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STATE-OF-THE-ART REVIEW
Association Between Coronary Artery
Spasm and Atherosclerotic Disease
Denise Peeters, MSC,a Eva Woelders, MD,a Tijn Jansen, MD,a Regina Konst, MD, PHD,a Caïa Crooijmans, MD,a
Tim van de Hoef, MD, PHD,b Frans Mensink, MD,a Jonathan Los, MD,a Dario Pellegrini, MD, PHD,c
Jan Hein Cornel, MD, PHD,a Peter Ong, MD, PHD,d Niels van Royen, MD, PHD,a Aukelien Leen, MD, PHD,a
Suzette Elias-Smale, MD, PHD,a Robert Jan van Geuns, MD, PHD,a Peter Damman, MD, PHDa
ABSTRACT
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In at least one-half of the patients with angina or ischemia and nonobstructive coronary arteries undergoing coronary
function testing, coronary artery spasm (CAS) is detected. CAS is associated with an adverse prognosis regarding
recurrent complaints and ischemic events. Current treatment options are mainly focused on the complaints, not on the
underlying pathophysiological process. In this review we discuss available evidence regarding the presence, amount, and
morphology of atherosclerosis in CAS patients. The reviewed evidence confirmed that atherosclerosis and vulnerable
plaque characteristics are often detected in patients with CAS. The amount of atherosclerosis is higher in patients with
focal CAS compared with patients with diffuse CAS. Severity of atherosclerosis is associated with the presence of CAS and
the prognosis in CAS patients with atherosclerotic stenosis is worse. Therefore, CAS patients with atherosclerosis might
benefit from targeted atherosclerotic treatment. Longitudinal studies are needed to elucidate the exact relation between
atherosclerosis and CAS. (JACC Cardiovasc Imaging. 2025;18:226–239) © 2025 The Authors. Published by Elsevier on
behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
A ngina pectoris is the most common symptom
of obstructive coronary artery disease (CAD).1
However, in about half of the patients who
undergo invasive coronary angiography (ICA) for
anginal complaints, no obstructive CAD is observed.2
In these patients with angina and nonobstructive cor-
onary arteries (ANOCA), coronary vasomotor
dysfunction including epicardial and/or microvas-
cular coronary artery spasm (CAS) is frequently
seen.3 Depending on the presence of ischemia, the
terms ANOCA and ischemia and nonobstructive
coronary arteries (INOCA) are most commonly used.
For consistency and because electrocardiographic
proven ischemia is one of the diagnostic criteria of
CAS, we will use INOCA in this review. To assess the
presence of CAS and microvascular dysfunction, inva-
sive coronary vasomotor function testing (CFT) is
N 1936-878X
m the aRadboudumc, Cardiology, Nijmegen, the Netherlands; bUMC Utre
leazzi-Sant’ Ambrogio, Cardiology, Milan, Italy; and the dRobert Bosch
ttgart, Germany.
e authors attest they are in compliance with human studies committe
titutions and Food and Drug Administration guidelines, including patien
it the Author Center.
nuscript received April 23, 2024; accepted May 23, 2024.
currently recommended by European and American
guidelines.1,4
In almost half of INOCA patients CFT reveals CAS.5
This percentage is even higher in selected pop-
ulations with persistent anginal complaints.6 Patients
with CAS have a considerable anginal burden. In
addition, CAS is associated with an adverse prognosis
with regard to myocardial infarction (MI) and
increased presentations at the emergency depart-
ment.7 Currently available treatment options focus on
reducing anginal complaints, while disease-
modifying therapies are lacking.
In obstructive CAD, persistence or recurrence of
angina after percutaneous coronary intervention
(PCI) is well recognized and affects around 20%-40%
of patients, even when PCI is optimized using intra-
coronary physiology.8 Significant CAS occurs in about
https://doi.org/10.1016/j.jcmg.2024.05.024
cht, Cardiology, Utrecht, the Netherlands; cOspedale
Hospital, Department of Cardiology and Angiology,
es and animal welfare regulations of the authors’
t consent where appropriate. For more information,
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http://crossmark.crossref.org/dialog/?doi=10.1016/j.jcmg.2024.05.024&domain=pdf
http://creativecommons.org/licenses/by/4.0/
AB BR EV I A T I O N S
AND ACRONYM S
ANOCA = angina with
nonobstructive coronary
arteries
CAD = coronary artery disease
CAS = coronary artery spasm
CFT = coronary function
testing
CCTA = coronary computed
tomography angiography
ICA = invasive coronary
angiography
INOCA = ischemia with
nonobstructive coronary
arteries
IVUS = intravascular
ultrasound
LAD = left anterior descending
LDL-C = low-density
lipoprotein cholesterol
MACE = major adverse
cardiovascular events
OCT = optical coherence
tomography
PCI = percutaneous coronary
intervention
J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 8 , N O . 2 , 2 0 2 5 Peeters et al
F E B R U A R Y 2 0 2 5 : 2 2 6 – 2 3 9 CAS and Atherosclerotic Disease
227
half of the patients undergoing coronary angiography
for post-PCI recurrent angina without hemodynami-
cally significant coronary stenoses.9 This might
be caused by mechanical stress or residual
atherosclerosis.
We hypothesize that atherosclerosis is a potential
central pathophysiological mechanism of CAS, based
on our recent work in which we demonstrate that CAS
is associated with atherosclerotic burden.10 To
strengthen this hypothesis we discuss and highlight
the current evidence regarding the relationship be-
tween atherosclerosis and CAS, and potential future
disease-modifying treatment options. We will first
discuss the evidence within INOCA, and thereafter in
obstructive CAD.
SEARCH OF PUBLISHED REPORTS
A PubMed search was performed in December 2022
including original articles, randomized controlled
trials, meta-analyses, and systematic reviews
published in English. The following Medical Subject
Heading (MeSH) terms were used: (artery vasospasm,
coronary[MeSH Terms] OR “epicardial spasm”
[tiab:w2] OR “epicardial spasms”[tiab:w2] OR “coro-
nary artery vasospasm”[tiab:w2] OR “coronary artery
spasm”[tiab:w2] OR “coronary vasospasm”[tiab:w2]
OR “coronary artery vasospasms”[tiab:w2] OR “coro-
nary artery spasms”[tiab:w2] OR “coronary vaso-
spasms”[tiab:w2] OR angina pectoris, variant[MeSH
Terms]) AND (atherosclerosis[MeSH Terms] OR “Pla-
que, Atherosclerotic”[MeSh] OR atherosclero*[tiab]).
Besides MeSH terms, tiab was used to search in
the title and abstract of articles. Studies with the
following criteria were included: 1) describing the
presence or morphologic features of atherosclerotic
CAD with ICA, intravascular ultrasound (IVUS),
and/or optical coherence tomography (OCT); and 2)
patients with CAS that was established with
acetylcholine (ACH) provocation or ergonovine
spasm provocation. Case reports and studies without
spasm provocation and/or without a comparison of
atherosclerosis were excluded. There was no limit to
the number of included studies. Of the 661
articles found, 21 articles were included in this re-
view. Studies were divided into 3 groups according to
the observed severity of atherosclerosis: non-
obstructive CAD (n ¼ 15), obstructive CAD (n ¼ 4), or
both (n ¼ 2).
CAS IN PATIENTS WITHangina. Eur Heart J. 2017;38:2565–
2568.
43. Crooijmans C, Jansen TPJ, Konst RE, et al.
Design and rationale of the NetherLands registry
of invasive Coronary vasomotor Function Testing
(NL-CFT). Int J Cardiol. 2023;379:1–8.
44. Zhang X, Li Q, Zhao J, et al. Effects of com-
bination of statin and calcium channel blocker in
patients with cardiac syndrome X. Coronary Artery
Dis. 2014;25:40–44.
45. Los J, Mensink FB, Mohammadnia N, et al.
Invasive coronary imaging of inflammation to
further characterize high-risk lesions: what op-
tions do we have? Front Cardiovasc Med. 2024;11:
352025.
46. Sidik NP, Stanley B, Sykes R, et al. Inva-
sive endotyping in patients with angina and no
obstructive coronary artery disease: a ran-
domized controlled trial. Circulation. 2024;149:
7–23.
KEY WORDS atherosclerosis, coronary
spasm, prognosis, treatment
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	Association Between Coronary Artery Spasm and Atherosclerotic Disease
	Search of Published Reports
	CAS in Patients With Ischemia and Nonobstructive Coronary Artery Disease
	Incidence and pathophysiology
	Atherosclerosis and CAS
	Prognosis
	Treatment
	CAS in Patients With Obstructive CAD
	Incidence and pathophysiology
	Atherosclerosis and CAS
	Prognosis
	Treatment
	Discussion
	Clinical implications
	Conclusions and Future Directions
	Funding Support and Author Disclosures
	ReferencesISCHEMIA AND
NONOBSTRUCTIVE CORONARY ARTERY DISEASE
INCIDENCE AND PATHOPHYSIOLOGY. Several studies
report on the assessment of CAS in INOCA patients. A
recent meta-analysis has shown that in
INOCA patients, epicardial spasm is demon-
strated in around 30% to 60% of patients,
whereas microvascular spasm is demon-
strated in 20% to 40%.11
The substrate of coronary spasm can be
found in abnormal function of both vascular
smooth muscle and endothelial cells. Spasm
typically has an origin in a hyper-reactive
coronary segment that undergoes maximal
contractionwhen exposed to a vasoconstrictor
stimulus such as smoking, drugs, peaks in
blood pressure, cold exposure, emotional
stressors, and hyperventilation.12 Atheroscle-
rosis and inflammation are factors hypothe-
sized to result in vascular smooth cell
hyper-reactivity and endothelial dysfunction.13
ATHEROSCLEROSIS AND CAS. In a prospec-
tive registry by Jo et al,14 1,744 INOCA pa-
tients with CAS were compared with 876
INOCA patients without CAS. Patients with
CAS had a higher burden of atherosclerotic
plaques in all coronary arteries with a higher
percentage diameter stenosis per lesion
(including nonspastic arteries) when
compared with patients without vasospasm. Most
importantly, atherosclerosis was more likely to be
observed in the spastic coronary artery compared
with nonspastic arteries in CAS patients.
This was confirmed by McChord et al,15 demon-
strating that epicardial atherosclerosis was an inde-
pendent predictor for epicardial spasm (OR: 2.1
[95% CI: 1.5-3.0]; P 75% of coronary plaques at mid–left
anterior descending (LAD) were categorized as mild
lesions with intimal thickening. Lipid-rich fibroa-
theroma was most often observed in patients with
focal CAS (Pin
this cohort multiple signs of plaque instability were
observed. First, fibrous cap disruption was seen at 3
spasm sites. Second, at 23 spasm sites the presence of
thrombus was shown, with the majority being white
thrombus. Lastly, lumen irregularity without
thrombus, another possible sign of endothelial
erosion, was found in 49 spasm sites. The endothe-
lium erosion could have occurred from constriction
leading to thrombus formation at a spasm site.24
Nonetheless, the temporal cause-and-effect
relationship between the occurrence of vasospasm
and the erosion of the endothelium is not clear.
To further elucidate the plaque vulnerability
characteristics in CAS, plaque components at coro-
nary sites with focal spasm in INOCA patients (n ¼ 30)
were compared with culprit lesions in patients with
unstable angina (UA) (n ¼ 32) using IVUS.25 The ab-
solute volume, necrotic core, dense calcium, and
plaque burden were lower in CAS sites when
compared with UA culprit lesions. Hypoechoic pla-
ques with less calcification were seen more often in
patients with focal CAS compared with UA patients.
In summary, all these studies in INOCA patients
(some cohorts mixed patients with myocardial
infarction with nonobstructive coronary arteries)
showed that nonobstructive atherosclerosis is
frequently present in patients with CAS. This was
observed for both epicardial and microvascular
spasm. However, not all atherosclerotic sites show
vasospasm, and it is unclear whether CAS is caused by
CAD or promotes CAD. Also, all discussed studies
were cross-sectional and only a selective patient
population was included. Besides the presence and
extent of atherosclerosis, the studies demonstrate
that INOCA patients with CAS often show markers of
plaque vulnerability (Table 1). The extensiveness of
spasm and vulnerability of atherosclerosis may be
related to different pathophysiological mechanisms
between microvascular dysfunction and epicardial
dysfunction and focal vs diffuse spasm.
PROGNOSIS. INOCA patients with CAS have a
decreased quality of life caused by recurrent anginal
complaints and a higher incidence of ischemic
events.26 Some studies highlight the potential role of
atherosclerosis in this adverse prognosis.
Hao et al27 observed a low incidence of major
adverse cardiovascular events (MACE), including
cardiovascular death, nonfatal MI, urgent PCI, and
hospitalization for UA in patients with stable angina
who underwent spasm provocation testing. Patients
without CAS, patients with CAS and normal coronary
arteries, and CAS patients with nonobstructive CAD
had low and comparable MACE during a median
follow-up period of 656 days (1.6%, 3.6%, and 5.6%,
respectively). However, patients with CAS and a he-
modynamically significant stenosis had a poor prog-
nosis with a MACE rate of 27.6%.
Radico et al28 investigated determinants of
long-term outcomes in INOCA patients. In this
meta-analysis, a main determinant of major adverse
events was the presence of “some” coronary athero-
sclerosis, with unequivocal myocardial ischemia be-
ing associated with worse clinical outcomes. The
FIGURE 1 Results of ACH Test and OCT Findings in ANOCA Patients
75 ANOCA patients
Acetylcholine Test
A B
C D
E F
79%: vasospasm (ACH+)
21%: negative test (ACH−)
Optical Coherence Tomography
Lipid index
Plaque vulnerability markers*
OCT Findings in Vasospasm
Higher lipid index
Higher plaque vulnerability
0
ACH− ACH+
Li
pi
d 
In
de
x
1,000
2,000
3,000
4,000
5,000
P = 0.036,000
0
ACH− ACH+
38%
66%
%
 P
at
ie
nt
s W
ith
≥V
ul
ne
ra
bi
lit
y 
M
ar
ke
r %
18
35
53
P = 0.0470
ACH test with an angiographically normal artery (A) or diffuse epicardial vasospasm (B). OCT with normal segments (C) or coronary plaques
with in this case thin-cap fibroatheroma (D). Lipid index was defined as the mean plaque arc multiplied by lipid-core longitudinal length.
Vessels prone to vasospasm were associated with a higher lipid index (E) and a higher prevalence of vulnerable and plaques (F). *Vulnerability
markers: thin-cap fibroatheroma, macrophage infiltration, neovascularization, and plaque erosion. Reprinted from Pellegrini et al.10
ACH ¼ acetylcholine; ANOCA ¼ angina with nonobstructive coronary arteries; OCT ¼ optical coherence tomography.
Peeters et al J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 8 , N O . 2 , 2 0 2 5
CAS and Atherosclerotic Disease F E B R U A R Y 2 0 2 5 : 2 2 6 – 2 3 9
230
presence of atherosclerosis resulted in a 2 times
higher incidence of all-cause mortality and nonfatal
MI in studies with INOCA patients compared with
studies with INOCA patients without any atheroscle-
rosis after a median follow-up of 5 years (1.32/100
person-years [95% CI: 1.02-1.62] vs 0.52/100 person-
years [95% CI: 0.34-0.79]; Pprevalence of neovascularization
compared with patients without CAS.
Tsujita et al,
2013
Retrospective
cross-sectional
INOCA patients with CAS
(n ¼ 26)
INOCA patients without
CAS (n ¼ 16)
IVUS Patients with CAS had diffusely thickened intima
compared with patients without CAS.
Study in
obstructive CAD
Nishi et al,
2022
Prospective
cross-sectional
INOCA patients with CAS
(n ¼ 23)
Patients without CAS
(n ¼ 16)
ICA, OCT The prevalence of layered plaques and
microchannels were higher in patients with CAS.
The prevalence of macrocalcification was lower in
patients with CAS.
CAD ¼ coronary artery disease; CAS ¼ coronary artery spasm; DC ¼ dense calcium; ICA ¼ invasive coronary angiography; INOCA ¼ ischemia with no obstructive coronary arteries; IVUS ¼ intravascular
ultrasound; NC ¼ necrotic core; OCT ¼ optical coherence tomography; TCFA ¼ thin cap fibroatheroma; UA ¼ unstable angina.
J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 8 , N O . 2 , 2 0 2 5 Peeters et al
F E B R U A R Y 2 0 2 5 : 2 2 6 – 2 3 9 CAS and Atherosclerotic Disease
231
INOCA patients had a higher incidence of MACE
(cardiac death, nonfatal MI, and urgent hospitaliza-
tion caused by either UA or heart failure) compared
with patients with diffuse CAS, microvascular spasm,
and no CAS (14%, 6%, 0%, and 0%, respectively; P ¼
0.005).
It seems that the main driver of worse outcomes in
CAS is the presence of atherosclerosis. All studies
discussing the relationship between atherosclerosis
and the prognosis in CAS patients are summarized in
Table 2.
TREATMENT. The treatment of patients with CAS
primarily targets complaints, with antianginal medi-
cation playing a central role. Furthermore, current
consensus documents focus on tailored counseling on
lifestyle factors and traditional cardiovascular risk
factors.4,12 Besides antianginal medication and life-
style and risk factor management, almost no data is
available on preventive or disease-modifying
treatment in INOCA patients. The little available data
is described as follows.
A retrospective study observed the impact of statin
therapy on clinical outcomes in patients with CAS free
of atherosclerotic stenosis ($75%).30 Patients with
CAS who were treated with statins (n ¼ 128) were
matched with patients with CAS without statin use
(n ¼ 128). Only the incidence of dyslipidemia was
higher in the statin group compared to the nonstatin
group (94.5% vs 39.1%; Pbranch
Coronary angiography with a mild lesion in the LAD (A); focal spasm in mid-LAD and diffuse spasm in distal-LAD (B); coronary angiography with mild stenosis in LAD
after intracoronary nitrate injection. Lines D through H indicate the sites where OCT images were acquired (C); OCT showed layered plaques (D to G) and intraplaque
microchannels (H). Reprinted from Nishi et al.36 LAD ¼ left anterior descending; other abbreviations as in Figure 1.
J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 8 , N O . 2 , 2 0 2 5 Peeters et al
F E B R U A R Y 2 0 2 5 : 2 2 6 – 2 3 9 CAS and Atherosclerotic Disease
233
ATHEROSCLEROSIS AND CAS. Four studies per-
formed ICA and spasm provocation in patients with
obstructive CAD. Sueda et al33 demonstrated an
incidence of 32.2% CAS in 685 Japanese patients.
Two-thirds of spasm was located on atherosclerotic
lesions, which was evenly distributed between
angiographic significant lesions (defined as >75%
angiographic stenosis) and nonsignificant lesions.
In a retrospective study of 1,760 patients with
angina, the presence of CAS and CAD was assessed.34
In 20% of the patients significant atherosclerotic
disease was observed, defined as $75% angiographic
stenosis. Among these patients, CAS was observed in
65%. In 82% of the 233 patients with CAS, spasm
occurred at the site of atherosclerotic disease.
In another retrospective study with 236 patients
with angina also fractional flow reserve measure-
ments were performed after spasm provocation
testing. In total, 29 patients had CAS and significant
stenosis of fractional flow reserveinduce (accelerated) atherosclerosis.
To further differentiate these mechanisms, further
studies with repeated intracoronary imaging and
vasomotor function testing are necessary.
Some ongoing trials might lead to new innovative
therapies. The Warrior trial is evaluating intensive
statin/angiotensin-converting enzyme inhibitor (or
angiotensin receptor blockers)/aspirin treatment
FIGURE 3 Protocol CFT
1
3
CFR = 3.0
IMR = 38
2
1. Invasive coronary
angiography
Obstructive CAD
No (obstructive) CAD
•the prevention or
reduction of CAS. Therefore, we advise inclusion of
atherosclerosis as an outcome in clinical studies
about atherosclerotic-modifying medication in
INOCA.
Because evidence of a prognostic association of
atherosclerosis in CAS patients with nonobstructive
disease is lacking, routine intracoronary imaging in
these patients is not recommended. However,
intracoronary imaging could be considered if
anatomical evidence regarding the presence of
atherosclerosis is helpful in the decision to prescribe
statins in INOCA. In this regard, we prefer OCT,
which provides the most anatomical information
based on the highest resolution of the various
intracoronary imaging modalities. However, IVUS
and near-infrared spectroscopy also disclose impor-
tant morphologic features of atherosclerotic plaque.
IVUS allows a rough estimation of plaque composi-
tion. Due to its superior penetration depth compared
with OCT, it can be used to asses lumen and vessel
borders to determine plaque burden. Near-infrared
spectroscopy depicts lesions with high probability
of lipid-rich plaque, expressed by a high lipid core
burden index.45 Also, longitudinal studies with
intracoronary imaging would be useful to get more
insight into the type of relationship between
atherosclerosis and CAS.
Although this review focuses on intracoronary
imaging, coronary computed tomography angiog-
raphy (CCTA) plays an increasing role in the diag-
nostic pathway of anginal complaints and might play
a central role in the distinction of INOCA vs obstruc-
tive CAD and the initiation and triage of therapy. This
is also shown in our proposed pathway in Figure 4.
CCTA could be primarily diagnostic in the distinction
between obstructive and nonobstructive CAD.
Furthermore, the presence of atherosclerosis could be
an indication for preventive pharmacotherapy. In
patients with angina and nonobstructive CAD on the
CCTA, vasomotor dysfunction should be suspected.
Recently, Sidik et al46 showed that CAS was often
observed in INOCA patients defined by CCTA.
CONCLUSIONS AND FUTURE DIRECTIONS
This review confirmed that atherosclerosis, including
vulnerable plaque characteristics, is often detected in
patients with CAS. A higher amount of atherosclerosis
is observed in patients with focal CAS compared with
patients with diffuse CAS. Severity of atherosclerosis
is associated with the presence of CAS and the prog-
nosis in CAS patients with atherosclerotic stenosis is
worse compared with patients with CAS without CAD.
Future studies with follow-up data regarding clinical
outcomes and diagnostic imaging are needed to
investigate the progression of plaques in patients with
CAS to create a better understanding of the temporal
relation between atherosclerosis and CAS, leading to
the development of possible novel treatment options.
This might have an important effect on anginal com-
plaints and ischemic outcomes. Until further evidence
is available, the current data support strict cardio-
vascular risk management in patients with CAS with
present atherosclerosis, regardless of the severity.
FUNDING SUPPORT AND AUTHOR DISCLOSURES
Dr Konst received a research grant from Abbott. Dr van de Hoef
received speaker fees and institutional research grants from Abbott
and Philips. Dr Ong received funding from the Berthold-Leibinger-
Foundation; and received speaking honoraria from Philips/Volcano,
Pfizer, Medtronic, Abbott, Amgen, and Bayer Healthcare. Dr van
Royen received speaker fees from Abbott; and has received institu-
tional research grants from Philips and Abbott. Dr Elias-Smale
received a research grant from Abbott. Dr van Geuns received grants
and personal fees from Boston Scientific, Abbott Vascular, AstraZe-
neca, Amgen, and Sanofi; and grants from InfraRedx. Dr Damman
received research grants, consultancy, and speaker fees from Abbott;
research grants and speakers fees from Abbott; and research grants
from AstraZeneca. All other authors have reported that they have no
relationships relevant to the contents of this paper to disclose.
ADDRESS FOR CORRESPONDENCE: Dr Peter Dam-
man, Radboudumc, Geert Grooteplein Zuid 10, 6526
GA, Nijmegen, the Netherlands. E-mail: peter.
damman@radboudumc.nl.
mailto:peter.damman@radboudumc.nl
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