Advances in understanding the mechanisms of angina pectoris in cardiac syndrome X.

Angina pectoris was initially described by Heberden in 1772 and is considered to be the hallmark of ischaemic heart disease. However, with the advent of selective coronary angiography, clinicians were confronted with a conundrum as some patients with ‘unmistakable’ angina had angiographically normal epicardial coronary arteries. This apparent disparity between the clinical symptoms and the angiographic findings appeared to be resolved when it was demonstrated that affected patients had electrocardiographic and metabolic evidence of ischaemia. Thus, it was hypothesized that the angina experienced by these patients was due to myocardial ischaemia secondary to coronary microvascular dysfunction. This new disorder was referred to as cardiac syndrome X and is typically characterized by exertional angina, electrocardiographic evidence of ischaemia on stress testing, angiographically smooth epicardial coronary arteries, and no other recognized cause for the chest pain. Multiple studies have subsequently demonstrated the presence of microvascular dysfunction in these patients. Controversy arose when several well-controlled studies failed to identify metabolic evidence of ischaemia in these patients despite reproducing the chest pain. This led to divided opinion among the researchers, with views ranging from an ‘ischaemic hypothesis’, where technical limitations account for the inability to detect the ischaemia, to a ‘non-ischaemic hypothesis’ where alternative mechanisms are proposed to be responsible for the chest pain. Recent technical advances have assisted in demonstrating surrogate markers of ischaemia in these patients, including subendocardial perfusion defects on magnetic resonance imaging, production of oxidative stress markers during pacing-induced angina, and a reduction of high-energy phosphates on nuclear magnetic spectroscopy. The ‘non-ischaemic hypothesis’ has been further advanced by the demonstration of altered pain perception in patients with syndrome X. Several studies investigating patients with this disorder have demonstrated an increased pain sensitivity to cardiac stimuli such as intracardiac catheter manipulation, radiographic contrast injection, intravenous adenosine administration, and atrial and ventricular pacing. Further studies suggested that the abnormal pain perception was a generalized phenomenon by demonstrating an increased pain sensitivity to a variety of peripheral stimuli including tourniquet application and electrical and thermal skin stimulation. The mechanism responsible for the increased pain sensitivity in syndrome X patients is likely to involve a defect in the nociceptive pathways responsible for angina pectoris. Our understanding of this pathway remains incomplete but the current perspective is summarized as follows. Noxious stimuli activate nociceptive receptors in sensory endings of thin myelinated (Ad fibres) and unmyelinated (C fibres) afferent nerve fibres. Several stimuli may be involved, but adenosine has received considerable attention because intravenous administration to healthy volunteers produces anginalike chest pain without associated ischaemic ECG changes. This algogenic effect is mediated via A1 receptors located on perivascular sympathetic nerves and is independent of adenosine’s vasodilatory effect mediated via A2 receptors. 5 The stimulated afferent cardiac pain fibres pre-dominantly ascend to the sympathetic ganglia (C7–T4) and synapse in the dorsal horn of the spinal cord along with other converging afferent nociceptive fibres. Subsequent nociceptive transmission is modulated by these converging impulses and by