3.1 Atherosclerosis

When explaining conditions like atherosclerosis, it’s important to clarify the terms acute and chronic. While these words may carry emotional meaning in lay terms, they have specific scientific meanings in medicine. Acute refers to changes that are short-term, with a rapid onset and requiring urgent management. In contrast, chronic describes changes that are long-term, with a gradual onset and management that is planned over an extended period.

Atherosclerosis is a chronic condition, characterised by gradual progression and long-term management, but its treatment is largely focused on preventing acute events - such as heart attacks and strokes - which can occur suddenly as a result of plaque rupture.

The development of an atherosclerotic plaque occurs in three main stages: endothelial injury, infiltration of cholesterol and fats, and formation of a fibrous cap.

Endothelial injury is the trigger for a plaque to start. The atherosclerotic plaque represents a normal physiological process - endothelial repair - that has become pathological, meaning it no longer serves to benefit the body. Under normal circumstances, endothelial repair is a healthy and necessary response to injury.

What makes plaque formation pathological is the nature of the injury involved. Many types of endothelial injury, such as those caused by external cuts, are self-limiting and resolve once the damage stops. In contrast, the injury that leads to atherosclerosis is chronic and sustained, driven by risk factors such as hypertension, smoking, and ageing. As a result, the immune response - which would typically resolve with removal of the trigger - is no longer self-limiting.

The immune response starts with LDL cholesterol. Endothelial injury allows LDL cholesterol to penetrate endothelium, where it causes an inflammatory response. This inflammation attracts macrophages - local immune cells - which ingest the LDL to form foam cells. The accumulation of these foam cells forms what is called the fatty streak.

Over time, two key changes transform the fatty streak into a full atherosclerotic plaque - also called an atheroma. First, the foam cells are not efficiently cleared and eventually undergo necrosis, where they form a necrotic core at the centre of the plaque. Second, cells from the surrounding vessel wall migrate over the lesion and transform, forming a fibrous cap that covers and isolates the necrotic core beneath.

Atheromas cause two main problems. First, they narrow blood vessels. When arteries become narrowed, blood flow is restricted, which leads to increased pressure. High blood pressure in turn damages the endothelial lining of blood vessels, further promoting the formation of atheromas. This creates a positive feedback loop - high blood pressure accelerates atherosclerosis, and atherosclerosis raises blood pressure.

Narrowed arteries may also cause ischaemia - a state in which tissues receive inadequate oxygen. This is the key mechanism of damage in cardiovascular disease. It makes intuitive sense: the primary role of the cardiovascular system is to deliver oxygen. When it’s impaired, tissues are starved of oxygen, leading to ischaemia.

The second major problem is the increased risk of blood clots. The fibrous cap covering an atheroma is thinner and more fragile than the surrounding endothelium. It can rupture easily, especially under high pressure. When it ruptures, the necrotic core - rich in collagen and other pro-coagulant substances - is exposed to circulating blood, triggering a hypercoagulable state.

These clots are not controlled as in healthy physiology and are likely to break off and travel through the bloodstream until they block a smaller artery. The clot attached to the endothelium is called a thrombus, and the travelling clot is called an embolism. If not quickly dissolved or removed, the resulting ischaemia from thrombi or emboli will cause infarction - tissue death from lack of oxygen. When this occurs in the coronary arteries, it's known as a myocardial infarction, or in lay terms, a heart attack.