Invasive Assessments For Coronary Vasomotor Disorders: Current State of the Art Methods Collection

In today’s era of personalized precision medicine, the aim of the clinical cardiologist should be to determine the underlying cause of the patient’s symptoms and to initiate the most appropriate therapy in order to improve their symptoms and prognosis. This holds true for many, if not all, areas of medicine but is especially challenging in areas where there is still limited evidence. In cardiology, one of these areas is patients with angina and unobstructed coronary arteries (ANOCA), of whom a substantial subgroup may have demonstrable myocardial ischemia (INOCA) on non-invasive or invasive testing yet no hemodynamically relevant epicardial stenoses.

Major advances in this field have been made in recent years, and it has now become apparent that patients with ANOCA represent a heterogeneous group with different and often overlapping mechanisms of angina¹. These groups with different mechanisms have been labeled “endotypes”, and the randomized CorMicA study has shown that stratified medicine, including coronary function testing and treatment mechanistically linked to the patient’s endotype, can improve symptoms and quality of life². While several other studies regarding the treatment of ANOCA patients are underway (e.g., EXAMINE-CAD and ILIAS-ANOCA), the definition of these endotypes and the development of diagnostic protocols have been challenging. The Coronary Vasomotion Disorders Study Group (COVADIS) has published several suggestions for standardizing the nomenclature and definitions for the diagnosis of coronary vasomotor disorders^3,5. Despite these publications, the diagnostic approaches in ANOCA patients still vary between centers. The current JoVE methods collection was composed to (a) describe the current invasive diagnostic armamentarium for assessing ANOCA patients, (b) stimulate clinical researchers to adopt these protocols, and (c) highlight the most practicable and useful approaches in clinical cardiology.

The current ESC guidelines recommend wire-based assessment of the coronary microcirculation as well as intracoronary provocation testing for coronary spasm in patients with ANOCA (both class IIa recommendations)^4,5. Ang et al.⁶ nicely describe how these assessments can be done using an intracoronary wire with the ability to measure pressure and flow followed by acetylcholine spasm testing. This approach uses the pressure wire X by Abbott, and the assessment of the coronary flow reserve (CFR) and the index of microvascular resistance (IMR) is done before the acetylcholine spasm testing. This has the advantage that the hemodynamic relevance of any intermediate epicardial stenosis can be assessed by measuring the fractional flow reserve (FFR) and/or the resting full-cycle ratio (RFR) at the same time as conducting the assessment of coronary microvascular function. Moreover, the thermodilution technique, which uses bolus thermodilution, is widely available. A potential disadvantage is the fact that the spasm testing may be negative in some patients due to the ongoing vasodilatory effect of any nitroglycerine given during the initial measurement of the abovementioned coronary physiology indices (FFR, RFR, CFR, and IMR). However, at the time of acetylcholine testing, this effect may often already be negligible.

Notably, the diagnostic yield of coronary function testing gives about 30% positive results for an abnormal CFR/IMR in comparison to approximately 80% for spasm testing¹. Thus, from a clinical point of view, spasm testing may be preferred as the initial test, since the likelihood of an abnormal result and, thus, finding the diagnosis may be higher. This approach is presented in another paper in this methods collection by Seitz et al.⁷, where acetylcholine spasm testing is followed by adenosine testing for the assessment of CFR and hyperemic microvascular resistance (HMR). In contrast to Ang et al.⁶, their protocol uses a Doppler wire to measure the coronary blood flow velocity instead of a thermodilution wire. Although both wires can measure CFR, their diagnostic accuracy is not the same. Recent studies have shown that CFR_Doppler is more accurate than CFR_Thermo using [¹⁵O]H­₂O positron emission tomography (PET) as the gold standard⁸. However, it should be mentioned that obtaining a good Doppler signal can sometimes be challenging. There are also substantial differences in the microvascular resistance indices assessed by the Doppler technique, which provides HMR values based on the coronary blood flow velocity, and the thermodilution technique, which provides IMR values based on the coronary bolus transit time⁹. While IMR and HMR automatically have different thresholds due to their different units, recent data suggest the use of different thresholds for CFR_Doppler and CFR_Thermo too⁹. Accordingly, a CFR range of <2.0 may be considered abnormal using CFR_Doppler, whereas a <2.5 cutoff may be considered abnormal, with a grey zone of 2.0–2.5, using CFR_Thermo. This is not a limitation of CFR; rather, the differences represent logical refinements reflecting the differences in methodology. Further studies are needed to improve our understanding of the diagnostic and prognostic meanings of these different indices.

An attractive addition to acetylcholine spasm provocation testing is the so-called acetylcholine re-challenge, which is nicely summarized by Feenstra et al.¹⁰. The re-challenge approach comprises the re-administration of the same dose of acetylcholine that led to coronary spasm after an intracoronary nitroglycerine injection. This approach has recently been shown to provide important information on concomitant microvascular spasm in patients with epicardial spasm, as well as the efficacy of nitroglycerine for preventing coronary spasm in individual patients¹¹. This acetylcholine re-challenge technique may be a valuable addition to coronary function testing since it can be helpful for targeted pharmacotherapy.

A particularly challenging group among patients with coronary vasomotor disorders are those with coronary microvascular spasm. This is because microvascular spasm cannot be visualized in vivo in humans, and, thus, indirect evidence is needed. While current clinical assessment includes the reproduction of the patient’s symptoms as well as any ischemic ECG shifts during acetylcholine testing without documentation of epicardial spasm^5,12, more objective evidence for making the diagnosis may be useful. Takahashi et al.¹³ present the measurement of myocardial lactate production during spasm testing. In patients who fulfill the clinical criteria for microvascular spasm, coronary sinus blood sampling can reveal myocardial lactate production as more objective evidence for microvascular myocardial ischemia. However, this evidence comes at the cost of additional instrumentation of the coronary sinus. Moreover, there is some variability in the measurements, indicating that even patients who fulfill the clinical criteria for microvascular spasm may not all be the same when their coronary sinus blood samples are assessed.

Finally, the paper by Konst et al.¹⁴ describes current developments in measuring coronary blood flow and resistance. As mentioned above, these measurements can be done using the bolus-thermodilution technique. The quantification of the continuous thermodilution-derived absolute coronary blood flow and resistance might represent a diagnostic advance compared to the currently used standard physiologic measures. Although the continuous thermodilution technique is currently used only for research purposes and an additional microcatheter is needed for the measurements, the technique will contribute to a better understanding of microvascular dysfunction. Interestingly, it was recently shown that hyperemia due to the continuous infusion of saline in this setting can be mediated by hemolysis and adenosine diphosphate release from the erythrocytes¹⁵.

Patients with ANOCA are frequently encountered in daily clinical practice. They should be managed according to the current guideline recommendations, and the underlying vasomotor disorder should be determined. This determination of the underlying disorder enables the use of targeted pharmacotherapy to improve the patient’s quality of life and symptoms. Future challenges are (a) the availability of diagnostic tools, (b) the simplification required for the use of these tools in routine invasive cardiology, and (c) the harmonization of diagnostic protocols. This methods collection may stimulate clinical research in this area but also help to understand the individual pros and cons of the different diagnostic approaches to eventually develop a unified protocol.

Peter Ong received speaker honoraria from Abbott and Philips.

Colin Berry is employed by the University of Glasgow, which holds consultancy and research agreements for his work with Abbott Vascular, AstraZeneca, Auxilius Pharma, Boehringer Ingelheim, Causeway Therapeutics, Coroventis, Genentech, GSK, HeartFlow, Menarini, Neovasc, Novartis, Siemens Healthcare, and Valo Health. Colin Berry receives research funding from the British Heart Foundation grant (RE/18/6134217), Chief Scientist Office, EPSRC (EP/R511705/1, EP/S030875/1), European Union (754946-2), Medical Research Council (MR/S018905/1), and UKRI (MC/PC/20014).

Andreas Seitz has nothing to disclose.

The authors acknowledge funding from the Berthold Leibinger Foundation, Ditzingen, Germany.