Pathophysiology

Myocardial infarction (MI) is defined as myocardial cell death in combination with symptoms suggestive of myocardial ischaemia. This is usually in association with ECG changes or new left bundle branch block (LBBB), as well as a rise and/or fall in cardiac biomarkers (from myocardial necrosis).1,2

 

Atherosclerosis is a chronic vascular disease that is characterized 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

Stages  of  atherosclerosis  to  thrombus  formation  causing  ischaemia obstruction of blood flow causing acute coronary syndrome

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

Triggering of plaque rupture Different risk factors causing plaque rupture

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 αIIbβ3 (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

Thrombus  formation  in  myocardial  infarction  and  other  acute  coronary  syndromes    cascade of events leading to thrombus formation in cardiovascular diseases

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

Acute  ischaemic  syndromes  A  broad  spectrum  of  cardiac  disorders  related  to  thrombosis    Increasing severity of cardiovascular diseases leading to death

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.

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 hour after onset no myocardium can be salvaged.5

Several factors influence the time-course of myocardial necrosis:

  • 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.

Myocardial tissue begins to die in as little as 20 minutes after an ischaemic event. It can take as long as 2-4 hours or longer for this necrosis to become complete. The time required for necrosis depends on several factors, including, collateral circulation, the type of occlusion, the sensitivity of affected myocytes to ischemia, pre-conditioning and individual demands for nutrients and oxygen.6

References: 
  1. Steg G, et al. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J 2012;33:2569-2619.
  2. American College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions; O’Gara et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61(4):e78-e140.
  3. Kumar, Arun, Subrata Kar, and William P. Fay. Thrombosis, physical activity, and acute coronary syndromes. J Appl Physiol 2011:111:599-605.
  4. Sharma M, et al. Current and Practical Management of Acute Myocardial Infarction. J Thromb Thromb 1997;4:375-396.
  5. Boersma E, et al. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet 1996;348:771-775.
  6. Thygesen K, et al. Universal definition of myocardial infarction. J Am Coll Cardiol 2012;60(16):1581-1598.
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