Ischaemic heart disease remains the number one cause of mortality worldwide, with chest pain being one of the most common presentations to both primary care and cardiology services. Suspected angina referral pathways have become well established within NHS practice through rapid access chest pain clinics (RACPC), allowing prompt specialist assessment. While the expansion of access to noninvasive imaging has significantly enhanced risk stratification and management of patients with obstructive coronary artery disease (CAD), questions remain about the suitability of this rule-in/rule-out approach for all individuals referred to RACPC.
“Listen to your patient – he’ll give you the diagnosis” Sir William Osler
A pivotal moment in clinical decision-making arises when patients presenting with typical – or indeed atypical – symptoms of angina receive noninvasive testing results indicating no evidence of obstructive CAD. This apparent discordance between the patient’s reported experience and the objective findings often presents a diagnostic dilemma. It is in our nature (and training) to question the subjective – the accuracy of the clinician’s initial assessment, the authenticity, or relevance, of the patient’s reported symptoms. This is especially likely if there is a delay between the clinical assessment and the diagnostic test, leading to the clinician having to rely on historical records, or assessments of others, to make a judgement. Not infrequently, patients with compelling anginal symptoms are discharged from cardiology follow-up, based on a ‘negative’ test result.
Obstructive CAD is present in a minority of patients presenting with anginal chest pain1 – but is the only one ordinarily assessed with the most utilised noninvasive imaging modality in the RACPC setting, the computed tomography coronary angiogram (CTCA). Most other endotypes of angina are also undetectable on other forms of noninvasive functional imaging, except for endothelium-independent coronary microvascular dysfunction (CMD), where quantitative stress perfusion cardiac magnetic resonance (CMR) or single-photon emission computed tomography (SPECT) has some utility.2,3 Although technological progress may allow noninvasive diagnosis of other angina endotypes in the future, at present, careful and thorough clinical history assessment is the best and only tool available to guide further management of these patients.
Arguably, a ‘one-stop’ RACPC, where the result of the CTCA is available at the time of the first clinic appointment, could equip the clinician with all the necessary information to make a clinical diagnosis of angina with non-obstructed coronary arteries (ANOCA), and collaborate with the patient regarding the ongoing management plan. Where the pretest probability for obstructive CAD is high, or when there is CAD of indeterminate severity seen on CTCA, the patients may be referred for invasive coronary angiography as a first- or second-line investigation. It is especially important in these patients that interpretation of coronary angiography findings is done in the context of their symptoms. The clinician should be prepared for the often-surprising scenario of non-obstructive CAD but typical anginal symptoms, and strongly consider the need for further investigation at the time of the index procedure, rather than declassify anginal pain as non-cardiac. This could include undertaking invasive coronary function testing (CFT) to confirm (or disprove) the diagnosis of a specific ANOCA endotype, and reduce clinical ambiguity.
The importance of confirming the diagnosis
In practice, many patients with ANOCA endure a prolonged wait, multiple investigations and recurrent presentations, before the diagnosis is reached, with some experiencing dismissal of their symptoms by generalists and specialists alike.4 Even if the diagnosis of ANOCA is recognised as a possibility, it is not uncommon for patients to be reassured regarding the presumed benign nature of the condition. However, evidence is mounting to suggest adverse long-term prognosis in patients with ANOCA, with increased risk of mortality and cardiovascular morbidity,5,6 let alone the impact on healthcare resource utilisation, quality of life, mental health and economic productivity.7,8 For an interventional cardiologist, completing invasive CFT in patients with apparently ‘normal’ coronary arteries may be a difficult ask – with the frequently quoted risk of 1:500 of significant adverse events (e.g. coronary wire complications necessitating percutaneous coronary intervention [PCI], intractable coronary spasm or arrhythmias secondary to acetylcholine [Ach] provocation), empirical management may be more palatable.
However, the CorMicA (Coronary Microvascular Angina) trial results suggest that stratified medical therapy based on the outcome of invasive CFT improves anginal symptoms and quality of life in patients with ANOCA, compared with those on empirical therapy.9 Additionally, undertaking formal invasive CFT may provide an important opportunity to address the underlying cardiovascular risk factors and detrimental aspects of patients’ lifestyles, which may overall contribute to an improved long-term prognosis. Equally, a negative CFT result offers the chance to discontinue the unnecessary medications, many of which are not only ineffective and may cause side effects, but also to consider alternative explanations for patients’ symptoms. This risk-versus-benefit balance is reflected in the current European Society of Cardiology (ESC) class 1B recommendation to offer invasive CFT in patients who have intractable chest pain symptoms, despite empirical management.10
Complete invasive coronary function quantification – could it be possible?
Despite this recommendation, provision of an invasive CFT service within cardiology departments in the UK is limited. There are multiple barriers to service adoption – for example, operator expertise, access to the necessary technology and pharmacology (especially ACh, for which coronary spasm provocation testing is an unlicensed indication) or increasing demands on interventional cardiology services. In recent years, a BHF-NIHR (British Heart Foundation/National Institute for Health Research) Partnership CMD Workstream has been established to coordinate and advance research efforts in this field. Notably, it has also produced a comprehensive consensus document detailing an invasive CFT protocol, thereby, contributing to the procedural standardisation.11 However, since publication, parts of this protocol have become obsolete due to commercial unavailability of the Doppler/pressure wire (ComboWire, Philips Volcano, CA, USA). Consequently, assessment of endothelial dysfunction or quantitative assessment of coronary spasm by volumetric flow is currently not possible in clinical practice.
Assessment of endothelium-independent coronary microvascular function has been evaluated in depth, with several invasive and noninvasive techniques showing reliability and reproducibility of the results. Recently, continuous thermodilution has emerged as a robust method of assessing endothelium-independent coronary microvascular function, validated against the gold-standard positron-emission tomography (PET) imaging.12,13 Although more time-consuming than bolus thermodilution or Doppler-based assessment, continuous thermodilution has the capability to measure absolute coronary flow, which is less dependent on intra- or inter-operator variability, not derived from coronary diameter measurement subject to substantial error, and does not require pharmacological agents to stimulate hyperaemia. Instead, 0.9% saline is infused at variable rates through a dedicated microcatheter with four infusion ports (Rayflow, Hexacath, Paris, France), and temperature deviations are measured with use of Pressure Wire X (Abbott Vascular, Santa Clara, CA, USA). It is thought that a hyperaemic response with high-rate infusion is produced by localised adenosine production within the coronary tree, reducing the risk of side effects.
The ability of continuous thermodilution to measure absolute flow presents an interesting opportunity in the diagnosis of endothelial dysfunction and quantification of coronary vasospasm. Endothelial dysfunction, similar to CMD and vasospastic angina (VSA), is correlated with adverse cardiac prognosis,14 and is an important ANOCA endotype. In healthy endothelium, ACh infusion results in nitric oxide-mediated vasodilatation of the coronary tree, thus, increasing coronary blood flow, with more than a 50% increase considered normal. In endothelial dysfunction, however, the vasodilatory response is inadequate, or, indeed, vascular smooth muscle cell activation by ACh overpowers the vasodilatory action, resulting in coronary vasospasm. Incremental concentrations of ACh can be infused through the Rayflow catheter, following which, absolute flow is measured and compared with resting flow. An ACh flow reserve (AChFR) value of ≤1.5 is considered abnormal. Three UK centres have assessed the feasibility of this method,15 and it will be further evaluated within the upcoming REDEFINE-CMD trial.
Another possible area where continuous thermodilution could potentially be used is quantification of coronary vasospasm. Currently, the diagnosis of VSA relies on fulfilling the COVADIS criteria (ischaemic electrocardiogram [ECG] changes in conjunction with symptoms typical for the patient, and angiographic evidence of >90% coronary artery diameter reduction during provocative manoeuvres or spontaneously).16 However, not infrequently, patients exhibit one or two of the above criteria without obvious evidence of spasm on coronary angiography, or conversely, profound angiographic evidence of epicardial spasm but no symptoms or ECG changes. The latter scenario can be explained by autoregulation, where the microcirculation responds to reduction in epicardial flow by vasodilatation. The former is currently considered a diagnosis of exclusion, vaguely termed ‘microvascular spasm’, with no specific diagnostic criteria, but some speculation that this condition may respond less well to nitrate therapy than epicardial coronary spasm.17 The continuous thermodilution method could potentially be utilised to determine absolute flow in the coronary tree following high-dose intracoronary ACh infusion, with flow reduction below baseline considered diagnostic for spasm (similar to the prior cut-off determined through Doppler-based volumetric flow measurement).11 Similarly, measurement of coronary flow during an episode of angiographically significant epicardial spasm, could potentially be used as a surrogate marker of coronary microvascular autoregulatory function.
Why coronary function quantification matters
At first glance, adding steps to the procedural protocol, rather than simplifying the approach, may seem counter-productive, however, coronary function quantification may have important implications for patients and ongoing development in the area. First, both microvascular and endothelial dysfunction are a spectrum of disease, with worse outcomes seen in those more significantly affected,11 thus, prognostication and treatment intensity could be personalised. Second, correct classification of endotypes and their severity would allow design of good quality randomised-controlled trials of therapeutics. Prior research often included patients with a diagnosis of ANOCA based simply on the absence of obstructive CAD on coronary angiography, which, given the current understanding of the condition, clearly would have included highly heterogenous samples. If eligibility criteria are strictly defined by the results of invasive CFT, this ambiguity can be reduced. Finally, a robust gold-standard investigation could act as a comparator for validation of greatly needed noninvasive diagnostic modalities for endotypes other than endothelium-independent CMD, which could avoid the small peri-procedural risk associated with invasive CFT.
Conclusion
In the fast-advancing era of modern medicine, ANOCA remains a diagnosis where the art of comprehensive and accurate clinical history taking prevails. Prompt and precise diagnosis and management could potentially lead to improved quality of life and symptom control for the affected patients. The diagnostic modalities landscape is constantly evolving, but exciting opportunities exist to explore the use of continuous thermodilution to quantify the most common ANOCA endotype, which could drive further research progress in this area and development of treatment options.
Conflicts of interest
None declared.
Funding
None.
References
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