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Relative effects of LDL-C on ischemic stroke and coronary disease: A Mendelian randomization study
Elsa Valdes-Marquez1, Sarah Parish1, Robert Clarke1
1From the Clinical Trial Service Unit and Epidemiological Studies Unit (E.V.-M., S.P., R.C., T.S., J.C.H.) and MRC Population Health Research Unit (S.P.), Nuffield Department of Population Health, University of Oxford, UK; and Departments of Neurology and Public Health Sciences (B.B.W.), University of Virginia School of Medicine, Charlottesville, VA.
Insights
Lifelong high low-density lipoprotein cholesterol (LDL-C) significantly increases coronary heart disease (CHD) risk. However, its causal effect on ischemic stroke (IS) is weaker, suggesting distinct IS subtypes influence outcomes.
Area of Science:
- Cardiovascular Genetics
- Epidemiology
- Genetic Epidemiology
Background:
- Low-density lipoprotein cholesterol (LDL-C) is a key risk factor for cardiovascular diseases.
- Understanding the causal relationship between lifelong LDL-C levels and specific cardiovascular outcomes like ischemic stroke (IS) and coronary heart disease (CHD) is crucial for targeted prevention strategies.
Purpose of the Study:
- To investigate the causal relevance of genetically determined lifelong differences in LDL-C for IS compared to CHD risk.
- To explore potential heterogeneity in the association between LDL-C and IS subtypes.
Main Methods:
- A two-sample Mendelian randomization study utilizing summary statistics.
- Employed 62 independent genetic variants strongly associated with LDL-C levels.
- Estimated causal effects of LDL-C on IS (12,389 cases) and CHD (60,801 cases), including IS subtypes.
Main Results:
- A 1 mmol/L increase in genetically predicted LDL-C was associated with a 49% higher risk of CHD (OR 1.49).
- The association between genetically predicted LDL-C and IS risk was substantially weaker (OR 1.12) and not statistically significant.
- A weaker, non-significant association was observed for cardioembolic stroke (OR 1.06).
Conclusions:
- Lifelong LDL-C differences exert a stronger causal effect on CHD risk than on IS risk.
- The weaker association with IS may be influenced by the etiological heterogeneity of stroke subtypes.
- Findings contrast with the established effects of LDL-C-lowering therapies on both IS and CHD.
Objective:
To examine the causal relevance of lifelong differences in low-density lipoprotein cholesterol (LDL-C) for ischemic stroke (IS) relative to that for coronary heart disease (CHD) using a Mendelian randomization approach.
Methods:
We undertook a 2-sample Mendelian randomization, based on summary data, to estimate the causal relevance of LDL-C for risk of IS and CHD. Information from 62 independent genetic variants with genome-wide significant effects on LDL-C levels was used to estimate the causal effects of LDL-C for IS and IS subtypes (based on 12,389 IS cases from METASTROKE) and for CHD (based on 60,801 cases from CARDIoGRAMplusC4D). We then assessed the effects of LDL-C on IS and CHD for heterogeneity.
Results:
A 1 mmol/L higher genetically determined LDL-C was associated with a 50% higher risk of CHD (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.32-1.68, p = 1.1 × 10-8). By contrast, the causal effect of LDL-C was much weaker for IS (OR 1.12, 95% CI 0.96-1.30, p = 0.14; p for heterogeneity = 2.6 × 10-3) and, in particular, for cardioembolic stroke (OR 1.06, 95% CI 0.84-1.33, p = 0.64; p for heterogeneity = 8.6 × 10-3) when compared with that for CHD.
Conclusions:
In contrast with the consistent effects of LDL-C-lowering therapies on IS and CHD, genetic variants that confer lifelong LDL-C differences show a weaker effect on IS than on CHD. The relevance of etiologically distinct IS subtypes may contribute to the differences observed.
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