroaki
AU - Lim, Elise
AU - Adrienne Cupples, L.
AU - Liu, Ching Ti
AU - Asztalos, Bela F.
AU - Schaefer, Ernst J.
N1 - Funding Information:
We dedicate this article to the memory of Dr Donald M. Small, former professor and chairman of the Department of Physiology and Biophysics, Boston University School of Medicine, who collaborated with us in our studies of low-density lipoprotein subfraction composition and made major contributions to plasma lipoprotein and bile acid physiology. He died January 25, 2019, at the age of 87 years. The authors thank Katalin V. Horvath for technical assistance; Drs Yasuki Ito and Asako Machida, of the Denka Corporation, Niigata, Japan, for developing and providing the research assays for this study; and Dr Margaret R. Diffenderfer, of Tufts University, for assistance in manuscript preparation.Dr Ikezaki was supported by research grants from the Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad Program, Tokyo, Japan, and from the Denka Corporation, Niigata, Japan, to the Dyslipidemia Foundation of Boston, MA. The statistical consultation and analysis performed by Drs Lim, Liu, and Cupples was supported in part by a grant from the Denka Corporation to the Dyslipidemia Foundation. Drs Lim, Liu, Cupples, and the FOS were supported by National Institutes of Health (NIH) grant National Heart, Lung, and Blood Institute N01-HC 25195 and HHSN268201500001I. Drs Asztalos and Schaefer were supported by the United States Department of Agriculture–Agricultural Research Service Specific Cooperative Agreements 58-1950-0-014 and 58-1950-4-003 and by NIH grants P50 HL083813-01 and HL117933. The sponsors had no role in the data analysis or interpretation of this study. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of Tufts University, Kyushu University, Boston University, the NIH, the United States Department of Agriculture Research Service, or the Denka Corporation.
Funding Information:
Dr Ikezaki was supported by research grants from the Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad Program, Tokyo, Japan, and from the Denka Corporation, Niigata, Japan, to the Dyslipidemia Foundation of Boston, MA. The statistical consultation and analysis performed by Drs Lim, Liu, and Cupples was supported in part by a grant from the Denka Corporation to the Dyslipidemia Foundation. Drs Lim, Liu, Cupples, and the FOS were supported by National Institutes of Health (NIH) grant National Heart, Lung, and Blood Institute N01-HC 25195 and HHSN268201500001I. Drs Asztalos and Schaefer were supported by the United States Department of Agriculture–Agricultural Research Service Specific Cooperative Agreements 58-1950-0-014 and 58-1950-4-003 and by NIH grants P50 HL083813-01 and HL117933. The sponsors had no role in the data analysis or interpretation of this study. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of Tufts University, Kyushu University, Boston University, the NIH, the United States Department of Agriculture Research Service, or the Denka Corporation.
Publisher Copyright:
© 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
PY - 2021
Y1 - 2021
N2 - BACKGROUND: Elevated plasma levels of direct low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C), low-density lipoprotein (LDL) triglycerides, triglycerides, triglyceride-rich lipoprotein cholesterol, remnant lipoprotein particle cho-lesterol, and lipoprotein(a) have all been associated with incident atherosclerotic cardiovascular disease (ASCVD). Our goal was to assess which parameters were most strongly associated with ASCVD risk. METHODS AND RESULTS: Plasma total cholesterol, triglycerides, high-density lipoprotein cholesterol, direct LDL-C, sdLDL-C, LDL triglycerides, remnant lipoprotein particle cholesterol, triglyceride-rich lipoprotein cholesterol, and lipoprotein(a) were measured using standardized automated analysis (coefficients of variation, <5.0%) in samples from 3094 fasting subjects free of ASCVD. Of these subjects, 20.2% developed ASCVD over 16 years. On univariate analysis, all ASCVD risk factors were significantly associated with incident ASCVD, as well as the following specialized lipoprotein parameters: sdLDL-C, LDL triglyc-erides, triglycerides, triglyceride-rich lipoprotein cholesterol, remnant lipoprotein particle cholesterol, and direct LDL-C. Only sdLDL-C, direct LDL-C, and lipoprotein(a) were significant on multivariate analysis and net reclassification after adjustment for standard risk factors (age, sex, hypertension, diabetes mellitus, smoking, total cholesterol, and high-density lipoprotein cho-lesterol). Using the pooled cohort equation, many specialized lipoprotein parameters individually added significant information, but no parameter added significant information once sdLDL-C (hazard ratio, 1.42; P<0.0001) was in the model. These results for sdLDL-C were confirmed by adjusted discordance analysis versus calculated non–high-density lipoprotein cholesterol, in contrast to LDL triglycerides. CONCLUSIONS: sdLDL-C, direct LDL-C, and lipoprotein(a) all contributed significantly to ASCVD risk on multivariate analysis, but no parameter added significant risk information to the pooled cohort equation once sdLDL-C was in the model. Our data indicate that small dense LDL is the most atherogenic lipoprotein parameter.
AB - BACKGROUND: Elevated plasma levels of direct low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C), low-density lipoprotein (LDL) triglycerides, triglycerides, triglyceride-rich lipoprotein cholesterol, remnant lipoprotein particle cho-lesterol, and lipoprotein(a) have all been associated with incident atherosclerotic cardiovascular disease (ASCVD). Our goal was to assess which parameters were most strongly associated with ASCVD risk. METHODS AND RESULTS: Plasma total cholesterol, triglycerides, high-density lipoprotein cholesterol, direct LDL-C, sdLDL-C, LDL triglycerides, remnant lipoprotein particle cholesterol, triglyceride-rich lipoprotein cholesterol, and lipoprotein(a) were measured using standardized automated analysis (coefficients of variation, <5.0%) in samples from 3094 fasting subjects free of ASCVD. Of these subjects, 20.2% developed ASCVD over 16 years. On univariate analysis, all ASCVD risk factors were significantly associated with incident ASCVD, as well as the following specialized lipoprotein parameters: sdLDL-C, LDL triglyc-erides, triglycerides, triglyceride-rich lipoprotein cholesterol, remnant lipoprotein particle cholesterol, and direct LDL-C. Only sdLDL-C, direct LDL-C, and lipoprotein(a) were significant on multivariate analysis and net reclassification after adjustment for standard risk factors (age, sex, hypertension, diabetes mellitus, smoking, total cholesterol, and high-density lipoprotein cho-lesterol). Using the pooled cohort equation, many specialized lipoprotein parameters individually added significant information, but no parameter added significant information once sdLDL-C (hazard ratio, 1.42; P<0.0001) was in the model. These results for sdLDL-C were confirmed by adjusted discordance analysis versus calculated non–high-density lipoprotein cholesterol, in contrast to LDL triglycerides. CONCLUSIONS: sdLDL-C, direct LDL-C, and lipoprotein(a) all contributed significantly to ASCVD risk on multivariate analysis, but no parameter added significant risk information to the pooled cohort equation once sdLDL-C was in the model. Our data indicate that small dense LDL is the most atherogenic lipoprotein parameter.
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U2 - 10.1161/JAHA.120.019140
DO - 10.1161/JAHA.120.019140
M3 - Article
C2 - 33586462
AN - SCOPUS:85102537390
SN - 2047-9980
VL - 10
SP - 1
EP - 15
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 5
M1 - e019140
ER -
