Introduction
Angina pectoris is considered the cardinal symptom of ischemic heart disease. However, large studies have demonstrated that obstructive coronary artery disease can be detected in less than 50% of patients with SIHD.¹ The remaining patients suffer from what we now call angina with nonobstructive coronary arteries, orANOCA. Pathophysiological mechanisms of angina in patients with ANOCA are diverse, and there is a growing body of evidence demonstrating a high prevalence of coronary vasomotor disorders in this patient population.^2-6 Coronary vasomotor disorders, also referred to as functional coronary artery diseases, are characterized by a dysfunctional coronary vasomotor tone comprising different pathophysiological mechanisms and localization in the coronary circulation.

Pathophysiology and Spectrum of Diseases
In contrast to other organs, oxygen extraction by the heart is already high at rest (75%).⁷ In combination with the limited anaerobic capacity of cardiomyocytes, changes in oxygen demand due to increase in cardiac work (e.g., during exercise), can be met only by adjustment of coronary blood flow. Coronary blood flow is regulated by coronary vasomotor tone, particularly in the microvasculature, where arterioles (<100 mcm in diameter) and pre-arterioles (100-500 mcm in diameter) make up 80% of the resistance of the coronary circulation.^8,9 Coronary vasomotor tone is regulated by vascular smooth muscle cell (VSMA) contractility in response to mechanical stimulation (e.g., coronary pressure and flow, shear-stress) and metabolites (e.g., nitric oxide, adenosine, prostaglandins, endothelin, endothelium-derived depolarization factor). Some of these stimuli exert their effect on VSMC indirectly via endothelial cells and are thus often referred to as endothelial-dependent vasomotor tone regulation, whereas other pathways involve mainly direct VSMC effects (e.g., adenosine) and are referred to as endothelial-independent vasomotor tone regulation.

Coronary vasomotor disorders are characterized by impaired ability to adequately adjust coronary blood flow to oxygen demand due to dysfunctional vasomotor tone autoregulation, leading to myocardial ischemia and angina pectoris in the absence (or co-existence) of obstructive coronary artery disease. Vasomotor disorders comprise spontaneous transient pathological vasoconstriction (coronary spasm) as well as impaired microvascular vasodilatation (impaired coronary flow reserve [CFR]). These two mechanisms can occur at the epicardial level as well as the microvascular level of the coronary circulation. From a pathophysiological perspective, considering the small fraction of resistance caused by the epicardial coronary arteries (conductance vessels) at rest, impaired epicardial vasodilatation is most likely less clinically relevant compared to impaired vasodilatory capacity of the coronary microvasculature, which is the key regulator of coronary resistance and, subsequently, coronary blood flow. Conversely, coronary artery spasm due to abnormal vasoconstriction substantially impacts on coronary resistance in the epicardial and microvascular compartments.

Thus, epicardial or microvascular spasm as well as impaired microvascular vasodilatation can be considered the most clinically relevant types of coronary vasomotor disorders.

Nomenclature
Despite an overwhelming body of evidence for the existence and clinical relevance of coronary vasomotor disorders, their acceptance among cardiologists and the implementation of respective vasomotor function testing are limited. We believe that this is in part due to the rather complex and not yet fully understood pathophysiological mechanisms. However, the transition from research to bedside might also be hampered by a broadly differing nomenclature in the field. In contrast to the above-described clinical classification based on the net vasomotor effect (increased vasoconstriction vs. impaired vasodilatation) and localization (epicardial vs. microvascular), other groups focus their nomenclature on the underlying mechanism on the cellular level (endothelial-dependent vs. endothelial-independent dysfunction). We have previously summarized concerns regarding the strict conceptual separation of endothelial and VSMC function¹⁰ and decided to use the clinical classifications described herein.

Diagnostic Assessment
Several diagnostic strategies can be applied to assess coronary vasomotor function directly or indirectly using invasive and noninvasive methods. Nevertheless, comprehensive functional assessment is challenging mainly due to the following two reasons:

1. Despite several noninvasive approaches (e.g., cold-pressure test or ergonovine echocardiography), invasive provocation testing is still considered the gold standard of reliable epicardial and microvascular coronary artery spasm assessment.
2. Direct visualization of the coronary microcirculation (<500 mcm) in vivo is technically still not possible due to the limits of spatial resolution and contrast opacification of invasive or computed tomography coronary angiography. Thus, assessment of vasodilatory capacity of the coronary microvasculature can be performed only indirectly via invasive physiological or noninvasive myocardial blood flow measurements.

Coronary Spasm Provocation Testing
The presence of coronary spasm is usually assessed using intracoronary injection of a provocative agent (e.g., acetylcholine or ergonovine). Standardized diagnostic criteria for the diagnosis of epicardial and microvascular spasm, respectively, have been published by the Coronary Vasomotor Disorders International Study Group. Epicardial spasm is defined as reproduction of angina, new ischemic electrocardiographic (ECG) shifts and ≥90% angiographic vasoconstriction.¹¹ The diagnosis of microvascular spasm can be made indirectly based on angina reproduction and new ischemic ECG shifts in the absence of significant epicardial vasoconstriction (<90%).¹² Instantaneous intracoronary blood flow measurements can help determine coronary blood flow response during spasm provocation and establish the diagnosis of microvascular spasm in some cases (e.g., patient with symptom reproduction without significant epicardial spasm and pre-existing bundle branch block). Moreover, coronary sinus lactate measurements are being used to establish the diagnosis of microvascular spasm.

Assessment of Microvascular Dilatation
For the assessment of microvascular vasodilatory function, both invasive as well as noninvasive methods are available. Invasive assessment is based on the measurement of CFR, which is the ratio of hyperemic coronary blood flow velocity divided by the coronary blood flow velocity under resting conditions. Coronary blood flow is determined using an intracoronary wire and the thermodilution or Doppler technique.^13,14 Because CFR is dependent on resting coronary flow, hyperemic microvascular resistance (MVR) indices (hyperemic MVR, index of microcirculatory resistance) have been developed,^15,16 providing information about MVR. Calculation of these indices does not require resting coronary flow.

Noninvasive assessment of microvascular vasodilatory function can be performed by myocardial perfusion imaging using positron emission tomography (PET), cardiac magnetic resonance (CMR), or cardiac computed tomography or transthoracic Doppler echocardiography (TTDE) of the left anterior descending coronary artery.¹⁷

Diagnostic Strategies
Current guidelines and position papers recommend comprehensive coronary vasomotor function testing in patients with ANOCA.^18-21 Recent studies applied comprehensive invasive coronary vasomotor testing including acetylcholine spasm provocation testing as well as intracoronary assessment of CFR and MVR (Figure 1).^2,6 Other groups focused on vasodilatory function and thus tested endothelial-dependent and endothelial-independent vasodilatation in response to adenosine and (low-dose) acetylcholine without performing explicit (high-dose) acetylcholine spasm testing.^3,22 However, the high prevalence of coronary artery spasm in patients with ANOCA underlines the importance of spasm provocation testing in this patient population.^2,4,6 Combined noninvasive/invasive diagnostic approaches using noninvasive adenosine perfusion imaging and intracoronary spasm testing might facilitate the introduction of comprehensive coronary function testing on a broader basis, particularly in regions with limited catheter laboratory capacity that impedes protracted interventional diagnostic procedures.

Figure 1: Proposed Protocol for Interventional Diagnostic Procedure

Prognostic and Therapeutic Implications
Traditionally, patients with ANOCA were reassured after exclusion of obstructive coronary artery disease, and often no further functional testing was performed. A growing body of evidence during the recent years, however, demonstrated substantial morbidity and mortality in patients with coronary vasomotor disorders. A group from Boston has demonstrated that patients with reduced CFR assessed noninvasively by PET have higher rates of adverse cardiac events compared to patients with normal CFR.^5,23,24 These observations are in accordance with a recent follow-up from the WISE (Women's Ischemia Syndrome Evaluation) study, in which patients with ANOCA with low CFR measured invasively had worse prognosis than those with high CFR.²² With regard to coronary artery spasm, our group recently reported the prognostic value of acetylcholine spasm testing in patients with ANOCA during a 7-year follow-up period, where epicardial spasm could be identified as an independent predictor of myocardial infarction and repeated coronary angiography and microvascular spasm was associated with persistent symptoms.²⁵ Another multicenter prospective registry of patients with microvascular dysfunction will soon provide further important data.²⁶ Taken together, the available data demonstrate that coronary function testing allows risk stratification of patients with ANOCA and suggests prognostic differences among the different types of vasomotor disorders.

Optimal treatment of patients with coronary vasomotor disorders is challenging and often performed on a trial-and-error basis due to the lack of randomized controlled trials. In the recently published CorMicA (Coronary Microvascular Angina) trial, Ford and colleagues for the first time demonstrated the benefit of a medical therapeutic intervention based on the result of an interventional diagnostic procedure in patients with ANOCA, underlining the importance of stratified medical therapy.^27,28

Past pharmacological trials have largely been sobering, like those for ranolazine.²⁹ This is most likely explained by the fact that coronary vasomotor disorders have long been treated as a single disease despite major differences regarding their pathophysiological background (e.g., coronary spasm vs. impaired microvascular vasodilatory function). In fact, coronary vasomotor disorders have the potential to become prime examples for the advent of precision therapy in medicine. Current research focuses on dissecting the disease into so-called "endotypes" that are characterized by different pathophysiological mechanisms (Figure 2). Some examples of targeted treatment studies have already been performed or are on their way (i.e., inhibitors of Rho-Kinase or endothelin receptors).^2,30

Figure 2: Work-Up Including Noninvasive and Invasive Techniques in Symptomatic Patients With Unobstructed Coronary Arteries and Suspected CMD

Conclusion
Coronary vasomotor disorders are frequent findings in patients with SIHD, particularly in the setting of ANOCA. The mechanisms of vasomotor disorders are enhanced vasoconstriction leading to spasm on the epicardial or microvascular level and impaired microvascular vasodilatory function. Comprehensive functional testing comprises intracoronary spasm provocation testing and assessment of CFR or hyperemic MVR indices. Perfusion imaging can be used to assess CFR noninvasively. Vasomotor disorders are associated with increased cardiovascular risk, and coronary function testing allows risk stratification as well as initiation of stratified therapies. Targeted treatments based on the underlying mechanisms of vasomotor disorder endotypes are currently being investigated.

References

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Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Stable Ischemic Heart Disease, Atherosclerotic Disease (CAD/PAD), EP Basic Science, Lipid Metabolism, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Nuclear Imaging, Chronic Angina

Keywords: Angina, Stable, Coronary Artery Disease, Acetylcholine, Nitric Oxide, Microcirculation, Bundle-Branch Block, Muscle, Smooth, Vascular, Ergonovine, Vasodilation, Vasoconstriction, Coronary Sinus, Arterioles, Adenosine, Prostaglandins, Lactic Acid, Coronary Angiography, Microvascular Angina, Myocardial Perfusion Imaging, Blood Flow Velocity, rho-Associated Kinases, Thermodilution, Receptors, Endothelin, Constriction, Pathologic

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