Expanding diagnostic horizons: the role of multivessel coronary function testing in angina with non-obstructive coronary arteries

Coronary artery spasm (CAS) has been suspected to play a role in the development of angina with non-obstructive coronary arteries (ANOCA) with up to 60% of these patients having epicardial spasms and up to 40% of patients having microvascular spasms (1). When these microvascular spasms occur at rest, or the microvasculature is unable to provide adequate perfusion during stress, coronary microvascular dysfunction (CMD) develops which has also been described as a pathophysiological mechanism of ANOCA (2).

A positive diagnosis of CAS is of paramount importance to guide treatment using nitrates, calcium channel blockers and beta blockers (3). Missing diagnoses of CAS and therefore, ANOCA, have long-term potential implications on patients through diminished quality of life and increased risk for adverse cardiovascular events such as myocardial infarction, left ventricular impairment and sudden cardiac death, especially in women (4,5).

In the article titled “Multivessel Coronary Function Testing Increases Diagnostic Yield in Patients with Angina and Nonobstructive Coronary Arteries”, the authors report results from a multicenter observational study evaluating the diagnostic accuracy and yield of multivessel vs. single-vessel invasive coronary function testing (CFT) in patients with ANOCA (6). ANOCA is defined as angina in patients with <50% epicardial stenosis, with an overall prevalence of about 40% in patients with stable angina undergoing invasive coronary angiography (ICA) (2,7).

In this study, patients suspected of coronary vasomotor dysfunction underwent diagnostic ICA to confirm the non-obstructive status of their coronary arteries, defined as having a visual stenosis of less than 50%, a resting full-cycle ratio of ≥0.89, and/or a fractional flow reserve (FFR) of ≥0.80. In the absence of significant stenosis, CFT was performed. The choice of vessels for testing was at the operator’s discretion, and coronary vasoreactivity was assessed using acetylcholine (ACH) provocation. Incremental doses of ACH were injected, and cine images were captured to evaluate changes in coronary diameter. If CAS was induced, accompanied by reproducible symptoms and ST-segment changes, the test was considered positive. Coronary physiology assessment focused on key parameters such as hyperemic mean proximal pressure, distal pressure, hyperemic mean transit time (TmnH) (assessed through thermodilution curves), FFR [calculated as distal coronary-to-aortic pressure ratio (Pd/Pa) during hyperemia], coronary flow reserve (CFR) calculated as resting mean transit time (TmnR)/TmnH, and index of microcirculatory resistance (IMR), calculated as Pd × TmnH.

The study found that multivessel CFT altered the final diagnosis in 33.8% of patients (n=27/80), with 15 patients having their diagnosis revised from non-cardiac chest pain to CAS and CMD. Additionally, multivessel CFT identified more cases of CAS, CMD, and coronary vasomotor dysfunction than single-vessel CFT (60.0% vs. 47.5%, P=0.004; 62.5% vs. 37.5%, P<0.001; 86.3% vs. 68.8%, P=0.005, respectively). The study concludes that multivessel CFT is a superior diagnostic modality compared to single-vessel testing for ANOCA and should be considered the diagnostic standard, as it more accurately identifies ANOCA endotypes and better informs patient management.

Over the past two decades, significant progress has been made in understanding nonobstructive angina, with the WISE study (8) being the first to identify the role of CFR in detecting ANOCA, later confirmed by other imaging modalities such as cardiac positron emission tomography (PET) (7).

In 2018, the CorMicA trial built on these findings and demonstrated that single-vessel CFT-based treatment stratification improved the quality of life in 42 ANOCA patients, resulting in lower rates of angina but similar rates of adverse cardiovascular events (9). Since then, single-vessel CFT has become the norm in ANOCA testing, focusing on testing only a single target vessel based on a combination of factors such as symptomatology and non-invasive imaging stress results. Targeted therapies for ANOCA are currently under development across various stages of different clinical trials (2), such as EXAMINE-CAD (NCT05294887), ILIAS registry (NCT04485234), COSIRA-2 (NCT05102019), and the PRIZE trial (10). These trials are anticipated to provide valuable data on the relationship between changes in CFT and patient outcomes. However, as the present study recommends multivessel CFT as the superior choice, it is essential to examine the limitations of using multivessel CFT for ANOCA, why single-vessel CFT remains the standard of practice, and whether the practical clinical implementation of multivessel CFT is feasible.

Firstly, multivessel CFT resulted in slightly (~1.5 times) longer procedural times (56 vs. 41 minutes) and increased contrast administration (155 vs. 110 mL). While longer procedural times can cause patient discomfort by reducing mobility and increasing exposure to procedural environments, as seen in a study on cardiac catheterization, the additional 15 minutes is marginal and unlikely to significantly affect patient comfort.

Additionally, one serious adverse event—a case of coronary dissection requiring emergency intervention—occurred. This major complication highlights the need for caution when conducting multivessel CFT. While it may seem that increased procedural time might contribute to a higher risk of complications, the rate of serious adverse events in this study (<1%) is consistent with single-vessel CFT across the literature. These risks can be mitigated by focusing on appropriate patient selection, high operator expertise, and following the procedural algorithm recommended by Rehan et al., which suggests initially focusing on a single-vessel (LAD or another coronary artery based on evidence) and considering multivessel testing only if symptoms persist despite negative results (6,11,12).

Current American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the evaluation of chest pain recommend that in the absence of obstructive coronary artery disease (CAD), when ANOCA is suspected, either invasive testing via CFT or non-invasive testing—such as cardiac PET MPI, and cardiac MRI with myocardial blood flow measurement—can be used for further assessment and diagnosis (13). Therefore, a holistic approach when selecting a diagnostic test may be a better course of action for optimizing outcomes.

Additionally, diagnostic fidelity varies depending on the pathology. For example, recent studies have shown low sensitivity for exercise electrocardiographic stress testing (EST) in detecting CMD (14,15). In the first study, in a cohort of 249 patients, the sensitivity of EST in detecting CMD identified by PET was only 34.7% [95% confidence interval (CI): 25.4–45.0%]. Specificity improved to a high level (86.8%; 95% CI: 80.3–91.7%) when the criterion for positivity was changed to ischemic changes lasting at least one minute into recovery. However, this further reduced sensitivity (15.3%; 95% CI: 8.8–24.0%) (14). The second study supports these findings of high specificity for CMD with ischemic changes on EST, though the low sensitivity again calls its diagnostic yield into question (15).

It should also be noted that prior studies support the conclusions of the present study. Firstly, the rates of CAS and CMD seen in this study are comparable to those seen in previous studies. Secondly, studies have suggested that CAS can occur in multiple vessels simultaneously and testing multiple vessels should provide a more accurate diagnosis (16,17). Thirdly, the limitations of single-vessel CFT become more apparent when focusing on CMD. CMD can be transient in nature, with its severity varying in different patient populations (18,19). For instance, in patients with a history of coronavirus disease 2019 (COVID-19), cardiac PET detected higher rates of CMD, defined as a myocardial flow reserve <2, which increased proportionally with the severity of infection experienced (20). Given that different coronary vessels may exhibit varying degrees of microvascular dysfunction and that CMD is often associated with diffuse abnormalities in the coronary microcirculation, the case for multivessel CFT becomes almost self-evident.

The authors report significant findings that could influence future practice guidelines. However, it is essential to recognize that cost, availability, the diagnostic accuracy of other available tests, and patient-related factors will influence the choice of testing. Additionally, the authors acknowledge that the recency of their data and the lack of information regarding the diagnostic and therapeutic effects on quality of life and angina burden limit the ability to draw definitive conclusions. We recommend further large-scale clinical studies on the impact of multivessel CFT for ANOCA, while also assessing practical aspects such as cost-effectiveness, patient uptake, and the effect on quality of life and angina burden. Until these questions are answered, recommending multivessel CFT over single-vessel CFT remains challenging, despite the promising results of the present study.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Cardiovascular Diagnosis and Therapy. The article has undergone external peer review.

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-476/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-476/coif). M.H.A. reports receiving research support from Siemens and General Electric unrelated to this work. He is also a consultant for General Electric, Medtrace, Jubilant and Pfizer. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Peeters D, Woelders E, Jansen T, et al. Association Between Coronary Artery Spasm and Atherosclerotic Disease. JACC Cardiovasc Imaging 2025;18:226-39. [Crossref] [PubMed]
2. Ashokprabhu ND, Quesada O, Alvarez YR, et al. INOCA/ANOCA: Mechanisms and novel treatments. Am Heart J Plus 2023;30:100302. [Crossref] [PubMed]
3. Lanza GA, Shimokawa H. Management of Coronary Artery Spasm. Eur Cardiol 2023;18:e38. [Crossref] [PubMed]
4. Reynolds HR, Bairey Merz CN, Berry C, et al. Coronary Arterial Function and Disease in Women With No Obstructive Coronary Arteries. Circ Res 2022;130:529-51. [Crossref] [PubMed]
5. Hung MJ, Yeh CT, Kounis NG, et al. Coronary Artery Spasm-Related Heart Failure Syndrome: Literature Review. Int J Mol Sci 2023;24:7530. [Crossref] [PubMed]
6. Rehan R, Wong CCY, Weaver J, et al. Multivessel Coronary Function Testing Increases Diagnostic Yield in Patients with Angina and Nonobstructive Coronary Arteries. JACC Cardiovasc Interv 2024;17:1091-102. [Crossref] [PubMed]
7. Al-Mallah MH, Nayfeh M, Alrifai M. The role of cardiac PET in diagnosis and prognosis of patients with ischemia with no obstructive coronary arteries (INOCA). Am Heart J Plus 2024;43:100399. [Crossref] [PubMed]
8. Olson MB, Kelsey SF, Matthews K, et al. Symptoms, myocardial ischaemia and quality of life in women: results from the NHLBI-sponsored WISE Study. Eur Heart J 2003;24:1506-14. [Crossref] [PubMed]
9. Ford TJ, Stanley B, Good R, et al. Stratified Medical Therapy Using Invasive Coronary Function Testing in Angina: The CorMicA Trial. J Am Coll Cardiol 2018;72:2841-55. [Crossref] [PubMed]
10. Morrow AJ, Ford TJ, Mangion K, et al. Rationale and design of the Medical Research Council's Precision Medicine with Zibotentan in Microvascular Angina (PRIZE) trial. Am Heart J 2020;229:70-80. [Crossref] [PubMed]
11. Huang J, Smilowitz NR, Quyyumi AA, et al. More testing, more findings: the evolving story of coronary vascular dysfunction. Cardiovasc Diagn Ther 2025;15:11-4. [Crossref] [PubMed]
12. Feenstra RGT, Seitz A, Boerhout CKM, et al. Principles and pitfalls in coronary vasomotor function testing. EuroIntervention 2022;17:1271-80. [Crossref] [PubMed]
13. Gulati M, Levy PD, Mukherjee D, et al. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2021;144:e368-454.
14. Lopez DM, Divakaran S, Gupta A, et al. Role of Exercise Treadmill Testing in the Assessment of Coronary Microvascular Disease. JACC Cardiovasc Imaging 2022;15:312-21. [Crossref] [PubMed]
15. Sinha A, Dutta U, Demir OM, et al. Rethinking False Positive Exercise Electrocardiographic Stress Tests by Assessing Coronary Microvascular Function. J Am Coll Cardiol 2024;83:291-9. [Crossref] [PubMed]
16. Aissaoui H, Boutaybi M, Ikbal A, et al. Fatal Multi-Vessel Coronary Vasospasm: A Case Report. Cureus 2020;12:e8271. [Crossref] [PubMed]
17. Teragawa H, Oshita C, Uchimura Y. Clinical Characteristics and Prognosis of Patients with Multi-Vessel Coronary Spasm in Comparison with Those in Patients with Single-Vessel Coronary Spasm. J Cardiovasc Dev Dis 2022;9:204. [Crossref] [PubMed]
18. Nayfeh M, Ahmed AI, Saad JM, et al. The Role of Cardiac PET in Diagnosis and Prognosis of Ischemic Heart Disease: Optimal Modality Across Different Patient Populations. Curr Atheroscler Rep 2023;25:351-7. [Crossref] [PubMed]
19. Al-Mallah MH. COVID-19 and the Heart. Methodist Debakey Cardiovasc J 2021;17:1-4. [Crossref] [PubMed]
20. Ahmed AI, Al Rifai M, Alahdab F, et al. Coronary microvascular health in symptomatic patients with prior COVID-19 infection: an updated analysis. Eur Heart J Cardiovasc Imaging 2023;24:1544-54. [Crossref] [PubMed]