Data Management And Sharing System of China National Clinical Research Center for Neurological Diseases

Journal：Journal of the American Heart Association

Publication type: Brief Reports

IF(IF): 6.106

PMID: 36565201 Link To Pubmed Full text Download

Lipoprotein(a) [Lp(a)] was first described in 1963 by Kaare Berg.1 In the past decades, Lp(a) has been recognized as a critical risk factor for cardiovascular disease (CVD)2,3. In recent years, the relationship between increased ischemic stroke risk and Lp(a) concentration has also been proven.4,5 A former retrospective study has proven that elevated Lp(a) levels were associated with a higher risk for combined vascular event recurrence in patients with acute, first-ever ischemic stroke.6 However, to the best of our knowledge, no prior study has specifically addressed whether Lp(a) has an impact on the recurrence of ischemic stroke. Lp(a) is formed by a low-density lipoprotein (LDL)-like particle and the glycoprotein, apolipoprotein(a) [apo(a)], linked to apolipoprotein B in the LDL by a single disulfide bond. For unknown etiological and physiological reasons, apo(a) gene has evolved from the plasminogen gene through duplication and remodeling over the millennia.7 Hence, it suggests that apo(a) can bind to lysine-rich vascular endothelium, similar to and also in competition with plasminogen. Thus, there are loads of in vitro evidence have proven that Lp(a) plays an important role in anti-fibrinolytic8 and pro-thrombotic9 processes. Homocysteine (Hcy) is an intermediate metabolite of methionine that contributes to arterial disease through several mechanisms, such as endothelial dysfunction, vascular inflammation, and abnormalities in the clotting cascade.10 In vitro studies have shown that Hcy enhances the binding of Lp(a) to fibrin by altering fibrinolysis.11 A past study has shown that by reducing the disulfide bonds between apo(a) and apoB-100, Hcy promotes the high-affinity binding of free apo(a) to fibrin, thereby inhibiting the formation of plasmin and blocking the fibrinolytic pathway.12 Nevertheless, only a few studies have evaluated the clinical effect of the biological interaction between Lp(a) and Hcy in the occurrence of coronary artery disease, finding that the associated risk was greater than the 2 risks independently.13,14,15 No prior study has specifically addressed whether this joint effect has an impact on the occurrence or recurrence of ischemic stroke. So based on the above-mentioned evidence, we hypothesize that the effect on stroke recurrence when the 2 risk factors are present simultaneously may exceed that which is expected based on their independent effects alone. And this joint effect may especially show in cardioembolic stroke rather than other ischemic stroke subtypes. We aim to explore the joint effect of Lp(a) and Hcy on stroke recurrence in patients with different TOAST subtypes, especially cardioembolic stroke from the Third China National Stroke Registry (CNSR-III).

Patients with complete baseline information in CNSR3 were classified into 5 groups by TOAST etiology after excluding those with missing baseline information of Lp(a) and Hcy were enrolled. Enrolled patients were classified according cut-off values (CFV) of Lp(a) and fibrinogen into 4 different groups. (Lp(a)CFV + fibrinogenCFV, Lp(a)>CFV + fibrinogen>CFV). The associations of Lp(a) and homocysteine with stroke recurrence were analyzed by Cox proportional hazards model and competing risk model. Variables were adjusted for age, sex, BMI, NIHSS, diabetes, hypertension, coronary artery disease, atrial fibrillation, systemic embolism, congestive heart failure, peripheral artery disease, LDL cholesterol, HDL cholesterol, smoking, antiplatelet drugs, anticoagulant drugs, statin drugs.