LDL-c not associated with future ASCVD in absence of coronary atherosclerosis at middle age

Low-Density Lipoprotein Cholesterol Is Predominantly Associated With Atherosclerotic Cardiovascular Disease Events in Patients With Evidence of Coronary Atherosclerosis: The Western Denmark Heart Registry

Literature - Mortensen MB, Dzaye O, Bøtker HE, et al. - Circulation. 2023 Jan 9 [Online ahead of print]. doi: 10.1161/CIRCULATIONAHA.122.061010

Introduction and methods


A significant proportion of patients with elevated LDL-c levels have no evidence of coronary atherosclerosis at middle age [1-4], nor do they develop ASCVD at old age [5-9]. This indicates that some patients may be resilient to the detrimental effects of LDL-c.

Aim of the study

The authors evaluated the association of LDL-c levels with future MI and ASCVD events in patients with and without coronary atherosclerosis, defined as the presence or absence of coronary artery calcification (CAC).


In this prospective observational cohort study, data from 23,132 consecutive symptomatic patients (median age: 57 years; IQR: 50–62) evaluated for coronary artery disease (CAD) using coronary CT angiography (CTA) were collected from the Western Denmark Heart Registry, a seminational, multicenter-based registry. Exclusion criteria were known CAD or a missing LDL-c or CTA measurement at baseline. Clinical outcomes were identified through linkage among national registries covering all hospitals in Denmark. Associations were adjusted for age, sex, DM, hypertension, Charlson Comorbidity Index score, smoking status, and statin use at baseline. Median follow-up time was 4.3 years (IQR: 2.4–6.1)

The authors validated their findings in the Multi-Ethnic Study of Atherosclerosis, an American prospective cohort enrolling participants with no known ASCVD that included baseline CAC scans and long-term follow-up for clinical ASCVD events.


The 2 clinical outcomes were MI and a composite ASCVD outcome, which consisted of fatal and nonfatal MI or ischemic stroke.

Main results

  • For each 38.7 mg/dL–increase in LDL-c level, the multivariable adjusted HR (aHR) for MI events was 1.28 (95%CI: 1.13–1.44) and for ASCVD events 1.14 (95%CI: 1.04–1.24).
  • When stratified by the presence or absence of baseline CAC, the LDL-c level was also associated with the occurrence of MI events (aHR: 1.30; 95%CI: 1.14–1.49) and ASCVD events (aHR: 1.18; 95%CI: 1.06–1.31) in the 10,792 patients with CAC (47%). However, no association was observed among the 12,340 patients without CAC (53%) between the LDL-c level and future MI events (aHR: 1.13; 95%CI: 0.90–1.40) or ASCVD events (aHR: 1.02; 95%CI: 0.87–1.18).
  • Similarly, a very high LDL-c level (>193 mg/dL) versus the generally recommended LDL-c level (<116 mg/dL) was associated with MI events (aHR: 3.53; 95%CI: 2.11–5.92) and ASCVD events (aHR: 2.42; 95%CI: 1.59–3.67) in patients with CAC but not in those without CAC.
  • In the overall population and in patients with CAC, all traditional risk factors (age, sex, DM, hypertension, current smoking, and low HDL-c level) were independently associated with future MI or ASCVD events. In patients without CAC, age, DM, current smoking, and HDL-c levels were also related to ASCVD events, while only current smoking was associated with MI events.
  • Sensitivity analyses and external validation in the Multi-Ethnic Study of Atherosclerosis (median age: 62 years; median follow-up duration: 16.6 years) yielded similar results.


In a large, real-world, Danish cohort of middle-aged individuals with symptoms of CAD, LDL-c levels were associated with both MI and ASCVD events (MI or ischemic stroke) over approximately 4 years of follow-up in the overall population and in patients with CTA evidence of coronary atherosclerosis at baseline but not in those without CAC. The authors believer their “results challenge the general assumption that LDL-c provides consistent and universal increases in risk throughout different patient populations. Instead, other risk factors such as current smoking, diabetes, and [a] low HDL-c level seem to be more important for near-term risk in middle-aged individuals without coronary atherosclerosis.”


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Find this article online at Circulation.

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