Introduction

Hyperlipidaemia is the elevated levels of cholesterol and triglycerides in the blood plasma, which leads to a multiple range of cardiovascular diseases like congestive heart failure (CHF), stroke, and chest pain, or ‘angina pectoris’. Its harmful effects are not restricted to lipid accumulation. Literature studies highlight oxidative stress as a key driver to inducing inflammation in hyperlipidaemia.¹ 

This article will explore the role of inflammation in hyperlipidemia, clinical symptoms, further consequences, and possible treatment strategies. 

What is the basic pathophysiology of hyperlipidaemia?

Homeostasis refers to the processes in the body which maintain internal balance, from body temperature to concentrations of certain substances in the blood or plasma. When the plasma levels of ‘bad’ lipids like low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), and triglycerides (TGs) go up, disturbances in lipid homeostasis occur. This condition is termed 'hyperlipidaemia' and may occur due to a number of processes:^1,2

• Increased synthesis and storage of lipids as a result of diet changes or stress
• Increased reuptake of lipoproteins
• Impaired removal or efflux of very low-density lipoproteins 

Such mechanisms accumulate lipoproteins within the walls of blood vessels, triggering plaque build up in the blood vessels via atherosclerosis and arteriosclerosis. Oxidised LDL (Ox-LDL) is formed by the reaction between LDL and reactive oxygen species (ROS) present in inflamed environments, and interacts with arterial proteoglycans to form aggregates of cholesterol crystals. This disrupts the normal functioning of endothelial cells which make up the lining of the arteries and stimulates leukocytes, a type of white blood cell usually involved in counteracting disease, which causes maladaptive changes in your vessels.^1,2

Does inflammation occur in hyperlipidaemia?

Yes, inflammation is triggered in hyperlipidaemia. Ox-LDL upregulates adhesion molecules (VCAM-1, ICAM-1, E-selectin) within endothelial cells, which secrete monocyte chemoattractant protein-1 (MCP-1) and T-cells. This leads to further inflammation and increases the size of atherosclerotic plaques. 

Monocytes modify themselves into macrophages, a type of white blood cell specialised in engulfing things, in an attempt to remove some LDL. Through doing so, they become ‘foam cells’, which further secrete pro-inflammatory chemicals, like tumour necrosis factor alpha (TNF-α) and interleukins like IL-1β and matrix metalloproteinases (MMP). This drives atherosclerotic disease progression, the main hallmarks being plaque/lesion growth and instability.^2,3

Additionally, neutrophils release neutrophil extracellular traps (NETs) to amplify inflammation of blood vessels and increase atherogenesis in hyperlipidaemia.^2,3

How does oxidative stress occur in hyperlipidaemia?

A literature survey validates that oxidative stress is the imbalance between oxidant and antioxidant species. This includes ROS, as well as nitrogenous species, which are produced during abnormal lipid-driven damage to blood vessels, causing retention of more lipids in the vessel walls, and further worsening the inflammation. 

ROS aggravate endoplasmic reticulum (ER) stress and impairs the electron transport chain (ETC) and the biochemical mechanism behind the formation of energy in mitochondria. This induces apoptosis and necrosis (cell death) of cells within the blood vessels. As a result, apoptotic bodies and cellular debris expand the necrotic core and exacerbate plaque instability.²

Is there any crosstalk between inflammation and oxidative stress in hyperlipidaemia?

Yes, there is a close bidirectional association between oxidative stress and inflammatory mechanisms in hyperlipidaemic conditions. When LDL enters the bloodstream/circulation, these molecules get entrapped within the endothelial space, where multiple stores of enzymes are present. For example^2,3

• Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase 
• Myeloperoxidase (MPO) 
• Xanthine oxidase 
• iNOS (inducible nitric oxide synthase) 

These enzymes produce ROS like peroxides and superperoxides, which have the potential to oxidise circulating LDL lipids to form Ox-LDL. This then behaves like danger-associated molecular patterns (DAMPs), triggering the immune system and increasing inflammation.^2,3

The role of DAMPs in inflammation and disease progression

DAMPs bind with receptors like CD36 and SR-A1 present on LOX-1, a ‘scavenger receptor’ for Ox-LDL present on endothelial and immune cells like macrophages. This initiates downstream signalling, thereby releasing pro-inflammatory mediators like the aforementioned TNF-α and IL-6 within the blood plasma. This causes vascular inflammation and consequently produces mitochondrially driven ROS, thereby perpetuating cellular damage and recruiting more inflammatory cells. 

This is called a self-propagating vicious cycle in which oxidative stress induces inflammation, and inflammation in return triggers oxidative stress. This positive feedback loop drives atherogenesis and exacerbates plaque instability.^2,3

Clinical consequences

An interlink between oxidative stress, inflammation and LDL accumulation leads to the following complications:^4,5,6

• Endothelial dysfunction
• Atherosclerotic plaque 
• Microvascular dysfunction
• Prothrombosis (abnormally high blood coagulation)

Further potential clinical consequences that are not directly linked to disease pathology however, may arise as a result of oxidative stress and hyperlipidemia and include:

• Metabolic complications like insulin resistance
• Organ complications like acute pancreatitis (chylomicronemia)
• Nonalcoholic fatty liver disease (NAFLD)
• Chronic kidney disease (CKD)

Biomarkers for inflammation and oxidative stress in hyperlipidaemia

Biomarkers are molecules, the levels of which can be measured in a clinical test, in order to predict or assess the presence or severity of a condition. In the case of hyperlipidaemia, molecular markers associated with inflammation and oxidative stress include the following:^7,8,9 

• C-reactive protein (CRP)
• Cytokines like IL-6, IL-1β, TNF-α
• Cell adhesion molecules (CAMs)
• E-selectin
• Myeloperoxidase (MPO)
• Lipoprotein-associated phospholipase A₂ (Lp-PLA₂)
• Ox-LDL (circulating)
• malondialdehyde (MDA/TBARS)
• Advanced oxidation protein products (AOPP).
• Glutathione (GSH/GSSG ratio) 
• Superoxide dismutases (SOD)
• Catalase
• NOx (nitrite/nitrate)

Therapeutic strategies

Changes in lifestyle are required to improve insulin sensitivity, reduce oxidative stress-driven inflammation, and modulate lipid profiles. These non-pharmacological strategies help with what are referred to as ‘modifiable risk factors’ and are most effective in combination with medical treatment. Some examples of lifestyle changes include:¹⁰

• A balanced diet (eating heart-healthy foods)
• Regular workout 
• Smoking cessation

Pharmacological interventions may have anti-inflammatory and/or lipid-lowering effects by targeting the nuclear factor kappa B (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), and peroxisome proliferator-activated receptor (PPAR) pathways, for instance:

1. Lipid-lowering agents like statins and fibrates for reducing LDL-C and triglycerides¹¹
2. Anti-inflammatory drugs like canakinumab and colchicine, at low doses¹²
3. Antioxidant therapies like vitamins C and E¹³
4. Potential novel immunological therapies like CXCL1/CXCR2 antagonists to block neutrophil recruitment and peptidyl arginine deiminase 4 (PAD4) inhibitors to reduce NET formation¹⁴

Some medicinal plants may also be used to provide adjunctive therapeutic value, for example:¹⁵

• Active constituents from Salvia miltiorrhiza (red sage)
• Polyphenols from Punica granatum (pomegranate)
• Curcumin from Curcuma longa (turmeric)

FAQs

Are there any symptoms of oxidative stress?

Yes, oxidative stress may manifest in the following ways: 

• Body (muscle and joint) pain 
• Fatigue
• Cognitive impairment (trouble with concentration, memory, or decision-making)
• Muscle and/or joint pain
• Increased appearance of wrinkles
• Loss or a dulling of hair colour
• Decreased eyesight
• Headaches
• Sensitivity to noise

Which vitamin deficiency leads to oxidative stress?

Vitamin B12 deficiency can lead to increased oxidative stress and ROS production. Supplementation with oral tablets such as cyanocobalamin, may therefore improve cardiovascular health.

Does magnesium have a role in causing oxidative stress?

Yes, magnesium deficiency impairs mitochondrial function, thereby disrupting the electron transport chain and producing ROS. Once again, supplementation dietary or otherwise may therefore be beneficial.

Summary

Hyperlipidaemia leads to cholesterol and triglyceride buildup in the walls of blood vessels, initiating atherosclerosis and multiple cardiovascular system (CVS) disorders, like strokes and aneurysms. Accumulated LDLs bind to surrounding immune cells and release signalling factors, which trigger an innate immune response and inflammation. Neutrophils are the first to adhere to the vessel wall through their receptor CXCR2, which induces histone citrullination in neutrophils via the PAD4 enzyme, thereby promoting adhesion. These immune cells, on top of increasing plaque size and instability, also release NETs into their surroundings which further induces inflammation in the blood vessel walls, although this is a fairly new area of research. 

Blocking pharmacological targets, like the aforementioned CXCR2 receptor or PAD4 enzyme, could attenuate neutrophil recruitment and adhesion to endothelial cells, as well as NET formation. Lipid-lowering drugs like permafibrate - a triglyceride-lowering drug currently in the research stage and yielding conflicting results - have been found to reduce both lipid levels and neutrophil activation. This association validates the interconnection between lipid accumulation and oxidative stress-induced inflammation. 

Therefore, targeting neutrophils and resultant inflammation of blood vessels, could provide novel pharmacological strategies to mitigate the progression of atherogenesis - a true pathological manifestation of hyperlipidaemia.