Concepts of pathophysiology

To understand CMD, notions of anatomy and pathophysiology are important. Two microcirculatory compartments are identified; the pre-arteriolar one consisting of vessels with a diameter >100 microns and capable of exerting resistance to flow, and the distal one with vessels having a caliber <100 microns and characterized by intramural arterioles that respond to the local concentration of metabolites.²

CMD can be caused by functional or structural changes. Functional CMD can be endothelium dependent; in these cases, the reduced production or increased degradation of NO (Nitric Oxide) can cause a vasospasm, in the most proximal compartment of the microcirculation or an alteration of the vasodilation mechanisms. There is also a non-endothelium-dependent CMD although the mechanism is less well known.¹

The structural causes of CMD include luminal narrowing of the arterioles, perivascular fibrosis or rarefaction of the capillaries, where there is an increase in the mass of the left ventricle.¹

Several invasive and non-invasive techniques are available to analyse the functional state of the coronary microcirculation.^3,4 In patients with epicardial vessels free from significant lesions, the coronary flow reserve (CFR) provides a reliable estimate of the function of the microcirculation. CFR is defined by the relationship between coronary flow at baseline and in conditions of maximal hyperemia obtained following infusion of adenosine (endothelium-dependent vasodilation) or acetylcholine (endothelium-independent vasodilation). The flow can be evaluated invasively through the use of a Doppler guide placed distally in the coronary artery.⁵ A CFR <2 is indicative of significant CMD. A further invasive index of microcirculation analysis is the index of microvascular resistance (IMR).⁶ The IMR exploits the thermo-dilution principle and can be easily determined through an intra-coronary pressure and temperature guide. Corresponds to the product of distal coronary pressure and mean transit time of a bolus of 3 cc of saline solution repeated three times at room temperature during maximum hyperemia. An IMR> 25 is an expression of impaired microvascular perfusion. IMR also offers the considerable advantage of not being influenced by haemodynamic conditions and epicardial stenosis.⁷

Among the non-invasive techniques, transthoracic echo-colour-Doppler certainly represents the most immediate and low-cost method, although often hampered by the intrinsic difficulty in obtaining an optimal coronary Doppler signal. The Doppler ultrasound allows the calculation of CFR by measuring the diastolic peak flow rate during adenosine infusion and at baseline.⁸ Furthermore, a reduction in eco-stress CFR with dipyridamole in the absence of alterations in regional kinetics is also indicative of CMD. The functional state of the microcirculation can also be investigated by cardiac magnetic resonance imaging (CMR), an instrument used in particular to study the phenomenon of no-reflow caused by obstruction of the microcirculation after restoration of the patency of the epicardial vessel responsible for infarction. Stress CMR with perfusion study allows the calculation of the myocardial perfusion reserve index (MPRI), surrogate of the CFR. It has been shown how MPRI correlates with CFR evaluated with invasive techniques.⁸ The investigation using positron emission tomography (PET), due to its ability to reliably quantify the blood flow per gram of myocardium, currently represents the gold standard among the imaging methods for the study of the microcirculation. The blood flow at baseline and after pharmacologically induced hyperemia, quantified through the use of radioactive tracers such as ammonia labelled with 13N, water labelled with 15O or rubidium82, allows a reliable determination of the CFR. PET, however, is limited by cost and low availability.

CMD as a cause of myocardial ischaemia or angina

In many cases, CMD simply causes exertion or resting ischaemia in the absence of angina. Similar to people with epicardial coronary artery disease, patients with CMD may experience typical angina pectoris, as well as atypical symptoms or exertion dyspnea. According to some studies, the angina symptom is observed in a percentage of cases that can reach 40%.⁹

Furthermore, angina in subjects with CMD can also appear at rest, especially in those who have a vasospastic mechanism or an increase in the tone of the small vessels. CMD is more common in women and it is no coincidence that many studies have been conducted in women.^2,10

There is no doubt that angina due to CMD worsens the quality of life.⁷ According to Taqueti et al.,¹¹ the use of a strategy aimed at identifying subjects with CMD and the mechanisms that are responsible for them translates into an improvement in the quality of life.

Furthermore, CMD can modulate the ischaemic threshold in patients with stable obstructive coronary artery disease. Pupita et al.¹² observed in patients with angiographic evidence of chronic total occlusion of a coronary artery and the presence of collateral circulation, a wide variability of the ischaemic threshold in the absence of spasm of the epicardial vessels, related to vasoconstriction phenomena of the microcirculation.

CMD and risk of acute coronary events or cardiac death

An element to be clarified is whether subjects with CMD and coronary tree without significant stenoses have an increased risk of major cardiovascular events, including myocardial infarction and sudden death.

Johnson et al.¹³ studied 673 women with precordial pain and suspected myocardial ischaemia. In 412 cases, there was no significant coronary disease while in the remaining 261 coronary angiography showed significant narrowing. In the group without coronary artery disease, 189 subjects had angina and were considered to have CMD.

In the group without obstructive disease, the composite event of non-fatal myocardial infarction, stroke, heart failure and cardiovascular death was observed in 16.6% of women with CMD vs. 5% of women with normal coronary artery tree (control group) (P = 0.03).

The incidence of events was lowest in women in the absence of symptoms and significant obstructive lesions (control group) and highest in the group with significant obstructive lesions and CMD. The role of precordial pain in predicting a composite cardiovascular event had an HR of 1.89 in women with CMD and no obstructive coronary artery disease (P = 0.03) and dropped to 1.17 in those with obstructive coronary artery disease (P = 0.49). The presence of significant coronary stenosis therefore had a great prognostic impact, while the presence of CMD contributed in predicting the prognosis to a lesser extent.

Pepine et al.¹⁴ studied 189 women with suspected ischaemia using CFR. The authors noted a significant association between CFR alteration (indicating CMD) and major cardiovascular events (death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure). Reduced CFR was associated with a risk of major adverse cardiovascular events (MACE) of 1.16 (P = 0.009). The incidence of cardiovascular events was as follows: myocardial infarction 1.7%, stroke 4.2%, heart failure 3.2%, angioplasty 6.4%, bypass 0.5%, angina 19%.

It is interesting to underline how the diagnosis of major cardiovascular CMD events (reduced CFR) improved the ability to predict cardiac events even in subjects with coronary heart disease. The work did not specify the percentage of cases with normal coronary trees (smooth coronaries). However, 51% had stenoses below 20%. In this subgroup of patients, an altered CFR identified subjects with a worse prognosis.

Gulati et al.¹⁵ studied 540 women with CMD (suspected ischaemia and no obstructive coronary disease) in the Women's Ischaemia Syndrome Evaluation (WISE) registry and compared them with 1000 female subjects in the St James Women Take Heart (WTH) registry, which included asymptomatic patients with no history of coronary heart disease. Women with CMD, belonging to the WISE registry, had a higher prevalence of obesity, family history of ischaemic heart disease, hypertension, and diabetes mellitus. The 5-year annual incidence of cardiovascular events was 16% in women with CMD and non-significant coronary artery disease, 7.9% in women with CMD and a completely normal coronary artery tree, and 2.4% in asymptomatic women without ischaemia of the WTH register (P ≤ 0.002). The analysis was performed after adjustment of the coronary risk variables. Cardiovascular events were also more frequent in women with at least four coronary risk factors; the risk of cardiovascular events at 5 years was 25.3% in the WISE group with coronary artery disease, 13.9% in the WISE subjects with completely normal coronary artery tree, and 6.5% in the WTH control group of asymptomatic women.

More specifically, the incidence of myocardial infarction was 3.9% in the group with non-significant coronary artery disease, 0.9% in the group with normal coronary arteries and 0.7% in the WTH group of asymptomatic women. The incidence of stroke was 5.2%, 2.4%, and 1.0%, respectively, while cardiac death occurred in 4.4%, 1.5%, and 0.6%, respectively.

Bugiardini et al.¹⁶ published in 2004 an interesting prospective study on 42 female subjects, with chest pain, ischaemia to Single Photon Emission Computed Tomography and the absence of coronary heart disease. The CMD study with acetylcholine identified endothelial dysfunction in 22 subjects (52.4%). After 10 years, 13 subjects continued to experience precordial pain and in all cases the formation of new coronary stenosis in the epicardial district was highlighted.