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.