Ischemia with no obstructive coronary arteries (INOCA) refers to myocardial ischemia with stable or unstable anginal symptoms in the setting of normal or nonobstructive coronary arteries.¹ Coronary microvascular dysfunction (CMD) and epicardial coronary artery spasm are pathophysiologic mechanisms of INOCA and are diagnosed in up to four in five patients undergoing invasive evaluation for suspected INOCA.^2-6

Patients with INOCA are often misdiagnosed as having symptoms of noncardiac origin, as traditional stress tests have low sensitivity for diagnosing CMD⁷ and diagnosis of vasospasm often requires acetylcholine provocation.⁸ As CMD and epicardial spasm are associated with adverse long-term prognosis in patients without obstructive coronary artery disease (CAD),^9-15 the diagnosis of these INOCA endotypes should be considered in patients with anginal symptoms. Furthermore, stratified medical therapy based on diagnosis of microvascular and/or vasospastic angina has demonstrated improved angina and quality of life in patients with INOCA.¹

The Coronary Vasomotor Disorders International Study (COVADIS) study group was established in 2012 to develop international standards for the diagnostic criteria of microvascular and vasospastic angina (Table),^17,18 now used in national and European guidelines.^19,20 The 2021 ACC/AHA chest pain guideline adopted these definitions and proposed a diagnostic evaluation pathway for patients with stable chest pain and suspected INOCA (Figure), including noninvasive and invasive testing strategies.¹⁹ Test selection should be guided by local availability and expertise.

Noninvasive Testing of CMD

Clinical noninvasive diagnosis of CMD relies on identification of impaired coronary flow reserve (CFR) in the absence of flow-limiting CAD. Impaired CFR, calculated as the ratio of hyperemic to rest coronary blood flow (or myocardial blood flow), reflects flow abnormalities within the epicardial coronary arteries and microvasculature.^21,22 Maximal hyperemia is induced with dipyridamole, adenosine or regadenoson. Caffeine and vasodilating medications are withheld for 24-48 hours prior to testing to avoid interference with pharmacologic stress. CMD can be measured by positron emission tomography (PET), myocardial flow reserve (MFR), cardiac magnetic resonance (CMR), myocardial perfusion reserve (MPR) and Doppler echocardiography coronary flow velocity reserve (CFVR).

Positron Emission Tomography

PET quantification of MFR has been highly validated in animals and humans, with standardized protocols and well-established reproducibility.²³ Commonly used tracers are 82Rb-chloride and 13N-ammonia. Quality control of dynamic images and time-activity curves are critical, and list-mode acquisition is recommended for reconstruction of static, gated and dynamic datasets.²³ Mean reference values for MFR in healthy young participants undergoing stress PET are 4.07 (for 82Rb PET) and 3.54 (for 13N-ammonia PET).²³ Risk factors such as diabetes, hypertension, age, obesity and smoking may decrease MFR in the absence of obstructive CAD.²⁴

Regardless of sex, PET MFR < portends increased risk of major adverse cardiac events (MACE) in patients without obstructive CAD9,²⁵ and appears to be a stronger predictor of cardiovascular mortality than hyperemic myocardial blood flow (MBF) in patients with no obstructive CAD.²⁶ Compared with patients with MFR >2, PET evidence supports that prognosis is worse regardless of whether MFR is low due to impaired hyperemic MBF or high resting MBF, the latter being more common among women than men.²⁶

Cardiac Magnetic Resonance

CMR measures of MPR and its index (MPRI) have emerged as diagnostic and prognostic measures of CMD.²⁷ Myocardial perfusion CMR should be acquired using standardized protocols under pharmacologic stress, with first-pass acquisition during rest and pharmacological stress.²⁸

Quantitative evaluations require dual bolus, dual contrast sequences or other algorithms to correct for nonlinearity of signal intensity, correction for baseline signal differences, and efficient motion correction.

Standards for semiquantitative or fully quantitative methods have not been well defined due to availability of many different sequences and postprocessing parameters. Semiquantitative MPRI is calculated as the relative upslope of stress to rest, with relative upslope defined as the ratio between the maximum upslope of the first-pass myocardial perfusion time-intensity curve divided by the maximum upslope of the first-pass left ventricular cavity time-intensity curve.

Prior studies have demonstrated a semiquantitative MPRI <1.84 and quantitative MPR <2.19 to be thresholds with high sensitivity and specificity for invasively determined CMD.^29,30 Both MPRI and MPR have been shown to provide risk stratification in patients with INOCA. MPRI is an independent predictor of MACE in patients with INOCA, with an MPRI ≤1.47 as the optimal prognostic threshold.³¹

Recently, a large quantitative CMR perfusion mapping study demonstrated MPR to be independently associated with mortality and MACE in patients with INOCA.³² CMR is a useful diagnostic tool in the evaluation of patients with myocardial infarction in the setting of no obstructive coronary arteries (MINOCA), particularly when acquired early after acute MINOCA.^33-35

Doppler Echocardiography

Transthoracic Doppler echocardiography can assess CMD by measuring CFVR in the large coronary arteries. Coronary flow velocity measurements are typically performed in the mid-distal left anterior descending (LAD) due to its position near the chest wall. Using foreshortened two- and three-chamber views to locate the vessel, pulsed-wave Doppler is then used to measure mean or maximum diastolic coronary flow velocities averaged over three heart beats.^36,37

CFVR is calculated as the ratio of stress to rest diastolic coronary flow velocity. Measurements including the surface anatomic position, degree of rotation of the transducer and LAD position should be carefully documented to ensure velocity measurements are in the same LAD segment at rest and hyperemia.

In a large study of women with suspected INOCA, CFVR predicted MACE, with an optimal cut-off value of CFVR <2.25 in the LAD.³⁸

Invasive Coronary Function Testing of CMD, Vasospasm

Invasive coronary function testing is recommended for select patients with frequent or persistent stable angina and suspected INOCA as an alternative or adjunct to noninvasive testing.^19,20 Similar with noninvasive testing, caffeine and vasodilating medications are withheld for 24-48 hours prior to avoid interference. As visualization of the microvasculature is beyond the resolution of angiography, its function is interrogated using pharmacologic agents, commonly adenosine and acetylcholine. While acetylcholine provocation is not commonly performed, it has been demonstrated to be safe with a low incidence of major complications.^2,5,8,39,40

Coronary Flow Reserve

CFR can be invasively assessed with two techniques: 1) flow velocity using a Doppler wire, and 2) thermodilution using a pressure-temperature sensor guidewire. In the Doppler method, the Doppler wire is positioned in a straight segment of the coronary artery until a stable and high-quality Doppler flow signal is obtained. Doppler peak flow velocities are then averaged over three consecutive heartbeats to derive average peak velocity. Intravenous or intracoronary adenosine is administered to achieve hyperemia.

Doppler-derived CFVR is the ratio between hyperemic average peak velocity and resting average peak velocity and has high correlation with coronary volumetric flow reserve.⁴¹ CFVR in response to intravenous adenosine infusion may result in lower values compared to intracoronary bolus injections of adenosine.⁴²

In the thermodilution method, an optimal and uniform saline bolus should be limited to 3-4 mL per injection.⁴³ Intravenous adenosine is administered to achieve hyperemia.

Thermodilution CFR is measured as the ratio of mean transit time for saline to pass between the proximal and distal sensors at rest and at hyperemia, has been validated in animals and humans,^44,45 and has modest correlation with Doppler CFVR.⁴³

CFR measurements in healthy asymptomatic participants are usually >3.0, indicating that coronary circulation can triple coronary blood flow when required.²¹ CFR is generally lower in women compared with men, possibly due to sex differences in resting coronary flow.^46,47

A CFR cutoff of <2.0 has been identified as significantly correlated with ischemia identified on SPECT imaging, with high sensitivity and specificity.^48,49 Therefore, this is often considered the threshold for abnormal microcirculatory function,^20,50 although recently a common threshold of <2.5 for both Doppler and thermodilution CFR has been proposed to optimize accuracy.⁴³ Among women with suspected INOCA, CFR <2.32 was found to be the best discriminating threshold for MACE.¹⁰

Index of Microcirculatory Resistance

A pressure sensor/thermistor-tipped wire is used to calculate the index of microcirculatory resistance (IMR) at maximal hyperemia during intravenous adenosine infusion.⁵¹ IMR is defined as the hyperemic mean distal pressure multiplied by hyperemic mean transit time. An IMR >25 is considered abnormal.⁵² IMR is specific to the microvasculature and is not affected by changes in patient hemodynamics.

Doppler-derived hyperemic microvascular resistance (hMR) is defined as the ratio between hyperemic mean distal pressure and hyperemic average peak velocity. An hMR >2.4 is considered abnormal.⁵³ The hMR correlates modestly with IMR and CFR.^47,54 Patients may have discordant CFR and IMR due to differences in resting flow.⁵⁵

Abnormal IMR in combination with low CFR has been associated with increased MACE in patients with INOCA, but an isolated elevated IMR did not portend worse outcomes.55

Epicardial and Microvascular Vasospasm

Epicardial and microvascular vasospasm may occur in the setting of smooth muscle hyperreactivity or endothelial dysfunction.^56-58 Provocation of vasospasm is performed with an intracoronary injection of incremental doses of acetylcholine in the right and left coronary arteries, each administered over at least 20 seconds.⁵³

Epicardial spasm is diagnosed when there is reduction in coronary diameter >90% following intracoronary acetylcholine with symptoms and ischemic electrocardiographic (ECG) changes. When angina and ischemic ECG changes occur without significant epicardial constriction (<90% reduction), then microvascular spasm is diagnosed.

Invasive provocative testing demonstrates that epicardial or microvascular spasm is highly prevalent in patients with suspected INOCA.⁵⁹ Epicardial spasm is associated with an increased hazard of myocardial infarction and repeat angiography, while microvascular spasm is associated with recurrent angina.¹⁴ As nitrates are much less effective in preventing microvascular spasm than epicardial spasm, acetylcholine rechallenge after administration of nitroglycerin may be helpful in diagnosing coexistent microvascular spasm in patients with epicardial spasm.⁶⁰

Coronary Endothelial Dysfunction

Although invasive coronary endothelial function testing is not mentioned in the ACC/AHA chest pain guideline,¹⁹ the diagnostic yield of coronary function testing is increased with additional endothelial function testing.⁶¹ While adenosine has partial endothelial effects,⁶² coronary endothelial dysfunction is typically defined as an attenuated increase or decrease in coronary blood flow (normal >50% increase) and coronary artery diameter (normal >5% dilation) in response to low dose acetylcholine.^3,5

While endothelial dysfunction may affect both epicardial and microvascular coronary arteries, coronary blood flow may be preserved or even increased in the setting of coronary epicardial vasoconstriction in response to acetylcholine, suggesting preserved microvascular endothelial function in the setting of epicardial coronary endothelial dysfunction.⁶³ Invasively determined coronary endothelial dysfunction portends increased MACE and mortality risk in patients with INOCA.^13,64

Future Considerations

Accumulating evidence demonstrates the clinical benefit of identifying pathophysiologic mechanisms for diagnosis, prognosis and tailored medical therapy in INOCA patients. The recent ACC/AHA chest pain guideline recommends considering invasive and noninvasive tools for the diagnosis of INOCA endotypes and to enhance risk stratification (class 2a).¹⁹ Widespread adoption of these tools requires standardized protocols and reporting tools, which are increasingly available. Future directions include clinical trials using these diagnostic strategies to investigate therapeutic advances and to determine optimal therapy for each INOCA endotype and impact on long-term cardiovascular outcomes.

This article was authored by Phillip R. Tacon, MD, internal medicine resident at Cedars-Sinai Medical Center, and Janet Wei, MD, FACC, assistant professor at the Cedars-Sinai Smidt Heart Institute and Biomedical Imaging Research Institute, all in Los Angeles, CA.

Special Engagement Spotlight Series: Small Vessel Impact on Angina and Ischemia

The diagnosis of coronary artery disease (CAD) has focused on the presence of obstructive epicardial CAD. Nonetheless, it is estimated that at least two in every five male and female patients with angina referred for elective coronary angiography have nonobstructive epicardial coronary arteries, with rates relatively higher in women.

Myocardial ischemia does not require the presence of obstructive coronary arteries. This is recognized in the recent ACC/American Heart Association guideline for chest pain, expanding the definition of CAD to include both obstructive and nonobstructive CAD. The new guideline includes a diagnostic pathway for evaluation of chest pain for those with evidence of myocardial ischemia but no obstructive coronary arteries (INOCA), often due to small vessel angina due to ischemia. Small vessel angina and ischemia is a common but heterogenous condition associated with elevated risk for cardiovascular events. Diagnostic criteria for the two primary mechanisms, small vessel coronary microvascular dysfunction (CMD) and vasospasm, have been established. The combination of microvascular angina and epicardial vasospastic angina is associated with a more adverse prognosis. These mechanisms can also occur in the setting of epicardial obstructive CAD, further impairing prognosis.

Patients with small vessel ischemia and angina can pose both a diagnostic and therapeutic challenge to cardiologists. Many patients struggle for years to have an accurate diagnosis made, due to lack of physician awareness and expertise along with limited availability of diagnostic testing.

With consideration of small vessel ischemia and angina now included within ACC/AHA evidence-based guidelines, improving quality of care to reduce adverse cardiac event risk and enhance quality of life for patients is critical.

Over the course of the next four issues of Cardiology, you will hear from Janet Wei, MD, FACC, on making the diagnosis in the catheterization laboratory and noninvasively, using new guidelines and expert consensus approaches to establishing small vessel ischemia. In addition, Cindy L. Grines, MD, FACC, will outline the limitations of PCI for proximal obstruction and why small vessel testing can enhance approaches to ischemia and angina. Also learn more about distal vessel abnormality in ischemic patients from Timothy D. Henry, MD, FACC, including the rationale and techniques for combining revascularization with other physical therapies such as enhanced external counter-pulsation for ischemia and angina relief. Carl J. Pepine, MD, MACC, will round out the series with a review of treatment options including up-to-date medical therapies for small vessel ischemia and angina and discuss ongoing randomized clinical trials for this enlarging group of patients.

The entire series will be available at ACC.org/Cardiology as the series rolls out.

This Spotlight Series of articles was developed by invited Guest Editor, C. Noel Bairey Merz, MD, FACC, a leading expert in small vessel disease. She is professor of cardiology, director of the Barbra Streisand Women's Heart Center, director of the Linda Joy Pollin Women's Heart Health Program and director of the Preventive and Rehabilitative Cardiac Center, all at the Cedars-Sinai Smidt Heart Institute, in Los Angeles, CA.

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