We provided an overview of currently used non-invasive imaging techniques and corresponding reference values for CMD in patients with AP and no or nonobstructive CAD as well as healthy subjects. Mean MPRI determined by CMR ranged from 1.47 ± 0.36 [31] to 1.83 ± 0.50 [32] in patients and from 1.50 ± 0.47 [31] to 2.23 ± 0.37 [6] in healthy controls, CFR by PET and TTE ranged from 1.39 ± 0.31 [33] to 2.85 ± 1.35 [34] and 1.69 ± 0.40 [35] to 2.40 ± 0.40 [36] for patients, and 2.68 ± 0.83 [37] to 4.32 ± 1.78 [38] and 2.65 ± 0.65 [39] to 3.31 ± 1.10 [40] for controls, respectively. Due to the heterogeneity between the included studies we were unable to perform a formal meta-analysis.
MPRI was found to correlate well with invasive measurements obtained with CRT, such as index of microcirculatory resistance and CFR [15, 23]. Therefore, MPRI could potentially serve as a non-invasive alternative to CRT. Current literature proposes two different cut-off values, namely 1.40 and 1.84 [6, 15], corresponding with the results found in this review. However, the results of this review suggest a grey area of MPRI values, as some overlap is seen between MPRI in patients and healthy controls. Stress MBF values can aid in differentiating CMD from normal coronary microvascular function. Liu et al. [15] have shown that a decreased stress MBF (i.e. less than 2.30 ml/min/g) is suggestive of CMD in patients with inconclusive MPRI values. Furthermore, some CMR studies now investigate the clinical applicability of quantitative myocardial tissue characterization with rest and stress T1 mapping as an alternative [29, 41]. Ischemic myocardial tissue can be differentiated from healthy tissue based on distinct properties at T1 mapping during rest and stress conditions, without the use of contrast agents. However, the diagnostic value of T1 mapping in diagnosing CMD still needs extensive validation [29].
Currently, PET is the most frequently applied and validated non-invasive imaging technique in quantifying microvascular blood flow. PET is considered the golden standard of non-invasive diagnosis of CMD, although discordance between invasive fractional flow reserve (FFR) and non-invasive CFR is reported in up to 30% of cases [16, 26, 27, 42]. CMD is generally diagnosed with a CFR less than 2.0 if corrected for RPP or less than 2.5 if uncorrected [28, 38, 43, 44]. However, no evidence-based cut-off values for CFR in PET are available yet. Similarly, no cut-off values for CFR in TTE have yet been determined and generally a cut-off value of less than 2.0 for the diagnosis of CMD is applied [18, 45–49]. TTE assessment of CFR with Doppler echocardiography has been validated against intracoronary Doppler measurements and outcomes correlate well [2, 5, 36, 50].
Causes of heterogeneity
Patient groups
The heterogeneity in outcomes observed in this systematic review is most likely the result of differences in inclusion criteria applied across several studies and differences in the use of imaging techniques. Although most studies investigated patients with typical AP and no or nonobstructive CAD during diagnostic CAG, the setting in which participants were recruited was not reported clearly. Furthermore, the definition of no or nonobstructive CAD was often unclear and, if documented, heterogeneous among the included studies (Additional file 7: Table S6). Therefore, a more homogeneous definition could not be applied in the search method. Hence, we suggest the use and documentation of standardized criteria as reported by COVADIS [12].
Methodological differences
Unclarity of the used reference standard, as reflected by the risk of bias assessment (Additional file 3: Table S2), may have introduced significant bias. Moreover, it was often unclear whether researchers were blinded to the reference standard when interpreting results from the index test.
Furthermore, measurement of MPRI in CMR might contribute to the inconsistent results observed in this systematic review. MPRI can be measured transmural, but also subendo- or epicardial. Several studies show subendocardial MPRI to be decreased more often than epicardial MPRI in CMD patients [31, 48, 51, 52], which might indicate subendocardial MPRI to be more valuable in diagnosing CMD as compared with epicardial or transmural MPRI. Unfortunately, in this systematic review only transmural MPRI values were included.
Regarding PET, correction for RPP is not standard which results in decreased comparability of outcomes. Moreover, the use of different radioactive tracers (15O-water, 13N-ammonia and Rubidium-82) could result in varying outcomes due to differences in characteristics and processing of images [14, 27, 28]. The use of a specific radiotracer might require a specific cut-off value to diagnose CMD [14]. Similar concerns apply to the use of various vasoactive agents to achieve hyperemia in stress perfusion imaging. Adenosine and dipyridamole are most commonly administered to achieve hyperemia. However, adenosine seems to be superior to dipyridamole with regard to attaining maximal hyperemia [27, 53, 54].
Lastly, this systematic review highlights the discordance in nomenclature and reporting of outcomes. Standardization of outcome parameters reported could increase comparability of studies assessing reference values for the diagnosis of CMD.
Sex differences
Sex differences could contribute to discrepancies between studies. Kobayashi et al. [17] measured coronary vascular diameter with quantitative CAG and intravascular ultrasound in patients with AP and nonobstructive CAD and found a smaller vascular diameter in women. Furthermore, they showed a significantly higher resting CBF in women. The latter is consistent with findings by Opstal et al. [55] and Chareonthaitawee et al. [56] who studied coronary blood flow in healthy subjects with 13N-ammonia PET (n = 206) and 15O-water PET (n = 169), respectively. These findings suggest sex differences in flow parameters. High resting myocardial flow volumes could decrease CFR (in PET and TTE) or MPRI (in CMR) in women compared to men as flow parameters are determined as the ratio of stress and rest perfusion. Although sex differences in resting MBF and CFR have been observed in invasive CRT [3, 17, 57], only one of the included studies included assessed sex differences regarding CBF and reported no significant sex differences [30]. These findings are consistent with another study comparing non-invasive CFR between men and women using PET [58]. Therefore, further research is needed to establish whether or not sex-specific cut-off values are required for the non-invasive diagnosis of CMD.
Recommendations for future research
The studies included in this review show heterogeneity in study methodology and outcome. This contributes to the discrepancies in outcomes between studies and to the lack of consensus regarding definition and cut-off values for CMD in non-invasive imaging modalities. We emphasize the need for large validation studies and suggest standardization of outcome parameters to reduce heterogeneity and increase comparability of studies. This is needed to provide clinically applicable, possibly sex-specific, reference values for the diagnosis of CMD in the future. Furthermore, during this systematic review, we found several other imaging modalities that are studied for their potential to diagnose CMD, such as myocardial contrast echocardiography (MCE) [47, 59, 60], CT-perfusion [61] and absolute quantification of myocardial perfusion by CMR [62]. However, current evidence is still limited so the clinical significance and applicability in regular care of these modalities in CMD diagnosis remains unclear.
Study limitations
The number of studies investigating non-invasive imaging techniques to diagnose CMD is limited. As such, the results of this systematic review are based on limited data. Hence, only an indication of reference and cut-off values could be provided. Furthermore, a formal meta-analysis could not be performed due to heterogeneity of included studies. In addition, the risk of selection bias in the included studies was high. These limitations emphasize the importance of standardization of imaging protocols and analyses, patient selection and reporting of outcome measurements to obtain reliable and clinically relevant cut-off values for CMD.