Learning objectives
Around one half of angina patients have no obstructive coronary disease; many of these
patients have microvascular and/or vasospastic angina.
Tests of coronary artery function empower clinicians to make a correct diagnosis (rule-in/rule-out),
complementing coronary angiography.
Physician and patient education, lifestyle, medications and revascularisation are
key aspects of management.
Introduction
Ischaemic heart disease (IHD) remains the leading global cause of death and lost life
years in adults, notably in younger (<55 years) women.1 Angina pectoris (derived from
the Latin verb ‘angere’ to strangle) is chest discomfort of cardiac origin. It is
a common clinical manifestation of IHD with an estimated prevalence of 3%–4% in UK
adults. There are over 250 000 invasive coronary angiograms performed each year with
over 20 000 new cases of angina. The healthcare resource utilisation is appreciable
with over 110 000 inpatient episodes each year leading to substantial associated morbidity.2
In 1809, Allen Burns (Lecturer in Anatomy, University of Glasgow) developed the thesis
that myocardial ischaemia (supply:demand mismatch) could explain angina, this being
first identified by William Heberden in 1768. Subsequent to Heberden’s report, coronary
artery disease (CAD) was implicated in pathology and clinical case studies undertaken
by John Hunter, John Fothergill, Edward Jenner and Caleb Hiller Parry.3 Typically,
angina involves a relative deficiency of myocardial oxygen supply (ie, ischaemia)
and typically occurs after activity or physiological stress (box 1).
Box 1
Definition of angina (NICE guidelines)32
Typical angina: (requires all three)
Constricting discomfort in the front of the chest or in the neck, shoulders, jaw or
arms.
Precipitated by physical exertion.
Relieved by rest or sublingual glyceryl trinitrate within about 5 min
Presence of two of the features is defined as atypical angina.
Presence of one or none of the features is defined as non-anginal chest pain.
Stable angina may be excluded if pain is non-anginal provided clinical suspicion is
not raised based on other aspects of the history and risk factors.
Do not define typical, atypical and non-anginal chest pain differently in men and
women or different ethnic groups.
Six decades have passed since the first reported invasive coronary angiogram; however,
many physicians still consider detecting obstructive epicardial CAD on coronary angiography
a ‘sine qua non’ for the diagnosis of angina.4 The detection of obstructive CAD allows
evidence-based medical treatment and consideration of myocardial revascularisation.
However, underlying pathophysiology is more nuanced with contributions from anatomical
atherosclerotic and/or functional alterations of epicardial vessels and/or microcirculation
(figure 1).5 ESC guidelines6 have revised nomenclature (‘Chronic Coronary Syndromes’)
in part reflecting the importance of patients with signs and symptoms of ischaemia
without obstructive coronary artery disease—INOCA.7 8 Around half of all patients
with angina undergoing elective coronary angiography have no obstructive epicardial
CAD.9 This large, heterogeneous chronic coronary syndrome is comprised of distinct
vasomotor disorders including microvascular angina (MVA) and/or vasospastic angina
(VSA)—the two most common underlying disorders of coronary vascular function in the
INOCA population. Crucially, we stress that there are often multiple mechanisms of
myocardial ischaemia occurring in various coronary compartments via different mechanisms.
These frequently coexist in combination; however, an appreciation of this fact can
help stratify treatment and help us understand patients with poor treatment response
(eg, angina after revascularisation).
Figure 1
Reappraisal of ischaemic heart disease pathophysiology. Distinct functional and structural
mechanisms can affect coronary vascular function and frequently coexist leading to
myocardial ischaemia. CAD, coronary artery disease.
We begin by classifying angina according to pathophysiology. We then consider the
current guidelines and their strengths and limitations for assessing patients with
recent onset of stable chest pain. We review non-invasive and invasive functional
tests of the coronary circulation with linked management strategies. Finally, we point
to future directions providing hope for improved patient outcomes and development
of targeted disease-modifying therapy. The aim of this educational review is to provide
a contemporary approach to diagnosis and management of angina taking into consideration
epicardial coronary disease, microcirculatory dysfunction and coronary vasospasm.
Contemporary angina classification by pathophysiology
The clinical history is of paramount importance to initially establish whether the
nature of the presenting symptoms is consistent with angina (box 1). Indeed, recent
data supports specialist physicians under-recognise angina in up to half of their
patients.10 Furthermore, contemporary clinical trials of revascularisation in stable
IHD including the ISCHEMIA trial highlight the importance of good clinical history
and listening to our patients to determine the nature and frequency of symptoms which
helps to plan management. We propose a classification of angina that aligns with underlying
aetiology and related management (table 1).
Table 1
Classification of angina by pathophysiology
Angina with obstructive CAD
Obstructive CAD
Flow limiting epicardial coronary artery disease*
>90% stenosis in a major coronary vessel
Fractional flow reserve ≤0.80 or NHPR<0.90
Intermediate coronary stenosis in single major vessel with documented ischaemia
Symptoms and/or signs of ischaemia but no obstructive CAD (INOCA)
Microvascular angina†17
1. Symptoms of myocardial ischaemia
Effort and/or rest angina
Angina equivalents (ie, shortness of breath)
2. Absence of obstructive CAD*
FFR>0.80
NHPR>0.89
Absence of flush ostial branch vessel occlusions
3. Objective evidence of myocardial ischaemia
Ischaemic ECG changes during an episode of chest pain
Stress-induced chest pain and/or ischaemic ECG changes in the presence or absence
of transient/reversible abnormal myocardial perfusion and/or wall motion abnormality
4. Coronary microvascular dysfunction
Impaired CFR (≤2.0 or≤2.5 depending on methods used)
Increased coronary microvascular resistance (eg, IMR>25, HMR≥2.5 mm Hg cm–1 s)
Coronary microvascular spasm, defined as reproduction of symptoms, ischaemic ECG shifts
but no epicardial spasm during acetylcholine testing.
Coronary slow flow phenomenon, defined as TIMI frame count >25
Vasospastic angina‡42
Nitrate-responsive angina
At least one of:
Rest angina—especially between night and early morning
Marked diurnal variation in exercise tolerance—reduced in morning
Precipitated by hyperventilation
Calcium channel blockers (but not β-blockers) suppress episodes
Ischaemic ECG changes
During spontaneous episode, any one of the following in at least two contiguous leads:
ST segment elevation ≥0.1 mV
ST segment depression ≥0.1 mV
New negative U waves
Coronary artery spasm
Either spontaneously or in response to provocation (eg, acetylcholine):
Transient total or subtotal coronary artery occlusion (>90% constriction)
Reproduction of angina symptoms
Ischaemic ECG changes
*The finding of obstructive epicardial disease does not exclude other important contributors
to ischaemia (microvascular dysfunction and/or vasospasm). The physiological ischaemic
lesion thresholds are drawn from 2018 ESC guidelines for myocardial revascularisation
and randomised trials; however, the authors acknowledge that majority of lesions with
grey-zone physiology values (eg, FFR 0.75–0.82) are not associated with downstream
myocardial ischaemia (NCT02425969—Dr B Hennigan, Personal Correspondence).
†Definitive MVA is only diagnosed if all four criteria are present. Suspected MVA
is diagnosed if criteria 1 and 2 are met but only one of the final two criteria are
met (either objective evidence of ischaemia (criterion 3) or evidence of coronary
microvascular dysfunction (criterion 4).
‡'Definitive vasospastic angina’ is diagnosed if nitrate-responsive angina is evident
during spontaneous episodes and either the transient ischaemic ECG changes during
the spontaneous episodes or coronary artery spasm criteria are fulfilled. ‘Suspected
vasospastic angina’ is diagnosed if nitrate-responsive angina is evident during spontaneous
episodes but transient ischaemic ECG changes are equivocal or unavailable and coronary
artery spasm criteria are equivocal. NHPR (eg, iwFR, dPR).
CAD, coronary artery disease; CFR, coronary flow reserve; CFR, coronary flow reserve;
dPR, diastolic pressure ratio; FFR, fractional flow reserve; HMR, hyperaemic microvascular
resistance; IMR, index of microcirculatory resistance; MVA, microvascular angina;
NHPR, non-hyperaemic pressure ratio.
Angina with obstructive coronary artery disease
2018 ESC guidelines on myocardial revascularisation define obstructive CAD as coronary
stenosis with documented ischaemia, a haemodynamically relevant lesion (ie, fractional
flow reserve (FFR) ≤0.80 or non-hyperaemic pressure ratio (NHPR) (eg, iwFR≤0.89))
or >90% stenosis in a major coronary vessel (table 1). There is renewed interest in
NHPRs (iwFR, resting full-cycle ratio (RFR) and diastolic pressure ratio (dPR)) as
data have emerged in support of numerical equivalency between these indices suggesting
all can be used to guide treatment strategy.11 Angina with underlying obstructive
CAD allows symptom guided myocardial revascularisation (often with percutaneous coronary
intervention (PCI)) and is effective in reducing ischaemic burden and symptoms (in
many patients). Recent studies have served evidence that functional coronary disorders
overlap and may contribute to angina even in patients with obstructive epicardial
CAD. Dynamic changes in lesion or vessel ‘tone’ and propensity to vasoconstriction
is important and may cause rest angina that is frequently overlooked in patients with
obstructive CAD.12 During invasive physiological assessment of ischaemia during exercise,
Asrress et al showed that ischaemia developed at FFR averaging≈0.76 which is not often
observed with adenosine induced hyperaemia.13 This finding implies there are other
important drivers of subendocardial ischaemia (myocardial supply:demand factors).
Furthermore, it reinforces that angina is not synonymous with ischaemia or flow-limiting
coronary disease (eg, abnormal FFR or NHPR). Coronary anatomy and physiology should
not be considered in isolation but in the context of the patient.
Angina-myocardial ischaemia discordance
Although obstructive CAD or microvascular dysfunction may be present, the link between
ischaemia and angina is not clearcut. The ‘ischaemic threshold’ (the heart rate-blood
pressure product at the onset of angina) has intraindividual and interindividual variability.14
Innate differences in vascular tone and endocrine changes (eg, menopause) may influence
propensity to vasospasm while environmental factors including cold environmental temperature,
exertion and mental stress are relevant. The large international CLARIFY registry
highlighted the importance of symptoms, showing that angina with or without concomitant
ischaemia, was more predictive of adverse cardiac events compared with silent ischaemia
alone.15 Other potential drivers of discordance between angina and ischaemia include
variations in pain thresholds and cardiac innervation (eg, diabetic neuropathy).
Symptoms and/or signs of ischaemia but no obstructive coronary artery disease (INOCA)
Cardiologists are inclined to adopt a ‘stenosis centric’ approach to patient management;
however, as clinicians we must appreciate that all factors are relevant, including
coronary anatomy and function but systemic health and the psychosocial background
(figure 2). First, systemic
factors including heart rate, blood pressure (and their product) and myocardial supply:demand
ratio (Buckberg index) are relevant.16 Reduced myocardial oxygen supply from problems
such as anaemia or hypoxaemia should always be considered.
Figure 2
Contributing factors to myocardial ischaemia. The contributors to the physiological
myocardial perfusion gradient and resultant ischaemia can be broken down at patient-level
into systemic, cardiac and coronary factors. CAD, coronary artery disease; SEVR, subendocardial
viability ratio.<Modified with permission from 47>.
Second, coronary
factors are well recognised but certain nuances are overlooked. In 2018, the first
international consensus guidelines clarify that a definite diagnosis of MVA may be
made in patients with angina with no underlying obstructive CAD, evidence of reversible
ischaemia on functional testing and objective evidence of coronary microvascular dysfunction
(table 1).17 ‘Probable MVA’ is defined by three of the above criteria. Coronary microvascular
dysfunction may be structural (eg, small vessel rarefaction or increased media: lumen
ratio) or functional (eg, endothelial impairment) and these disorders may coexist.
Other coronary causes of INOCA include intramyocardial ‘tunnelled’ segments of epicardial
arteries (myocardial ‘bridging’) who may have ischaemia on exercise. These segments
are particularly susceptible to vasoconstriction due to endothelial impairment.18
Coronary arteriovenous malformations are rare but may also cause of myocardial ischaemia.
Vasospastic angina (‘Prinzmetal’s angina’) is typically described as recurrent rest
angina with focal occlusive proximal epicardial often seen in young smokers with characteristic
episodic ST segment elevation during attacks. Notably, the more common form of VSA
is distal and diffuse subtotal epicardial vasospasm and is characterised by ST segment
depression and may occur during exertion. Typical cardiac risk factors and endothelial
impairment may be implicated.19
The long-term (sometimes lifelong) burden of MVA and/or VSA on physical and mental
well-being can be profound. Patients with these conditions commonly attend primary
care and are repeatedly hospitalised with acute coronary syndromes, arrhythmias and
heart failure driving up health resource utilisation, morbidity and reducing quality
of life.20 21
The third and final group of factors that drive ischaemia in patients with angina
but without obstructive CAD include cardiac
factors. These include left ventricular hypertrophy or restrictive cardiomyopathy
where subendocardial ischaemia results impaired perfusion from arterioles penetrating
deeper into myocardial tissue with shorter diastole, enhanced systolic myocardial
vessel constriction and enhanced interstitial matrix.22 Heart failure (with reduced
or preserved ejection fraction) can lead to elevated left ventricular end diastolic
pressure which reduces the diastolic myocardial perfusion gradient. Valvular heart
disease (eg, aortic stenosis (AS)) is an important consideration in patients with
INOCA. In AS, most experts support haemodynamic factors as the main cause of ischaemia,
especially since symptoms and coronary flow reserve (CFR) improve immediately after
valve replacement.23 Patients with INOCA may have increased painful sensitivity to
innocuous cardiac stimuli (eg, radiographic contrast) without inducible ischaemia.
Furthermore, some affected patients have a lower pain threshold and tolerance to the
algogenic effects of adenosine (thought to be the main effector of ischaemia mediated
chest pain).24
Gender differences and angina presentation
The WISE (Women’s Ischemia Syndrome Evaluation) study highlighted that over 2/3 of
women with angina had no obstructive CAD and the majority of these had functional
impairments in the coronary microcirculation associated with significant impairments
in health-related quality of life.25 Indeed, women have more non-obstructive CAD and
functional IHD which are frequently overlooked and hence undertreated.26 27 Over time
and at different ages, women have a similar or slightly higher prevalence of angina
than men across countries independent of diagnostic and treatment practices.28 Different
patterns of IHD may be anticipated to cause different angina symptoms between genders.
Nonetheless, recent evidence moves the field away from the ‘male-typical, female-atypical’
model of angina towards a ‘gender continuum’ whereby the objective reports between
men and women’s symptoms are more similar than treating physicians perceive. Interestingly,
dyspnoea was a feature in around ¾ of angina presentations without any significant
difference between the sexes.29
Assessment: current guidelines
Assessment strategies in current major international guidelines focus on the detection
of underlying obstructive CAD. European and American guidelines (ESC and ACC/AHA,
respectively) favour a Bayesian approach whereby overall probability of obstructive
CAD after testing is determined from pretest probability modified by the diagnostic
test results. The ACC/AHA guidelines determine pretest risk from a modified Diamond
Forrester model,30 whereas the Europeans favour the CADC (Coronary Artery Disease
Consortium) model which avoids overestimation seen with Diamond-Forrester and appears
a more accurate assessment of pretest risk.31 Both current guidelines stratify pretest
risk into low, intermediate or high groups with use of non-invasive testing suggested
in the intermediate group (ACC/AHA arbitrarily defined as 10%–90% or 15%–85% in ESC).
In stark contrast, the NICE CG95 2016 update ‘chest pain of recent onset: assessment
and diagnosis’ discarded the Bayesian pretest risk assessment. NICE advocates first-line
multidetector CT coronary angiography (CTCA) in all patients with typical or atypical
chest pain (box 1), those whose history does not suggest angina but who have ST changes
or Q waves on a resting ECG.32 Functional testing (eg, exercise stress echo or stress
perfusion magnetic resonance—CMR) are relegated to second-line if CTCA is non-diagnostic
or the clinical significance of known CAD needs clarified. Potential benefits of this
approach include a much higher diagnostic accuracy for detection of atherosclerotic
heart disease than functional testing which potentially carries the best long-term
prognostic information for patients with CAD.27 Extended 5-year outcomes from SCOTHEART
showed a reduction in the combined endpoint of death from coronary heart disease or
non-fatal myocardial infarction among the group randomised to CTCA compared with standard
care (2.3% vs 3.9%; absolute risk reduction (ARR) 1.6% number needed to treat (NNT)
63). This effect was driven by better targeting of preventative therapies. The authors
report that although overall prescriptions of preventive cardiovascular medications
were only modestly increased (~10% higher) in the CTCA arm, changes in such therapies
occurred in around one in four patients allowing more personalised treatment to patients
with most coronary atheroma in the CT group.
These results should be considered in relation to design limitations of this trial.
There was no control procedure (test vs no test), the threshold for prescribing preventive
therapy with statins was 20%–30% likelihood of a CHD event in 10 years (much higher
than many contemporary healthcare systems), CTCA was performed on top of treadmill
exercise testing which has poor test accuracy in distinct patient groups, notably
women, and the procedures were unblinded and open-label. Outcome reporting that is
narrowly focused on CHD does not take account of other cardiovascular events, such
as hospitalisation for arrhythmias and heart failure, which have implications for
quality of life. In PROMISE, a ‘head-to-head’ trial of CTCA versus functional testing,
there were no differences in health outcomes.33 In the interests of providing patients
and clinicians with a reliable and accurate test result, a strategy based on anatomical
CTCA has fundamental limitations. SCOT-HEART identified that obstructive CAD affects
the minority (one in four) patients presenting to the Chest Pain Clinic with known
or suspected angina. This means that an anatomical test strategy with CTCA leaving
the aetiology and treatment unexplained in the majority of affected patients, which
becomes all the more relevant considering that anginal symptoms and quality of life
are worse when CTCA is used.34 Diagnostic options are enhanced by advances in technology
and tests for the functional significance of CAD are now feasible, but at significant
cost.35 NICE guidelines state that HeartFlow FFRCT should be considered as an ‘option
for patients with stable, recent onset chest pain who are offered CCTA as part of
the NICE pathway on chest pain’. Using HeartFlow FFRCT may avoid the need for invasive
coronary angiography and revascularisation; however, major randomised controlled trials
are ongoing (eg, FORECAST study NCT03187639).
We support efforts to provide a definitive diagnosis for patients with ongoing angina
symptoms after a ‘negative’ CTCA, initially using non-invasive ischaemia testing.
Notably, the recent International Standardised Criteria for diagnosing ‘suspected’
MVA would be met in patients with symptoms of myocardial ischaemia, no obstructive
CAD and objective evidence of myocardial ischaemia (table 1). Invasive testing for
diagnosis of MVA could be reserved for subjects with refractory symptoms and negative
ischaemia testing or diagnostic uncertainty. The criteria for ‘definite MVA’ require
the above AND objective evidence of microvascular dysfunction (eg, reduced CFR or
raised microvascular resistance).
Limitations of current guidelines
There are limitations to the current NICE-95 guideline, not least the logistics and
cost of service provision with an estimated 700% increase in cardiac CT required across
the UK.36 Importantly, what do we report to the majority of patients with anginal
chest pain but no obstructive CAD on the CTCA? In fact, only 25% of patients had obstructive
CAD and at 6 weeks based on the CTCA findings, 66% of patients were categorised as
not having angina due to coronary heart disease. The possibility of false reassurance
for the patients with angina and INOCA is an open question and may be one contributing
factor for the lack of improvement in angina and quality of life in the CTCA group
vs standard care.34 We must strive to deliver patient-centred care, recognising that
most patients seek explanation for their symptoms in combination with effective treatment
options.37 CTCA is an insensitive test for disorders of coronary vascular function,
which may affect the majority of patients attending with anginal symptoms. Since the
majority of affected patients have no obstructive CAD, and the majority of them are
women, an anatomical strategy introduces a sex-bias into clinical practice, whereby
a positive test result (obstructive CAD) is more likely to occur in men and a positive
test for small vessel disease is less likely to occur in women. Furthermore, patient-reported
outcomes including angina limitation, frequency and overall quality of life improve
less after CTCA compared with standard care, notably in patients with no obstructive
CAD.34 Non-invasive functional testing with positron emission tomography (PET), echo
and most recently stress perfusion CMR has diagnostic value for stratified medicine.
Finally, stratification of patients using luminal stenosis severity on angiography
overlooks the spectrum of risk associated with overall plaque burden and may miss
functional consequences associated with diffuse but angiographically mild disease
(particularly when subtending large myocardial mass).
Non-invasive functional testing includes myocardial perfusion scintigraphy, exercise
treadmill testing (including stress echocardiography) or contrast-enhanced stress
perfusion MRI depending on local availability. Novel pixel-wise absolute perfusion
quantification of myocardial perfusion by CMR will likely improve the efficiency of
absolute quantification of myocardial blood flow by CMR.38 PET is the reference-standard
non-invasive assessment of myocardial blood flow permitting quantitative flow derivation
in mL/g/min. Clinically, PET-derived quantification of myocardial blood flow (MBF)
can assist in the diagnosis of diffuse epicardial or microvascular disease; however,
limitations include poor availability and exposure to ionising radiation. Non-invasive
workup often provides important insights on coronary microvascular function and are
reviewed in detail elsewhere.39
With functional testing relegated to second-line testing, clinicians may forgo additional
tests after a negative CTCA particularly in an era of fiscal restraint and if patients’
symptoms are viewed as atypical. One important group that will be disparately affected
by an ‘anatomy first’ strategy are women—over half of all patients with suspected
angina in the large prospective trials of CTCA are female. While the benefits of CTCA
to diagnose CHD and prevent CHD events are similar in women and men, the large majority
of patients undergoing CTCA do not have obstructive CAD potentially leading to misdiagnosis
and suboptimal management in patients with INOCA.33 Women, are most likely to have
no obstructive CAD and their cardiac risk is associated with severely impaired CFR
and not obstructive CAD.40 Overall, there is growing awareness of sex-specific differences
in coronary pathophysiology and potential for different patterns of CAD in women.
This is a rapidly evolving fertile area for further research.
Invasive coronary angiography and physiological assessment
UK NICE guidelines suggest that invasive coronary angiography is a third-line investigation
for angina when the results of non-invasive functional imaging are inconclusive. Patients
with typical symptoms, particularly those in older age groups with higher probability
of non-diagnostic CTCA scans, often proceed directly to invasive coronary angiography.
During cardiac catheterisation, assuming that epicardial CAD is responsible for their
symptoms, visual assessment for severe angiographic stenosis (>90%) is sufficient
to establish significance and treatment plan for these patients. Two common pitfalls
for visual interpretation of angiograms were recently highlighted by two coronary
physiology pioneers Gould and Johnson. Using their quantitative myocardial perfusion
database of over 5900 patients showing that occult coronary diffuse obstructive coronary
disease or flush ostial stenosis may be both be overlooked on angiography and mislabelled
as microvascular angina with suboptimal treatment.41 The ischaemic potential of indeterminate
coronary lesions (~40%–70% diameter stenosis) is best assessed using pressure-derived
indices, such as FFR, and non-hyperaemic pressure ratios (NHPR: dPR, nstantaenous
wave free ratio (iwFR) and others) to guide revascularisation decisions. However,
as is the case with coronary angiography, these indices do not inform the clinician
about disorders of coronary artery vasomotion.
Invasive tests of coronary artery function are the reference standard for the diagnosis
of coronary microvascular dysfunction17 and vasospastic angina (table 1; figure 1).42
Coronary microvascular resistance may be directly measured using guidewire-based physiological
assessment during adenosine induced hyperaemia. Methods to assess this include using
a pressure-temperature sensitive guidewire by thermodilution (index of microcirculatory
resistance; IMR) or Doppler ‘ComboWire’ (hyperaemic microvascular resistance; HMR).
These metrics have been the focus of a recent review article in Heart.43 There are
several other haemodynamic indices of microvascular function including instantaneous
hyperaemic diastolic pressure velocity slope, wave intensity analysis and zero flow
pressure. A detailed description of these parameters is out with the scope of this
review.41 Elevated coronary microvascular resistance (eg, IMR >25) carries prognostic
utility in patients with reduced CFR but unobstructed arteries. Lee et al found over
fivefold higher risk of adverse cardiac events in these subjects compared with controls
with normal microvascular function.44
CFR is the ratio of maximum hyperaemic blood flow to resting flow. CFR in the absence
of obstructive CAD can signify impaired microvascular dilation. Lance Gould first
introduced this concept almost 50 years ago but more recently proposed that CFR should
be considered in the context of the patient and the hyperaemic flow rate.41 The absolute
threshold for abnormal CFR varies depending on the method of assessment, the patient
population studies and the controversy reflects the dichotomous consideration of the
continuous physiological spectrum of ischaemia. Abnormal CFR thresholds vary from
≤2.0 or ≤2.5 with more restrictive criteria for abnormal CFR (<1.6) being more specific
for myocardial ischaemia and worse outcomes but at the cost of reduced sensitivity.
On the other hand, studies of transthoracic Doppler derived CFR (which has less reproducibility)
often use cut-offs of 2.5 with some observational evidence of worse outcomes in the
INOCA population with CFR below this threshold.45 The influence of rate-pressure product
on resting flow and its correction for CFR determination should be considered.
Systolic endocardial viability ratio (SEVR) is a ratio of myocardial oxygen supply:demand
derived from the aortic pressure-time integral (diastole:systole). However, it is
well known that blood pressure, pulse and SEVR perturbations influence CFR more closely
than microcirculatory resistance. Reduced CFR without raised microvascular resistance
still portends increased cardiovascular risk44 and may be a distinct subgroup with
different drivers of ischaemia (eg, abnormal supply:demand systemic haemodynamic factors;
figure 2). Alternatively, these patients may be at an earlier stage of disease prior
to more established structural microvascular damage. Sezer et al showed the pattern
of coronary microvascular dysfunction early in type II diabetes was driven by disturbed
coronary regulation and high resting flow.46 In longstanding diabetes however, elevated
microvascular resistance was observed reflecting established structural microvascular
disease. This process matches the paradox of microvascular disease in diabetic nephropathy
where increased glomerular filtration rate (GFR) typifies the early stages of disease
prior to later structural damage and reduction in GFR.
The third mechanism of microvascular dysfunction is inappropriate propensity to vasoconstriction
of the small coronary arteries, typically this is assessed using intracoronary acetylcholine
infusions as a pharmacological probe.
Rationale and benefit of invasive coronary function testing in INOCA
We contend that a complete diagnostic evaluation of the coronary circulation should
assess structural and functional pathology.47 The British Heart Foundation CorMicA
trial provides evidence about the opportunity to provide a specific diagnosis to patients
with angina using an interventional diagnostic procedure (IDP) when obstructive CAD
is excluded by invasive coronary angiography. Consenting patients were randomised
1:1 to the intervention group (stratified medical therapy, IDP disclosed) or the control
group (standard care, IDP sham procedure, results not disclosed). The diagnostic intervention
included pressure guidewire-based assessment of FFR, CFR and IMR during adenosine
induced hyperaemia (140 µg/kg/min). Vasoreactivity testing was performed by infusing
incremental concentrations of acetylcholine (ACh) followed by a bolus vasospasm provocation
(up to 100 µg). The diagnosis of a clinical endotype (microvascular angina, vasospastic
angina, both, none) was linked to guideline-based management. The primary endpoint
was the mean difference in angina severity at 6 months (as assessed by the Seattle
Angina Questionnaire summary score—SAQSS) which was analysed using a regression model
incorporating baseline score. A total of 391 patients were enrolled between 25/11/2016
and 11/12/2017. Coronary angiography revealed obstructive disease in 206 (53.7%).
One hundred and fifty-one (39%) patients without angiographically obstructive CAD
were randomised. The underlying abnormalities revealed by the IDP included: isolated
microvascular angina in 78 (51.7%), isolated vasospastic angina in 25 (16.6%), mixed
(both) in 31 (20.5%) and non-cardiac chest pain in 17 (11.3%). The intervention was
associated with a mean improvement of 11.7 units in the SAQSS at 6 months (95% CI
5.0 to 18.4; p=0.001). In addition, the intervention led to improvements in the quality
of life (EQ5D index 0.10 units; 0.01 to 0.18; p=0.024). After disclosure of the IDP
result, over half of treating clinicians changed their diagnosis about the aetiology
of their patients’ symptoms. There were no procedural serious adverse events and no
differences in major adverse cardiac events (MACE) at 6 months. Interestingly, there
were sustained quality of life benefits at one year for INOCA patients helped by correct
diagnosis and linked treatment started at the index invasive procedure.48 Future trials
are anticipated to determine the wider external validity of this approach.
Management
Medical therapy to prevent new vascular events should be considered and these include
consideration of aspirin, ACE inhibitors (ACEi) and statins. The latter two agents
have pleiotropic properties including beneficial effects on endothelial function and
so may be helpful in treating coronary microvascular dysfunction. Sublingual glyceryl
trinitrate tablets or spray should be used for the immediate relief of angina and
before performing activities known to bring on angina.
Non-pharmacological
As with many cardiovascular diseases, lifestyle modification including risk factor
control and patient education are key. Lifestyle recommendations are covered in detail
in recent ESC guidelines. The adverse effect of angina on patient well-being and quality
of life can be substantial. It is crucial that we assess for this and manage appropriately.
After diagnosis with angina, cardiac rehabilitation can be useful to educate and build
confidence. One useful patient led education aid is called the ‘Angina plan’. This
tool is a workbook and relaxation plan delivered in primary care, which helps improve
angina symptoms (frequency and limitation) while reducing anxiety and depression.49
The ORBITA trial highlights the benefits of placebo effect and we support that the
positive diagnosis may be therapeutic in itself. Angina symptoms are often subjective
and multifactorial in origin, so patient education and validation of symptoms may
facilitate further improvement.
Management: Non-obstructive CAD
Generic guidelines on angina management frequently overlooks the precision medicine
goal whereby treatment is targeted to underlying pathophysiology. There is a lack
of high-quality clinical trial data for treating microcirculatory dysfunction. The
current article thus proposes a reasoned approach to management based on evaluation
of pathophysiological mechanisms.
We contest that angina and INOCA are syndromes and not a precise diagnosis (akin to
myocardial infarction with no obstructive CAD—MINOCA). As such, by stratifying treatment
according to underlying pathophysiology, we may realise better outcomes for our patients.
Impaired coronary vasodilator capacity (reduced CFR)
Bairey Merz et al performed a randomised controlled trial of ranolazine in the WISE
population. Notably, there was no net benefit effect on the INOCA population as a
whole; however, in patients with reduced CFR (<2.5), there was a benefit suggestion
of improved myocardial perfusion reserve index (MPRi) after established treatment.50
Lanza and Crea highlight that subjects with reduced CFR might preferentially be treated
with drugs that reduce myocardial oxygen consumption (eg, beta-blockers (BB)—for example,
Nebivolol 1.25–10 mg daily).51 There is accumulating evidence that long acting nitrates
are ineffective or even detrimental in MVA. Lack of efficacy may relate to poor tolerability,
steal syndromes through regions of adequately perfused myocardium and/or related to
the reduced responsiveness of nitrates within the coronary microcirculation.52 Furthermore,
chronic therapy with nitrate may induce endothelial dysfunction and oxidative stress,
predominantly via endothelin dependent pathways.53
Increased microvascular constriction (structurally increased microvascular resistance
or functional propensity to microvascular spasm)
Subjects with increased microvascular vasoconstriction may be treated with vasodilator
therapies acting on the microcirculation. These include calcium channel blockers (CCB—for
example, amlodipine 2.5–10 mg daily) or nicorandil (eg, 5–30 mg two times a day).
Hyper-reactivity to constrictor stimuli resulting in propensity to microvascular spasm
may be provoked by endothelial dysfunction. This was first described my Mohri et al
over three decades ago with recent physiological studies suggesting treatment aimed
at improving endothelial function (eg, ACEi, Ramipril 2.5–10 mg) may improve the microvascular
tone and/or the susceptibility to inappropriate spasm.54 55 A detailed discussion
of all potentially therapeutic options for coronary microvascular dysfunction is beyond
the scope of this article; however, a systematic review by Marinescu et al may be
of interest to readers wishing further information.56
Epicardial spasm (vasospastic angina)
The poor nitrate response or tolerance seen in MVA contrasts with patients with vasospastic
angina, in whom nitrates are a cornerstone of therapy and BB are relatively contraindicated.7
Dual pathologies (VSA with underlying microvascular disease) is increasingly recognised.
A diagnosis of VSA facilitates treatment using non-dihydropiridine calcium antagonists
(eg, diltiazem-controlled release up to 500 mg daily). Overall, CCB are effective
in treating over 90% of patients.57 High doses of calcium antagonists (non-dihydropiridine
and dihydropyridine) may be required either alone or in combination. Unfortunately,
ankle swelling, constipation and other side effects may render some patients intolerant.
In these cases, long-term nitrates may be used with good efficacy in this group. In
about 10% of cases, coronary artery spasm may be refractory to optimal vasodilator
therapy. Japanese VSA registry data shows nitrates were not associated with MACE reduction
in VSA, and importantly when added to Nicorandil were potentially associated with
higher rates of adverse cardiac events.58 Alpha blockers (eg, clonidine) may be helpful
in selected patients with persistent vasospasm. In patients with poor nitrate tolerance
the K+-channel opener nicorandil (5–10 mg two times a day) can be tried. Consider
secondary causes in refractory VSA (eg, coronary vasculitis) and in selected patients
with ACS presentations, coronary angioplasty may be considered as a bailout option.
Management: Obstructive CAD
Pharmacological
Although NICE guidelines offer either BB or CCB first line, although we support BB
initially because they are generally better tolerated (table 2).59 Long-term evidence
of efficacy is limited between BB and CCB and there are no proven safety concerns
favouring one or the other. Dihydropyridine calcium may be added to BB if blood pressure
permits. NICE CG126 states third line options can be either added on (or substituted
if BB/CCB not tolerated). These include nitrates (eg, isosorbide mononitrate 30–120 mg
controlled release), ivabradine (eg, 2.5–7.5 mg two times a day), nicorandil (5–30 mg
two times a day) or ranolazine (375–500 mg two times a day). These are all third line
medications that can be used based and combined with BB and/or CCB depending on comorbidities,
contraindications, patient preference and drug costs (figure 3). The RIVER-PCI study
found that anti-ischaemic pharmacotherapy with ranolazine did not improve the prognosis
of patients with incomplete revascularisation after percutaneous coronary intervention.60
This was a reminder that alleviation of ischaemia may not improve ‘hard’ endpoints
in patients with chronic coronary syndromes but helps us to remain focused on improving
their quality of life.
Table 2
Angina pharmacotherapy
Treatment
Angina type
Example
Investigation
Mechanism of action
Common side-effects
ß-blockers
MVA, CAD
Bisoprolol: 1.25–10 mg
Reduced CFR and/or structural microvascular dysfunction (raised microvascular resistance)
Reduction in myocardial oxygen consumption
Fatigue, blurred vision,cold hands
Calcium channel antagonists
All
Dihydropyridine (amlodipine: 2.5–10 mg daily)Non-dihydropyridine (verapamil: 40–240
or diltiazem up to 500 mg; controlled release)
Propensity to coronary vasospasm (epicardial and/or microvascular)
↓ spontaneous and inducible coronary spasm via vascular smooth muscle relaxation and
↓ oxygen demandVascular smooth muscle relaxation, reduction in myocardial oxygen consumption
Constipation, ankle swelling, flushing
Vasodilators
Nitrates
CAD, VSA
Isosorbid mononitrate: 30–120 mg one time a day (controlled released)
Propensity to epicardial coronary vasospasm
↓ spontaneous and inducible coronary spasm via large epicardial vasodilation, ↓ oxygen
demand. Lack of efficacy in microvascular angina with potential deleterious effect
Headaches, dizziness, flushing
Nicorandil
All
Nicorandil: 5–30 mg two times a day
All
Potassium channel activator with coronary microvascular dilatory effect
Dizziness, flushing, weakness, nausea
Rho kinase inhibitors
VSA, CMD
Fasudil: 5–20 mg; three times a day
Epicardial and/or microvascular vasospasm
Reduce calcium sensitisation of vascular smooth muscle, maintains coronary vasodilation
Rashes, flushing, hypotension
Late Na+Current Inhibitors
MVA, CAD
Ranolazine: 375–500 mg two times a day
Reduced CFR
Improves MPRi in patients with MVA and reduced CFR
Nausea, dizziness, headache
If channel blockers
CAD, MVA
Ivabradine: 2.5–7.5 mg two times a day
All
Ivabradine has shown anti-ischaemic and antianginal activity
Bradycardia, AF, headache
Partial fatty-acid oxidation inhibitors
CAD, MVA
Perhexiline: 50–400 mg daily or Trimetazidine
Plasma concentration required for dose titration.
Perhexiline Inhibits carnitine O-palmitoyltransferase 1 and 2, which transfer free
fatty acid from the cytosol into mitochondria.
Dizziness, unsteady, nausea and vomiting
Improved endothelial function/pleiotropic
ACE inhibitors
MVA, CAD
Ramipril: 2.5–10 mg daily
Hyper-reactivity to stimuli (eg, acetylcholine, exercise, stress)
Improve CFR, reduce workload, may improve small vessel remodelling. Improves endothelial
vasomotor dysfunction
Cough, renal impairment, hyperkalaemia
Statins
All
Atorvastatin: 10–80 mg dailyRosuvastatin: 5–40 mg daily
All
Improved coronary endothelial function reduced vascular inflammation
Myalgia, headache, cramps
Hormone-replacement therapy*
MVA
Oestradiol: 1 mg daily
Angina in early menopause
Oestrogen therapy improves endothelial function short-term in CMD
↑ Risk of breast cancer, marginally ↑ risk of CVD
Tricyclic antidepressants (TCA)
MVA with abnormal pain processing
Amitriptyline: 5–10 mg nocteImipramine: 10–200 mg daily
All
Counteracts enhanced nociception. Thought to exert an analgesic effect on the visceral
component associated with cardiac pain.
Blurred vision, dry mouth, drowsiness, impaired coordination
Non-pharmacological
All
Smoking cessation, Exercise, cardiac rehabilitation, Mediterranean diet, cognitive
behavioural therapy, weight loss, Yoga
Metabolic syndrome, endothelial dysfunction, cardiovascular risk factors, anxiety/depression
Adjunctive non-pharmacological interventions
*May be helpful in some postmenopausal women. More information on experimentary pharmacotherapy
in refractory angina can be found in review by Henry et al.62
CAD, angina with obstructive coronary artery disease; MPRi, myocardial perfusion reserve
index; MVA, microvascular angina; VSA, vasospastic angina.
Figure 3
Empirical pharmacological treatments for patients with angina. ACEi, Angiotensin converting
enzyme inhibitor; ASP, aspirin; BB, beta-blocker; Endo, endothelial; IVA, ivabradine;
MVA, microvascular angina; NIC, nicorandil; NIT, nitrate; Obs CAD, obstructive coronary
artery disease;, RAN, ranolazine; RF, risk factor.
Revascularisation
Recently revised 2018 ESC guidelines suggest that myocardial revascularisation is
indicated to improve symptoms in haemodynamically significant coronary stenosis with
insufficient response to optimised medical therapy. Patients’ wishes should be accounted
for in relation to the intensity of antianginal therapy as PCI can offer patients
with angina and obstructive CAD a reduced burden from polypharmacy. Angina persists
or recurs in more than one in five patients following PCI and microvascular dysfunction
may be relevant. Guidelines support consideration of revascularisation for prognosis
in asymptomatic ischaemia in patients with large ischaemic burden (left main/proximal
left anterior descending artery stenosis >50%) or two/three vessel disease in patients
with presumed ischaemia cardiomyopathy (LVEF<35%).
Refractory angina is common in patients with complex CAD including those with previous
coronary artery bypass grafting (CABG) and chronic total occlusions (CTOs). Over the
last decade, vast strides in technique, training and tools have delivered major increases
in the success of CTO PCI. These angina patients often have incomplete revascularisation
with lesions or anatomy previously considered ‘unsuitable for intervention’ but now
amenable to treatment by trained operators. A recent review article in Heart summarises
non-pharmacological therapeutic approaches to patients with refractory angina including
cognitive behavioural therapy (CBT), stellate ganglion nerve blockade, Transcutaneous
Electrical Nerve Stimulation (TENS)/spinal cord stimulation and pain modulating antidepressants
(eg, imipramine).61 Of note, coronary sinus reducers deployed using a transcatheter
venous system have shown early promise in clinical studies.
Future directions
Based on test accuracy, health and economic benefits, non-invasive and invasive functional
tests should be considered a standard of care in patients with known or suspected
angina, especially if obstructive CAD has been excluded by CT or invasive coronary
angiography. Computational fluid dynamic modelling of the functional significance
of CAD, notably with FFRct, is an emerging option and clinical trials, including FORECAST
(ClinicalTrials.gov Identifier: NCT03187639) and PRECISE (NCT03702244), are ongoing.
The use of computational modelling as a diagnostic tool in patients with microvascular
angina or coronary vasomotion disorders remains to be determined.
Systemic vascular abnormalities were recently highlighted in patients with INOCA potentially
supporting a therapeutic role for targeted vascular therapy, for example, using selective
endothelin-A receptor antagonists.19 The MRC Framework for Stratified Medicine is
applicable to patients with angina and we believe genetic testing with precision medicine
holds future promise.
Conclusion
The optimal management of patients with known or suspected angina begins with establishing
the correct diagnosis. Around one half of angina patients have no obstructive coronary
disease; many of these patients have microvascular and/or vasospastic angina. Non-invasive
assessment with CTCA is a sensitive anatomical test for plaque which assists in initial
treatment and risk stratification. Anatomical imaging has fundamental limitations
to rule in or rule out coronary vasomotion disorders in patients with symptoms and/or
signs of ischaemia but no obstructive CAD (INOCA). Women are disproportionately represented
in this group with MVA and/or VSA, the two most common causes of diagnoses. A personalised
approach to invasive diagnostic testing permits a diagnosis to be made (or excluded)
during the patients’ index presentation. This approach helps stratify medical therapy
leading to improved patient health and quality of life. Physician appraisal of ischaemic
heart disease (IHD) should consider all pathophysiology relevant to symptoms, prognosis
and treatment to improve health outcomes for our patients. More research is warranted,
particularly to develop disease modifying therapy.
ESC curriculum: stable CAD
Precipitants of angina.
Prognosis of chronic IHD.
Clinical assessment of known or suspected chronic IHD.
Indications for, and information derived from, diagnostic procedures including ECG,
stress test in its different modalities (with or without imaging, exercise and stress
drugs) and coronary angiography.
Management of chronic IHD, including lifestyle measures and pharmacological management.
Indications for coronary revascularisation including PCI/stenting and CABG.
Key points
Angina pectoris is a clinical syndrome occurring in patients with or without obstructive
epicardial coronary artery disease.
Diagnostic testing in angina is symptom driven and so should provide patients and
their physicians with an explanation for their symptoms and used to stratify management
and offer prognostic insights.
Microvascular and/or vasospastic angina are common disorders of coronary artery function
that may be overlooked by anatomical coronary testing, leading to false reassurance
and adverse prognostic implications.
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10.1136/heartjnl-2018-314661.supp1
Supplementary data