Cardiovascular (CV) diseases, responsible for more than 17.5 million deaths per year worldwide, represent a health and socioeconomic problem of huge magnitude. Increased CV disease prevalence in recent decades is largely due to the higher incidence of CV risk-associated pathologies, such as diabetes, dyslipidemia, obesity, and hypertension, with population ageing, unhealthy eating habits, and sedentary lifestyles undoubtedly acting as contributing factors (1).

Early development of atherosclerosis is a main underlying cause of CV disease, resulting in a condition known as atherosclerotic CV disease (ASCVD). Atherosclerosis is defined as a thickening and loss of elasticity in the arterial wall of large- and medium-sized arteries, and particularly in zones of curvature or bifurcation with turbulent flows, leading to a narrowing (stenosis) of the vascular lumen (2). Low-shear stress zones are susceptible to atherosclerotic plaque development, with rupture eventually leading to reduced blood flow and the onset of CV events (3). Vessels more prone to developing atherosclerosis are the abdominal aorta, and peripheral, coronary, and carotid arteries, leading, respectively, to the following forms of ASCVD: aortic atherosclerotic disease, peripheral artery disease (claudication), coronary heart disease (myocardial infarction, angina pectoris), and cerebrovascular disease (transient ischemic attack, ischemic stroke).

Atherosclerosis is a long-term process that is initially triggered by lipoprotein entry and retention in the artery wall, leading to intracellular and extracellular lipid accumulation in the subendothelial space. The progressive and slow deposition of lipids, occurring in parallel with an inflammatory response and monocyte recruitment from circulating blood to the arterial intima, together result in a narrowing of the artery wall, referred to as atherosclerotic plaque (2).

Low-density lipoprotein (LDL) plays a major role in different stages of the atherosclerotic plaque formation (Figure 1) (4). LDL entry to the microenvironment of the subendothelial space favors chemical modifications resulting from oxidative stress and the actions of lipolytic and proteolytic enzymes. Modified LDL, with the acquired pro-atherogenic properties, favors subendothelial retention and induces endothelial dysfunction, the recruitment of leukocytes with enhanced inflammatory response, the differentiation of monocytes into macrophages, the emergence of apoptotic processes, and the formation of lipid-loaded foam cells (5–7). To attract leukocytes to the lesioned area, modified LDL promotes the expression of adhesion molecules and chemokines by endothelial cells. In monocyte-derived macrophages, modified LDL promotes the release of more chemokines and cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1β), in addition to growth factors. This response contributes to the proliferation and activation of smooth muscle cells (SMCs), which together with macrophages, uptake modified LDL becoming lipid-loaded foam cells, a hallmark of atherosclerosis (8, 9).

Contrasting with LDL, high-density lipoprotein (HDL) is considered athero-protective (Figure 1), owing to its capacity to induce cholesterol efflux from tissues (10, 11) and to its anti-oxidant and anti-inflammatory properties (12). Of note, HDL's effects include the inhibition of LDL modification and mitigation of the atherogenic effects of modified LDL (12, 13).

The contribution of LDL cholesterol (LDL-C) to CV risk has been extensively studied, given its role in progression of atherosclerosis (14), which contrasts with the inverse association with vascular risk of HDL cholesterol (HDL-C) (15). However, the fact that therapies to regulate HDL-C or LDL-C levels do not eliminate vascular risk would suggest that, over and above concentration levels, the actual quality of lipoproteins is crucial to determining susceptibility to CV disease development.

Stroke represents the third cause of mortality in western countries and is a leading cause of disability and dementia worldwide. Furthermore, its impact is aggravated by the fact that around 20% of patients experience recurrence within 5 years of follow-up, increasing the risk of severe disability (16). Around 80% of strokes are ischemic in origin (17), and in approximately 20% of those cases, the cause is large-vessel atherosclerosis (18), referred to as atherothrombotic stroke (19). Plaques in the internal carotid artery are most frequently involved in this subtype (20), with stroke triggered by plaque rupture leading to thrombus formation and subsequent distal embolism (3), and/or by hemodynamic insufficiency, possibly attributable to progressive vessel occlusion caused by atherosclerotic plaque development (21).

The distribution of the modifiable vascular risk factors differs according to the type of stroke and the patient's sex and age (22). Stroke incidence is higher in women than in men for those younger than 30 years, whereas rates are higher in men during midlife. In subjects older than 80 years the incidence is slightly higher in women. Regarding carotid stenosis, women have a higher degree of stenosis, but less carotid plaque area (23) and less vulnerable plaques with lower risk than men (24, 25).

In atherothrombotic stroke, the recurrence risk of major vascular events is much higher than for other stroke subtypes (26), for which reason secondary prevention is essential. The main therapeutic approach is carotid endarterectomy, implemented according to the degree of stenosis (27). In addition to luminal narrowing, the inflammatory state and lipid content of the plaque are considered key factors in determining carotid plaque vulnerability. As explained above, lipoproteins play a key role in the progression of atherosclerosis, with LDL—most particularly when modified in the arterial wall—acting as a stimulus that strongly promotes inflammation and lipid accumulation (5).

Although elevated serum lipids and lipoproteins have been extensively associated with CV disease, there is little information regarding cerebrovascular disease. However, coronary patients are reported to have an increased risk of stroke (28), and the relationship between lipids/lipoproteins and ischemic stroke, and particularly atherothrombotic stroke, has been addressed in several epidemiological studies.

High plasma levels of total cholesterol, and particularly of LDL-C, have been associated with atherothrombotic stroke (29, 30) and progressive carotid stenosis (31). In line with those findings, lipid-lowering therapy to decrease total cholesterol and LDL-C levels has been shown to mitigate the progression of carotid atherosclerosis (32, 33). According to the SPARCL study (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), high-dose statins reduce the overall occurrence of strokes and CV events, with only a slight increase in the rate of hemorrhagic strokes (34). Likewise, PCSK9 inhibitors have been reported to reduce the incidence of stroke by 25% (35). Although some studies have pointed to an association between aggressive LDL-C-lowering therapies and an increased risk of hemorrhagic stroke, this association has not been conclusively demonstrated (36).

Notably, Sniderman et al. (37) argued that actual quantification of LDL particles or of apolipoprotein (apo) B was more important than LDL-C plasma levels in coronary artery disease. For ischemic stroke, the risk attributable to elevated apoB or non-HDL-C has been reported to be higher than the risk attributable to elevated LDL-C (38).

Elevated levels of lipoprotein(a) [Lp(a)] are postulated to contribute to so-called residual CV risk, i.e., risk not directly derived from elevated LDL-C (39, 40). Lp(a) consists of an LDL molecule that also contains the apolipoprotein (a) [apo(a)], covalently linked to apoB-100. Apo(a) is formed by multiple repetitions of structures called kringles, and depending on the number of repetitions differ in the CV risk, having small apo(a) isoforms a greater CV risk compared to larger isoforms (41). Higher Lp(a) concentrations are independently associated with long-term ASCVD risk and may amplify CV risk when concomitant with carotid plaque (42). Referring specifically to ischemic stroke, Lp(a) may play an especially relevant role, since its antifibrinolytic action may be determinant in the surge of thrombotic processes leading to an ischemic event (43, 44). Besides this antifibrinolytic action, the atherogenic effect of Lp(a) seems to be related to its ability to bind highly inflammatory oxidized phospholipids. These phospholipids include a soluble fraction in the surface of the lipoprotein particle and a fraction of these phospholipids covalently bound to apo(a) (45, 46). Indeed, Lp(a) is the main plasma transporter of oxidized phospholipids (47). Consequently, Lp(a) could play a role in the oxidative stress associated with the development of arteriosclerosis (48) and, therefore, be related to the oxidative modifications of LDL described in the following sections, which play a prominent role in the early appearance of ischemic events. Elevated Lp(a) levels have been associated with a high incidence of ischemic stroke in most (49–51)—but not all (52)—studies, and have also been associated with a greater vascular event recurrence risk in patients with acute first-ever ischemic stroke (53) and with vulnerable carotid plaque and plaque development (54, 55). The association of Lp(a) with carotid plaque vulnerability is sex-specific, since it was associated with presence of intraplaque hemorrhage in women and with stenosis degree in men (54). A recent meta-analysis concluded that increased Lp(a) concentrations could be considered a predictive marker for identifying individuals at risk of developing ischemic stroke (56).

Triglycerides may be independently associated with the risk of ischemic stroke (57), while elevated remnant cholesterol, i.e., the cholesterol transported in triglyceride-rich lipoproteins, has likewise been associated with a higher risk of ischemic stroke in the general population (58). A recent genome-wide association study (GWAS), using Mendelian randomization, has suggested that remnant cholesterol is causally associated with large-artery atherothrombotic stroke (59). Moreover, remnant cholesterol levels in patients with ischemic stroke have been positively associated with carotid artery intima-media thickness (60), with the concentration of triglyceride-rich particles predicting the presence of vulnerable carotid plaque independently of LDL-C (61, 62).

Despite the well-known inverse association between HDL-C levels and coronary heart disease, findings have not been so consistent for stroke. HDL-C levels are weakly or not at all associated with the incidence or prevalence of ischemic events, and do not predict recovery from stroke. However, some studies have shown an inverse association in the specific case of atherothrombotic stroke (63, 64). As occurs with LDL, the HDL particle count is a promising risk prediction parameter. While most studies to date have been single-cohort studies assessing only coronary disease or composite vascular outcomes, a study by Singh et al. (65) has reported that HDL particles is a robust marker for ischemic stroke in the overall population, and also that it inversely correlates with both myocardial infarction and stroke, albeit displaying racial disparities.

Conflicting results regarding the predictive power of lipid and lipoprotein blood levels for stroke may be partly due to the time of blood collection in patients, because, as already described in the 1980s (28), stroke itself exerts a lipid-lowering effect. Growing evidence suggests that—in addition to lipoprotein quantitative parameters—certain lipoprotein component concentrations and functional alterations are relevant to the pathology of ischemic stroke, and particularly to the atherothrombotic subtype.

Despite the association between plasma lipoprotein levels and ASCVD (including atherothrombotic stroke), mounting evidence points to the fact that lipoprotein concentration is not always the key, as the presence of atherosclerosis is not exclusively determined by quantitative lipid parameters such as high LDL-C levels (66). The importance of other lipoprotein-related factors is suggested by subjects with normal LDL-C still having residual CV risk and by a diminished association with LDL-C when adjusting for other lipoproteins (67, 68). Those observations are likely based on the fact that circulating lipoproteins comprise subclasses that are heterogeneous in size, density, composition, and function, and with different involvement in ASCVD.

Alterations in HDL and LDL particle size in ischemic stroke occur parallel to changes in chemical composition, as reported in several studies (69–74). Just beginning to be deciphered is the specific lipid and protein composition of lipoproteins involved in atherothrombotic stroke, with interesting preliminary data obtained from lipidomic and proteomic studies of lipoproteins isolated from ischemic patients. Lepedda et al. (72) showed increased acute-phase serum amyloid A (SAA) levels in all lipoprotein fractions obtained from the patients in their study, while a proteomic study by Finamore et al. (71) revealed that mainly LDL, but also HDL, showed a higher content of proteins associated with inflammation, immunity, and coagulation, and specific protein signatures for patients with hypoechoic plaques. Regarding lipids, a preliminary lipidomic study in lipoproteins isolated from patients who had undergone carotid endarterectomy showed lipid alterations, particularly in specific phospholipids in the LDL of patients with hypoechoic plaques (73). It is very feasible to consider that such physical and chemical alterations in LDL might lead to a higher prevalence of modified LDL particles in ischemic stroke. The role of modified LDL and the influence of altered qualitative properties of HDL, specifically in relation to atherothrombotic stroke, are discussed in the following sections.

The main lipid-related therapy to reduce ischemic stroke risk is statin administration, whose main beneficial effects—derived from their inhibition of HMG-CoA reductase—are to reduce cholesterol biosynthesis and modulate lipid metabolism. Statins can also improve the biological characteristics of lipoproteins, by changing their chemical composition and decreasing oxLDL and LDL(-) levels (143–145). The additional fact that statins exert pleiotropic and anti-atherosclerotic effects, independently of their hypolipidemic action, significantly contributes to reduce CV event and mortality rates, with greater benefits in patients at high risk (146). Regarding ischemic stroke, several studies [summarized in (147)] have reported statins to reduce the ischemic stroke risk without increasing the hemorrhagic stroke risk.

Other more recently developed lipid-lowering agents demonstrate strong efficacy and are useful to prevent ASCVD. For patients at very high or high CV risk who are not responsive to or are intolerant of statins, ezetimibe, alone or in combination with statins, and PCSK9 inhibitors may reduce stroke risk (148). In the FOURIER study of patients with established atherosclerosis, PCSK9 inhibition with evolocumab added to statins reduced the risk of ischemic stroke (149). Bempedoic acid is a new lipid-lowering medication for the prevention and treatment of CV disease; currently in Phase III clinical trials (150), its effect on ischemic stroke is still pending of evaluation. Likewise, not yet tested for ischemic stroke is icosapent ethyl, an omega-3 fatty acid with triglyceride-lowering action that has shown promising results in reducing plasma triglyceride levels and major adverse CV events (151).

Given that lipoprotein function more than concentration plays a key role in ischemic stroke, future studies should address the qualitative properties of LDL and HDL and strategies to mitigate the generation of oxLDL and LDL(-). In this regard, the ability of statins to normalize alterations in lipoprotein composition and size and to reduce elevated modified lipoprotein levels is well known (152, 153). A recent study has reported that PCSK9 inhibition lowers LDL aggregation susceptibility, an LDL modification associated with future CV-related death (154). Antibodies against LDL(-) with athero-protective action have been detected in human and murine model blood and atherosclerotic plaques (155, 156), and based on one of those antibodies, a peptide with inflammatory properties has been designed that has potential to generate vaccines to immunize against LDL(-) and prevent atherosclerosis (157).

In sum, further investigations focused on the qualitative properties of lipoproteins and overcoming their impaired functioning are essential to understanding and preventing ischemic stroke, and particularly the atherothrombotic stroke subtype.

The particularities of ischemic stroke of atherothrombotic origin make it necessary to further explore alterations in lipoprotein functioning in stroke patients. In contrast with coronary disease, where these alterations have been extensively studied, for ischemic stroke, relatively few studies have explored abnormal lipoprotein functioning. The fact that quantitative alterations in the lipid profile are less frequent in patients with ischemic stroke than in patients with coronary atherosclerosis would suggest that in the former qualitative lipoprotein alterations may play a key role. In this context, to decipher the contribution of such alterations to this disease and to determine the molecular mechanisms involved poses a challenge in terms of designing new therapies addressed at preventing ischemic stroke.