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Multicenter Study
. 2021 Dec 1;6(12):1406-1413.
doi: 10.1001/jamacardio.2021.3508.

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

Yiyi Zhang  1 , Mark J Pletcher  2 , Eric Vittinghoff  2 , Autumn M Clemons  3 , David R Jacobs Jr  4 , Norrina B Allen  5 , Alvaro Alonso  6 , Brandon K Bellows  1 , Elizabeth C Oelsner  1 , Adina Zeki Al Hazzouri  3 , Dhruv S Kazi  7 , Sarah D de Ferranti  8 , Andrew E Moran  1
Affiliations
Multicenter Study

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

Yiyi Zhang et al. JAMA Cardiol. .

Abstract

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Pletcher reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Vittinghoff reported receiving salary support from the NIH during the conduct of the study. Dr Allen reported receiving grants from the NIH and the American Heart Association outside the submitted work. Dr de Ferranti reported receiving personal fees from UpToDate Online outside the submitted work. Dr Alonso reported grants from NIH during the conduct of the study. Dr Oelsner reported grants from NIH during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Associations of Cumulative Low-Density Lipoprotein Cholesterol (LDL-C), Time-Weighted Average (TWA) LDL-C, and LDL-C Slope During Young Adulthood and Middle Age With Incident Coronary Heart Disease (CHD)
Models were stratified by study cohort and adjusted for race and ethnicity, sex, birth year, body mass index, smoking status, high-density lipoprotein cholesterol level, systolic blood pressure, diastolic blood pressure, diabetes status, use of lipid-lowering and antihypertensive medications, and LDL-C levels at the index visit. HR indicates hazard ratio; Q, quartile.
Figure 2.
Figure 2.. Associations of Cumulative Low-Density Lipoprotein Cholesterol (LDL-C), Time-Weighted Average (TWA) LDL-C, and LDL-C Slope During Young Adulthood and Middle Age With Incident Ischemic Stroke
Models were stratified by study cohort and adjusted for race and ethnicity, sex, birth year, body mass index, smoking status, high-density lipoprotein cholesterol level, systolic blood pressure, diastolic blood pressure, diabetes status, use of lipid-lowering and antihypertensive medications, and LDL-C levels at the index visit. HR indicates hazard ratio; Q, quartile.
Figure 3.
Figure 3.. Associations of Cumulative Low-Density Lipoprotein Cholesterol (LDL-C), Time-Weighted Average (TWA) LDL-C, and LDL-C Slope During Young Adulthood and Middle Age With Incident Heart Failure (HF)
Models were stratified by study cohort and adjusted for race and ethnicity, sex, birth year, body mass index, smoking status, high-density lipoprotein cholesterol level, systolic blood pressure, diastolic blood pressure, diabetes status, use of lipid-lowering and antihypertensive medications, and LDL-C levels at the index visit. HR indicates hazard ratio; Q, quartile.
Figure 4.
Figure 4.. Adjusted Hazard Ratios (HRs) for Coronary Heart Disease (CHD) by Levels of Cumulative Low-Density Lipoprotein Cholesterol (LDL-C), Time-Weighted Average (TWA) LDL-C, and LDL-C Slope During Young Adulthood and Middle Age
The solid curve represents the adjusted HR for CHD associated with restricted cubic splines for cumulative LDL-C, TWA LDL-C, and LDL-C slope. Shaded areas represent 95% CIs. The reference values (diamond dots) were set at 4000 mg/dL × years for cumulative LDL-C, 100 mg/dL for TWA LDL-C, and 0 mg/dL/y for LDL-C slope. Models were stratified by study cohort and adjusted for race and ethnicity, sex, birth year, body mass index, smoking status, high-density lipoprotein cholesterol level, systolic blood pressure, diastolic blood pressure, diabetes status, and use of lipid-lowering and antihypertensive medications.
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