Main findings are as follows: 1) AIS patients with a high level of cumulative ox-LDL exposure (tertile 3) had poor functional prognosis at 90 days; 2) cumulative ox-LDL exposure was significantly correlated with neurological impairment at admission and acute cerebral infarct volumes; 3) compared with cumulative LDL exposure, cumulative ox-LDL exposure was more accurate on predicting the prognosis of AIS.
In 2018, the American College of Cardiology proposed a new concept: cumulative LDL exposure. They suggested that a person’s total atherosclerotic plaque load can be roughly estimated by multiplying age by LDL concentration, defined as cumulative LDL exposure [14]. As the main modification form of LDL, ox-LDL acts as a more direct and important mechanism in atherosclerosis, associated with various atherosclerotic diseases including coronary heart disease, stroke, diabetes, and so on [8]. Clinical researches have shown that a high ox-LDL level in the acute stage is relevant to a poor 90-day clinical prognosis of stroke [21]. Considering the level fluctuation of ox-LDL, our previous research has found that a significant decrease in ox-LDL is also related to favorable function outcomes of stroke [13]. However, the effect of cumulative ox-LDL exposure on AIS prognosis has not been studied. Our study found that AIS patients with high cumulative ox-LDL exposure had a poor functional prognosis at 90 days. The OR adjusted by multivariate logistic regression analysis was 9.92 (95%CI, 1.23–79.76, p = 0.031). These results suggested that high cumulative ox-LDL exposure is an independent risk factor for AIS. Cumulative ox-LDL exposure can estimate the degree of atherosclerosis more accurately by combining concentration and exposure duration of ox-LDL. Therefore, cumulative ox-LDL exposure may be helpful for neurologists to screen out high-risk populations and judge the prognosis of AIS patients, thus guiding clinical diagnosis and treatment better.
Impairing the blood-brain barrier and promoting thrombosis are possible mechanisms of cumulative ox-LDL exposure in AIS. ox-LDL impairs the blood-brain barrier directly or indirectly. Firstly, ox-LDL can damage endothelial cell structural integrity after being engulfed. On the one hand, ox-LDL induces the damage of endothelial cells through oxidative stress, inflammation, and endoplasmic reticulum stress[22]. On the other hand, ox-LDL destroys the critical structures on the surface of endothelial cells that maintain the integrity of the blood-brain barrier, such as glycocalyx[23]. Moreover, ox-LDL can stimulate endothelial cells to transform into interstitial-like cells[22]. These factors cause the endothelial cells to lose their original cellular characteristics, thus promoting the instability of Lipid plaques. Secondly, ox-LDL influences the function of eNOS, resulting in the reduction of NO and the increase of superoxide anions. As a result, the vasodilation function is impaired, as well as the aggravation of intravascular inflammation [24, 25]. Thirdly, ox-LDL can induce leukocytes to adhere to endothelial cells, mainly macrophages and T cells [26]. As macrophages release inflammatory factors and proteolytic enzymes, the vascular matrix is degraded, which also leads to the instability of lipid plaques. Through LOX-1, ox-LDL participates in platelet adhesion to endothelial cells as well. Subsequently, activated platelets release chemokines mediating endothelial dysfunction, foam cell formation, and ROS production[27, 28]. This mechanism further promotes the progress of atherosclerosis. In addition, long-term exposure to a high concentration of ox-LDL also promotes the progress of hypertension [29, 30] and diabetes [31, 32], which are closely related to AIS.
Atherosclerosis is a complex chronic pathological process. The long-term effect of these ox-LDL-related mechanisms makes atherosclerosis enter vicious circles, eventually leading to the occurrence of AIS and further impacting the recovery of patients.
Some limitations have to be mentioned. Firstly, this is a single-center research with a relatively small sample size. Thus, this study may lake of strong representation. Secondly, the cumulative ox-LDL exposure we used here ignores ox-LDL fluctuation. It is necessary to regularly measure ox-LDL levels to evaluate the progress of atherosclerosis and the risk of cerebrovascular diseases. Thirdly, we did not consider genetic factors, whose role in AIS should not be underestimated [33].