Open Access, Peer-reviewed
pISSN 2508-707X
eISSN 2508-7088
    Cardiovasc Imaging Asia. 2021 Jul;5(3):83-93. English.
    Published online Jul 13, 2021.
    https://doi.org/10.22468/cvia.2021.00129
    Copyright © 2021 Asian Society of Cardiovascular Imaging
    Review

    Invasive and Non-Invasive Imaging for Ischaemia with No Obstructive Coronary Artery Disease

    Ming-Yen Ng,1,2 Hok Shing Tang,1 Lucas Chun Wah Fong,1 Victor Chan,1 Roxy Senior,3,4 and Dudley John Pennell3,4
      • 1Department of Diagnostic Radiology, The University of Hong Kong, Hong Kong, China.
      • 2Department of Medical Imaging, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
      • 3Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom.
      • 4Imperial College, London, United Kingdom.
    • Corresponding author: Ming-Yen Ng, BMedSci, BMBS, FRCR, FSCMR, FACC. Department of Diagnostic Radiology, The University of Hong Kong, Room 406, Block K, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China. Tel: 852-2255-4524, Fax: 852-2855-1652, Email: myng2@hku.hk
    Received April 02, 2021; Revised May 24, 2021; Accepted May 24, 2021.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Ischaemia with no obstructive coronary artery disease (INOCA) affects up to 50% of patients referred for coronary angiography for suspected angina. Although originally thought to be benign, recent data shows that patients with INOCA have an adverse prognosis. There are challenges in identifying and managing the underlying cause, which is most often attributed to coronary microvascular disease or coronary vasospasm. This review will cover the clinical relevance and prognosis of INOCA as well as the invasive and non-invasive imaging techniques available to identify the underlying aetiology. Upcoming technological advancements will also be discussed.

    Keywords
    Ischemia; Coronary artery disease; Angina; Imaging; Invasive

    INTRODUCTION

    Angina without obstructive coronary artery disease (CAD) or the more commonly termed ischaemia with no obstructive coronary artery disease (INOCA) occurs in up to 50% of patients referred for coronary angiography for suspected obstructive CAD (Fig. 1) [1, 2]. The medical community used to consider this a benign situation, but meta-analysis and subsequent large scale studies have demonstrated the contrary with INOCA patients having worse outcomes in terms of death and cardiac hospitalization [2, 3] compared to the general population. INOCA can be attributed to coronary microvascular disease (CMD) and coronary vasospasm [1]. Although invasive catheter coronary angiography can identify these two pathologies [4, 5, 6], non-invasive imaging methods have made significant progress in identifying these pathologies and are at lower risk to patients. For CMD and coronary artery vasospasm, this review aims to provide an overview of the: 1) clinical significance, 2) coronary artery anatomy and pathophysiology, 3) diagnosis and prognosis, and 4) invasive and non-invasive imaging techniques for assessment.

    Fig. 1
    Case study: a 60-year-old male with a past medical history of hypertension and obstructive sleep apnea was reviewed for the symptoms of exertional chest pain typical of angina. A: His ECG was unremarkable. A CCTA was performed, revealing normal coronary arteries and no narrowing. The patient was hence reassured. However, the angina did not resolve and he was seen again in clinic 3 years later. A subsequent stress CMR demonstrated no stress induced perfusion defect or infarct. Again the patient was reassured. However, the patient continued to have chest pain and re-presented 1 year later and underwent an invasive catheter coronary angiogram. The coronary angiogram showed no coronary artery narrowing. Although no specific provocation testing was performed, no evidence of coronary vasospasm was observed. This patient had normal anatomical and functional imaging studies but suffered from persistent angina. Differential diagnoses at this juncture would include non-cardiac chest pain, coronary vasospasm or CMD. B: Retrospective analysis of the CMR MPRI was found to be 1.17. This is considerably low, and would suggest a diagnosis of CMD, which placed the patient at significant risk for major adverse cardiovascular events [13]. CMD: coronary microvascular disease, CMR: cardiac magnetic resonance, CCTA: coronary computed tomography angiography, MPRI: myocardial perfusion reserve index, ECG: electrocardiogram.

    Clinical significance of INOCA

    Multiple imaging studies confirming INOCA have shown a poorer prognosis in patients with INOCA [7, 8]. These studies show that in patients with no obstructive CAD there was an annualised event rate of 0.6% to 3.4%. Whilst patients with normal coronary arteries had an annualized event rate of 0% to 1.8%. Interestingly, patients with undiagnosed chest pain but likely to consist of patients with INOCA patients have also been shown to have poorer clinical outcomes. A large cohort study of 172180 patients in the United Kingdom in 2017 [3], evaluated fatal or non-fatal cardiovascular events over a 5.5-year follow-up. The main clinical outcomes were major adverse cardiovascular events (MACE) in patients with angina, patients with unattributed chest pain and those with non-cardiac chest pain. In this study, the long-term incidence of cardiovascular events was higher in patients with undiagnosed chest pain after 6 months (4.7%) compared with patients with an initial diagnosis of non-coronary pain (3%). Patients who had cardiac-related diagnostic work-up in the beginning (i.e., first 6 months) had a higher long-term risk of cardiovascular events. However, even if the patients having early MACE were removed from the analysis, the study demonstrated that patients with unattributed chest pain still had a poorer clinical outcome.

    Beyond just the increased risk posed by having INOCA, there are also potential patient benefits of diagnosing INOCA. In one study, 89% of INOCA could be attributed to either coronary vasospasm (17%), CMD (52%), or both (20%).

    Subsequent implementation of the appropriate therapy based on a diagnosis of CMD or coronary vasospasm led to an improvement in patient symptoms and quality of life [9].

    Looking at CMD alone, there is now a body of evidence from several imaging modalities which indicates that patients with CMD have a more than three-fold increase in mortality and a two-to-five-fold increase in MACE [10, 11]. Much of the early evidence indicating prognosis is based on positron emission tomography-computed tomography (PET-CT), echocardiography and invasive catheter coronary angiography studies [10, 11]. However, recently there have been CMR studies which have also demonstrated the prognostic significance of CMD [12, 13]. Thus prognostication of CMD using non-invasive imaging is now potentially more widely available than it ever has been.

    Coronary macrovascular and microvascular circulation

    The coronary circulation is much more complex and extensive than usually visualized with invasive or non-invasive imaging. The coronary artery vasculature can be subdivided into the epicardial, pre-arteriole, arteriole and capillaries segments. The microcirculation comprises of vessels with diameters <300 µm [14]. The spatial resolution of CT and catheter coronary angiography are 0.5 and 0.3 mm, respectively [15], which indicate that at best, one is able to visualise pre-arterioles, but arterioles and capillaries are beyond current capabilities for visualisation.

    At the microvascular level, the pathways that lead to CMD are multifactorial in nature. In a hypertrophied heart, whether in hypertrophic cardiomyopathy or hypertensive heart disease, the microvasculature develops an increase in wall thickness due to collagen deposition and smooth wall muscle thickening [16]. This in turn results in a narrowing of the vessel lumen. Other issues with the microvasculature can be summarized as impaired vasodilation or increased vasoconstriction. This is usually due to conditions such as diabetes, obesity, dyslipidaemia, smoking, and other cardiovascular risk factors causing impaired vasodilation or increased vasoconstriction thus limiting blood flow into the myocardium (Fig. 2) [16].

    Fig. 2
    CMD and established imaging methods for assessment. CFR: coronary flow reserve, IMR: index of microcirculatory resistance, PET-CT: positron emission tomography-computed tomography, CMD: coronary microvascular disease.

    Coronary vasospasm

    Vasospastic angina (VSA), which is also known as Prinzmetal or variant angina, is a clinical entity characterised by angina induced by coronary artery vasospasm (Fig. 3). Coronary vasospasm can occur in the epicardial coronary arteries or microvascular coronary arteries. In a 2017 publication, the Coronary Vasomotion Disorders International Study group (COVADIS) highlighted three key features of VSA in order to create international diagnostic criteria. These features were 1) nitrate-responsive angina, 2) transient ischaemic electrocardiogram (ECG) changes associated with the angina episode, and 3) coronary artery vasospasm (i.e., ≥90% constriction in a major epicardial artery during invasive catheter angiography) [17]. It should be noted that coronary microvascular vasospasm has been well documented to cause ischaemia [18, 19] (Fig. 2) but would not fulfil this diagnostic criteria. Therefore, coronary microvascular vasospasm would be diagnosed as CMD unless dedicated provocation testing was performed with invasive quantitative coronary blood flow measurements and lactate measurements [20].

    Fig. 3
    Coronary Vasospasm Provocation Testing and COVADIS diagnostic criteria for coronary vasospasm. Green arrowheads demonstrate the region of coronary vasospasm. COVADIS: Coronary Vasomotion Disorders International Study group.

    The underlying cause of VSA is multifactorial. The contributing factors include vascular smooth muscle hyper-reactivity, imbalance of the autonomic nervous system, and endothelial dysfunction. In smooth muscle hyper-reactivity, an increase in intracellular calcium in the smooth muscle cells is thought to be a key contributor to the coronary smooth muscle hypercontractility. Thus calcium channel blockers are routinely prescribed for patients with VSA. Evidence of autonomic nervous system imbalance partly stems from the common finding that patients with VSA can have coronary artery vasospasm induced by acetylcholine, the neurotransmitter of the parasympathetic system [21]. Furthermore, medically refractory VSA has been shown to be responsive to surgical sympathetic denervation [22]. The endothelium is thought to play a role in VSA due to its regulation of the coronary vascular tone by releasing vasodilator substances. Therefore, endothelial dysfunction resulting in a reduction of vasodilator substances like nitric oxide may play a role in VSA.

    Imaging assessment for coronary artery vasospasm

    There are two main investigative modalities for the assessment of coronary artery vasospasm which are invasive catheter coronary angiography and ergonovine echocardiography [23].

    Invasive assessment

    The more common and accepted technique is invasive catheter coronary angiography provocation testing, requiring intracoronary injections of acetylcholine or ergonovine. The COVADIS symposium consensus to diagnose coronary vasospasm was a coronary segment with >90% constriction during angiography [17]. Studies to determine the diagnostic accuracy of ergonovine and acetylcholine have shown sensitivities and specificities of 91% and 97% for ergonovine [24] and 90% and 99% for acetylcholine [25]. Thus invasive catheter coronary angiography provocative testing is regarded as the definitive test for diagnosing coronary vasospasm. However, despite the test being present in the clinical arena for >40 years, the test is largely confined to specialist centres and there are inherent risks such as causing arrhythmia, myocardial infarction, and even death. The indications and contraindications for such an invasive test are stated in Table 1.

    Table 1
    Indications for provocative invasive coronary angiography testing for coronary vasospasm

    Echocardiography

    The second but less well-known method is ergonovine echocardiography, a non-invasive method in which the baseline or rest echocardiography images are obtained and intravenous ergonovine is subsequently injected. Assessment for wall motion abnormality is then undertaken whilst the patient is on continuous ECG monitoring. Currently, there are no other accepted methods for assessing coronary vasospasm. The reported sensitivity and specificity of ergonovine echocardiography is 93% and 91%, respectively [23]. Complications that have been documented with ergonovine echocardiography include headache, nausea, anxiety, hypertensive reaction, and myocardial infarction [26]. Although, not documented during ergonovine echocardiography, during bedside ergonovine testing, death has occurred when higher doses of ergonovine were administered [27]. Therefore, this test should only be performed in controlled environments with nitroglycerin available to reverse the coronary vasospasm.

    CT

    Attempts have been made using CT as an investigative tool and there has been preliminary evidence that this could have a potential role. In a 2016 study [28], baseline coronary CT angiography (CCTA) was first performed without nitrates followed by a second CCTA 3 days later with the administration of intravenous nitrate injection. Coronary vasospasm was diagnosed if one of two findings were identified. Firstly, a ≥50% stenosis with negative remodeling and no definite plaque was identified. Secondly, a diffusely small diameter (<2 mm) of a major coronary artery with a beaded appearance on baseline CT that completely dilated on the subsequent intravenous nitrate CT. All patients also underwent ergonovine provocation testing during catheter coronary angiography. At the patient level, the results demonstrated an overall accuracy of 70%, a sensitivity of 73%, and a specificity of 100%. The degree of accuracy for the detection of VAS was reduced when the analysis was performed at a per-vessel and per-segment level. In another study also involving CT, Ito et al. [29] characterised the segments with vasospasm in order to determine which variables would be positive on subsequent provocation testing. In this study, the authors found that non-calcified plaques with intermediate attenuation and negative remodelling on CCTA were more likely to indicate coronary vasospasm [odds ratio (OR) 48.7, 95% confidence interval (CI) 8.81–269]. Males were also more likely (OR 4.55, 95% CI 1.24–16.6) to have coronary vasospasm. These study results are indeed promising and further research could establish a role for CT to non-invasively assess for VSA.

    CMD

    Definition and classification of CMD

    CMD is a subset of disorders affecting the function and structure of the coronary microvasculature [15].

    There are 4 types of CMD (Table 2) which are primary CMD, secondary CMD [further subdivided into secondary CMD with obstructive CAD (second type) and secondary CMD with myocardial disease (third type)], and iatrogenic CMD. Primary CMD has no obstructive CAD or myocardial disease. Typical conditions which would fall under this category are cigarette smoking, dyslipidaemia, diabetes mellitus, and microvascular angina. Examples of secondary CMD with myocardial disease are hypertrophic cardiomyopathy, aortic stenosis, hypertension, and infiltrative cardiomyopathies. Iatrogenic CMD is usually due to two types of scenarios. One is a consequence of coronary intervention resulting in coronary vasoconstriction at the site of stenting or distal to the stent. The other is a plaque fissuring with embolization of debris into the distal microvasculature [15].

    Table 2
    Classification of coronary microvascular disease

    Imaging assessment of CMD

    Invasive assessment

    Invasive assessment for CMD is regarded as the reference standard for identifying CMD (Table 3). Two different techniques have been utilised to diagnose CMD which are coronary flow reserve (CFR) and the other is index of microcirculatory resistance (IMR).

    Table 3
    Benefits and limitations of invasive coronary angiography, echocardiography, CT, MRI, and PET in assessment of CMD

    CFR requires a Doppler wire (Philips/Volcano Inc.) or a coronary pressure wire (Abbott Vascular) to measure the coronary blood flow velocity at rest and during hyperaemia. The CFR is commonly calculated by comparing the coronary blood flow at rest to the coronary blood flow during peak hyperaemia [30, 31]. Thus CFR is expressed as a ratio of coronary blood flow during hyperaemia vs. coronary blood flow at rest. CFR has been used to assess epicardial CAD as well as CMD. Generally a cut-off <2.0 is regarded as diagnostic of CMD [31]. CFR has some inherent weaknesses which include the requirement of having resting flow in the equation which can be hard to reproduce [30]. Furthermore, there is no clear normal value and newer methods for assessing microvascular coronary circulation have been shown to be more predictive of outcome [32].

    IMR uses a coronary pressure wire to measure resistance and temperature. The wire is specially designed to act as a thermistor at two points along the wire. One in the shaft of the wire and the other at the distal end of the wire. This allows the wire to measure the mean transit time of room temperature saline injected into the coronary artery. The IMR is calculated by multiplying the mean transit time at peak hyperaemia by the distal coronary pressure at peak hyperaemia [30]. An IMR <25 is considered normal based on previous studies in normal subjects [33, 34, 35]. Whilst an IMR ≥25 is utilised for diagnosing CMD. IMR in comparison to CFR has higher inter- and intra-observer reproducibility [36, 37]. IMR also shows low coefficient of variation and high correlation despite pacing, changes in heart rate and blood pressure [38]. One pitfall of IMR is the presence of severe epicardial coronary artery narrowing which can result in IMR being falsely elevated. However, in order to overcome this the collateralisation flow needs to be accounted for. One method of overcoming this is via coronary wedge pressure measurements but achieving hyperaemia is critical in order to acquire accurate measurements [30].

    Echocardiography

    Echocardiography can be used to assess for CMD using two methods, myocardial contrast or Doppler (Table 3). Myocardial contrast echocardiography identifies CMD by calculating the myocardial blood flow (MBF) during rest and stress. This is achieved with a continuous infusion of microbubbles which allows visualisation of myocardial capillaries. At a steady state the signal intensity from the myocardium denotes relative microvascular volume. The icrobubbles can then be cleared from the myocardium with a transient increase in transmit power. The steady state of the circulatory microbubbles allows the myocardium to be replenished which denotes the velocity of the capillary blood. The product of microvascular volume and blood velocity denotes MBF. This assessment of MBF at rest and stress allows microvascular blood flow reserve to be a calculated-marker of CMD [39, 40]. Doppler echocardiography identifies CMD via the calculation of CFR. The Doppler sample volume is placed along the length of the left anterior descending coronary artery and the ratio of blood velocity at stress and rest is defined as the CFR [41].

    Stress echocardiography is already a well-established technique and thus it is also readily available to be used for assessing CMD. In most hospital settings, echocardiography is readily accessible making this an appealing tool for CMD assessment. One area of novel interest is the use of artificial intelligence for myocardial contrast echocardiography to increase workflow efficiency of MBF calculation as this is manually tedious and time consuming [42]. However, some issues of concern include the presence of noise and artefact in the acquired images [40]. Adequate training and clinical experience are also vital to ensure reproducibility and consistent image quality.

    CT

    CT has made significant technological advancements which can assist in the assessment of CMD (Table 3). Firstly, the development of CT-fractional flow reserve (CT-FFR) has improved the functional assessment of epicardial coronary artery narrowing. In the past and in some centres today, obstructive CAD is still determined anatomically rather than with the gold standard of invasive FFR. Thus, coronary artery narrowings which may appear anatomically insignificant (e.g., 50% narrowing) could be functionally significant/obstructive; whilst an anatomically significant narrowing may be functionally insignificant/non-obstructive. Thus CT-FFR allows more confident identification of INOCA. This has helped to overcome the relatively high false positive rate of standard CCTA. A second development is CT myocardial perfusion, which although initially developed to assess the significance of a potentially obstructive lesion, can quantify MBF, which CT-FFR is not designed to do. However, no major studies have confirmed the diagnostic utility of CT myocardial perfusion in the identification of CMD.

    There is anecdotal evidence that CT myocardial perfusion could be useful. In a sub-analysis of the multi-centre CORE-320 study [43], the investigators described the prevalence of INOCA with CT perfusion imaging and associated clinical and atherosclerotic characteristics. In addition to coronary angiography and CT myocardial perfusion, patients also underwent nuclear single photon emission CT (SPECT) and invasive coronary angiography. The authors analyzed the proportion of their cohort with no or <50% coronary artery narrowing, but with ischemia detected on the CT myocardial perfusion scan. Here, the investigators found that 8% of patients fulfilled the criteria of INOCA (31 patients out of 381) using CT angiography/perfusion.

    Another CT study has indicated that total coronary lumen volume, mean myocardial mass and the ratio of the coronary lumen volume and myocardial mass can help identify CMD [44]. However, utilising this in the clinical environment currently would not be practical due to the significant post-processing required.

    CT as described earlier has significant benefits in being able to combine anatomical and functional assessment to potentially identify CMD and can be further enhanced by advanced postprocessing such as CT-FFR. In the future, more high resolution CT scanners will be widely available further boosting CT's spatial resolution to 0.25 mm from the already high spatial resolution of 0.5 mm to 0.625 mm [45]. However, the limitations of CT include the lack of studies confirming its diagnostic ability in CMD. Radiation exposure is also a concern and repeated scans to analyse an improvement in perfusion as a result of treatment may not outweigh the risks of radiation. Furthermore, iodinated contrast agents can cause vasodilation resulting in overestimation of MBF [46]; iodinated contrast agents are also limited in its use in patients with renal impairment due to the their known nephrotoxic effects.

    CMR

    CMR has two variables for assessing CMD which are the semiquantitative myocardial perfusion reserve index (MPRI) and more recently, fully quantitative MBF. MPRI is a measurement based on the myocardial perfusion and arterial input function during stress compared to rest. MBF measurements yield perfusion in mL/g/min.

    MPRI is obtained by contouring the stress, rest and blood pool images. This allows software to derive perfusion curves for the myocardium and blood pool, resulting in the calculation of MPRI. At the University of Hong Kong, a recent 3-centre study [13] gathered clinical data of patients with angina without obstructive CAD and analyzed clinical outcomes using MPRI. Using a cut-off of 1.47, patients with an MPRI ≤1.47 had more MACE compared to those with MPRI above that threshold. On applying multivariable Cox regression analysis, MPRI remained an independent variable after adjustment for hypertension and age. This was the first study that indicated that CMR MPRI in patients with angina without obstructive CAD is a predictor of clinical outcome.

    Other studies have also indicated the potential of utilising fully quantitative CMR. Knott et al. [12] performed a 2-centre study of patients with both suspected and established CAD and used artificial intelligence to assess the perfusion, thereby providing near-instantaneous quantification. They showed that patients in the lowest 50th centile of MBF and MPR had higher rates of death (p=0.032 and p=0.01, respectively). Further work has provided complimentary data that MBF could be used to differentiate normal coronary physiology from CMD and triple vessel disease [47]. In this study, patients with obstructive triple vessel disease had the lowest MBF, followed by CMD and then normal coronary physiology. A flow chart was also created by the authors for the diagnosis of CMD, region CMD, obstructive single vessel, two-vessel, triple-vessel disease, or normal coronary physiology. This was based on the presence or absence of a regional perfusion defect and the acquired MBF values.

    Another study by Rahman et al., [48] looked at MBF and MPR for accuracy at identifying CMD. Their data indicated that subendocardial MPR had the best diagnostic accuracy for CMD. Subendocardial and transmural MPR for the detection of CMD had an area under the curve (AUC) of 0.9 and 0.88, respectively, whilst MBF had an AUC of 0.64. However, as their study contained 75 patients from a single centre, larger studies and studies from other sites are required to confirm this.

    CMR has significant benefits as an imaging modality due its lack of ionizing radiation (Table 3). This therefore places CMR in a favorable position to potentially monitor treatment response in terms of MBF as repeated follow-up imaging can be performed. There is now evidence suggesting that automated quantification yields prognostically significant results. In addition, CMR can combine and quantify function, perfusion and tissue characterization in a single scan. However, CMR has limitations such as the common acquisition of only 3 slices of the left ventricle. Nonetheless, progress in performing dynamic 3-dimensional whole heart perfusion [49] or an improvement in rapid image acquisition to acquire more slices in more modern scanners will likely make this less of an issue. For MBF quantification, a dual sequence or dual bolus technique is required. Furthermore, dedicated software is required for contouring and analysis purposes. Lastly, CMR coronary angiograms have not shown significant additive value when added to perfusion imaging in terms of excluding obstructive CAD [50]. Therefore, CMR will be largely confined as a functional imaging test in the assessment of CMD until there are significant improvements in CMR coronary angiography.

    Nuclear-PET and SPECT

    PET is well-established in the assessment of CMD. Several radiotracers can be used, but [13N]NH3 (ammonia) and 82Rb (rubidium) are most often used in clinical practice. Of the other radioisotopes, [15O] Water and [18F] Flurpiridaz are not Food and Drug Administration approved. Ammonia and rubidium, have short half-lives (9.96 minutes and 75 seconds, respectively) [51], hence a generator or cyclotron is required to be near the PET scanner.

    Similar to other modalities, MBF and MPR have been used for CMD diagnosis and are prognostically significant [52, 53]. One area of interest, is the hybrid imaging approach of combining CCTA with PET [54]. This has benefits compared to CCTA with dynamic CT myocardial perfusion in terms of lower radiation dose [55, 56]. However, PET has a lower spatial resolution than CT or CMR. In addition, there are significant logistical issues in terms of obtaining a generator or having a nearby or on-site cyclotron. PET is also expensive, and therefore, doubts remain over its overall cost-effectiveness. Nonetheless, PET is considered the reference standard as it has substantial validation data available. It is able to glean functional data, viability and perfusion information in a single scan (Table 3).

    SPECT is well used and widely available for assessment of myocardial ischaemia [57]. Technical developments to adapt SPECT for myocardial perfusion quantification have been attempted [58] and the advances in solid state detectors using cadmium-zinc-telluride have allowed SPECT to reduce radiation dose and improve image quality [40]. However, large studies have not been undertaken and widespread use of SPECT for myocardial quantification still requires further development [40, 59]. Therefore, SPECT may in the future be used for CMD assessment, but this awaits future studies confirming its feasibility. Furthermore, PET has several advantages compared to SPECT. PET has higher temporal resolution, spatial resolution (PET: 4–7 mm vs. SPECT: 1–15 mm) [60], lower radiation dose (PET: 3.2–4.1 mSv vs. SPECT: 12.2–14.3 mSv) [56] and is well-validated in the use of CMD assessment.

    TREATMENT IMPACT OF IMAGING DIAGNOSIS OF CORONARY VASOSPASM AND CMD

    The CORonary MICrovascular Angina (CorMicA) study was the first randomised controlled trial to determine if invasive imaging diagnosis had an impact on patients' quality of life [9]. The study showed that by diagnosing patients with epicardial coronary vasospasm, CMD or mixed coronary vasospasm and CMD there was an improvement in patient symptoms and quality of life related to angina. For patients with coronary vasospasm, calcium channel blockers (e.g., verapamil) was recommended as first line whilst nitrate or nicorandil were recommended as 2nd or 3rd line treatments, respectively. In patients diagnosed with CMD, aspirin, statin, angiotensin converting enzyme inhibitors and nitroglycerin spray were recommended in all patients. Beta-blockers such as carvedilol were recommended with regards to managing angina symptoms as first line, followed by calcium channel blockers, nicorandil/ranolazine as 2nd and 3rd line treatments, respectively. Currently, there are no randomised controlled trials to indicate improvement in major adverse cardiovascular outcomes.

    CONCLUSION

    INOCA is a frequently encountered clinical problem. It is clinically significant and should not be perceived as benign. The main coronary-related aetiologies are coronary vasospasm and CMD. There are many benefits and limitations of the various investigative modalities. The assessment of CMD can be achieved by invasive catheter coronary angiography, PET, CMR, and echocardiography. Further research is required for CT and SPECT to become established investigative modalities in the evaluation of CMD.

    Notes

    Conflicts of Interest:The authors have no potential conflicts of interest to disclose.

    Author Contributions:

    • Conceptualization: Ming-Yen Ng.

    • Data curation: Ming-Yen Ng.

    • Formal analysis: Ming-Yen Ng, Hok Shing Tang, Lucas Chun Wah Fong, Victor Chan.

    • Funding acquisition: Ming-Yen Ng.

    • Investigation: Ming-Yen Ng, Hok Shing Tang, Lucas Chun Wah Fong, Victor Chan.

    • Methodology: Ming-Yen Ng.

    • Project administration: Ming-Yen Ng.

    • Resources: Ming-Yen Ng.

    • Software: Ming-Yen Ng.

    • Supervision: Ming-Yen Ng, Dudley John Pennell.

    • Validation: Ming-Yen Ng.

    • Visualization: Ming-Yen Ng.

    • Writing—original draft: Ming-Yen Ng, Hok Shing Tang, Victor Chan.

    • Writing—review & editing: all authors.

    Acknowledgments

    We would like to thank Ms Tiffany Law for her help producing Figures 2 and 3.

    References

      1. Ford TJ, Yii E, Sidik N, Good R, Rocchiccioli P, McEntegart M, et al. Ischemia and no obstructive coronary artery disease: prevalence and correlates of coronary vasomotion disorders. Circ Cardiovasc Interv 2019;12:e008126.
      1. Jespersen L, Hvelplund A, Abildstrøm SZ, Pedersen F, Galatius S, Madsen JK, et al. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J 2012;33:734–744.
      1. Jordan KP, Timmis A, Croft P, van der Windt DA, Denaxas S, González-Izquierdo A, et al. Prognosis of undiagnosed chest pain: linked electronic health record cohort study. BMJ 2017;357:j1194.
      1. Bairey Merz CN, Pepine CJ, Walsh MN, Fleg JL. Ischemia and no obstructive coronary artery disease (INOCA) developing evidence-based therapies and research agenda for the next decade. Circulation 2017;135:1075–1092.
      1. Ford TJ, Corcoran D, Berry C. Stable coronary syndromes: pathophysiology, diagnostic advances and therapeutic need. Heart 2018;104:284–292.
      1. Kaski JC, Crea F, Gersh BJ, Camici PG. Reappraisal of ischemic heart disease: fundamental role of coronary microvascular dysfunction in the pathogenesis of angina pectoris. Circulation 2018;138:1463–1480.
      1. Shaw LJ, Merz CN, Pepine CJ, Reis SE, Bittner V, Kip KE, et al. The economic burden of angina in women with suspected ischemic heart disease. Circulation 2006;114:894–904.
      1. Herscovici R, Sedlak T, Wei J, Pepine CJ, Handberg E, Bairey Merz CN. Ischemia and no obstructive coronary artery disease (INOCA): what is the risk. J Am Heart Assoc 2018;7:e008868.
      1. Ford TJ, Stanley B, Good R, Rocchiccioli P, McEntegart M, Watkins S, et al. Stratified medical therapy using invasive coronary function testing in angina: the CorMicA trial. J Am Coll Cardiol 2018;72:2841–2855.
      1. Gdowski MA, Murthy VL, Doering M, Monroy-Gonzalez AG, Slart R, Brown DL. Association of isolated coronary microvascular dysfunction with mortality and major adverse cardiac events: a systematic review and meta-analysis of aggregate data. J Am Heart Assoc 2020;9:e014954.
      1. Brainin P, Frestad D, Prescott E. The prognostic value of coronary endothelial and microvascular dysfunction in subjects with normal or non-obstructive coronary artery disease: a systematic review and meta-analysis. Int J Cardiol 2018;254:1–9.
      1. Knott KD, Seraphim A, Augusto JB, Xue H, Chacko L, Aung N, et al. The prognostic significance of quantitative myocardial perfusion: an artificial intelligence–based approach using perfusion mapping. Circulation 2020;141:1282–1291.
      1. Zhou W, Lee JCY, Leung ST, Lai A, Lee TF, Chiang JB, et al. Long-term prognosis of patients with coronary microvascular disease using stress perfusion cardiac magnetic resonance. JACC Cardiovasc Imaging 2021;14:602–611.
      1. Pries AR, Reglin B. Coronary microcirculatory pathophysiology: can we afford it to remain a black box. Eur Heart J 2017;38:478–488.
      1. Taqueti VR, Di Carli MF. Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review. J Am Coll Cardiol 2018;72:2625–2641.
      1. Camici PG, d'Amati G, Rimoldi O. Coronary microvascular dysfunction: mechanisms and functional assessment. Nat Rev Cardiol 2015;12:48–62.
      1. Beltrame JF, Crea F, Kaski JC, Ogawa H, Ong P, Sechtem U, et al. International standardization of diagnostic criteria for vasospastic angina. Eur Heart J 2017;38:2565–2568.
      1. Mohri M, Koyanagi M, Egashira K, Tagawa H, Ichiki T, Shimokawa H, et al. Angina pectoris caused by coronary microvascular spasm. Lancet 1998;351:1165–1169.
      1. Ohba K, Sugiyama S, Sumida H, Nozaki T, Matsubara J, Matsuzawa Y, et al. Microvascular coronary artery spasm presents distinctive clinical features with endothelial dysfunction as nonobstructive coronary artery disease. J Am Heart Assoc 2012;1:e002485.
      1. Suzuki S, Kaikita K, Yamamoto E, Jinnouchi H, Tsujita K. Role of acetylcholine spasm provocation test as a pathophysiological assessment in nonobstructive coronary artery disease. Cardiovasc Interv Ther 2021;36:39–51.
      1. Yasue H, Horio Y, Nakamura N, Fujii H, Imoto N, Sonoda R, et al. Induction of coronary artery spasm by acetylcholine in patients with variant angina: possible role of the parasympathetic nervous system in the pathogenesis of coronary artery spasm. Circulation 1986;74:955–963.
      1. Bertrand ME, Lablanche JM, Tilmant PY, Ducloux G, Warembourg H Jr, Soots G. Complete denervation of the heart (autotransplantation) for treatment of severe, refractory coronary spasm. Am J Cardiol 1981;47:1375–1378.
      1. Song JK, Park SW, Kang DH, Hong MK, Kim JJ, Lee CW, et al. Safety and clinical impact of ergonovine stress echocardiography for diagnosis of coronary vasospasm. J Am Coll Cardiol 2000;35:1850–1856.
      1. Heupler FA Jr, Proudfit WL, Razavi M, Shirey EK, Greenstreet R, Sheldon WC. Ergonovine maleate provocative test for coronary arterial spasm. Am J Cardiol 1978;41:631–640.
      1. Okumura K, Yasue H, Matsuyama K, Goto K, Miyagi H, Ogawa H, et al. Sensitivity and specificity of intracoronary injection of acetylcholine for the induction of coronary artery spasm. J Am Coll Cardiol 1988;12:883–888.
      1. Cortell A, Marcos-Alberca P, Almería C, Rodrigo JL, Pérez-Isla L, Macaya C, et al. Ergonovine stress echocardiography: recent experience and safety in our centre. World J Cardiol 2010;2:437–442.
      1. Buxton A, Goldberg S, Hirshfeld JW, Wilson J, Mann T, Williams DO, et al. Refractory ergonovine-induced coronary vasospasm: importance of intracoronary nitroglycerin. Am J Cardiol 1980;46:329–334.
      1. Kang EJ, Kim MH, De Jin C, Seo J, Kim DW, Yoon SK, et al. Noninvasive detection of coronary vasospastic angina using a double-acquisition coronary CT angiography protocol in the presence and absence of an intravenous nitrate: a pilot study. Eur Radiol 2017;27:1136–1147.
      1. Ito T, Terashima M, Kaneda H, Nasu K, Ehara M, Kinoshita Y, et al. In vivo assessment of ergonovine-induced coronary artery spasm by 64-slice multislice computed tomography. Circ Cardiovasc Imaging 2012;5:226–232.
      1. Fearon WF, Kobayashi Y. Invasive assessment of the coronary microvasculature: the index of microcirculatory resistance. Circ Cardiovasc Interv 2017;10:e005361.
      1. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med 2007;356:830–840.
      1. Carrick D, Haig C, Ahmed N, Carberry J, Yue May VT, McEntegart M, et al. Comparative prognostic utility of indexes of microvascular function alone or in combination in patients with an acute st-segment–elevation myocardial infarction. Circulation 2016;134:1833–1847.
      1. Melikian N, Vercauteren S, Fearon WF, Cuisset T, MacCarthy PA, Davidavicius G, et al. Quantitative assessment of coronary microvascular function in patients with and without epicardial atherosclerosis. EuroIntervention 2010;5:939–945.
      1. Luo C, Long M, Hu X, Huang Z, Hu C, Gao X, et al. Thermodilution-derived coronary microvascular resistance and flow reserve in patients with cardiac syndrome X. Circ Cardiovasc Interv 2014;7:43–48.
      1. Solberg OG, Ragnarsson A, Kvarsnes A, Endresen K, Kongsgård E, Aakhus S, et al. Reference interval for the index of coronary microvascular resistance. EuroIntervention 2014;9:1069–1075.
      1. Pagonas N, Gross CM, Li M, Bondke A, Klauss V, Buschmann EE. Influence of epicardial stenosis severity and central venous pressure on the index of microcirculatory resistance in a follow-up study. EuroIntervention 2014;9:1063–1068.
      1. Payne AR, Berry C, Doolin O, McEntegart M, Petrie MC, Lindsay MM, et al. Microvascular resistance predicts myocardial salvage and infarct characteristics in ST-elevation myocardial infarction. J Am Heart Assoc 2012;1:e002246.
      1. Ng MK, Yeung AC, Fearon WF. Invasive assessment of the coronary microcirculation: superior reproducibility and less hemodynamic dependence of index of microcirculatory resistance compared with coronary flow reserve. Circulation 2006;113:2054–2061.
      1. Hayat SA, Dwivedi G, Jacobsen A, Lim TK, Kinsey C, Senior R. Effects of left bundle-branch block on cardiac structure, function, perfusion, and perfusion reserve: implications for myocardial contrast echocardiography versus radionuclide perfusion imaging for the detection of coronary artery disease. Circulation 2008;117:1832–1841.
      1. Dewey M, Siebes M, Kachelrieß M, Kofoed KF, Maurovich-Horvat P, Nikolaou K, et al. Clinical quantitative cardiac imaging for the assessment of myocardial ischaemia. Nat Rev Cardiol 2020;17:427–450.
      1. Meimoun P, Tribouilloy C. Non-invasive assessment of coronary flow and coronary flow reserve by transthoracic Doppler echocardiography: a magic tool for the real world. Eur J Echocardiogr 2008;9:449–457.
      1. Li Y, Ho CP, Toulemonde M, Chahal N, Senior R, Tang MX. Fully automatic myocardial segmentation of contrast echocardiography sequence using random forests guided by shape model. IEEE Trans Med Imaging 2018;37:1081–1091.
      1. Kugiyama K, Ohgushi M, Motoyama T, Sugiyama S, Ogawa H, Yoshimura M, et al. Nitric oxide-mediated flow-dependent dilation is impaired in coronary arteries in patients with coronary spastic angina. J Am Coll Cardiol 1997;30:920–926.
      1. Grover R, Leipsic JA, Mooney J, Kueh SH, Ohana M, Nørgaard BL, et al. Coronary lumen volume to myocardial mass ratio in primary microvascular angina. J Cardiovasc Comput Tomogr 2017;11:423–428.
      1. Takagi H, Tanaka R, Nagata K, Ninomiya R, Arakita K, Schuijf JD, et al. Diagnostic performance of coronary CT angiography with ultra-high-resolution CT: comparison with invasive coronary angiography. Eur J Radiol 2018;101:30–37.
      1. Goossens A, Vander Elst L, Van Haverbeke Y, Muller RN. Mechanical and biochemical cardiac disturbances induced by bolus administration of iodinated contrast media and noniodinated solutions. Invest Radiol 1995;30:1–9.
      1. Kotecha T, Martinez-Naharro A, Boldrini M, Knight D, Hawkins P, Kalra S, et al. Automated pixel-wise quantitative myocardial perfusion mapping by CMR to detect obstructive coronary artery disease and coronary microvascular dysfunction: validation against invasive coronary physiology. JACC Cardiovasc Imaging 2019;12:1958–1969.
      1. Rahman H, Scannell CM, Demir OM, Ryan M, McConkey H, Ellis H, et al. High-resolution cardiac magnetic resonance imaging techniques for the identification of coronary microvascular dysfunction. JACC Cardiovasc Imaging 2021;14:978–986.
      1. McDiarmid AK, Ripley DP, Mohee K, Kozerke S, Greenwood JP, Plein S, et al. Three-dimensional whole-heart vs. two-dimensional high-resolution perfusion-CMR: a pilot study comparing myocardial ischaemic burden. Eur Heart J Cardiovasc Imaging 2015;17:900–908.
      1. Greenwood JP, Maredia N, Younger JF, Brown JM, Nixon J, Everett CC, et al. Cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC): a prospective trial. Lancet 2012;379:453–460.
      1. Sciagrà R, Lubberink M, Hyafil F, Saraste A, Slart RHJA, Agostini D, et al. EANM procedural guidelines for PET/CT quantitative myocardial perfusion imaging. Eur J Nucl Med Mol Imaging 2021;48:1040–1069.
      1. Murthy VL, Naya M, Taqueti VR, Foster CR, Gaber M, Hainer J, et al. Effects of sex on coronary microvascular dysfunction and cardiac outcomes. Circulation 2014;129:2518–2527.
      1. Ziadi MC, Dekemp RA, Williams KA, Guo A, Chow BJ, Renaud JM, et al. Impaired myocardial flow reserve on rubidium-82 positron emission tomography imaging predicts adverse outcomes in patients assessed for myocardial ischemia. J Am Coll Cardiol 2011;58:740–748.
      1. Kaufmann PA, Di Carli MF. Hybrid SPECT/CT and PET/CT imaging: the next step in noninvasive cardiac imaging. Semin Nucl Med 2009;39:341–347.
      1. Patel AR, Bamberg F, Branch K, Carrascosa P, Chen M, Cury RC, et al. Society of cardiovascular computed tomography expert consensus document on myocardial computed tomography perfusion imaging. J Cardiovasc Comput Tomogr 2020;14:87–100.
      1. Desiderio MC, Lundbye JB, Baker WL, Farrell MB, Jerome SD, Heller GV. Current status of patient radiation exposure of cardiac positron emission tomography and single-photon emission computed tomographic myocardial perfusion imaging. Circ Cardiovasc Imaging 2018;11:e007565.
      1. Asher A, Ghelani R, Thornton G, Rathod K, Jones D, Wragg A, et al. UK perspective on the changing landscape of non-invasive cardiac testing. Open Heart 2019;6:e001186.
      1. Shrestha U, Sciammarella M, Alhassen F, Yeghiazarians Y, Ellin J, Verdin E, et al. Measurement of absolute myocardial blood flow in humans using dynamic cardiac SPECT and 99mTc-tetrofosmin: method and validation. J Nucl Cardiol 2017;24:268–277.
      1. Slomka P, Berman DS, Germano G. Myocardial blood flow from SPECT. J Nucl Cardiol 2017;24:278–281.
      1. Driessen RS, Raijmakers PG, Stuijfzand WJ, Knaapen P. Myocardial perfusion imaging with PET. Int J Cardiovasc Imaging 2017;33:1021–1031.
    MeSH Terms
    Coronary Angiography
    Coronary Artery Disease*
    Coronary Vasospasm
    Coronary Vessels*
    Humans
    Ischemia
    Prognosis
    Thinking
    Metrics
    Share
    Figures
    slide
    slide
    slide

    1 / 3

    Tables
    slide
    slide
    slide

    1 / 3

    ORCID IDs
    PERMALINK