• coronary slow flow phenomenon;
  • microvascular angina;
  • microvascular spasm;
  • syndrome X;
  • variant angina


  1. Top of page
  2. Abstract
  3. Introduction
  4. Long-term cardiac outcomes
  5. The differential diagnosis
  6. Large vessel coronary vasomotor disorders
  7. Microvascular coronary vasomotor disorders
  8. Future directions and conclusions
  9. References
  10. Appendices

Approximately 20% of patients undergoing diagnostic angiography for the evaluation of chest pain are found to have a normal coronary angiogram. Although this finding is generally associated with a low risk of cardiac events, approximately half will continue to experience chest pain over the next 12 months. Therefore, the finding of normal angiography warrants further evaluation of the potential causes for the presenting chest pain if we are to improve the disability suffered by these patients. In this review, the potential non-cardiac and cardiac causes for the chest pain in patients with normal angiography are briefly discussed with an in-depth focus on coronary vasomotor disorders including coronary artery spasm (variant angina) and microvascular disorders such as syndrome X, microvascular angina, the coronary slow flow phenomenon and microvascular spasm.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Long-term cardiac outcomes
  5. The differential diagnosis
  6. Large vessel coronary vasomotor disorders
  7. Microvascular coronary vasomotor disorders
  8. Future directions and conclusions
  9. References
  10. Appendices

Experiencing chest pain causes alarm in most people, particularly as it may arise from the heart and result in dire consequences. Clinical assessment of the pain is especially focused on the exclusion of significant cardiac disease as well as identifying the potential source of the pain. A number of non-invasive cardiac investigations are available, but when the clinician is very concerned, invasive angiography is undertaken. If this reveals ‘normal coronary arteries’, the patient is reassured and often informed that the pain is ‘non-cardiac’ in nature. However, whether this is an appropriate assessment is uncertain, and this review will provide more insights into cardiac diagnoses that need to be considered.

Consistent with the above scenario, approximately 20% of invasive coronary angiograms performed for the evaluation of chest pain do not reveal significant coronary artery disease (CAD). This paper will provide a brief overview of the important clinical considerations in this common presentation and particularly focus on coronary vasomotor disorders (i.e. those involving an inappropriate vasoconstriction or impaired vasodilation) that need to be considered. Thus, the specific aspects relating to patients with ‘chest pain and normal angiography’ that will be discussed include (i) cardiac outcomes, (ii) important differential diagnoses, (iii) large vessel coronary vasomotor disorders, and (iv) microvascular vasomotor disorders.

Before embarking on this discussion, it is necessary to clarify what constitutes ‘normal angiography’. This definition varies between studies with some including only those with a smooth angiographic silhouette, whereas others also include those with minor irregularities. As outlined in the clinical outcomes section below, patients with smooth coronary arteries have less cardiac events than those with minor irregularities thereby providing a rationale to separate these angiographically distinct conditions. However, there are two reasons that justify grouping those with smooth and mildly irregular angiographic outlines. Firstly, both the pathological studies of Glagov[1] and intravascular ultrasound studies[2] demonstrate that encroachment on the lumen is a late finding in the atherosclerotic process. Thus, many patients with ‘normal smooth’ angiographic silhouettes will have significant atherosclerotic disease that could be contributing to their presentation. Thus, delineating between those who have no apparent atherosclerosis on angiography from those with minor disease is arbitrary, although the latter may have a greater atherosclerotic burden. Secondly, the purpose of the angiogram was to determine if the patient had obstructive CAD that could account for their chest pain presentation. If either smooth or minor irregularities are observed on angiography, then no significant obstruction to coronary blood flow has been demonstrated to account for the chest pain and an alternative explanation must be sought. Thus, from a functional perspective, normal and minor CAD are clinically similar. Accordingly, this review will consider patients with both angiographically normal arteries and those with minor disease, both being defined by the absence of angiographic lesions ≥50% in any vessel.

Long-term cardiac outcomes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Long-term cardiac outcomes
  5. The differential diagnosis
  6. Large vessel coronary vasomotor disorders
  7. Microvascular coronary vasomotor disorders
  8. Future directions and conclusions
  9. References
  10. Appendices

Since the advent of coronary angiography some 50 years ago, clinicians have been intrigued with patients who undergo angiography for investigation of ‘unmistakable angina’ yet are found to have normal epicardial vessels.[3] In the following two decades, many studies were undertaken to ascertain the subsequent cardiac outcomes of patients with chest pain and normal angiography. These were undertaken in an era when angiography was not as frequently performed and generally reserved for patients with very suspicious symptoms.

Table 1 summarises the studies evaluating subsequent cardiac events in patients with chest pain and normal angiography. Generally, these studies report a favourable outcome with <1% risk of all-cause death and <1% risk of myocardial infarction at 12-month follow-up. From Table 1, it is also evident that patients with minor CAD tend to have a higher risk of death/myocardial infarction than those with completely smooth angiographic silhouettes.

Table 1. Cardiac events in patients with chest pain and ‘normal angiography’
Studyn% of femalesMedian follow-up (months)All cause death at end of follow-up (%)All cause death yearly event rateCV death at end of follow-up (%)Non-fatal MI at end of follow-upNon-fatal MI yearly event rate
  1. Included prognostic studies with ≥100 patients followed for a median period of ≥12 months.

  2. *Adjusted for missing data. CAD, coronary artery disease; MI, myocardial infarction.

Normal smooth coronaries on angiography
Bruschke, 1973[52]3424560–91Not statedNA0.91.2%0.2%
Proudfit, 1980[53]357431200.80.1%0.60.6%0.1%
Wielgosz, 1984[54]41757120.50.5%0.50.5%0.5%
Kemp, 1986[55]313654841.30.2%0.4Not statedNA
Sanchez-Recalde, 2009[56]14758842.00.3%0.02.0%0.3%
Total (adjusted*)43995112–120 months1.20.2%/year0.50.9%0.3%/year
Minor CAD on angiography
Bruschke, 1973[52]1014560–91Not statedNA2.02.0%0.3%–0.4%
Kemp, 1973[57]20050363.01.0%0.50.0%0.0%
Pasternak, 1980[58]15945430.00.0%0.00.6%0.2%
Proudfit, 1980[53]101371203.00.3%2.07.9%0.8%
Isner, 1981[59]12160512.50.6%2.53.3%0.8%
Papanicolaou, 1986[60]149158762.00.3%0.81.9%0.3%
Kemp, 1986[55]405152844.80.7%2.0Not statedNA
Sullivan, 1994[61]13860292.20.9%0.00.7%0.3%
Sicari, 2005[62]45746858.31.2%3.11.3%0.2%
Total (adjusted*)68195029–120 months1.90.3%/year1.71.8%0.3%/year

More recently, some investigators have reported a more guarded prognosis in subgroups of patients with chest pain and normal angiography. Bugiardini et al.[4] pooled the findings of three non-ST elevation acute coronary syndrome studies and reported that in the 710 patients who did not have obstructive CAD (almost half had completely normal angiography), death/myocardial infarction had occurred in 2% at 12-month follow-up. Furthermore, Johnson et al.[5] described the 5-year outcomes in women with chest pain and evidence of myocardial ischaemia yet no obstructive CAD and found that those with persistent chest pain had a doubling of cardiovascular events compared with those whose pain improved. Hence, further studies in this area are warranted.

In contrast to the cardiac event risks, many patients with chest pain and normal angiography experience significant functional disability, as summarised in Table 2. These smaller studies report that up to 15% of patients are readmitted with chest pain in the following 12 months, despite the absence of significant CAD on angiography. Furthermore, about half of the patients report ongoing chest pain, which is unchanged or worse and half remain on anti-anginal medications (Table 2). Unlike the cardiac events described above, these disabling outcomes appear to be independent of the extent of the non-obstructive CAD (Table 2). Thus, although patients with chest pain and normal angiography have a low risk of cardiac events, approximately half appear to remain disabled from their chest pain at follow-up. Accordingly, it is important to identify the underlying causes of the chest pain so that appropriate therapeutic measures can be instigated.

Table 2. Cardiac symptomatic status in patients with chest pain and ‘normal angiography’
Studyn% of femalesMedian follow-up (months)Readmission rate at end of follow-up (%)12 month readmission rateChest pain unchanged/worse at end of follow-up (%)Cardiac medications continued at end of follow-up (%)
  1. *Adjusted for missing data. CAD, coronary artery disease.

Normal smooth coronaries on angiography
Bemiller, 1973[63]37434900.02075
Day, 1976[64]45502552.42725
Ockene, 1980[65]5760161511.55847
DeMaria, 1980[66]97Not stated32208.060Not stated
Wielgosz, 1984[54]4175712Not statedNA26Not stated
Lantinga, 1988[67]24812Not statedNA7179
Radice, 1995[68]3073147131.14070
Sanchez-Recalde, 2009[56]1475884458.2Not stated59
Total (adjusted*)8545012–147 months246.03557
Minor CAD on angiography
Kemp, 1973[57]200503693.13650
Lavey, 1979[69]4569426727.23356
Pasternak, 1980[58]1594543175.14740
Isner, 1981[59]1216051184.67064
Faxon, 1982[70]7242242010.62161
Bass, 1983[71]46551222.04148
Papanicolaou, 1986[60]14915876132.27027
Juelsgaard, 1993[72]854644Not statedNA58Not stated
Sullivan, 1994[61]1386029146.17030
Total (adjusted*)23575412–76 months143.36234

The differential diagnosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Long-term cardiac outcomes
  5. The differential diagnosis
  6. Large vessel coronary vasomotor disorders
  7. Microvascular coronary vasomotor disorders
  8. Future directions and conclusions
  9. References
  10. Appendices

A normal coronary angiogram excludes obstructive epicardial CAD as the cause of the patient's chest pain; however, as summarised in Table 3, there are a variety of non-cardiac and cardiac causes that may be responsible and warrant consideration. The most common non-cardiac causes include gastro-oesophageal, musculoskeletal and anxiety disorders, although important life-threatening conditions such as recurrent pulmonary emboli must also be considered. The physical disorders can often be excluded by appropriate investigations; however, determining whether anxiety symptoms are a cause or effect of the chest pain can be challenging. Certainly, the limited ability of clinicians to firmly establish the cause of the chest pain can be anxiety provoking for the patient.

Table 3. Causes of recurrent chest pain in patients with ‘normal angiography’
Non-cardiac aetiologies
Gastro-oesophageal reflux
Oesophageal motility disorders
Biliary colic
Tietze syndrome (sternal costochondritis)
Cervical radiculopathy
Severe pulmonary hypertension
Recurrent pulmonary emboli
Panic attacks
Cardiac neurosis
Cardiac aetiologies
Non-coronary disorders
Valvular heart disease
Coronary disorders
Variant angina
Cardiac syndrome X
Microvascular angina
Microvascular spasm
Coronary slow flow phenomenon

The potential cardiac causes for the chest pain include both non-coronary and coronary conditions. The non-coronary causes are usually readily recognisable because of associated structural valvular or myocardial pathology. Examples include aortic stenosis, mitral valve prolapse and hypertrophic cardiomyopathy, all of which are identifiable by cardiac structural imaging techniques.

Identifying coronary dysfunction as a cause for the chest pain is more elusive as the diagnosis may require invasive coronary functional testing to assess dynamic changes in coronary vascular reactivity. These coronary vasomotor disorders may involve dysfunction of either the large coronary vessels (coronary spasm) or the microvasculature. Prinzmetal variant angina is the classical disorder that manifests as coronary artery spasm and will be discussed in detail in the following section. The coronary microvascular disorders are a more heterogeneous group that requires a more detailed discussion.

Large vessel coronary vasomotor disorders

  1. Top of page
  2. Abstract
  3. Introduction
  4. Long-term cardiac outcomes
  5. The differential diagnosis
  6. Large vessel coronary vasomotor disorders
  7. Microvascular coronary vasomotor disorders
  8. Future directions and conclusions
  9. References
  10. Appendices

Large vessel coronary artery spasm as a cause of myocardial ischaemia and angina has been discussed for more than a century but only came to the attention of mainstream medicine following the seminal report of Prinzmetal et al.[6] Coronary artery spasm in patients with normal angiography needs to be distinguished from microvascular dysfunction, although it is possible for the two pathophysiologic entities to coexist. The clinical characteristics, outcomes and response to therapy of patients with coronary artery spasm or ‘vasospastic angina’ differ to those with microvascular dysfunction, underscoring the need to delineate these two conditions.

Defining vasospastic angina

In 1959, Prinzmetal et al. described 12 patients who clinically differed from classical angina as (i) the chest pain occurred at rest (rather than exertion) and (ii) was associated with ST elevation (rather than ST depression).[6] He described this syndrome as ‘variant angina’ and speculated that this was due to coronary artery spasm at the site of a subcritical atherosclerotic stenosis. In the ensuing decade, case reports appeared of patients with variant angina who had minor CAD[7] or normal smooth vessels[8] on angiography, until Cheng et al. finally described a ‘variant of the variant’ where variant angina patients with normal angiography were shown to have severe coronary spasm.[9]

As coronary artery spasm is the underlying mechanism responsible for variant angina and spontaneous episodes may be missed, provocation tests for inducing spasm were developed. In North America and Europe, ergot alkaloids were used in provocation testing, whereas in Japan, the use of cholinergic agents (methacholine and acetylcholine) were favoured.[10] With a focus on provocative testing in making the diagnosis of vasospastic syndromes, the term ‘vasospastic angina’ evolved, particularly in the Japanese literature, and was characterised as (i) rest angina; (ii) reversible ischaemic electrocardiogram (ECG) changes; and/or (iii) spontaneous/induced coronary spasm on angiography.[11] Thus, the distinction between ‘Prinzmetal variant angina’ and ‘vasospastic angina’ is largely historical with the former based on clinical criteria alone, whereas the latter is based upon findings during provocative spasm testing; both characterise an anginal syndrome attributable to coronary artery spasm.

Clinical characteristics

Unlike classical angina, the conventional atherosclerotic risk factors are not associated with variant angina, except for cigarette smoking. Eliciting the chest pain history is particularly important in the diagnosis of variant angina with some of the salient features including: (i) the presence of rest angina with preserved effort tolerance; (ii) nocturnal angina, with episodes frequently occurring between midnight and early morning; (iii) precipitation by exposure to cold; (iv) pain associated with arrhythmias, manifesting as palpitations or pre-syncope; and especially (v) rapid resolution of symptoms with sublingual nitrates. The angina symptoms may wax and wane over weeks to months, so that for a short period, symptoms may occur on daily basis then resolve spontaneously for many months.

Diagnostic investigations

The diagnosis of vasospastic angina involves the demonstration of characteristic rest angina with the above associated features, reversible ischaemic ECG changes and/or evidence of coronary artery spasm. Transient ST segment elevation documented on a resting ECG during pain is the classic finding; however, transient ST depression may also occur. The ECG changes are typically in the distribution of a large epicardial coronary artery, reflecting the culprit spastic vessel/s. Multiple ischaemic territories may be involved as a manifestation of multi-vessel coronary spasm.

Ambulatory ECG monitoring is a useful tool in the diagnosis of vasospastic angina when episodes are occurring frequently, but ECG documentation of a chest pain episode can be elusive. This may not only reveal reversible ECG ischaemic changes during episodes of pain but also associated arrhythmias. Furthermore, silent ischaemic episodes have been reported in 67% of patients with vasospastic angina.[12]

Exercise stress testing is typically negative in patients with vasospastic angina. However, some patients may have positive stress tests, typically occurring during a ‘hot phase’ when even minor vasospastic stimuli (such as the adrenaline surge associated with exercise) will provoke vasospasm.

If the diagnosis is unclear from the above investigations, provocative spasm testing becomes a key diagnostic tool in evaluating patients suspected of vasospastic angina. The test is usually performed during invasive coronary angiography, although previously it has been performed as a bedside test with ECG monitoring. This later approach has resulted in iatrogenic deaths as the presence of severe atherosclerotic CAD may not have been excluded, and the ECG changes associated with spasm occur later than angiographic evidence of spasm. Some researchers have proposed provocative spasm testing using echocardiographic evaluation of left ventricular function, as a marker of ischaemia.

The provocation test is performed after vasodilator therapies are suspended for 24–48 h to minimise the risk of false negative tests. Provocative stimuli that have been used include ergonovine, acetylcholine, serotonin and hyperventilation with a TRIS-buffer infusion (Fig. 1). Following administration of the provocative stimulus, the patient's symptoms, ECG and angiographic changes are monitored.[13] The presence of typical angina, ischaemic ECG changes and subtotal/total occlusion (≥90% vessel constriction) of an epicardial vessel are considered positive findings for vasospastic angina. Some investigators consider >75% constriction of a vessel as evidence of coronary spasm.


Figure 1. Findings in a 39-year-old man with Prinzmetal angina. (a) During an episode of angina, transient ST segment elevation (in lead II) was noted on continuous telemetry. (b) Hyperventilation-induced total occlusion of the proximal left circumflex artery (visible on angiography from the right anterior oblique caudal view). (c) Spasm that resolved with the administration of intracoronary nitroglycerine and diltiazem. The patient's symptoms were controlled with oral nitrates and calcium channel blockade during a follow-up of 2 years. Adapted from: Chen H & Pinto D, 2003.

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Smoking cessation is paramount in patients with vasospastic angina. Medical therapies are largely confined to vasodilator treatments and include nitrates, calcium channel blockers, nicorandil and rho kinase inhibitors. Calcium channel blockers have been shown to be particularly effective and are often used in combination with nitrates as first-line therapy. In patients unresponsive to these therapies, other vasodilators have been used as well as mechanical approaches such as stenting of focal spastic sites and cardiac sympathetic denervation. These later approaches have been of limited value to date.


The independent predictors of infarct-free survival in patients with vasospastic angina include extent and severity of CAD, use of calcium channel blockers and the presence of simultaneous inferior and anterior ST elevation (a marker of multi-vessel spasm).[14] Also, the outcomes among Caucasian patients appear to be less favourable than among Japanese[11] (Fig. 2).


Figure 2. Infarct-free survival in variant angina. Five-year survival without myocardial infarction in Japanese (filled shapes) and white (open shapes) variant angina patients. Adapted from: Beltrame et al. 1999[11].

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Microvascular coronary vasomotor disorders

  1. Top of page
  2. Abstract
  3. Introduction
  4. Long-term cardiac outcomes
  5. The differential diagnosis
  6. Large vessel coronary vasomotor disorders
  7. Microvascular coronary vasomotor disorders
  8. Future directions and conclusions
  9. References
  10. Appendices

Large vessel coronary vasomotor disorders are definable as coronary spasm and can be visualised on angiography with provocative vasospastic investigations being readily available. However, microvascular dysfunction cannot be readily visualized, and thus its presence is inferred by identifying coronary haemodynamic abnormalities or the presence of ischaemia in the absence of obstructive CAD or coronary spasm.

In addition to the difficulty in assessing these disorders, secondary causes of microvascular dysfunction need to be considered. For example, left ventricular hypertrophy or the no-reflow phenomenon may give rise to microvascular dysfunction because of microvascular compression or embolisation, respectively. This paper will focus on patients with primary coronary microvascular dysfunction[15] who experience angina episodes in the absence of any contributory cardiac or systemic disease. For details relating to secondary causes of coronary microvascular dysfunction, the reader is referred to other sources.[16]

The interest in primary coronary microvascular dysfunction arose from a landmark study by Arbogast and Bourassa[17] in 1973 that investigated the haemodynamic and metabolic differences between patients with normal coronary angiograms and ST segment depression during stress testing (group X) and those with angiographically documented atherosclerotic CAD (group C). Both groups of patients underwent rapid atrial pacing, with the results obtained following atrial pacing quite puzzling. They found that patients in both group C and group X had increased transmyocardial lactate production but differences in cardiac index. Group C, predictably, had a fall in cardiac index, whereas group X had a rise in cardiac index. This prompted the author of the accompanying editorial[18] to label the group X patients as having ‘Syndrome X’. Clearly, the mechanism of cardiac ischaemia between the two groups is different, but it remains unexplained nearly 40 years later.

Defining coronary microvascular disorders

Following the above description of syndrome X, the term was adopted in a broader context to incorporate all patients with angina and normal coronary angiography. As evident from the discussion earlier in this paper, the causes of chest pain in such patients may not be microvascular in origin thereby limiting the usefulness of a broader term. Furthermore, the term ‘syndrome X’ has also been used to describe patients with the metabolic syndrome, which adds further to the confusion.

In the context of this paper, the term syndrome X will be exclusively used to describe patients with (i) exertional angina; (ii) a positive exercise stress test for myocardial ischaemia; (iii) normal smooth angiography; and (iv) an absence of coronary artery spasm. This definition is thought to be more specific for a coronary microvascular disorder with the abnormal exercise test implicating the presence of coronary microvascular dysfunction resulting in myocardial ischaemia. Other approaches that have been adopted to identify patients with coronary microvascular dysfunction among those with chest pain and normal angiography include (i) assessing abnormal coronary blood flow responses to vasomotor stimuli (e.g. coronary flow reserve) as in microvascular angina; (ii) evaluating spontaneous delayed filling of epicardial coronary arteries implicating increased coronary resistance as in the coronary slow flow phenomenon (CSFP); or (iii) transmyocardial lactate production in response to provocation testing with intracoronary acetylcholine but in the absence of coronary artery spasm. Hence, these different approaches have evolved into four coronary microvascular disorders being described including syndrome X, microvascular angina, the CSFP and microvascular spasm.

Cardiac syndrome X

Cardiac syndrome X has been the most extensively studied of the coronary microvascular disorders. Its prevalence has been described as 3–10% of coronary angiograms undertaken.[19]

Clinical features

Typically, syndrome X patients present with prolonged episodes of exertional angina with an inconsistent response to sublingual nitrates. The disorder is more prevalent in females, with up to 70% being peri- or postmenopausal females.[20] Functional testing findings are compatible with myocardial ischaemia/coronary microvascular dysfunction on diagnostic investigation with exercise stress testing or myocardial perfusion imaging findings indistinguishable from those of patients with CAD. The ST depression on stress testing tends to occur at higher workloads, and continuous ambulatory electrocardiographic monitoring demonstrates transient ST segment depression. Myocardial perfusion imaging demonstrates a reversible defect in approximately a third of patients. Stress echocardiography studies frequently demonstrate hyperdynamic ventricular responses.


Multiple pathophysiological abnormalities have been reported in patients with syndrome X. Many of these are summarised in Table 4; however, there is no unifying hypothesis to explain the observed differences. Fundamental differences in opinion remain, such as whether the pain is due to myocardial ischaemia or affected patients have an abnormal pain perception in the absence of ischaemia. The heterogeneous nature of patients with syndrome X may account for these differences as both mechanisms could give rise to the pain and our limited clinical ability to delineate these subgroups may be relevant. Thus, further studies are still required to understand the mechanisms involved in this puzzling disorder.

Table 4. Pathophysiological abnormalities in patients with syndrome X
  1. Modified from: Beltrame, 2006. ECG, electrocardiogram.

Presence of myocardial ischaemia

  • Variable evidence of transmyocardial lactate production with rapid pacing[73, 74]
  • Large transmyocardial lipid peroxidation product release with rapid pacing[75]

Abnormal coronary blood flow/myocardial perfusion responses

  • Variable coronary blood flow responses to vasodilator stimuli[23, 76-78]
  • Subendocardial hypoperfusion on stress cardiac magnetic resonance imaging[79]

Coronary microvascular abnormalities

  • Coronary arteriolar narrowing due to basement membrane thickening, medial thickening and endothelial cell proliferation[80, 81]
  • Endothelial progenitor cell abnormalities[82]

Abnormal cardiac autonomic regulation

  • Abnormal cardiac adrenergic function[83]
  • Reduced vagal influence prior to ischaemic ECG changes[84]

Endothelial dysfunction

  • Impaired coronary endothelium-dependent vasodilation[85]
  • Increased asymmetric dimethylarginine levels[86]
  • Endothelin-1 levels are increased at rest and during rapid pacing[87]

Low-grade systemic inflammatory response

  • Inflammatory markers increased (C-reactive protein, interleukin-1 receptor antagonist, P-selectin, E-selectin, monocyte chemotactic protein-1)[88-93]
  • C-reactive protein correlates with ECG markers of ischaemia[94]

Haematological abnormalities

  • Platelet hyperaggregability at rest[95]
  • Increased red blood cell aggregability[96]
  • Decreased red blood cell deformability[96]
  • Increased plasma viscosity[96]

Metabolic and hormonal abnormalities

  • Oestrogen deficiency[97, 98]
  • Insulin resistance[99]
  • Enhanced sodium–lithium[100] or sodium–hydrogen countertransport[101]
  • Localized interstitial potassium accumulation[102, 103]
  • Preference for fatty acid oxidation during chest pain[104]

Systemic vascular abnormalities

  • Rarefaction of capillaries peripherally[105]
  • Abnormal conjunctival, nailfold and gingival capillaries[93]
  • Impaired brachial flow-mediated dilatation[106, 107]
  • Increased systemic arterial stiffness[108]

Abnormal pain perception

  • Increased pain sensitivity to cardiac stimuli[109-111]
  • Abnormal cortical pain processing (impaired habituation to pain stimuli)[112, 113]

Considering the limited understanding of the mechanisms responsible for this disorder, it is not surprising that the optimal therapy remains to be defined. However, the management of coronary risk factors needs to be considered as with most patients with coronary heart disease. A more difficult prospect is controlling the angina symptoms, which frequently respond poorly to conventional anti-anginals such as long-acting nitrates. Considering the exertional nature of the chest pain, beta-blockers have been shown to be helpful particularly in those with increased sympathetic activity and are therefore considered as first-line therapy. The response to calcium channel blockers is variable. Other agents that have been shown to be of some benefit in small studies include enalapril, aminophylline, pravastatin, simvastatin, nicorandil, doxazosin, trimetazidine, ranolazine, long-chain n-3 polyunsaturated fatty acids, metformin, and oestradiol patches in women. Therapies altering pain perception (imipramine, transcutaneous nerve stimulators and spinal cord stimulators) have also been shown to be of benefit.[21]

Microvascular angina

In 1981, Opherk et al.[22] reported an impaired coronary flow reserve in patients with syndrome X, thereby providing evidence of impaired coronary vasodilator capacity in these patients as a potential pathogenetic mechanism. Subsequently, Cannon et al.[23] focused on the detection of abnormal coronary blood flow responses, reporting that not all of these patients had evidence of stress-induced ischaemia on ECG[24] or transmyocardial lactate production. Accordingly, this group believed that many patients with chest pain and normal angiography did not necessarily have ischaemia as a cause of their chest pain but coronary microvascular dysfunction manifesting as an abnormal response to vasomotor stimuli. They therefore coined the term ‘microvascular angina’ to delineate these patients from those with classical syndrome X.[25]

Clinical features

The diagnosis of microvascular angina focuses upon replicating the chest pain during coronary haemodynamic testing and the demonstration of an abnormal coronary blood flow response. Thus, in contrast to patients with syndrome X, less than a third of patients with microvascular angina have ischaemic ST changes on exercise stress testing and many do not exhibit reversible perfusion defects on myocardial scintigraphy. Moreover, this group of patients has a dynamic coronary microvascular disorder, and therefore exertional angina is less frequently observed. Females are more often affected than males, and the resting left ventricular ejection fraction is usually normal. However, those patients with left bundle branch block are more likely to experience a decline in their left ventricular function over the following years.[26]

Pathophysiological aspects

Cannon et al. demonstrated that these patients also had abnormal forearm blood flow responses, abnormal bronchial reactivity[27] and oesophageal motility[28] suggesting that they had a generalised disorder of smooth muscle function. Furthermore, they demonstrated that the patients had an abnormal pain perception suggesting that the pain was due to an abnormal perception to the coronary microvascular dysfunction rather than myocardial ischaemia.[29] Hence, similar to the ‘syndrome X’ story, microvascular angina appeared to be an elusive disorder.


Initially, Cannon et al. demonstrated that calcium channel blockade was effective in many patients with microvascular angina but some still experienced ongoing chest pain.[30] Considering the evidence of abnormal pain perception, low dose imipramine was examined in a placebo-controlled, double-blind trial.[31] The study demonstrated a reduction of chest pain frequency in approximately half of the patients, providing some support for the altered nociception hypothesis but still not providing an effective therapy for many of these patients.


In 1972, Tambe et al.[32] described an angiographic phenomenon that was considered little more than an angiographic curiosity until recently. Despite the presence of angiographically normal epicardial coronary arteries, these investigators described strikingly slow passage of contrast medium through the coronary arterial tree, referred to as the CSFP. How slow the angiographic flow must be to be considered diagnostic of the CSFP varies between investigators and only recently has a quantitative definition been proposed.[33] Furthermore, the clinical features, pathophysiological characteristics and therapeutics of this condition have been described and delineated from the above two microvascular conditions prompting some researchers to refer to the CSFP as syndrome Y.[34]

Clinical features

The clinical characteristics of patients with angiographic evidence of the CSFP was first detailed by Beltrame et al., who reported a preponderance in males, smokers and those presenting with an acute coronary syndrome.[35] Subsequent studies have supported the male predominance in the CSFP and also reported an association with the metabolic syndrome.[36] Table 5 compares the clinical characteristics of both large and microvascular coronary vasomotor disorders, demonstrating a continuum in the presentation from exertional angina in syndrome X to prolonged rest pain in the CSFP, more akin to variant angina.

Table 5. Clinical characteristics of coronary syndromes in patients with chest pain and normal coronary angiography
Coronary syndromeMicrovascular disordersLarge Vessel Disorders
Cardiological syndrome XMicrovascular anginaCoronary slow flow phenomenonMicrovascular spasmVariant Angina
  1. Modified from: Beltrame, 2006; Beltrame et al. 2009[16]. BMI, body mass index; MI, myocardial infarction.

Putative vasomotor mechanismMicrovascular dysfunctionMicrovascular dysfunctionMicrovascular (spasm) dysfunctionMicrovascular spasmCoronary artery spasm
Patient characteristicsPostmenopausal femalesPredominantly femalesYoung male smokers, increased BMIPredominantly femalesSmokers
Clinical presentationStable exertional angina (often prolonged pain) Rarely MIOften rest angina Rarely MI

Unstable angina

Occasional MI

Unstable angina.

Unstable Angina

Occasional MI

Nitrate responsive

ST changes on exercise testPositive test = 100%Positive test <30%Positive test <20%Positive test <20%Usually Negative Test
Coronary angiographyNormal angiographyNormal angiographyNon-obstructive coronaries with delayed opacificationNon-obstructive coronariesNon-obstructive coronaries with provoked vasospasm
Response to nitratesLimitedLimitedVariableVariablePrompt response

Similar to syndrome X, a multitude of biochemical and haemodynamic abnormalities have been reported in CSFP patients. Important haemodynamic features include the documentation of an increased resting coronary microvascular resistance by coronary sinus oxygen saturation markers[37] and the index of microvascular resistance but unlike microvascular angina, a normal coronary flow reserve.[38] The cause of this increased microvascular resistance is unclear with some studies reporting intact endothelial function,[39] whereas other report significant dysfunction.[40] The potent microvascular vasoconstrictor, endothelin, has also been implicated in the pathogenesis of the CSFP.[41]


Several studies have investigated potential therapies for the CSFP. Mangieri et al.[42] demonstrated that dipyridamole improved the angiographic flow when administered acutely, and this was confirmed by Kurtoglu et al.,[43] who also showed a long-term improvement in flow with chronic use. However, the clinical evidence for its anti-anginal benefit is less robust.

The benefit of mibefradil, a combined L- and T-channel calcium channel blocker, warrants further discussion. Unlike most clinically utilised calcium channel blockers that only block the long-acting (or L-) calcium channel, this unique agent also blocks the transient-acting (or T-) channel. This agent was not only shown to improve angiographic blood flow in CSFP patients (Fig. 3) but also reduce angina frequency in a randomised, double-blind, placebo-controlled cross-over study.[44] Moreover, subsequent isolated blood vessel studies demonstrated that mibefradil's inhibition of vasoconstrictor responses was more effective than L-channel blockers in the microvasculature and that there were disproportionately more T-channels in the microvessels.[45] Despite these promising results, mibefradil was withdrawn from the market because of its potent inhibition of the cytochrome P450 3A4 system resulting in many clinically important drug interactions.


Figure 3. Acute angiographic response to mibefradil. The snapshot images are recorded at three heart beats with the left-hand panel showing delayed filling of the left coronary system that was improved 30 min after 50 mg of mibefradil as shown in the right-hand panel. Adapted from: Beltrame et al. 2004[44].

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Other agents reported to be effective in the management of the CSFP include nebivolol, nicorandil and trimetazidine. Nebivolol is a beta-blocker with nitric oxide-releasing properties and has been shown to improve symptoms as well as other surrogate measures in patients with the CSFP.[46] Nicorandil has been shown to improve angiographic flow, although its effect on symptoms is unclear.[47] Similarly, trimetazidine may have some beneficial effects but requires further investigation.[48]

Microvascular spasm

In 1998, Mohri et al.[49] reported the findings of provocative acetylcholine testing in 117 consecutive Japanese patients undergoing angiography for the investigation of chest pain and non-obstructive CAD. In 63 patients (54%), acetylcholine provocation induced large vessel coronary artery spasm. In contrast, in 29 patients (25%), acetylcholine did not provoke epicardial artery spasm but did induce angina-like chest pain and/or ischaemic ECG changes. These patients were labelled as having ‘Microvascular Spasm’ and differed to those with large vessel vasospastic angina or those who did not experience chest pain or ECG changes during acetylcholine administration. Furthermore, subsequent coronary sinus lactate measurements demonstrated lactate production in 82% of the microvascular spasm patients but in none of the controls.

Clinical features

Patients with microvascular spasm were more often female and typically experience rest or mixed-pattern angina.[49] They had similar cardiovascular risk factors to controls and were less likely to be smokers than large vessel vasospastic angina patients.

In contrast to Mohri et al. findings, the ACOVA study recruited 144 patients with stable exertional chest pain, near normal angiography (0–20% stenosis) and no history of Prinzmetal angina and performed acetylcholine provocation testing using high-dose acetylcholine (up to 200 mcg). They reported microvascular spasm (defined as acetylcholine-induced chest pain and ischaemic ECG changes) in 55% of patients. Multivariate logistic regression identified female gender, effort-induced angina and a positive family history as predictors of microvascular spasm. Thus, the recruitment strategy and microvascular spasm definition in the ACOVA identified a slightly different cohort although still a predilection for the condition among females.


There are few studies examining the underlying mechanisms of microvascular spasm. The pioneers of this disorder have explored the role of the rho kinase system, demonstrating that blockade of this system with fasudil inhibited the acetylcholine-induced microvascular spasm.[50] The rho kinase system modulates calcium sensitivity of vascular smooth muscle myosin light chain, preventing its dephosphorylation thereby promoting a constrictive state. The role of other excitatory/inhibitory vasomotor mechanisms within vascular smooth muscle cells requires further investigation in this disorder.


Three-year follow-up of microvascular spasm patients treated with calcium channel blockers revealed myocardial infarction in <1% of these patients and persistent pain in a third.[51] The combination of calcium channel blockers and angiotensin blockers may be more efficacious;[51] however, controlled therapeutic studies are required.

Future directions and conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Long-term cardiac outcomes
  5. The differential diagnosis
  6. Large vessel coronary vasomotor disorders
  7. Microvascular coronary vasomotor disorders
  8. Future directions and conclusions
  9. References
  10. Appendices

Patients with chest pain and normal coronary angiography remain an enigma, and it is essential that we expand our research efforts to further understand these disorders. An improved understanding of the above coronary disorders will (i) provide patients and their medical practitioners with an explanation for their symptoms and natural history of these disorders; (ii) allow the identification of appropriate therapy for these disabling disorders to not only improve the patient's quality of life but also reduce the burden on the health care system; and (iii) provide insights into other coronary disorders such as the role of the microvasculature in atherosclerotic epicardial CAD.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Long-term cardiac outcomes
  5. The differential diagnosis
  6. Large vessel coronary vasomotor disorders
  7. Microvascular coronary vasomotor disorders
  8. Future directions and conclusions
  9. References
  10. Appendices
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  1. Top of page
  2. Abstract
  3. Introduction
  4. Long-term cardiac outcomes
  5. The differential diagnosis
  6. Large vessel coronary vasomotor disorders
  7. Microvascular coronary vasomotor disorders
  8. Future directions and conclusions
  9. References
  10. Appendices

Appendix I. Definitions of MI in Quoted Studies

  1. MI = Myocardial infarction

  2. ECG = electrocardiogram

  3. CK = creatine kinase

  4. CK – MB = MB fraction of creatine kinase

  5. LDH = lactate dehydrogenase

Bruschke, 1973Clinician or patient report, ECG changes and/or enzyme rise (not specified)
Kemp, 1973Clinician report
Pasternak, 1980Clinician report
Proudfit, 1980Clinician or patient report, ECG changes (not specified)
Isner, 1981Clinician or patient report, ECG changes and/or enzyme rise (not specified)
Wielgosz, 1984Clinician report
Kemp, 1986Clinician report
Papanicolaou, 1986Definite MI: New Q wave on the standard ECG, elevation of CK-MB or reversal of the normal LDH-1 to LDH-2 ratio, symptoms compatible with acute MI
Probable MI: 2 of 3 criteria are met
Possible MI: patient report only available
Sullivan, 1994Clinician report
Sicari, 2005Clinician report, ECG changes and enzyme rise (not specified)
Sanchez – Recalde, 2009CK and CK – MB levels >2 times upper limit with or without new ST – segment elevation (>0.1 mV) in at least 2 contiguous leads