European Heart Journal (2021) 00, 1–4 EDITORIAL

doi:10.1093/eurheartj/ehab534

Microvascular angina: quo tendimus?

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Ranil de Silva * and Kevin Cheng
National Heart and Lung Institute, Imperial College London, Royal Brompton and Harefield NHS Trust, London, UK

This editorial refers to ‘Clinical characteristics and prognosis of patients with microvascular angina: an international and
prospective cohort study by the Coronary Vasomotor Disorders International Study (COVADIS) Group’, by H. Shimokawa
et al., doi:10.1093/eurheartj/ehab282.

Epicardial spasm
Myocardial bridge

Normal Microvascular Angina

Microvascular spasm
Pre-arteriolar
Endothelial dysfunction
Arteriolar remodelling
(e.g. intimal thickening, smooth muscle
cell proliferation, perivascular fibrosis)

Arteriolar Coronary Microvascular Dysfunction

Structural Endotype
Normal rest CBF
Inability to dilate
Èstress CBF
High vascular Low vascular ÈCFR
tone at rest tone at stress High vascular High vascular ÇhMR
tone at rest tone at stress
Normal rest CBF Capillaries
Normal stress CBF Functional Endotype
Exhausted dilatory Ç rest CBF
Normal CFR
capacity Normal stress CBF
Normal hMR
ÈCFR
Capillary rarefaction Low vascular Low vascular Normal hMR
tone at rest tone at stress

Graphical abstract Summary of known mechanisms that cause ischaemia with normal coronary arteries at the level of both the epicardial cor-
onary arteries (coronary vasospasm and intramyocardial muscle bridging) and the coronary microcirculation [microvascular spasm, endothelial dys-
function, arteriolar remodelling, two endotypes of coronary microvascular dysfunction (structural due to failure to maximally vasodilate and
functional due to exhausted vasodilatory capacity), and capillary rarefaction]. cMVD, coronary microvascular dysfunction; CBF, coronary blood flow;
CFR, coronary flow reserve; hMR, hyperaemic index of microcirculatory resistance.

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponding author. NHLI (Brompton Campus), Imperial College London, Sydney Street, London SW3 6NP, UK. Tel: þ44 20 73518626, Email: r.desilva@imperial.ac.uk
Published on behalf of the European Society of Cardiology. All rights reserved. VC The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.
2 Editorial

..
Up to 40% of patients undergoing investigation for angina pectoris .. countries. The main ethnicities represented were Caucasian (61%),
have no evidence of significant epicardial coronary disease by either .. Asian (29%), and Hispanic (6%). Females comprised 64% of the study
..
elective computed tomography coronary angiography or invasive .. population, and median follow-up was 398 days, with a completed
cardiac catheterization. Myocardial ischaemia can be detected in a .. follow-up rate of 97%. No control group was recruited. The hetero-
..
large proportion of these patients. There is a wide spectrum of .. geneity of the enrolled cohort is demonstrated through 34% of
pathophysiological mechanisms that can be responsible for myocar- .. patients having a prior history of coronary artery disease (CAD)
..
dial ischaemia in the absence of significant epicardial coronary athero- .. including stable angina and acute coronary syndrome, 9% of patients
..

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sclerotic disease which can occur in different compartments of the .. having a previous percutaneous coronary intervention (PCI), and
coronary circulation.1 (Graphical abstract). However, in many cases, .. 38% of patients having documented epicardial coronary vasospasm
these are not fully appreciated or routinely pursued in clinical prac- .. with acetylcholine testing. The rate of invasive coronary microvascu-
..
tice, resulting in many patients continuing to experience reduced .. lar function testing was high (89%), though no data on the functional
quality of life and increased risk of adverse events. .. significance of epicardial coronary lesions were provided. The annual
..
The Coronary Vasomotor Disorders International Study .. incidence of the primary composite outcome of major adverse car-
(COVADIS) Group was convened in 2013 to establish international
.. diovascular events (MACE: cardiovascular death, non-fatal myocar-
..
standards to diagnose disorders of coronary vasomotion. The study .. dial infarction, non-fatal stroke, and hospitalization due to heart
from this group in this issue of the European Heart Journal by
.. failure or unstable angina) was 7.7% per patient-year, driven predom-
..
Shimokawa et al.2 focuses on the group of patients with microvascu- .. inantly by hospitalization for unstable angina (81% of all MACE, 5.9%
lar angina (MVA) for whom the COVADIS group has recommended
.. per patient-year) compared with the low rates of cardiovascular
..
the following diagnostic criteria:3 (i) presence of symptoms suggestive .. death (1.0% per patient year) and non-fatal myocardial infarction
of myocardial ischaemia; (ii) objective demonstration of myocardial
.. (0.5% per patient year). In multivariate analysis, prior history of CAD
..
ischaemia by functional testing; (iii) absence of obstructive epicardial .. [hazard ratio (HR) 2.03, 95% confidence interval (CI) 1.31–3.15, P =
..
coronary disease (<50% coronary diameter reduction on angiog- .. 0.001] and hypertension (HR 1.70, 95% CI 1.07–2.68, P = 0.03) were
raphy and/or non-significant hyperaemic or non-hyperaemic wire- .. found to be independent predictors of MACE. No gender- or
..
based pressure indices); and (iv) demonstration of reduced coronary .. ethnicity-related differences in prognosis were observed after pro-
blood flow reserve and/or inducible microvascular spasm with pro- .. pensity matching, although significantly reduced quality of life as
..
vocative pharmacological testing. Establishing such standardized crite- .. measured by the Seattle Angina Questionnaire was reported in
ria provides a framework for undertaking studies to investigate the .. women as compared with men (P < 0.05).
..
pathophysiology, diagnosis, treatment, and prognosis of MVA. .. The majority of studies on prognosis in MVA have focused on
Patients with MVA according to the above definition are not a .. white Caucasian patients (Table 1). There is a significant knowledge
..
homogeneous group. By definition, functionally significant epicardial .. gap on the impact of ethnicity on symptoms, quality of life, and clinical
coronary disease is excluded, and ischaemia can occur due to several .. outcomes in patients with MVA,5 though it is plausible that differen-
..
mechanisms including microvascular spasm or coronary microvascu- .. ces from previous studies may exist, suggesting different patterns of
lar dysfunction. The latter is characterized by a reduced quantitative .. abnormal coronary vasomotion between Caucasian and Japanese
..
blood flow response to pharmacological vasodilator stress or exer- .. populations.12 Whilst the present study sought to examine the influ-
cise, and can result from functional and structural endotypes
.. ence of ethnicity, it is predominantly a comparison between
..
characterized by normal or elevated minimal resting microvascular .. Caucasians and Japanese Asians. Only 4% of the study population
resistance, respectively,4 as well as anatomical abnormalities such as
.. were from a Black or other ethnicity. No patients were recruited
..
altered arteriolar structure and reduced capillary density. These .. from the Middle East, South Asia, South America, or Africa.
mechanisms of ischaemia may not necessarily occur in isolation, and
.. Comparing clinical characteristics between Caucasian and Asian
..
the prognostic significance attributable to each is not known. .. study participants, there was a significantly greater proportion of
The high prevalence and increased healthcare burden associated
.. females (74% Caucasian vs. 43% Asian, P < 0.0001) and conventional
..
with MVA are being increasingly recognized. Conventional cardiovas- .. cardiovascular risk factors in the Caucasian group (mean body mass
..
cular risk scores fail to accurately predict outcomes in patients with .. index, 26.9 vs. 24.0 kg/m2, P < 0.0001; dyslipidaemia, 61% vs. 39%, P <
MVA. Several studies have reported clinical outcomes of patients .. 0.0001; previous history of CAD, 38% vs. 18%, P < 0.0001).
..
with MVA (Table 1).2,5–11 Interpretation of these data is confounded .. Conversely, Asians had a greater proportion of participants with dia-
by variability in diagnostic criteria, cohort heterogeneity such as inclu- .. betes mellitus (21% vs. 13%; P = 0.02), current smoking (21% vs. 14%;
..
sion of patients with non-flow-limiting or previously treated epicar- .. P = 0.03), and previous PCI (13% vs. 5%; P = 0.002). In addition, the
dial coronary artery disease, sample size, as well as differing endpoint .. pattern of presenting symptoms differed by ethnicity. For example, a
..
definitions and follow-up periods. However, there appears to be a .. greater proportion of Asians experienced rest angina (50% vs. 30%; P
consistent signal that angina associated with demonstrable ischaemia .. < 0.0001). Combined rest and effort angina (20% vs. 10%; P =
..
in the absence of functionally significant epicardial coronary disease is .. 0.0005) and shortness of breath (26% vs. 2%; P < 0.0001) were more
not a benign condition. .. common in Caucasians. The reasons for these ethnic differences in
..
Shimokawa and colleagues conducted an international multicentre, .. clinical presentation may be explained by the differing prevalence of
longitudinal, observational cohort study describing the clinical charac- .. pathophysiological mechanisms. For instance, the more frequent
..
teristics and prognosis of patients with MVA diagnosed according to .. presentation with rest pain in Asians may be explained by an
the COVADIS criteria, by gender and ethnicity. Over a 3-year period,
.. increased prevalence of coronary vasospasm in this population.12
..
686 patients with MVA were recruited from 14 centres in seven . Further research on the prevalence of MVA in a wider range of
Table 1 Observational studies investigating the prognosis of microvascular angina

Study Study Follow-up Diagnostic criteria for MVA Outcome Risk

Editorial

size (n)
................................................................................................................................................................................................................................................................................................
Shimokawa et al. 20212 686 Median 398 days COVADIS diagnostic criteria MACE: sex and 6.4% in men; 8.6% in women
ethnic (P = 0.19)
differences No sex or ethnic differences in
MACE
Gulati et al. 20095 540 Mean 5.2 years Suspected ischaemia but no MACE Non-obstructive CAD (1–49% sten-
evidence of obstructive CAD osis in any artery): 16.0%
on angiography Normal coronary arteries (0% in all
arteries): 7.9%
Schroder et al. 20216 1853 Median 4.5 years No obstructive CAD on MACE HR 1.05 (95% CI 1.01–1.09) per 0.1
angiography with evidence of unit decrease in coronary flow
CMD through impaired velocity reserve
coronary flow velocity reserve
on Doppler echocardiography
Zhou et al. 20217 218 Median 5.5 years Stress perfusion CMR (MPRI) in MACE MACE: 15.6%
the absence of obstructive MPRI <_1.47 associated with three-
epicardial CAD fold increase in MACE (HR 3.14;
95% CI 1.58–6.25; P = 0.001)
Seitz et al. 20208 736 Median 7.2 years Unobstructed coronary arteries MACE Death 7.5%
undergoing acetylcholine test- Non-fatal MI 1.4%
ing to detect epicardial or Stroke 2.2%
microvascular spasm
Gdowski et al. 20209 1970 (meta-analysis of Median 19 months Invasive or Primary: all-cause mortality All-cause mortality
11 studies) to 8.5 years non-invasive CFR Secondary: MACE OR 3.93 (95% CI 2.91–5.30; P <
measurement 0.001)
MACE
OR 5.16 (95% CI 2.81–9.47; P <
0.001)
Murthy et al. 201410 1218 Median 1.3 years CFR <2.0 on rest/stress positron MACE CFR is a good independent predict-
emission tomography myocar- or of MACE (0.8 per 10% in-
dial perfusion imaging crease in CFR) regardless of
gender
Pepine et al. 201011 152 Mean 5.4 years CFR in women with non-ob- MACE Lower CFR associated with
structive coronary arteries increased risk of MACE (HR 1.20,
referred to evaluate suspected 95% CI 1.05–1.38; P = 0.008)
ischaemia

CAD, coronary artery disease; CFR, coronary flow reserve; CI, confidence interval; CMD, coronary microvascular dysfunction; CMR, cardiac magnetic resonance; HR, hazard ratio; MACE, major adverse cardiovascular events; MI, myocar-
dial infarction; MPRI, myocardial perfusion reserve index; MVA, microvascular angina; OR, odds ratio.
3

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4 Editorial

..
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