Atherosclerotic cardiovascular disease risk and small dense low-density lipoprotein cholesterol in men, women, African Americans and non-African Americans: The pooling project

Ernst J. Schaefer, Hiroaki Ikezaki, Margaret R. Diffenderfer, Elise Lim, Ching Ti Liu, Ron C. Hoogeveen, Weihua Guan, Michael Y. Tsai, Christie M. Ballantyne

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Background and aims: Elevated small dense low-density lipoprotein-cholesterol (sdLDL-C) has been reported to be associated with increased atherosclerotic cardiovascular disease (ASCVD) risk. Our aims were to determine whether direct and calculated sdLDL-C were significant independent ASCVD risk factors in sex and race subgroups. Methods: In a total of 15,933 participants free of ASCVD at baseline (median age 62 years, 56.7% female, 19.7% African American) fasting plasma lipids and sdLDL-C were measured by standardized automated methods. All subjects were followed for 10 years for incident ASCVD, which developed in 9.7% of subjects. SdLDL-C values were also calculated. Univariate and multivariate analyses were carried out to assess for independent associations with incident ASCVD after adjustment for all standard risk factors. Results: All standard risk factors were significantly associated with incident ASCVD on univariate analysis, as were direct and calculated sdLDL-C. These latter parameters were also significant when added to the pooled cohort risk equation. However, associations were significantly stronger for direct sdLDL-C and were not significant for calculated values once direct values were in the model. In contrast to calculated values, top quartile direct sdLDL-C was significantly independently associated with incident ASCVD versus bottom quartile values in all subjects and subgroups, except African Americans (hazard ratios ≥1.50, p < 0.01). Subjects with direct values ≥ 50 mg/dL versus <25 mg/dL had significantly higher independent ASCVD risk in all groups (hazard ratios >1.49, all p < 0.01). Conclusions: Having a direct small dense low-density lipoprotein cholesterol value ≥ 50 mg/dL is a significant independent ASCVD risk-enhancer.

Original languageEnglish (US)
Pages (from-to)15-23
Number of pages9
JournalAtherosclerosis
Volume367
DOIs
StatePublished - Feb 2023

Bibliographical note

Funding Information:
EJS was supported by the U.S. Department of Agriculture – Agricultural Research Service Specific Cooperative Agreements #58-1950-0-014 and #58-1950-4-003 and by grants P50 HL083813-01 and HL117933 from the National Institutes of Health . HI was supported by research grants from the Japan Heart Foundation / Bayer Yakuhin Research Grant Abroad Program , Tokyo, Japan, and from the Denka Corporation, Tokyo, Japan to the Dyslipidemia Foundation of Boston, MA. The statistical consultation and analysis was carried out by EL and C-TL and was supported in part by a grant from the Denka Corporation to the Dyslipidemia Foundation . EL, C-TL, and the Framingham Offspring Study were supported by contracts NHLBI N01-HC 25195 and HHSN268201500001I from the National Institutes of Health . MYT, WG, and the Multi-Ethnic Study of Atherosclerosis were supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the National Institutes of Health , National Heart, Lung, and Blood Institute , and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS) . CMB, RCH, and the Atherosclerosis Risk in Communities Study were supported by contract HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, and HHSN268201700004I from the National Institutes of Health .

Funding Information:
Our study supports prior reports from Japan, the United States, and Denmark that elevated direct sdLDL-C is significantly related to prospective ASCVD and CHD risk [ 24–32]. Moreover, our findings extend prior conclusions to indicate that sdLDL-C provides additional information about ASCVD risk even after controlling for all risk factors, including HDL-C, total cholesterol, and cholesterol-lowering medication [32]. We observed that the direct sdLDL-C relationship with ASCVD risk was incremental, increasing with each quartile of direct sdLDL-C concentration. We also documented the significance of direct sdLDL-C as an ASCVD risk factor using univariate analysis and using multivariate analysis after adjustment for the PCE or after adjustment for all other risk factors using either quartile or cutpoint analysis. These results indicate that direct sdLDL-C is a significant independent risk-enhancer for ASCVD. Importantly for the clinician, our data indicate that a direct sdLDL-C value ≥ 50 mg/dL is a significant risk-enhancer for ASCVD after controlling for all standard risk factors. It is well known that the five criteria used for the metabolic syndrome (diabetes, hypertension, hypertriglyceridemia, elevated body mass index, and low HDL-C) are all correlated with one another and with direct sdLDL-C. However, in our analyses, diabetes, hypertension, low HDL-C, and elevated sdLDL-C were all independent ASCVD risk factors; but this was not the case for TG.EJS was supported by the U.S. Department of Agriculture – Agricultural Research Service Specific Cooperative Agreements #58-1950-0-014 and #58-1950-4-003 and by grants P50 HL083813-01 and HL117933 from the National Institutes of Health. HI was supported by research grants from the Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad Program, Tokyo, Japan, and from the Denka Corporation, Tokyo, Japan to the Dyslipidemia Foundation of Boston, MA. The statistical consultation and analysis was carried out by EL and C-TL and was supported in part by a grant from the Denka Corporation to the Dyslipidemia Foundation. EL, C-TL, and the Framingham Offspring Study were supported by contracts NHLBI N01-HC 25195 and HHSN268201500001I from the National Institutes of Health. MYT, WG, and the Multi-Ethnic Study of Atherosclerosis were supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the National Institutes of Health, National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). CMB, RCH, and the Atherosclerosis Risk in Communities Study were supported by contract HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, and HHSN268201700004I from the National Institutes of Health.

Publisher Copyright:
© 2023 The Authors

Keywords

  • Atherosclerotic cardiovascular disease
  • Pooled cohort equation
  • sdLDL cholesterol

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