The term coronary artery spasm (CAS) refers to a sudden, intense vasoconstriction of an epicardial coronary artery that causes vessel occlusion or near occlusion. Although CAS may be involved in other coronary syndromes, it represents the usual cause of variant angina. The variant form of angina was first described in 1959 by Prinzmetal et al,1 who used this term to indicate that angina attacks, unlike the most common form of effort angina, occurred at rest and were associated with ST-segment elevation, rather than ST-segment depression, on the ECG (Figure 1). Because myocardial ischemia occurred in the absence of any change in myocardial oxygen demand, the authors hypothesized that it was caused by an increased tonus of vessels at the level of coronary stenoses.1 Figure 1. (Top) ST-segment elevation in anterior leads, with reciprocal mild ST-segment depression in inferior leads and V6, during an angina attack in a patient with variant angina. (Bottom) Normalization of the ECG after spontaneous resolution of chest pain. Some years later, in fact, coronary angiography, performed during spontaneous angina attacks, demonstrated that CAS is the usual cause of variant angina.2–4 Coronary angiography also showed that CAS could occur at the site of a stenosis (either minor or severe) or in angiographically normal coronary arteries,5 usually at a localized segment of an epicardial artery (focal spasm) (Figure 2).6 However, sometimes CAS involves 2 or more segments of the same (multifocal spasm) or of different (multivessel spasm) epicardial coronary arteries, or may also involve diffusely one or multiple coronary branches.7 Figure 2. Occlusive spasm of the left circumflex coronary artery and near occlusive spasm of the left anterior descending coronary artery (arrows) during coronary angiography (left, top), associated with dramatic ST-segment elevation at monitoring ECG leads (left, bottom). Complete resolution of spasm (right, …

The development of novel, non-invasive techniques and standardization of protocols to assess microvascular dysfunction have elucidated the key role of microvascular changes in the evolution of cardiovascular (CV) damage, and their capacity to predict an increased risk of adverse events. These technical advances parallel with the development of novel biological assays that enabled the ex vivo identification of pathways promoting microvascular dysfunction, providing novel potential treatment targets for preventing cerebral-CV disease. In this article, we provide an update of diagnostic testing strategies to detect and characterize microvascular dysfunction and suggestions on how to standardize and maximize the information obtained from each microvascular assay. We examine emerging data highlighting the significance of microvascular dysfunction in the development CV disease manifestations. Finally, we summarize the pathophysiology of microvascular dysfunction emphasizing the role of oxidative stress and its regulation by epigenetic mechanisms, which might represent potential targets for novel interventions beyond conventional approaches, representing a new frontier in CV disease reduction.

The classic definition of cardiac syndrome X (CSX) seems inadequate both for clinical and research purposes and should be replaced with one aimed at including a sufficiently homogeneous group of patients with the common plausible pathophysiological mechanism of coronary microvascular dysfunction. More specifically, CSX should be defined as a form of stable effort angina, which, according to careful diagnostic investigation, can reasonably be attributed to abnormalities in the coronary microvascular circulation.