Editor's Note: Below is an excellent review of an important topic that is growing in recognized significance regarding chest pain/ischemic syndromes occurring particularly in women in the absence of significant obstructive coronary artery disease (CAD). This article succinctly outlines the science underlying this evolving ischemic syndrome. This is important reading for all who are involved in angina management regardless of invasive or noninvasive.
George W. Vetrovec, MD, MACC

When invasive coronary angiography reveals obstructive CAD in patients with angina, there are well-established guidelines and diagnostic algorithms for the management of these patients. However, when the angiogram does not reveal obstructive CAD, the subsequent evaluation and management is not defined and highly variable among clinicians. This article addresses the utility of undertaking invasive coronary hemodynamic studies in patients with angina with nonobstructive coronary arteries, specifically focusing upon 1) why these investigations should be performed, 2) what measures should be assessed, 3) how the findings impact management, and 4) where the knowledge gaps are for future research.

Despite the absence of management guidelines, angina with nonobstructive coronary arteries is highly prevalent, accounting for over 60% of elective diagnostic angiograms performed.¹ The finding is particularly prevalent among women and contributes to the challenges in managing women's heart disease. To some clinicians, the finding of angina with nonobstructive coronary arteries on angiography is interpreted as an absence of cardiac disease and thus a diagnosis of "noncardiac chest pain." However, since the advent of angiography, astute clinicians have appreciated that some of these patients have an ischemic basis for their chest pain.

Why Perform Invasive Coronary Hemodynamic Studies in Patients With Angina With Nonobstructive Coronary Arteries?

Coronary hemodynamic studies assess the vasomotor function of the coronary circulation, typically evaluating both large coronary artery and microvascular function. The studies' utility in patients with angina with nonobstructive coronary arteries includes providing 1) a comprehensive diagnostic evaluation, 2) direction on further management, and 3) prognostic insights that outweigh the risks of invasive testing.²

Comprehensive Diagnostic Evaluation

Patients seek medical attention to identify the cause of their chest pain and in particular if it is cardiac in nature. Coronary angiography excludes significant obstructive CAD but does not exclude functional coronary disorders,³ so that cardiac evaluation of the chest pain is incomplete in patients with angina with nonobstructive coronary arteries in the absence of coronary hemodynamic assessment.

Impact on Management

In the absence of coronary hemodynamic assessment, the patient may be misdiagnosed and thus inappropriately managed. In the past, women with evidence of myocardial ischemia on exercise testing were considered to have a "false positive exercise test" in the absence of obstructive CAD and thus dismissed without any further cardiac follow-up or therapy. Cardiac hemodynamic testing would not only provide the supporting evidence that many of these women had coronary microvascular dysfunction but also ensure that they were appropriately managed.

In addition to avoiding misdiagnosis and thus inappropriate management, coronary hemodynamic testing provides important directions into the type of therapy that should be initially instigated. By delineating large vessel coronary dysfunction (vasospastic angina) from coronary microvascular dysfunction (although the two may coexist), the established therapies for vasospastic angina may be promptly introduced⁴ and thus minimize its associated morbidity and mortality. In contrast, coronary microvascular disorders have a more heterogeneous etiology so that first line therapy is more empiric.

Prognostic Insights

The mortality risk of vasospastic angina is well-established, as are the benefits of calcium channel blockers for this condition. Coronary microvascular disorders have a guarded prognosis particularly in women, whereas the role of endothelial dysfunction appears to be an important determinant to prognosis.

What Coronary Hemodynamic Measures Should Be Assessed in Patients With Angina With Nonobstructive Coronary Arteries?

Coronary hemodynamic assessment varies considerably between laboratories because there is no established protocol. Intuitively, comprehensive coronary hemodynamic assessment should involve the evaluation of both coronary large vessel and microvascular vasomotor function. Thus we propose that comprehensive coronary hemodynamic assessment should involve 1) provocative coronary artery spasm testing, 2) coronary microvascular function assessment, and 3) coronary endothelial function testing.

Provocative Coronary Spasm Testing

This investigation identifies patients with a predilection to epicardial coronary artery spasm and is often required in the diagnosis of vasospastic angina. It has been utilized for over 30 years, but only recently has there been an international consensus on its methodology and interpretation.⁵ Figure 1 describes a clinical case of a patient with angina with nonobstructive coronary arteries with a positive provocative spasm test.

Figure 1. Vasospastic Angina Case

Case History 66-year-old woman with 6-month history of recurrent episodes of rest angina Cardiovascular risk factors are hypertension, dyslipidemia, and ex-smoker Noninvasive Investigations No evidence of ischemia on treadmill exercise test Coronary Angiography Angina with nonobstructive coronary arteries (no significant coronary stenoses) Coronary Microvascular and Endothelial Function Assessment Unremarkable Provocative Coronary Spasm Testing Vasoactive medications withheld for 48 hours prior to testing Temporary basing wire inserted after baseline angiographic views Incremental intracoronary acetylcholine (left coronary artery [LCA] = 25, 50, & 100 mcg; right coronary artery [RCA] = 25 & 50 mcg) administered as boluses over 20 secs while monitoring chest pain, electrocardiogram changes, and angiogram. Acetylcholine chloride (available as ophthalmic preparation 20 mg) is an off-label use. Test ceased after administering 50 mcg acetylcholine into LCA (A), whereupon patient experienced usual chest pain, ST depression in V5-6, and subtotal distal left anterior descending (LAD) occlusion. Intracoronary glyceryl trinitrate 150 mcg bolus administered to LCA (B). Diagnosis Vasospastic angina Management Commence diltiazem 240 mg/day

Coronary Microvascular Function Assessment

There are multiple approaches in the diagnosis of coronary microvascular dysfunction, and the optimal method is still to be determined. A simple initial approach is evaluating the presence of delayed epicardial coronary artery opacification (Thrombolysis in Myocardial Infarction frame count), which reflects an increased microvascular resistance. This finding is consistent with the coronary slow flow phenomenon (Figure 2).

Figure 2. Microvascular Dysfunction Case

Case History 49-year-old woman with 6-month history of recurrent episodes of angina at rest and on exertion No cardiovascular risk factors Noninvasive Investigations No evidence of ischemia on treadmill exercise test Normal endoscopy, esophageal motility studies, and biliary ultrasound Coronary Angiography Angina with nonobstructive coronary arteries (no significant coronary stenoses) Coronary slow flow (Thrombolysis in Myocardial Infarction frame count for LAD = 58 frames; normal reference range < 27 frames) Coronary Microvascular Function Testing Combined Doppler/pressure wire inserted into mid LAD artery Obtain stable baseline recording Intravenous adenosine 140 mg/kg infusion over 2 minutes, recording hyperemic parameters Parameters assessed: Coronary flow reserve (CFR), hyperemic microvascular resistance Findings (Figure 2): CFR = 2.1 (normal reference range ≥ 2.5); hyperemic microvascular resistance = 2.7 (normal reference range < 2.0) Conclusion: Increased microvascular resistance with impaired CFR Endothelial Function Assessment Intact endothelium-dependent vasodilation Provocative Coronary Spasm Testing No inducible spasm at maximal doses in LCA and RCA Diagnosis Coronary slow phenomenon Management Commence atenolol 50 mg daily Combo map showing coronary hemodynamic parameters at peak hyperemia

CFR is a well-established marker of coronary microvascular dysfunction, with an impaired hyperemic vasodilator response (i.e., CFR < 2.5) being fundamental in the diagnosis of microvascular angina. Limitations in the CFR methodology have recently prompted the development of microvascular resistance indices.

Microvascular resistance indices include the index of microvascular resistance derived from a pressure wire with thermodilution capabilities and the hyperemic microvascular resistance index obtained from a pressure wire with coronary Doppler capabilities. These have been validated in animal models and found to be abnormal in over 20% of patients with angina with nonobstructive coronary arteries.⁶ In Figure 2, it is noteworthy that the patient has angiographic evidence of microvascular dysfunction (the coronary slow flow phenomenon), an abnormal CFR, with an increased microvascular resistance.

Coronary Endothelial Function Testing

Multiple studies have demonstrated that an impaired coronary vasodilator response to acetylcholine is associated with an increased risk of cardiac events in patients with angina with nonobstructive coronary arteries. Although acetylcholine is the most frequently used endothelium-dependent vasodilating agent for this assessment, the dose and method of acetylcholine administration differs markedly to that used in provocative spasm testing.⁷

In Figure 3, a woman with recurrent chest pain with angina with nonobstructive coronary arteries has no inducible large vessel spasm, intact coronary microvascular resistance, but evidence of an impaired coronary endothelium-dependent vasodilation. Accordingly, this patient would have a guarded prognosis, and efforts to restore the coronary endothelium-dependent vasodilation should be considered.

Figure 3. Endothelial Dysfunction Case

Case History 59-year-old woman with 1-year history of exertional chest pressure and shortness of breath Cardiovascular risk factors are preeclampsia, pre-diabetes, and hyperlipidemia Noninvasive Investigations No evidence of ischemia or pulmonary hypertension on bicycle exercise stress echocardiogram Coronary Angiography Angina with nonobstructive coronary arteries (no significant coronary stenoses) Coronary Microvascular Function Testing Combined Doppler/pressure wire inserted into mid LAD artery Obtain stable baseline recording Intracoronary adenosine 18 mcg over 5 seconds, recording hyperemic parameters Parameters assessed: CFR Findings: CFR = 2.8 (normal reference range ≥ 2.5) Conclusion: normal non-endothelial-dependent function Endothelial Function Assessment Incremental intracoronary acetylcholine (0.364 mcg [10-6 mol/L], 36.4 mcg [10-4 mol/L]) administered over 3 minutes while monitoring chest pain, electrocardiogram changes, and angiogram. Findings: 10% coronary artery vasoconstriction (normal reference range = any dilation) Conclusion: Impaired endothelium-dependent vasodilation Provocative Coronary Spasm Testing No inducible spasm with intracoronary acetylcholine 100 mcg in the LCA Normal coronary artery dilation >20% after intracoronary nitroglycerin 200 mcg Diagnosis Impaired endothelium-dependent vasodilation Management Commence angiotensin converting enzyme inhibitor and statin, exercise training, and enhanced external counterpulsation

How Does This Impact Management?

Firstly, identifying the presence of a functional coronary disorder has a major impact on subsequent management because the patient can be provided with an explanation for his or her symptoms. This often allays the patient's concerns that "the symptoms are merely in their mind" and avoids misdiagnoses such as "cardiac neuroses."

Secondly, the findings from comprehensive coronary hemodynamic assessment provide a direction for ongoing therapy. If inducible coronary spasm is identified, then calcium channel blockers should be introduced because these have been shown to reduce cardiovascular events in patients with vasospastic angina. If coronary microvascular dysfunction is detected, then coronary microvascular vasodilator therapies should be considered. If coronary endothelial dysfunction is demonstrated, then therapies that restore endothelial function should be considered.

Where Are the Knowledge Gaps?

Considerable efforts are required in understanding and managing functional coronary vasomotor disorders. The Coronary Vasomotion Disorders International Study Group (COVADIS) has been established to internationally unify the nomenclature of these heterogeneous disorders thereby allowing collaborative efforts to investigate the pathophysiology and management of these disorders. Important steps have been made with vasospastic angina⁵ and allowed the establishment of an international coronary spasm registry.

In contrast, coronary microvascular disorders are a heterogeneous group of conditions, and, unlike vasospastic angina, there is no single diagnostic investigation for these disorders. Discussions at the COVADIS Summit have begun to address some of these issues and should be aided by the establishment of an international coronary microvascular disorders registry. With improved clinical characterization of these patients and a better understanding of the underlying pathophysiological mechanisms, advances in effective therapies for these disorders should be achieved.

References

1. Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elective coronary angiography. N Engl J Med 2010;362:886-95.
2. Wei J, Mehta PK, Johnson BD, 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. JACC Cardiovasc Interv 2012;5:646-53.
3. Di Fiore DP, Beltrame JF. Chest pain in patients with 'normal angiography': could it be cardiac? Int J Evid Based Healthc 2013;11:56-68.
4. Beltrame JF, Crea F, Kaski JC, et al. The Who, What, Why, When, How and Where of Vasospastic Angina. Circ J 2016;80:289-98.
5. Beltrame JF, Crea F, Kaski JC, et al. International standardization of diagnostic criteria for vasospastic angina. Eur Heart J 2015 Aug 4 [Epub ahead of print].
6. Lee BK, Lim HS, Fearon WF, et al. Invasive evaluation of patients with angina in the absence of obstructive coronary artery disease. Circulation 2015;131:1054-60.
7. Sheikh AR, Zeitz C, Beltrame JF. Letter by Sheikh et al Regarding Article, "Invasive Evaluation Of Patients With Angina in the Absence of Obstructive Coronary Artery Disease". Circulation 2015;132:e242.

Keywords: Acetylcholine, Adenosine, Angina Pectoris, Variant, Angina, Unstable, Angiotensin-Converting Enzyme Inhibitors, Calcium Channel Blockers, Coronary Angiography, Coronary Circulation, Coronary Stenosis, Coronary Vasospasm, Coronary Vessels, Counterpulsation, Diabetes Mellitus, Diagnostic Errors, Diltiazem, Dyslipidemias, Dyspnea, Electrocardiography, Endoscopy, Endothelium, Hyperemia, Hyperlipidemias, Hypertension, Hypertension, Pulmonary, Microvascular Angina, Neurocirculatory Asthenia, Nitroglycerin, No-Reflow Phenomenon, Pre-Eclampsia, Prognosis, Risk Factors, Spasm, Thermodilution, Vasoconstriction, Vasodilation, Vasodilator Agents

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