Beyond Structural Angiography: The Emergence of Functional Coronary Angiography*

Beltrame J, Tavella R, Zeitz C, et al. Beyond Structural Angiography. J Am Coll Cardiol. 2022 Jun, 79 (24) 2379–2382.


The evaluation of stable chest pain suspected to be cardiac in nature has traditionally involved the use of a screening noninvasive investigation, with invasive selective coronary angiography being the benchmark investigation. Moreover, if the noninvasive investigation implicates the presence of myocardial ischemia (ie, new ischemic electrocardiographic [ECG] changes, perfusion defect, or regional wall abnormality) and the invasive coronary angiogram shows no evidence of obstructive coronary artery disease (CAD), then the noninvasive investigation is considered a false positive and the patient receives a diagnosis of “noncardiac chest pain.” This issue involving noninvasive tests for myocardial ischemia has prompted the UK National Institute on Health and Care Excellence to recommend computed tomographic coronary angiography as the routine noninvasive investigation for stable chest pain with low to intermediate risk of CAD. Thus, in contemporary practice for the diagnosis of stable chest pain, the focus is on structural coronary angiography (either invasive or noninvasive angiography techniques), with noninvasive investigations for ischemia considered inaccurate despite providing different pathophysiological insights.

Beyond Structural Coronary Angiography

Using a structural coronary angiography approach as the benchmark investigation of chest pain, data from the National Cardiovascular Data Registry CathPCI Registry suggest that almost 60% of patients undergoing elective invasive coronary angiography do not have evidence of obstructive CAD (ie, no lesion ≥50%). Although this may reflect inappropriate use of this investigation, a more contemplative analysis is worthy of consideration. From a clinical perspective, this hazardous invasive procedure was warranted because the clinician was sufficiently concerned as to the presence of obstructive CAD. With its exclusion, the clinician can simply inform the patient that it is noncardiac chest pain and discharge the patient from the clinic. From a patient perspective, this hazardous procedure was warranted to identify whether the chest pain had a potentially life-threatening cardiac cause, yet the patient is now discharged with a diagnosis of noncardiac chest pain with no explanation provided as to the cause of the pain or the prognosis. However, studies have suggested that patients without obstructive CAD have an increased risk of death or myocardial infarction compared with the general population and a risk of ongoing chest pain at 12 months similar to that of individuals with obstructive CAD. Finally, from a biological perspective, standard structural coronary angiography does not exclude important coronary causes of chest pain, including macrovascular dysfunction (ie, epicardial coronary artery spasm) and microvascular dysfunction (ie, the resistance microvessels that are not visualized on angiography but may responsible for myocardial ischemic symptoms). These pathophysiological mechanisms may be responsible for the patient’s symptoms and can be readily addressed by undertaking functional coronary angiography immediately after structural coronary angiography, thereby excluding a coronary cause of the chest pain (Figure 1).

Figure 1: Structural and Functional Coronary Angiography in Comprehensive Chest Pain Evaluation
Invasive structural coronary angiography is the benchmark clinical investigation for obstructive atherosclerotic coronary artery disease (CAD). In the absence of obstructive atherosclerotic CAD, functional coronary angiography provides the benchmark diagnosis for coronary macrovascular (vasospastic angina) and microvascular (microvascular angina) dysfunction. ACh = acetylcholine; IC = intracoronary; IV = intravenous; IVUS = intravascular ultrasound; OCT = optical coherence tomography; TIMI = Thrombolysis In Myocardial Infarction.

Evolution of Functional Coronary Angiography

As summarized in Figure 1, comprehensive assessment of potential coronary causes of chest pain requires both structural and functional coronary angiography. In standard structural coronary angiography, the focus is on assessing for a tight angiographic stenosis, which can be further investigated with intravascular ultrasonography or optical coherence tomography. Careful analysis of the angiographic images should ensure that subtotally or totally occluded vessels and muscle bridges are not overlooked. Routine diagnostic angiography may also provide insight into microvascular dysfunction by the presence of the coronary slow flow phenomenon.

Limited functional coronary angiography is being increasingly practiced in elective angiography, with fractional flow reserve (FFR) being used to confirm whether intermediate lesions are functionally obstructive in nature. Inasmuch as the FFR investigation may routinely involve the administration of intracoronary nitrates, prenitrate and postnitrate images can reveal the fixed or dynamic nature of the lesion. Although resolution of a tight stenosis after intracoronary nitrates confirms the presence of spontaneous coronary artery spasm, patients with vasospastic angina seldom experience a spontaneous episode during elective angiography and typically require provocative spasm testing with intracoronary acetylcholine (icACh) to diagnose this potentially life-threatening disorder. This procedure is extensively described in the literature, typically involving incremental administration of icACh boluses (>20 seconds) into the left and right coronary arteries with angiogram images recorded after each dose to ascertain whether there is diagnostic angiographic coronary spasm (>90% constriction). This approach should be delineated from icACh infusions over 2-3 minutes, which uses lower doses of icACh and is designed to assess endothelial function.

The use of icACh is useful not only in the diagnosis of macrovascular (epicardial artery) spasm but also for microvascular spasm, where the icACh induces chest pain and ischemic ECG changes in the absence of epicardial spasm and are thus attributed to the microvessels. This form of microvascular dysfunction reflects an inappropriate microvascular constrictor response to icACh (Figure 1). It may differ from the conventional definition of microvascular dysfunction, where there is an inadequate microvascular vasodilatory response to a standard hyperemic stimulus (eg, adenosine). Hence, a comprehensive functional coronary angiography study requires the evaluation of coronary blood flow (Doppler or thermodilution wire) in combination with intracoronary pressure measurements to enable the assessment of coronary microvascular resistance (index of microvascular resistance or hyperemic microvascular resistance). Thus, a reduced blood flow response or elevated microvascular resistance after intravenous or intracoronary adenosine is a diagnostic marker of coronary microvascular dysfunction.

To summarize, contemporary practice in the evaluation of stable chest pain suspected to be cardiac in nature should involve structural coronary angiography to assess for obstructive CAD; if no cause is identified, then functional coronary angiography with a comprehensive assessment of macrovascular and microvascular dysfunction is performed (Figure 1). The utility of functional coronary angiography with a corresponding stratified treatment program has been assessed in the CorMicA study and shown to improve patient symptomatic status at 12 months. Consequently, these procedures have been recommended in current clinical guidelines.

Safety of Functional Coronary Angiography

In spite of the above-mentioned considerations, comprehensive functional coronary angiography is seldom performed in contemporary clinical practice and is largely confined to specialized centers. Interventional cardiologists are accustomed to undertaking FFR measurements using intravenous adenosine and therefore are comfortable with coronary microvascular dysfunction assessment, although they require a specialized wire and software that measures not only intracoronary pressure but also blood flow. The main obstacle to performing comprehensive functional coronary angiography is concern over the safety of provocative spasm testing. After the initial description by Prinzmetal of spontaneous variant angina episodes (characterized by transient ST-segment elevation), bedside testing for coronary artery spasm with incremental doses of intravenous ergonovine and ECG monitoring was developed in the 1970s. This bedside approach was precarious because: 1) ST-segment elevation is a relatively late marker of coronary spasm; 2) the incremental dose may have been given in haste before the full effect of the previous dose was realized; and 3) the therapeutic response to the induced spasm was limited to the judicious use of sublingual nitrates (because calcium-channel blockers were still in development). Consequently, this bedside approach precipitated acute myocardial infarcts and even deaths, causing the technique to fall into disrepute. Subsequently, Japanese investigators developed an angiography-based approach using icACh. Despite the invasive approach, this was considerably safer because: 1) icACh has a very short half-life; 2) the coronary spasm could be immediately imaged on angiography (before no or minimal ST-segment elevation evolved); and 3) the coronary spasm could be promptly treated with intracoronary nitrates.

In this issue of the Journal of the American College of Cardiology, Takahashi et al report a well-structured systematic review and meta-analysis addressing the safety of icACh testing. Moreover, they were able to delineate those studies focusing on endothelial function testing with an icACh infusion in comparison with studies using icACh boluses. Having produced the largest review examining the safety of icACh spasm provocation, the authors noted a 0.5% risk of major complications (defined as death, ventricular tachycardia or fibrillation, or shock requiring resuscitation) with no recorded deaths. Furthermore, the malignant ventricular arrhythmias associated with induced spasm may provide insights into a patient’s consequential risks with vasospastic angina (particularly if it has not been diagnosed). Minor procedural complications occurred in 3.3% of patients and included paroxysmal atrial fibrillation, ventricular ectopic beats, transient hypotension, and icACh-induced bradycardia requiring intervention. The icACh-induced bradycardia is an expected physiological response to icACh (particularly with right coronary artery injection); therefore, many institutions insert a temporary venous pacemaker before right coronary artery provocation testing.

Overall, as the authors conclude, icACh provocative spasm testing is a safe procedure and is thus reassuring in relation to functional coronary angiography. Hopefully this study will be the catalyst to reassure clinicians and prompt the widespread adoption of functional coronary angiography, thereby facilitating the appropriate diagnosis and treatment of coronary vasomotor disorders. Furthermore, this review highlights that these methods can be safely used in patients with acute coronary syndromes who do not have obstructive CAD and thus should be considered in the assessment of hemodynamically stable patients with myocardial infarction with nonobstructive coronary arteries (MINOCA).

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.


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Authors: John F. Beltrame, BMBS, PhD Rosanna Tavella, PhD Christopher J. Zeitz, MBBS, PhD

Publication: Journal of the American College of Cardiology

Publisher: Elsevier

Date published: June 13th, 2022


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