Myocardial Contrast Stress Echo Versus Fractional Flow Reserve

HomeCirculation: Cardiovascular ImagingVol. 9, No. 8Myocardial Contrast Stress Echo Versus Fractional Flow Reserve Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBMyocardial Contrast Stress Echo Versus Fractional Flow ReserveA Fair Fight Among Ischemic Tests? Morton J. Kern, MD and Arnold H. Seto, MD Morton J. KernMorton J. Kern From the Departments of Medicine (M.J.K.) and Cardiology (A.H.S.), Veterans Administration Long Beach Health Care System, CA; and Department of Medicine, University of California, Irvine (M.J.K., A.H.S.). and Arnold H. SetoArnold H. Seto From the Departments of Medicine (M.J.K.) and Cardiology (A.H.S.), Veterans Administration Long Beach Health Care System, CA; and Department of Medicine, University of California, Irvine (M.J.K., A.H.S.). Originally published10 Aug 2016https://doi.org/10.1161/CIRCIMAGING.116.005327Circulation: Cardiovascular Imaging. 2016;9:e005327The ischemic potential of a coronary artery stenosis is revealed by physiological challenges, manifesting as myocardial malperfusion, and depending on the severity and duration of ischemia, mechanical and electric dysfunctions. Coronary pathophysiological changes can be measured either directly by translesional coronary pressure and flow or indirectly by positron emission tomography perfusion studies or nuclear scintigraphy. Real-time myocardial contrast stress echocardiography (RTMCE) is another technique that provides a measure of myocardial perfusion, while simultaneously demonstrating abnormal regional LV contraction, one of the most concrete functional consequences of ischemia.1See Article by Wu et alIn the invasive assessment of coronary disease, several translesional pressure/flow metrics, both at rest and during hyperemic stress, have been examined, the most well-known (and well studied) of which is fractional flow reserve (FFR), a pressure-derived measurement of the hemodynamic significance of an epicardial stenosis. It has an ischemic threshold value of <0.75 to 0.80 below which there is a strong association with ischemia as defined by a composite of 3 noninvasive stress tests. Initially, FFR was, thus, compared against the best "gold" standards then available and subsequently validated in multiple large clinical outcome studies.2,3 When comparing FFR to other invasive physiological indices or newer noninvasive stress tests, recall that FFR is specific only for the epicardial resistance and does not inform us the status of the microcirculation. In contrast, techniques such as Doppler flow wire, coronary thermodilution, and RTMCE flow measure coronary flow itself, which is affected by both the epicardial and coronary microvascular resistances. These techniques permit the computation of coronary flow reserve (CFR, ratio of maximal to basal coronary blood flow [CBF]); thus, providing complementary information to FFR for a complete assessment of the coronary circulation. However, for the very reason that FFR cannot assess the microcirculation, it is no surprise that there is only fair correspondence between FFR and those tests that principally depend on changes in the microcirculation, such as CFR4 or nuclear scintigraphy. The strongest correlations among FFR and CFR and its noninvasive kin occur when the extremes of stenosis severity are included.In this issue of Circulation: Cardiovascular Imaging, Wu et al5 compared RTMCE CBF (ie, capillary) and left ventricular wall motion abnormality (LVWMA) to FFR in 58 patients with 67 intermediate coronary stenosis, ranging in severity from 50% to 80%. Dobutamine (n=32) or exercise (n=26) stress was performed before angiography. An FFR ≤0.8 was present in 18 of 67 stenoses (27%); 17 of 18 FFR-positive stenoses had abnormal MCE CBF. However, 28 of 49 FFR-negative stenoses (57%) also had abnormal CBF and 24 of 49 (49%) had abnormal wall motion. Wu et al5 concluded that a large percentage of intermediate stenoses with nonischemic FFR values (ie,>0.80) had reduced MCE CBF during demand stress, resulting in myocardial ischemia. Thus, abnormal CBF during demand stress RTMCE had high sensitivity (94%) for detecting a hemodynamically significant epicardial stenosis (ie, abnormal FFR) but a low specificity (57% for nonischemic FFR).How can we reconcile these discordant results? The controversy about which metric is the better test for ischemia, as noted previously,6,7 remains fueled by lack of a true and readily obtained ischemic gold standard in patients. However, unique to this study is that inducible wall motion dysfunction has a particular relevance to ischemia and may be closer to a true standard, with the caveat of the inherent limitations of the method.Microvascular circulatory impairment with reduced CBF may occur in the absence of epicardial stenosis resistance (as measured by FFR), thereby accounting for an anticipated disparity between negative FFR and abnormal CBF. However, unlike studies comparing FFR to traditional stress tests (and measures of CFR alone), RTMCE couples LVWM abnormality with reduced CBF, suggesting a more definitive detector of true ischemia.1 While acknowledging the many contributions to the field of MCE and the extensive expertise of the authors, the RTMCE with LVWMA assessment seems to be more sensitive and specific than both invasive FFR and CFR and potentially could serve as a superior marker of ischemia. However, before demoting FFR, an examination of RTMCE and its limitations is necessary. Could the degree of microvascular dysfunction as measured by microbubble contrast echo flow be sufficiently reduced to induce LVWMA in the absence of an epicardial stenosis? Is RTMCE sufficiently free of test artifact and false positives/negatives (Table)8 to serve as a useful ischemic standard?Table. False-Negative and False-Positive Stress EchocardiogramsFalse NegativeFalse PositiveInadequate stressOver interpretation, biasAntianginals, eg, BBLocal basal inferior wall abnormalitiesMild stenosesAbnormal septal motion, (LBBB, post CABG)Poor image qualityCardiomyopathyDelayed images post stressHypertensive response to stressBB indicates beta blockers; LBBB, left bundle branch block; and CABG, coronary artery bypass graft surgery. Reprinted from Marwick et al8 with permission of the publisher. Copyright ©BMJ Publishing Group Ltd, 2003.Many clinicians would agree that RTMCE is a difficult test to perform and reliably interpret in routine practice, given the limitations of resolution with ultrasound and interobserver variation. Among the technical limitations is the complexity of determining quantitative blood flow data.9,10 Microbubble blood flow is dependent on the myocardial blood volume fraction and microbubble flow velocity. Factors influencing either volume or velocity can produce variations in CBF results. Although MCE does have the potential for quantification of blood flow, Wu et al5 defined it in a binary fashion. An abnormal CBF during stress imaging was defined as a delay in subendocardial or transmural myocardial contrast replenishment of >2 s after a high mechanical index impulse that was in 2 contiguous segments, and which exhibited normal replenishment under resting conditions. Does this translate into a high-, moderate-, or low-flow state? Equally relevant to the ischemic standard question is the potential for over interpretation of LVWMA. If the same reader identifies impaired flow by MCE, is their interpretation of LVWM influenced, biasing the association? In addition, because of signal attenuation, false-positive contrast imaging defects may appear more commonly in the inferior and lateral regions (14 territories), and LVWMA in multivessel CAD may confound the correlation with FFR. Caution in accepting the LVWMA finding as independent confirmation of the RTMCE ischemic results is, thus, justified.In addition, the author's enumerated limitations of small patient numbers, a single-center retrospective design, and available technical expertise should include the higher prevalence of diabetics and smokers in the study group, which also increases the likelihood of stress-induced microvascular abnormalities. Given the small and selected patient population, would these findings be reproducible in a larger and more varied patient group with CAD or in a multicenter trial?We compliment the authors on including clinical outcomes, the most important product of medical decision making. The abbreviated outcomes during a 2-month (median) follow-up period noted that 16 of 26 (59%) patients who had abnormal CBF with negative FFR had Canadian Cardiovascular Functional Class II to III symptoms or had revascularization because of symptoms. Ten patients remained asymptomatic on medical therapy. The comparison of events rates from FFR-negative stenoses (3%) in outcome studies of patients with known intermediate coronary stenoses to those in their normal registries in angina patients (1%) unfairly stacks the deck in favor of RTMCE outcomes. These limited outcome data are not comparable to the 15-year outcome data of deferring interventions based on FFR.11The study by Wu et al5 reminds us that an ischemic gold standard in man is hard to come by. The most definitive evidence of ischemia is the induced mechanical failure of the myocardium to shorten and thicken. More subtle evidence of ischemia, depending on the duration and intensity of the ischemia, can be obtained from methods measuring myocardial malperfusion, a phenomenon occurring early in the ischemic cascade associated with local tissue acidosis followed by contractile dysfunction, and electrocardiographic changes. Unfortunately, our stress testing modalities will always have shortcomings of false-positive and false-negative results making any one of them only a semi–gold ischemic standard.RTMCE in theory has great potential as a noninvasive measure of ischemic malperfusion and myocardial dysfunction, but will require more comparative data across the spectrum of CAD before it can be widely applied and successfully compete with FFR.12 Although far from perfect, FFR remains an often challenged yet durable standard to guide decision making in patients with CAD.DisclosuresDr Kern is a speaker and consultant for companies manufacturing pressure/flow sensor guidewires or FFRCT software, which include St. Jude Medical, Volcano Therapeutics, Acist Medical, Opsens Inc and Heartflow Inc. Dr Seto is receiving research support from Acist Medical, Minneapolis, MN.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Morton J. Kern, MD, VA Long Beach Health Care System, 5901 E 7th Street, Long Beach, CA 90822. E-mail [email protected]References1. Shimoni S, Zoghbi WA, Xie F, Kricsfeld D, Iskander S, Gobar L, Mikati IA, Abukhalil J, Verani MS, O'Leary EL, Porter TR. Real-time assessment of myocardial perfusion and wall motion during bicycle and treadmill exercise echocardiography: comparison with single photon emission computed tomography.J Am Coll Cardiol. 2001; 37:741–747.CrossrefMedlineGoogle Scholar2. Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van' t Veer M, Klauss V, Manoharan G, Engstrøm T, Oldroyd KG, Ver Lee PN, MacCarthy PA, Fearon WF; FAME Study Investigators. 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Stillman A, Oudkerk M, Bluemke D, de Boer M, Bremerich J, Garcia E, Gutberlet M, van der Harst P, Hundley W, Jerosch-Herold M, Kuijpers D, Kwong R, Nagel E, Lerakis S, Oshinski J, Paul J, Slart R, Thourani V, Vliegenthart R and Wintersperger B (2018) Imaging the myocardial ischemic cascade, The International Journal of Cardiovascular Imaging, 10.1007/s10554-018-1330-4, 34:8, (1249-1263), Online publication date: 1-Aug-2018. August 2016Vol 9, Issue 8 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/CIRCIMAGING.116.005327PMID: 27511973 Originally publishedAugust 10, 2016 Keywordscoronary stenosisartifactEditorialsmyocardial ischemiaangiographyPDF download Advertisement SubjectsDiagnostic TestingEchocardiography