INTRODUCTION — A sizeable number of patients referred for evaluation of anginal symptoms and evidence of myocardial ischemia on noninvasive testing have angiographically normal epicardial coronary arteries or coronary arteries with mild atherosclerotic disease (ASCVD). In the past, this condition was labeled as cardiac syndrome X due to uncertainty about its pathogenesis. The more appropriate term, however, is microvascular angina (MVA). (See 'Pathogenesis' below.)
This topic will discuss the pathogenesis, clinical features, diagnosis, and treatment of microvascular angina. Related topics include:
●(See "Vasospastic angina".)
●(See "Myocardial infarction or ischemia with no obstructive coronary atherosclerosis".)
●(See "Mechanisms of acute coronary syndromes related to atherosclerosis".)
DEFINITIONS — The terms "MVA," "cardiac syndrome X," and "chest pain with normal coronary arteries" have been used interchangeably in the literature to describe patients with angina symptoms despite having angiographically normal coronary arteries. MVA is a more appropriate term to define patients with myocardial ischemia triggered by coronary microvascular dysfunction (CMD). Although MVA implies patients with no obstructive coronary artery disease (CAD), CMD can be also responsible for myocardial ischemia in patients with epicardial coronary artery disease. Thus, these conditions are not mutually exclusive, as MVA and CAD-related angina can coexist. The term ischemia with no obstructive coronary arteries (INOCA) is also gaining acceptance in the medical literature.
In this topic, the following definitions apply:
●Chest pain with normal coronary arteries – This is the broadest term and is used to refer to anyone with angina-like chest pain and normal epicardial coronary arteries on coronary angiography.
●MVA – Applies to any patient with angina and/or evidence of myocardial ischemia who is thought to have coronary microvascular dysfunction by either clinical presentation or confirmatory testing.
●Microvascular disease (MVD) – This is another term for coronary microvascular disease and includes patients with MVA.
●INOCA – Refers to ischemia with no obstructive coronary artery disease. In INOCA, the mismatch between blood supply and myocardial oxygen demands may be caused by CMD and/or epicardial coronary artery spasm (also known as vasospastic angina), typically in the setting of nonobstructive coronary atherosclerosis. Therefore, persons with INOCA can have angina from CMD and/or epicardial coronary artery spasm. This topic will address angina from CMD [1]. Vasospastic angina in discussed separately. (See "Vasospastic angina".)
●MINOCA – Refers to myocardial infarction with no obstructive coronary atherosclerosis. MINOCA is a clinical syndrome characterized by evidence of myocardial infarction (MI) with normal or near normal coronary arteries on angiography (stenosis severity ≤50 percent) in the absence of obvious noncoronary causes of MI, such as severe hemorrhage or severe respiratory failure. MINOCA is discussed separately. (See "Myocardial infarction or ischemia with no obstructive coronary atherosclerosis" and "Myocardial infarction or ischemia with no obstructive coronary atherosclerosis", section on 'Coronary microvascular dysfunction'.)
●Primary MVA – Refers to MVA in the absence of underlying other coexisting conditions that underlie MVA pathogenesis.
●Secondary MVA – Refers to MVA secondary to coexisting conditions such as hypertension or diastolic dysfunction. (See 'Secondary microvascular' below.)
●Coronary microvascular dysfunction (CMD) – Abnormal vasodilatory capacity or intense vasoconstriction affecting smaller coronary arteries (less than 500 micrometers in diameter). These are prearterioles and arterioles that feed the capillaries and regulate myocardial blood flow. CMD is characterized by reduced coronary flow reserve (CFR), microvascular spasm, and/or coronary endothelial dysfunction. A clinical classification of CMD has been proposed [2].
•CMD in the absence of obstructive CAD or other myocardial disease. This has been termed primary MVA.
•CMD in the presence of myocardial diseases. This has been termed secondary MVA. (See 'Differential diagnosis' below.)
•CMD in the presence of obstructive CAD. This is a form of secondary MVA.
•Iatrogenic CMD. This may be seen after coronary revascularization and is caused by vasoconstriction or distal embolization.
●Vasospastic angina – Also known as "variant angina," this is spasm of epicardial coronary artery and is different from microvascular angina. It will not be discussed here. (See "Vasospastic angina".)
●Vasoconstriction and vasospasm – These have been used interchangeably in the literature. For clarity, we use vasospasm to refer to the presence of epicardial arterial smooth muscle spasm that causes severe obstruction (>80 to 90 percent arterial diameter reduction) and myocardial ischemia. We refer to microcirculatory vasoconstriction, as representing visible constriction distal to the epicardial coronary arteries [3], and "microvascular spasm" to refer to occlusive or subocclusive vasomotor changes in the coronary microvessels leading to myocardial ischemia [4-6].
●Coronary flow reserve (CFR) — A key component of both the pathophysiology and diagnosis of microvascular disease (MVD) is a reduction in CFR. CFR refers to the magnitude of increase in coronary flow (per unit of time) that can be achieved between basal coronary perfusion to maximum coronary vasodilation. It is expressed as ratio of blood flow during hyperemia to blood flow at rest. (See 'Coronary flow reserve on angiography' below.)
PATHOGENESIS — Several pathogenic features underlie microvascular disease (MVD), with a subset of patients having prominent vasoconstriction. Structural remodeling of coronary microvasculature occurs more frequently in persons with cardiovascular risk factors (eg, smoking, diabetes, atherosclerosis, and hypertension). Microvascular endothelial dysfunction from lower vasodilatory capacity of microvasculature and microvascular vasoconstriction from hypersensitivity to vasoconstrictor stimuli are key disease mechanisms. Anxiety was shown to be associated with microvascular endothelial dysfunction [7]. In addition, functional dysregulation in medium to large arterioles can cause paradoxical vasoconstriction when myocardial oxygen demands increase [8].
Other established and possible mechanisms for primary MVA:
●Viral illness – In some patients, MVA is precipitated by an acute illness. Presentation of MVA after a viral infection is a relatively common scenario in our experience.
●Hormonal mechanisms − Studies have shown that there is a higher proportion of females, especially postmenopausal, among patients referred for coronary angiography for evaluation of chest pain and positive stress test. This suggests hormonal mechanisms, possibly estrogen deficiency, as a possible contributing factor, but no studies have conclusively shown estrogen deficiency or hormonal imbalance as a definite cause of MVA [9].
●Inflammation – Studies suggest that inflammation may contribute to MVA and MVA severity:
•In patients with MVA, biomarkers of systemic inflammation are related to lower coronary flow reserve (CFR) [10].
•High sensitivity C-relative protein correlates with a greater number of MVA symptoms and electrocardiogram (ECG) marker abnormalities [11].
•MVA is associated with inflammatory diseases such as systemic lupus erythematosus and rheumatoid arthritis [12].
•Ectopic fat depots that exert paracrine inflammatory effects on adjacent tissues may be involved in MVA pathogenesis. In a retrospective study of 399 patients who underwent coronary angiography, epicardial adipose tissue was associated with coronary microvascular disease, independent of BMI (OR 1.30, 95% CI 1.00-1.70) [13].
●Autonomic dysfunction – Studies are mixed as to whether autonomic dysfunction contributes to MVD [14].
Secondary microvascular — MVD secondary to other conditions has unique pathogenic mechanisms. For example, extramural compression can be present in conditions such as aortic valve stenosis, hypertrophic cardiomyopathy, or arterial hypertension. Pathogenic mechanisms for conditions that cause secondary MVA include the following:
●Microembolization in acute coronary syndrome – In the initial event or with recanalization, there can be microembolization causing luminal obstruction [15,16].
●Left ventricular hypertrophy (LVH) – Extramural compression can be present in conditions with LVH, such as aortic valve stenosis and arterial hypertension [2]. Abnormal CFR has been demonstrated in patients with left ventricular hypertrophy despite presence of angiographically normal coronary arteries. This occurs due to remodeling of vascular and extravascular structures and to coronary hemodynamics. This includes remodeling of intramural arterioles and interstitial fibrosis, which leads to a decreased density of vessels in the coronary microvasculature [2]. An imbalance between supply and demand is also an important determinant of myocardial ischemia in these patients. (See "Approach to the patient with suspected angina pectoris".)
•Essential hypertension − Abnormal CFR has been demonstrated in patients with essential hypertension despite presence of angiographically normal coronary arteries and absence of LVH. This has been attributed to remodeling of vascular and extravascular structures, capillary rarefaction, and to coronary hemodynamics [2].
•Aortic valve stenosis – MVA in patients with aortic stenosis is thought to be due to the development of LVH. There is reduced diastolic coronary perfusion time, perimyocytic fibrosis, and a reduction in the number of resistance vessels per unit of weight, which leads to reduced coronary flow reserve [2].
●Heart failure with preserved ejection fraction (HFpEF) – The majority of patients with HFpEF have MVD. In a study of 202 patients with HFpEF without obstructive epicardial coronary artery disease, 75 percent had coronary flow reserve <2.5 [17]. In another study of 62 patients with HFpEF, endothelium-independent MVD (defined as coronary flow reserve <2 and/or index of microvascular resistance ≥25) was identified in 66 percent of participants [18]. Some patients studied had obstructive epicardial coronary disease. Indices of MVA, such as coronary flow reserve, are discussed elsewhere. (See 'Additional invasive testing' below.)
●Hypertrophic cardiomyopathy and dilated cardiomyopathy – MVA in this setting is due to widespread remodeling of intramural arterioles. Severity of coronary microvascular dysfunction in affected patients has been shown to be an independent predictor of cardiac events and mortality [2]. Hypertrophic cardiomyopathy can create extramural compression.
●Infiltrative heart disease − In conditions like Anderson-Fabry disease, there is severely blunted coronary flow reserve due to glycosphingolipid deposition in myocytes, conduction tissue and vascular endothelium leading to myocyte hypertrophy/fibrosis, endothelial dysfunction, and perivascular fibrosis [2]. (See "Fabry disease: Cardiovascular disease".)
Cardiac amyloidosis may cause patients to have angina despite angiographically normal coronary arteries. Coronary flow reserve is severely blunted in these patients, leading to MVA [2]. Occasional patients with angina and angiographically normal coronary arteries (5 of 153 in one report) have underlying systemic amyloidosis in which the chest pain may result from amyloid deposits in the intramyocardial coronary arteries [19,20]. The diagnosis of amyloidosis may not be made for several years after the onset of chest pain, usually due to the development of kidney disease or heart failure. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)
●Rheumatologic disease – Both systemic lupus erythematosus and rheumatoid arthritis are more prevalent in patients with angina and coronary microvascular dysfunction [12].
Enhanced pain sensitivity — In some patients with MVA, enhanced pain sensitivity (hyperalgesia or cardiac nociception abnormality) is an alternative explanation for chest pain [21,22]. This hypothesis is indirectly supported by studies that could not demonstrate evidence of ischemia in patients with typical chest pain and coronary microvascular dysfunction after stresses such as exercise, dobutamine, dipyridamole, or transesophageal atrial pacing. Despite the frequent provocation of chest pain with these stresses, some patients do not have perfusion defects, regional wall motion abnormalities, or a decline in left ventricular function or myocardial blood flow [23-26]. It has been suggested that in the presence of increased pain perception/reduced pain threshold (eg, as a result of estrogen deficiency), minor degrees of subendocardial ischemia, patchy foci of reduced blood flow in the subendocardium, or even a marked redistribution of intramyocardial blood flow may result in severe chest discomfort in some patients.
In addition, in patients with this "hyperalgesia syndrome," chest pain can be provoked in the cath lab by moving the catheter within the right atrium or the right ventricle, without evidence of myocardial ischemia [27]. It has been suggested that this type of hyperalgesia may result from sympathovagal imbalance with sympathetic predominance [28] or reduced activity of the endogenous opioid system [29].
EPIDEMIOLOGY — MVA is common. A meta‐analysis of 56 studies of over 14,400 patients with suspected coronary disease and no epicardial obstructive coronary lesions showed the prevalence of MVA is 41 percent (95% CI 36–47 percent) [30]. The following demographic and clinical risk factors for MVA have been identified:
●Younger age – Patients with MVA are younger at the time of diagnosis (mean age 49 years) and are more often female than those with atherosclerotic cardiovascular disease (ASCVD) in most [23,31,32] but not all series [33].
●Female sex – The following studies highlight the relationship between female sex and MVA:
•Myocardial ischemia and/or coronary microvascular dysfunction (CMD) is present in 20 to 50 percent of females with chest pain and normal coronary arteries [34-38].
•In a study of 886 patients referred for angiographic evaluation of chest pain, normal coronary arteries were found in 41 percent of the females compared with only 8 percent of the males (16 percent overall) [31].
•Similar findings were noted in a series of 323 females (mean age 59) with suspected or possible ischemic chest pain: 37 percent had normal coronary arteries (less than 20 percent stenosis) [39].
●Traditional cardiovascular risk factors – These are found more often in patients with MVA than in the general population [40]. Diabetes mellitus is often associated with microvascular disease (MVD). Cigarette smoking has been associated with MVD, and coronary flow reserve may be reduced by up to 21 percent in these patients [2]. Reductions in coronary flow reserve have also been observed in asymptomatic subjects with hypercholesterolemia and angiographically normal coronary arteries. (See "Coronary artery endothelial dysfunction: Basic concepts", section on 'Diabetes mellitus'.)
●Anxiety – In a single-institution retrospective study of 1974 patients who underwent invasive coronary reactivity testing for angina and were evaluated for anxiety, anxiety disorders were significantly more common in patients with any type of coronary endothelial dysfunction (OR 1.36, 95% CI 1.10-1.68) [7]. Among patients with anxiety, there was a higher prevalence of coronary endothelial dysfunction (62.7 versus 56.4 percent). After stratifying by sex, anxiety was related to coronary endothelial dysfunction in females but not in males.
CLINICAL PRESENTATION — Most patients with MVA-related chest discomfort are evaluated for obstructive coronary artery disease, given that the clinical presentation is often indistinguishable from that in patients with coronary artery disease (CAD)-related angina. A complete history, physical examination, resting electrocardiogram (ECG), and stress test are most often carried out in these patients and the diagnosis of MVA is usually considered after coronary angiography has been performed and has shown no significant epicardial coronary artery disease.
History
●Angina characteristics – Most often, patients present with a chronic pattern of recurrent episodes of chest pain on effort that is similar to classic angina pectoris and others (less commonly) with angina at rest suggestive of coronary artery spasm. Some patients have atypical chest pain that is interpreted to be noncardiac. In some patients, chest pain may be severe and debilitating to a point where it affects daily activities [32]. The duration of chest pain episodes is often prolonged compared with that with effort angina [32]. Some patients have dyspnea on exertion as the only manifestation of microvascular angina. Dyspnea is an established anginal equivalent in patients with obstructive coronary disease [41]. (See "Approach to the patient with suspected angina pectoris".)
There are four common clinical patterns of MVA that have different treatment approaches:
•Effort-related angina – This occurs in about half of the patients with MVA [26,42]. (See 'Initial therapy for effort angina' below.)
•Rest angina – Often episodes occur in the early morning. Importantly, if rest angina is present (with or without effort angina), vasoconstriction is likely involved. (See 'Initial therapy for rest or mixed angina' below.)
•Mixed effort and rest angina. (See 'Initial therapy for rest or mixed angina' below.)
•In a minority of patients, MVA is precipitated by an acute illness such as a viral infection. After resolution of the illness, in our experience, the angina symptoms usually (but not always) become less troublesome.
●Reduced exercise tolerance – Several studies have found that exercise capacity is reduced in patients with microvascular disease (MVD) [43,44], perhaps in part related to deconditioning.
●Acute myocardial infarction – Some patients with MVA can present with an acute myocardial infarction. Support for the possible role of MVA as a cause of acute coronary syndrome (ACS) is the observation that normal coronary vessels or no vessel with ≥50 percent stenosis have been reported in approximately 9 to 14 percent of patients with a non-ST elevation ACS [45-49], but prevalence of MVA as a causal mechanism in this population is not known. (See "Acute coronary syndrome: Terminology and classification" and "Diagnosis of acute myocardial infarction", section on 'Definitions'.)
Physical examination — Although physical examination is very important in all patients with angina, there are no findings that are specific for MVA. However, during an episode, tachycardia, hypertension, diaphoresis, and an S3 or S4 may be heard. These exam findings are also seen in classic angina. (See "Auscultation of heart sounds", section on 'Third (S3) and fourth (S4) heart sounds'.)
Electrocardiogram — A 12-lead ECG should be performed in all patients with a history of chest pain. The ECG is usually normal between episodes. Transient ECG changes, including ST-segment depression with anginal pain, are common [50], but the absence of ECG changes does not exclude a cardiac etiology, because of the low sensitivity of the ECG. ST-segment elevation that is the hallmark of vasospastic angina is not a feature of MVA [51]. (See "Vasospastic angina", section on '12-lead ECG during chest pain'.)
Ambulatory ECG monitoring for 24 hours may be helpful for documenting ST-segment changes.
DIAGNOSTIC EVALUATION — Most patients with chest pain suspicious for myocardial ischemia undergo a noninvasive evaluation for both diagnostic and prognostic purposes. Once obstructive epicardial coronary artery disease has been ruled out with angiography or other testing, the diagnosis of MVA becomes more likely, and MVA-focused evaluation is performed. Therefore, having a high degree of suspicion can help in earlier identification of MVA.
It should be kept in mind that noncardiac causes of chest pain must be considered and potentially investigated before the diagnosis of MVA can be made.
Initial noninvasive evaluation — Most stable patients with chest pain that has characteristics of myocardial ischemia will be referred for stress testing with or without perfusion imaging, echocardiography, or coronary computed tomographic angiography [52]. (See "Stress testing for the diagnosis of obstructive coronary heart disease" and "Selecting the optimal cardiac stress test" and "Overview of stress echocardiography" and "Exercise ECG testing: Performing the test and interpreting the ECG results" and "Overview of stress radionuclide myocardial perfusion imaging" and "Clinical use of coronary computed tomographic angiography".)
Some information is known about the results of these noninvasive tests performed in individuals who are later given the diagnosis of MVA. If an exercise electrocardiogram (ECG) is used, the typical finding in patients with MVA is horizontal or downsloping ST-segment depression, as seen in patients with obstructive coronary artery disease (CAD). Exercise stress myocardial perfusion scintigraphy may demonstrate regional myocardial perfusion defects during exercise [53,54]. However, some reports have demonstrated neither perfusion defects nor regional wall motion abnormalities after dobutamine or transesophageal atrial pacing, despite the frequent provocation of chest pain [23,24]. It is possible that ischemia is limited to the subendocardium, or is "patchy" in character, which could explain the absence of wall motion abnormalities as assessed by echocardiography [55] (see 'Additional invasive testing' below). Some studies have found that exercise perfusion imaging demonstrates evidence of left ventricular systolic and diastolic dysfunction, which is consistent with ischemia [56], while others have not [23-25].
Some patients are referred for computed tomography angiography rather than coronary angiography when their first noninvasive test gives a low or intermediate probability result. Patients with possible MVA will not have coronary artery stenoses of more than 50 percent. (See "Cardiac imaging with computed tomography and magnetic resonance in the adult".)
Finally, some patients are evaluated at the time of an anginal episode and are given sublingual nitroglycerin (NTG) both as a diagnostic test and to relieve symptoms due to angina. In MVA, as the small arterioles are less directly affected by the vasodilatory effects of NTG compared with the epicardial arteries, the drug may not be reliably effective [57]. Thus, when a patient is felt to have angina but does not respond rapidly to NTG, MVA should be considered. However, it should be kept in mind that the absence of response to NTG has a low predictive value for MVA.
Diagnostic coronary angiography — In some patients with chest pain, coronary angiography is indicated for further diagnostic testing or as a prelude to revascularization. In patients with MVA, the coronary angiogram will show normal epicardial coronary arteries or mild coronary artery disease (<30 percent stenosis). In patients with lesions between 30 and 50 percent, further evaluation with fractional flow reserve should be carried out to make sure that the lesion(s) is not hemodynamically significant. (See "Clinical use of coronary artery pressure flow measurements" and "Intravascular ultrasound, optical coherence tomography, and angioscopy of coronary circulation", section on 'Ultrasonic image of an atherosclerotic plaque'.)
Additional invasive testing — For patients without obstructive CAD as the cause of myocardial ischemia and in whom the diagnosis of MVA is considered, additional testing, usually performed at the time of coronary angiography, may be helpful. Local availability and expertise will dictate which test is chosen, and it may be necessary to perform more than one to establish the diagnosis of MVA due to heterogeneity of underlying mechanisms. If these tests are not available, the clinical presentation can be used as an indication that vasoconstriction is present and can help direct therapy. (See 'History' above.)
Coronary flow reserve on angiography — Measurement of coronary flow reserve (CFR) during invasive coronary angiography using a Doppler flow wire to measure coronary blood velocity reserve or pressure/thermodilution wire to measure coronary blood flow reserve can be useful [58,59]. CFR is the ratio of maximal hyperemic coronary blood flow measured after infusion of a coronary vasodilator, such as adenosine, to resting, or basal coronary blood flow. Normal CFR ranges from 2.5 to 5; occasionally, it is greater than 5. Maximal coronary blood flow should be at least two and a half times the resting blood flow. When there is no significant epicardial coronary artery disease, CFR shows the degree of resistance to blood flow in the microcirculation. It can be measured invasively using a Doppler wire placed into the coronary artery, and then infusing adenosine either intravenously or directly into the coronary artery [2]. CFR values below or equal to 2 or 2.5, depending on methodology used, are indicative of coronary microvascular dysfunction [60]. (See "Clinical use of coronary artery pressure flow measurements".)
Coronary microvascular vasoconstriction — Coronary microvascular vasoconstriction (different from focal epicardial coronary artery spasm) can be detected during angiographic studies in patients with chest pain despite angiographically normal coronary arteries using intracoronary acetylcholine (Ach) testing [4]. Ach produces coronary vasodilation in presence of healthy endothelium and paradoxical vasoconstriction in the presence of endothelial dysfunction.
At least two studies of patients with chest pain and nonobstructive coronary artery disease (all lesions <50 percent diameter stenosis) have demonstrated the potential use of intracoronary acetylcholine for the diagnosis of MVA [61,62]. In a study of 921 patients who underwent diagnostic coronary angiography for suspected myocardial ischemia and who did not have high-grade coronary stenoses, 847 underwent testing with relatively high-dose Ach [62]. Microvascular vasoconstriction (angina and ischemic ECG shifts without epicardial spasm) was found in about one-quarter. No fatal or irreversible nonfatal complications occurred [63].
In an Ach test, incremental doses of intracoronary Ach are administered over three minutes until response is produced or target dose is reached.
●Positive response for epicardial coronary spasm is >75 percent focal or diffuse coronary artery diameter reduction (compared with relaxed state). Patients have reproduction of angina and ischemic ECG changes. These patients will be considered to have vasospastic angina, not MVA.
●Positive response for microvascular vasoconstriction is absence of epicardial coronary spasm (<75 percent diameter reduction). Patients have reproduction of angina and ischemic ECG changes (ST depression or ST elevation 0.1 mV in two contiguous leads). These patients will be considered to have MVA.
●Negative response to Ach test is absence of epicardial coronary spasm (no or <75 percent diameter reduction), no angina, and no ischemic ECG changes. These patients are further evaluated with intracoronary adenosine.
Adenosine test — We further evaluate patients who have a "negative" response to Ach with intracoronary adenosine. In adenosine test, bolus adenosine doses (18 micrograms in left coronary artery and 12 micrograms in right coronary artery) are injected into the coronary arteries followed by 5 mL saline solution flush. Coronary flow velocities (CFVs) are measured using sensor-tipped guidewire (with either a Doppler probe or thermistor/pressure sensor). CFR is calculated from CFVs (ratio of peak CFV to baseline CFV). CFR <2.5 indicates endothelium-independent coronary microvascular dysfunction. These patients with abnormal CFR will also be considered to have MVA [64].
Noninvasive testing — The following noninvasive tests may be used in patients who are not able to undergo the invasive tests described above or who do not have a clear diagnosis after completion of an invasive evaluation:
●Computed tomography fractional flow reserve – Fractional flow reserve can be estimated from a computed tomography-derived model of the coronary circulation, which is based on computational fluid dynamic principles [65,66]. This method does not require a vasodilator or physiologic stress.
●Positron emission tomography coronary flow reserve – Positron emission tomography images can provide an estimate of coronary flow reserve by comparing myocardial blood flow at rest with blood flow acquired during stress [33].
●Cardiovascular magnetic resonance imaging coronary flow reserve – Cardiovascular magnetic resonance imaging provides a measure of coronary flow reserve (ie, myocardial perfusion reserve index) by comparing perfusion (first-pass gadolinium uptake) at rest with perfusion during vasodilator or dobutamine stress [67,68].
●Echocardiographic coronary flow reserve – Echocardiographic coronary flow reserve is measured by comparing velocities obtained from the left anterior descending artery at rest with velocities obtained during stress [69]. Echocardiographic myocardial perfusion reserve is measured by comparing contrast echocardiography-derived myocardial replenishment curves obtained at rest with curves obtained with peak adenosine infusion.
DIAGNOSIS — Our criteria for establishing the diagnosis of MVA are in accord with the criteria established by the Coronary Vasomotion Disorders International Study Group (COVADIS) [70] and are as follows:
●Clinical features consistent with the diagnosis. (See 'Clinical presentation' above.)
●Objective documentation of myocardial ischemia. (See 'Initial noninvasive evaluation' above.)
●Absence of obstructive coronary artery lesions on coronary angiography. (See 'Diagnostic coronary angiography' above.)
●Completion of an intracoronary evaluation with measurement of fractional flow reserve as well as acetylcholine and adenosine testing. (See 'Additional invasive testing' above.)
In lieu of this intracoronary evaluation, patients who are given a clinical diagnosis of MVA are treated as discussed below (see 'Management' below). Patients who do not respond should be referred for further invasive or noninvasive diagnostic testing. (See 'Additional invasive testing' above and 'Noninvasive testing' above.)
●Similar to the evaluation of all patients with chest pain, noncardiac causes should be considered and potentially investigated before the diagnosis of MVA can be given.
COVADIS has proposed the following clinical criteria for suspecting MVA (definitive MVA diagnosed if all four criteria are present) [70]:
●Symptoms of myocardial ischemia. Effort and/or rest angina or angina equivalent (eg, dyspnea).
●Objective evidence of myocardial ischemia. Ischemic electrocardiographic (ECG) changes during an episode of chest pain, stress-induced chest pain, and/or ischemic ECG changes, and/or presence of transient/reversible abnormal myocardial perfusion or wall motion abnormality.
●Absence of obstructive coronary artery disease (CAD) (<50 percent stenosis or fractional flow reserve >0.8) by coronary computed tomography angiogram or invasive coronary angiography. An important clarification to this criterion is that the fractional flow reserve (FFR) is >0.8 despite or in the absence of obstructive CAD.
●Evidence of impaired coronary microvascular function:
•Impaired coronary flow reserve (CFR) (<2 to <2.5). (See "Clinical use of coronary artery pressure flow measurements" and 'Definitions' above.)
•Coronary microvascular vasoconstriction. Reproduction of symptoms; ischemic ECG changes but no epicardial vasospasm during acetylcholine testing.
•Abnormal coronary microvascular resistance indices (eg, index of microcirculatory resistance >25).
•Coronary slow flow phenomenon. TIMI frame count >25.
Our approach — Securing the diagnosis of MVA is challenging [71]. Ideally, patients should be investigated for MVA at the time of diagnostic angiography, with the assessment of CFR and other coronary physiology techniques. We have found the following approach to be applicable to many patients in whom coronary angiography has not found epicardial coronary artery disease sufficient to explain the presence of myocardial ischemia.
●When a subcritical or intermediate coronary lesion is documented, FFR is used to exclude functional significance (FFR value >0.8 indicates that the lesion is not functionally significant).
●If significant epicardial coronary artery stenoses are excluded with FFR, acetylcholine (Ach) testing is performed to rule out epicardial coronary spasm and microvascular endothelial dysfunction.
●When epicardial coronary spasm and microvascular endothelial dysfunction are both excluded with Ach test, presence of endothelium independent microvascular dysfunction is ruled out using adenosine test.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis for MVA consists primarily of obstructive coronary artery disease, vasospastic angina and other causes of ischemia with nonobstructive coronary arteries (INOCA), and other conditions that cause chest pain. These are discussed separately. (See "Vasospastic angina", section on 'Differential diagnoses'.)
Diseases that cause secondary MVA must also be considered and treated. (See 'Secondary microvascular' above.)
Patients with right ventricular hypertrophy due to pulmonary hypertension may also have anginal symptoms. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations'.)
PROGNOSIS — For the majority of patients, primary MVA is a chronic condition that usually can be managed with lifestyle changes and pharmacotherapy but does not completely resolve. Accordingly, we have early and frequent discussions with our patients with MVA in which we explain the mechanisms responsible for their anginal pain and ways of dealing with a condition that is unlikely to completely resolve. We discuss that at times the angina will get worse and at times it will improve or be better controlled.
Contrary to initial belief, MVA is not necessarily a benign condition. Patients with primary and secondary MVA may have a poorer prognosis and more adverse cardiovascular events than the general population. Evidence of this includes the following:
●In one study, impaired coronary flow reserve (CFR) was independently associated with diastolic dysfunction and hospitalization from heart failure with preserved ejection fraction in patients undergoing evaluation for suspected coronary artery disease who did not have flow-limiting coronary artery disease or reduced left ventricular ejection fraction [72]. (See 'Additional invasive testing' above.)
●In another study, patients with stable angina referred for coronary angiography who had normal coronary arteries or diffuse nonobstructive coronary artery disease had a higher risk of major adverse cardiovascular events (cardiovascular mortality and hospitalization for myocardial infarction, heart failure, and stroke) and all-cause mortality compared with asymptomatic patients [73].
●Additional studies showed that coronary microvascular dysfunction (CMD), as measured by CFR, may identify patients at higher risk of cardiovascular mortality [74], and it is a stronger independent predictor of cardiovascular mortality than absolute maximal myocardial blood flow beyond traditional cardiovascular risk factors [75].
•Impaired CFR with preserved maximal myocardial blood flow identified patients at higher risk of cardiovascular mortality despite lack of myocardial ischemia [75]. These patients may be an appropriate target for initiation or intensification of lifestyle or pharmacologic preventive therapies for cardiovascular risk reduction.
•Preserved CFR, even in the presence of impaired maximal myocardial blood flow, identified low-risk patients (<1 percent annual cardiovascular mortality risk) [75]. CMD has been associated with more adverse outcomes and poorer prognosis [33,73]. It is unclear if treatment directed toward CMD improves prognosis of these patients.
In the subset of patients with MVA and an acute coronary syndrome, the outcome is not benign but better than in those with a culprit coronary lesion [46,47,76]. This was best illustrated in the PURSUIT trial of 5767 patients with unstable angina or a non-ST elevation myocardial infarction; 6 percent had mild coronary disease (>0 to ≤50 percent stenosis) and 6 percent had no disease [47]. The patients with no or mild coronary disease had a much lower rate of death or nonfatal myocardial infarction at 30 days than those with significant disease (2 and 6 versus 17 percent).
An international study of 686 patients with MVA showed that cardiac events (eg, unstable angina, cardiovascular disease, myocardial infarction, and heart failure) did not differ by sex or race/ethnicity (ie, White, Japanese, Hispanic, Black) [77]. Among persons with MVA, a history of prior coronary artery disease (HR 2.03, 95% CI 1.31-3.15) and hypertension (HR 1.69, 95% CI 1.07-2.68) were each associated with increased cardiovascular events. Females with MVA reported lower angina-related quality of life compared with males (quality of life was measured with the Seattle Angina Questionnaire [78]).
MANAGEMENT — Unlike patients with chronic stable angina from obstructive coronary disease, patients with primary microvascular disease (MVD) are not candidates for revascularization and their treatment algorithms for angina differ according to their specific MVA history. A practical therapeutic approach is depicted in an algorithm (algorithm 1).
Goals of treatment — For all patients with MVA, we have three main treatment goals:
●To prevent and treat angina.
●To get patients to their desired level of exercise tolerance.
●To prevent long-term atherosclerotic cardiovascular disease and related adverse outcomes.
For most patients, in order to achieve their desired level of exercise tolerance, we need to first treat angina symptoms.
General measures for all patients — We suggest prescribing sublingual nitroglycerin (NTG) for all patients with MVA. We aggressively modify elevated atherosclerotic cardiovascular disease (ASCVD) risk factors and prescribe regular exercise.
●Nitroglycerin – Patients should be given a prescription for sublingual NTG, which can be used to relieve or prevent angina. Sublingual NTG is not effective for all patients with MVA. One study showed improvement with sublingual nitrates in about 40 percent of patients with MVD [32]. (See "Nitrates in the management of chronic coronary syndrome", section on 'Sublingual nitroglycerin'.)
Patients can also take long-acting nitrate therapy (in either a pill or patch formulation). Studies of long-acting nitrate therapy on relieving angina in MVD have yielded mixed results. A study of oral isosorbide mononitrate in MVD did not demonstrate efficacy [79]. Even though no randomized control trials have shown a clear benefit, they are widely used in patients with angina and normal coronary arteries. NTG patch at a dose of 0.2 to 0.4 mg/hour may be added to beta blocker or calcium channel blocker and may be effective at relieving angina.
If long-acting nitroglycerin therapy is effective in reducing a patient's MVA symptoms, we continue daily therapy. If long-acting nitroglycerin is not effective in relieving MVA, we stop it and prescribe other medication.
In patients with effort-induced angina and a good response to nitrates, one approach we use is to have the patient apply a nitroglycerin patch 30 to 45 minutes before they undertake an activity known to trigger usual chest pain. The patch can be removed shortly after the end of the activity.
●ASCVD prevention
•Primary ASCVD prevention – Patients with MVA who have modifiable risk factors for ASCVD (ie, hypertension, diabetes, dyslipidemia, obesity, smoking) should be treated with aggressive risk factor reduction, including lifestyle changes and pharmacotherapy, as indicated. (See "Overview of primary prevention of cardiovascular disease" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)
Hypertension should be treated to goal blood pressure. (See "Goal blood pressure in adults with hypertension".)
We prefer an angiotensin-converting enzyme (ACE) inhibitor for blood pressure control. Several studies demonstrate a potential benefit of therapy with an ACE inhibitor in MVA [80-82]. As examples:
-In one randomized trial, 45 patients with MVA were assigned to treatment with either ramipril (10 mg daily) plus atorvastatin (40 mg daily) or placebo [82]. After six months, patients treated with atorvastatin and ramipril had significant improvements in brachial artery flow-mediated vasodilation (a marker of endothelial function), exercise duration, and angina frequency compared with placebo.
-In a randomized trial of 61 females with MVA as part of the Women's Ischemia Syndrome Evaluation study, women who received quinapril had improved coronary flow reserve (CFR) after 16 weeks compared with the placebo group [81]. In addition, the experimental group had improvement in angina symptoms based on the Seattle Angina Questionnaire [78].
•Secondary ASCVD prevention – While there is no clear evidence for benefit of aspirin in patients with microvascular dysfunction, many of these patients have multiple cardiovascular risk factors, and it is reasonable to prescribe aspirin 81 mg daily). (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Prevention of cardiovascular disease events'.)
One of our contributors does not routinely prescribe statins for patients with MVA, unless there is another indication. However, another contributor does treat with statins as they have been shown to improve coronary artery endothelial function [83]. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease", section on 'Reversal of endothelial dysfunction'.)
●Exercise – We routinely recommend a physical training program to improve exercise capacity and reduce the frequency of chest pain episodes. We refer patients with MVA to cardiac rehabilitation if their health insurance can cover the costs and/or the patient can pay the out-of-pocket costs. If the patient cannot participate in cardiac rehabilitation, we recommend regular symptom-limited exercise, with a gradual increase in duration and intensity as tolerated. (See "Cardiac rehabilitation programs" and "Cardiac rehabilitation: Indications, efficacy, and safety in patients with coronary heart disease".)
Exercise training may increase exercise capacity and relieve angina in patients with MVD. The potential benefit of physical training was demonstrated in a randomized trial including 26 patients with MVD [43]. Exercise training improved exercise capacity by 34 percent and delayed the onset of angina during exercise from 3±2 to 6±3 minutes. Addition of body awareness training to exercise therapy did not alter the pain response to exercise or affect maximal pain.
Initial therapy for effort angina — For patients who return with unacceptable effort-induced angina after one month of general therapy, further interventions are aimed at relief of angina [22,32,84]. Therapy is largely empiric, and optimal therapy may vary with the mechanism of MVA [22]. We suggest beta blockers as the initial therapy for most patients with persistent effort angina. (See 'Combination therapy for persistent symptoms' below.)
●Beta blockers – We use beta blockers for initial treatment of persistent effort-induced angina. We generally start with metoprolol succinate 50 mg daily and increase the dose to as much as 100 to 200 mg daily by one month if symptoms remain unacceptable. Metoprolol tartrate (same total daily dose given twice a day) may also be used in place of metoprolol succinate. Bisoprolol is an alternative (initial dose 2.5 mg daily and increase the dose to 10 mg daily if necessary). Nebivolol 5 mg daily is another choice. Although definitive controlled trials are not available, beta blockers seem to be most effective in reducing the frequency and severity of angina and in improving exercise tolerance [79,85-87].
●Alternative monotherapy for effort angina – For most patients with effort-induced angina and an intolerance to beta blockers, we suggest administering a calcium channel blocker.
Initial therapy for rest or mixed angina — Calcium channel blockers are the initial therapy in patients whose underlying pathogenetic mechanism includes microvascular vasoconstriction/vasospasm. (See 'Coronary microvascular vasoconstriction' above.)
We use extended-release diltiazem 180 mg daily and increase the dose at two- to four-week intervals to a maximum dose of 540 mg daily, as necessary. Short-acting calcium channel blockers should not be used, because of safety concerns. (See "Major side effects and safety of calcium channel blockers".)
The literature on the efficacy of calcium channel blockers for patients with MVD is conflicting.
●Two small trials of 10 and 16 patients with MVD compared the effects of beta blockers and with those of calcium channel blockers and showed efficacy for beta blockers but not calcium channel blockers in reducing ischemic episodes [79,85].
●Calcium channel blockers showed greater benefit in patients whose underlying pathogenetic mechanism is primarily microvascular vasoconstriction. (See 'Coronary microvascular vasoconstriction' above.)
•A study compared patients with documented coronary epicardial vasospasm with patients with microvascular dysfunction and found that half the patients with microvascular dysfunction showed symptomatic improvement with calcium channel blockers while almost all patients who were given a combination of calcium channel blockers and angiotensin-converting enzyme (ACE) inhibitors showed substantial relief of angina [88]. (See 'Pathogenesis' above.)
•A cohort study of 50 patients with MVD and microvascular vasoconstriction documented by invasive acetylcholine (Ach) testing evaluated symptoms after individuals took a calcium channel blocker [61]. Anginal episodes decreased in half of the patients, decreased substantially in 30 percent, and remained frequent in 20 percent of patients. This study is limited by lack of a control group.
Combination therapy for persistent symptoms — For most patients with persistent angina, we suggest adding an additional agent (ie, a beta blocker or calcium channel blocker as appropriate). If MVA symptoms persist, we add ranolazine and/or ivabradine. Subsequent therapy for persistent angina is tailored based on the patient’s other comorbidities.
●Ranolazine – This is a novel antianginal agent that is a late sodium current inhibitor. We start with the lowest available dose and titrate upwards as tolerated. In the United States, this would mean prescribing 500 mg twice daily; in other countries, it would mean prescribing 375 mg twice daily.
In a study with crossover design of females with MVD diagnosed by cardiac magnetic resonance imaging perfusion, 20 individuals were randomly assigned to either ranolazine or placebo. After four weeks of therapy, ranolazine resulted in significantly better scores on the Seattle Angina Questionnaire and a trend toward improved myocardial perfusion [89].
●Ivabradine – Ivabradine is a selective If channel blocker that causes sinus bradycardia by inhibiting If current in the sinus node. Unlike beta blockers, ivabradine does not cause vasoconstriction or have negative inotropic effects. We recommend starting at the lowest dose of 2.5 mg twice daily and increasing to 5 mg twice daily if needed for symptom relief. In a study, 46 patients with MVA were randomly assigned ivabradine, ranolazine, and placebo and followed for angina symptoms, coronary microvascular dilation, exercise tolerance and ST-segment depression on stress testing [90]. Patients with ivabradine had improvement in angina symptoms when compared with the control group. However, there were no improvements in coronary microvascular dilation, exercise stress test duration, or time-to-ST-segment depression. Patients assigned ranolazine had greater improvement in angina, exercise duration, and time-to-ST-segment duration compared with the ivabradine or control groups.
●Imipramine – For patients with depression or in whom hyperalgesia is suspected, and in whom further therapy is needed, we add imipramine. We suggest a starting dose of 25 mg at night. Patients sensitive to side effects and the older adults can start with a dose of 10 mg at bedtime. The dose can be increased by 25 to 50 mg every three to four days, as side effects allow, to a target dose range of 100 to 300 mg daily. Imipramine is a tricyclic antidepressant medication, which has been used successfully in the management of chronic pain syndromes. It may be effective in some patients with MVA when used at a low dose. One study evaluated 60 patients with chest pain and normal coronary angiograms [91]. Of these patients, 38 had one or more psychiatric disorders. The patients were randomly assigned to imipramine (50 mg nightly), clonidine (0.1 mg twice daily), or placebo. A benefit was seen only with imipramine, which reduced the frequency of chest pain in patients with MVA by approximately 50 percent. The psychiatric profile during treatment improved in all groups, and the benefit was seen in both males and females. In a separate, smaller crossover randomized controlled trial in 18 females with persistent angina, adding imipramine for five weeks resulted in lower angina scores [92]. In both studies, females reported a high burden of side effects with imipramine [91,92], which may have prevented any apparent improvement in quality of life.
●Metformin – In patients with MVA and metabolic syndrome or pre-/diabetes, metformin may be particularly helpful. There is no standard dosing regimen for metformin in MVD treatment. Studies have used a dose of 500 mg twice a day; we use 1 g daily. We would use it if there were persistent angina on initial therapy plus ranolazine. However, we do not feel there is sufficient evidence to support its widespread use [93]. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Prevention of type 2 diabetes' and "Prevention of type 2 diabetes mellitus", section on 'Metformin'.)
Other therapy — A subset of patients will not respond to general measures, initial, and/or combination therapy. In this case, the following medications have been useful in treating MVA but have little published evidence to support their use, and in the case of hormone replacement therapy, the risks may outweigh benefit.
●Sildenafil – (A phosphodiesterase 5 inhibitor) 25 mg daily has been used for relief of symptoms in patients with MVA when all other therapies have failed [94]. This intervention requires further study, but we consider it for treatment in refractory angina cases.
●Hormone replacement therapy – Studies of hormone replacement therapy (HRT) have shown no definite cardioprotective effect, and, overall, HRT appears to increase the risk of coronary disease, stroke, venous thromboembolism, and breast cancer (see "Menopausal hormone therapy and cardiovascular risk").
We do not routinely recommend HRT in postmenopausal females with MVA. However, there appears to be an association between anginal symptoms and estrogen deficiency in some women with postmenopausal symptoms and MVA. In these select women, it is reasonable to have a shared decision-making discussion about HRT between patient and providers with expertise in this area (either gynecologist or endocrinologist).
Management of refractory angina — Patients who have inadequate response to the therapy above should be referred for confirmatory testing as described if not yet done. (See 'Additional invasive testing' above and 'Noninvasive testing' above.)
In the United States and elsewhere, many patients who present with anginal-quality chest pain and have no significant epicardial coronary artery do not undergo additional invasive confirmatory testing. A lack of expertise or equipment is often the explanation.
For patients who do not respond to treatment aimed at MVA, we recommend referring these patients to medical centers where these intracoronary tests can be performed or where a positron emission tomography scan and/or a cardiac magnetic resonance image perfusion scan are available to get a better understanding of the mechanism of MVA responsible for symptoms in a given patient. (See 'Additional invasive testing' above and 'Noninvasive testing' above.)
●Spinal cord stimulation – For patients in whom the diagnosis of MVA is confirmed and who have persistent unacceptable angina, we refer patients for evaluation for spinal cord stimulation. Spinal cord stimulation has been successful in the treatment of refractory angina due to coronary heart disease [95]. Spinal cord stimulation also improves angina and increases exercise tolerance in patients with refractory angina and normal coronary arteries [96]. (See "New therapies for angina pectoris", section on 'Spinal cord stimulation'.)
Other possible therapies for refractory angina with mixed or limited evidence:
●Enhanced external counter-pulsation (EECP) – This therapy is U S Food and Drug Administration approved for treatment of angina and used in some refractory MVA cases in the United States. EECP is not recommended by the National Institute for Health and Care Excellence in United Kingdom [97]. (See "New therapies for angina pectoris", section on 'External counterpulsation'.)
●Coronary sinus reduction – This surgical device has been studied for relief of refractory angina in patients with obstructive coronary disease; however, it has not been extensively tested in MVA. (See "New therapies for angina pectoris", section on 'Coronary sinus reducing device'.)
In a preliminary study of eight patients, coronary sinus reduction was effective in reducing angina, increasing exercise tolerance, and improving ischemia on myocardial perfusion imaging tests [98]. However, larger randomized studies are needed prior to recommending this therapy for patients with MVA and refractory angina.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic coronary syndrome".)
SUMMARY AND RECOMMENDATIONS
●Definition and epidemiology – Microvascular angina (MVA) refers to angina-like symptoms or ischemia in patients with normal coronary arteries. Patients with MVA are presumed or found to have microvascular dysfunction. (See 'Definitions' above.)
Compared with patients with obstructive coronary artery disease (CAD), patients with MVA are typically younger at the time of presentation, are more often female, and have a higher prevalence of anxiety and depression. (See 'Epidemiology' above.)
●Cardiovascular risk – Most patients with MVA have a higher burden of classic cardiovascular disease (CVD) risk factors and are at higher risk of major adverse cardiac events compared with similar patients without MVA. (See 'Prognosis' above.)
●Clinical features
•In half of patients, MVA chest pain is similar to classic angina pectoris. The pain may be precipitated by effort but may also occur at rest, particularly in the presence of coronary microvascular spasm as a pathogenic mechanism.
•Other patients have chest pain and/or dyspnea thought to be noncardiac, which may be severe and debilitating to a point where it affects daily activities.
•The duration of episodes of MVA is often prolonged compared with effort angina.
•Exercise capacity is often reduced in microvascular disease (MVD). (See "Approach to the patient with suspected angina pectoris", section on 'Symptoms' and 'Clinical presentation' above.)
●Diagnosis – The diagnosis of MVA is considered after coronary angiography has found that obstructive CAD is not the likely cause of chest pain. The diagnosis is definitively made by documentation of abnormal coronary microvascular response to functional testing with the reproduction of symptoms. In some patients, the diagnosis is made clinically. We assume that vasoconstriction is present in patients with rest angina or mixed rest/effort angina. (See 'Our approach' above.)
Diagnostic testing includes invasive and noninvasive testing aimed at detecting low coronary flow reserve, provoked microvascular spasm, and microvascular endothelial dysfunction. (See 'Diagnostic evaluation' above.)
●Management – The management of patients with confirmed or highly suspected MVA is depicted in a practical algorithm (algorithm 1).
•General measures – For all patients with MVA, we suggest prescribing sublingual nitroglycerin (NTG) (Grade 2C), which can be used for prevention or treatment of angina. For patients with effort angina, we also use an NTG patch prior to activity. Long-acting NTG can be tried but is not very effective for MVA treatment. We aggressively modify atherosclerotic cardiovascular disease (ASCVD) risk factors in particular, aggressively treating hypertension (ACE inhibitor is the preferred agent), secondary ASCVD prevention (where appropriate), and exercise. (See 'Goals of treatment' above.)
•Initial therapy for effort angina – For patients with MVA who have unacceptable effort-induced angina after one month of general measures, we suggest initial treatment with a beta blocker rather than other therapies (Grade 2C). We start with metoprolol succinate 50 mg daily. Calcium channel blockers are a reasonable first choice for patients with an intolerance to beta blockers. (See 'Initial therapy for effort angina' above.)
•Initial therapy for rest or mixed angina – For patients with MVA with rest or mixed angina or documented vasoconstriction and who have unacceptable angina after one month of general measures, we suggest adding a calcium channel blocker (Grade 2C).
•Combination therapy – For patients with persistent angina on initial therapy, we use combination therapy (ie, addition of beta blocker or calcium channel blocker). If there is persistent angina, we next add ranolazine and/or ivabradine. For patients with persistent angina, we next add therapy based on patient comorbidities. (See 'Combination therapy for persistent symptoms' above.)
-For patients with depression or hyperalgesia, we add imipramine.
-For patients with metabolic syndrome or prediabetes, we add metformin.
•Other medications – Sildenafil is an option for treatment of MVA though evidence of efficacy is not robust. (See 'Other therapy' above.)
-We do not routinely use hormone replacement therapy (HRT) in postmenopausal women with MVA. (See 'Other therapy' above and "Menopausal hormone therapy and cardiovascular risk".)
•Refractory angina – If all other therapies do not yield adequate treatment of MVA, a definitive diagnosis should be pursued if it has not been done, and spinal cord stimulation can be tried. (See 'Management of refractory angina' above.)
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