Angina module 3: pathophysiology

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Pathophysiology of angina

Angina pectoris is most commonly caused by myocardial ischaemia which results from a mismatch between myocardial blood flow (supply) and oxygen demand. Restriction of myocardial blood flow usually results from atherosclerotic narrowing of an epicardial (surface) coronary artery, though abnormal vasodilatation or even vasoconstriction resulting from impaired endothelial function are also important mechanisms.

Figure 1. Diagram showing the reduced production of nitric oxide by the endothelium in atherosclerosis

Heart rate is a major determinant of myocardial ischaemia,1 principally through increased myocardial oxygen demand and reduced diastolic perfusion. These pathophysiologic features have provided the rationale for development of current pharmacotherapeutic strategies in patients with angina pectoris, namely, heart rate reduction, vasodilatation, and modification of atherosclerosis progression (see Angina module 6: secondary prevention and treatment).

Mechanisms of atherosclerosis

The pathophysiology of atherosclerosis, development of symptomatic angina and subsequent, acute coronary syndrome (ACS) is well characterised.  The earliest visible atherosclerotic lesion appears to be the fatty streak.  Beginning in early life, these fatty streaks, or type II lesions, are slightly raised above the intimal surface and predominantly contain foam cells derived from tissue macrophages and T lymphocytes.  Many of these fatty streaks progress to become advanced atherosclerotic plaques.  The earliest detectable physiological manifestation of atherosclerosis is reduced production of the endothelium-dependent vasodilator, nitric oxide (NO)(figure 1).

Figure 2. Forearm venous occlusion plethysmography with local brachial artery infusion has become one of the ‘gold-standards’ in the assessment of vascular function in health and disease, and an accurate, reproducible and convenient method with which to assess the effect of new vasoactive drugs and hormones in humans in vivo

NO is synthesised from the amino acid L-arginine by means of the enzyme NO synthase (e-NOS). It is released from endothelial cells in response to shear stress from blood flow and the activation of a variety of receptors.  NO also has important anti-inflammatory, antithrombogenic and antiproliferative properties.  Endothelial function can be assessed in a number of ways, notably with forearm strain gauge plethysmography (figure 2) or high-resolution ultrasound to measure changes in flow-mediated endothelium-dependent vasodilators such as acetylcholine.

Endothelial dysfunction is characterised by a reduction of the bioavailability of vasodilators, such as NO, and an increase in endothelium-derived contracting factors,
including endothelin and angiotensin II (AII).