Fluorouracil-induced coronary artery spasm

Abstract

Coronary artery spasm can cause angina, arrhythmic sudden cardiac death, and myocardial infarction. All these cardiac events have been occasionally reported during 5-fluorouracil (5-FU) chemotherapy. In this issue of the Journal, Lestuzzi et al. (1) report three cases in which effort angina developed during 5-FU treatment, most likely as a result of coronary artery spasm. This small series follows two isolated case reports (1). The documentation produced by the authors, although indirect, is convincing for a vasospastic origin of effort-induced angina in their patients because of the combination of angina with electrocardiographic ST-segment elevation during the recovery phase of the exercise test and the negativity of the test after treatment interruption. Elevation of the ST segment indicates a complete interruption of coronary artery blood flow and transmural myocardial ischemia rather than an inadequate increase limited by a critical coronary artery stenosis, which is known to cause subendocardial ischemia and ST-segment depression. The appearance of ischemia during the recovery phase rather than at peak exercise also indicates a sudden reduction of blood supply rather than an inadequate flow increase to meet the increased myocardial oxygen consumption. Finally, the negativity of the test after 5-FU interruption indicates the absence of chronic, flow-limiting coronary stenoses (2). In the typical clinical presentation of “variant” angina described by Prinzmetal et al. (3), spasm develops at the site of a subcritical coronary stenosis, but a variant of the variant form was subsequently described in which spasm develops also in angiographically normal coronary arteries; and such a variant is much more common among oriental than white patients (4). In this clinical syndrome, although angina typically occurs while resting, often in the early morning hours, it may also occur with effort, in about 50% of cases. Spasm can be triggered by an array of stimuli acting on different receptors, such as ergonovine, histamine, serotonin, and acetylcholine, as well as by severe alkalosis by handgrip and cold pressor tests. Thus, localized postreceptor alterations that make the coronary artery smooth muscle hypereactive to a variety of constrictor stimuli appear likely pathogenetic mechanisms for the typical clinical syndromes of variant angina (5). The nature of such postreceptor alteration remains unknown. Its appears unrelated to the atherosclerotic process or to the associated endothelial dysfunction, because in patients with very severe coronary atherosclerosis, coronary spasm is very uncommon. So far, its causes have not been investigated, largely because of the impossibility of obtaining tissue samples from the coronary artery spastic segments. The mechanisms of 5-FU-induced coronary artery spasm also remain speculative: The activation of proteinkinase C (6) may be one of the mechanisms of enhanced constrictor response of the coronary artery smooth muscle. Physical exercise is a known potential vasoconstrictor trigger, possibly through noradrenergic sympathetic stimulation. Why spasm develops in a minority of treated patients is unknown; however, awareness that it may occur should sound an important warning when a patient being treated with 5-FU has anginal chest pain. A history of syncope or of cardiac arrhythmias occurring during angina, or immediately after, is particularly suggestive of vasospastic angina and is a strong indication for interrupting the 5-FU treatment and for prescribing full antivasospastic therapy. In patients with the clinical syndrome of variant angina, such episodes are known to herald sudden cardiac death, and coronary artery spasm can be one of the causes of myocardial infarction (7). As beta-blockers are totally ineffective, antivasospastic therapy should be based on a full dose of calcium antagonists and also of nitrates, administered to cover the time when attacks occur most often, to avoid the development of tolerance. Careful observations, case reports, and small series studied by open-minded, curious physicians retain a unique role in revealing previously unsuspected mechanisms of disease. Indeed, basic molecular and cellular biology techniques can only be applied, like powerful microscopes, to clarify finer and finer details of the already established disease mechanisms on which they are focused. Clinical research should select for basic research homogeneous groups of patients whose diseases have the same pathogenetic mechanisms, to advance beyond the present era of evidence-based medicine—which implies “blanket,” good for all treatment of broad clinical syndromes—toward individual targeting of specific disease mechanisms (8).