Introduction
Angina and stable coronary syndromes (SCSs)
Ischaemic heart disease is the leading cause of mortality standardised by age and sex.1 In clinical practice, the diagnostic management of patients with angina pectoris focuses on the detection of obstructive epicardial coronary artery disease (CAD).2 In this stenosis-centred concept of myocardial ischaemia, angina is synonymous with obstructive CAD.3 There are well established treatment options for patients with epicardial CAD, namely optimal medical therapy and myocardial revascularisation by either percutaneous coronary intervention or coronary artery bypass grafting.3 However, the paradigm of angina pectoris resulting from obstructive epicardial CAD fails to account for the approximately one-third of patients who suffer from angina in whom obstructive CAD is excluded.4
Patients with angina and no obstructive coronary artery disease (ANOCA) present a diagnostic conundrum.5 The management of these patients is varied, and most patients fail to have a diagnosis made for the cause of their symptoms, receive no further diagnostic work-up, and have no therapeutic intervention. The underlying aetiology of chest pain symptoms and a ‘negative’ coronary angiogram is heterogeneous. However, a significant number of patients may have a disorder of coronary vascular function due to abnormal microvascular resistance or vasodilator capacity (coronary microvascular dysfunction (CMD)) or abnormal endothelial function (vasospastic disease).
The underlying pathogenesis in patients with ANOCA is unclear, as specific disease endotypes are not routinely tested for. CMD may result from coronary structural abnormalities, whereby decreased capillary luminal size and number result in increased microvascular resistance to myocardial blood flow (MBF) and reduced vasodilatory capacity.6 Functional abnormalities of the coronary epicardial vessels and microvasculature may result in either abnormal vasoconstriction or impaired vasodilatation, and these abnormalities may be secondary to either endothelium-dependent or endothelium-independent mechanisms.7
Abnormalities of coronary vascular function portend a worse prognosis in patients with both obstructive epicardial CAD and ANOCA.8–12 Therapeutic interventions are lacking in patients with ANOCA, and historical therapeutic studies have been performed in heterogeneous patient cohorts due to a lack of diagnostic tests to appropriately define endotypes of disease.13–15 There is a missing link between the use of diagnostic tests of coronary artery function, therapeutic agents with proven efficacy and health outcomes of patients with angina secondary to disorders of coronary vascular function. The term stable coronary syndrome (SCS) has been proposed to increase physician awareness of these conditions.5 CMD and vasospastic disease may result in ANOCA and myocardial ischaemia, and are recognised as a condition of unmet clinical need.16 The Coronary Vasomotion Disorders International Study Group (COVADIS) working group have proposed diagnostic criteria for disease endotypes in patients with ANOCA.17 COVADIS recommend a comprehensive testing strategy incorporating tests of coronary pressure, flow, resistance and endothelial function, in addition to the assessment of objective evidence of myocardial ischaemia.17
Diagnostic testing in patients with ANOCA
Diagnosis of coronary microvascular and vasomotor dysfunction is challenging due to the heterogeneity of underlying disease mechanisms, the potentially patchy distribution of disease throughout the myocardium, and limited spatial resolution of existing diagnostic tests.18 19 There is no available in vivo technique for imaging the coronary microcirculation, and anatomical tests are fundamentally limited by their spatial resolution and the small size of the coronary microvasculature. Therefore, the diagnosis of microvascular angina and vasospastic angina is predominantly made with functional tests.
There is no accepted guideline-directed diagnostic algorithm for coronary vascular dysfunction in routine clinical practice.17 20 Invasive coronary angiography combined with adjunctive tests of coronary artery function represents the reference diagnostic approach for disorders of coronary vascular function. In contrast, non-invasive imaging involves less discomfort for patients, is safer than invasive procedures and is generally less expensive and more widely available. Recent developments with cardiovascular magnetic resonance (CMR) imaging now enable measurement of MBF with high spatial and temporal resolution.21 In addition, CMR permits the reference standard non-invasive assessment of left ventricular (LV) function and myocardial tissue characterisation.22
Non-invasive ischaemia testing in ANOCA
The available non-invasive ischaemia tests were all validated for the detection of obstructive epicardial CAD. There has been a low yield of inducible myocardial ischaemia in ANOCA patients with traditional non-invasive ischaemia tests (e.g. exercise ECG testing, myocardial perfusion scintigraphy and stress echocardiography).23 However, non-invasive methods (namely stress perfusion positron emission tomography (PET) and CMR which image earlier in the ischaemic cascade and have greater spatial resolution) may provide new insights into the burden of myocardial ischaemia in patients with ANOCA. PET is the most studied modality for the assessment of myocardial perfusion and is considered to provide the reference standard assessment of MBF, but in real-world clinical practice, availability is limited due to cost. Conversely, CMR is more widely available and use is increasing.24 25
Coronary microvascular disease may be revealed by a deficit in MBF during stress CMR. The spatial distribution of this abnormality typically involves the subendocardium, which is the location of the microvascular plexus.26 In contrast, vasospastic angina occurs due to spontaneous spasm of the epicardial and microvascular vasculature. Vasospastic angina may not be detected by conventional stress testing that routinely use adenosine (an endothelial-independent vasodilator). The available data are conflicting on the role of perfusion CMR in patients with ANOCA.26–28 In contrast to qualitative analysis, semiquantitative perfusion methods have been investigated, and reduced myocardial perfusion reserve index (MPRi) has been found in patients with ANOCA.29 The incremental diagnostic value of fully quantitative perfusion CMR in patients with ANOCA is unknown.
Associations between invasive and non-invasive diagnostic tests in patients with ANOCA
There are uncertain associations between the results of invasive diagnostic tests and the non-invasive ischaemia test results in patients with ANOCA. There is no accepted objective diagnostic threshold for the diagnosis of coronary vascular dysfunction (either abnormal myocardial flow or microvascular resistance), with either PET or perfusion CMR. Recent studies have investigated the relationships between invasive tests of coronary artery function and semiquantitative perfusion CMR analysis.30 31 Importantly, these patients have not undergone comprehensive coronary vascular function testing and in general moderate correlations were demonstrated (MPRi and index of microcirculatory resistance (IMR): r=−0.67; MPRi and coronary flow reserve (CFR): r=0.41).30
The Stratified Medical Therapy Using Invasive Coronary Function Testing In Angina (CorMicA) trial
The Stratified Medical Therapy Using Invasive Coronary Function Testing In Angina (CorMicA) clinical trial is a proof-of-concept, prospective, blinded, randomised, sham-controlled study comparing two management approaches to the clinical problem of patients with ANOCA.32 CorMicA tests the hypothesis that stratified medicine guided by invasive coronary artery function testing (interventional diagnostic procedure (IDP)) in patients with ANOCA will facilitate diagnosis of the underlying disease endotype, direct therapeutic interventions aligned to the endotype and result in improved angina and well-being.32 Patients undergoing elective invasive coronary angiography for investigation of angina at two UK centres will be screened. Eligible patients with ANOCA (n=150) will be immediately randomised 1:1 to either coronary vascular function-guided diagnosis and treatment (intervention group/IDP disclosed) or not (control group/IDP sham procedure, results not disclosed) (figure 1).
CorCMR substudy flow diagram. ANOCA, angina with no obstructive coronary artery disease; CMR, cardiovascular magnetic resonance; CorCMR, Coronary Microvascular Angina Cardiac MRI; CorMicA, coronary microvascular angina.
The IDP consists of coronary artery function testing using a dual pressure-sensitive and temperature-sensitive guidewire and adenosine followed by intracoronary acetylcholine provocation testing. Assessment of microvascular resistance (IMR), microvascular vasodilatory capacity (resistance reserve ratio (RRR)), epicardial and microvascular vasodilatory capacity (CFR), endothelial function (acetylcholine provocation testing) and epicardial CAD (fractional flow reserve (FFR)) will be performed. Following these invasive tests of coronary artery function, patients will be classified into the following ANOCA disease endotypes (table 1): (1) microvascular angina; (2) vasospastic angina; (3) mixed microvascular angina and vasospastic angina; (4) obstructive epicardial CAD; and (5) non-cardiac chest pain. The disease endotypes are aligned with the COVADIS working group definitions.17
Patients in the control group will receive standard care based on the interpretation of the invasive coronary angiogram alone. Patients in the intervention group will have care based on the disease endotypes disclosed by invasive tests of artery function, and pharmacotherapy linked to the underlying disease endotype will be commenced.32 In each case, the diagnosis (endotype) will be assessed by the attending cardiologist before and after the coronary angiogram. In the intervention group, the diagnosis is re-evaluated after disclosure of the coronary function test results at the end of the invasive procedure. The primary outcome is the mean difference in the within-subject change in Seattle Angina Questionnaire score between the groups at 6 months from baseline. A prespecified substudy of the CorMicA trial investigated the frequency of peripheral microvascular dysfunction in patients with ANOCA.33
Coronary Microvascular Angina Cardiac Magnetic Resonance Imaging (CorCMR) sub-study
Novel CMR methods for measuring MBF have not been validated in patients with ANOCA and underlying microvascular and vasospastic angina. The CorCMR substudy of the CorMicA clinical trial presents a unique opportunity to assess and validate the diagnostic accuracy of fully quantitative stress perfusion CMR in patients with ANOCA and comprehensive invasive coronary artery function testing.
Hypothesis
We hypothesise that abnormal myocardial perfusion, as revealed by a novel fully quantitative pixel-wise CMR perfusion sequence, will be prevalent in a contemporary UK cohort of patients presenting with ANOCA and that multiparametric CMR imaging will be clinically useful in the diagnostic pathway of patients with ANOCA.
Aims
We aim to assess the diagnostic validity of quantitative stress perfusion CMR in patients with ANOCA and specific disease endotypes of coronary vascular dysfunction. Our specific aims are to assess:
The proportion of ANOCA patients with abnormal myocardial perfusion. There is no accepted threshold for abnormal MPR. Thresholds for reduced CFR of 1.5–2.6 have been described,however <2.0 is commonly used.10 34–38 We will therefore assess the concordance of patient classification using this MPR <2.0 threshold against endotypes determined by invasive testing. Second, we will assess the MPR value with the highest area under the curve (AUC) for classification of microvascular angina based on the invasive tests (reference classification). Third, we will assess the proportion of ANOCA endotypes with other abnormal perfusion metrics (reduced stress MBF, abnormal endocardial:epicardial MBF ratio and abnormal myocardial dyssynchrony index).39
The diagnostic accuracy of the perfusion CMR metrics for abnormal invasive tests of coronary artery function (IMR >25, CFR <2.0 and RRR <2.0) and the associations between specific disease endotypes and myocardial perfusion in patients with ANOCA. We also aim to assess the correlation between abnormal CMR-derived perfusion and invasive tests of coronary artery function, of qualitative versus quantitative perfusion methods.
The proportion of patients with ANOCA and abnormal myocardial tissue characterisation derived from CMR (as revealed by T1 parametric mapping and late gadolinium enhancement (LGE) imaging) and its association with abnormal myocardial perfusion.
The associations between baseline patient characteristics and abnormal myocardial perfusion.
The proportion of patients with a change in diagnosis based on quantitative CMR findings, as compared with the initial diagnosis by the attending cardiologist based on the coronary angiogram.