Non-Invasive Estimation of Left Heart Filling Pressures: Another Nail in the Coffin for E/e'?

European Journal of Heart FailureVolume 19, Issue 12 p. 1661-1663 Editorial CommentFree Access Non-invasive estimation of left heart filling pressures: another nail in the coffin for E/e'? Erwan Donal, Corresponding Author Erwan Donal erwan.donal@chu-rennes.fr orcid.org/0000-0002-9083-1582 CHU Rennes, Service de Cardiologie et Maladies Vasculaires, CIC-IT 1414 Rennes, France INSERM, U1099, Rennes, France Université de Rennes 1, LTSI, Rennes, FranceCorresponding author. Hôpital Pontchaillou–CHU Rennes, Service de Cardiologie, 2 rue Henri Le Guillou, 35000 Rennes, France. Tel: +33 2 99 28 25 25, Fax: +33 2 99 28 25 10, E-mail: erwan.donal@chu-rennes.frSearch for more papers by this authorElena Galli, Elena Galli CHU Rennes, Service de Cardiologie et Maladies Vasculaires, CIC-IT 1414 Rennes, France INSERM, U1099, Rennes, France Université de Rennes 1, LTSI, Rennes, FranceSearch for more papers by this authorAlan G. Fraser, Alan G. Fraser Department of Cardiology, University Hospital of Wales, Cardiff, UK Cardiovascular Imaging and Dynamics, Department of Cardiovascular Sciences, Katholieke University Leuven, Leuven, BelgiumSearch for more papers by this author Erwan Donal, Corresponding Author Erwan Donal erwan.donal@chu-rennes.fr orcid.org/0000-0002-9083-1582 CHU Rennes, Service de Cardiologie et Maladies Vasculaires, CIC-IT 1414 Rennes, France INSERM, U1099, Rennes, France Université de Rennes 1, LTSI, Rennes, FranceCorresponding author. Hôpital Pontchaillou–CHU Rennes, Service de Cardiologie, 2 rue Henri Le Guillou, 35000 Rennes, France. Tel: +33 2 99 28 25 25, Fax: +33 2 99 28 25 10, E-mail: erwan.donal@chu-rennes.frSearch for more papers by this authorElena Galli, Elena Galli CHU Rennes, Service de Cardiologie et Maladies Vasculaires, CIC-IT 1414 Rennes, France INSERM, U1099, Rennes, France Université de Rennes 1, LTSI, Rennes, FranceSearch for more papers by this authorAlan G. Fraser, Alan G. Fraser Department of Cardiology, University Hospital of Wales, Cardiff, UK Cardiovascular Imaging and Dynamics, Department of Cardiovascular Sciences, Katholieke University Leuven, Leuven, BelgiumSearch for more papers by this author First published: 06 October 2017 https://doi.org/10.1002/ejhf.944Citations: 12 The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Heart Failure or of the European Society of Cardiology. doi:10.1002/ejhf.957 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat This article refers to ‘Echocardiographic estimation of left ventricular and pulmonary pressures in patients with heart failure and preserved ejection fraction: a study utilizing simultaneous echocardiography and invasive measurements’, by Y.M. Hummel et al., published in this issue on pages 1651–1660. The non-invasive diagnosis of left ventricular (LV) filling pressures is important in the management of heart failure (HF) patients with reduced as well as preserved LV ejection fraction (LVEF). To that end, a new expert consensus has proposed a diagnostic algorithm based on the ratio of the early diastolic velocities of mitral inflow and mitral annular motion (E/e'; abnormal when >14), the indexed left atrial volume (LAVi; abnormal when >34 mL/m2), and the maximal velocity of tricuspid regurgitation (TR; abnormal when >2.8 m/s).1 The recommendations have now been tested in two multicentre studies of heterogeneous populations. The first enrolled 450 patients, with a mean LVEF of 47%, including 209 with LVEF <50%. It demonstrated that the echocardiographic algorithm diagnosed elevated LV filling pressure [defined as either mean pulmonary capillary wedge pressure (PCWP) or pre-‘a’ LV diastolic pressure >12 mmHg] with an accuracy of 87%.2 The second, called Euro-Filling, was designed and conducted by the European Association of Cardiovascular Imaging (EACVI) and enrolled 159 patients undergoing elective coronary arteriography, including 39 with LVEF <50%. The new algorithm identified patients with LV end-diastolic pressure (LVEDP) ≥15 mmHg with sensitivity 75%, specificity 74%, positive predictive value 39%, and negative predictive value 93%; the area under the receiver-operating characteristic curve (C statistic) was 0.78, compared with 0.68 using the 2009 recommendations.3 The respective authors concluded that the algorithm had ‘good accuracy’ and was ‘fairly reliable’. This is the context in which Hummel et al. now report their commendably detailed retrospective analysis of 98 patients with HF and preserved LVEF (>45%), including 30% with atrial fibrillation.4 Subjects were selected if they had suspected pulmonary hypertension (for example from previously documented TR >2.8 m/s) so that they could be recruited for a trial of sildenafil to lower pulmonary vascular resistance.5 Echocardiographic measurements and invasive haemodynamic data were obtained simultaneously while patients were supine. Their C statistics for identifying LVEDP ≥15 mmHg are reported as 0.64 for E/e' and 0.76 for LAVi, compared with 0.75 for the algorithm proposed in the American Society of Echocardiography/EACVI recommendations (although their Figure 1 suggests that they did not test a range of discrimination thresholds). Importantly, the results were similar in patients in sinus rhythm and in atrial fibrillation. Perhaps their most thought-provoking finding is that E/e' was unrelated to LVEDP (r = 0.08, P = 0.45) and only weakly related to PCWP (r = 0.24, P = 0.02). When tested as single indices, LAVi and TR velocity also did not predict LVEDP (r = 0.07, P = 0.06; and r = −0.04, P = 0.73, respectively). Figure 1Open in figure viewerPowerPoint Echocardiographic studies in patients with diastolic dysfunction. (A–E) Echocardiographic findings in a 45-year-old man who presented with acute pulmonary oedema due to severe aortic regurgitation in sinus rhythm. The mitral inflow velocity (A, pulsed Doppler, in cm/s) and early diastolic velocities of medial (B) and lateral (C) mitral annular motion give an E/e' ratio of 12.7. Severe diastolic dysfunction with a very high left ventricular end-diastolic pressure is indicated by the short mitral E deceleration time (in A, measured at 70 ms) with absent forward flow during atrial contraction, the finding of severe diastolic mitral regurgitation at a velocity of 2 m/s (continuous wave Doppler, D, arrow), and markedly prolonged retrograde flow into the right upper pulmonary vein during atrial systole (E, measured between dotted vertical white lines, 180 ms). (F–J) Echocardiographic findings in a 50-year-old woman with class III dyspnoea on exertion, and atrial fibrillation. The mitral inflow velocity (F, pulsed Doppler, in cm/s) and early diastolic velocities of medial (G) and lateral (H) mitral annular motion give an E/e' ratio of 4.8. The deceleration time of the E wave of mitral inflow (F) at 79 ms, and the duration of isovolumetric relaxation (I, between dotted lines) at 83 ms, are both very short. M-mode echocardiography of the left ventricle (J) shows very rapid early diastolic filling (arrow) with no further increase in left ventricular diameter. The diagnosis is severe restrictive cardiomyopathy. The E/e' index was first reported in 1997 as a predictor of mean PCWP from a study of 60 patients (with r = 0.87).6 In a recent meta-analysis of data from 24 studies in patients with LVEF >50%, however, there was insufficient evidence that E/e' can reliably estimate LV filling pressure; the sensitivity of E/e' > 13 was only 36% (3–74%) while its specificity was 83% (49–100%).7 In the two recent multicentre studies, the correlations between E/e' and LVEDP were 0.652 and 0.34.3 Elsewhere, limitations of E/e' for predicting LV filling pressure have been reported in patients with HF with reduced ejection fraction8 and in subjects with hypertrophic cardiomyopathy.9 So, is it time to pronounce the death of the E/e' ratio? Probably not—but we do need to exercise caution and be smarter when we use it. The E/e' ratio is not synonymous with LV filling pressure, and it has significant limitations.10 It is just one of many indicators of different aspects of LV diastolic function, and using it as a single index above all other measurements is no more logical than defining systolic function by LVEF alone.11 In patients with quite severe diastolic dysfunction, the E/e' ratio can be uninformative (Figure 1), so a comprehensive study of indicators of preload, LV elastic recoil, early diastolic relaxation, suction, and end-diastolic pressure is more helpful. Hummel et al. have reinforced the message that LV filling pressure is estimated best by using a combination of variables; in their study, the most accurate (but still suboptimal) prediction came from a combination of left atrial reservoir function measured by strain, and LV isovolumetric relaxation time (r = 0.66).4 In patients in sinus rhythm, the duration of retrograde flow in the pulmonary veins during atrial systole is more useful when estimating LVEDP. New methods to assess LV diastolic stiffness using ultrafast plane wave imaging are also promising.12 We should also be considering whether or not estimating LV filling pressure at rest is still the most appropriate diagnostic objective in a subject with suspected HF. The e' velocity declines with age, so E/e' is affected by age and gender as well as by the degree of LV hypertrophy and the LVEF.13 Von Bibra et al. proposed that measurements of e' should be indexed to age.14 The value of e' itself as a diagnostic and prognostic discriminant in addition to LAVi and E/e' has been underscored in the recommendations on diastolic function.1 Since patients with preserved ejection fraction may have relatively normal LV function at rest, exercise echocardiography is important. The E/e' ratio is mildly correlated with LV filling pressure during handgrip stress in supine patients, but less well than at rest.15 In the study by Tan et al.,16 it did not change during exercise. This is probably explained by the fact that both E and e' are preload-dependent indices and their ratio remains unaltered during exercise. Perhaps we have over-used E/e' since it is a simple index when diastolic function is complex and diagnosis difficult. Perhaps it should be considered as a prognostic marker more than a diagnostic one.17, 18 What we need are new methods to integrate all the information from sophisticated non-invasive diagnostic tests at rest and during exercise, and to identify from large prospective studies which tools are the best for diagnosis, prognosis, and monitoring; they may be different. The application of machine learning to this field is one way in which we might achieve these results.19 Conflict of interest: none declared. References 1Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T, Flachskampf FA, Gillebert TC, Klein AL, Lancellotti P, Marino P, Oh JK, Alexandru Popescu B, Waggoner AD. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2016; 17: 1321– 1360. 2Andersen OS, Smiseth OA, Dokainish H, Abudiab MM, Schutt RC, Kumar A, Sato K, Harb S, Gude E, Remme EW, Andreassen AK, Ha JW, Xu J, Klein AL, Nagueh SF. Estimating left ventricular filling pressure by echocardiography. J Am Coll Cardiol 2017; 69: 1937– 1948. 3Lancellotti P, Galderisi M, Edvardsen T, Donal E, Goliasch G, Cardim N, Magne J, Laginha S, Hagendorff A, Haland TF, Aaberge L, Martinez C, Rapacciuolo A, Santoro C, Ilardi F, Postolache A, Dulgheru R, Mateescu AD, Beladan CC, Deleanu D, Marchetta S, Auffret V, Schwammenthal E, Habib G, Popescu BA. Echo-Doppler estimation of left ventricular filling pressure: results of the multicentre EACVI Euro-Filling study. Eur Heart J Cardiovasc Imaging 2017;18:961–968. 4Hummel YM, Liu LC, Lam CS, Fonseca-Munoz DF, Damman K, Rienstra M, van der Meer P, Rosenkranz S, van Veldhuisen DJ, Voors AA, Hoendermis ES. Echocardiographic estimation of left ventricular and pulmonary pressures in patients with heart failure and preserved ejection fraction: a study utilizing simultaneous echocardiography and invasive measurements. Eur J Heart Fail 2017. doi:10.1002/ejhf.957 5Hoendermis ES, Liu LC, Hummel YM, van der Meer P, de Boer RA, Berger RM, van Veldhuisen DJ, Voors AA. Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial. Eur Heart J 2015; 36: 2565– 2573. 6Nagueh SF, Middleton KJ, Kopelen HA, Zoghbi WA, Quinones MA. Doppler tissue imaging: a noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997; 30: 1527– 1533. 7Sharifov OF, Schiros CG, Aban I, Denney TS, Gupta H. Diagnostic accuracy of tissue doppler index E/e' for evaluating left ventricular filling pressure and diastolic dysfunction/heart failure with preserved ejection fraction: a systematic review and meta-analysis. J Am Heart Assoc 2016; 5: e002530. 8Mullens W, Borowski AG, Curtin RJ, Thomas JD, Tang WH. Tissue Doppler imaging in the estimation of intracardiac filling pressure in decompensated patients with advanced systolic heart failure. Circulation 2009; 119: 62– 70. 9Geske JB, Sorajja P, Nishimura RA, Ommen SR. Evaluation of left ventricular filling pressures by Doppler echocardiography in patients with hypertrophic cardiomyopathy: correlation with direct left atrial pressure measurement at cardiac catheterization. Circulation 2007; 116: 2702– 2708. 10Mitter SS, Shah SJ, Thomas JD. A test in context: E/A and E/e' to assess diastolic dysfunction and LV filling pressure. 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Quantification of diastolic dysfunction via the age dependence of diastolic function - impact of insulin resistance with and without type 2 diabetes. Int J Cardiol 2015; 182: 368– 374. 15Obokata M, Kane GC, Reddy YN, Olson TP, Melenovsky V, Borlaug BA. Role of diastolic stress testing in the evaluation for heart failure with preserved ejection fraction: a simultaneous invasive-echocardiographic study. Circulation 2017; 135: 825– 838. 16Tan YT, Wenzelburger F, Lee E, Heatlie G, Leyva F, Patel K, Frenneaux M, Sanderson JE. The pathophysiology of heart failure with normal ejection fraction: exercise echocardiography reveals complex abnormalities of both systolic and diastolic ventricular function involving torsion, untwist, and longitudinal motion. J Am Coll Cardiol 2009; 54: 36– 46. 17Donal E, Lund LH, Oger E, Hage C, Persson H, Reynaud A, Ennezat PV, Bauer F, Drouet E, Linde C, Daubert C; KaRen investigators. New echocardiographic predictors of clinical outcome in patients presenting with heart failure and a preserved left ventricular ejection fraction: a subanalysis of the Ka (Karolinska) Ren (Rennes) Study. Eur J Heart Fail 2015; 17: 680– 688. 18Holland DJ, Prasad SB, Marwick TH. Prognostic implications of left ventricular filling pressure with exercise. Circ Cardiovasc Imaging 2010; 3: 149– 156. 19Omar AM, Narula S, Abdel Rahman MA, Pedrizzetti G, Raslan H, Rifaie O, Narula J, Sengupta PP. Precision phenotyping in heart failure and pattern clustering of ultrasound data for the assessment of diastolic dysfunction. JACC Cardiovasc Imaging 2017;10:1291–1303. Citing Literature Volume19, Issue12December 2017Pages 1661-1663 FiguresReferencesRelatedInformation