More testing, more findings: the evolving story of coronary vascular dysfunction

Approximately 50% of symptomatic patients with objective evidence of ischemia or suspected angina, even with normal stress test results, show no obstructive coronary artery disease (INOCA/ANOCA) on coronary angiography (1). Despite ongoing symptoms, once conventional stress testing is normal or when significant obstructive coronary artery disease (CAD) has been ruled out by coronary angiography, symptoms are often attributed to non-cardiac chest pain and patients are improperly dismissed from cardiology care. Unfortunately, a subset of these patients with INOCA/ANOCA are at risk of future cardiovascular events, including myocardial infarction and heart failure (1). Long-term adverse outcomes also include recurrent chest pain symptoms (2), increased anxiety (3), repeated hospitalization for angina and repeated non-invasive and invasive testing (4), and overall decreased quality of life (5).

With advances in non-invasive cardiac imaging and invasive coronary function testing (CFT), it is now known that a substantial proportion of patients with no obstructive CAD have coronary vascular dysfunction, either due to coronary microvascular dysfunction (CMD) or coronary artery vasospasm (CAS), as a potential explanation of their symptoms. Diagnostic clarity can inform optimal medical therapy. Tailoring therapy based on findings of CFT was shown to have a positive impact on patient-oriented outcomes in the Coronary Microvascular Angina (CorMicA) trial (6). Indeed, European Society of Cardiology (ESC) guidelines recommend that in patients with angiographically normal coronary arteries or moderate stenosis with preserved fractional flow reserve who have persistent symptoms, intracoronary testing for coronary flow reserve (CFR), index of microcirculatory resistance (IMR), and acetylcholine (Ach) provocation testing should be considered (7,8). The 2021 American College of Cardiology/American Heart Association guidelines state that in patients with persistent stable chest pain and nonobstructive CAD, it is reasonable to consider invasive CFT to clarify diagnosis of vascular dysfunction (9).

In the manuscript entitled “Multivessel coronary function testing increases diagnostic yield in patients with angina and nonobstructive coronary arteries”, Rehan et al. reported that a comprehensive contemporary protocol of multivessel CFT improved detection of coronary vascular dysfunction compared with single-vessel CFT in patients with ANOCA (10). In the study, comprehensive coronary physiology testing was performed in both left and right coronary arteries (LCA and RCA), with assessments in 228 vessels from 80 patients. Coronary reactivity testing was performed using intracoronary Ach provocation in LCA (20–200 µg) and RCA (20–80 µg). Multivessel CFT protocol yielded a significantly greater prevalence of coronary vascular dysfunction (86.3%, 69/80) compared to a single-vessel CFT protocol (68.8%, 55/80), P=0.0005, with greater proportions of patients with both CAS and CMD. The multivessel CFT protocol led to a change in the final diagnosis in 33.8% of patients. Importantly, 15 participants who would have been assigned a diagnosis of non-cardiac chest pain after single vessel CFT were found to have CAS (n=1), CMD (n=10), or mixed CAS and microvascular dysfunction (n=4) after multi-vessel testing. Interestingly, patients with multivessel CMD had a significantly worse angina-related quality of life scores compared to single-vessel CMD group (P=0.045). Comparing multivessel CAS to single-vessel CAS, there was a trend towards greater angina severity and frequency with multivessel CAS (P=0.092).

While there is variability in CFT protocols and techniques, CFT is traditionally performed in the left anterior descending artery (LAD), which perfuses the largest portion of the myocardial microcirculatory bed (11,12). However, CMD can be patchy in distribution and predisposition to CAS may vary by vessel; therefore, limiting CFT to the LAD may result in a missed or incomplete diagnosis of coronary vascular dysfunction (13,14). There are some important downsides to multivessel CFT. Although CFT is considered to be relatively safe, invasive testing is not without risk. In most protocols the RCA is not routinely tested because of transient bradycardia or atrioventricular block (AVB) with intracoronary ACh administration. In this study, either femoral (42.5%) or radial (57.5%) approach were used and during Ach provocation test, 46 (57.5%) patients required temporary pacing during RCA testing, while only 12 (15.0%) required it during LCA testing. A recent meta-analysis reported that the overall pooled estimate of the incidence of major complications associated with intracoronary Ach administration was 0.5% (95% confidence interval: 0.0–1.3%) with no deaths in the included studies. As with any diagnostic test, the risks and benefits should be carefully considered for individualized patient care. The potential consequences of additional testing should be weighed against the benefits of obtaining a diagnosis. While CFT results are prognostic for Major adverse cardiovascular event (MACE) and can guide therapy to reduce symptoms and improve quality of life, there is no evidence yet that CFT reduces MACE. However, the improvement in patient-oriented outcomes, such as reduced angina and enhanced quality of life, represents a significant benefit, underscoring the importance of making an individualized decision after thorough patient discussion. Bradycardia and AVB are more frequently observed during ACh testing of the RCA compared to LCA (15). Perhaps more concerning, in the current study, 2 (2.5%) participants had CFT are complicated by iatrogenic coronary dissection, with one required percutaneous coronary intervention (PCI), demonstrating a high rate of potentially serious complications in a population of patients free of epicardial coronary disease. Finally, the time required for additional testing must also be considered. Although the authors report a median procedural time of 56 minutes, it is unclear whether this would be easily replicated in routine clinical practice and this could be a significant barrier to widespread use.

Structural and/or functional alterations along the coronary vascular bed (macro and micro) can impact myocardial blood flow during periods of increase in hemodynamic demand or during mental stress. While there has been long-standing skepticism of whether there is an ischemic basis of symptoms in ANOCA patients, coronary physiology assessments from contemporary CFT studies point to substantial vascular abnormalities among those who are selected to undergo CFT. In the current study, among the 80 participants who were referred for CFT, 86.3% were diagnosed with coronary vascular dysfunction (either CMD or CAS or both) with multi-vessel testing. This high yield diagnostic test highlights the high pre-test probability of vasomotor disorders in patients with ANOCA and suggests that antianginal therapy is reasonable for symptoms relief, especially for patients who may not have access to CFT.

Our evolving understanding of symptoms in chronic stable ischemic heart disease has expanded from primarily emphasizing obstructive CAD to also considering coronary vascular dysfunction in the setting of ANOCA. Rehan et al. should be congratulated on comprehensively testing ANOCA patients with multivessel testing to improve our diagnostic protocols. While multivessel CFT identified more patients with coronary vasomotor abnormalities, even single vessel CFT is not available or performed in most hospitals in the United States or worldwide. Future studies should consider increases in time, cost, and potential patient risks associated with multivessel CFT and balance these parameters against improved patient-oriented outcomes.

While improvement in diagnostic CFT protocols may incrementally improve diagnostic accuracy, broader questions remain. Mechanisms of sex differences in ANOCA prevalence requires further study and interactions between hormonal and autonomic mechanisms that may affect vasoreactivity are unknown. The role of enhanced cardiac nociception contributing to symptoms is poorly understood. Furthermore, research is needed to identify which patients with ANOCA are at risk for MACE. Finally, optimal treatment is uncertain. We eagerly await findings of the large WARRIOR trial that is testing optimal medical therapy among those with nonobstructive CAD (16,17).

In summary, this study contributes valuable diagnostic insights in ANOCA, which remains a clinically challenging condition. By appropriately diagnosing a greater proportion of patients with CAS or CMD, tailored management approaches (pharmacologic and non-pharmacologic) may improve quality of life and clinical outcomes. Despite significant strides in understanding the role of coronary vascular disorders in patients with INOCA/ANOCA, diagnosis is just the first step, and much work remains to be done to improve care of these challenging conditions.

Acknowledgments

We acknowledge Mrs. Marcia Taylor for her support.

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-24-549/prf

Funding: This work was supported by the National Institutes of Health (No. 1R01HL157311).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-549/coif). The authors have no conflicts of interest to declare.

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