Cumulative LDL-c exposure earlier in life associated with increased CVD

Time Course of LDL Cholesterol Exposure and Cardiovascular Disease Event Risk

Literature - Domanski MJ, Tian X, Wu CO, et al. - J Am Coll Cardiol 2020;76:1507–16 doi: 10.1016/j.jacc.2020.07.059.

Introduction and methods

Risk burden of LDL-c exposure over time (cumulative risk) can be quantified as calculation of area under the curve relating LDL-c concentration to age (expressed as mg/dL × years). This single risk parameter consisting of LDL-c concentration and exposure duration makes sense, but data-based use of this parameter is not available. Also, it is not clear whether the time course of LDL-c accumulation is important for modulation of CV risk. It is not known whether CV risk depends on whether more of LDL-c is accumulated at earlier vs. later ages prior to the landmark age (e.g. 40 years [1]).

Recent studies exploring long-term exposure to lower LDL-c levels, due to genetic polymorphisms or healthier life style or in primary prevention trials of LDL-c lowering, suggest that accumulated LDL-c concentrations over time is an important risk factor for incident CVD [2-5]. But these studies have unfortunately not fully quantified and explored the age-dependent aspect of this association with LDL-c exposure.

This study assessed whether cumulative exposure to LDL-c over time and the time course of LDL-c concentration were independently associated with risk of CVD events by examining 1) the association of area under the LDL-c concentration versus age curve prior to the specific landmark of 40 years with incident CVD and 2) whether the time course of LDL-c accumulation affected the CVD risk, using data from the Coronary Artery Risk Development on Young Adults (CARDIA) longitudinal study.

The CARDIA study (n=4958, 18-30 years) is a multicenter, longitudinal cohort study that enrolled healthy black and white people from 4 US cities (Birmingham, AL; Oakland, CA; Chicago, IL; Minneapolis, MN) from 1985-1986 (year 0: Y0). The study was designed to have an observation window (18 to 40 years; max. 22 years) for longitudinal measurements of risk exposure and accumulation, and a prediction window (40 to 66 years; max. 26 years) for long-term CV event follow-up. The landmark age was set at 40 years. Median follow-up was 16 years (0.2-26.3 years) after age 40 years.

The primary outcome was a composite of incident CVD events that included non-fatal CHD (MI and ACS), stroke, transient ischemic attack, HF hospitalization, cardiac revascularization, intervention for PAD, or CV death.

Risk models were generated to determine the risk associated with cumulative exposure to LDL-c over time by calculating the area under LDL-c vs. age curve (AUC[18-40y]). The time course of LDL-c exposure was characterized by two ways: estimating the slope of LDL-c vs. age curve from age 18-40 years, or calculating the AUC of LDL-c over the age 18 to 30 years (AUC[18-30y]) and 30 to 40 years (AUC[30-40y]) as the early and late LDL-c exposure measurements, respectively. The relationship between LDL-c risk exposure and CVD events after the age of 40 was assessed in multivariable Cox proportional hazards regression models, adjusted for participants’ sex, race, and other traditional CV risks.

Main results

  • The average cumulative LDL-c exposure before the age of 40 years was AUC[18-40y] 2520.6±577.7 mg/dL × years over 22 years of exposure. Per year, individuals were exposed to an average of 114.6±26.3 mg/dL of LDL-c. Even though the average LDL-c levels of all participants were stable (slope of 0.10±0.53 mg/dL/year) during this period, individual patterns of LDL-c levels varied considerably, ranging from 2.75 to 3.36 mg/dL/year.
  • Stratification by quartiles of AUC[18-40y] LDL-c levels showed that greater cumulative LDL-c exposure was associated with more CVD events after the age of 40 (P<0.0001).
  • The CVD event rates in participants grouped according to median AUC of LDL-c levels (> or ≤) and slope of the LDL-c vs age curve (positive or negative), showed that the risk of an incident event was dependent on the cumulative LDL-c exposure and the time course of LDL-c (P<0.0001).
  • Multivariable models, adjusted for sex and race, showed a significant association with risk of incident CVD event with both single LDL-c concentration measurement at age 40 (P<0.0001) and cumulative LDL-c exposure from age 18 to 40 years (P<0.0001). Nevertheless, the LDL-c concentration at age 40 was not significantly (P=0.42) associated with incident CVD when the model was adjusted for LDL-c AUC[18-40y], indicating that LDL-c AUC[18-40y] LDL-c levels is a better metric to measure cumulative LDL-c exposure.
  • Risk models adjusted for cumulative LDL-c exposure using AUC[18-40y] values, resulted in an decreased CVD risk in participants with increasing LDL-c time course slopes compared to participants with decreased LDL-c time course slopes (HR 0.709 per mg/dL/year, 95% CI: 0.567-0.885, P=0.002).
  • A multivariable model looking at early and late LDL-c time exposures showed that early LDL-c cumulative exposure (AUC[18-30y]) was associated with increased CVD risk (HR 1.279, 95% CI:1.104-1.483, P=0.01), while late LDL-c exposure (AUC[30-40y]) was not associated with CVD risk (HR 0.858, 95% CI: 0.716-1.027, P=0.096).
  • Multivariable Cox regression analysis, additionally adjusted for multiple CV risk factors, for the final CVD risk prediction models, confirmed a significant association with incident CVD events for cumulative LDL-c exposure (P<0.0001) as well as time course of LDL-c (P=0.045).


This study showed that cumulative LDL-c exposure and time course of LDL-c accumulation before the age of 40 were independently associated with incident CVD. More importantly, individuals with accumulated LDL-c levels exposed to this at an earlier age (18-30 years) were at higher risk for a CVD event than those exposed to the same accumulated LDL-c concentration later on in life (30-40 years). These findings highlight the importance of optimal LDL-c levels early In life.


1) Gidding SS, Robinson J. It is now time to focus on risk before age 40. J Am Coll Cardiol 2019;74: 342–5.

2) Cohen JC, Boerwinkle E, Mosley TH Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264–72.

3) Ference BA, Yoo W, Alesh I, et al. Effect of long-term exposure to lower low-density lipoproteincholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol 2012; 60:2631–9.

4) Navar-Boggan AM, Peterson ED, D’Agostino RB Sr., Neely B, Sniderman AD, Pencina MJ. Hyperlipidemia in early adulthood increases long-term risk of coronary heart disease. Circulation 2015;131:451–8.

5) Perak AM, Ning H, de Ferranti SD, Gooding HC, Wilkins JT, Lloyd-Jones DM. Long-term risk of atherosclerotic cardiovascular disease in us adults with the familial hypercholesterolemia phenotype. Circulation 2016;134:9–19.

Find this article online at JACC

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