Carl J Pepine

Domenico G Della

Rocca

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EDITORIAL
Some thoughts on the continuing dilemma
of angina pectoris
Domenico G. Della Rocca and Carl J. Pepine*
Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA
Online publish-ahead-of-print 7 October 2012
This editorial refers to ‘Stable angina pectoris with no
obstructive coronary artery disease is associated with
increased risks of major adverse cardiovascular events’†,
by L. Jespersen et al., 33(6): 734-744
It is indeed surprising that, several hundred years after its elegant de-
scription and almost 100 years since its seemingly secure link with
severeobstructive coronaryartery disease (CAD), we are still uncer-
tain about critically important aspects of a condition as common as
angina pectoris. To this end, Jespersen and colleagues1 provide
new data, confirming data from the Women’s Ischemic Syndrome
Evaluation (WISE) study,2,3 that stable angina without obstructive
CAD is associated with increased risk for adverse outcomes
among women. Their findings also extend this conclusion to men
for the first time.
Why the uncertainty?
The classical study on the relationship of angina to pathological find-
ings concluded that ‘no patients with angina pectoris failed to show
. . . occlusion in at least one of the major coronary arteries.’4 This
concept was reinforced by early coronary angiography reports,
and angina relief with occlusion relief by revascularization seemed
to ‘close the loop’. Flow-limiting stenosis causing ischaemia was
accepted as the aetiological explanation for angina. This association
was not absolute, since in the occasional patient without severe
stenosis, angina could be explained by other diseases that either
markedly increased myocardial oxygen demand (e.g. severe aortic
stenosis, hypertrophic cardiomyopathy, severe hypertension, etc.)
or limited myocardial oxygen delivery (e.g. coronary spasm, pro-
found anaemia, etc.). However, in the absence of these conditions
or coronary obstruction, the clinician was at a loss to explain
angina. The usual defaults were that (i) the patient really did not
have angina; and/or (ii) the non-invasive findings suggesting ischae-
mia were ‘false positive’; and/or (iii) the patient had an undetected
non-cardiac explanation for their symptoms.
This clinical ‘paradox of normal selective coronary arteriograms in
patients considered to have unmistakable CAD’ was first placed into
focus in 1967 by the report of 15 such women with ischaemic elec-
trocardiographic abnormalities.5 Many reports followed document-
ing ischaemia by different methods in such patients but, in contrast to
ischaemia associated with obstructive CAD, left ventricular wall
motion appeared to be preserved. This finding led to speculation
about long-term outcomes of such patients. Indeed multiple early
reports suggested that outcomes were similar to those of selected
subjects without angina and obstructive CAD. Unfortunately, this
conclusion was widely embraced and led to dismissal of such patients
from subspecialty care and also from general medical care.
During our attempts to identify reasons for higher ischaemic heart
disease (IHD)event rates among womenvs. men, it became clear that
there was a strong bias against evaluation of women with chest pain
and other findings suggesting IHD. The public message about this
gender inequity then prompted referral of more women with these
findings to coronary angiography. We began to see increasing
numbers of such women who were not only disabled by persistent
angina, but had serious adverse outcomes. These concerns led to
the WISE study in 1996, and about two-thirds of the initial consecu-
tive cohort of women with chest pain and other findings suggesting
IHD were found to have no obstructive CAD: their adverse out-
comes confirmed that this was not a benign syndrome, as initially
believed.2
Also important was the application of coronary artery reactivity
testing for endothelial and microvascular function (Figure 1).
Among women with normal coronary arteries and non-obstructive
CAD, WISE study data showed that most had endothelial and/or
microvascular dysfunction. The latter was defined by low coronary
flow reserve and independently predicted adverse cardiovascular
events (e.g. first occurrence of death, myocardial infarction, stroke,
or hospitalization for heart failure) after 5.4 years follow-up.3
These serious events are consistent with the cardiovascular disease
continuum expected for a disorder involving the microvasculature.
Furthermore, they consume a large amount of healthcare resources.
Cardiac magnetic resonance imaging provided superior resolution to
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.
† doi:10.1093/eurheartj/ehr331.
* Corresponding author. Tel: +1 352 273 9082, Fax: +1 352 371 0370, Email: carl.pepine@medicine.ufl.edu
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: journals.permissions@oup.com
European Heart Journal (2014) 35, 1361–1364
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evaluate perfusion, and these patients were found to have a relative
failure of subendocardial perfusion to increase with adenosine,
which could explain the absence of major changes in left ventricular
wall motion.6
What could cause angina
in patients without obstructive
coronary artery disease?
Although Jespersen and colleagues1 did not explore mechanisms, the
evidence is strong for several inter-related mechanisms contributing
to angina and findings for ischaemia among patients without flow-
limiting stenosis. They include (i) endothelial dysfunction (ED); (ii)
microvascular dysfunction (MVD); and (iii) coronary artery spasm
(CAS) (Figures 1 and 2). Several, or all of these, may contribute in
the same patient.
Endothelial dysfunction is a systemic disorder resulting from injury
related to essentially all known atherosclerosis risk conditions. Thus
it is present at the earliest stages of CAD before angiographic evi-
dence of ‘raised lesions’ obstructing the lumen. Endothelial dysfunc-
tion has been linked with adverse outcomes in many conditions
including women with and without coronary artery obstruction in
the WISE study7 and men and women with non-obstructive CAD.8
Endothelial dysfunction is also seen among angina patients with
CAS and those with MVD.
The term ‘microvascular angina’ was proposed9 to explain in-
appropriate vasodilation of the coronary microcirculation. This
concept of MVD has received increasing attention10 and is defined
as ‘a dysregulation of coronary blood flow, not attributable to ob-
structive CAD that results from either structural or functional
mechanisms in the coronary microvasculature.’ A clinical classifica-
tion of pathogenetic mechanisms has been proposed, and MVD has
been linked with adverse outcomes in an increasing number of con-
ditions.10 Recent data from the WISE study found that half of the
women with angina and no obstructive CAD tested with adenosine
had MVD, and this was an independent predictor of adverse events
as noted above.3
Coronary artery spasm is an established mechanism for angina
and ischaemia resulting from increased vascular smooth muscle
sensitivity to agonists usually at sites of non-obstructive athero-
sclerosis, and may even occur in the microvessels. In the WISE
study, only 3–4% of unselected, consecutive women receiving
acetylcholine (1024 M into the left coronary) testing had CAS (un-
published data). This frequency is similar to that observed with
unselected methylergonovine testing in stable angina patients.11
Figure 1 Coronary reactivity testing (top panels). With the use of different techniques (e.g. quantitative coronary angiography, intracoronary
Doppler ultrasound, magnetic resonance imaging, etc.), large vessel reactivity and coronary blood flow (microvessel reactivity) can be assessed
with infusion of endothelium-dependent [e.g. acetylcholine (ACh)] and endothelium-independent [e.g. nitroglycerin (NTG) and adenosine
(Ado)] vasodilators. Endothelial dysfunction (bottom left) is indicated by an attenuated increase or decrease in the size of the macro- and micro-
vessels in response to ACh. These patients also may have an exaggerated increase in coronary size in response to NTG. Microvascular dysfunction
(bottom right) is indicated by an attenuated increase in coronary blood flow due to impaired dilation of pre-arteriolar vessels after Ado infusion.
Spasm (bottom middle) is indicated by a decrease in coronary size and flow due to segmental or diffuse epicardial and/or microvascular constriction
after ACh or methylergonovine. These patients also have exaggerated dilation with NTG.
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Among patients with angina and findings of IHD without obstructive
CAD, spasm testing is strongly recommended since a positive result
provides direction for specific treatment. Also, recent data show
that when patients without obstructive CAD evolve with acute cor-
onary syndromes, CAS may be detected in half or more.12
How large is this problem?
An estimated 10 million Americans (4 million males and .5 million
females) have angina,13 and  3 million coronary angiograms were
done in 2010. Although exact frequencies for referral of angina
patients to angiography are unknown, at least half of the women
and about a third of the men referred for angiography have non-
obstructive CAD.14 These frequency estimates are supported by
data from Jespersen et al.1 Thus millions of women and men with
angina without obstructive CAD will probably be identified each
year.
Do patients classed as having
‘normal coronary arteries’ truly
have normal arteries?
A WISE substudy addressed this question by targeting a consecutive
sample of 100 women with angina and ‘normal coronary angiograms’
as read onsite to estimate the frequency of coronary plaque by intra-
vascular ultrasound (IVUS).15 About 80% of the women had athero-
sclerotic plaques. Considering the sampling limitations of IVUS, this
probably underestimates plaque frequency among women with
angina and findings of IHD. Evidence of positive remodelling, as the
explanation for plaque concealment on angiography, was present in
about a third. Accordingly, we have stopped using the term ‘normal
coronary arteries’ in angiography reporting and believe that it is
more appropriate simply to say that there is ‘no evidence for ob-
structive CAD’. If we extrapolate these finding to the Jespersen
et al.1 data, and considering their risk factors, most of the 48%
women with ‘normal coronary arteries’ would probably have coron-
ary plaque.
What is the aetiology of adverse
events among these patients?
Non-obstructiveCADis complex, and encompassesdifferentpatho-
physiological substrates but, based on findings reported by Jespersen
et al.1 and by others,2,3 it is associated with impaired prognosis. While
ED, MVD, and/or CAS may explain angina and ischaemia, most acute
coronary events are believed to result from thrombi associated with
disruption (rupture orerosion)of ‘vulnerable’ plaques that are other-
wise not detected by angiography. Among sudden coronary deaths,
the underlying cause in the majority was plaque rupture; in a third,
erosion; and in a fewpercent, the thrombiwereattributed to calcified
nodules.16 Plaque erosion was the cause of death in about one-third
of women and less than one-sixth of men. However, in women ,50
years old, erosion was the predominant cause of the acute coronary
thrombi, while plaque rupture was the mechanism in women .50
Figure 2 Proposed mechanisms for angina and their possible inter-relationships among patients without obstructive coronary artery disease
(CAD). Endothelial dysfunction (ED) probably underlies most cases, with microvascular dysfunction (MVD) and/or coronary artery spasm
(CAS) and other mechanisms (not shown) contributing in some cases. While these mechanisms contribute to ischaemia, other processes
[plaque disruption (rupture or erosion), heightened coagulation, inflammation, etc.] are responsible for the acute thrombotic clinical events.
However, ED, MVD, and/or CAS have the potential to limit collateral perfusion and/or reperfusion during and following non-fatal thrombotic
events to worsen ischaemia-related injury and increase adverse outcomes.
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yearsold and in men regardless of age.16 Also ischaemic injury, caused
by the acute plaque disruption, may be exacerbated in the presence
of ED, MVD, and/or CAS, leading to worsened clinical outcomes.
The report by Jespersen et al.1 clearly contributes to advance our
understanding of angina. In women, as well as men, angina with non-
obstructive CAD requires further investigation. Dismissing this as a
benign condition cannot be justified. While emerging evidence has
linked MVD with adverse outcomes,3 the specific mechanisms and
therapeutic targets remain to be clarified.17
Conflict of interest: none declared.
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Some thoughts on the continuing dilemma of angina pectoris

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Some thoughts on the continuing dilemma of angina pectoris

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