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Original Investigation
September 22, 2021

Association Between Cumulative Low-Density Lipoprotein Cholesterol Exposure During Young Adulthood and Middle Age and Risk of Cardiovascular Events

Author Affiliations
  • 1Division of General Medicine, Columbia University Medical Center, New York, New York
  • 2Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, San Francisco
  • 3Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York
  • 4Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis
  • 5Department of Preventive Medicine, Northwestern University, Chicago, Illinois
  • 6Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
  • 7Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 8Department of Cardiology, Boston Children’s Hospital, Boston, Massachusetts
JAMA Cardiol. Published online September 22, 2021. doi:10.1001/jamacardio.2021.3508
Key Points

Question  Is cumulative exposure to low-density lipoprotein cholesterol (LDL-C) during young adulthood and middle age a stronger risk factor of future cardiovascular disease risk than LDL-C level at middle age?

Findings  In this cohort study of 18 288 participants in 4 US cohorts, cumulative LDL-C exposure during young adulthood and middle age was associated with the risk of incident coronary heart disease events, independent of midlife LDL-C level.

Meaning  The findings suggest that maintaining an optimal level of LDL-C throughout young adulthood and middle age can minimize the lifetime risk for atherosclerotic cardiovascular disease; understanding young adult levels of LDL-C may help inform strategies for preventing coronary heart disease.


Importance  Low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease (CVD). Most observational studies on the association between LDL-C and CVD have focused on LDL-C level at a single time point (usually in middle or older age), and few studies have characterized long-term exposures to LDL-C and their role in CVD risk.

Objective  To evaluate the associations of cumulative exposure to LDL-C, time-weighted average (TWA) LDL-C, and the LDL-C slope change during young adulthood and middle age with incident CVD later in life.

Design, Setting, and Participants  This cohort study analyzed pooled data from 4 prospective cohort studies in the US (Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Framingham Heart Study Offspring Cohort, and Multi-Ethnic Study of Atherosclerosis). Participants were included if they had 2 or more LDL-C measures that were at least 2 years apart between ages 18 and 60 years, with at least 1 of the LDL-C measures occurring during middle age at 40 to 60 years. Data from 1971 to 2017 were collected and analyzed from September 25, 2020, to January 10, 2021.

Exposures  Cumulative exposure to LDL-C, TWA LDL-C, and LDL-C slope from age 18 to 60 years.

Main Outcomes and Measures  Incident coronary heart disease (CHD), ischemic stroke, and heart failure (HF).

Results  A total of 18 288 participants were included in this study. These participants had a mean (SD) age of 56.4 (3.7) years and consisted of 10 309 women (56.4%). During a median follow-up of 16 years, 1165 CHD, 599 ischemic stroke, and 1145 HF events occurred. In multivariable Cox proportional hazards regression models that adjusted for the most recent LDL-C level measured during middle age and for other CVD risk factors, the hazard ratios for CHD were as follows: 1.57 (95% CI, 1.10-2.23; P for trend = .01) for cumulative LDL-C level, 1.69 (95% CI, 1.23-2.31; P for trend <.001) for TWA LDL-C level, and 0.88 (95% CI, 0.69-1.12; P for trend = .28) for LDL-C slope. No association was found between any of the LDL-C variables and ischemic stroke or HF.

Conclusions and Relevance  This cohort study showed that cumulative LDL-C and TWA LDL-C during young adulthood and middle age were associated with the risk of incident CHD, independent of midlife LDL-C level. These findings suggest that past levels of LDL-C may inform strategies for primary prevention of CHD and that maintaining optimal LDL-C levels at an earlier age may reduce the lifetime risk of developing atherosclerotic CVD.

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    1 Comment for this article
    More to be taken into account for imputation and analysis
    Jinyun Chen, Ph.D. | Third Affiliated Hospital of Soochow University
    The CARDIA cohort had 30 years of follow-up, but the median follow-up was 4 years in eTable 3, which seemed to be an error. Secondly, the authors leveraged the risk factor patterns observed in the CARDIA cohort to impute LDL-C values from age 18 years for each participant in the other 3 cohorts. We should caution the decade-difference of birth year among the four cohorts. It may influence their social environment, food, lifestyle, etc, and subsequently their patterns of LDL-C, though they included adjustment for birth year and cohort. Addtionally, MESA included participants aged 45 to 84 years without CVD, who had to survive until cohort entry. So they may be somewhat atypical of the younger adult populations they are taken to represent (PMID: 30535320). Lastly, menopause should be taken into account as a confounder, since the study showed us the importance of duration and its influence on CHD.