Lipoprotein Quality including increased negative electric charge in LDL and HDL may predict ischemic stroke: Study

Findings of a new study suggest that the quality of LDL and HDL cholesterol, rather than their quantity, is more important in determining the residual risk of ischemic stroke. It highlights that certain qualitative changes in lipoproteins-such as an increased negative electric charge in LDL and HDL (referred to as LDL(-) and HDL(-))—may contribute to the progression of cardiovascular diseases.

The findings underscore the importance of going beyond traditional quantitative cholesterol levels to evaluate the risk of these pathologies.

Dr Sonia Benítez, a researcher in the Cardiovascular Biochemistry Research Group at IR Sant Pau and one of the study’s authors, emphasised that "it is not so much the amount of LDL or HDL as their quality that determines the residual risk of ischaemic stroke. This study confirms that some qualitative alterations in lipoproteins, such as the increased negative electric charge in LDL and HDL (LDL(-) or HDL(-)), could play a causal role in the progression of cardiovascular diseases."

The relationship between ischaemic stroke and lipoproteins

Ischaemic stroke, one of the leading causes of mortality and disability worldwide, is often linked to carotid atherosclerosis. Approximately 20% of strokes are directly associated with the presence of atheromatous plaques in the carotid arteries, significantly increasing the risk of severe vascular events. Traditionally, the clinical management of these patients has focused on reducing LDL and HDL cholesterol levels. However, this new study from IR Sant Pau highlights that the qualitative characteristics of lipoproteins are also crucial in the development and progression of these diseases. This new perspective creates opportunities to innovatively address lipoprotein alterations and associated risks.

The study was conducted as an observational cohort study at Sant Pau Hospital between January 2016 and March 2019. The population studied included adult patients who had experienced anterior circulation ischaemic stroke and recently diagnosed carotid atherosclerosis, as well as a control group of healthy subjects. Lipoproteins were isolated from blood samples of 27 healthy subjects and 64 patients with carotid atherosclerosis seven days and one year after the stroke.

Alterations in qualitative properties

Seven days after the first stroke, LDL showed an increase in negative charge, an elevation of pro-inflammatory ceramides and triacylglycerols, and a decrease in phospholipids and cholesterol. A comprehensive lipidomic study of LDL was conducted in collaboration with Dr Öörni’s group at the Wihuri Research Institute in Helsinki. These LDL modifications are associated with inflammatory and atherogenic processes that increase the vulnerability of carotid plaques. Regarding HDL, protein composition alterations were identified, such as a reduction in apoA-I levels and an increase in apoA-II and apoC-III, impairing their antioxidant and anti-inflammatory properties and compromising their ability to prevent LDL modification and its inflammatory effect.

A notable aspect is that these qualitative alterations persist despite the early introduction of medications like statins. “This suggests that these modifications are deeply rooted in the patient’s pathophysiology. However, one year after the stroke, thanks to therapeutic interventions such as statins and antiplatelet agents, as well as possible lifestyle improvements, lipoproteins showed significant improvement,” adds Dr Sonia Benítez.

Thus, LDL became less prone to oxidation and aggregation, while HDL partially recovered its protective properties. Additionally, a reduction in LDL(-) and HDL(-) levels—electronegative lipoprotein subtypes with high atherogenic potential-was observed. “This may mean that therapeutic interventions can partially reverse the harmful effects of these alterations,” adds Dr Núria Puig, also a researcher in the Cardiovascular Biochemistry Group and the first author of the publication.

A paradigm shift

This research introduces a paradigm shift in understanding the functional role of lipoproteins in cardiovascular diseases, particularly in ischaemic stroke associated with carotid atherosclerosis. The findings underscore the need for an integrative approach to explore the qualitative properties of lipoproteins to identify patients at high risk of complications, even when their quantitative lipid levels appear normal.

This can help personalise treatments based on the specific characteristics of each patient and better tailor pharmacological and non-pharmacological interventions. The researchers also point towards developing therapeutic strategies aimed at modifying lipoprotein composition, with a potential positive impact on preventing cardiovascular complications. This includes reducing LDL(-) and HDL(-) through dietary changes, physical exercise, and more consistent adherence to statin treatments.

Clinical implications and future directions

However, the study has some limitations, such as the small sample size, which makes it difficult to generalise the results. This highlights the need for studies with larger cohorts to confirm the findings and analyse specific subgroups, such as by sex or type of therapeutic intervention. In this regard, Dr Pol Camps from the Stroke Unit, second author of the publication, and Dr Benítez have recently formed, along with other European groups, a consortium called BioStroke focused on stroke biomarker research, aiming to establish collaborations that will allow for expanding studies to larger patient cohorts.

According to Dr Benítez, “translational research in this field is key to bringing these findings into clinical practice. Our future goal is to develop tools to identify patients at higher risk and eventually design therapeutic strategies aimed at reversing these lipoprotein alterations.” This research opens a promising avenue for future clinical approaches that focus not only on traditional lipid levels but also on the qualitative properties of lipoproteins, thereby complementing current therapeutic strategies and reducing the risk of stroke recurrence and other cardiovascular complications.

Reference:

Puig, Núria et al., Alterations in LDL and HDL after an ischemic stroke associated with carotid atherosclerosis are reversed after 1 year ‡, Journal of Lipid Research, DOI:10.1016/j.jlr.2024.100739