The risk of ischemic stroke and hemorrhagic stroke in Chinese adults with low-density lipoprotein cholesterol concentrations < 70 mg/dL

Authors: WU, ZHIJUN - Shanghai University; HUANG, ZHE - Kailuan Hospital; LICHTENSTEIN, ALICE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; CHEN, SHUOHUA - Kailuan Hospital; JIN, YAO - Shanghai Jiaotong University; NA, MUZI - Pennsylvania State University; BAO, LE - Pennsylvania State University; WU, SHOULING - Kailuan Hospital; GAO, XIANG - Pennsylvania State University

Submitted to: BioMed Central (BMC) Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/20/2021
Publication Date: 6/16/2021
Citation: Wu, Z., Huang, Z., Lichtenstein, A.H., Chen, S., Jin, Y., Na, M., Bao, L., Wu, S., Gao, X. 2021. The risk of ischemic stroke and hemorrhagic stroke in Chinese adults with low-density lipoprotein cholesterol concentrations < 70 mg/dL. BioMed Central (BMC) Medicine. 19:142. https://doi.org/10.1186/s12916-021-02014-4.
DOI: https://doi.org/10.1186/s12916-021-02014-4

Interpretive Summary: High concentrations of low density lipoprotein cholesterol (LDL-C) are a major risk factor for cardiovascular diseases (CVD). However, the residual risk of cardiovascular disease (CVD) in individuals with very low LDL-C concentrations (<70mg/dL) remains relatively underexplored. To address this gap machine-learning in the form of survival conditional inference tree (SCTREE) modeling was used to analyze data from the ongoing prospective community-based Chinese Kailuan I study. Determined was the effect of very low LDL-C concentrations on CVD events during the 8.5 year study follow-up period. Only individuals not using lipid-modifying drugs were included in the analyses. The findings were validated using data from the Kailuan II study. In the Kailuan I study the top hierarchical predictors of CVD events were poorly-controlled blood pressure and blood glucose concentrations, very low LDL-C concentrations, and older age. In the validation Kailuan II study, those individuals in the highest-risk group, defined as having 2 or more of the top predictors identified in the Kailuan I study, had a significantly higher CVD event rate than those with less than 2 risk factors. These data suggestions that individuals with very low LDL-C concentrations may be at elevated risk of CVD morbidity and mortality if they have other risk factors; older age, and poorly-controlled blood pressure and blood glucose concentrations.

Technical Abstract: Background: The risk of stroke in individuals with very low low-density lipoprotein cholesterol (LDL-C) concentrations remains high. We sought to prioritize predictive risk factors for stroke in Chinese participants with LDL-C concentrations < 70 mg/dL using a survival conditional inference tree, a machine learning method. Methods: The training dataset included 9327 individuals with LDL-C concentrations < 70 mg/dL who were free of cardiovascular diseases and did not use lipid-modifying drugs from the Kailuan I study (N = 101,510). We examined the validity of this algorithm in a second Chinese cohort of 1753 participants with LDL-C concentrations < 70 mg/dL from the Kailuan II study (N = 35,856). Results: During a mean 8.5-9.0-year follow-up period, we identified 388 ischemic stroke cases and 145 hemorrhagic stroke cases in the training dataset and 20 ischemic stroke cases and 8 hemorrhagic stroke cases in the validation dataset. Of 15 examined predictors, poorly controlled blood pressure and very low LDL-C concentrations (= 40 mg/dL) were the top hierarchical predictors of both ischemic stroke risk and hemorrhagic stroke risk. The groups, characterized by the presence of 2-3 of aforementioned risk factors, were associated with a higher risk of ischemic stroke (hazard ratio (HR) 7.03; 95% confidence interval (CI) 5.01-9.85 in the training dataset; HR 4.68, 95%CI 1.58-13.9 in the validation dataset) and hemorrhagic stroke (HR 3.94, 95%CI 2.54-6.11 in the training dataset; HR 4.73, 95%CI 0.81-27.6 in the validation dataset), relative to the lowest risk groups (presence of 0-1 of these factors). There was a linear association between cumulative average LDL-C concentrations and stroke risk. LDL-C concentrations = 40 mg/dL was significantly associated with increased risk of ischemic stroke (HR 2.07, 95%CI 1.53, 2.80) and hemorrhagic stroke (HR 2.70, 95%CI 1.70, 4.30) compared to LDL-C concentrations of 55-70 mg/dL, after adjustment for age, hypertension status, and other covariates. Conclusion: Individuals with extremely low LDL-C concentrations without previous lipid-modifying treatment could still be at high stroke risk.