Index of microcirculatory resistance: state-of-the-art and potential applications in computational simulation of coronary artery disease

Index of microcirculatory resistance: state-of-the-art and potential applications in computational simulation of coronary artery disease 微循环阻力指数（IMR）：冠状动脉疾病计算仿真的最新和潜在应用 1 first-author 1 2 2 corresp Dingchang ZHENG, dingchang.zheng@coventry.ac.uk Dingchang ZHENG, dingchang.zheng@coventry.ac.uk dingchang.zheng@coventry.ac.uk https://orcid.org/0000-0001-8077-4548 1 corresp Ling XIA, xialing@zju.edu.cn Ling XIA, xialing@zju.edu.cn xialing@zju.edu.cn https://orcid.org/0000-0002-1937-9693 Key Laboratory for Biomedical Engineering of Ministry of Education, Institute of Biomedical Engineering, Zhejiang University, Hangzhou 310027, China Key Laboratory for Biomedical Engineering of Ministry of Education, Institute of Biomedical Engineering, Zhejiang University, Hangzhou 310027, China Research Centre of Intelligent Healthcare, Faculty of Health and Life Science, Coventry University, Coventry CV1 5FB, UK Research Centre of Intelligent Healthcare, Faculty of Health and Life Science, Coventry University, Coventry CV1 5FB, UK The dysfunction of coronary microcirculation is an important cause of coronary artery disease (CAD). The index of microcirculatory resistance (IMR) is a quantitative evaluation of coronary microcirculatory function, which provides a significant reference for the prediction, diagnosis, treatment, and prognosis of CAD. IMR also plays a key role in investigating the interaction between epicardial and microcirculatory dysfunctions, and is closely associated with coronary hemodynamic parameters such as flow rate, distal coronary pressure, and aortic pressure, which have been widely applied in computational studies of CAD. However, there is currently a lack of consensus across studies on the normal and pathological ranges of IMR. The relationships between IMR and coronary hemodynamic parameters have not been accurately quantified, which limits the application of IMR in computational CAD studies. In this paper, we discuss the research gaps between IMR and its potential applications in the computational simulation of CAD. Computational simulation based on the combination of IMR and other hemodynamic parameters is a promising technology to improve the diagnosis and guide clinical trials of CAD. 冠状动脉微循环功能异常是冠状动脉疾病（CAD）发生的重要原因。微循环阻力指数（IMR）是定量评价冠状动脉微循环功能的指标，为冠状动脉疾病的早期预测、诊断、治疗及预后提供了重要参考。IMR在研究心外膜和微循环功能障碍之间的相互作用方面起着关键作用，并与一些血流动力学参数（例如流速、远端冠脉压力和主动脉压力）密切相关，这些参数已广泛应用于CAD的计算研究。然而，目前IMR的正常范围与病理范围缺乏一致性。IMR与其他血流动力学参数之间的关系尚未被准确量化，这限制了IMR在CAD计算研究中的应用。在这篇文章中，我们讨论了IMR与CAD计算仿真方面的研究空白和应用潜力。在未来，将IMR与其他血流动力学结合应用在计算模拟中，有望提高CAD诊断水平以及为相关临床实验提供重要参考。 Index of microcirculatory resistance (IMR) Coronary artery disease (CAD) Computational simulation 微循环阻力指数（IMR） 冠状动脉疾病（CAD） 计算仿真 1 Introduction 1 1.1 Index of microcirculatory resistance (IMR): definition and measurement methods 2 In coronary circulation, over 90% of the total flow resistance originates from the pre-arterioles (vessels 200‒500 μm in diameter), arterioles (vessels < 200 μm in diameter), and capillaries (vessels 5‒10 μm in diameter) in the microvasculature system. Microcirculatory resistance (i.e., microvascular resistance) plays an important role in regulating coronary flow conductance and the balance between oxygen supply and nutrient demand ( Patel and Fisher, 2010 Patel and Fisher, 2010 ; Herrmann et al., 2012 Herrmann et al., 2012 ). The IMR has been proposed as a simple and effective parameter to evaluate coronary microcirculation ( Fearon et al., 2003 Fearon et al., 2003 ). Currently, IMR is regarded as the gold standard for evaluating coronary microcirculatory dysfunction (i.e., microvascular dysfunctions) ( Fearon and Kobayashi, 2017 Fearon and Kobayashi, 2017 ). In vivo measurement of IMR is achieved invasively by using an intravascular guide wire. A guide catheter is inserted through the coronary orifice, and then the pressure and temperature are measured by an extending guide wire. In a state of maximal hyperemia induced by adenosine or papaverine, room-temperature saline is injected into the coronary artery three times consecutively to obtain reproducible and consistent thermodilution curves ( Fig. 1 Fig. 1 b), from which the mean transit time ( <math id="M1"><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669202&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669201&type= 4.74133301 3.72533321 ) is calculated. The distal coronary pressure ( <math id="M2"><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669043&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669028&type= 3.47133350 3.72533321 ) is measured by a pressure-temperature sensor. In coronary microcirculation, perfusion pressure approaches distal coronary pressure, and myocardial flow is inversely related to the <math id="M3"><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669202&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669201&type= 4.74133301 3.72533321 assessed by thermodilution. The resistance of microcirculation is related to the perfusion pressure and myocardial flow ( Fig. 1 Fig. 1 a). According to thermodilution theory, the IMR can be derived from the following equation ( Camici et al., 2015 Camici et al., 2015 ) ( Fig. 1 Fig. 1 ): <math display="block" id="M4"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub><mo>,</mo></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669049&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669056&type= 25.39999962 4.31799984 1;2;3; where the unit of IMR is mmHg·s (i.e., U; 1 mmHg=0.133 kPa). In the presence of epicardial stenosis in proximal coronary arteries, collateral blood flow contributes greatly to myocardial blood flow, and the IMR can be derived by the following equation ( Fearon et al., 2004 Fearon et al., 2004 ): <math display="block" id="M9"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub><mfenced open="[" close="]" separators="|"><mrow><mrow><mrow><mfenced separators="|"><mrow><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>-</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">w</mi></mrow></msub></mrow></mfenced></mrow><mo>/</mo><mrow><mfenced separators="|"><mrow><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub><mo>-</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">w</mi></mrow></msub></mrow></mfenced></mrow></mrow></mrow></mfenced><mo>,</mo></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669113&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669104&type= 61.38333893 6.85799980 where <math id="M10"><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669108&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669117&type= 3.38666677 3.72533321 is the aortic pressure measured by a guiding catheter, <math id="M11"><mi mathvariant="normal">a</mi><mi mathvariant="normal">n</mi><mi mathvariant="normal">d</mi><mtext> </mtext><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">w</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669111&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669120&type= 9.99066734 3.80999994 is the coronary wedge pressure, defined as the mean distal coronary pressure measured by the central lumen of a balloon catheter during at least a 30-s occlusion of the culprit vessel, representing recruitable collateral vessels ( Meier et al., 1987 Meier et al., 1987 ). In the situation where it is inconvenient to measure <math id="M12"><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">w</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669123&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669121&type= 3.89466691 3.72533321 , based on the linear correlation between the myocardial fractional flow reserve (FFR) and the coronary FFR, the IMR can be derived by the following equation ( Yong et al., 2013 Yong et al., 2013 ): <math display="block" id="M13"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub><mfenced separators="|"><mrow><mn mathvariant="normal">1.35</mn><mo>×</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>/</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub><mo>‒</mo><mn mathvariant="normal">0.32</mn></mrow></mfenced><mo>.</mo></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669125&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669128&type= 56.30332947 5.16466665 1.2 Clinical significance of IMR 2 IMR directly reflects the intensity of coronary microcirculation and the hemodynamic resistance, providing important references for the prediction, diagnosis, treatment, and prognosis of coronary artery disease (CAD) ( Martinez et al., 2015 Martinez et al., 2015 ; Jiao et al., 2021 Jiao et al., 2021 ). IMR has been used as a predictor of myocardial infarct size, myocardial viability, myocardial salvage, and long-term mortality in patients with ST-elevation myocardial infarction (STEMI) ( Clarke et al., 2020 Clarke et al., 2020 ), which is useful to guide early clinical intervention. Besides, the difference between postoperative and preoperative IMR values can be used to evaluate the state of periprocedural myocardial injury (PMI) after percutaneous coronary intervention (PCI), which can serve as a predictor of PMI in patients with acute coronary syndrome or stable angina pectoris ( You et al., 2019 You et al., 2019 ). Regarding applications in diagnosis, IMR has been used to evaluate the recovery of left ventricular function after elective PCI ( Kitabata et al., 2013 Kitabata et al., 2013 ), and assess the microcirculatory dysfunction in patients with STEMI ( Konstantinou et al., 2020 Konstantinou et al., 2020 ) or unstable angina pectoris ( Yong et al., 2011 Yong et al., 2011 ). It has been suggested that IMR can be applied in the assessment of coronary microvascular endothelial function in patients with cardiac syndrome X (CSX) ( Long et al., 2017 Long et al., 2017 ). IMR can also provide information on transplant arteriopathy in the case of cardiac transplantation ( Fearon et al., 2006 Fearon et al., 2006 ). In the evaluation of the microcirculation state of some complicated CADs, such as the Takotsubo syndrome ( Cuisset et al., 2011 Cuisset et al., 2011 ), IMR suggests myocardial reperfusion and elucidates the severity of myocardial ischemia, improving understanding of the mechanisms of CADs. IMR plays an important role in guiding microcirculation-related coronary treatments, including the customization of suitable stents and implementation of pharmacological interventions. This promotes the recovery of myocardial blood flow and improves the prognosis ( Fujii et al., 2011 Fujii et al., 2011 ; Mangiacapra et al., 2013 Mangiacapra et al., 2013 ). IMR has become an increasingly important reference for quantitative assessment of microcirculation in various CAD-related clinical applications ( Martinez et al., 2015 Martinez et al., 2015 ). Furthermore, IMR has a certain prognostic value in patients with STEMI, where IMR > 40 mmHg·s is associated with higher rehospitalization and mortality rates because of heart failure (hazard ratios (HRs)‍=2.1, P =0.034) after primary PCI ( Fearon et al., 2013 Fearon et al., 2013 ). A large-scale assessment of 283 patients with STEMI indicated that IMR > 40 mmHg·s is independently associated with myocardial infarct pathology, left ventricular function changes, and heart failure, which supports the sufficient prognosis of IMR > 40 mmHg·s for patients with STEMI ( Carrick et al., 2016 Carrick et al., 2016 ). However, IMR reflects only hyperemic coronary microcirculation. It does not show high prognostic value in chronic coronary syndrome, which limits the application of this unique index. In comparison, coronary flow reserve (CFR) is another important index for microvascular function, defined as the ratio of the maximum hyperemia flow to the resting flow, and includes the effects of the epicardial and microvascular vessels on myocardial perfusion. The combination of IMR and CFR could lead to higher prognostic efficacy. Park et al. (2016) Park et al. (2016) comprehensively analyzed the IMR and CFR values of 89 patients with STEMI and found that a comprehensive assessment of microcirculation using combined IMR and CFR may discriminate the presence of myocardial viability and predict the long-term prognosis of STEMI patients. Ahn et al. (2016) Ahn et al. (2016) investigated the accuracy of IMR and CFR for early detecting microvascular obstruction in STEMI patients undergoing primary PCI, and found that the combination of CFR and IMR had incremental prognostic value (area under the curve (AUC): 0.941) in comparison with IMR (AUC: 0.868) or CFR (AUC: 0.706) alone. The prognostic capacity of IMR in chronic coronary syndrome deserves further investigation. 1.3 Aim of this review 2 Different cardiac hemodynamic models have been proposed to evaluate CAD. Computational models based on patient-specific CFR, FFR, and instantaneous wave-free ratio (iFR) have been developed to improve the clinical diagnosis and treatment of CAD. IMR, as the gold standard for evaluating microcirculatory function in the clinic, shows promise for the computational study of CAD. We searched the peer-reviewed literature published from 2000 with the keywords of "coronary," "index of microcirculatory resistance," and "computational fluid dynamics" in combination with "microcirculatory resistance" or "microvascular resistance," on the Web of Science, PubMed, IEEE Xplore, Scopus, and Google Scholar. More than 100 studies were found. After reading the abstracts, we excluded some studies unrelated to the measurement or application of IMR. These publications suggest that despite the wide application of IMR in the prediction, diagnosis, treatment, and prognosis of CAD, there are some research gaps that deserve in-depth discussion. Firstly, there is a lack of consensus across studies on the normal range of IMR ( Knaapen et al., 2009 Knaapen et al., 2009 ; Martinez et al., 2015 Martinez et al., 2015 ; Fearon and Kobayashi, 2017 Fearon and Kobayashi, 2017 ). In addition, there is a lack of a quantitative relationship between IMR and coronary hemodynamic parameters such as flow rate, pressure, and microcirculatory resistance. Meanwhile, studies of the application of IMR to computational models of coronary arteries are still lacking. In this review, by analyzing the merits and limitations of existing studies on IMR, we discuss the causes of inconsistencies among IMR values, the key role of IMR in investigating epicardial and microvascular interaction, and the potential application of IMR in the computational simulation of CAD. 2 Normal and pathological ranges of IMR values: a lack of consistency 1 In this review, we included studies in which IMR measurement was performed on healthy subjects and patients with CAD (e.g., CSX and stable angina) or other diseases (e.g., epicardial atherosclerosis and renal microcirculatory dysfunction), as listed in Table 1 Table 1 . These studies were conducted mainly in middle-aged and elderly populations, comprising from 8 to 1096 subjects. The target populations were highly heterogeneous and could be divided into the following categories: (1) patients with CAD: patients with symptomatic coronary atherosclerosis ( Melikian et al., 2010 Melikian et al., 2010 ) or non-obstructive coronary atherosclerotic stenosis ( Li Y et al., 2020 Li Y et al., 2020 ), and patients suffering from CSX ( Luo et al., 2014 Luo et al., 2014 ; Long et al., 2017 Long et al., 2017 ); (2) patients with CAD under treatment: patients undergoing PCI using metal stents ( Ng et al., 2012 Ng et al., 2012 ; Murai et al., 2016 Murai et al., 2016 , 2017 2017 ) or bioresorbable scaffolds ( Rampat et al., 2019 Rampat et al., 2019 ); (3) patients with other cardiovascular diseases including hypertensive renal microcirculatory dysfunction ( Lin et al., 2017 Lin et al., 2017 ), non-ST-segment elevation acute coronary syndrome ( Murai et al., 2018 Murai et al., 2018 ), left ventricular dilatation without coronary artery lesions ( Tebaldi et al., 2020 Tebaldi et al., 2020 ), stable angina, myocardial ischemia, or diabetes mellitus ( Lee et al., 2015 Lee et al., 2015 ); (4) CAD-free subjects: subjects with structurally normal hearts with minimal or no CAD ( Solberg et al., 2014 Solberg et al., 2014 ). In these studies, the values of IMR differed significantly between the patients with microcirculatory lesions and the subjects (healthy or with CAD) without microcirculatory dysfunction ( P < 0.05 for normal IMR values and pathological IMR values). The patients with these pathological conditions differed in their microcirculatory function, which led to the differences in IMR values. Data are expressed as number, mean±SD (range), or median (range). <math id="M27"><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669230&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669229&type= 2.70933342 2.87866688 : aortic pressure; <math id="M28"><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669233&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669231&type= 2.79399991 2.87866688 : distal coronary pressure; <math id="M29"><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669248&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669232&type= 3.97933316 2.87866688 : mean transit time; <math id="M30"><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">w</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669199&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669183&type= 3.13266683 2.87866688 : coronary wedge pressure; IMR: index of microcirculatory resistance; <math id="M31"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><msub><mrow><mi mathvariant="normal">R</mi></mrow><mrow><mi mathvariant="normal">a</mi><mi mathvariant="normal">p</mi><mi mathvariant="normal">p</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669185&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669200&type= 8.04333401 2.79399991 : apparent IMR; <math id="M32"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><msub><mrow><mi mathvariant="normal">R</mi></mrow><mrow><mi mathvariant="normal">c</mi><mi mathvariant="normal">o</mi><mi mathvariant="normal">r</mi><mi mathvariant="normal">r</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669187&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669186&type= 8.29733276 2.79399991 : corrected IMR; SD: standard deviation; CSX: cardiac syndrome X; CAD: coronary artery disease; PCI: percutaneous coronary intervention; FFR: fractional flow reserve; NSTE-ACS: non-ST-segment elevation acute coronary syndrome. 1 mmHg=0.133 kPa; F: a worldwide standard for medical tubing outside diameter, 1 F=1/3 mm. To be continued Reference Disease Number of subjects Age (years) Inclusion/exclusion standard IMR measurement Pathological IMR (mmHg·s) Normal IMR (mmHg·s) Control group Melikian et al., 2010 Melikian et al., 2010 Epicardial atherosclerosis 116 48±16 (15 subjects); 63±11 (101 subjects) Exclusion: patients with diameter severity of >50% in left coronary artery, unstable coronary syndrome, left ventricular ejection fraction of<50%, previous coronary artery bypass surgery, impaired right ventricular function, elevated pulmonary pressures, and valvular heart disease. Thermal dilution theory; <math id="M14"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub><mo>;</mo></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669136&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669143&type= 22.26733208 3.72533321 a 6-F guide catheter; a pressure guide wire (Radi Pressure Wire ® 5, Radi Medical Systems, Uppsala, Sweden) 25.0±13.0 (12.0‒38.0) 19.0±5.0 (14.0‒24.0) 15 subjects without coronary atherosclerosis Luo et al., 2014 CSX 36 54.1±9.2 (18 subjects); 55.3±10.1 (18 subjects) Inclusion: CSX patients with exertional angina, positive exercise treadmill test, and normal epicardial coronary arteries. Exclusion: patients with other coronary artery disease (variant angina, cardiomyopathies, and valvular or congenital heart disease), ejection fraction of <50%, atrial fibrillation or left bundle branch block, uncontrolled hypertension or diabetes mellitus, systemic disorders, and liver or renal insufficiency. Thermal dilution theory; <math id="M15"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669217&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669226&type= 20.91266632 3.21733332 ; a coronary pressure wire (PressureWire-4; Radi Medical Systems, Wilmington, MA, USA) 33.1±7.9 (25.2‒41.0) 18.8±5.6 (13.2‒24.4) 18 subjects with normal coronary arteries at angiography Solberg et al., 2014 Solberg et al., 2014 Healthy subjects 20 47.0±5.5 Exclusion: patients with cardiopulmonary diseases, diabetes mellitus, atrial fibrillation or flutter, significant coronary atheromatosis, and atrial flutter. Thermal dilution theory; <math id="M16"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669217&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669226&type= 20.91266632 3.21733332 ; a pressure guide wire (PressureWire TM Certus TM ; St. Jude Medical, St. Paul, MN, USA) 12.6 (8.9‒22.7) Lee et al., 2015 Lee et al., 2015 Stable angina and asymptomatic CAD 1096 61.1±9.7 Exclusion: patients with acute myocardial infarction and the postinterventional data. Thermal dilution theory; <math id="M17"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><msub><mrow><mi mathvariant="normal">R</mi></mrow><mrow><mi mathvariant="normal">a</mi><mi mathvariant="normal">p</mi><mi mathvariant="normal">p</mi></mrow></msub><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669220&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669211&type= 23.62199974 3.21733332 ; <math id="M18"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><msub><mrow><mi mathvariant="normal">R</mi></mrow><mrow><mi mathvariant="normal">c</mi><mi mathvariant="normal">o</mi><mi mathvariant="normal">r</mi><mi mathvariant="normal">r</mi></mrow></msub><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub><mo>×</mo><mo stretchy="false">(</mo><mn>1.35</mn><mo>×</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>/</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub><mo>-</mo><mn>0.32</mn><mo stretchy="false">)</mo><mo>;</mo></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669153&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669152&type= 56.72666931 3.89466691 a 5‍‒ ‍ 7-F guiding catheter; guide wire (St. Jude Medical, St. Paul, MN, USA) Median IMR app : 17.0 (13.0‒23.5); Median IMR corr : 16.6 (12.4‒23.0) Murai et al., 2016 Murai et al., 2016 Stable angina pectoris undergoing elective PCI 71 64.8±7.7 Inclusion: stable angina patients undergoing PCI and older than 20 years. Exclusion: patients with chronic total occlusion, congestive heart failure, myocardial infarction, arrhythmias, renal insufficiency, previous coronary artery bypass graft, extremely tortuous vessels or heavy calcification, significant valvular disease, and periprocedural myocardial necrosis. Thermal dilution theory; <math id="M19"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669164&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669163&type= 20.91266632 3.21733332 ; a 6-F catheter; a coronary 0.014-inch pressure wire (St. Jude Medical, St. Paul, MN, USA) Pre-PCI: 19.8 (14.6‒28.9); Post-PCI: 16.2 (11.8‒22.1); Follow-up: 14.8 (11.8‒18.7) Lin et al., 2017 Lin et al., 2017 Renal microcirculation 96 56±12 (52 subjects); 56±11 (44 subjects) Inclusion: epicardial stenosis patients with diameter severity from 50% to 70%. Exclusion: patients with diabetes, acute and chronic myocardial infarction or kidney diseases, uncontrolled heart failure, acute and chronic infection, chronic kidney diseases, asthma or smoke or cancer, collateral circulation, and connective tissue disease. Thermal dilution theory; when FFR > 0.80: <math id="M20"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669217&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669226&type= 20.91266632 3.21733332 ; when FFR≤0.80: <math id="M21"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub><mo>×</mo><mo stretchy="false">[</mo><mo stretchy="false">(</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>-</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">w</mi></mrow></msub><mo stretchy="false">)</mo><mo>/</mo><mo stretchy="false">(</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub><mo>-</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">w</mi></mrow></msub><mo stretchy="false">)</mo><mo stretchy="false">]</mo></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669166&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669155&type= 55.03333664 3.89466691 ; 6-F Judkins catheters; a pressure guide wire (St. Jude Medical, Inc., USA) 31.0±5.0 22.0±6.0 44 subjects with normal renal microcirculation Long et al., 2017 Long et al., 2017 CSX 40 53.6±9.8 (20 subjects); 54.7±10.0 (20 subjects) Inclusion: CSX patients with exertional angina, positive exercise treadmill test, and normal epicardial coronary arteries. Exclusion: patients with other coronary artery diseases (angina, cardiomyopathies, valvular or congenital heart disease, regional wall motion abnormalities, atrial fibrillation or left bundle branch block), ejection fraction of <50%, hypertension or diabetes mellitus, and liver or renal insufficiency. Thermal dilution theory; <math id="M22"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669217&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669226&type= 20.91266632 3.21733332 ; a coronary pressure wire (PressureWire-4, Radi Medical Systems, Wilmington, Mass., USA) 32.2±8.0 (24.2‒40.2) 19.5±5.5 (14.0‒25.0) 20 patients with normal coronary arteries at angiography Murai et al., 2018 Murai et al., 2018 NSTE-ACS 83 63.7±9.7 Inclusion: patients with NSTE-ACS undergo PCI. Exclusion: patients with chronic total occlusion or visible side branch occlusion, congestive heart failure, significant valvular disease, myocardial infarction, arrhythmias, renal insufficiency, previous coronary artery bypass graft, significant arrhythmia, and multivessel PCI cases or ST segment elevation after PCI. Thermal dilution theory; <math id="M23"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669217&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669226&type= 20.91266632 3.21733332 ; a 6-F system; a Certus coronary pressure wire (St. Jude Medical, St. Paul, MN, USA) 27.2 (22.9‒46.5) 16.3 (10.7‒29.2) Rampat et al., 2019 Rampat et al., 2019 Bifurcation disease of Medina (Medina type 1,1,0 or 1,0,0 or 0,1,0) 38 62.5±10.4 Inclusion: patients with ABSORB bioresorbable vascular scaffold implantation for coronary bifurcation disease. Exclusion: patients with false bifurcation disease, severe coronary stenosis with diameter severity of>70%. Thermal dilution theory; Pre-PCI: <math id="M24"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub><mo>×</mo><mo stretchy="false">[</mo><mo stretchy="false">(</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>-</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">w</mi></mrow></msub><mo stretchy="false">)</mo><mo>/</mo><mo stretchy="false">(</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub><mo>-</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">w</mi></mrow></msub><mo stretchy="false">)</mo><mo stretchy="false">]</mo></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669176&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669169&type= 55.03333664 3.89466691 ; after PCI and at follow-up: <math id="M25"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669171&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669170&type= 20.91266632 3.21733332 ; a 0.014-inch pressure guidewire (St. Jude Medical Inc., MN, USA) Pre-PCI: 27.7 (18.1‒37.6); Post-PCI: 17.9 (12.1‒29.3); Follow-up: 19.5 (15.7‒30.0) Li Y et al., 2020 Li Y et al., 2020 Coronary tortuosity without apparent coronary atherosclerosis 8 58±6 Inclusion: patients with coronary tortuosity and without coronary atherosclerosis. Exclusion: patients with acute coronary syndrome, previous myocardial infarction or coronary revascularization, myocardial diseases, tachycardia, diabetes, hypotension, or heart failure. Thermal dilution theory; <math id="M26"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669217&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669226&type= 20.91266632 3.21733332 ; 0.014-inch coronary pressure 26.7±2.3 (24.4‒29.0) To be continued However, even in healthy subjects or patients with the same type of physiological diseases, the values of IMR showed some variation. In these studies, the cut-off thresholds of normal IMR were 23 mmHg·s ( Solberg et al., 2014 Solberg et al., 2014 ; Lee et al., 2015 Lee et al., 2015 ), 25 mmHg·s ( Luo et al., 2014 Luo et al., 2014 ; Long et al., 2017 Long et al., 2017 ), or 29 mmHg·s ( Rampat et al., 2019 Rampat et al., 2019 ; Li Y et al., 2020 Li Y et al., 2020 ). The pathological IMR of CSX ranged from 24.2 to 41.0 mmHg·s, the pathological IMR of stable angina ranged from 12.4 to 28.9 mmHg·s, and the pathological IMR of other diseases (e.g., epicardial atherosclerosis and renal microcirculation) ranged from 11.8 to 106.4 mmHg·s. The ranges of IMR values among these studies overlapped greatly. In addition, the distribution of IMR values differed among the three major coronary arteries. The right coronary artery (RCA) had higher IMR values than the left anterior descending artery (LAD) and left circumflex artery (LCX) under the same physiological conditions, and the cut-off values for normal IMR were 22, 24, and 28 mmHg·s for LAD, LCX, and RCA, respectively ( Lee et al., 2015 Lee et al., 2015 ). These inconsistencies in IMR range can be related to differences in sample size, target population, measurement/operation method, and some physiological factors (e.g., distal coronary pressure and blood flow velocity). In terms of statistics, the accuracy of IMR ranges is influenced by the sample size. The target populations came from different countries or regions with different living environments and physical conditions. Although no studies have explicitly shown that IMR values are ethnically-related, we cannot rule out the possibility of differences in coronary microcirculation. Meanwhile, differences in IMR values under the same physiological conditions may come from the lack of standardization of IMR measurement methods. Firstly, the induction of maximal hyperemia is indispensable in the assessment of IMR. The intensity of hyperemia is closely related to drug dosage and route of administration. In some patients, it is difficult to reach maximal hyperemia or to determine the state of maximal hyperemia ( McGeoch and Oldroyd, 2008 McGeoch and Oldroyd, 2008 ). Secondly, during repeated IMR measurements, the different locations of the guide wire cause deviations of the IMR value, as the guide wire should be advanced to at least two thirds of the way down the coronary artery ( Ng et al., 2006 Ng et al., 2006 a). Thirdly, a 6-F ( <math id="M33"><mi mathvariant="normal">F</mi></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669204&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669203&type= 2.11666679 2.62466669 : a worldwide standard for medical tubing outside diameter, 1 F=1/3 mm) guide catheter without a side hole is commonly used in IMR measurement, whereas the accuracies of other catheters (e.g., 4-, 5-, and 7-F guide catheters) remain to be evaluated ( Resar et al., 1994 Resar et al., 1994 ). The IMR value is also sensitive to some physiological factors related to the local hemodynamics of distal arteries, such as vessel geometry, distal coronary pressure, blood flow velocity ( Heller et al., 1994 Heller et al., 1994 ), and the myocardial mass supplied by the specific target vessel ( Echavarría-Pinto et al., 2017 Echavarría-Pinto et al., 2017 ). These factors commonly contribute to differences in IMR values among the branches of the coronary artery. A longer vessel and a larger diameter each contribute to a longer <math id="M34"><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669202&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669201&type= 4.74133301 3.72533321 , resulting in higher IMR values ( Murai et al., 2013 Murai et al., 2013 ; Lee et al., 2015 Lee et al., 2015 ). 3 IMR and CAD: interaction between the epicardial and microcirculatory dysfunctions 1 3.1 Interaction between epicardial and microvascular flow resistance 2 It has been proven that the resistance of downstream small arteries and microcirculation has negligible impact on upstream epicardial resistance ( Kelsey et al., 2016 Kelsey et al., 2016 ). However, there are different viewpoints on the effect of the epicardial (proximal) on microvascular (distal or microcirculatory) flow resistance in coronary circulation. The related publications are summarized in Table 2 Table 2 . Data are expressed as number or mean±SD. <math id="M46"><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669230&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669229&type= 2.70933342 2.87866688 : aortic pressure; <math id="M47"><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669233&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669231&type= 2.79399991 2.87866688 : distal coronary pressure; <math id="M48"><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669248&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669232&type= 3.97933316 2.87866688 : mean transit time; <math id="M49"><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">w</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669250&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669249&type= 3.13266683 2.87866688 : coronary wedge pressure; IMR: index of microcirculatory resistance; IMR app : apparent IMR; IMR true : true IMR; MI: myocardial infarction; PCI: percutaneous coronary intervention; QCA: quantitative coronary angiography; CAD: coronary artery disease; CMS-MEDIS system: Medis Medical Imaging Systems, Leiden, the Netherlands. To be continued Reference Disease Number of subjects Age (years) Inclusion/exclusion standard Treatment Follow-up How was microvascular flow resistance or IMR measured? How was stenosis measured? Conclusion Sambuceti et al., 2001 Sambuceti et al., 2001 Stable angina and single-vessel disease 6 59±11 Inclusion: patients with stable angina. Exclusion: patients with myocardial infarction, preserved left ventricular function, collateral circulation, left ventricular hypertension, and diabetes. Adenosine; coronary angioplasty Microvascular resistance index was calculated as the ratio of distal coronary pressure to flow index. An automated edge-detection system Severe stenosis can lead to increased resistance in the distal coronary arteries, which will be abolished after angioplasty. Chamuleau et al., 2003 Chamuleau et al., 2003 CAD and stable angina 27 60.5±17.5 Inclusion: patients with CAD and angina. Exclusion: patients with coronary occlusions or anatomy, Q-wave myocardial infarction, insulin-dependent diabetes, left ventricular hypertrophy or dysfunction, severe valvular heart disease, and previous coronary bypass grafting. Microvascular resistance was defined as the ratio of mean distal pressure to average peak blood flow velocity. An automated contour detection algorithm during QCA The severity of epicardial stenosis was positively correlated with distal microcirculatory resistance after angioplasty. Aarnoudse et al., 2004a Aarnoudse et al., 2004a Patients scheduled for PCI 30 59±11 Inclusion: patients with single coronary stenosis undergoing elective PCI. Exclusion: patients with acute coronary syndrome or total coronary occlusion. PCI <math id="M35"><mtable columnalign="left"><mtr><mtd><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub><mo>×</mo></mtd></mtr><mtr><mtd><mo stretchy="false">[</mo><mo stretchy="false">(</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>-</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">w</mi></mrow></msub><mo stretchy="false">)</mo><mo>/</mo></mtd></mtr><mtr><mtd><mo stretchy="false">(</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub><mo>-</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">w</mi></mrow></msub><mo stretchy="false">)</mo><mo stretchy="false">]</mo></mtd></mtr></mtable></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669206&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669205&type= 23.45266724 20.99733353 Minimal microcirculatory resistance was independent of epicardial stenosis when considering collateral circulation. Fearon et al., 2004 Fearon et al., 2004 6 pigs <math id="M36"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669219&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669218&type= 20.91266632 3.21733332 Microcirculatory resistance was not affected by epicardial stenosis severity after considering collateral circulation. Ng et al., 2012 Ng et al., 2012 Periprocedural MI 50 61.7±9.4 (10 subjects); 64.5±10.2 (40 subjects) Inclusion: epicardial stenosis patients with diameter severity of ≥50%, and MI grade 3 flow. Exclusion: patients with recent or prior MI. PCI <math id="M37"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub><mo>×</mo><mo stretchy="false">[</mo><mo stretchy="false">(</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>-</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">w</mi></mrow></msub><mo stretchy="false">)</mo><mo>/</mo><mo stretchy="false">(</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub><mo>-</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">w</mi></mrow></msub><mo stretchy="false">)</mo><mo stretchy="false">]</mo></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669208&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669207&type= 55.03333664 3.89466691 Percentage diameter stenosis was measured during QCA. The state of microcirculation has important benefits for MI guides. Yong et al., 2013 Yong et al., 2013 Stable angina or unstable angina 122 62.0±10.2 (50 subjects); 61.9±11.2 (72 subjects) Inclusion: angina patients undergoing elective PCI. Exclusion: patients with MI or previous infarction. PCI <math id="M38"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub><mo>×</mo><mo stretchy="false">(</mo><mn>1.35</mn><mo>×</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>/</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub><mo>-</mo><mn>0.32</mn><mo stretchy="false">)</mo></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669210&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669209&type= 52.57799911 3.89466691 Microcirculatory resistance can be assessed in combination with coronary fractional flow reserve without measuring wedge pressure in the presence of severe epicardial stenosis. Yong et al., 2012 Yong et al., 2012 Undergoing elective PCI of the left anterior descending artery 43 64±9 Inclusion: patients with left descending artery undergo PCI. Exclusion: patients with periprocedural MI. 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Murai et al., 2016 Murai et al., 2016 Stable angina pectoris undergoing elective PCI 71 64.8±7.7 Exclusion: patients with chronic total occlusion, congestive heart failure, MI within the past month or in the target vessel territory, arrhythmias or renal insufficiency, previous coronary artery bypass graft, significant valvular disease or arrhythmias, extremely tortuous vessels or heavy calcification, and periprocedural myocardial necrosis. 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Murai et al., 2017 Murai et al., 2017 Stable angina pectoris 229 66.1±9.6 Exclusion: patients with chronic total occlusion, congestive heart failure, MI within the past month or in the target vessel territory, arrhythmias, or renal insufficiency, previous coronary artery bypass graft, significant valvular disease or arrhythmias, extremely tortuous vessels or heavy calcification, periprocedural myocardial necrosis. 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Rampat et al., 2019 Rampat et al., 2019 Bifurcation disease of Medina 38 62.5±10.4 Exclusion: patients with false bifurcation disease, or epicardial stenosis with diameter severity of >70%. PCI A mean follow-up of 9 months Pre-PCI: <math id="M44"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub><mo>×</mo><mo stretchy="false">(</mo><mn>1.35</mn><mo>×</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>/</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">a</mi></mrow></msub><mo>-</mo><mn>0.32</mn><mo stretchy="false">)</mo></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669225&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669216&type= 52.57799911 3.89466691 ; After PCI and at follow-up: <math id="M45"><mi mathvariant="normal">I</mi><mi mathvariant="normal">M</mi><mi mathvariant="normal">R</mi><mo>=</mo><msub><mrow><mi>P</mi></mrow><mrow><mi mathvariant="normal">d</mi></mrow></msub><mo>×</mo><msub><mrow><mi>T</mi></mrow><mrow><mi mathvariant="normal">m</mi><mi mathvariant="normal">n</mi></mrow></msub></math> http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669217&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=26669226&type= 20.91266632 3.21733332 PCI with ABSORB bioresorbable vascular scaffold implantation could reduce coronary microcirculatory resistance. To be continued In patients with CAD, with an increasing degree of proximal stenosis or atherosclerotic plaque in a coronary artery, the changes in distal hemodynamics (e.g., pressure and flow rate) lead to changes in microcirculatory resistance. The microcirculatory resistance in a distal coronary artery with hemodynamically significant stenosis is higher than that in arteries without stenosis ( Chamuleau et al., 2003 Chamuleau et al., 2003 ). However, after PCI or angioplasty treatment ( Sambuceti et al., 2001 Sambuceti et al., 2001 ), the abnormally high distal minimal microcirculatory resistance of the stenosed artery decreases to a relatively normal range, with an immediate improvement in microcirculatory function ( Ng et al., 2012 Ng et al., 2012 ; Murai et al., 2016 Murai et al., 2016 , 2017 2017 ; Rampat et al., 2019 Rampat et al., 2019 ). With stent implantation or plaque removal, the coronary arteries are restored to patency and then microcirculatory resistance returns to within a normal range ( Rampat et al., 2019 Rampat et al., 2019 ). Furthermore, microcirculatory resistance in follow-up remains at the post-procedural level ( Murai et al., 2016 Murai et al., 2016 ; Rampat et al., 2019 Rampat et al., 2019 ). Some studies have suggested that distal microcirculatory resistance is not affected by proximal coronary arteries ( Fearon et al., 2004 Fearon et al., 2004 ; de Waard et al., 2020 de Waard et al., 2020 ). This phenomenon might be related to two factors. Firstly, it has been demonstrated that with the development collateral circulation, the aortic pressure, distal coronary pressure, and coronary wedge pressure contribute to the stability of the minimum microcirculatory resistance. Therefore, epicardial stenosis has a limited effect on distal minimal microcirculatory resistance ( Aarnoudse et al., 2004a Aarnoudse et al., 2004a ; Fearon et al., 2004 Fearon et al., 2004 ; Layland et al., 2012 Layland et al., 2012 ; Yong et al., 2013 Yong et al., 2013 ). Secondly, in a recent study, it was observed that the geometry of coronary arteries (e.‍g., vessel diameter and lumen area) did not significantly influence distal microcirculatory parameters (e.‍g., capillary density and arteriolar density), and proximal arterial remodeling did not incur severe microcirculatory dysfunction due to the existence of a parallel circulation network ( de Waard et al., 2020 de Waard et al., 2020 ). Considering the interaction between the distal and proximal coronary arteries, the coronary microvascular system is extremely complex. The accurate investigation of the relationship between epicardial and microvascular flow resistance deserves further investigation, as it plays a key role in quantifying coronary blood flow, accurately assessing the severity of coronary microcirculatory dysfunction, and improving the diagnosis of CAD and the prognosis of PCI ( Herrmann et al., 2012 Herrmann et al., 2012 ). 3.2 Key roles of IMR in investigating epicardial and microvascular interaction 2 The measurement of IMR can shed light on the interaction between epicardial and microcirculatory dysfunctions ( Eshtehardi et al., 2011 Eshtehardi et al., 2011 ). Firstly, IMR provides a more accurate representation of microcirculatory resistance in patients with CAD in epicardial arteries compared with FFR or iFR ( Aarnoudse et al., 2004b Aarnoudse et al., 2004b ; Ng et al., 2006 Ng et al., 2006 b). Secondly, during the measurement of IMR, hemodynamic parameters related to epicardial and microcirculatory circulations can be simultaneously obtained ( Aarnoudse et al., 2004a Aarnoudse et al., 2004a ; Fearon et al., 2004 Fearon et al., 2004 ). This makes it possible to perform a synchronized analysis of the interaction between proximal and distal flow resistance. In future studies, more accurate anatomic observations of human coronary microcirculation and large-scale clinical trials on coronary microcirculatory dysfunction could provide more data for quantitative analysis to reveal the details of the interaction between epicardial and microvascular flow resistance. 4 IMR in computational studies of CAD 1 4.1 Relationship between IMR and hemodynamic parameters in computational studies on CAD 2 Computational modelling and simulation have been widely applied in the investigation of coronary hemodynamics. Computational models of arteries include zero-dimensional (0D) models based on lump-parameter Windkessel elements, one-dimensional (1D) models based on pulse wave analysis using simplified Navier-Strokes equations, three-dimensional (3D) models using computational fluid dynamics (CFD) simulation, and fluid-structure interaction (FSI) models, in which the effects of myocardial contraction and coronary artery motion can be considered ( Sinclair et al., 2015 Sinclair et al., 2015 ; Liu et al., 2020b Liu et al., 2020b ). Compared with the 0D and 1D models, the 3D CFD models can represent 3D blood flow in the patient-specific geometry of coronary arteries. CFD simulation has been applied to the non-invasive evaluation of hemodynamic parameters such as FFR ( Tesche et al., 2017 Tesche et al., 2017 ), iFR ( Liu et al., 2020a Liu et al., 2020a ), and parameters difficult to measure directly, such as wall shear stress (WSS) ( Ladisa et al., 2005 Ladisa et al., 2005 ; Karmonik et al., 2013 Karmonik et al., 2013 ; Liu et al., 2018 Liu et al., 2018 ) and filtration rate of low-density lipoprotein ( Liu et al., 2018 Liu et al., 2018 ). These hemodynamic parameters are closely related to the pathophysiology of CAD. However, the cyclic bending motion of coronary arteries ( Hasan et al., 2013 Hasan et al., 2013 ) and myocardial contraction ( Smith, 2004 Smith, 2004 ) have non-negligible effects on coronary hemodynamic parameters. The compression pressure of myocardial contraction on the epicardial vascular wall can be up to 40 kPa (about 300 mmHg) ( Vis et al., 1995 Vis et al., 1995 ), which greatly decreases systolic blood flow. Additionally, the stretching-bending motion causes a large displacement of the coronary arteries, which influences the coronary blood flow in a cardiac cycle. In normal LAD branches, the circumferential strain and axial strain from diastole to systole range from 2.0% to 10.8% and from 1.5% to 14.0%, respectively ( Meza et al., 2018 Meza et al., 2018 ). As a result, the velocity profile of a coronary artery in a cardiac cycle differs greatly from those of other arteries. Considering these characteristics, it is challenging to perform real-time simulation of coronary hemodynamic parameters. Accordingly, FSI simulation incorporating coronary artery motion and myocardial contraction has been extensively used in CAD-related biomechanical studies on plaque progression ( Liang et al., 2013 Liang et al., 2013 ; Javadzadegan et al., 2017 Javadzadegan et al., 2017 ), arterial geometry ( Dong et al., 2015 Dong et al., 2015 ), and heart movement ( Meza et al., 2018 Meza et al., 2018 ; Carpenter et al., 2020 Carpenter et al., 2020 ). Non-invasive hemodynamic assessment of coronary arteries based on computational simulation has been widely investigated and applied in the diagnosis, treatment, and management of CAD ( Serruys et al., 1993 Serruys et al., 1993 ; Pennati et al., 2013 Pennati et al., 2013 ; Coverstone et al., 2015 Coverstone et al., 2015 ; Morris et al., 2016 Morris et al., 2016 ; Li YC et al., 2020 Li YC et al., 2020 ; Wu et al., 2021 Wu et al., 2021 ). In particular, as one of the most important hemodynamic parameters, the flow resistance originates from the frictional resistance between blood components or between blood flow and the vessel wall. The flow resistance of the whole coronary artery tree is often approximately calculated as the mean aortic pressure divided by coronary flow ( di Mario et al., 1994 di Mario et al., 1994 ). Given that microcirculatory resistance plays an important role in flow resistance, the true microcirculatory resistance (TMR), defined as the distal coronary pressure divided by the hyperemic flow, is another essential parameter for coronary hemodynamic assessment. Based on the linear relationship between IMR and TMR ( Fearon et al., 2003 Fearon et al., 2003 ; Aarnoudse et al., 2004b Aarnoudse et al., 2004b ), the pathological changes of microcirculatory resistance can be characterized by IMR values, which makes IMR-based computational simulation of coronary arteries possible. Currently, the intracoronary hemodynamic indicators characterizing microcirculatory resistance include IMR and Doppler flow-derived hyperemic microcirculatory resistance (hMR). Both IMR and hMR are credible in the quantitative assessment of microcirculatory resistance ( Ng et al., 2006 Ng et al., 2006 b; de Waard et al., 2015 de Waard et al., 2015 ), but hMR may have a higher accuracy in the diagnosis of microcirculatory dysfunction ( Williams et al., 2018 Williams et al., 2018 ). Currently, hMR has been recognized as a promising parameter to reliably reflect coronary microcirculatory resistance. However, its large-scale validation and application in computational simulation need further investigation. 4.2 Potential opportunities and research gaps of IMR in computational studies of CAD 2 Coronary hemodynamic assessment has been widely translated to the clinical realm, and has become an effective tool to diagnose the severity of CAD ( Kern and Samady, 2010 Kern and Samady, 2010 ). Using hemodynamic models to assess microcirculatory dysfunction has the potential to reduce the cost and risk of clinical trials. Therefore, the outlook for non-invasive coronary hemodynamic assessment has attracted increasing attention ( Radaelli et al., 2008 Radaelli et al., 2008 ). Limited by the resolution of clinical imaging technologies (500–625 μm in z -axis and 500 μm in the x - to y -axis spatial resolution for computed tomography; 70 to 200 μm axial resolution for intravascular ultrasound) ( Lin and Alessio, 2009 Lin and Alessio, 2009 ; Eshtehardi et al., 2011 Eshtehardi et al., 2011 ; Lempel and Frishman, 2019 Lempel and Frishman, 2019 ) and reproducible image quality, the current non-invasive imaging techniques to evaluate coronary microcirculation have great limitations ( Ahmed, 2014 Ahmed, 2014 ). Despite the high resolution of optical coherence tomography (12‒18 μm axial resolution and 20‒90 μm lateral resolution), it is operator-dependent ( Eshtehardi et al., 2011 Eshtehardi et al., 2011 ). IMR can characterize the minimum microcirculatory resistance of the distal coronary artery, thereby providing more accurate hemodynamic information for related pathophysiological studies and clinical applications. Based on patient-specific IMR values, the individual value of microcirculatory resistance can be roughly inferred according to the linear relationship between IMR and TMR ( Fearon et al., 2003 Fearon et al., 2003 ; Aarnoudse et al., 2004b Aarnoudse et al., 2004b ). Therefore, patient-specific IMR values could be converted to the flow resistance value and applied as the outlet boundary condition of distal artery branches in CFD or FSI models to simulate microcirculatory dysfunction. Based on the thermodilution curves during IMR measurements and coronary downstream resistance changes in a cardiac cycle ( Pijls et al., 2002 Pijls et al., 2002 ), the dynamics of pathological microcirculatory resistance can be calculated and used in a transient simulation of coronary blood flow. With dynamic clinical imaging data, FSI models based on patient-specific estimation of cyclic coronary artery deformation and IMR values might achieve an accurate estimation of cyclic coronary blood flow. However, there are some research gaps limiting the application of IMR in computational studies. Firstly, there have been very few studies on the measurement of flow resistance in coronary arteries, and a lack of large-scale validation ( Fearon and Kobayashi, 2017 Fearon and Kobayashi, 2017 ; Murai et al., 2017 Murai et al., 2017 ; Ai et al., 2020 Ai et al., 2020 ). Furthermore, despite the significant correlation between IMR and flow resistance, there is a lack of knowledge of the quantitative relationship between IMR values and microcirculatory resistance. Compared with flow resistance, IMR is more sensitive to physiological conditions. There have been few clinical studies on the linear relationship between IMR and microcirculatory resistance evaluated in vivo ( Fearon et al., 2003 Fearon et al., 2003 ; Aarnoudse et al., 2004b Aarnoudse et al., 2004b ). Hemodynamic parameters such as flow rate ( Lee and Smith, 2012 Lee and Smith, 2012 ), distal coronary pressure, and aortic pressure ( Morris et al., 2016 Morris et al., 2016 ) are closely associated with IMR, and the quantitative relationship between IMR and these parameters requires further investigation. Finally, as summarized in Table 1 Table 1 , the computational estimation of IMR has not been directly applied in clinical practice, because of inconsistency in the IMR range and the difficulty of distinguishing normal from pathological cases. 5 Conclusions 1 As a direct assessment of coronary microcirculatory dysfunction, IMR is an increasingly important parameter for the diagnosis, treatment, and management of CAD. IMR is closely related to many hemodynamic parameters, especially the flow resistance in coronary arteries, making possible the development of IMR-based computational models of coronary circulation. The major research gaps between IMR and its application in computation models include the lack of consistency in the range of normal IMR values, and the lack of a quantitative relationship between IMR and hemodynamic parameters such as flow rate, distal coronary pressure, and aortic pressure, which deserve in-depth studies in the future. 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Circ Cardiovasc Interv , 5 ( 1 ): 103 - 108 . https://doi.org/10.1161/CIRCINTERVENTIONS.111.966556 https://doi.org/10.1161/CIRCINTERVENTIONS.111.966556 Coronary microcirculatory resistance is independent of epicardial stenosis You W , Yang ZJ , Ye F , 2019 . Value of index of microcirculatory resistance for early prediction of periprocedural myocardial microcirculatory injury after percutaneous coronary intervention in patients with coronary heart disease . Chin J Cardiol , 47 ( 11 ): 894 - 900 (in Chinese) . https://doi.org/10.3760/cma.j.issn.0253-3758.2019.11.008 https://doi.org/10.3760/cma.j.issn.0253-3758.2019.11.008 Value of index of microcirculatory resistance for early prediction of periprocedural myocardial microcirculatory injury after percutaneous coronary intervention in patients with coronary heart disease Yingyi GENG and Xintong WU searched the literature. Yingyi GENG and Haipeng LIU drafted the manuscript. Haipeng LIU, Dingchang ZHENG, and Ling XIA contributed to the revision of this manuscript. Dingchang ZHENG and Ling XIA contributed the framework of the manuscript. All authors have read and approved the final manuscript. This work was supported by the Natural Science Foundation of China (Nos. 61527811 and 61701435), the Key Research and Development Program of Zhejiang Province (No. 2020C03016), the Zhejiang Provincial Natural Science Foundation of China (No. LY17H180003), and the Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (No. 2020RC094), China. 10.1631/jzus.B2100425 1673-1581（2022）02-0123-18 This work was supported by the Natural Science Foundation of China (Nos. 61527811 and 61701435), the Key Research and Development Program of Zhejiang Province (No. 2020C03016), the Zhejiang Provincial Natural Science Foundation of China (No. LY17H180003), and the Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (No. 2020RC094), China. 2021-05-14 2021-10-15 2022-02-15 2022-04-19 2022-01-04 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2022 2022 浙江大学出版社 Yingyi GENG, Xintong WU, Haipeng LIU, Dingchang ZHENG, and Ling XIA declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors. Compliance with ethics guidelines 浙江大学学报（英文版）（B辑：生物医学和生物技术） 2 23