1. Introduction
Coronary artery spasm (CAS, variant angina) comprises both Prinzmetal’s angina (PA: predominantly large vessel vasospasm) (Prinzmetal et al. , 1959) and the coronary slow flow phenomenon (CSFP: predominantly small coronary artery spasm) (Beltrame et al. , 2003). Both of these disorders are characterized by cyclic fluctuation of symptoms, irrespective of treatment status (Waters et al. , 1983; Sakata et al. , 1996; Kopetz et al. , 2012) and a poor symptomatic response to treatment with sublingual nitrates (Ninomiya et al. , 2008; Morikawa et al. , 2010). CAS occurs frequently, but represents an ongoing clinical challenge both diagnostically and therapeutically (Teragawa et al. , 2018). These difficulties are compounded by incomplete understanding of the pathogenesis of CAS and of its typically cyclical symptomatic course. Previous investigations have generally focused on potential anomalies in vascular reactivity. Although it has always been assumed that the pathogenesis of CAS relates primarily to increased constrictor stimulation and/or responsiveness of coronary vascular smooth muscle, prophylactic treatment with L-channel calcium antagonists (to diminish responses to vasoconstrictor stimuli) has yielded only limited symptomatic benefit (Picard et al. , 2019).
Recently, there have been a number of reports suggesting that pathogenesis of CAS may extend beyond vascular reactivity and be associated with coronary plaque erosion (Shin et al. , 2015) with associated platelet aggregation and frank thrombosis at sites of such fissures and elsewhere within the coronary circulation in CAS patients. Furthermore, a number of studies provided evidence of increased platelet activation and release of platelet-derived vasoactive substances such as β-thromboglobulin (Ogasawara et al. , 1986), 5-hydroxytryptamine (Murakami et al. , 1998), and thromboxane A2 (Lewyet al. , 1979; Robertson et al. , 1980; Hamm et al. , 1987) detected increased concentrations of platelet aggregates in the coronary venous circulation during symptomatic exacerbations of CAS, without evidence of this phenomenon within the systemic circulation. However, (Miyamoto et al. , 2000)(were able to detect release of platelet aggregates into the systemic venous circulation following induction of coronary spasm in the cardiac catheterization laboratory with acetylcholine (ACh) provocation. Interestingly, in a wider context, it has recently been shown that activation of platelets can induce interleukin 1β- dependent activation of endothelial cells, indicating apotentially primary role for platelets in the pathogenesis of cardiovascular disease crises (Nheket al. , 2017).
Furthermore, associations have been established between CAS and Kounis syndrome (Kounis et al. , 1991), which involves episodic mast cell and platelet activation. Correspondingly, (Forman et al. , 1985) demonstrated that a coronary artery of a CAS patient who had died following an attack was focally infiltrated with adventitial mast cells.
There is also evidence that CAS per se is associated with more extensive inflammatory activation, although the precise mechanisms whereby inflammation induces spasm remain uncertain (Picard et al. , 2019). Systemic inflammatory markers, including C-reactive protein and white blood cell count, were shown by (Ong et al. , 2015b) to be elevated during acute presentation of CAS.
CAS may be engendered in part by impairment of local or systemic generation of, and/or responsiveness to, nitric oxide (NO), which is also the active metabolite of glyceryl trinitrate (GTN). Indeed, the “gold standard” for definitive diagnosis of CAS requires diagnostic coronary injection of acetylcholine (ACh): the induction of vasospasm with ACh implies a net vasoconstrictor effect, despite the NO-releasing effect of ACh. In a murine model of coronary artery spasm, coronary vasodilator effects of ACh changed (reversibly) to constrictor responses in the presence of thiol oxidation (Yamadaet al. , 2013), suggesting that oxidation of SH groups on the soluble guanylate cyclase (sGC) molecule might be critically important as a CAS precipitant. Further, inherited defects of endogenous NO generation from endothelial NO synthase (NOS) have also been implicated as potential causes of CAS (Closs et al. , 2012).
One potential link between inflammatory activation and impaired NO signaling would be inflammatory induction of NO resistance , or diminished end-organ responsiveness to NO, including its vasodilator, anti-aggregatory and anti-inflammatory actions (Chirkov et al. , 2001; Willoughby et al. , 2005; Chirkov et al. , 2007; Willoughby et al. , 2012). We have previously shown that NO resistance is present in platelets from patients with both stable and unstable angina pectoris (Chirkov et al. , 2001), and that NO resistance may reflect increased “scavenging” of NO and/or partial inactivation of its intracellular “receptor” soluble guanylate cyclase (sGC) (Chirkov et al. , 2007) . Evaluation of the anti-aggegatory effects of NO represents the most convenient method for assessing responsiveness to NO in humans, and has been utilized extensively by us to explore determinants of the presence, extent and prognostic significance (Willoughby et al. , 2005) of NO resistance, and strategies to either ameliorate or circumvent the problem (Chirkov et al. , 2007; Willoughby et al. , 2012).
We now report the results of an investigation into the mechanisms underlying CAS, in both its chronic phases and during acute exacerbations, focusing on the hypotheses that CAS is engendered, at least in part, by impairment of endogenous anti-aggregatory mechanisms, and that these anomalies are exacerbated during symptomatic crises. The results provide evidence to support this hypothesis, shed light on the possibility that abnormal platelet-endothelial interactions are central to the pathogenesis of CAS, delineate the molecular mechanisms underlying both occurrence and exacerbations of CAS, and provide bases for potential therapeutic amelioration of the condition.