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A Practical Approach to Invasive Testing in Ischemia With No Obstructive Coronary Arteries (INOCA)

Open AccessPublished:May 04, 2022DOI:https://doi.org/10.1016/j.cjco.2022.04.009

      Abstract

      Up to 65% of women and approximately 30% of men have ischemia with no obstructive coronary artery disease (CAD; commonly known as INOCA) on invasive coronary angiography performed for stable angina. INOCA can be due to coronary microvascular dysfunction or coronary vasospasm. Despite the absence of obstructive CAD, those with INOCA have an increased risk of all-cause mortality and adverse outcomes, including recurrent angina and cardiovascular events. These patients often undergo repeat testing, including cardiac catheterization, resulting in lifetime healthcare costs that rival those for obstructive CAD. Patients with INOCA often remain undiagnosed and untreated. This review discusses the symptoms and prognosis of INOCA, offers a systematic approach to the diagnostic evaluation of these patients, and summarizes therapeutic management, including tailored therapy according to underlying pathophysiological mechanisms.

      Résumé

      Jusqu’à 65 % des femmes et environ 30 % des hommes présentent une ischémie sans coronaropathie obstructive (INOCA [ischemia with no obstructive coronary artery disease]) révélée à la faveur d’une angiographie coronarienne invasive réalisée pour une angine stable. L’INOCA peut être attribuable à une dysfonction microvasculaire coronaire ou à un vasospasme coronaire. Malgré l’absence de coronaropathie obstructive, les patients atteints d’une INOCA présentent un risque accru de décès toutes causes confondues et d’événements indésirables, notamment l’angine récurrente et des événements cardiovasculaires. Ces patients sont souvent soumis à des examens répétés, dont le cathétérisme cardiaque, ce qui représente des dépenses de santé à vie qui rivalisent avec celles associées aux coronaropathies obstructives. Dans bien des cas, l’INOCA échappe au diagnostic et n’est pas traité. Dans le présent article de synthèse, nous nous penchons sur les symptômes et le pronostic de l’INOCA. Nous proposons une méthode systématique d’évaluation diagnostique de ces patients et résumons les modalités de sa prise en charge thérapeutique, notamment un traitement adapté aux mécanismes physiopathologiques sous-jacents.
      Ischemic heart disease (IHD) is quite common, occurring in approximately 8%-9% of Canadian adults.

      Public Health Agency of Canada. Report from the Canadian Chronic Disease Surveillance System: Heart Disease in Canada, 2018. Public Health Agency of Canada. Available at: https://www.canada.ca/content/dam/phac-aspc/documents/services/publications/diseases-conditions/report-heart-disease-canada-2018/pub1-eng.pdf. Accessed July 22, 2022.

      Over the past few decades, interest has been growing in patients with stable IHD and no obstructive coronary arteries, commonly known as ischemia with no obstructive coronary arteries (INOCA). The literature suggests that up to 65% of women and 32% of men undergoing invasive coronary angiography for stable angina have INOCA.
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      Historically, the findings of no obstructive coronary arteries in the presence of symptoms and signs of ischemia was thought to be benign and was labelled as “cardiac syndrome X,”
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      but more recent studies have shown that the diagnosis of INOCA is associated with poor outcomes.
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      INOCA can be due to coronary microvascular dysfunction (CMD) or epicardial vasospasm, which are important to distinguish from one another, given that the medical management for these conditions is different.
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      Despite the absence of obstructive CAD, patients with signs and symptoms of ischemia have a higher risk of all-cause mortality.
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      Furthermore, CMD predicts worse long-term outcomes, including the occurrence of death, myocardial infarction (MI), stroke, and heart failure.
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      Prognosis in women with myocardial ischemia in the absence of obstructive coronary disease: results from the National Institutes of Health-National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE).
      In addition, INOCA patients have high rates of recurrent angina and repeat angiography, poor quality of life, and high cardiovascular and estimated lifetime costs that rival those for obstructive CAD.
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      The economic burden of angina in women with suspected ischemic heart disease: results from the National Institutes of Health—National Heart, Lung, and Blood Institute–sponsored Women's Ischemia Syndrome Evaluation.
      Given the lack of guidelines for the diagnostic workup for INOCA, these patients often are not provided with any diagnosis after angiography reveals “normal” coronary arteries. As a result, patients with INOCA are often untreated, are repeatedly hospitalized, and undergo numerous unnecessary repeat procedures without any diagnosis or relief from their symptoms.
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      Diagnosis of patients with angina and non-obstructive coronary disease in the catheter laboratory.
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      Invasive evaluation of patients with angina in the absence of obstructive coronary artery disease.
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      Coronary endothelial function testing may improve long-term quality of life in subjects with microvascular coronary endothelial dysfunction.
      Recent interest in developing new techniques and revising old testing protocols has expanded the available armamentarium of tests focusing on INOCA. The purpose of this review is to discuss what is known about INOCA and offer a systematic approach to the evaluation and management of patients with INOCA.

      Coronary Microvascular Dysfunction

      Microcirculation vessels contribute significantly to vascular resistance and the regulation of coronary blood flow (CBF). They are responsible for maintaining a coronary perfusion pressure above 40 mm Hg, which is considered the lower limit of pressure required to prevent myocardial ischemia.
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      • Zipes D.P.
      • Braunwald E.
      Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine.
      ,
      • Canty Jr., J.M.
      Coronary pressure-function and steady-state pressure-flow relations during autoregulation in the unanesthetized dog.
      Below this threshold, subendocardial vessels are fully dilated to compensate. Under normal circumstances, coronary flow can increase up to 4-5 times above resting values with vasodilatation. Factors increasing resting flow include heart rate, systolic blood pressure, and left ventricular contractility. The ability to maintain constant CBF is termed autoregulation, and the capacity to increase flow above resting values is referred to as coronary flow reserve (CFR).
      The vascular endothelium is responsible for regulating vascular homeostasis. Vascular tone is modulated by metabolic substances that promote vasodilatation and allows adequate increase in flow. Acetylcholine (ACh) is an important factor in this vascular response,
      • Furchgott R.F.
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      The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.
      causing arterial dilatation through receptors on endothelial cells. However, it will cause paradoxical vasoconstriction when the endothelium is dysfunctional.
      Nitric oxide (NO) is another important endothelium-derived substance involved in the regulation of vascular function. Patients with CMD have increased vascular tone, resulting in limited ability to dilate in response to stress.
      • Sinha A.
      • Rahman H.
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      Ischaemia without obstructive coronary artery disease: the pathophysiology of microvascular dysfunction.
      ,
      • Rahman H.
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      • Khan F.
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      Physiological stratification of patients with angina due to coronary microvascular dysfunction.
      Impaired vasodilatation also contributes to CMD, and it can be attributed to reduced production or action of mediators such as endothelium-derived prostaglandins.
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      • Takahashi J.
      • Yasuda S.
      • Shimokawa H.
      Coronary microvascular dysfunction.
      This type of dysfunction is referred to as structural CMD. Increased endothelin activity may also contribute to microvascular endothelial dysfunction.
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      • Bøtker H.E.
      • Bagger J.P.
      • et al.
      Elevated endothelin concentrations are associated with reduced coronary vasomotor responses in patients with chest pain and normal coronary arteriograms.
      Other patients have functional CMD, characterized by increased CBF at rest, which is likely to be caused by an increased resting NO synthase, the enzyme responsible for catalyzing the production of NO.
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      • Khan F.
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      Physiological stratification of patients with angina due to coronary microvascular dysfunction.
      On the other hand, some potential mechanisms for CMD may be sex-specific, thereby explaining the increased prevalence of CMD in women. The difference between sexes can be explained by the loss of estrogen protective effect after menopause.
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      • Quyyumi A.A.
      • Cannon 3rd, R.O.
      Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women.
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      • Holubkov R.
      • Conrad Smith A.J.
      • et al.
      Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study.
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      Cardiac syndrome X in women: the role of oestrogen deficiency.
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      • et al.
      Prevalence of coronary microvascular dysfunction among patients with chest pain and nonobstructive coronary artery disease.
      Estrogen induces NO production via activation of NO synthase, but after menopause, the reduction in estrogen may result in reduced NO production and impaired coronary microvascular dilatation.
      • Godo S.
      • Shimokawa H.
      Gender differences in endothelial function and coronary vasomotion abnormalities.
      Estrogen also prevents collagen deposition in tissues. Therefore, after menopause, perivascular fibrosis can occur, possibly leading to microvascular stiffening, dysfunction, and in some cases, vessels rarefaction. The decreased NO availability also causes impaired coronary microvascular dilatation.
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      • et al.
      Sex-specific aspects in the pathophysiology and imaging of coronary macro- and microvascular disease.
      Finally, high levels of high sensitivity C-reactive protein (hs-CRP), a marker of chronic inflammation, have been found to be associated with increased frequency of ischemic episodes in patients with INOCA.
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      C-reactive protein, clinical presentation, and ischemic activity in patients with chest pain and normal coronary angiograms.
      Systemic inflammation has been demonstrated to correlate with microvascular abnormalities, the fact that women have more inflammatory biomarkers at baseline, including hs-CRP, is well established. Also, some evidence indicates that psychosocial stress may play a role in the pathophysiology of INOCA.
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      • Elias-Smale S.E.
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      • Bode C.
      • Maas A.H.
      Different cardiovascular risk factors and psychosocial burden in symptomatic women with and without obstructive coronary artery disease.
      Other phenomena have been identified also as possible mechanisms for CMD, including microvascular remodeling, smooth muscle dysfunction, extramural compression, reduced diastolic perfusion time, and vascular rarefaction.
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      • d'Amati G.
      • Rimoldi O.
      Coronary microvascular dysfunction: mechanisms and functional assessment.

      Clinical presentation

      The classic symptoms of CMD include angina, exertional dyspnea, and possible heart failure.
      • Sara J.D.
      • Widmer R.J.
      • Matsuzawa Y.
      • et al.
      Prevalence of coronary microvascular dysfunction among patients with chest pain and nonobstructive coronary artery disease.
      ,
      • Mygind N.D.
      • Michelsen M.M.
      • Pena A.
      • et al.
      Coronary microvascular function and cardiovascular risk factors in women with angina pectoris and no obstructive coronary artery disease: the iPOWER study.
      Many patients with CMD have a normal physical exam, unless they are in heart failure. Although a positive stress test is one of the criteria for the diagnosis of CMD, conventional stress testing, with or without imaging, is not sensitive or specific for CMD, and it is no longer necessary to establish a diagnosis of CMD (Table 1).
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      • Michelsen M.M.
      • Pena A.
      • et al.
      Coronary microvascular function and cardiovascular risk factors in women with angina pectoris and no obstructive coronary artery disease: the iPOWER study.
      • Ong P.
      • Camici P.G.
      • Beltrame J.F.
      • et al.
      International standardization of diagnostic criteria for microvascular angina.
      • Kunadian V.
      • Chieffo A.
      • Camici P.G.
      • et al.
      An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.
      CMD is most frequently diagnosed in women, usually at midlife. Traditional cardiovascular risk factors, such as smoking, diabetes, hypertension, dyslipidemia, and older age, are associated with CMD.
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      ,
      • Mygind N.D.
      • Michelsen M.M.
      • Pena A.
      • et al.
      Coronary microvascular function and cardiovascular risk factors in women with angina pectoris and no obstructive coronary artery disease: the iPOWER study.
      ,
      • Park K.
      • Quesada O.
      • Cook-Wiens G.
      • et al.
      Adverse pregnancy outcomes are associated with reduced coronary flow reserve in women with signs and symptoms of ischemia without obstructive coronary artery disease: a report from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Study.
      ,
      • Pepine C.J.
      • Anderson R.D.
      • Sharaf B.L.
      • et al.
      Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women's Ischemia Syndrome Evaluation) study.
      Also inflammatory diseases are associated with CMD.
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      Chronic inflammation and coronary microvascular dysfunction in patients without risk factors for coronary artery disease.
      Table 1Clinical criteria for microvascular angina
      1. Symptoms of myocardial ischemia
       a. Exertional and/or rest angina
       b. Angina equivalents (eg, shortness of breath)
      2. Absence of obstructive coronary artery disease (< 50% diameter reduction or FFR > 0.80) by:
       a. Coronary computed tomographic angiography
       b. Invasive coronary angiography
      3. Objective evidence of myocardial ischemia
       a. Ischemic ECG changes during an episode of chest pain
       b. Stress-induced chest pain and/or ischemic ECG changes in the presence or absence of transient/reversible abnormal myocardial perfusion and/or wall motion abnormality
      4. Evidence of impaired coronary microvascular function
       a. Impaired coronary flow reserve (≤ 2.5)
       b. Coronary microvascular spasm, defined as reproduction of symptoms, ischemic ECG shifts but no epicardial spasm during acetylcholine testing.
       c. Abnormal coronary microvascular resistance indices (IMR > 25)
       d. Coronary slow flow phenomenon, defined as TIMI frame count > 25
      ECG, electrocardiogram; FFR, fractional flow reserve; IMR, index of microcirculatory resistance; TIMI, thrombolysis in myocardial infarction.

      Documentation of myocardial ischemia

      Noninvasive stress testing is often the initial step in assessment of chest pain. Using either noninvasive functional imaging of ischemia or anatomic imaging using coronary computed tomography angiography (CCTA) is currently recommended for establishing a diagnosis of IHD in patients with symptoms suggestive of angina.
      • Knuuti J.
      • Wijns W.
      • Saraste A.
      • et al.
      2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes.

      Excluding significant CAD

      To make a diagnosis of CMD, ruling out obstructive CAD is necessary. Lesions causing < 50% of diameter reduction with conventional angiography are usually considered nonsignificant and are less likely to cause myocardial ischemia and symptoms. Arterial narrowing in the range of 50%-70% may benefit from coronary artery pressure flow measurements to assess the physiologic impact of the lesions. Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are the 2 recommended techniques (Fig. 1).
      • Levine G.N.
      • Bates E.R.
      • Blankenship J.C.
      • et al.
      2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions.
      ,
      • Neumann F.J.
      • Sousa-Uva M.
      • Ahlsson A.
      • et al.
      2018 ESC/EACTS guidelines on myocardial revascularization.
      Both modalities determine the hemodynamic impact of a lesion by measuring pressure differences across the coronary artery stenosis, from which a ratio of pressures is derived. FFR measurement is performed at maximal hyperemia following adenosine injection. A value of < 0.80 is considered significant and suggests a high likelihood that the lesion will cause ischemia.
      • Levine G.N.
      • Bates E.R.
      • Blankenship J.C.
      • et al.
      2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions.
      ,
      • Tonino P.A.L.
      • De Bruyne B.
      • Pijls N.H.J.
      • et al.
      Fractional flow reserve versus angiography for guiding percutaneous coronary intervention.
      • Pijls N.H.J.
      • Fearon W.F.
      • Tonino P.A.L.
      • et al.
      Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2-year follow-up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study.
      • Neumann F.J.
      • Hochholzer W.
      • Siepe M.
      [ESC/EACTS guidelines on myocardial revascularization 2018: the most important innovations].
      iFR, however, is obtained in a non-hyperemic setting, with significant values being < 0.90 (Fig. 1).
      Figure thumbnail gr1
      Figure 1Invasive evaluation of ischemia with no obstructive coronary artery disease (INOCA).
      Ach, acetylcholine; CFR, coronary flow reserve; CMD, coronary microvascular dysfunction; ECG, electrocardiogram; FFR, fractional flow reserve; IC, intracoronary; iFR, instant flow reserve (also known as instantaneous wave-free ratio); IMR, index of microcirculatory resistance. ∗Intravenous infusion of adenosine (140 μg/kg per minute). ∗∗Incremental concentrations of ACh (10−6, 10−5, 10−4 mol/L) sequentially infused over 2 minutes, followed by vasospasm provocation testing (ACh bolus, 100 μg for left coronary artery or 50 μg right coronary artery). Adapted from: Kunadian et al.
      • Kunadian V.
      • Chieffo A.
      • Camici P.G.
      • et al.
      An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.
      with permission from Europa Group.

      Assessment of the microvasculature

      Given poor anatomic visualization of the microcirculation, functional assessment is critical. Such assessment is considered a class IIa (level B) recommendation in patients with symptoms of angina and no evidence of significant obstructive CAD.
      • Kunadian V.
      • Chieffo A.
      • Camici P.G.
      • et al.
      An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.
      ,
      • Knuuti J.
      • Wijns W.
      • Saraste A.
      • et al.
      2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes.
      The Coronary Microvascular Angina (CorMicA) study demonstrated that patients benefit when CMD is accurately diagnosed and properly treated.
      • Ford T.J.
      • Stanley B.
      • Sidik N.
      • et al.
      1-year outcomes of angina management guided by invasive coronary function testing (CorMicA).
      Many noninvasive modalities allow for the assessment of CFR. For instance, transthoracic Doppler echocardiography of the left anterior descending coronary artery has been documented to assist in the diagnosis of CMD.
      • Hozumi T.
      • Yoshida K.
      • Akasaka T.
      • et al.
      Noninvasive assessment of coronary flow velocity and coronary flow velocity reserve in the left anterior descending coronary artery by Doppler echocardiography: comparison with invasive technique.
      • Caiati C.
      • Zedda N.
      • Montaldo C.
      • Montisci R.
      • Iliceto S.
      Contrast-enhanced transthoracic second harmonic echo Doppler with adenosine: a noninvasive, rapid and effective method for coronary flow reserve assessment.
      • Michelsen M.M.
      • Mygind N.D.
      • Pena A.
      • et al.
      Transthoracic Doppler echocardiography compared with positron emission tomography for assessment of coronary microvascular dysfunction: the iPOWER study.
      • Caiati C.
      • Montaldo C.
      • Zedda N.
      • et al.
      Validation of a new noninvasive method (contrast-enhanced transthoracic second harmonic echo Doppler) for the evaluation of coronary flow reserve: comparison with intracoronary Doppler flow wire.
      Unfortunately, this technique requires extensive training to use and can be very difficult to perform on the other coronary arteries. Positron emission tomography (PET) scanning is another technique that is well validated, accurate, and reproducible.
      • Kaufmann P.A.
      • Gnecchi-Ruscone T.
      • Yap J.T.
      • Rimoldi O.
      • Camici P.G.
      Assessment of the reproducibility of baseline and hyperemic myocardial blood flow measurements with 15O-labeled water and PET.
      ,
      • Nagamachi S.
      • Czernin J.
      • Kim A.S.
      • et al.
      Reproducibility of measurements of regional resting and hyperemic myocardial blood flow assessed with PET.
      Cardiac magnetic resonance imaging has greater availability than PET scanning.
      • Kunadian V.
      • Chieffo A.
      • Camici P.G.
      • et al.
      An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.
      These modalities allow the assessment of non-endothelial dysfunction, and both PET and cardiac magnetic resonance imaging have been recommended by the 2021 American Heart Association/American College of Cardiology Guidelines for Evaluation and Diagnosis of Chest Pain, for the diagnosis of CMD in patients with INOCA.
      • Gulati M.
      • Levy P.D.
      • Mukherjee D.
      • et al.
      2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis of chest pain: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
      However, only invasive coronary angiography allows for direct assessment of the coronary microvasculature pathophysiology, as described in the following section.

      Periprocedural medication management

      Prior to microvascular testing, all beta-blockers, alpha-blockers, calcium-channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists (ARAs), and diuretics should be held for at least 48 hours.
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      ,
      JCS Joint Working Group
      Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina) (JCS 2013).
      ,
      • Wei J.
      • Mehta P.K.
      • Johnson B.D.
      • et al.
      Safety of coronary reactivity testing in women with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study.
      Nitrates should also be held, except for sublingual spray that can be used up to 4 hours before the procedure. Caffeinated products should be avoided for 24 hours before the procedure.
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      ,
      • Wei J.
      • Mehta P.K.
      • Johnson B.D.
      • et al.
      Safety of coronary reactivity testing in women with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study.
      Nicotine should be avoided for at least 4 hours prior.
      • Wei J.
      • Mehta P.K.
      • Johnson B.D.
      • et al.
      Safety of coronary reactivity testing in women with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study.

      CFR

      As a surrogate of myocardial blood supply, CFR accounts for both epicardial and microvascular capacity, and it is obtained by the ratio between maximal and resting CBF.
      Two invasive methods are presently available to measure CFR. The first technique involves a guidewire tipped with a piezoelectric ultrasound transducer. This Doppler guidewire, which is also equipped with a pressure sensor, allows phasic CBF velocity measurements. The second technique requires a pressure/temperature sensor-tipped guidewire that produces a thermodilution curve. CFR can then be derived from the numbers obtained.
      Studies have shown good correlation between the 2 approaches, with some evidence suggesting that CFR obtained with thermodilution tends to be higher than when measured by Doppler.
      • Everaars H.
      • De Waard G.A.
      • Driessen R.S.
      • et al.
      Doppler flow velocity and thermodilution to assess coronary flow reserve: a head-to-head comparison with [(15)O]H2O PET.
      ,
      • Barbato E.
      • Aarnoudse W.
      • Aengevaeren W.R.
      • et al.
      Validation of coronary flow reserve measurements by thermodilution in clinical practice.
      Unfortunately, obtaining high-quality signals using the Doppler guidewire method of measuring flow velocity can be challenging, with the quality of CFR Doppler tracing being insufficient in approximately 8%-15% of patients.
      • Everaars H.
      • De Waard G.A.
      • Driessen R.S.
      • et al.
      Doppler flow velocity and thermodilution to assess coronary flow reserve: a head-to-head comparison with [(15)O]H2O PET.
      ,
      • Pijls N.H.
      • De Bruyne B.
      • Smith L.
      • et al.
      Coronary thermodilution to assess flow reserve: validation in humans.

      Index of microcirculatory resistance

      The index of microcirculatory resistance (IMR) assesses the microcirculation without being affected by hemodynamics in the epicardial vessels.
      • Fearon W.F.
      • Balsam L.B.
      • Omar Farouque H.M.
      • et al.
      Novel index for invasively assessing the coronary microcirculation.
      The inverse of the mean transit time (Tmn) is strongly correlated with the absolute flow.
      • Pijls N.H.
      • De Bruyne B.
      • Smith L.
      • et al.
      Coronary thermodilution to assess flow reserve: validation in humans.
      ,
      • De Bruyne B.
      • Pijls N.H.
      • Smith L.
      • Wievegg M.
      • Heyndrickx G.R.
      Coronary thermodilution to assess flow reserve: experimental validation.
      With the thermodilution method, using the same pressure/temperature guidewire used for CFR, IMR is derived by dividing the distal coronary pressure (Pd) by the inverse of the Tmn, a surrogate for coronary flow (Fig. 2). In theory, this index is independent of epicardial anatomy, since both distal pressure and flow tend to drop in the presence of significant epicardial coronary lesions. The Tmn must be obtained in a state of maximal hyperemia, during which minimal microvascular resistance is achieved. The equation for the calculation of IMR is derived from the relation between resistance (R), pressure gradient (ΔP), and flow (Q; Table 2). IMR has better reproducibility than CFR, as it is not significantly altered by hemodynamic fluctuations in heart rate, blood pressure, and contractility.
      • Ng M.K.
      • Yeung A.C.
      • Fearon W.F.
      Invasive assessment of the coronary microcirculation: superior reproducibility and less hemodynamic dependence of index of microcirculatory resistance compared with coronary flow reserve.
      ,
      • Lee J.M.
      • Jung J.H.
      • Hwang D.
      • et al.
      Coronary flow reserve and microcirculatory resistance in patients with intermediate coronary stenosis.
      Figure thumbnail gr2
      Figure 2Practical measurements of index of microcirculatory resistance (IMR), where IMR = Pd × Hyp Tmn; IMR = 79 × 0.44; IMR = 35. Bas, baseline; CFR, coronary flow reserve; FFR, fractional flow reserve; Hyp, hyperemic; Pa, aortic pressure; Pd, distal pressure; Tmn, mean transit time.
      Table 2Derivation of index of microcirculatory resistance (IMR)
      Absolute coronary flow ≈ 1/Tmn
      R = Δ P / Q
      Δ P = Pd – Pv and Q ≈ 1 / Tmn
      IMR = Pd – Pv / (1 / Tmn), where Pv is neglectable and can therefore be removed from the formula
      When simplified, becomes: IMR = Pd × Tmn
      R = IMR.
      Δ P, pressure gradient; Pd, distal pressure; Pv, venous pressure; Q, flow; Tmn, mean transit time.

      Measurement technique

      The thermodilution-based system allows the measurement of both CFR and IMR. Currently, the most-used system is the RadiAnalyzer console (Abbott Vascular, Santa Clara, CA). A therapeutic dose of intravenous (IV) heparin should be administered to achieve an activating clotting time of at least 250 seconds.
      • Kunadian V.
      • Chieffo A.
      • Camici P.G.
      • et al.
      An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.
      Following diagnostic angiography, the pressure/temperature sensor guidewire (PressureWire X Guidewire, Abbott Vascular) is flushed with normal saline (NS). The wire should then be connected to the transducer, and the whole system, including the aortic pressure transducer, should be set to zero. Following the aortic pressure and wire calibration, the wire should be inserted in the guide catheter and positioned at the tip of the catheter. After proceeding to equalization, the wire should be advanced into the distal two-thirds of the chosen vessel (> 6 cm).
      • Fearon W.F.
      • Kobayashi Y.
      Invasive assessment of the coronary microvasculature: the index of microcirculatory resistance.
      The left anterior descending coronary artery is usually the target vessel.
      • Kunadian V.
      • Chieffo A.
      • Camici P.G.
      • et al.
      An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.
      ,
      • Pepine C.J.
      • Anderson R.D.
      • Sharaf B.L.
      • et al.
      Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women's Ischemia Syndrome Evaluation) study.
      The right coronary artery (RCA) or a dominant left circumflex may also be interrogated. Before starting the measurements, the operator should flush the guide catheter with room temperature NS for at least 30 seconds to clear contrast and air bubbles.
      • Barbato E.
      • Aarnoudse W.
      • Aengevaeren W.R.
      • et al.
      Validation of coronary flow reserve measurements by thermodilution in clinical practice.
      The guide catheter should be well engaged in the coronary ostium. Once the coronary flow is back to baseline, the operator will rapidly inject 3 mL of room-temperature saline a total of 3 times. Ideally, a 3-mL syringe and a 3-way valve stopcock should be used for injections. After the injections, the console will determine the resting mean Tmn. The operator will assess the recorded values and examine the Tmn curves. The temperature should decline by at least 2 °C. The difference between the 3 numbers should not be > 30%. Variations may happen due to instability of guide catheter engagement in the coronary ostium, coupled with a fast and strong NS injection. If variability is significant or if all 3 Tmn are > 0.25, measures should be repeated. The value found to be the outermost from the mean Tmn should be excluded and replaced with a new measurement. These are the baseline values.
      Once baseline values have been properly documented, hyperemia is then induced with IV adenosine. Adenosine allows the evaluation of non-endothelial-dependent microvascular reactivity. The target infusion rate is 140 mcg/kg per minute. Although the IV method is regarded as the gold standard, intracoronary (IC) adenosine also can be used to achieve hyperemia.
      • Wei J.
      • Mehta P.K.
      • Johnson B.D.
      • et al.
      Safety of coronary reactivity testing in women with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study.
      ,
      • De Bruyne B.
      • Pijls N.H.J.
      • Barbato E.
      • et al.
      Intracoronary and intravenous adenosine 5'-triphosphate, adenosine, papaverine, and contrast medium to assess fractional flow reserve in humans.
      ,
      • Adjedj J.
      • Toth G.G.
      • Johnson N.P.
      • et al.
      Intracoronary adenosine: dose-response relationship with hyperemia.
      Side effects are more prevalent with IV infusion of adenosine.
      • Cerqueira M.D.
      • Verani M.S.
      • Schwaiger M.
      • Heo J.
      • Iskandrian A.S.
      Safety profile of adenosine stress perfusion imaging: results from the Adenoscan Multicenter Trial Registry.
      • Cerqueira M.D.
      • Nguyen P.
      • Staehr P.
      • et al.
      Effects of age, gender, obesity, and diabetes on the efficacy and safety of the selective A2A agonist regadenoson versus adenosine in myocardial perfusion imaging integrated ADVANCE-MPI trial results.
      • Bernhardt P.
      • Steffens M.
      • Kleinertz K.
      • et al.
      Safety of adenosine stress magnetic resonance imaging using a mobile cardiac magnetic resonance system.
      However, because of a short-acting duration (∼20 seconds), IC administration of adenosine is not the route of choice when a steady-state hyperemia is required.
      • McGeoch R.J.
      • Oldroyd K.G.
      Pharmacological options for inducing maximal hyperaemia during studies of coronary physiology.
      ,
      • Pijls N.H.
      • Sels J.W.
      Functional measurement of coronary stenosis.
      The clinician should wait 2 minutes to ensure a proper physiological response to the drug has occurred. Before proceeding to the measurements, the guide catheter should be flushed once again to clear any saline that may have warmed in the catheter. Three new thermodilution curves will then be obtained.
      Once 3 values of Tmn are obtained in a state of hyperemia, the CFR can be calculated by dividing the resting Tmn by the one obtained in hyperemia. IMR can be calculated as well, by multiplying the mean Pd (measured simultaneously during hyperemia with the same wire) by the Tmn obtained with hyperemia (Fig. 3).
      Figure thumbnail gr3
      Figure 3Invasive evaluation of ischemia with no obstructive coronary artery disease (INOCA I). CFR, coronary flow reserve; FFR, fractional flow reserve; iFR, instant flow reserve; IMR, index of microcirculatory resistance.
      ACh evokes an endothelial-dependent vascular response. It acts on epicardial vessels as well as on the microvasculature, allowing assessment of microvascular spasm, defined as the presence of chest pain and ischemic electrocardiogram (ECG) changes without evidence of coronary spasm during angiogram.
      • Kunadian V.
      • Chieffo A.
      • Camici P.G.
      • et al.
      An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.
      Change in CBF should be measured after ACh infusion to assess microvascular vasospasm (class IIb).
      • Silber S.
      [ESC guidelines 2019 on chronic coronary syndrome (CCS, previously "stable coronary artery disease") : What is new? What is particularly important?].
      A normal response is defined as coronary artery dilatation of > 5%, which suggests normal endothelial-dependent microvascular function.
      • Wei J.
      • Mehta P.K.
      • Johnson B.D.
      • et al.
      Safety of coronary reactivity testing in women with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study.
      An increase in CBF of > 50% at the highest dose of ACh also suggests a normal endothelial-dependent microvascular function.
      • Wei J.
      • Mehta P.K.
      • Johnson B.D.
      • et al.
      Safety of coronary reactivity testing in women with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study.
      Different protocols of ACh administration have been described.
      • Kunadian V.
      • Chieffo A.
      • Camici P.G.
      • et al.
      An EAPCI expert consensus document on ischaemia with non-obstructive coronary arteries in collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation endorsed by Coronary Vasomotor Disorders International Study Group.
      The first method uses sequential infusion of incremental IV ACh at concentrations of 0.182, 1.82, and 18.2 mcg/mL at 1 mL/min for 2-minute periods using a mechanical infusion pump.
      • Kunadian V.
      • Chieffo A.
      • Camici P.G.
      • et al.
      An EAPCI expert consensus document on ischaemia with non-obstructive coronary arteries in collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation endorsed by Coronary Vasomotor Disorders International Study Group.
      ,
      • Wei J.
      • Mehta P.K.
      • Johnson B.D.
      • et al.
      Safety of coronary reactivity testing in women with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study.
      ,
      • Ford T.J.
      • Stanley B.
      • Good R.
      • et al.
      Stratified medical therapy using invasive coronary function testing in angina: the CorMicA trial.
      Measures of CFR and IMR are recorded with each dose. An alternative, more straightforward approach is manual intracoronary (IC) injection of Ach, starting with a test dose of 20 mcg followed by incremental doses of 20, 50, and 100 mcg injected at 5-minute intervals, over 20 seconds, into the left coronary artery (LCA).
      • Okumura K.
      • Yasue H.
      • Matsuyama K.
      • et al.
      Sensitivity and specificity of intracoronary injection of acetylcholine for the induction of coronary artery spasm.
      Each dose should be diluted in NS to achieve a total volume of 5 mL.
      • Okumura K.
      • Yasue H.
      • Matsuyama K.
      • et al.
      Sensitivity and specificity of intracoronary injection of acetylcholine for the induction of coronary artery spasm.
      ,
      • Ong P.
      • Athanasiadis A.
      • Sechtem U.
      Intracoronary acetylcholine provocation testing for assessment of coronary vasomotor disorders.
      Some centers inject this dosage over a 3-minute period.
      • Kunadian V.
      • Chieffo A.
      • Camici P.G.
      • et al.
      An EAPCI expert consensus document on ischaemia with non-obstructive coronary arteries in collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation endorsed by Coronary Vasomotor Disorders International Study Group.
      ,
      • Ong P.
      • Athanasiadis A.
      • Borgulya G.
      • et al.
      Clinical usefulness, angiographic characteristics, and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive White patients with unobstructed coronary arteries.
      The last and highest dose in either protocol is the dose used to assess for the presence of epicardial coronary vasospasm, in patients with suspected vasospastic angina (see below). A diagnostic angiogram is performed 1 minute after the start of each injection, as well as if angina symptoms or ECG changes occur. If the LCA shows no abnormal result, the same procedure can be repeated in the RCA with an incremental dose of 20-50 mcg. The maximal dose in the RCA is 80 mcg, and in the LCA, 200 mcg.
      • Kunadian V.
      • Chieffo A.
      • Camici P.G.
      • et al.
      An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.
      ,
      • Sueda S.
      • Kohno H.
      • Ochi T.
      • Uraoka T.
      Overview of the acetylcholine spasm provocation test.
      The final step is to repeat the angiography of the tested arteries after administration of IC nitroglycerin.
      If the Doppler technique is chosen, the operator will be working with the ComboWire XT or the FloWire Doppler guide wire, both from Philips Healthcare. Only the ComboWire XT allows for measurement of pressure and flow velocity (FFR or iFR) without need of exchanging the guidewire. Once the wire is positioned into the artery, the console records a Doppler-derived blood flow velocity, and automatically derives the average peak average. Then, the CBF can be estimated with the following formula:
      CBF = 0.5×APV×(D2π)/4,


      where APV is the average peak average, and D represents the vessel diameter usually measured by quantitative coronary arteriography or IC imaging 5 mm distal to the Doppler wire. The CFR can be calculated by dividing the CBF during hyperemia by the value at rest.
      • Wei J.
      • Mehta P.K.
      • Johnson B.D.
      • et al.
      Safety of coronary reactivity testing in women with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study.
      ,
      • Diez-Delhoyo F.
      • Gutiérrez-Ibañes E.
      • Loughlin G.
      • et al.
      Coronary physiology assessment in the catheterization laboratory.
      This technology does not allow for measurement of IMR.

      Reference values of CFR and IMR

      According to most studies, a CFR value ≥ 2.0 is considered normal (Fig. 1).
      • Reis S.E.
      • Holubkov R.
      • Lee J.S.
      • et al.
      Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease. Results from the pilot phase of the Women's Ischemia Syndrome Evaluation (WISE) study.
      • Joye J.D.
      • Schulman D.S.
      • Lasorda D.
      • et al.
      Intracoronary Doppler guide wire versus stress single-photon emission computed tomographic thallium-201 imaging in assessment of intermediate coronary stenoses.
      • Miller D.D.
      • Donohue D.J.
      • Younis L.T.
      • et al.
      Correlation of pharmacological 99mTc-sestamibi myocardial perfusion imaging with poststenotic coronary flow reserve in patients with angiographically intermediate coronary artery stenoses.
      • Deychak Y.A.
      • Segal J.
      • Reiner J.S.
      • et al.
      Doppler guide wire flow-velocity indexes measured distal to coronary stenoses associated with reversible thallium perfusion defects.
      • Heller L.I.
      • Cates C.
      • Popma J.
      • et al.
      Intracoronary Doppler assessment of moderate coronary artery disease: comparison with 201Tl imaging and coronary angiography. FACTS Study Group.
      • Schulman D.S.
      • Lasorda D.
      • Farah T.
      • et al.
      Correlations between coronary flow reserve measured with a Doppler guide wire and treadmill exercise testing.
      • Danzi G.B.
      • Pirelli S.
      • Mauri L.
      • et al.
      Which variable of stenosis severity best describes the significance of an isolated left anterior descending coronary artery lesion? Correlation between quantitative coronary angiography, intracoronary Doppler measurements and high dose dipyridamole echocardiography.
      In the WISE study, a threshold of 2.5 was chosen, which was also the lower limit of normal in studies with PET and other ischemia-identifying modalities.
      • Reis S.E.
      • Holubkov R.
      • Lee J.S.
      • et al.
      Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease. Results from the pilot phase of the Women's Ischemia Syndrome Evaluation (WISE) study.
      ,
      • Bergmann S.R.
      • Herrero P.
      • Markham J.
      • Weinheimer C.J.
      • Walsh M.N.
      Noninvasive quantitation of myocardial blood flow in human subjects with oxygen-15-labeled water and positron emission tomography.
      ,
      • Geltman E.M.
      • Henes C.G.
      • Senneff M.J.
      • Sobel B.E.
      • Bergmann S.R.
      Increased myocardial perfusion at rest and diminished perfusion reserve in patients with angina and angiographically normal coronary arteries.
      The cutoff for normal IMR is < 25, a value derived from the 3 main studies that reported IMR in healthy subjects (Fig. 1).
      • Melikian N.
      • Vercauteren S.
      • Fearon W.F.
      • et al.
      Quantitative assessment of coronary microvascular function in patients with and without epicardial atherosclerosis.
      • Luo C.
      • Long M.
      • Hu X.
      • et al.
      Thermodilution-derived coronary microvascular resistance and flow reserve in patients with cardiac syndrome X.
      • Solberg O.G.
      • Ragnarsson A.
      • Kvarsnes A.
      • et al.
      Reference interval for the index of coronary microvascular resistance.

      Vasospastic Angina

      Dysfunction involving the epicardial arteries usually presents as vasospastic angina (VSA), also known as Prinzmetal angina or variant angina, in which clinical manifestations are caused by reversible vasoconstriction of one or multiple epicardial segments of a coronary artery. Vascular smooth muscle hyperreactivity seems to be the driving mechanism. Endothelial dysfunction also contributes to the occurrence of this disorder. A contemporary study suggests that approximately 30% of patients with nonobstructive CAD undergoing coronary functional testing have both epicardial coronary spasm and increased microvascular resistance.
      • Sara J.D.
      • Widmer R.J.
      • Matsuzawa Y.
      • et al.
      Prevalence of coronary microvascular dysfunction among patients with chest pain and nonobstructive coronary artery disease.
      The coexistence of these 2 conditions also was associated with a worse prognosis.
      • Suda A.
      • Takahashi J.
      • Hao K.
      • et al.
      Coronary functional abnormalities in patients with angina and nonobstructive coronary artery disease.

      Clinical presentation

      Episodes of VSA occur more often when patients are at rest, especially between midnight and early morning, and they can be precipitated by hyperventilation and by certain drugs, such as ephedrine-based products, cocaine, sumatriptan, and amphetamines.
      • Lange R.A.
      • Cigarroa R.G.
      • Yancy Jr., C.W.
      • et al.
      Cocaine-induced coronary-artery vasoconstriction.
      • Stricker B.H.
      Coronary vasospasm and sumatriptan.
      • El Menyar A.A.
      Drug-induced myocardial infarction secondary to coronary artery spasm in teenagers and young adults.
      These angina episodes will be associated with ischemic changes on ECG.
      • Beltrame J.F.
      • Crea F.
      • Kaski J.C.
      • et al.
      International standardization of diagnostic criteria for vasospastic angina.
      The prevalence of VSA remains unknown, but it appears to be more frequent in Japanese populations, compared with White persons.
      • Kusama Y.
      • Kodani E.
      • Nakagomi A.
      • et al.
      Variant angina and coronary artery spasm: the clinical spectrum, pathophysiology, and management.
      Smoking appears to be a risk factor for VSA, whereas diabetes, hypertension, and dyslipidemia are not associated with VSA.
      • Sato K.
      • Kaikita K.
      • Nakayama N.
      • et al.
      Coronary vasomotor response to intracoronary acetylcholine injection, clinical features, and long-term prognosis in 873 consecutive patients with coronary spasm: analysis of a single-center study over 20 years.
      ,
      • Nobuyoshi M.
      • Abe M.
      • Nosaka H.
      • et al.
      Statistical analysis of clinical risk factors for coronary artery spasm: identification of the most important determinant.
      The majority of VSA patients have a normal stress test, but in 10%-30% of cases, patients have exercise-induced spasm.
      • Matsuda Y.
      • Ozaki M.
      • Ogawa H.
      • et al.
      Coronary arteriography and left ventriculography during spontaneous and exercise-induced ST segment elevation in patients with variant angina.
      • Minoda K.
      • Yasue H.
      • Kugiyama K.
      • et al.
      Comparison of the distribution of myocardial blood flow between exercise-induced and hyperventilation-induced attacks of coronary spasm: a study with thallium-201 myocardial scintigraphy.
      • Lahiri A.
      • Subramanian B.
      • Millar-Craig M.
      • Crawley J.
      • Raftery E.B.
      Exercise-induced S-T segment elevation in variant angina.
      The Japanese Circulation Society (JCS) guidelines suggest a 24-48-hour Holter monitor recording to observe for ischemic ECG changes associated with chest pain episodes, particularly overnight episodes.
      JCS Joint Working Group
      Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina) (JCS 2013).

      Indications for coronary vasospasm testing

      Provocative testing is indicated in patients suspected to suffer from VSA based on symptoms (class I indication).
      • Beltrame J.F.
      • Crea F.
      • Kaski J.C.
      • et al.
      International standardization of diagnostic criteria for vasospastic angina.
      Table 3 shows the diagnostic criteria for VSA. Testing is a class II indication for symptomatic patients who have been diagnosed with coronary spasm by noninvasive evaluation.
      • Beltrame J.F.
      • Crea F.
      • Kaski J.C.
      • et al.
      International standardization of diagnostic criteria for vasospastic angina.
      Episodes of VSA can be associated with transient ischemic ECG changes, which can be observed on a Holter or other monitor. Unfortunately, documentation of VSA on an ECG remains infrequent. The 2 main agents used for provocative testing for coronary reactivity and spasm are ACh and ergonovine (ER). A positive reaction is defined as a transient coronary narrowing of ≥ 90% associated with ischemic ECG changes and anginal pain.
      • Beltrame J.F.
      • Crea F.
      • Kaski J.C.
      • et al.
      International standardization of diagnostic criteria for vasospastic angina.
      Catheter-induced spasm, which tends to happen in the proximal RCA, should not be considered a positive response.
      Table 3Diagnostic criteria for vasospastic angina
      Nitrate-responsive angina, with at least one of the following:
       Rest angina, especially between night and early morning
       Marked diurnal variation in exercise tolerance, with worst capacity in the morning
       Symptoms possibly precipitated by hyperventilation
       Symptoms suppressed by calcium-channel blockers
      Transient ischemic ECG changes during episodes, with 2 of the following in at least 2 contiguous leads:
       ST segment elevation ≥ 0.1 mV
       ST segment depression ≥ 0.1 mV
       New negative U waves
      Coronary artery spasm, defined as transient coronary narrowing of > 90% associated with ischemic ECG changes and anginal pain, either spontaneously or in response to a provocative stimulus (acetylcholine, ergonovine or hyperventilation)
      ECG, electrocardiogram.

      Procedure

      All anti-anginal medications should be stopped 24-48 hours prior to testing, which should be performed in the morning if possible.
      • Sueda S.
      • Kohno H.
      • Ochi T.
      • Uraoka T.
      Overview of the acetylcholine spasm provocation test.
      The standard method for provocation with ACh requires the insertion of a temporary pacing electrode in the right ventricle, with backup pacing at 40-50 beats per minute, as testing the RCA can result in refractory bradycardia.
      JCS Joint Working Group
      Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina) (JCS 2013).
      Before provocation, an angiogram should be performed. The same views will be repeated after administration of the provocation drug. To document ischemic changes, a standard 12-lead ECG should be recorded either continuously or every 30 seconds.

      Injection of Ach

      The doses are similar to what is used for microvascular spasm testing: incremental doses of 20, 50, and 100 mcg, up to 200 mcg. If the LCA provocation does not evoke ischemia, the same procedure can be repeated in the RCA with an incremental dose of 20-50 mcg, up to 80 mcg (Table 4).
      Table 4Provocation testing intracoronary (IC) dosing protocols
      Acetylcholine20–100 (LCA); 20–50 (RCA)
      • Okumura K.
      • Yasue H.
      • Matsuyama K.
      • et al.
      Sensitivity and specificity of intracoronary injection of acetylcholine for the induction of coronary artery spasm.
      ,
      • Takagi Y.
      • Yasuda S.
      • Takahashi J.
      • et al.
      Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications, and prognostic impact: multicentre registry study of the Japanese Coronary Spasm Association.
      ,
      JCS Joint Working Group
      Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2008): digest version.
      ,
      • Okumura K.
      • Yasue H.
      • Horio Y.
      • et al.
      Multivessel coronary spasm in patients with variant angina: a study with intracoronary injection of acetylcholine.


      20–100 (LCA); 20–80 (RCA)
      • Sueda S.
      • Kohno H.
      • Fukuda H.
      • et al.
      Induction of coronary artery spasm by two pharmacological agents: comparison between intracoronary injection of acetylcholine and ergonovine.
      • Sueda S.
      • Ochi N.
      • Kawada H.
      • et al.
      Frequency of provoked coronary vasospasm in patients undergoing coronary arteriography with spasm provocation test of acetylcholine.
      • Sueda S.
      • Kohno H.
      • Fukuda H.
      • et al.
      Clinical impact of selective spasm provocation tests: comparisons between acetylcholine and ergonovine in 1508 examinations.
      • Sueda S.
      • Ochi T.
      • Yano K.
      • et al.
      New combined spasm provocation test in patients with rest angina: intracoronary injection of acetylcholine after intracoronary administration of ergonovine.
      ,
      • Sueda S.
      • Ochi N.
      • Kawada H.
      • Uraoka T.
      [Usefulness of intracoronary injection of acetylcholine and ergonovine in patients with variant angina].


      10–100 μg for suspected vessel; for contralateral vessel: 20–100 μg if LCA, 20–50 μg if RCA
      • Song J.K.
      • Park S.W.
      • Kang D.H.
      • et al.
      Safety and clinical impact of ergonovine stress echocardiography for diagnosis of coronary vasospasm.
      ,
      • Yasue H.
      • Horio Y.
      • Nakamura N.
      • et al.
      Induction of coronary artery spasm by acetylcholine in patients with variant angina: possible role of the parasympathetic nervous system in the pathogenesis of coronary artery spasm.
      Ergonovine20–60 (LCA); 20–60 (RCA)
      • Takagi Y.
      • Yasuda S.
      • Takahashi J.
      • et al.
      Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications, and prognostic impact: multicentre registry study of the Japanese Coronary Spasm Association.
      ,
      JCS Joint Working Group
      Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2008): digest version.


      1–30 (Reference
      • Song J.K.
      • Park S.W.
      • Kang D.H.
      • et al.
      Safety and clinical impact of ergonovine stress echocardiography for diagnosis of coronary vasospasm.
      )

      6–50 (Reference
      • Hackett D.
      • Larkin S.
      • Chierchia S.
      • et al.
      Induction of coronary artery spasm by a direct local action of ergonovine.
      )

      64 (LCA); 40 (RCA)
      • Sueda S.
      • Kohno H.
      • Fukuda H.
      • et al.
      Induction of coronary artery spasm by two pharmacological agents: comparison between intracoronary injection of acetylcholine and ergonovine.
      ,
      • Sueda S.
      • Kohno H.
      • Fukuda H.
      • et al.
      Clinical impact of selective spasm provocation tests: comparisons between acetylcholine and ergonovine in 1508 examinations.
      ,
      • Sueda S.
      • Ochi T.
      • Yano K.
      • et al.
      New combined spasm provocation test in patients with rest angina: intracoronary injection of acetylcholine after intracoronary administration of ergonovine.
      ,
      • Sueda S.
      • Ochi N.
      • Kawada H.
      • Uraoka T.
      [Usefulness of intracoronary injection of acetylcholine and ergonovine in patients with variant angina].
      Values are μg IC, unless otherwise indicated.
      LCA, left coronary artery; RCA, right coronary artery.

      Injection of ER

      Both IV and IC administration of ER have been described,
      • Sueda S.
      • Kohno H.
      Overview of complications during pharmacological spasm provocation tests.
      but IC injection is preferred, to avoid the risk of diffuse or multivessel spasm and possible hemodynamic instability that occurs with IV administration.
      • Hackett D.
      • Larkin S.
      • Chierchia S.
      • et al.
      Induction of coronary artery spasm by a direct local action of ergonovine.
      In the largest cohort of patients undergoing provocation testing with IV administration of ER, the risk of major adverse reaction, including MI and ventricular tachycardia, was 0.03%.
      • Harding M.B.
      • Leithe M.E.
      • Mark D.B.
      • et al.
      Ergonovine maleate testing during cardiac catheterization: a 10-year perspective in 3,447 patients without significant coronary artery disease or Prinzmetal's variant angina.
      An additional advantage of IC injection is the possibility of individual evaluation of each coronary artery, for which numerous protocols have been previously described (Table 4).
      The dose of ER is 20-60 mcg into the LCA. Testing in the RCA should be performed only if provocation fails in the LCA. ER should be injected over a period of 3-5 minutes, and angiography should be performed 1-2 minutes after injection, or with the development of chest pain and ECG changes.
      JCS Joint Working Group
      Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina) (JCS 2013).
      A final angiography test post-IC injection of nitroglycerin should always be performed.

      ACh vs ER

      No significant difference in spasm provocation was shown when ACh and ER were administered in the same patients to check their response.
      • Sueda S.
      • Kohno H.
      • Fukuda H.
      • et al.
      Induction of coronary artery spasm by two pharmacological agents: comparison between intracoronary injection of acetylcholine and ergonovine.
      ,
      • Sueda S.
      • Ochi N.
      • Kawada H.
      • et al.
      Frequency of provoked coronary vasospasm in patients undergoing coronary arteriography with spasm provocation test of acetylcholine.
      Different findings were observed in a retrospective analysis, in which the frequency of provoked spasm with ACh was significantly higher than that with ER tests.
      • Sueda S.
      • Kohno H.
      • Fukuda H.
      • et al.
      Clinical impact of selective spasm provocation tests: comparisons between acetylcholine and ergonovine in 1508 examinations.
      ACh tends to cause a more diffuse spasm, compared to a more focal pattern with ER.
      • Sueda S.
      • Kohno H.
      • Fukuda H.
      • et al.
      Clinical impact of selective spasm provocation tests: comparisons between acetylcholine and ergonovine in 1508 examinations.
      Testing with ACh followed by ER testing is safe. ACh should be tested before ER, given its shorter effect duration. A period of 10 minutes between the 2 is sufficient and safe.
      • Sueda S.
      • Kohno H.
      • Ochi T.
      • Uraoka T.
      Overview of the acetylcholine spasm provocation test.
      Adding ACh to ER provoked spasm in 92% of the subjects who did not react to either ACh or ER alone.
      • Sueda S.
      • Ochi T.
      • Yano K.
      • et al.
      New combined spasm provocation test in patients with rest angina: intracoronary injection of acetylcholine after intracoronary administration of ergonovine.

      Hyperventilation

      The hyperventilation test is a class II recommendation for patients suspected of having VSA.
      JCS Joint Working Group
      Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina) (JCS 2013).
      A resting ECG should be obtained. Patients are then instructed to breathe rapidly (rate > 30 respirations per minute) for 5 minutes.
      • Chauhan A.
      • Mullins P.A.
      • Taylor G.
      • Petch M.C.
      • Schofield P.M.
      Effect of hyperventilation and mental stress on coronary blood-flow in syndrome-X.
      ,
      • Previtali M.
      • Ardissino D.
      • Barberis P.
      • et al.
      Hyperventilation and ergonovine tests in Prinzmetal's variant angina-pectoris in men.
      An arterial pH > 7.65 confirms effective hyperventilation.
      • Weber S.
      • Cabanese L.
      • Simon J.C.
      • et al.
      Systemic alkalosis as a provocative test for coronary-artery spasm in patients with infrequent resting chest pain.
      • Girotti L.A.
      • Crosatto J.R.
      • Messuti H.
      • et al.
      The hyperventilation test as a method for developing successful therapy in Prinzmetal's angina.
      • Yasue H.
      • Nagao M.
      • Omote S.
      • et al.
      Coronary arterial spasm and Prinzmetal's variant form of angina induced by hyperventilation and Tris-buffer infusion.
      At the onset of chest pain, hyperventilation should be stopped, and an ECG should be performed to document ischemic changes.

      Complications

      Serious cardiac complications, including sustained MI, ventricular arrhythmias, cardiogenic shock, and cardiac arrest, occur rarely with the administration of these vasoactive agents.
      • Sueda S.
      • Saeki H.
      • Otani T.
      • et al.
      Major complications during spasm provocation tests with an intracoronary injection of acetylcholine.
      In a large cohort, the occurrence of serious cardiac complications on the day of the provocation test was studied. The rate of complications remained low, at < 1% in the group overall, with the risk being significantly higher with ACh use compared to ER use (0.4% vs 0.9%, P < 0.001).
      • Isogai T.
      • Yasunaga H.
      • Matsui H.
      • et al.
      Serious cardiac complications in coronary spasm provocation tests using acetylcholine or ergonovine: analysis of 21 512 patients from the diagnosis procedure combination database in Japan.
      A large cohort study (n = 21,512) assessed the occurrence of serious cardiac complications on the day of the provocation test. The rate remained low, at < 1% in the group overall, with the risk being significantly higher with ACh use compared to ER use (0.4% vs 0.9%, P < 0.001).
      • Isogai T.
      • Yasunaga H.
      • Matsui H.
      • et al.
      Serious cardiac complications in coronary spasm provocation tests using acetylcholine or ergonovine: analysis of 21 512 patients from the diagnosis procedure combination database in Japan.
      Defibrillation occurred in 0.6% of cases, with 1 periprocedural death. Previous smaller studies have reported a rate of cardiovascular death ranging from 0% to 3.2%
      • Ong P.
      • Athanasiadis A.
      • Borgulya G.
      • et al.
      Clinical usefulness, angiographic characteristics, and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive White patients with unobstructed coronary arteries.
      ,
      • Sato K.
      • Kaikita K.
      • Nakayama N.
      • et al.
      Coronary vasomotor response to intracoronary acetylcholine injection, clinical features, and long-term prognosis in 873 consecutive patients with coronary spasm: analysis of a single-center study over 20 years.
      ,
      • Harding M.B.
      • Leithe M.E.
      • Mark D.B.
      • et al.
      Ergonovine maleate testing during cardiac catheterization: a 10-year perspective in 3,447 patients without significant coronary artery disease or Prinzmetal's variant angina.
      ,
      • Sueda S.
      • Saeki H.
      • Otani T.
      • et al.
      Major complications during spasm provocation tests with an intracoronary injection of acetylcholine.
      ,
      • Bertrand M.E.
      • La Blanche J.M.
      • Tilmant P.Y.
      • et al.
      Frequency of provoked coronary arterial spasm in 1089 consecutive patients undergoing coronary arteriography.
      ,
      • Takagi Y.
      • Yasuda S.
      • Takahashi J.
      • et al.
      Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications, and prognostic impact: multicentre registry study of the Japanese Coronary Spasm Association.

      Prognosis and Treatment

      CMD is known to predict increased risk for major adverse cardiac events (MACE), including cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for congestive heart failure.
      • Pepine C.J.
      • Anderson R.D.
      • Sharaf B.L.
      • et al.
      Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women's Ischemia Syndrome Evaluation) study.
      ,
      • Suwaidi J.A.
      • Hamasaki S.
      • Higano S.T.
      • et al.
      Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction.
      ,
      • Lee J.M.
      • Choi K.H.
      • Hwang D.
      • et al.
      Prognostic implication of thermodilution coronary flow reserve in patients undergoing fractional flow reserve measurement.
      CMD also is associated with progression to unstable angina.
      • Schachinger V.
      • Britten M.B.
      • Zeiher A.M.
      Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease.
      This entity is a potential precursor of atherosclerosis and an independent predictor of cardiac mortality.
      • Lee J.M.
      • Choi K.H.
      • Hwang D.
      • et al.
      Prognostic implication of thermodilution coronary flow reserve in patients undergoing fractional flow reserve measurement.
      ,
      • Widlansky M.E.
      • Gokce N.
      • Keaney Jr., J.F.
      • Vita J.A.
      The clinical implications of endothelial dysfunction.
      ,
      • Murthy V.L.
      • Naya M.
      • Foster C.R.
      • et al.
      Association between coronary vascular dysfunction and cardiac mortality in patients with and without diabetes mellitus.
      An abnormal IMR value also has been found to be associated with a poor prognosis.
      • Lee J.M.
      • Jung J.H.
      • Hwang D.
      • et al.
      Coronary flow reserve and microcirculatory resistance in patients with intermediate coronary stenosis.
      Abnormal CBF response to ACh ialso is associated with an 8%-12% increase in the hazard of MACE over a median of 9.7 years.
      • AlBadri A.
      • Bairey Merz C.N.
      • Johnson B.D.
      • et al.
      Impact of abnormal coronary reactivity on long-term clinical outcomes in women.
      INOCA occurs more frequently in women. Additionally, women with INOCA appear to have worse outcomes, compared with those of men. A large Canadian study of 13,695 patients demonstrated that women with INOCA had an almost 3-fold higher risk of MACE (adjusted hazard ratio = 2.43, 95% confidence interval 1.08-5.49) within the first year of cardiac catheterization, compared with that for men.
      • Sedlak T.L.
      • Lee M.
      • Izadnegadhar
      • et al.
      Sex differences in clinical outcomes in patients with stable angina and no obstructive coronary artery disease.
      The optinal management of patients with INOCA remains unclear. Strict control of cardiovascular risk factors such as hypertension, diabetes, dyslipidemia, and smoking, is essential.
      • Kunadian V.
      • Chieffo A.
      • Camici P.G.
      • et al.
      An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.
      Patients with CMD and microvascular angina likely will benefit from treatment with a beta-blocker, to which a CCB may be added if needed. Treatment with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker should be considered in all patients with coronary dysfunction, as these agents improve CFR and small-vessel remodeling,
      • Ong P.
      • Athanasiadis A.
      • Sechtem U.
      Pharmacotherapy for coronary microvascular dysfunction.
      and they also may contribute to symptom reduction.
      • Pizzi C.
      • Manfrini O.
      • Fontana F.
      • Bugiardini R.
      Angiotensin-converting enzyme inhibitors and 3-hydroxy-3-methylglutaryl coenzyme A reductase in cardiac Syndrome X: role of superoxide dismutase activity.
      ,
      • Pauly D.F.
      • Johnson B.D.
      • Anderson R.D.
      • et al.
      In women with symptoms of cardiac ischemia, nonobstructive coronary arteries, and microvascular dysfunction, angiotensin-converting enzyme inhibition is associated with improved microvascular function: A double-blind randomized study from the National Heart, Lung and Blood Institute Women's Ischemia Syndrome Evaluation (WISE).
      Patients with low CFR may also benefit from ranolazine, although the evidence to date is conflicting, in terms of symptom benefit,
      • Mehta P.K.
      • Sharma S.
      • Minissian M.
      • et al.
      Ranolazine reduces angina in women with ischemic heart disease: results of an open-label, multicenter trial.
      ,
      • Bairey Merz C.N.
      • Handberg E.M.
      • Shufelt C.L.
      • et al.
      A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve.
      and it has no known prognostic benefit.
      • Kofler T.
      • Hess S.
      • Moccetti F.
      • et al.
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      Short-acting nitrates may be used, but long-acting nitrates are usually not effective and/or are not well tolerated, and they may in fact worsen symptoms in this population, owing to a steal effect.
      • Kunadian V.
      • Chieffo A.
      • Camici P.G.
      • et al.
      An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.
      ,
      • Russo G.
      • Di Franco A.
      • Lamendola P.
      • et al.
      Lack of effect of nitrates on exercise stress test results in patients with microvascular angina.
      Statins also should be considered for their anti-inflammatory properties and their beneficial effect on coronary endothelial dysfunction.
      • Baller D.
      • Notohamiprodjo G.
      • Gleichmann U.
      • et al.
      Improvement in coronary flow reserve determined by positron emission tomography after 6 months of cholesterol-lowering therapy in patients with early stages of coronary atherosclerosis.
      • Ridker P.M.
      • MacFadyen J.
      • Libby P.
      • Glynn R.J.
      Relation of baseline high-sensitivity C-reactive protein level to cardiovascular outcomes with rosuvastatin in the Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER).
      • Zhang X.
      • Li Q.
      • Zhao J.
      • et al.
      Effects of combination of statin and calcium channel blocker in patients with cardiac syndrome X.
      • Ballantyne C.M.
      • Raichlen J.S.
      • Nicholls S.J.
      • et al.
      Effect of rosuvastatin therapy on coronary artery stenoses assessed by quantitative coronary angiography: a study to evaluate the effect of rosuvastatin on intravascular ultrasound-derived coronary atheroma burden.
      Vasospastic angina is often underdiagnosed, but it has important clinical consequences, including ischemia, acute coronary syndrome, arrhythmia, and sudden cardiac arrest.
      • Wang C.H.
      • Kuo L.T.
      • Hung M.J.
      • Cherng W.J.
      Coronary vasospasm as a possible cause of elevated cardiac troponin I in patients with acute coronary syndrome and insignificant coronary artery disease.
      • MacAlpin R.N.
      Cardiac arrest and sudden unexpected death in variant angina: complications of coronary spasm that can occur in the absence of severe organic coronary stenosis.
      • Togashi I.
      • Sato T.
      • Soejima K.
      • et al.
      Sudden cardiac arrest and syncope triggered by coronary spasm.
      A small study showed that positive spasm testing (n = 174 of 240) after injection of ACh was associated with death, recurrent acute coronary syndrome, and revascularisation.
      • Wakabayashi K.
      • Suzuki H.
      • Honda Y.
      • et al.
      Provoked coronary spasm predicts adverse outcome in patients with acute myocardial infarction: a novel predictor of prognosis after acute myocardial infarction.
      However, another study (n = 437) found no such association.
      • Deyama J.
      • Nakamura T.
      • Saito Y.
      • et al.
      Effect of coronary artery spasm on long-term outcomes in survivors of acute myocardial infarction.
      The importance of identifying vasospasm resides in the benefit of tailored therapy, which has been shown to reduce angina and improve quality of life.
      • Ford T.J.
      • Stanley B.
      • Sidik N.
      • et al.
      1-year outcomes of angina management guided by invasive coronary function testing (CorMicA).
      These patients should be started on a CCB as a first-line therapy, as this is an independent predictor of MI-free survival in patients with VSA.
      • Yasue H.
      • Takizawa A.
      • Nagao M.
      • et al.
      Long-term prognosis for patients with variant angina and influential factors.
      Long-acting nitrates also can be used as adjuvant anti-anginal therapy.
      • Kunadian V.
      • Chieffo A.
      • Camici P.G.
      • et al.
      An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.
      ,
      • Takahashi J.
      • Nihei T.
      • Takagi Y.
      • et al.
      Prognostic impact of chronic nitrate therapy in patients with vasospastic angina: multicentre registry study of the Japanese Coronary Spasm Association.
      With its coronary microvascular dilatory effect, nicorandil may be added to the therapy, but patients often report significant side effects.
      • Guarini G.
      • Huqi A.
      • Morrone D.
      • et al.
      Pharmacological approaches to coronary microvascular dysfunction.
      Patients with VSA should receive lipid-lowering therapy if they meet the criteria based on current guidelines.
      • Pearson G.J.
      • Thanassoulis G.
      • Anderson T.J.
      • et al.
      2021 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in adults.

      Conclusion

      Among patients, those with ischemic symptoms and no significant CAD are an important group. Standard evaluation with a uniform approach is needed. Evaluating patients for microvascular dysfunction and coronary vasospasm is safe. Identifying the underlying etiology for symptoms has prognostic value and allows initiation of appropriate therapy to improve quality of life. Additional studies are required to evaluate the effect of tailored therapy for microvascular disease or coronary vasospasm on other cardiovascular outcomes, including mortality.

      Funding Sources

      The authors have no funding sources to declare.

      Disclosures

      The authors have no conflicts of interest to disclose.

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