epicardial atherosclerotic CAD. However, it has become increasingly recognised that abnormalities in coronary microvascular function can cause or contribute to ischaemia in various situations. Over one-third of patients undergoing elective coronary angiography for the investigation of angina have no obstructive
epicardial CAD.117 This group includes patients with coronary microvascular
and/or endothelial dysfunction.
1.3.1 Definition of coronary microvascular dysfunction
Coronary microvascular dysfunction (CMD) is defined as a mismatch of
myocardial blood supply and oxygen consumption due to a dysfunction of the
coronary microvessels with a diameter <500 µm.79 The pathophysiology of CMD
is not well understood. It can be the result of several pathophysiological
mechanisms, including structural alterations (e.g. vascular remodelling, vascular rarefaction, perivascular fibrosis) and functional abnormalities (e.g. endothelial dysfunction, vascular smooth muscle dysfunction). The relative importance of each of these mechanisms varies depending on the aetiology, but they
frequently coexist in the same patient.
CMD is currently subcategorised into four distinct types depending on the clinical
setting (Table 1-5).118 CMD in the absence of myocardial disease or obstructive
CAD (type 1 CMD) is usually associated with CV risk factors, such as hypertension and diabetes mellitus. This form of microvascular dysfunction is thought to be due to functional abnormalities and appears to be at least partially reversible. Type 2 CMD occurs in the presence of myocardial diseases (e.g. hypertrophic or dilated cardiomyopathy). This subtype is generally the result of structural alterations, such as vascular remodelling, and it is unclear whether this process is reversible. CMD in the context of obstructive epicardial CAD (type 3 CMD) can occur in chronic CAD or acute coronary syndrome, and various functional and structural factors may be implicated. In certain circumstances, specific interventions can limit or prevent CMD in this context. The fourth subtype represents iatrogenic CMD, typically following coronary revascularisation. The mechanisms involved are coronary vasoconstriction and distal embolisation,
which can result in both functional and structural changes. There is evidence to suggest that vasoconstriction can be corrected with pharmacological therapy and distal embolisation can be prevented or reduced with specific interventions.
CAD, coronary artery disease.
Table 1-5: Classification of CMD.
1.3.2 Diagnosis of coronary microvascular dysfunction
Clinical features
Coronary microvascular dysfunction (CMD) most frequently presents with symptoms similar to obstructive epicardial CAD. Microvascular angina (MVA) is more prevalent in women and is generally first suspected in patients presenting with typical exertional angina who are found to have no obstructive epicardial CAD at coronary angiography, especially in those patients with evidence of
ischaemia on non-invasive stress testing.119 In contrast to classical angina due to
epicardial CAD, MVA may persist or predominate in the post-exercise period and
the symptomatic response to nitrates is often less marked than typical angina.120
Clinical setting Main pathogenetic mechanisms
Type 1: in the absence of myocardial diseases and obstructive CAD
Risk factors
Microvascular angina Endothelial dysfunctionSmooth muscle cell dysfunction Vascular remodeling
Type 2: in myocardial
diseases Hypertrophic cardiomyopathyDilated cardiomyopathy Anderson-Fabry’s disease Amyloidosis
Myocarditis Aortic stenosis
Vascular remodeling
Smooth muscle cell dysfunction Extramural compression
Luminal obstruction
Type 3: in obstructive
CAD Stable anginaAcute coronary syndrome Endothelial dysfunctionSmooth muscle cell dysfunction Luminal obstruction
Type 4: iatrogenic Percutaneous coronary intervention
Coronary artery bypass grafting
Luminal obstruction Autonomic dysfunction
Non-invasive diagnostic testing
Various non-invasive modalities have been utilised in the diagnosis of CMD. Importantly, obstructive epicardial CAD must be excluded before CMD can be diagnosed by any method. Coronary flow reserve (CFR) represents the
vasodilator capacity of the coronary circulation and is determined by coronary blood flow during hyperaemia (with vasodilator stress) divided by blood flow at rest. In the absence of epicardial CAD, CFR represents endothelium-
independent coronary microvascular function. The normal value of CFR in dependent on the technique used, but most studies consider a CFR <2.0
sufficient to cause ischaemia.79
Positron emission tomography (PET) is the non-invasive reference standard modality to assess coronary microvascular function. PET-derived CFR is
measured by quantification of absolute myocardial blood flow at rest and during
vasodilator stress.119 While PET is an established method for detection of
CMD,121 its limited availability, cost and exposure to ionising radiation has
restricted its use in clinical practice. Quantitative and semi-quantitative CMR
techniques have been established to diagnose CMD.122 However, to date, their
use has been limited to small cohorts. Similarly, transthoracic Doppler echocardiography (TTDE) of coronary blood flow (usually the LAD) has been assessed in several small studies. However, this technique can be challenging,
lacks precision and requires specialist expertise.123 Both CMR and TTDE methods
require validation in larger populations before they can be considered in routine clinical practice. Novel CT and SPECT techniques are also under evaluation and
show potential for the determination of CMD.124
Invasive diagnostic testing
Invasive coronary guidewire-based physiological testing is the gold standard for
the diagnosis of endothelium-independent CMD.83,118
Coronary flow reserve
CFR is measured invasively using a Doppler velocity wire or by a thermodilution- derived method using a coronary pressure wire (Figure 1-3). As described above, CFR reflects the combined vasodilator capacity of the epicardial and
is affected by haemodynamic conditions and it can be difficult to establish
resting coronary blood flow during invasive coronary angiography.125 However,
an abnormal CFR has been shown to be associated with microvascular disease
and poor prognosis in patients with non-obstructive CAD.126
Index of microcirculatory resistance
The index of microvascular resistance (IMR) is a specific measurement of microcirculatory resistance, independent of epicardial CAD. IMR is measured invasively by thermodilution and is calculated from distal coronary pressure (Pd) multiplied by the mean transit time of room temperature saline during
hyperaemia (Figure 1-3). As the hyperaemic transit time is inversely correlated with flow, it provides a quantitative measure of coronary microvascular
resistance. An IMR ≥25 is consistent with microvascular dysfunction.127–129 As
IMR is measured during hyperaemia, it is independent of haemodynamic
variations, therefore, it has better repeatability than CFR.130
*Response to ACh is a function of endothelium and vascular smooth muscle cell responses.
ACh, acetylcholine; CFR, coronary flow reserve; FFR, fractional flow reserve; IMR, index of microcirculatory resistance; Pa, aortic pressure; Pd, distal coronary pressure.
Figure 1-3: Overview of coronary physiology testing.
FFR IMR
ACh provocation test
CFR
Graded ACh infusions Endothelium-dependent coronary function testing*
Endothelium-independent coronary function testing
Microcirculation
Pa (aorta)
Pd Epicardial system
1.3.3 Treatment of coronary microvascular dysfunction
Evidence, in terms of RCTs, to support the use of specific treatments for CMD is
very limited, therefore, treatment is empirical.84 Management of patients with
CMD is focused on optimal control of CV risk factors. Patients with MVA are generally treated with traditional anti-anginal therapy, similar to those with epicardial CAD. Beta-blockers are preferred as first-line therapy, with evidence
of symptomatic benefit in small studies.131 In patients with persisting symptoms,
small trials have suggested that ACE inhibitors and statins may improve microvascular function, resulting in improved symptoms and exercise
tolerance.132–134 One single-centre trial found that stratified medical treatment
(based on the results of CFR, IMR and acetylcholine [ACh] testing) improved symptoms and quality of life compared with standard care in patients with
ischaemia and no obstructive CAD (INOCA).135
1.3.4 Summary
CMD is defined as myocardial ischaemia due to dysfunction of the coronary microcirculation. It is a heterogeneous condition which can be the result of various structural and functional abnormalities. Invasive physiological testing is the gold standard for the diagnosis of endothelium-independent CMD. Evidence for specific therapies for CMD is lacking, therefore, treatment is empirical and is generally focused on management of CV risk factors.