The clinical hallmark of stable coronary artery disease is angina pectoris caused by physical or emotional stress that is relieved by rest or nitroglycerine intake. In addition, many patients with suspected coronary artery disease report angina pectoris at rest and the Canadian Cardiovascular Society Classification for stable angina states that resting angina may occur at every class together with angina on exertion.¹ Despite signs and symptoms of myocardial ischemia convincing enough for a cardiologist to refer the patient for invasive diagnostic coronary angiography, a substantial number of these patients does not have a relevant stenosis. In case of an intermediate stenosis assessment with FFR is indicated to determine the relevance of a lesion; however, in case of a non-hemodynamically relevant stenosis or even no stenosis at all the question remains whether or not the patient's symptoms are of cardiac origin. This scenario is not infrequent as more than 50% of patients with suspected coronary artery disease are found to have unobstructed coronary arteries when coronary angiography is performed.² One may argue that patient selection and non-invasive ischemia testing needs to be improved in order to enhance the number of patients with significant epicardial stenosis. However, recent studies have shown that even in the presence of an abnormal non-invasive imaging stress test the frequency of unobstructed coronary arteries on diagnostic coronary angiography was 54%.³ Moreover, a negative non-invasive stress test does not rule out the possibility of a functional coronary vasomotor disorder as a cardiac cause for the clinical presentation.⁴

It is well documented that patients with chest pain and unobstructed coronary arteries have a high morbidity with more depression and anxiety, premature loss of workforce and more need for antianginal medication causing higher costs to the healthcare systems than patients with obstructive coronary artery disease.^5,6,7 Moreover, recent studies have suggested that this group of patients has an increased risk of approximately 1,7%/year for myocardial infarction or death which is significantly higher than in a matched healthy cohort.⁸

As such patients are often discharged with a diagnosis of non-cardiac chest pain and hence without any anti-anginal medication, it is important to recognize that functional coronary disorders can be responsible for a presentation of stable angina not due to an epicardial stenosis (it is assumed that obvious cardiac diseases such as hypertrophic cardiomyopathy, aortic valve disease, congenital heart disease et cetera were ruled out during the initial work-up of the patient).

One of the functional abnormalities causing stable angina despite unobstructed coronary arteries is coronary artery spasm which can occur at the epicardial level as well as in the coronary microcirculation.⁹ Although epicardial coronary artery spasm is frequently associated with angina pectoris at rest, it has been also described in patients with purely exercise-related symptoms.^10,11,12 Vasomotion disorders of the small coronary vessels were demonstrated more than 20 years ago by Pupita et al. who described findings from ambulatory ECG recordings and exercise testing following intravenous ergonovine application in patients with a chronic total occlusion who had no other coronary lesions.¹³ They showed that ischemia occurred earlier following ergonovine administration indicating that ergonovine-induced constriction of peripheral coronary arteries or collaterals was responsible for this observation. When these patients had coronary angiography following intracoronary ergonovine administration constriction of collateral vessels associated with angina and ST-segment depression could be demonstrated in some patients. This suggests that vasoconstriction of small coronary vessels modulates the angina threshold and may be solely responsible for the occurrence of anginal symptoms during exercise.

A tendency for coronary vasospasm seems to be rather common in patients with chronic stable angina irrespective of the degree of epicardial narrowing suggesting that functional coronary abnormalities may be the only cause of angina but may also be superimposed in patients who have significant coronary narrowings (≥50%). Vasospasm was common in patients with no or only mild epicardial coronary irregularities enrolled in the ACOVA study. Of the 376 European patients with stable angina and suspected coronary artery disease 47% had no epicardial stenosis (≤20% narrowings).¹⁴ Of these, 86% underwent intracoronary acetylcholine (ACH) testing and 28% had epicardial and 34% microvascular spasm. Of note, women were more likely to have unobstructed coronary arteries and they were more often found to have a pathologic ACH-test. A positive family history for cardiovascular disease was more often present in patients with abnormal coronary vasomotion compared to those with an uneventful ACH-test. A recent study from Japan reported a similar frequency of 57% of pathologic ACH-tests (88% epicardial, 12% microvascular) among 1760 patients with typical or atypical angina-like chest pain who were referred for invasive diagnostic coronary angiography.¹⁵ This study also included patients (approximately 20%) with an epicardial stenosis of >75% indicating that an impaired coronary vasomotion also contributes to symptoms in patients with relevant epicardial narrowings.

Another group of patients with stable angina in whom coronary artery spasm has been described as being responsible for the clinical presentation are those with ongoing or recurrent angina despite successful stent implantation. Several studies in Asian and Caucasian patients have shown that coronary spasm occurs in a diffuse manner distal to the stent in approximately 70% of patients assessed.^16,17,18 The underlying mechanisms are still incompletely understood and there is currently an ongoing debate whether or not the drug coating of drug eluting stents may facilitate such a pathologic vasoreaction.¹⁹

Coronary artery spasm can be diagnosed e.g. using intracoronary acetylcholine provocation testing that can be performed immediately following diagnostic coronary angiography. Standardized testing protocols have been developed in the past decades in specialized institutions using incremental doses of 2µg, 20µg, 100µg and up to 200µg for assessment of the left coronary artery and 50µg, 80µg in the right coronary artery. Continuous 12-lead-ECG registration during the test is mandatory and the patient should be interrogated about any symptoms occurring during the test after each step. Epicardial spasm is usually defined as reproduction of the patient's symptoms, ischemic ECG shifts and epicardial vasoconstriction >90% during acetylcholine provocation (Figure 1A+B).⁸ Microvascular spasm is defined as reproduction of the patient's symptoms, ischemic ECG shifts but no relevant epicardial vasoconstriction (Figure 1C+D).²⁰ A detailed description of the diagnostic tools for assessment of coronary spasm and its interpretation can be found elsewhere.^21,22 It is important to remember that such invasive coronary reactivity testing is safe with a reported complication rate of around 1% ^23,24 which is comparable to the complication rate of invasive diagnostic coronary angiography.^25,26 Once the diagnosis is established, patients should be treated with calcium channel blockers and short acting nitrates in addition to cardiovascular prevention drugs in accordance with current guidelines. We hope to encourage interventional cardiologists to implement intracoronary reactivity testing for the assessment of coronary artery spasm in their daily routine. Multicenter international studies may be useful to better understand the complex interplay between anatomic and functional coronary artery disease and their relation to angina symptoms. Such studies will be conducted by the Coronary Vasomotor Disorders International Study Group (COVADIS)²⁷ with the intention to address current knowledge gaps regarding pharmacological treatment, ethnic and gender differences as well as prognosis.

Figure 1

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Keywords: Acetylcholine, Angina Pectoris, Angina, Stable, Angina, Unstable, Anxiety, Calcium Channel Blockers, Cardiomyopathy, Hypertrophic, Cardiovascular Agents, Constriction, Constriction, Pathologic, Coronary Angiography, Coronary Artery Disease, Coronary Vasospasm, Drug-Eluting Stents, Electrocardiography, Ergonovine, Heart Valve Diseases, Microcirculation, Myocardial Infarction, Nitrates, Nitroglycerin, Patient Selection, Physical Exertion, Pipecolic Acids, Prevalence, Spasm, Stress, Psychological, Vasoconstriction

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