Invasive Coronary Microcirculation Assessment - J-STAGE Home

Circulation Journal Vol.78, May 2014

Circulation JournalOfficial Journal of the Japanese Circulation Societyhttp://www.j-circ.or.jp

Development of IMR TheoryThe technological advance of the coronary pressure wire enabled simultaneous measurement of coronary artery pressure and cor-onary artery flow. With commercially available software, the pressure sensor of the wire acts as a distal thermistor, while the shaft of the wire serves as a proximal thermistor. In this manner, the mean transit time (Tmn) of room-temperature sa-line injected into a coronary artery can be determined from a thermodilution curve (Figure 1).

De Bruyne and Pijls et al applied the thermodilution tech-nique in an experimental model and found a strong correlation between the inverse of Tmn and absolute coronary flow.9,10 They also showed that the thermodilution-derived coronary flow reserve (CFRthermo), defined as the resting mean transit time (TmnRest) divided by the hyperemic mean transit time (TmnHyp), correlated well with the standard CFR, both in their experimen-tal model and in humans.

Fearon et al6,11 further elucidated the usefulness of CFRthermo in open-chest porcine models. Using an ultrasonic flow probe placed around the proximal left anterior descending coronary artery (LAD) and a vascular occluder placed distal to the flow probe, the resting and hyperemic absolute coronary flow could be measured at baseline and after creation of an epicardial stenosis. CFRthermo showed better correlation with the absolute coronary flow-derived CFR than the Doppler velocity-derived CFR, which further validated the thermodilution technique as a method of estimating coronary flow.11

ecent studies have demonstrated the importance of the coronary microvasculature in various clinical settings and in the development of non-invasive tests for assess-

ing it, including Doppler echocardiography, contrast echocar-diography, cardiovascular magnetic resonance, and positron emission tomography.1–4 However, conventional invasive pa-rameters for assessing the microvasculature such as coronary flow reserve (CFR), Thrombolysis In Myocardial Infarction (TIMI) flow grade, corrected TIMI frame count, and TIMI myo-cardial perfusion grades5 have important limitations, including their dependence on resting hemodynamics, semiquantitative nature, and lack of independence of the epicardial vessel. For these reasons, it became important to develop an invasive meth-od for independently, quantitatively and reproducibly assessing the microvasculature, which is predictive of outcomes in various settings.

Against this background and with the development of a ther-modilution technique for estimating coronary flow while simul-taneously measuring coronary pressure, the index of microcir-culatory resistance (IMR) was first described just over 10 years ago.6,7 This method enables investigation of the coronary mi-crovasculature directly with high reproducibility and reliabil-ity in the cardiac catheterization laboratory where many patients in the USA first present for evaluation of their coronary circu-lation.8 This review discusses the development of IMR, tips and tricks for its measurement, and its usefulness in various clinical settings.

R

Received March 25, 2014; accepted March 25, 2014; released online April 16, 2014Division of Cardiovascular Medicine, Stanford University Medical Center, Stanford, CA, USAMailing address: William F Fearon, MD, Division of Cardiovascular Medicine, Stanford University Medical Center, 300 Pasteur Drive

H2103, Stanford, CA 94305-5218, USA. E-mail: [email protected] doi: 10.1253/circj.CJ-14-0364All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

Invasive Coronary Microcirculation Assessment– Current Status of Index of Microcirculatory Resistance –

Yuhei Kobayashi, MD; William F Fearon, MD

Assessment of the coronary microvasculature in the clinical setting is a key issue, given that microvascular dysfunc-tion itself has a predictive value for cardiovascular events. The index of microcirculatory resistance (IMR) is an inva-sive method of interrogating the microvasculature and provides further insight into the physiology of cardiovascular diseases. It is simple and readily applicable in the cardiac catheterization laboratory where many patients first present for evaluation of their coronary circulation. In contrast to other invasive and non-invasive tests, this method is known to be stable and reproducible under various hemodynamics and even in the presence of epicardial coronary artery stenosis. IMR has been shown to have prognostic value in patients with ST-segment elevation myocardial infarction; therefore it can be a surrogate marker of cardiovascular events. At the same time, it has the potential to be a therapeu-tic as well as an investigational tool in the physiology of cardiovascular diseases. This review summarizes the devel-opment of IMR, tips and tricks for its measurement, and its usefulness in various clinical settings. (Circ J 2014; 78: 1021 – 1028)

Key Words: Coronary artery disease; Microcirculation; Physiology

REVIEW


1022 KOBAYASHI Y et al.

function.13 IMR, calculated in its simplest form, is falsely ele-vated in the presence of significant epicardial stenosis, because Tmn is a measurement of coronary flow alone. In the presence of a severe epicardial stenosis, both coronary flow and collat-eral flow contribute to overall myocardial flow, and if one does not account for collateral flow, the denominator in the calcula-tion of resistance will be underestimated and resistance will be overestimated. However, when collateral flow is taken into ac-count by incorporating the coronary wedge pressure into a more complex formula (Figure 2B), IMR remains stable in the pres-ence of increasing epicardial stenosis severity both in an ex-perimental model15 and humans.16–18 Recently, Yong et al de-scribed a method of estimating IMR without coronary wedge pressure measurement (calculated IMR: IMRcalc) in the pres-ence of significant epicardial stenosis, and showed excellent correlation and agreement with true IMR (IMRtrue).19 Details of IMR measurement in the presence of epicardial stenosis will be discussed later.

Standard Measurement Technique of IMRIn this section, specific measurement methods and pitfalls of IMR are discussed.

As in conventional interventional therapy, systemic admin-istration of heparin (50–100 IU/kg) and intracoronary nitroglyc-erin (100–200 μg) is necessary before the procedure. A coro-nary pressure-temperature sensor guide wire (Certus Pressure Wire, St. Jude Medical, St. Paul, MN, USA) is calibrated, equal-ized to the guide catheter pressure with the pressure wire sen-sor positioned at the tip of the catheter, and advanced to the distal two-thirds of the target vessel. Next, 3 ml of room-temperature saline are briskly injected through the guide catheter. With com-mercially available software (Radi Analyzer, St. Jude Medical), the transit time of the room-temperature saline injected into a coronary artery can be automatically determined with a ther-

The derivation of IMR is based on Ohm’s law (the potential difference across an ideal conductor is proportional to the cur-rent through the conductor) applied to the coronary microcir-culation. IMR is defined as the mean distal coronary pressure (Pd) minus venous pressure divided by flow. Because venous pressure is generally negligible relative to distal coronary pres-sure, it is ignored. Because flow is inversely proportional to the mean transit time, IMR is therefore defined as Pd divided by the inverse of the mean transit time or as Pd multiplied by TmnHyp (Figure 2). Because the IMR incorporates only hyper-emic parameters, it eliminates the variability of resting vascu-lar tone and hemodynamics and estimates the minimum achiev-able microvascular resistance.

Using the same porcine model, the true microvascular re-sistance (defined as Pd divided by the absolute coronary flow measured with a flow probe around the LAD [mmHg · ml−1 · min−1] at hyperemia) was compared with IMR (defined as Pd × TmnHyp [mmHg · s or units]) at baseline and after disruption of microcirculation. The IMR and true microvascular resis-tance correlated significantly, as did the percent change from baseline to after disruption of the microcirculation.6

Advantage of IMR Compared With CFRHemodynamic Stability As previously described,12,13 CFR is affected by hemodynamic changes because of the resting parameter included in its for-mula. IMR has shown superior reproducibility and less hemo-dynamic dependence in humans under several hemodynamic perturbations including rapid ventricular pacing, intravenous nitroprusside infusion, and intravenous dobutamine infusion.14

Effect of Epicardial Stenosis CFR interrogates the entire coronary circulation and is there-fore affected by both epicardial stenosis and microvascular dys-

Figure 1. Calculation of the mean tran-sit time using thermodilution technique. Blue line indicates the temperature change detected by the shaft of the wire. Red line indicates the temperature change detected at the distal thermis-tor. Tmn, mean transit time.


1023Assessment of Microcirculation Using IMR

Figure 2. (A) Understanding the index of microcirculatory resistance (IMR) based on Ohm’s law (the potential difference across an ideal conductor is proportional to the current through it). In this image, the potential difference is Pd–Pv, the conductor is micro-circulatory resistance, and the current is myocardial flow. (B) IMR formula in the presence of a severe epicardial stenosis. Col-lateral flow is taken into account by incorporating the coronary wedge pressure (Pw) into a more complex formula. Pa, mean proximal coronary pressure; Pd, mean distal coronary pressure; Pv, mean central venous pressure; Pw, coronary wedge pressure; RA, right atrium.



Figure 3. Schematic of physiological assessment using a single coronary pressure wire. CFRthermo, thermodilution-derived coro-nary flow reserve; FFR, fractional flow reserve; IMR, index of microcirculatory resistance; Pa, mean proximal coronary pressure; Pd, mean distal coronary pressure; TmnHyp, hyperemic mean transit time; TmnRest, resting mean transit time.

Figure 4. Example of physiologic assessment using a pressure wire. CFR, coronary flow reserve; FFR, fractional flow reserve; IMR, index of microcirculatory resistance; Pa, mean proximal coronary pressure; Pd, mean distal coronary pressure; TmnHyp, hy-peremic mean transit time; TmnRest, resting mean transit time.14



follows:

IMR = Pd × TmnHyp = 76 × 0.26 = 19.8.

The normal range of IMR is generally thought to be <25, based on a study by Melikian et al demonstrating a mean IMR value of 19±5 (range 8–28) in a small, healthy control group.21 Luo et al reported a similar mean IMR value of 18.9±5.6 in a small control group referred for coronary angiography but with com-pletely normal angiographic findings.22

IMR Measurement in the Presence of Epicardial StenosisAs previously discussed, the simple formula for IMR can over-estimate microvascular resistance in the presence of a signifi-cant epicardial stenosis because collateral flow is not taken into account. In such cases, coronary wedge pressure (Pw) during

modilution technique (Figure 1).9,10 After repeating the injec-tion of saline 3 times, the resting mean transit time (TmnRest) can be calculated from the average transit time of the 3 injec-tions. Maximal hyperemia is then induced by infusing intrave-nous adenosine (140 μg · kg–1 · min–1) or by injecting intra-coronary papaverine (10–20 mg). During maximal hyperemia, TmnHyp is measured again as has been described. Together with the TmnHyp measurement, Pd measured simultaneously with the same pressure wire and Pa measured with the guide cath-eter are automatically recorded during maximal hyperemia.

Fractional flow reserve (FFR) is defined as Pd divided by Pa during maximal hyperemia, CFRthermo is defined as TmnHyp divided by TmnRest, and IMR is defined as Pd multiplied by TmnHyp (Figure 3).20 Figure 4 shows an example of physio-logic assessment. In this particular case, IMR is calculated as

Figure 5. (A) Kaplan-Meier curves display-ing the relationship between IMR and sur-vival free of death or rehospitalization for heart failure after primary PCI for STEMI. (B) Kaplan-Meier curves displaying the relation-ship between IMR and survival free of death after primary PCI for STEMI. IMR, index of microcirculatory resistance; PCI, percutane-ous coronary intervention; STEMI, ST-seg-ment elevation myocardial infarction.20



vascular dysfunction assessed by the IMR were described by Ito et al (intracoronary nicorandil [2 mg])30 and Camici et al (intracoronary streptokinase [250 kU]).31 Another study showed the effectiveness of using a distal protection device (Filtrap, Nipro, Japan) to minimize microvascular damage during pri-mary PCI at the time of STEMI.32

An important aspect of IMR measurement in this setting is that STEMI patients can be stratified immediately after primary PCI. Therefore, operators do not have to postpone a decision regarding adjunctive therapy until other clinical markers (eg, peak CK) can be obtained.

Stable Patients Undergoing PCIBeneficial effects of adjunctive therapy to improve the IMR were also shown in stable patients undergoing PCI. Mangiacapra et al demonstrated that an intracoronary bolus injection of angio-tensin-converting enzyme inhibitor (enalaprilat [50 μg]) before PCI could result in a significant reduction in the post-proce-dural IMR.33 Another study described that pretreatment with HMG-CoA reductase inhibitors (pravastatin [20 mg/day]) was associated with reduced microvascular dysfunction induced by PCI regardless of side branch occlusions.34

Regarding the detection of high-risk plaque causing micro-vascular dysfunction, Yamada et al found that target lesion thin-cap fibroatheroma detected by virtual histology intravascular ultrasound may be related to a high IMR after PCI.35 Cuisset et al showed, even in stable angina patients, that a direct stent-ing strategy led to a lower post-PCI IMR value compared with conventional stenting with predilatation.36 In addition to those findings, Ng et al reported that a pre-PCI IMR ≥27 was associ-ated with a 23-fold risk of developing periprocedural MI dur-ing elective PCI; therefore, the pre-PCI IMR can predict the subsequent risk of periprocedural myocardial necrosis by de-termining susceptibility and may guide adjunctive prevention strategies.37

Patients With Angina and Normal-Appearing Coronary ArteriesDiagnosis of the source of angina in patients with normal coro-nary arteries is challenging. Lee et al recently reported their results of a thorough invasive assessment including assessment of endothelial function and performance of intravascular ultra-sound, FFR, CFRthermo and IMR measurements in 139 patients with angina without angiographic epicardial disease. Microvas-cular dysfunction (IMR ≥25) was present in 29 patients (20.9%), suggesting that microvascular dysfunction is the source of an-gina in a significant minority of these patients.38 There is an-other publication in which the microvascular function of car-diac syndrome X patients was compared with that of age- and sex-matched control subjects. Although the IMR and CFRthermo revealed significantly worse microvasculature than in the con-trols (IMR 33.1±7.9 vs. 18.8±5.6, and CFRthermo 2.37±0.81 vs. 3.68±0.72, P<0.001 for both), the correlation with disease severity assessed by Duke treadmill score was better with the IMR than with CFRthermo (IMR r=−0.742, P<0.001; CFRthermo r=0.539, P=0.021).22

Application of IMR in Other Clinical SettingsThe contribution of abnormal microvasculature to various car-diovascular diseases can be clarified by measuring the IMR.

Transplant Arteriopathy The IMR can be measured to interrogate the microvasculature in orthotopic heart transplant recipients.39–42 Hirohata et al dem-

balloon inflation should be measured. Then, IMRtrue can be obtained using the following more complex formula:

IMRtrue = Pa × TmnHyp × [Pd-Pw] / [Pa-Pw].17

A recent study described a simple method of calculating IMR without measuring coronary wedge pressure in the presence of significant epicardial stenosis. IMRcalc is obtained using the following formula:

IMRcalc = Pa × TmnHyp × ([1.35 × Pd / Pa-0.32).19

Pitfalls of IMR Measurement and Interpretation There are several pitfalls of IMR measurement. First, a char-acteristic of the IMR is its independence of resting hemody-namic parameters.14 To maximize this characteristic, care must be taken to ensure maximal hyperemia (drug type, dose, infu-sion route, contraindication for drug etc.).23–26

Second, to obtain accurate coronary pressures and Tmn, wedg-ing of the guide catheter and using a guide catheter with side holes should be avoided. A 6Fr guide catheter is generally rec-ommended, because the accuracy of the IMR using a smaller guide catheter has not been fully evaluated.

Third, the pressure wire should be advanced to the distal two-thirds of the target coronary artery and kept in the same posi-tion during repeated measurement, because Tmn can be influ-enced by the distance of the thermistor from the ostium of the coronary artery.

IMR Measurement in STEMI or Stable Patients Undergoing PCI, and in Patients With Angina and

Normal-Appearing Coronary ArteriesIn this section, IMR measurement in ST-segment elevation myocardial infarction (STEMI) or stable patients undergoing percutaneous coronary intervention (PCI), and in patients with angina and normal-appearing coronaries will be discussed separately.

STEMI The IMR can be readily and safely measured after primary PCI in patients with STEMI. In the first study examining IMR in this setting, patients with an IMR below the median value of 32 had significantly lower peak creatine kinase (CK) concen-trations and improved echocardiography-derived wall motion scores at 3 months.27,28 A second study performed in South Korea found similar results with an optimal cutoff value of 33 for predicting LV wall motion recovery based on PET and echo imaging.31 Another study from Scotland reported that the IMR was significantly higher in patients with microvascular obstruc-tion detected by contrast-enhanced cardiac magnetic resonance than in patients without microvascular obstruction (27 [inter-quartile range (IQR) 18–36] without microvascular obstruction vs. 38 [IQR 29–55] with microvascular obstruction).29 Recent-ly, a large multicenter registry including 253 patients in whom the IMR was measured immediately after primary PCI for STEMI found that patients with an IMR ≤ the mean value of 40 had significantly lower rates of death or rehospitalization for congestive heart failure and death alone (Figure 5). It was also shown in multivariate analysis that the IMR was an indepen-dent predictor of both survival alone and survival or rehospi-talization for congestive heart failure, whereas other common invasive methods for assessing microvasculature (CFR, TIMI myocardial perfusion grade and TIMI frame count) were not.20

Beneficial effects of adjunctive therapy to improve micro-



6. Fearon WF, Balsam LB, Farouque HM, Caffarelli AD, Robbins RC, Fitzgerald PJ, et al. Novel index for invasively assessing the coro-nary microcirculation. Circulation 2003; 107: 3129 – 3132.

7. Aarnoudse W, van den Berg P, van de Vosse F, Geven M, Rutten M, Van Turnhout M, et al. Myocardial resistance assessed by guidewire-based pressure-temperature measurement: In vitro validation. Cath-eter Cardiovasc Interv 2004; 62: 56 – 63.

8. Topol EJ, Ellis SG, Cosgrove DM, Bates ER, Muller DW, Schork NJ, et al. Analysis of coronary angioplasty practice in the United States with an insurance-claims data base. Circulation 1993; 87: 1489 – 1497.

9. De Bruyne B, Pijls NH, Smith L, Wievegg M, Heyndrickx GR. Coronary thermodilution to assess flow reserve: Experimental vali-dation. Circulation 2001; 104: 2003 – 2006.

10. Pijls NH, De Bruyne B, Smith L, Aarnoudse W, Barbato E, Bartunek J, et al. Coronary thermodilution to assess flow reserve: Validation in humans. Circulation 2002; 105: 2482 – 2486.

11. Fearon WF, Farouque HM, Balsam LB, Caffarelli AD, Cooke DT, Robbins RC, et al. Comparison of coronary thermodilution and Doppler velocity for assessing coronary flow reserve. Circulation 2003; 108: 2198 – 2200.

12. de Bruyne B, Bartunek J, Sys SU, Pijls NH, Heyndrickx GR, Wijns W. Simultaneous coronary pressure and flow velocity measurements in humans: Feasibility, reproducibility, and hemodynamic dependence of coronary flow velocity reserve, hyperemic flow versus pressure slope index, and fractional flow reserve. Circulation 1996; 94: 1842 – 1849.

13. Kern MJ. Coronary physiology revisited: Practical insights from the cardiac catheterization laboratory. Circulation 2000; 101: 1344 – 1351.

14. Ng MK, Yeung AC, Fearon WF. Invasive assessment of the coronary microcirculation: Superior reproducibility and less hemodynamic de-pendence of index of microcirculatory resistance compared with coro-nary flow reserve. Circulation 2006; 113: 2054 – 2061.

15. Fearon WF, Aarnoudse W, Pijls NH, De Bruyne B, Balsam LB, Cooke DT, et al. Microvascular resistance is not influenced by epicardial coro-nary artery stenosis severity: Experimental validation. Circulation 2004; 109: 2269 – 2272.

16. Aarnoudse W, Fearon WF, Manoharan G, Geven M, van de Vosse F, Rutten M, et al. Epicardial stenosis severity does not affect mini-mal microcirculatory resistance. Circulation 2004; 110: 2137 – 2142.

17. Yong AS, Ho M, Shah MG, Ng MK, Fearon WF. Coronary microcir-culatory resistance is independent of epicardial stenosis. Circ Cardio-vasc Interv 2012; 5: 103 – 108, S101 – S102.

18. Layland J, MacIsaac AI, Burns AT, Somaratne JB, Leitl G, Whitbourn RJ, et al. When collateral supply is accounted for epicardial stenosis does not increase microvascular resistance. Circ Cardiovasc Interv 2012; 5: 97 – 102.

19. Yong AS, Layland J, Fearon WF, Ho M, Shah MG, Daniels D, et al. Calculation of the index of microcirculatory resistance without coro-nary wedge pressure measurement in the presence of epicardial ste-nosis. JACC Cardiovasc Interv 2013; 6: 53 – 58.

20. Fearon WF, Low AF, Yong AS, McGeoch R, Berry C, Shah MG, et al. Prognostic value of the Index of Microcirculatory Resistance mea-sured after primary percutaneous coronary intervention. Circulation 2013; 127: 2436 – 2441.

21. Melikian N, Vercauteren S, Fearon WF, Cuisset T, MacCarthy PA, Davidavicius G, et al. Quantitative assessment of coronary microvas-cular function in patients with and without epicardial atherosclerosis. EuroIntervention 2010; 5: 939 – 945.

22. 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.

23. McGeoch RJ, Oldroyd KG. Pharmacological options for inducing maximal hyperaemia during studies of coronary physiology. Catheter Cardiovasc Interv 2008; 71: 198 – 204.

24. Pijls NH. Fractional flow reserve to guide coronary revascularization. Circ J 2013; 77: 561 – 569.

25. Pijls NH, Tonino PA. The crux of maximum hyperemia: The last re-maining barrier for routine use of fractional flow reserve. JACC Car-diovasc Interv 2011; 4: 1093 – 1095.

26. Nair PK, Marroquin OC, Mulukutla SR, Khandhar S, Gulati V, Schindler JT, et al. Clinical utility of regadenoson for assessing frac-tional flow reserve. JACC Cardiovasc Interv 2011; 4: 1085 – 1092.

27. Fearon WF, Shah M, Ng M, Brinton T, Wilson A, Tremmel JA, et al. Predictive value of the index of microcirculatory resistance in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2008; 51: 560 – 565.

28. Lim HS, Yoon MH, Tahk SJ, Yang HM, Choi BJ, Choi SY, et al. Usefulness of the index of microcirculatory resistance for invasively assessing myocardial viability immediately after primary angioplas-ty for anterior myocardial infarction. Eur Heart J 2009; 30: 2854 –

onstrated progression of epicardial cardiac allograft vasculopa-thy on early follow-up, with subsequent spread to the micro-circulation on later follow-up, after heart transplantation (IMR 24.1±14.3 for early group vs. 29.4±18.8 for later group, P=0.05)41 The IMR was also measured to demonstrate the beneficial ef-fect of the immunosuppressant, rapamycin, in this patient pop-ulation.42

Takotsubo Cardiomyopathy (Ampulla Cardiomyopathy) The IMR has been measured to assess acute hemodynamics in takotsubo cardiomyopathy.43–45 Kume et al originally showed impaired Doppler-derived CFR in the acute phase of takotsubo cardiomyopathy, which had improved at 2-week follow-up.46 The IMR was reported to be high (36 [IQR: 23–48]) in the acute phase of takotsubo cardiomyopathy, suggesting the ex-istence of microvascular dysfunction though it is still an ongo-ing debate.45

Assessment of Stem Cell TherapyTayyareci et al47 investigated the microvasculature after intra-coronary autologous bone marrow-derived mononuclear cell transplantation in 15 patients with ischemic cardiomyopathy. They reported a substantial decrement of the IMR from 44.9±24.4 to 21.2±14.1 (P=0.001) during 6-month follow-up and also found improvement in coronary collateral vessel for-mation, resulting from myocardial regeneration.

We have summarized what is currently known about the IMR. It is important to note that IMR studies have been mainly per-formed in the LAD, otherwise focused on serial changes with intervention in the respective arteries.48 Therefore, care must be taken when extrapolating the results of these studies to daily clinical practice and clinical decision-making.

ConclusionsThe IMR is a simple and readily applicable method of assess-ing microvascular function during cardiac catheterization. It is useful for stratifying STEMI patients, as well as for assessing the effect of adjunctive therapy. Furthermore, it can predict periprocedural MI and assess the effect of therapeutic inter-ventions in stable patients undergoing PCI. Finally, it has been shown to help diagnose the etiology of chest pain in patients with normal-appearing coronary arteries. Future studies will be needed to determine whether a high IMR should trigger a par-ticular therapeutic intervention to improve outcome.

Conflict of Interest DisclosuresDr Fearon receives institutional research support from St. Jude Medical. Dr Kobayashi has no conflict to report.

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