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?
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.
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.
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.
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.
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).
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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Zhang Y, Pletcher MJ, Vittinghoff E, et al. Association Between Cumulative Low-Density Lipoprotein Cholesterol Exposure During Young Adulthood and Middle Age and Risk of Cardiovascular Events. JAMA Cardiol. Published online September 22, 2021. doi:10.1001/jamacardio.2021.3508
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