Atherothrombotic stroke represents approximately 20% of all ischemic strokes. It is caused by large-artery atherosclerosis, mostly in the internal carotid artery, and it is associated with a high risk of early recurrence. After an ischemic stroke, tissue plasminogen activator is used in clinical practice, although it is not possible in all patients. In severe clinical situations, such as high carotid stenosis (≥70%), revascularization by carotid endarterectomy or by stent placement is carried out to avoid recurrences. In stroke prevention, the pharmacological recommendations are based on antithrombotic, lipid-lowering, and antihypertensive therapy. Inflammation is a promising target in stroke prevention, particularly in ischemic strokes associated with atherosclerosis. However, the use of anti-inflammatory strategies has been scarcely studied. No clinical trials are clearly successful and most preclinical studies are focused on protection after a stroke. The present review describes novel therapies addressed to counteract inflammation in the prevention of the first-ever or recurrent stroke. The putative clinical use of broad-spectrum and specific anti-inflammatory drugs, such as monoclonal antibodies and microRNAs (miRNAs) as regulators of atherosclerosis, will be outlined. Further studies are necessary to ascertain which patients may benefit from anti-inflammatory agents and how.

Owing to the high risk of recurrence, identifying indicators of carotid plaque vulnerability in atherothrombotic ischemic stroke is essential. In this study, we aimed to identify modified LDLs and antioxidant enzymes associated with plaque vulnerability in plasma from patients with a recent ischemic stroke and carotid atherosclerosis. Patients underwent an ultrasound, a CT-angiography, and an ¹⁸F-FDG PET. A blood sample was obtained from patients (n = 64, 57.8% with stenosis ≥50%) and healthy controls (n = 24). Compared to the controls, patients showed lower levels of total cholesterol, LDL cholesterol, HDL cholesterol, apolipoprotein B (apoB), apoA-I, apoA-II, and apoE, and higher levels of apoJ. Patients showed lower platelet-activating factor acetylhydrolase (PAF-AH) and paraoxonase-1 (PON-1) enzymatic activities in HDL, and higher plasma levels of oxidized LDL (oxLDL) and electronegative LDL (LDL(−)). The only difference between patients with stenosis ≥50% and <50% was the proportion of LDL(−). In a multivariable logistic regression analysis, the levels of LDL(−), but not of oxLDL, were independently associated with the degree of carotid stenosis (OR: 5.40, CI: 1.15–25.44, p < 0.033), the presence of hypoechoic plaque (OR: 7.52, CI: 1.26–44.83, p < 0.027), and of diffuse neovessels (OR: 10.77, CI: 1.21–95.93, p < 0.033), indicating that an increased proportion of LDL(−) is associated with vulnerable atherosclerotic plaque.

Electronegative LDL (LDL(−)) is a minor form of LDL present in blood for which proportions are increased in pathologies with increased cardiovascular risk. In vitro studies have shown that LDL(−) presents pro-atherogenic properties, including a high susceptibility to aggregation, the ability to induce inflammation and apoptosis, and increased binding to arterial proteoglycans; however, it also shows some anti-atherogenic properties, which suggest a role in controlling the atherosclerotic process. One of the distinctive features of LDL(−) is that it has enzymatic activities with the ability to degrade different lipids. For example, LDL(−) transports platelet-activating factor acetylhydrolase (PAF-AH), which degrades oxidized phospholipids. In addition, two other enzymatic activities are exhibited by LDL(−). The first is type C phospholipase activity, which degrades both lysophosphatidylcholine (LysoPLC-like activity) and sphingomyelin (SMase-like activity). The second is ceramidase activity (CDase-like). Based on the complementarity of the products and substrates of these different activities, this review speculates on the possibility that LDL(−) may act as a sort of multienzymatic complex in which these enzymatic activities exert a concerted action. We hypothesize that LysoPLC/SMase and CDase activities could be generated by conformational changes in apoB-100 and that both activities occur in proximity to PAF-AH, making it feasible to discern a coordinated action among them.