4. Discussion
CAS remains a serious clinical problem because, despite recent progress
including apparent improvement in the diagnostic process
(Elbadawi et al. , 2019), it
remains under-diagnosed, its epidemiology is poorly understood, there is
no consensus as to its precise pathogenesis, and because the only
well-validated prophylactic treatment modality, that of calcium
antagonists, yields only moderate symptomatic improvement. The
importance of constrictor hyperactivity, in general, to the
pathophysiology of CAS, and its link to vascular endothelial
dysfunction, has recently been summarized
(Ong et al. , 2015a) and is beyond
dispute. However, there is also increasing evidence that platelet-based
impairment of circulatory homeostasis may be involved
(Robertson et al. , 1980;
Ogasawara et al. , 1986;
Murakami et al. , 1998). In the
current study, we investigated whether abnormal platelet reactivity is
present in CAS patients and whether symptomatic crises reflect
platelet-endothelial interactions. In the current study, we sought to
delineate the demographics of patients with CAS, to understand its
pathophysiology, and that of the episodic crises which characterize the
condition, and to identify a potential “screening test” for acute
episodes (to distinguish such episodes from “non-cardiac chest pain”).
A central basis for our undertaking the current study was continuing
uncertainty about the pathogenesis of CAS, despite increasing evidence
of vascular hyporesponsiveness to NO
(Folts et al. , 1991;
Yamada et al. , 2013), inflammatory
activation (Ong et al. , 2015b)
(sometimes involving mast cell activation
(Forman et al. , 1985;
Kounis et al. , 1991)), a tendency
for intracoronary thrombi to be formed at sites of (ill-defined) plaque
“erosion” (Shin et al. , 2015),
and potentially activation of platelet aggregation
(Hamm et al. , 1987;
Miyamoto et al. , 2000).
In a series of ex vivo and in vitro experiments, we have
now shown that patients with CAS have hyperaggregable platelets which
exhibit marked impairment of the anti-aggregatory effects of the NO
donor SNP, even during the chronic phases of the disorder. This finding
almost certainly has parallels within coronary vascular smooth muscle,
which represent the basis for the precipitation of CAS by intracoronary
ACh injection (Goto et al. , 1999)
. Thus our findings provide a basis for regarding CAS as a combined,
biochemically-based disorder of NO signaling (rather than of NO
generation in most cases), differentially affecting both the coronary
vasculature and circulating platelets in individual patients
(Crea et al. , 2017). Importantly,
the current findings appear to apply equally for patients with
macrovascular (PA) or microvascular (CSFP) types of CAS.
Platelet aggregatory responses to ADP were greater, and their inhibition
by SNP was impaired, in chronic CAS patients relative to control
subjects. During symptomatic crises, platelet responses to SNP tended to
decrease further, together with substantial release of SD-1 (implying
acute damage to the vascular glycocalyx as a contributing factor
incremental to endothelial dysfunction). The damaged glycocalyx provides
an environment favouring platelet adhesion/activation, with consequent
release of pro-constrictor autacoids, such as thromboxane
A2 and serotonin, which in turn may contribute to
coronary vasoconstriction. This is accompanied by elevated plasma
tryptase concentrations (implying mast cell activation) and formation of
PMPs, the most abundant type of circulating microparticles, the
generation of which implies platelet activation and apoptosis
(Rosinska et al. , 2017) . Overall,
these data provide strong evidence that CAS crises are associated with
mast cell activation and both vascular and platelet damage, and thus
provide a basis for the potential diagnostic utility of SD-1 assay for
exclusion of “non-cardiac pain” in patients presenting with acute
episodes of CAS.
The finding that intravenous infusion of GTN/NAC reversed the anomalies
of platelet SNP responses and of plasma SD-1 concentrations was novel,
even though a therapeutic effect based on potentiation of responses to
NO was certainly consistent with previous clinical
(Pasupathy et al. , 2017) and
physiological (Horowitz et al. ,
1983; Loscalzo, 1985) studies with
GTN/NAC. Although no controlled clinical observations were made of the
impact of GTN/NAC infusion on resolution of symptoms, it seems, from the
rapid fall in plasma SD-1 concentrations associated with this treatment,
that there was associated cessation of acute vascular damage
(Mulivor et al. , 2004). These data
are reminiscent of the findings of (Foltset al. , 1991) in a canine model of intimal injury to the
circumflex coronary artery. These investigators demonstrated that NAC
potentiated the effects of GTN in reversing cyclical coronary flow
reductions, which resulted from periodic platelet adhesion to the
injured vessel wall.
The performance of exploratory in vitro studies shed completely new
light on the mechanism of beneficial effect of NAC in a number of acute
cardiovascular disease states, with the revelation that potentiation of
SNP anti-aggregatory effects by NAC was inhibited in the presence of
antagonists (Paul et al. , 2012) of
the enzymatic release of H2S from cysteine. Although NAC
is known to be a potential donor of H2S
(DiNicolantonio et al. , 2017;
Bankhele et al. , 2018), and there
is also some evidence that H2S and NO may have
synergistic effects under some circumstances
(Altaany et al. , 2013;
Zhou et al. , 2016) , the current
findings represent the first data to suggest that previously described
potentiation of the effects of NO donors by high doses of NAC
(Horowitz et al. , 1983;
Loscalzo, 1985) may be primarily mediated
by H2S release.
In this regard, the current results reinforce those of recent studies
suggesting that disordered microvascular reactivity
(Levy et al. , 2019) and overt CAS
(Ong et al. , 2008) may contribute
to the pathogenesis of many forms of acute coronary syndrome. Indeed,
the concept that CAS is associated with coronary plaque erosion and
associated focal coronary thrombus formation in a substantial minority
of cases (Ong et al. , 2015a)
suggests that at least the acute phases of the disorder are pivotally
related to vssel wall: platelet interactions. The current clinically
used definition of plaque erosion (Jiaet al. , 2017) includes the presence of thrombus on an apparently
intact coronary plaque , but such erosions have been associated with the
release into blood of vascular glycocalyx products
(Quillard et al. , 2017). These
data therefore are consistent with our current findings for acute CAS.
The study has a number of limitations. First, the role of adventitial
and/or systemic mast cell activation in precipitation of acute crises
remains incompletely delineated. Aggravation of platelet NO resistance
during acute crises should be studied in larger cohorts of patients. The
precise mechanism(s) whereby NTG/NAC infusion rapidly reverses the
glycocalyx shedding which underlies SD-1 release remain uncertain
(although there is an implication of decreased generation of at least
one “sheddase” enzyme) (Mulivor et
al. , 2004), and need both to be correlated with symptomatic effects of
this treatment modality and with changes within the cascade of matrix
metalloproteinase release associated with mast cell activation. In this
regard, it is unfortunate that optical coherence tomography was not
performed in CAS patients during acute presentations, in order that
plaque erosion and associated focal coronary thrombosis could be
diagnosed. The precise mechanisms underlying potentiation of platelet NO
signaling by H2S also remain to be elucidated, although
a recent report (Miyamoto et al. ,
2017) suggests that combination of H2S and NO may lead
to synergistic vascular effects via polysulphide formation. Finally, the
possibility that CAS might fundamentally represent a disorder of
H2S generation remains to be explored.
The importance of the current findings therefore rests in three main
areas:-
The results reinforce previous, less definitive data, to suggest that
fluctuating severity of symptoms in CAS patients reflects, at least in
parts, episodic platelet aggregation at sites of vessel wall
damage and emphasize that the pathogenesis of CAS is fundamentally
related to combined impairment of vasodilator and anti-aggregatory
mechanisms. These findings, in the acute context, probably represent
an indirect reflection of the phenomenon of plaque erosion and
associated thrombosis. Clinical findings of plaque erosion
(Crea et al. , 2019) and hospital
admissions with CAS crises (Elbadawiet al. , 2019) are occurring more frequently. It is also likely
that there is a “grey area” of pathogenesis across the whole
spectrum of acute coronary syndromes, with plaque erosion increasingly
implicated in the pathogenesis of S-T segment elevation acute
myocardial infarction (Crea et
al. , 2019).
(2) The findings of substantial elevation of SD-1 concentrations during
acute attacks could be utilized as a means for provisional diagnosis of
CAS in patients with prolonged chest pain who have no definitive changes
on ECG or cardiac troponin concentrations. This would reduce the
possibility that CAS patients will continue to remain undiagnosed,
simply because there is no available screening test.
(3) The finding that there is likely to be an impaired
H2S generation and/or a deficient
NO/H2S interaction during both the chronic and
acute phases of the disorder, could be a basis for new therapeutic
modalities, both for prophylaxis and treatment of crises. Similarly, the
finding of acute mast cell activation carries many potential therapeutic
implications (Siebenhaar et al. ,
2018). Exploration of such therapeutic options for CAS, coupled with an
improvement in diagnostic efficiency, represents a considerable
therapeutic priority.
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