Multiple facets of HDLs as modifiable risk factors in stroke—the good, the bad, and the ugly

Abstract

HDL as a component of the lipid profile has been extensively studied for its link to CVDs, particularly its relationship with atherogenesis. It has been observed that plasma levels of HDL-C display an inverse relationship with stroke as well, suggesting that higher levels could potentially reduce the risk of stroke. Nevertheless, recent studies suggest that HDL-C alone may not fully predict stroke risk. The complexity of HDL particles arises from their diverse nature, showing significant heterogeneity in various dimensions. The functional quality of HDL extends beyond its quantity, with factors like lipoprotein subspecies (varying in size, lipid compositions, microRNA, and protein content) influencing HDL functionality under different pathophysiological conditions. This heterogeneity of HDL, particularly in the context of stroke, has received limited attention in reviews. While some studies have suggested that higher levels of HDL-C are linked to a reduced risk of stroke, others have found no such association. While HDL is known for its atheroprotective effects, its antioxidant and anti-inflammatory properties may be as vital as cholesterol efflux in preventing atherosclerosis-related stroke. This review emphasizes the importance of exploring various functionalities of HDL in the context of stroke. By elucidating the multifaceted relationship between HDL and stroke as demonstrated by contemporary literature, we aim to enhance the understanding of HDL's influence on stroke pathophysiology and identify avenues for future research in this field.

Graphical abstract

Stroke is the second leading cause of global mortality and the third leading cause of death and disability combined (measured as disability-adjusted life-years lost), as reported by the latest Global Burden of Disease (1). Ischemic strokes that account for approximately 87% of all reported stroke cases (2) are caused by thrombi or emboli obstructing the cerebral vasculature (3). This obstruction leads to arterial stenosis or complete occlusion, interrupting blood flow and resulting in the death of brain cells (3). Between 1990 and 2019, global annual deaths from ischemic strokes rose from 2 million to 3.2 million, with projections estimating an increase to 4.9 million by 2030 (4).

Atherosclerosis, a primary cause of vascular diseases, is the predominant pathophysiological mechanism observed in the large vessel disease and small vessel disease subtypes of ischemic stroke (5, 6). Ischemic strokes are commonly classified using the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) system into large-artery atherosclerosis, small-vessel occlusion, cardioembolism, other determined etiology, and undetermined etiology (7).

The progression of atherosclerosis is a complex and highly regulated process that begins with the formation of fatty streaks (8). Circulating LDL contains small amounts of lipid peroxides (8), which, upon reaching the subendothelial layer, can further contribute to atherosclerosis progression (9). The process involves complex interactions among endothelial cells, smooth muscle cells, and macrophages and various proteins, ultimately leading to clinical manifestations (10). This process, illustrated in Fig. 1, causes the accumulation of oxidized LDL in the arterial wall and is a pivotal mechanism in the development of atherosclerotic plaques (10, 11).

Fig. 1.

HDL-mediated RCT in preventing foam cell formation and atherosclerosis.

HDL exerts its antiatherogenic effects primarily through its role in macrophage reverse cholesterol transport (RCT)—the process by which excess cholesterol is removed from lipid-laden macrophage foam cells within atherosclerotic plaques and transported to the liver for excretion via bile (12, 13, 14, 15, 16). This process mitigates atheromatous plaque accumulation and helps to restore vascular health (10, 17). Additionally, HDL prevents LDL oxidation through mechanisms such as scavenging free radicals, donating antioxidants, and modulating enzymes involved in lipid peroxidation (16). These activities significantly reduce the oxidative stress that drives atherogenesis. Since atherosclerosis is a major underlying cause of both CVD and ischemic stroke, the protective effects of HDL may extend beyond coronary arteries to the cerebral vasculature, reducing the risk of cerebrovascular events. For a comprehensive discussion on the role of HDL in CVD, including its impact on atherosclerosis progression and RCT, which is beyond the scope of this review, see the study by Rosenson et al., 2012, and other references (18, 19, 20, 21).

While an inverse relationship between HDL-C levels and CVD is well documented, the relationship between HDL-C levels and stroke pathophysiology is less straightforward. Recent cohort studies and Mendelian randomization trials have challenged the notion that higher HDL-C levels are inherently protective against incident and recurrent strokes, pointing to a more complex stroke pathophysiology (22, 23). Conflicting findings regarding baseline HDL-C levels and ischemic stroke risk suggest that factors beyond plasma levels play a significant role (24, 25, 26). The multifaceted attributes of HDL, including its subspecies and its anti-inflammatory, antioxidant, and antithrombotic functions, may influence its role in stroke risk (12, 15, 27, 28). These functions actively modulate the inflammatory processes and oxidative stress linked to cerebrovascular events (3, 29). Scavenger receptor class B type 1 (SR-B1), a key HDL receptor, plays a dual role in vascular biology by mediating both the selective uptake of cholesteryl esters by the liver and the transcytosis of LDL into the arterial wall, thereby influencing atherosclerosis progression. In addition, HDL-associated microRNAs (miRNAs), such as miR-223, miR-92a, and miR-126, can exert antithrombotic and vascular protective effects by regulating gene expression in endothelial cells and monocytes, potentially contributing to stroke prevention. Furthermore, the antithrombotic effects of HDL may help prevent thrombus formation, thereby reducing ischemic stroke incidence (16). This evolving understanding signals a potential paradigm shift from focusing solely on HDL quantity to considering the role of HDL quality, not only in assessing but potentially altering stroke risk.

The review delves into the multifaceted role of HDL in stroke, exploring its tripartite nature: “the good” (protective effects), “the bad” (dysfunctional potential), and “the ugly” (conflicting findings). It emphasizes the key protective mechanisms of HDL while also addressing the challenges posed by dysfunctional HDL and its paradoxical contributions to the disease, highlighting and underscoring the complex role of HDL in stroke pathophysiology.

The good: the role of HDL in reducing stroke risk through cholesterol efflux and neuroprotective mechanisms

HDL is traditionally recognized for its protective role in stroke, primarily through its cholesterol efflux, anti-inflammatory, antioxidant, and antithrombotic properties. HDL-associated miRNAs support stroke protection by regulating vascular function, thrombosis, and atherogenesis (30). This section explores the beneficial functions of HDL, focusing on its ability to facilitate cholesterol efflux, reduce oxidative stress, and modulate the inflammatory response.

It is well studied that HDL promotes RCT, which prevents lipid accumulation in atherosclerotic plaques (31). In clinical practice, HDL-C, which constitutes 25–30% of the proteins involved in lipid transport, is typically measured as a single entity based on its cholesterol content (32, 33). This can be directly assessed in serum through enzymatic methods involving cholesteryl esterase and cholesterol, following the precipitation of lipoproteins containing Apo B (34). The quantitative significance of HDL is primarily attributed to its role in cholesterol efflux and RCT (12, 35).

HDL-C and stroke risk

Extensive epidemiological and case-control studies have identified HDL-C levels as independent predictors of stroke risk (25, 26, 36, 37, 38, 39, 40). Elevated HDL-C levels are associated with a reduced susceptibility to stroke (41), observing a graded, inverse correlation (24). In a large retrospective cohort study, higher HDL-C levels were inversely associated with the risk of total, ischemic, and hemorrhagic strokes in patients with type 2 diabetes mellitus (42). A 21-year follow-up study revealed an independent inverse association between a lower percentage of total cholesterol as HDL-C fraction with an increased long-term mortality from ischemic strokes in middle-aged and older men (43). In men with hypertension, elevated HDL-C levels were linked to a 50% reduced risk of nonfatal strokes compared with those in the lowest HDL quintile (36). The SPARCL trial found that higher baseline HDL-C levels were linked to a lower risk of stroke, with each standard deviation increase corresponding to a 13% reduction in recurrent stroke risk (44).

In addition, HDL-C is inversely associated with carotid intima-media thickness in acute ischemic stroke (AIS) patients, reinforcing its potential role in stroke pathophysiology and possibly as a therapeutic target for stroke prevention (45).

HDL, atherothrombosis, and stroke protection

HDL protects against atherosclerosis and stroke through multiple mechanisms, including removal of cellular cholesterol, reducing cell death, mitigating vascular constriction, lowering platelet activation, decreasing reactive oxygen species (ROS) levels, reducing inflammation, enhancing glucose metabolism, and regulating gene expression via miRNAs (46). Cholesterol efflux from macrophage foam cells primarily involves the interaction between ABC transporters—such as ABCA1—and cholesterol-deficient Apo A1 complexes (pre-β HDL or very small HDL) (18), whereas ABCG1 mediates cholesterol efflux through interactions with α-HDL particles of varying sizes (47, 48). Dysfunction in ABCA1 is associated with lower HDL-C levels and an increased risk of atherosclerosis (49).

Notably, higher cholesterol efflux capacity (CEC)—reflecting the functional efficiency of HDL in removing cellular cholesterol—has been associated with improved vascular health and may contribute to favorable stroke outcomes. A clinical study demonstrated that individuals with low HDL because of ABCA-1 gene mutations exhibited impaired endothelial function; however, their vasomotor responses were restored within 5 h post-stroke following Apo A1/phosphatidylcholine infusion (50). Recent in vitro studies have explored leveraging HDL functionality as a targeted therapy for atherothrombosis in stroke (32).

In an embolic stroke model, intravenous HDL administration reduced stroke-related mortality within 24 h by decreasing blood-brain barrier (BBB) permeability and brain edema (51). In stroke rat models, reconstituted HDL administration reduced brain necrosis by 60% and lowered ROS levels in the infarct zone (52). Experimental studies have shown the antiatherogenic effects of HDL by inhibiting monocyte chemoattractant protein-1 (MCP-1) release and monocyte migration, thus protecting LDL from oxidation (31). In addition, HDL strongly activates endothelial nitric oxide synthase, promoting the dilation of blood vessels and enhancing blood flow (53). Sphingosine-1-phosphate (S1P) in HDL both promotes endothelial nitric oxide production and vasodilation while inhibiting platelet aggregation by activating S1P receptors on platelets (54). Low serum S1P levels in acute stroke patients correlate with increased severity, larger infarct volumes, and poorer outcomes, suggesting S1P mimetics as a potential therapeutic strategy (55). Phosphatidylserine and lysophosphatidylcholine in HDL may enhance antithrombotic activities by interacting with platelet receptors, coagulation factors, and endothelial cells (56, 57).

Unlike ABC transporters, SR-B1 enables bidirectional lipid transport in macrophages and selective cholesteryl ester uptake from HDL by the liver (58). Mature spherical HDL can increase in size by effluxing cellular cholesterol and phospholipids through SR-B1 (35). Endothelial SR-B1 facilitates LDL transport into the subendothelial layer, promoting foam cell formation and atherosclerosis progression (59). In mouse models, the absence of SR-B1 in endothelial cells reduces LDL transport into the arterial wall, indicating its potential protective role against atherosclerosis (60). Mice lacking the SR-B1 gene in hepatocytes exhibited increased atherosclerosis, highlighting the differing roles of SR-B1 in hepatocytes and endothelial cells for cardiovascular health (60).

HDL subfractions and their functional diversity

HDL is a heterogeneous mixture of subfractions differing in density, size, charge, and composition (61). Their size and density are determined by their composition: a core of cholesteryl esters and triglycerides surrounded by a surface layer of phospholipids, free cholesterol, and apolipoproteins (34). HDL particle size varies with protein-to-lipid composition, enzymatic activity, and lipoprotein interactions, undergoing continuous remodeling in circulation, where higher cholesterol content produces larger particles and greater triglyceride content leads to smaller ones (62). Their protective properties include antiprotease, antioxidant, and anti-inflammatory effects, all contributing to neuroprotection (12, 14, 63). Distinct HDL subfractions may play unique protective roles, indicating that their distribution and functionality could serve as better predictors of cardiovascular risk than HDL-C levels alone (12). For example, HDL particle concentration has shown a stronger inverse association with atherosclerotic events than HDL-C levels (64).

HDL-associated miRNAs in vascular protection

HDL-associated miRNAs may exert protective effects against thrombosis by influencing vascular cell functions and transporting small noncoding RNAs for intercellular signaling (46). They reach target cells either via direct HDL particle delivery or through the SR-B1-mediated mechanism (35). HDL-miR-223 suppresses tissue factor expression, a key coagulation initiator, in endothelial cells and monocytes (30). HDL-miR-92a inhibits integrin subunit alpha V, a platelet adhesion molecule, whereas HDL-miR-126 enhances the expression of vascular endothelial growth factor, a proangiogenic factor, in endothelial cells (30). Other miRNAs, including miR-96, miR-125a, miR-185, and miR-455, modulate HDL uptake via SR-B1, suggesting their potential role in reducing atheroma formation (30). Taken together, these findings underscore the multifaceted role of HDL in vascular protection and stroke prevention. Table 1 provides an overview of the relationship between HDL-C levels, stroke incidence, and risk.

Table 1.

Summary table of studies correlating HDL with stroke risk

Studies	Population	Findings overview	HDL function	Inference
Tanne et al. 1997 (43), Hu et al. 2023 (65)	Cohort studies	The study found that men who died from ischemic stroke had lower HDL-C levels and a smaller HDL fraction of serum cholesterol than survivors. A 5% decrease in HDL percentage was linked to higher mortality risk, with those in the lowest HDL-C tertile facing greater risk than those in the highest	HDL-C was associated with reduced risk of ischemic stroke mortality, with higher percentage of HDL linked to lower stroke mortality rates	These studies underscore the independent negative association between low HDL-C levels and ischemic stroke mortality over a long-term follow-up period in a middle-aged and elderly population
Sacco et al. 2001 (25)	Multiethnic, population-based, incident case-control study	Increased HDL-C levels are associated with reduced risk of ischemic stroke in the elderly and among different racial or ethnic groups. These data add to the evidence relating lipids to stroke and support HDL-C as an important modifiable stroke risk factor	Higher HDL-C levels were associated with a reduced risk of ischemic stroke, with levels of at least 35 mg/dl showing a protective effect that was dose dependent	Increased HDL-C levels are associated with a reduced risk of ischemic stroke across different racial or ethnic groups, highlighting HDL-C as an important modifiable stroke risk factor. The study underscores the potential role of HDL-C in stroke prevention, especially in older populations
Ali et al. 2024 (66)	Cohort study: Patients admitted to the Qatar Stroke Database between 2014 and 2022, stratified into sex-specific HDL quartiles	Low HDL levels were linked to poorer long-term outcomes, including a 2.24-fold higher risk of stroke recurrence, a 1.99-fold higher risk of major cardiovascular events, and a 2.27-fold higher mortality rate at 1 year compared to those with high HDL	Lower HDL levels were independently linked to a higher risk of 1-year post-stroke mortality, stroke recurrence, and major adverse cardiovascular events	Multivariate binary logistic regression analyses demonstrated that sex-specific HDL levels were significant predictors of adverse long-term stroke outcomes, highlighting the importance of HDL in stroke risk management and outcome prediction

The bad: HDL particles and impaired HDL function in the risk and severity of stroke

In oxidative or inflammatory states, HDL may lose its protective functions and become proinflammatory (67). Rather than consistently preventing disease, HDL has been shown to promote processes such as apoptosis, atherogenesis, and inflammation, in these altered states. Moreover, despite its involvement in RCT and immune modulation, measuring HDL-C alone does not reflect these potentially detrimental functional changes (31). In addition, enzymes such as lecithin-cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) regulate HDL particle remodeling—LCAT enhances maturation, whereas CETP transfers cholesteryl esters to LDL/VLDL, reducing HDL size and cholesterol content (31, 67). Hepatic and endothelial lipases further modify HDL, potentially impairing function and increasing atherosclerosis risk. This process may impair HDL function and elevate atherosclerosis risk (67). Notably, HDL particle size influences the activity of paraoxonase-1 (PON-1), a key enzyme in mitigating oxidative stress. Larger particles support PON-1 function, whereas smaller ones may exacerbate oxidative stress, contributing to ischemic stroke risk (68).

HDL subspecies and the risk of ischemic stroke

Apo A2, E, and C modulate HDL size and function by influencing lipid metabolism and interactions with lipoproteins and receptors (31). Certain HDL particles, particularly those lacking Apo C3, J, or E, were associated with fewer small ischemic brain lesions and a lower stroke risk (69). Similar to PON-1, myeloperoxidase, an HDL-associated protein, can impair Apo A1 during inflammation and is a source of ROS. Myeloperoxidase is found in lesion-derived HDL within the arterial wall, indicating its potential role in stroke pathophysiology (70, 71). Stroke patients exhibit significantly lower levels of Apo A1 and PON-1 in HDL compared with healthy individuals, with inflammatory and immune-related HDL protein alterations linked to acute-phase responses and platelet activation in AIS (72, 73).

Emerging evidence highlights that HDL functional impairment, driven by oxidation and glycation, significantly impacts stroke severity and outcomes. Post-translational modifications of HDL subspecies may further contribute to stroke risk by disrupting HDL metabolism and lipid flux regulation (35). Stroke patients with poor outcomes following thrombolysis showed a decreased ratio of large to small HDL subspecies at 3-month follow-up, along with impaired suppression of proinflammatory cytokines like IL-8 and MCP-1, indicating dysfunctional anti-inflammatory properties (27). Notably, plasma HDL-C levels did not differ between these groups (27). In a cross-sectional analysis, higher plasma Apo A1 and lower Apo E levels in HDL were linked to a reduced likelihood of focal lesions on brain imaging without clinically recognized stroke symptoms (69). Among Japanese adults, small- to medium-sized HDL-C levels were inversely associated with total stroke risk, whereas large HDL levels showed no significant association (74).

HDL dysfunction on stroke severity and outcome

Recent studies highlight that HDL dysfunction—rather than HDL-C levels—may be a critical factor in determining stroke severity and clinical outcomes. A study involving statin-naïve AIS patients found increased oxidative stress and HDL dysfunction despite normal HDL-C levels (75). This dysfunction was observed consistently across ischemic stroke subtypes, indicating that HDL impairment is independent of cholesterol content and may play a role in stroke pathophysiology (75). The HDL oxidative index serves as a marker of oxidative stress on HDL particles. Elevated HDL oxidative index levels have been associated with an increased risk of cardiovascular events (76).

CEC is a key metric of HDL functionality, which measures the ability of HDL to remove cholesterol from cells and transport it to the liver. The CEC assay quantifies this process by labeling cellular cholesterol and tracking its movement to an extracellular acceptor in a serum-free medium (77). Research shows that while HDL-C levels remain comparable in mild and severe strokes, severe strokes are associated with reduced HDL-C efflux capacity, reduced HDL phospholipid content, higher serum amyloid A1, and decreased PON-1 antioxidant activity (78). Alterations in HDL protein composition and CEC after AIS have been correlated with functional recovery, suggesting specific HDL proteins may serve as clinical biomarkers for stroke rehabilitation (73). This growing body of evidence paints a compelling picture of HDL dysfunction as a critical and actionable axis in stroke biology, with far-reaching implications for treatment and prognosis. Table 2 provides an overview of HDL dysfunction, including supporting evidence, clinical implications, and potential therapeutic interventions for stroke.

Table 2.

Key mechanisms of HDL dysfunction and their impact on stroke risk and outcomes

Aspect	Supporting evidence	Clinical implications	Potential interventions
HDL oxidative index (HOI)	Elevated oxidative stress leads to dysfunction in HDL among AIS patients, impacting stroke severity compared with a control group, even with normal HDL-C levels (75)	Higher HOI was reported in stroke patients (75)	Antioxidant therapy to reduce oxidative stress
HDL-CEC	Stroke severity correlates with lower HDL CEC, reduced phospholipid content in HDL, higher serum amyloid A1 levels, and decreased antioxidant activity of PON-1 (78)	Impaired cholesterol efflux may contribute to plaque development and vascular inflammation	Lifestyle changes (diet, exercise) to enhance efflux capacity
HDL particle subfraction or size	In stroke patients with unfavorable outcomes at a 3-month follow-up, a significant decrease in the ratio of large to small HDL particles was observed, along with impaired anti-inflammatory properties (27)	Altered particle composition could indicate a heightened risk for adverse cardiovascular events	Pharmacological agents targeting HDL particle remodeling
Apo A1 and Apo E levels	Higher plasma levels of Apo A1 and lower levels of Apo E in HDL are associated with a decreased likelihood of focal lesions detected by brain imaging, even in the absence of clinically recognized stroke symptoms (69)	Balancing Apo A1 and Apo E levels may be essential for preventing asymptomatic cerebrovascular lesions	Apo A1 mimetic peptides or Apo E enhancing therapies
HDL particle size variations	The presence of small-sized HDL particles in stroke patients suggests potential HDL dysfunction in this population, correlating with increased stroke risk and short-term mortality (79) S-HDL and M-HDL levels inversely related to stroke risk (74)	Small HDL particles may indicate a pathological state and a higher risk of stroke and other cardiovascular events	Strategies to increase the size of HDL particles through lifestyle modifications or medications

The ugly: conflicting findings and potential limitations of HDL as a therapeutic target in stroke

Despite several findings on HDL in stroke, studies report conflicting evidence—some suggesting a protective role, others indicating no association, or even a paradoxical increase in stroke risk with high HDL-C levels (12, 80). These discrepancies may stem from multiple factors, including genetic influences, ethnic and gender differences, and functional heterogeneity of HDL (81). This final section explores the conflicting findings and potential limitations of HDL as a therapeutic target in stroke, ethnic and gender variations in HDL dynamics, the dual role of HDL in stroke-related pathways, and its role in maintaining neurovascular health.

Variability in HDL and its relationship to stroke

Elevated HDL-C levels do not consistently correlate with reduced stroke risk, with some evidence suggesting a U-shaped relationship where both low and extremely high levels are associated with increased ischemic stroke risk (61, 82). Genetic variations in CETP, hepatic lipase, and SR-B1 can lead to excessively high HDL-C (83). In addition, both low and very high HDL-C levels are associated with impaired flow-mediated vasodilation, indicative of endothelial dysfunction (84).

Large cohort studies, including the Northern Manhattan Study and the Women's Health Initiative Observational Study, found no consistent association between baseline HDL-C and stroke risk during long-term follow-up (85, 86). However, the LDL-C/HDL-C ratio has emerged as a significant predictor in specific stroke subpopulations. In patients with nonvalvular atrial fibrillation, a higher LDL-C/HDL-C ratio was independently associated with ischemic stroke risk (87). Yet, its role in stroke outcomes remains inconsistent. Some studies link an elevated LDL-C/HDL-C ratio alongside lower baseline HDL-C and higher triglycerides to an increased risk of stroke recurrence (44). Conversely, a higher LDL-C/HDL-C ratio has been associated with a lower risk of mortality, recurrence, and moderate disability at 3 months post-stroke, though this effect does not persist at 12 months (88). Furthermore, a case-control study found no direct association between HDL-C and ischemic stroke risk, although a higher TC/HDL-C ratio in the highest quartile suggested a potential increased risk (89).

HDL-C levels are influenced by multiple confounding factors such as diet, physical activity, lifestyle habits, and smoking, causing fluctuations in circulating HDL-C levels (34). Age, gender, and disease states, including acute infections and chronic inflammation, can also lower HDL-C levels, whereas regular aerobic exercise and a healthy diet may elevate it (34, 90). Comorbidities like diabetes further complicate this relationship—hyperglycemia impairs HDL function, as glycated HDL has a reduced ability to prevent monocyte adhesion to endothelial cells exposed to oxidized LDL, exacerbating atherosclerosis (91). Individuals with type 2 diabetes, high triglycerides, and low HDL-C levels face an elevated stroke risk, particularly when LDL-C levels exceed 130 mg/dl (92). Interestingly, the protective role of HDL-C appears to be modified by BMI, as higher HDL-C levels reduce stroke risk in hypertensive individuals with a BMI <24 kg/m² but show no such benefit in those with a BMI above this threshold (93).

Although cholesterol efflux from macrophages is generally protective against coronary artery disease, paradoxically, increased efflux activity has been linked to higher future risks of myocardial infarction (MI), stroke, and major adverse cardiovascular events (94). This contradiction may be attributed to dysfunctional HDL—characterized by reduced antioxidant function and increased protein modifications—which may heighten cardiovascular risk even in individuals with normal or elevated HDL-C levels (95). This dysfunction is particularly pronounced in type 1 diabetes patients, where irreversible post-translational modifications in key apolipoproteins impair HDL quality regardless of glycemic control (95).

The relationship between HDL particle size and stroke risk remains complex. Some studies associate a higher proportion of small HDL particles with stroke, suggesting HDL dysfunction (79). Conversely, an observational cohort study indicated that a higher concentration of large HDL particles is linked to a reduced risk of stroke (24). Conflicting findings, including reports of increased large HDL proportions in stroke patients (72), highlight the need for further research to clarify the role of HDL in ischemic stroke pathophysiology.

Population variability in HDL function and stroke risk

The role of HDL in stroke appears to be more complex than previously assumed, with ethnicity and gender potentially influencing its protective effects (96). Ethnic-specific differences in HDL composition have been observed in individuals with type 2 diabetes mellitus (97, 98) and those at cardiovascular risk (99, 100). For stroke, however, findings from the Multi-Ethnic Study of Atherosclerosis revealed significant ethnic differences in the relationship between HDL particles and ischemic events, particularly among African Americans (24). On the other hand, Singh et al. (28) found no significant ethnic modification in the relationship between HDL parameters and ischemic stroke, but HDL particle concentration showed consistent inverse associations with both MI and ischemic stroke in the general population and women. Further complicating the picture, the Atherosclerosis Risk in Communities study reported conflicting gender-based findings—higher HDL-C levels were associated with a reduced ischemic stroke risk in women, but in men, the association was inconsistent (101). Similarly, the EUROSTROKE study highlighted gender-specific variations in the role of HDL in stroke risk, suggesting a potentially distinct impact in men versus women (96). One possible explanation for this disparity is estradiol's influence on HDL functionality, which fluctuates during critical life stages, such as pregnancy and menopause (102, 103). Beyond gender, vitamin D levels have also been proposed as a factor influencing HDL function, with potential ethnic variations because of differences in melanin levels (24). However, while vitamin D supplementation has been shown to lower TC, LDL-C, and triglycerides, it appears to have no direct effect on HDL-C levels, regardless of seasonal changes (104).

Pathophysiological interfaces between HDL and stroke

The neuroprotective effects of HDL are attributed to its anti-inflammatory actions, prevention of oxidative damage, and enhancement of cerebral blood flow (105). While early ischemia activates genetic responses—including heat shock proteins, proinflammatory cytokines, and growth factors—rare genetic variations affecting HDL-associated PON-1 function have been strongly linked to ischemic stroke, particularly in individuals of African ancestry (106). This suggests that the protective influence of HDL is not universal and may be modified by genetic and population-specific factors.

Inflammation plays a key role in the pathophysiology of ischemic stroke and atherothrombosis, and HDL is thought to counteract this process by modulating vascular inflammation (14, 63). However, emerging evidence suggests that HDL may also exert proinflammatory effects under certain conditions (29, 34). The HDL inflammatory index helps assess whether HDL acts as an anti-inflammatory or proinflammatory agent, but findings remain inconsistent (107). A nested case-control study from the JUPITER trial, which included incident cases of cardiovascular events—including MI, stroke, unstable angina, arterial revascularization, and CVD-related mortality—found a nonlinear association between HDL inflammatory index and incident CVD/mortality in individuals with chronic inflammation (108).

During the acute phase of stroke, endothelial activation facilitates leukocyte recruitment to the infarct site, a process that may be influenced by the anti-inflammatory properties of HDL, which could in turn hinder cytokine infiltration (3, 27). HDL is known to regulate the expression of cytokine-induced adhesion molecules, MCP-1, and oxidized phospholipids, suggesting a protective role in vascular inflammation (105). However, its impact on thrombosis further complicates this narrative. While HDL has demonstrated antithrombotic properties, preventing platelet hyper-reactivity and reducing coagulation through mechanisms involving SR-B1-mediated platelet signaling and inhibition of coagulation factors (16, 46, 54), these effects may not translate into a consistent reduction in stroke risk. Some studies suggest that the antithrombotic properties of HDL might be overshadowed by other stroke risk determinants, raising questions about whether HDL is a primary factor in stroke pathogenesis, despite its well-established role in coronary heart disease (109).

Ultimately, the dual nature of HDL in stroke—protective under certain conditions but potentially ineffective or even detrimental in others—highlights the need for a nuanced approach in considering HDL as a therapeutic target.

HDL, neuroprotection, and BBB integrity in stroke

The impact of HDL on AIS has been investigated using both in vivo and in vitro models of the BBB (110). In mice, HDL administration reduced infarct size and BBB leakage, but these protective effects were lost when the endothelial SR-B1 receptor was deleted, underscoring its role in HDL-mediated neuroprotection (110). Similarly, in vitro studies revealed that HDL preserved BBB integrity during oxygen-glucose deprivation, an effect that was diminished with an SR-B1 inhibitor, reinforcing the importance of SR-B1 in HDL-based therapies for AIS (110).

Proteomic analysis of HDL composition identified protein clusters within specific HDL particles linked to antioxidative function, using liquid chromatography and mass spectrometry to analyze 28 proteins across five HDL subclasses (111). Their findings suggest that the function of HDL varies based on its protein composition, size, and density, with certain proteins correlating with its ability to protect LDL from oxidation (111). However, these variations introduce complexity, raising questions about whether all HDL particles exert the same protective effects. Further longitudinal studies are needed to determine whether the composition and function of HDL can reliably track stroke recovery or predict recurrence. Figure 2 summarizes these inconsistencies, highlighting the complexity of HDL biology and underscoring the need for studies focusing on HDL functionality rather than simply HDL-C levels. Table 3 provides an overview of the protective mechanisms of HDL, clinical evidence, and therapeutic potential in stroke, while also addressing key limitations in its therapeutic application.

Fig. 2.

The multifaceted properties of HDL.

Table 3.

Summary of the protective mechanisms, clinical evidence, and therapeutic potential of HDL in stroke prevention

Protective mechanisms and components	Function	Clinical evidence	Potential therapeutic implications	Limitations
RCT	Facilitates the removal of excess cholesterol from arterial walls, reducing atherosclerotic plaque formation and the risk of thrombotic events, including stroke (18)	Higher HDL levels correlated with reduced incidence of ischemic stroke (25, 26, 36, 37, 38, 39, 40)	Cumulative control of HDL-C and LDL-C correlated with a decreased risk of stroke, highlighting HDL-C as a potential therapeutic target in ischemic stroke prevention (44)	Not all studies agree on the protective role of HDL; further research is needed (112, 113)
Antioxidant properties	HDL contains enzymes such as PON-1 that enhance cholesterol efflux and protect against oxidative stress, which is implicated in stroke pathophysiology (114)	Higher baseline serum PON1 activity is significantly associated with better functional outcomes in acute ischemic stroke patients, making it a potential independent prognostic marker (115)	Enhancing antioxidant properties of HDL may be a viable strategy for reducing stroke risk	Mechanisms still not fully understood; need for precise therapeutic targets
Anti-inflammatory effects	Exhibits anti-inflammatory properties by inhibiting adhesion molecule expression and decreasing leukocyte recruitment in the vascular system (27)	HDL levels corresponded with inflammatory markers post-stroke (108) A study showed that HDL anti-inflammatory effects can reduce the risk of vascular diseases, including stroke (116)	May lead to drug development focused on modulating the anti-inflammatory effects of HDL to mitigate stroke risk	Potential variability in HDL composition can affect its anti-inflammatory functions
Neuroprotection	Reduces neuronal apoptosis and inflammation in the brain, potentially mitigating the brain's response to stroke (31)	Clinical data indicate that higher HDL levels are associated with improved neurological outcomes post-stroke (110)	Neuroprotective therapy involving HDL could improve recovery following ischemic events	Needs robust clinical trials to confirm efficacy and safety in specific populations
Intravenous administration of HDL	Significantly reduces stroke-related mortality within 24 h by decreasing BBB permeability and brain edema, in addition to lowering ROS levels in the infarct zone (51). Intravenous HDL therapy showed promise in reducing acute stroke risks in experimental settings (52)	No known clinical studies	Administration of HDL directly to stroke patients may serve as adjunctive treatments for stroke prevention in high-risk patients	Requires further exploration into long-term effects and overall safety profile
Antithrombotic properties	Modulates coagulation factors and enhances fibrinolysis, which collectively reduces thrombosis risk (16)	A study found that the platelet-to-HDL-C ratio was positively associated with both stroke incidence and CVD mortality among stroke survivors, whereas HDL-C levels alone showed no significant association with stroke risk (117)	Thromboprophylaxis strategies could benefit from HDL modulation to enhance stroke prevention measures	Thrombotic risk reduction efficacy may differ among various populations
Regulation of immune response	Modulates inflammation, which may reduce the severity of immune-mediated damage (31)	Alterations identified in specific HDL proteins, some of which are involved in inflammatory and immune responses, were linked to the acute phase response and platelet activation in AIS (73)	Developing therapies to enhance the immunomodulatory effects of HDL could improve patient outcomes following stroke	Individual responses to HDL may vary with coexisting inflammatory conditions
Antiatherogenic effects	Inhibits MCP-1 release and protects LDL from oxidation in the vascular endothelium, thus preventing atherosclerosis (105)	Observational studies have shown that HDL inversely correlates with markers of atherosclerosis (26) and with the risk of atherosclerotic events (64)	Enhancing the atheroprotective properties f HDL could be an important strategy in preventive cardiology	Possible discrepancies in the atheroprotective role of HDL necessitate further research
S1P	A bioactive lipid in HDL that augments endothelial nitric oxide production, promoting vasodilation and inhibiting platelet aggregation (54)	Low serum S1P levels in acute stroke patients are associated with greater stroke severity, larger infarct volumes, and worse outcomes (55)	The potential of S1P-mimics as a therapeutic strategy could lead to advanced therapeutic options in cerebrovascular health	More studies needed to fully elucidate its role in vascular health post-stroke
SR-B1	Mediates cholesterol ester uptake, promoting RCT, indicating a protective role against atherosclerosis (59)	No known clinical studies	SR-B1 modulation might provide a novel approach to enhance HDL functionality in stroke prevention	May lack effectiveness in certain populations; personalized approaches might be needed
HDL-associated miRNAs	HDL-associated miRNAs, such as miR-223 and miR-92a, exhibit protective effects against thrombosis and vascular dysfunction (30)	Evidence supports the role of HDL-miR in cardiovascular health and their potential to reduce stroke risk, as HDL transports small noncoding miRs that facilitate intercellular signaling (118)	Targeting the HDL-miR pathway could lead to innovative therapies that enhance vascular health and reduce stroke risk	Need to establish the precise mechanisms through which these miRNAs exert their effects

Future perspectives and conclusion

The role of HDL in stroke prevention extends beyond its plasma levels, with recent research highlighting its functionality—anti-inflammatory, antithrombotic, and antioxidant effects—as key to its protective potential. However, while HDL functionality may offer protection, more research is needed to confirm these effects and explore underlying mechanisms. The composition, size, and integrity of HDL, influenced by factors such as oxidative stress, inflammation, and diabetes, affect its functionality. The interaction with particles of similar size, like the extracellular vesicles, exosomes, and others, could alter the function via exchange of contents between these moieties. Although in vitro studies show that lipoproteins impact extracellular vesicle effects on cells, in vivo studies are required for a better understanding (119). Large cohort studies on HDL composition across ethnic groups could uncover new biomarkers associated with stroke risk, given the varying prevalence across populations.

In conclusion, high HDL-C levels alone do not guarantee reduced stroke risk, especially if HDL is dysfunctional. Future research should focus on measuring HDL functionality and conducting randomized controlled trials on its anti-inflammatory and antioxidant properties to develop more effective stroke prevention strategies.

Data and material availability

The data and materials associated with this article are not applicable, as this review article does not involve the analysis of original data or the use of specific materials.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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This review does not include the enrollment of any participants and is based on the existing literature.

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All authors have read and agreed to the published version of the article.

Conflict of interest

The authors declare that they have no conflicts of interest with the contents of this article.