Pathophysiology

Atherosclerosis is a chronic vascular disease that is characterised by endothelial dysfunction, intimal hyperplasia, inflammation, smooth muscle proliferation, and deposition of lipids and formation of microvessels within the vascular wall. The focal nature of atherosclerosis results in formation of discrete plaques. Key components of the plaque include a fibrous cap, composed of smooth muscle cells and fibroblasts, an overlying layer of endothelial cells, and an internal core that contains cholesterol and other lipids, macrophages, foam cells (which are derived from macrophages), other inflammatory cells, and extracellular matrix. Some plaques are more vulnerable to rupture than others. Important characteristics of the vulnerable plaque include a thin fibrous cap, a large, lipid-rich, hypocellular core, and the presence of leukocytes, which produce metalloproteinases (MMPs) and other factors that trigger extracellular matrix degradation and apoptosis, within the fibrous cap.³

Stages of atherosclerosis to thrombus formation, causing ischaemia³

An acute coronary syndrome (ACS) is generally triggered by the disruption of an atherosclerotic plaque. This can be caused by a variety of factors, which may operate independently or in combination.

Triggering of plaque rupture⁴

Thrombosis plays a critical role in the pathogenesis of ACS, as disruption of an atherosclerotic plaque exposes flowing blood to sub-endothelial collagen, tissue factor, and other pro-coagulant molecules that trigger activation of platelets and formation of fibrin within the vessel lumen. If the thrombotic response to plaque disruption is limited, coronary blood flow is not altered significantly and the plaque disruption remains clinically silent. However, if platelets and fibrin amass in sufficient quantity to obstruct coronary blood flow, symptoms of ischaemia ensue.³

Atherosclerotic plaque disruption triggers platelet activation by multiple pathways. Endothelial disruption exposes subendothelial collagen, which activates platelets by binding glycoprotein VI (GPVI) and integrin α₂ β₁ on the platelet surface. After plaque rupture, plasma von Willebrand factor (vWF) binds to collagen, and platelets adhere to immobilised vWF via GPIb-GPV-GPIX and integrin α_IIbβ₃ (GPIIb/IIIa). GPIIb/IIIa also binds fibrinogen, which drives platelet aggregation and thrombus growth. Adenosine diphosphate (ADP) and thromboxane A2 bind to specific receptors on platelets to amplify their aggregation after plaque rupture.³

Thrombus formation in myocardial infarction and other acute coronary syndromes

The primary activator of the blood coagulation system is tissue factor (TF), a cell-membrane-anchored protein that is abundant in the adventitia of normal blood vessels and the intima and media of atherosclerotic arteries. In response to plaque disruption, plasma factor VIIa (“a” denotes the activated form of the blood coagulation proteins) binds TF to produce a complex that converts factor X to factor Xa. Factor Xa, in complex with factor Va, calcium, and phospholipid, converts prothrombin to thrombin.

In addition to activating platelets and clotting fibrinogen, thrombin activates factor XIII, which cross-links fibrin monomers. The contact activation pathway, consisting of prekallikrein, high-molecular-weight kininogen, factor XI, and factor XII, produces factor IXa, which, in complex with factor VIIIa, activates factor X, i.e., factor X can be activated by both the TF and contact activation pathways. While the TF pathway is the dominant initiator of haemostasis and thrombosis, the contact activation pathway plays an important amplification role.³

Acute coronary syndromes

Acute coronary syndrome is a term used to describe a broad spectrum of cardiac disorders related to thrombosis and ischaemia. All have a common disease process – thrombosis, superimposed on atherosclerosis – but with different clinical manifestations.

Acute ischaemic syndromes: A broad spectrum of cardiac disorders related to thrombosis

From here on, we focus on the management of acute ST-elevation myocardial infarction (STEMI), that is, the management of patients presenting with ischaemic symptoms and persistent electrocardiographic evidence of ST-segment elevation.

Cell death does not occur immediately, depending on the collateral circulation, extent of the arterial occlusion, and other factors (see below).⁶ At 30-40 min, irreversible cell death of the myocardium begins and function is disrupted.^5,6 After approximately 6-8 min, necrosis of the ischaemic myocardium sets in.^5,6

Several factors influence the time-course of myocardial necrosis, including, collateral circulation, the type of occlusion, the sensitivity of affected myocytes to ischaemia, pre-conditioning and individual demands for nutrients and oxygen.^5,6

• The time window for effective treatment is shortest in previously healthy (young) patients with abrupt occlusion of a coronary artery.
• Patients with a history of pre-infarction angina have an increased tolerance to subsequent coronary occlusion and tend to have less myocardial damage, less cardiac failure, better left ventricular function and therefore lower mortality.
• Intermittent spontaneous reperfusion may limit myocardial damage and patients may benefit from relatively late therapeutic interventions.
• Elderly patients, especially those who are older than 75 years, have an increased risk of myocardial injury.

Time course of myocardial ischaemia

Animal experiments with anaesthetised dogs have shown that infarct size increases with the duration of coronary occlusion for up to 6 hours. After this time only 10–15% of the ischaemic myocardium remains viable.⁵

In humans, the time-course is very similar. The average infarct size without reperfusion therapy is about 20% of the left ventricle. Thrombolytic treatment, starting 1 hour after onset, salvages 70% of the jeopardised myocardium, but starting 5 hours after onset no myocardium can be salvaged.⁵

Early reperfusion is essential to prevent loss of myocardial function.