Optimal Measurement of Coronary Flow and Microvascular Function in Animals and Humans

HomeCirculation ResearchVol. 133, No. 8Optimal Measurement of Coronary Flow and Microvascular Function in Animals and Humans Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBOptimal Measurement of Coronary Flow and Microvascular Function in Animals and Humans Lennert Minten, Michiel Algoet, Johan Bennett, Wouter Oosterlinck, Bart Meuris, Tom Langenaeken, Stephanie Bézy, Laurine Wouters, Jürgen Duchenne, Alexis Puvrez, Senne De Groote, Pierluigi Lesizza, Pascal Frederiks, Laurens De Vos, Tom Adriaenssens, Peter Sinnaeve, Walter Desmet, Keir McCutcheon and Christophe Dubois Lennert MintenLennert Minten Correspondence to: Lennert Minten, MD, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium. Email E-mail Address: [email protected] https://orcid.org/0000-0001-5290-6320 Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Belgium (L.M., M.A., J.B., W.O., B.M., T.L., S.B., L.W., J.D., A.P., S.D.G., T.A., P.S., W.D., K.M., C.D.). Departments of Cardiovascular Medicine (L.M., J.B., P.L., P.F., L.D.V., T.A., P.S., W.D., C.D.), University Hospitals Leuven (UZ Leuven), Belgium. , Michiel AlgoetMichiel Algoet https://orcid.org/0000-0002-4763-7426 Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Belgium (L.M., M.A., J.B., W.O., B.M., T.L., S.B., L.W., J.D., A.P., S.D.G., T.A., P.S., W.D., K.M., C.D.). Cardiac Surgery (M.A., W.O., B.M., T.L.), University Hospitals Leuven (UZ Leuven), Belgium. , Johan BennettJohan Bennett https://orcid.org/0000-0002-8301-4517 Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Belgium (L.M., M.A., J.B., W.O., B.M., T.L., S.B., L.W., J.D., A.P., S.D.G., T.A., P.S., W.D., K.M., C.D.). Departments of Cardiovascular Medicine (L.M., J.B., P.L., P.F., L.D.V., T.A., P.S., W.D., C.D.), University Hospitals Leuven (UZ Leuven), Belgium. , Wouter OosterlinckWouter Oosterlinck Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Belgium (L.M., M.A., J.B., W.O., B.M., T.L., S.B., L.W., J.D., A.P., S.D.G., T.A., P.S., W.D., K.M., C.D.). Cardiac Surgery (M.A., W.O., B.M., T.L.), University Hospitals Leuven (UZ Leuven), Belgium. , Bart MeurisBart Meuris Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Belgium (L.M., M.A., J.B., W.O., B.M., T.L., S.B., L.W., J.D., A.P., S.D.G., T.A., P.S., W.D., K.M., C.D.). Cardiac Surgery (M.A., W.O., B.M., T.L.), University Hospitals Leuven (UZ Leuven), Belgium. , Tom LangenaekenTom Langenaeken https://orcid.org/0000-0001-6781-1148 Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Belgium (L.M., M.A., J.B., W.O., B.M., T.L., S.B., L.W., J.D., A.P., S.D.G., T.A., P.S., W.D., K.M., C.D.). Cardiac Surgery (M.A., W.O., B.M., T.L.), University Hospitals Leuven (UZ Leuven), Belgium. , Stephanie BézyStephanie Bézy Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Belgium (L.M., M.A., J.B., W.O., B.M., T.L., S.B., L.W., J.D., A.P., S.D.G., T.A., P.S., W.D., K.M., C.D.). , Laurine WoutersLaurine Wouters Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Belgium (L.M., M.A., J.B., W.O., B.M., T.L., S.B., L.W., J.D., A.P., S.D.G., T.A., P.S., W.D., K.M., C.D.). , Jürgen DuchenneJürgen Duchenne https://orcid.org/0000-0003-0221-5753 Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Belgium (L.M., M.A., J.B., W.O., B.M., T.L., S.B., L.W., J.D., A.P., S.D.G., T.A., P.S., W.D., K.M., C.D.). , Alexis PuvrezAlexis Puvrez https://orcid.org/0000-0002-9454-7706 Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Belgium (L.M., M.A., J.B., W.O., B.M., T.L., S.B., L.W., J.D., A.P., S.D.G., T.A., P.S., W.D., K.M., C.D.). , Senne De GrooteSenne De Groote Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Belgium (L.M., M.A., J.B., W.O., B.M., T.L., S.B., L.W., J.D., A.P., S.D.G., T.A., P.S., W.D., K.M., C.D.). , Pierluigi LesizzaPierluigi Lesizza Departments of Cardiovascular Medicine (L.M., J.B., P.L., P.F., L.D.V., T.A., P.S., W.D., C.D.), University Hospitals Leuven (UZ Leuven), Belgium. , Pascal FrederiksPascal Frederiks https://orcid.org/0000-0001-7580-9718 Departments of Cardiovascular Medicine (L.M., J.B., P.L., P.F., L.D.V., T.A., P.S., W.D., C.D.), University Hospitals Leuven (UZ Leuven), Belgium. , Laurens De VosLaurens De Vos Departments of Cardiovascular Medicine (L.M., J.B., P.L., P.F., L.D.V., T.A., P.S., W.D., C.D.), University Hospitals Leuven (UZ Leuven), Belgium. , Tom AdriaenssensTom Adriaenssens https://orcid.org/0000-0001-9892-5420 Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Belgium (L.M., M.A., J.B., W.O., B.M., T.L., S.B., L.W., J.D., A.P., S.D.G., T.A., P.S., W.D., K.M., C.D.). Departments of Cardiovascular Medicine (L.M., J.B., P.L., P.F., L.D.V., T.A., P.S., W.D., C.D.), University Hospitals Leuven (UZ Leuven), Belgium. , Peter SinnaevePeter Sinnaeve Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Belgium (L.M., M.A., J.B., W.O., B.M., T.L., S.B., L.W., J.D., A.P., S.D.G., T.A., P.S., W.D., K.M., C.D.). Departments of Cardiovascular Medicine (L.M., J.B., P.L., P.F., L.D.V., T.A., P.S., W.D., C.D.), University Hospitals Leuven (UZ Leuven), Belgium. , Walter DesmetWalter Desmet https://orcid.org/0000-0003-4607-6572 Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Belgium (L.M., M.A., J.B., W.O., B.M., T.L., S.B., L.W., J.D., A.P., S.D.G., T.A., P.S., W.D., K.M., C.D.). Departments of Cardiovascular Medicine (L.M., J.B., P.L., P.F., L.D.V., T.A., P.S., W.D., C.D.), University Hospitals Leuven (UZ Leuven), Belgium. , Keir McCutcheonKeir McCutcheon Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Belgium (L.M., M.A., J.B., W.O., B.M., T.L., S.B., L.W., J.D., A.P., S.D.G., T.A., P.S., W.D., K.M., C.D.). and Christophe DuboisChristophe Dubois https://orcid.org/0000-0001-5255-1443 Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Belgium (L.M., M.A., J.B., W.O., B.M., T.L., S.B., L.W., J.D., A.P., S.D.G., T.A., P.S., W.D., K.M., C.D.). Departments of Cardiovascular Medicine (L.M., J.B., P.L., P.F., L.D.V., T.A., P.S., W.D., C.D.), University Hospitals Leuven (UZ Leuven), Belgium. Originally published31 Aug 2023https://doi.org/10.1161/CIRCRESAHA.123.323341Circulation Research. 2023;133:720–722is related toMeet the First AuthorsOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: August 31, 2023: Ahead of Print Meet the First Author, see p 657Coronary microvascular dysfunction plays a major role in patients with cardiac ischemia without flow limiting epicardial coronary stenosis, Takotsubo cardiomyopathy, aortic valve stenosis (AS), and heart failure. Therefore, it is increasingly important to correctly assess microvascular function. The index of microvascular resistance (IMR) and coronary flow reserve (CFR) are used in routine clinical practice. More recently, absolute coronary blood flow (ABF), absolute coronary resistance (ACR), and microvascular resistance reserve (MRR) were introduced as new microvascular indices using continuous coronary thermodilution. It has been demonstrated that no hyperemic agent is needed to induce maximal hyperemia at higher saline infusion speeds, and this enables assessment of the microcirculation without using adenosine or papaverine. The purpose of this study was to validate ABF measurements and to assess reliability of different microvascular indices, with a special focus on the reproducibility of the IMR versus the MRR.For the purpose of this study, coronary measurements were conducted in 2 large sheep animal models with approval from the Animal Ethics Committee (KU Leuven). In the open-chest model, perivascular ultrasonic flow probes (MA4PSB; Transonic Systems, Inc) were placed around the proximal left circumflex coronary artery and left anterior descending coronary artery to perform simultaneous Doppler flow measurements. As per gold standard, maximal hyperemia was induced by releasing a 45-s proximal total occlusion using a vessel loop. In the closed-chest study, 14 sheep underwent repeated paired measurements of ABF and ACR at different saline infusion speeds with and without adenosine, as well as IMR, CFR, and MRR in both coronary vessels. Measurements were performed according to previously described standards.1,2 In the open-chest model, 7 sheep underwent identical measurements while having direct and simultaneous assessment of flow with epicardial Doppler flow probes (gold standard) as a validation method. In addition to the animal measurements, in 41 patients undergoing routine microvascular assessment in clinical practice, CFR and IMR measurements were repeated after a 5-minute waiting time, recalibration, and rewiring of the same blood vessel by the same operator.Intracoronary flow measurements were compared with simultaneous epicardial flow probe measurements with saline infusion speeds from 5 to 30 mL/min. This resulted in 59 paired flow measurements. In sheep, ABF measured with continuous thermodilution was accurate when compared with epicardial flow measurements (Figure [A and B]). There was a significant correlation (Pearson r, 0.918; R2=0.843; P=1.31×10−24) between both types of measurement, and there was no clinically relevant or significant bias in the fractional measurement difference (Bland-Altman: bias±SD, −8.733±21.75; 95% limits of agreement, −51.37 to 33.91; Figure [D]). The 2 methods were equivalent within 15% (2 one-sided tests: mean difference, −8.73% [95% CI, −14.40% to −3.06%]; P=0.016). When comparing reliability and test-retest reproducibility between the indices, CFR performed the worst, whereas ACR and MRR performed the best (Figure [D]). IMR performed better with regard to reliability than CFR measurements but not as good as the absolute flow indices. ACR had better reliability than ABF. MRR had a significantly better reproducibility than IMR (Figure [C and D]).Download figureDownload PowerPointFigure. Accuracy and reproducibility of absolute flow measurements and microvascular resistance reserve (MRR). A, Linear regression of simultaneous epicardial and continuous coronary thermodilution measurements of absolute coronary blood flow (ABF) in sheep with the line of equality, the regression line, and the 95% prediction interval of the regression. 5 mL/min: green dots; 8 mL/min: yellow dots; 10 mL/min: blue dots; 20 mL/min: gray dots; 30 mL/min: purple dots. B, Bland-Altman plot of the percentage difference between these measurements with the bias and the 95% limits of agreement. C, Graph comparing the fractional measurement error of the index of microvascular resistance (IMR) with the MRR. The bars represent the 95% CI of the mean fractional errors in repeated measurements. The result of a t test is reported. D, Reliability and test-retest reproducibility of indices of microvascular function. ACR indicates absolute coronary resistance; CFR, coronary flow reserve; CR, repeatability coefficient; CV%, coefficient of variation percentage; ICC, intraclass correlation; IMR, index of microvascular resistance; R, Pearson correlation coefficient; and SEM%, standard error (SE) of measurement percentage.The present study assessed the validity and usefulness of absolute intracoronary flow measurements and the MRR. We report the following main findings: (1) ABF measured with continuous coronary thermodilution in a large animal model is accurate and reproducible when compared with epicardial Doppler-measured flow and (2) ACR and MRR have the best reliability and reproducibility of all the different microvascular indices. MRR outperforms the IMR, which is currently the most used index of microvascular dysfunction in clinical practice. Since MRR is not dependent on the size of the interrogated vessel or territory, unlike the ACR, our data support MRR as the index of choice for optimal reliability and test-retest reproducibility during microvascular interrogation. Our study results confirm a previous clinical report in which continuous thermodilution demonstrated significantly less variability on repeated measurements than bolus thermodilution.3Correct assessment of microvascular function could be essential to better understand many cardiac diseases and to improve available treatments. For example, microvascular dysfunction in patients with valvular heart disease such as severe AS is, at this point, incompletely understood. Continuous coronary thermodilution measurements have already increased our understanding of the complex physiological changes in myocardial blood flow related to AS, which are essential for correct physiological assessment of the microcirculation and epicardial coronary artery disease in these patients.2,4 The latter seems critical to improve patient outcomes in AS, since the presence of complex coronary artery disease in AS has been shown to be an independent predictor for worse cardiovascular survival after transcatheter aortic valve replacement.5 Although MRR seems to be the best microvascular index, more human data are needed: (1) to determine normal values and define microvascular dysfunction and (2) to show a potential correlation between low MRR values and clinical outcomes or signs and symptoms of cardiac disease.In conclusion, ABF can be accurately determined by continuous coronary thermodilution in sheep. MRR and ACR have significantly superior reliability and reproducibility compared with IMR and CFR. Unlike ACR, MRR is not vessel or territory size dependent and is, therefore, the index of choice for assessment of the microcirculation.ARTICLE INFORMATIONData AvailabilityThe data that support the findings of this study are available from the corresponding author upon reasonable request. Information regarding methods used in the analysis and materials used to conduct the research is available in the Major Resources Table.AcknowledgmentsWe would like to express our greatest gratitude toward Patricia Holemans, Hilde Gillijns, David Celis, Mieke Ginckels, and Hanne Van Dessel for all the hard work and expertise regarding the animal anesthesia and excellent periprocedural care of the animals.Sources of FundingThe Research Foundation Flanders (FWO) supported L. Minten, M. Algoet and J. Duchenne with a personal research grant (1194521N, 11A2423N and 12ZZN22N, respectively).Nonstandard Abbreviations and AcronymsABFabsolute coronary blood flowACRabsolute coronary resistanceASaortic valve stenosisCFRcoronary flow reserveIMRindex of microvascular resistanceMRRmicrovascular resistance reserveDisclosures None.FootnotesFor Sources of Funding and Disclosures, see page 722.Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCRESAHA.123.323341.Correspondence to: Lennert Minten, MD, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium. Email Lennert.minten@gmail.comREFERENCES1. De Bruyne B, Pijls Nico HJ, Gallinoro E, Candreva A, Fournier S, Keulards Danielle CJ, Sonck J, van't Veer M, Barbato E, Bartunek J, et al. Microvascular resistance reserve for assessment of coronary microvascular function.J Am Coll Cardiol. 2021; 78:1541–1549. doi: 10.1016/j.jacc.2021.08.017CrossrefMedlineGoogle Scholar2. Minten L, McCutcheon K, Jentjens S, Vanhaverbeke M, Segers VFM, Bennett J, Dubois C. The coronary and microcirculatory measurements in patients with aortic valve stenosis study: rationale and design.Am J Physiol Heart Circ Physiol. 2021; 321:H1106–H1116. doi: 10.1152/ajpheart.00541.2021CrossrefMedlineGoogle Scholar3. Gallinoro E, Bertolone Dario T, Fernandez-Peregrina E, Paolisso P, Bermpeis K, Esposito G, Gomez-Lopez A, Candreva A, Mileva N, Belmonte M, et al. Reproducibility of bolus versus continuous thermodilution for assessment of coronary microvascular function in patients with ANOCA.EuroIntervention. 2023; 19:e155–e166. doi: 10.4244/EIJ-D-22-00772CrossrefMedlineGoogle Scholar4. Paolisso P, Gallinoro E, Vanderheyden M, Esposito G, Bertolone DT, Belmonte M, Mileva N, Bermpeis K, Colle CD, Fabbricatore D, et al. Absolute coronary flow and microvascular resistance reserve in patients with severe aortic stenosis.Heart. 2023; 109:47–54.CrossrefGoogle Scholar5. Minten L, Wissels P, McCutcheon K, Bennett J, Adriaenssens T, Desmet W, Sinnaeve P, Verbrugghe P, Jacobs S, Guler I, et al. The effect of coronary lesion complexity and preprocedural revascularization on 5-year outcomes after TAVR.JACC Cardiovasc Interv. 2022; 15:1611–1620. doi: 10.1016/j.jcin.2022.06.019CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesMeet the First AuthorsCirculation Research. 2023;133:656-657 September 29, 2023Vol 133, Issue 8 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.123.323341PMID: 37650288 Originally publishedAugust 31, 2023 Keywordscoronary circulationfractional flow reservehumansischemiamicrocirculationmicrovascular anginareproducibility of resultsPDF download Advertisement SubjectsCoronary CirculationPhysiologyTranslational Studies