An often found phenomenon in the cath lab is the presence of localized ischemia, e.g., in stress-cardiac magnetic resonance imaging (cMRI), in the absence of obstructive coronary artery disease (CAD) (ischemia with no obstructive CAD, INOCA). Coronary microvascular dysfunction (CMD) causes ischemia via a mismatch between demand and supply of blood flow due to structural and/or functional impairment of coronary microvessels (1). In order to cause ischemia, CMD does therefore not need obstruction of a major epicardial coronary vessel (1)—although CMD and obstructive CAD may coexist and contribute to patient symptoms. CMD may be assessed invasively by functional coronary angiography, which, however, bears patient risks due to pharmacological stimulation and wire advancement, as well as increased costs, radiation and procedural duration. Recently, approaches to assess CMD based only on coronary angiograms (angiography-derived index of microvascular resistance, aIMR) have emerged (2, 3).

Our hypothesis is that CMD as assessed by aIMR co-localizes with and explains ischemia in stress-cMRI in the absence of CAD; This was investigated in the present study.

This retrospective study included 286 vessels from 102 patients undergoing both coronary angiography and cMRI. Groups were:

Clinical exclusion criteria were acute coronary syndromes, hemodynamic instability with use of vasopressors and/or assist devices, chronic total occlusions, arrhythmia, pregnancy, age < 18 years. Insufficient image quality (e.g., with excessive vessel overlap, insufficient vessel filling or lack of two suitable projections) was assessed case-by-case by researchers and led to study exclusion.

According to internal standard operating procedures, angiography was acquired at a minimum frame rate of 10 frames/second. Angiographies with lower frame rates were excluded from the analysis. Contrast dye injection was automatically performed by means of an ACIST injector. aIMR measurement was performed by an experienced, licensed cardiologist blinded to the clinical presentation of the patient and to the results of other tests (including cMRI). A commercially available software (QAngio XA 3D, Medis Medical Imaging System, Leiden, The Netherlands) was used to determine aIMR in all suitable vessels according to previously described protocols (4). As suggested (2), in a non-hyperemic state a⁢I⁢M⁢R=0.9*⁢P⁢a*⁢Q⁢F⁢R*⁢V⁢e⁢s⁢s⁢e⁢l⁢L⁢e⁢n⁢g⁢t⁢hV⁢h⁢y⁢p⁢e⁢r⁢e⁢m⁢i⁢a, where Vhyperemia = 0.1 + 1.55*Vcontrast−0.93*Vcontrast².

aIMR measurement was feasible in at least two coronary vessels in 102 patients of the initially 141 screened according to inclusion/exclusion criteria, with a success rate of 72.3%. Reasons for exclusion were poor image quality in 21 patients (53.8% of the exclusions), technical issues such as low frame rate or missing calibration in 11 (28.2%) and arrhythmia in 7 (17.9%).

INOCA patients presented a highly significant increase in mean aIMR (28.3 ± 5.7) compared to both CAD patients (17.4 ± 5.7, p < 0.001) and controls (22.1 ± 5.9, p < 0.001, Figure 1A). In addition, to investigate if a localized increase in CMD as demonstrated by 3-vessel aIMR co-localizes with areas of ischemia in cMRI and might explain INOCA, we compared aIMR between vessels with and without ischemia in cMRI in INOCA patients. aIMR was significantly increased (33.0 ± 8.1 vs. 25.8 ± 6.3, p = 0.021, Figure 1B) in vessels with vs. without ischemia.

After we could demonstrate that elevated aIMR co-localizes with and therefore may explain ischemia as shown by cMRI, we next assessed the diagnostic efficiency of aIMR in predicting the presence of localized INOCA. Including all vessels in the analysis, single vessel aIMR presented a very good diagnostic efficiency in detecting this localized phenotype of INOCA [AUC 0.861 (0.804–0.925), optimal cut-off 27.1, p < 0.001, Figure 1C]. Similar results were obtained when only the maximal single vessel aIMR for each patient was used for the analysis [AUC 0.856 (0.780–0.931), optimal cut-off 29.7, p < 0.001, Figure 1D].

In this work we could demonstrate that CMD as determined by aIMR is significantly increased in INOCA patients compared to both, patients with obstructive CAD as well as control patients without ischemia. Furthermore, a localized increase in CMD as demonstrated by 3-vessel aIMR co-localizes with areas of ischemia in cMRI and thus may explain INOCA.

We are first to show that CMD as assessed with aIMR may explain ischemia as detected by stress cMRI in the absence of obstructive coronary disease. Our data is in line with previous studies which compared wire-based assessment of CMD with aIMR (2, 3). Our study extends the current knowledge by demonstrating that the often found phenomenon of the presence of ischemia in stress-cMRI in the absence of CAD co-localizes with and can be explained by CMD as assessed by aIMR. Therefore, in these INOCA patients the localized ischemia in cMRI derives from a relevant CMD rather than from an obstructive CAD; this is demonstrated by the elevated aIMR in comparison with the CAD group, where on the contrary the leading mechanism for ischemia is represented by a stenosis of epicardial vessels.

Furthermore, using aIMR we could detect the presence of INOCA and therefore validate aIMR as a wire- and medication-free method to determine CMD. Importantly, aIMR, compared to invasive functional coronary angiography, can measure CMD in all coronary arteries without repeated wire advancement or pharmacological stimulation and, therefore, without additional patient risk.

More interestingly, the co-localization of CMD as determined by an increased aIMR with areas of ischemia in cMRI generates hypotheses on the pathophysiology of such a localized INOCA phenotype. If CMD were solely the product of systemic risk factors, in fact, their effect would be diffuse and ubiquitous, similarly affecting all coronary vessels. Systemic risk factors, such as aging, hypertension, diabetes or nicotine use, definitely play a role in the pathogenesis of INOCA, as shown by their high prevalence in previous studies (5, 6). This is reflected by the overall elevated average aIMR in INOCA patients compared to both control groups in our study. However, this effect is not sufficient to explain our observations alone: the pronounced increase in aIMR in a single vessel territory and its association with localized ischemia may hint to local phenomena as possible causes. Previous studies, for instance, suggested that a low endothelial sheer-stress or paracrine effects may play a role in the genesis of INOCA (7), possibly by more heavily affecting a single vessel; this needs to be analyzed in further studies, but may shed further light on pathogenesis of CMD.

Despite being the first study to investigate the association of aIMR with localized ischemia in INOCA patients, the findings of our study need confirmation in larger, prospective studies. Although our data may pave the way to a more widespread use of non-invasive coronary physiology in the evaluation of CMD, further prospective studies are required to assess the clinical use of aIMR in guiding therapy of INOCA patients. Furthermore, due to study design and insufficient sample size, we are unable to draw any conclusion regarding prognosis and follow-up data is not available.

In conclusion, CMD as assessed by 3-vessel aIMR co-localizes with and may explain the presence of ischemia in stress-cMRI in the absence of CAD as an often found phenomenon in the cath lab.

The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by the EK 098/22 Ethikkommission RWTH Aachen. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

AM, RD, RL, SR, NM, and MB contributed to conception and design of the study. AM and RD performed the measurements. AM, RD, KB, and MB organized the database and performed the statistical analysis. AM wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.