Introduction

Hyperlipidaemia is a common condition that is crucial to the onset of atherosclerosis. Hyperlipidemia can be defined as having high low-density lipoprotein (LDL), total cholesterol, triglyceride levels, or lipoprotein levels or low high-density lipoprotein (HDL) levels. Atherosclerosis, on the other hand, is a long-lasting inflammatory condition affecting the arteries. It is a disease of the arteries that is caused by lipid accumulation and plaque formation, and it is a silent killer.^1,2

Understanding hyperlipidaemia and atherosclerosis is important for people affected by these conditions, as early intervention and prevention can stop the risk factors for cardiovascular disease. Elevated blood lipid levels and plaque formation in the arteries can lead to more severe complications such as thrombosis (formation of blood clots), angina, myocardial infarction (MI) (heart attacks) and even death.

Lipid metabolism

Starting with the fundamentals of lipid metabolism, we need to understand what lipoproteins are and their role in the human body. 

Lipoproteins are particles composed of fat and protein that act as shuttles for cholesterol and lipids, transporting them throughout the body to their final destinations in peripheral tissues or the liver. There are 4 main classes of lipoproteins in the body: 

• High-density lipoprotein (HDL)
• Low-density lipoprotein (LDL) 
• Very low-density lipoprotein (VLDL)
• Chylomicrons

Certain types are regarded as “better” than others. In this context, LDL is referred to as “bad cholesterol,” while HDL is often called “good cholesterol”.³

Pathways

There are multiple pathways in the body responsible for cholesterol and lipid metabolism that, if disrupted, may cause hyperlipidaemia and accelerate the onset of atherosclerosis.⁴

• The endogenous pathway: describes the process by which cholesterol is synthesised inside the body, primarily in the liver. A chain of chemical reactions that begins with acetyl-CoA turning into mevalonate by the enzyme 3‐hydroxy‐3‐methylglutaryl coenzyme reductase (HMGCR), which is then further converted into squalene, then lanosterol and ultimately the production of cholesterol
• The exogenous pathway: humans can also intake cholesterol externally through their diet. Meats and dairy products are a huge source of cholesterol, where in the intestine, the cholesterol content is absorbed by epithelial cells

Causes of hyperlipidaemia

There are multiple causes of elevated lipid and cholesterol levels in the body, all of which can be categorised under either primary or secondary hyperlipidaemia. Primary hyperlipidaemia’s cause is more genetic, whereas secondary hyperlipidaemia is the result of underlying conditions such as diabetes.

Primary hyperlipidaemia 

Primary hyperlipidaemia is also known as familial hypercholesterolaemia. It is associated with mutations in genes that affect cholesterol clearance and overall lipid levels in the body. A mutation in the gene responsible for the low-density lipoprotein receptor (LDLR) causes a reduced absorption of LDL by cells, leading to elevated levels in the bloodstream and contributing to the development of atherosclerosis. Genetic defects of proprotein convertase subtilisin/kexin type 9 (PCSK9) and apolipoprotein B (APOB) can also cause increased binding to LDLR, resulting in decreased levels of LDL uptake in the cells.⁵

Secondary hyperlipidaemia

Secondary hyperlipidaemia is caused by underlying conditions which are not genetic. For example, a poor and unbalanced diet that contains excessive cholesterol increases the overall lipid levels circulating in the blood, which can contribute to the development of atherosclerosis. 

Conditions such as type 2 diabetes mellitus lead to an overall rise in lipid levels due to the presence of insulin resistance. The concentration of VLDL in the plasma rises, and LDL also increases, albeit not to the same degree. There is also a rise in lipoprotein levels overall, which contributes to the development of secondary hyperlipidaemia.

Another condition that leads to elevated levels of circulating lipids in the body is hypothyroidism, which disrupts hormone regulation and affects lipid metabolism as a whole. Moreover, certain medications can influence lipid metabolism or directly elevate lipid and cholesterol levels in the body.⁶

The development of atherosclerosis in hyperlipidaemia

The initial phase of atherosclerosis development involves endothelial dysfunction. The endothelial surface of the arteries is the innermost layer, and damage to it can lead to increased permeability. One contributor to the damage of the endothelial layer is oxidative stress, which adversely affects nitric oxide metabolism, essential for maintaining vascular health. Various factors contribute to the impairment of the endothelial cell layer. They include:

• Cigarette smoke
• Elevated lipid levels
• Diabetes
• Hypertension

When this layer is compromised, LDL permeability increases, allowing it to penetrate beneath this layer.⁷

The next stage involves the infiltration of LDL, as they penetrate beneath the endothelial cell layer and undergo oxidation. The oxidation of LDL initiates an inflammatory reaction, leading to the recruitment of monocytes to the endothelial cell layers. This process is crucial for the subsequent stage, where foam cells are attracted and contribute to the advancement of atherosclerosis.⁸

After monocytes are drawn to the site, they develop into macrophages, which subsequently evolve into macrophage foam cells. While foam cells resemble macrophages, they are specifically located in fatty deposits to take up LDLs. The gathering of numerous foam cells results in the development of a fatty streak. Over time, this fatty streak can progress into plaque formation, ultimately causing the narrowing of the arteries.

The continuous arrival of monocytes and the buildup of foam cells, along with the movement of smooth muscle cells from the underlying layer beneath the endothelial cell layer, contribute to the creation of a fibrous cap (FC). If inflammation continues within this FC, it may eventually rupture due to plaque instability, resulting in thrombosis. This leads to the formation of a blood clot in the vessel, obstructing blood flow, which can result in potentially life-threatening consequences if it happens in specific circulations.⁹ 

Consequences

The advancement of atherosclerosis or the development of thrombosis can lead to various issues, including cardiovascular, cerebrovascular, peripheral complications, or aneurysms. Cardiovascular problems include angina and heart attacks.

Angina occurs as a result of atherosclerosis, which causes a blockage in the coronary artery. This artery is responsible for supplying blood to the heart, and any obstruction here can lead to pain during physical activity. Likewise, a heart attack is caused by a blockage in an artery that delivers blood to specific regions of the heart. This blockage ultimately leads to cell death, resulting in a heart attack.

Cerebrovascular complications, like an ischemic stroke, occur when the arteries in the brain become narrowed or obstructed due to atherosclerosis or the formation of a thrombus. The consequences vary depending on which area of the brain the affected artery supplies. If the arteries supply Broca's area, which is responsible for speech, people with this condition may struggle with speaking. This is why early intervention is necessary to prevent complications as a result of hyperlipidaemia and atherosclerosis.¹⁰

Diagnosis, prevention and management

Diagnosis, prevention, and management of hyperlipidaemia and atherosclerosis are crucial to reduce life-threatening risks for affected individuals. Blood tests, called lipid panels, measure cholesterol and triglyceride levels.

Preventing these conditions involves reducing the risks of endothelial dysfunction and adopting a healthier lifestyle. Avoiding lipid-rich foods and engaging in physical exercise are effective prevention methods, along with quitting smoking, which causes oxidative stress and worsens endothelial dysfunction. 

Although maintaining a healthy lifestyle can be challenging, there are medication options for managing atherosclerosis. Statins and PCSK9 inhibitors are common treatments. Statins lower cholesterol by inhibiting an enzyme, while PCSK9 inhibitors help increase LDL uptake by cells, reducing lipid levels in the body.^1,2,11

Summary

Hyperlipidaemia is a common condition characterised by high levels of low-density lipoprotein (LDL), total cholesterol, triglycerides, or low high-density lipoprotein (HDL) levels. It is linked to the development of atherosclerosis, a long-lasting inflammation of the arteries that results in lipid accumulation and plaque formation. Understanding these conditions is important since they can lead to severe cardiovascular issues like blood clots, angina, heart attacks, and even death. 

Lipoproteins, which are particles made of fat and protein, transport cholesterol and lipids in the body. The four main types of lipoproteins are HDL, LDL, very low-density lipoprotein (VLDL), and chylomicrons. LDL is often referred to as "bad cholesterol," while HDL is known as "good cholesterol. " Disruptions in lipid metabolism can cause hyperlipidaemia and accelerate atherosclerosis onset. There are two types of hyperlipidaemia: primary and secondary. Primary hyperlipidaemia, often hereditary, is caused by genetic mutations affecting cholesterol clearance. Secondary hyperlipidaemia arises from non-genetic conditions, such as poor diet or diabetes, leading to elevated lipid levels. Atherosclerosis begins with endothelial dysfunction, where the inner layer of arteries becomes damaged, often due to oxidative stress from factors like smoking, high lipid levels, and diabetes. Once the endothelial layer is compromised, LDL can enter and undergo oxidation, triggering inflammation and attracting monocytes, which develop into macrophages and then foam cells. These foam cells lead to the formation of fatty streaks and, eventually, plaques that narrow arteries.

The progression of atherosclerosis can result in serious health issues such as angina and heart attacks, as well as cerebrovascular complications like strokes. Early intervention is crucial to prevent these outcomes. Diagnosis usually involves lipid panels to measure cholesterol and triglyceride levels. Prevention includes lifestyle changes, such as a healthier diet, exercise, and quitting smoking. For management, medications like statins and PCSK9 inhibitors can help lower lipid levels and reduce atherosclerosis risk.