European Heart Journal Advance Access published April 11, 2007
European Heart Journal How to diagnose diastolic heart failure: a consensusstatement on the diagnosis of heart failure with normalleft ventricular ejection fraction by the Heart Failureand Echocardiography Associations of the EuropeanSociety of Cardiology Walter J. Paulus1*, Carsten Tscho ¨pe2, John E. Sanderson3, Cesare Rusconi4, Frank A. Flachskampf5, Frank E. Rademakers6, Paolo Marino7, Otto A. Smiseth8, Gilles De Keulenaer9, Adelino F.
Leite-Moreira10, Attila Borbe ´des11, Martin Louis Handoko1, Stephane Heymans12, Natalia Pezzali4, Burkert Pieske13, Kenneth Dickstein14, Alan G. Fraser15, and Dirk L. Brutsaert9 1Laboratory of Physiology, VU University Medical Center, Van der Boechorststraat, 7, 1081 BT, Amsterdam, The Netherlands;2Charite´ Universita¨tskliniken, Campus Benjamin Franklin, Berlin, Germany; 3Keele University, Stoke-on-Trent, UK; 4S.OrsolaHospital, Brescia, Italy; 5University of Erlangen, Germany; 6University of Leuven, Belgium; 7Universita degli Studi delPiemonte Orientale, Novara, Italy; 8Rikshospitalet, Oslo, Norway; 9Middelheim Ziekenhuis, Antwerp, Belgium; 10Universityof Porto, Portugal; 11Institute of Cardiology UDMHSC, Debrecen, Hungary; 12University Hospital Maastricht, The Netherlands;13Georg-August-Universita¨t, Go¨ttingen, Germany; 14Stavanger University Hospital, Norway; and 15University of WalesCollege of Medicine, Cardiff, UK Received 28 November 2006; accepted 23 February 2007 Diastolic heart failure (DHF) currently accounts for more than 50% of all heart failure patients. DHF is also referred to as heart failure with normal left ventricular (LV) ejection fraction (HFNEF) to indicate that HFNEF could be a precursor of heart failure with reduced LVEF. Because of improved cardiac imaging and because of widespread clinical use of plasma levels of natriuretic peptides, diagnostic criteria for Natriuretic peptides; HFNEF needed to be updated. The diagnosis of HFNEF requires the following conditions to be satisfied: Ejection fraction (i) signs or symptoms of heart failure; (ii) normal or mildly abnormal systolic LV function; (iii) evidenceof diastolic LV dysfunction. Normal or mildly abnormal systolic LV function implies both an LVEF . 50%and an LV end-diastolic volume index (LVEDVI) ,97 mL/m2. Diagnostic evidence of diastolic LV dysfunctioncan be obtained invasively (LV end-diastolic pressure .16 mmHg or mean pulmonary capillary wedgepressure .12 mmHg) or non-invasively by tissue Doppler (TD) (E/E0 . 15). If TD yields an E/E0 ratio sug-gestive of diastolic LV dysfunction (15 . E/E0 . 8), additional non-invasive investigations are required fordiagnostic evidence of diastolic LV dysfunction. These can consist of blood flow Doppler of mitral valve orpulmonary veins, echo measures of LV mass index or left atrial volume index, electrocardiographic evi-dence of atrial fibrillation, or plasma levels of natriuretic peptides. If plasma levels of natriuretic peptidesare elevated, diagnostic evidence of diastolic LV dysfunction also requires additional non-invasive inves-tigations such as TD, blood flow Doppler of mitral valve or pulmonary veins, echo measures of LV massindex or left atrial volume index, or electrocardiographic evidence of atrial fibrillation. A similar strategywith focus on a high negative predictive value of successive investigations is proposed for the exclusion ofHFNEF in patients with breathlessness and no signs of congestion.
The updated strategies for the diagnosis and exclusion of HFNEF are useful not only for individual patient management but also for patient recruitment in future clinical trials exploring therapies forHFNEF.
In 1998, the European Study Group on Diastolic Heart Failurepublished a set of criteria for the diagnosis of diastolic heartfailure (DHF).1 At that time, DHF was presumed to account * Corresponding author. Tel: þ31 20 4448110; fax: þ31 20 4448255.
for approximately one-third of all patients with heart E-mail address: & The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: W.J. Paulus et al.
failure and its natural history was considered to be more remodelling are already occurring in HFNEF.38 Such an evol- benign than systolic heart failure (SHF) with a lower mor- ution has also been observed in hypertensive heart tality and morbidity rate.2–7 Over the last two decades, disease,39–42 especially in African43–45 and Asian46,47 popu- these perspectives have changed substantially with an lations. In many of these studies, interval clinical events, increase in the prevalence of DHF from 38 to 54% of all such as myocardial infarction, were, however, not reported heart failure cases.8,9 Moreover, the prognosis of patients or significantly higher39 in the patients, who subsequently suffering from DHF is as ominous as the prognosis of patients developed a depressed LVEF. An occasional (3.5%) evolution suffering of SHF.10–15 Predisposing conditions for DHF are to eccentric LV remodelling is also observed in patients older age, female gender, diabetes and obesity, arterial with hypertrophic cardiomyopathy,48 a disease characteri- hypertension, and left ventricular (LV) hypertrophy.16,17 zed in its initial stages by concentric LV remodelling and Even following a myocardial infarction, many elderly prominent diastolic LV dysfunction. A small, serial echocar- patients still present with DHF.18 diographic study of HFNEF patients observed in one-fifth of Because of this epidemiological evolution towards a the patients a decline in LVEF below 45% after a 3-month predominance of DHF in western populations, a re-appraisal follow-up period.49 Larger follow-up studies, preferably of the original set of criteria for the diagnosis of DHF is with sequential coronary angiograms, are required to inves- required. This re-appraisal should address the critiques, tigate whether HFNEF is indeed a precursor stage to HFREF which have been phrased concerning the original set of and to identify patient characteristics, such as female criteria, and should accommodate new pathophysiological gender,50 regular aerobic exercise,51 chronic alcohol inges- insights, modern cardiac imaging technology, and the wide- tion,52 genetic background,53 and comorbidities, such as spread clinical use of heart failure biomarkers.
diabetes,54,55 that may prevent or retard the evolutionfrom HFNEF to HFREF.
Structural, functional, and molecular biological argu- Heart failure with normal left ventricular ments support the theory that clinical heart failure presents ejection fraction or diastolic heart failure and evolves not as a single syndrome but as two syndromes,one with depressed LVEF and other with normal LVEF and Heart failure with normal LV ejection fraction (HFNEF) is specific mechanisms responsible for diastolic LV dysfunction frequently referred to as DHF because of the presence of (Figure 1). Patients with SHF have eccentric LV hypertrophy diastolic LV dysfunction evident from slow LV relaxation in contrast to patients with DHF, who have concentric and increased LV stiffness.19 Diastolic LV dysfunction, LV hypertrophy56,57 as evident from the numerous studies, however, is not unique to patients with DHF but also which reported a high LV wall mass–volume ratio in DHF occurs in heart failure patients with SHF, and in this last and a low LV wall mass–volume ratio in SHF.58–61 Differences group, it even correlates better with symptoms than between DHF and SHF have also been reported at the LVEF.20,21 Furthermore, although global LV systolic perform- ultrastructural level:61 patients with DHF have a 50% larger ance is preserved,22 HFNEF patients have reduced myo- cardiomyocyte diameter than patients with SHF and myofila- cardial tissue Doppler (TD) velocities23–28 and abnormal mentary density is also higher in the myocardium of patients ventriculo-arterial coupling.29,30 On the basis of these with DHF. Cardiomyocytes isolated from biopsies of DHF and observations, the distinction between DHF and SHF is chal- SHF patients also differ functionally. In vitro cardiomyocyte lenged,31,32 and heart failure is considered to be a single resting tension is higher in DHF,62 and together with collagen syndrome characterized by a progressive decline in systolic volume fraction, this higher cardiomyocyte resting tension performance appreciated better by TD velocities than by significantly contributes to in vivo myocardial stiffness.
LVEF (Figure 1). The concept of a single syndrome is The cytoskeletal protein titin63 likely accounts for this reinforced by the unimodal distribution of LVEF in large higher resting tension. Titin functions as a bidirectional heart failure trials that recruited both patients with spring responsible for early diastolic LV recoil64 and late reduced and normal LVEF.33 According to the single syn- diastolic resistance to stretch.65,66 Isoform expression of drome hypothesis, diastolic LV dysfunction is of similar titin differs in patients with SHF and DHF: in patients with origin in all heart failure patients and consists primarily SHF, titin isoform expression shifts towards the more compli- of increased interstitial deposition of collagen and modified ant isoform,67–69 whereas in patients with DHF the shift is matricellular proteins.34,35 In the absence of a discrimina- towards the less compliant isoform.61 Apart from distinct tory role for diastolic LV dysfunction, patients presenting isoforms of cytoskeletal proteins in the LV myocardium of with heart failure without depressed LVEF are better patients with SHF and DHF, expression patterns of matrix characterized by the term ‘HFNEF'36 or the term ‘heart metalloproteinases (MMPs) and tissue inhibitors of MMPs failure with preserved left ventricular ejection fraction'37 (TIMPs) also differ. In the myocardium of hypertensive than by the term ‘DHF'.
patients with DHF70 and in aortic stenosis,71 there is a In the single syndrome hypothesis, the major difference decreased matrix degradation because of downregulation between the two ends of the spectrum [HFNEF and heart of MMPs and upregulation of TIMPs, whereas in dilated car- failure with reduced LVEF (HFREF)] is the degree of LV ven- diomyopathy, there is an increased matrix degradation tricular dilatation and shape change or LV remodelling.36 because of upregulation of MMPs.72 In patients with aortic Thus, it is postulated that there is an evolution or pro- stenosis, who develop a depressed LVEF, this balance gression from HFNEF to HFREF with the onset of LV between proteolysis and antiproteolysis shifts73 and impor- remodelling. LV volumes measured by three-dimensional tant cardiomyocyte degeneration occurs.74 Furthermore, in echocardiography are indeed already increased in HFNEF trabeculae of explanted human hearts, alterations of patients compared with normal subjects after matching for calcium handling have been observed which selectively age, gender, and body size suggesting that early stages of disturb relaxation and diastole.75–81 These alterations may How to diagnose diastolic heart failure Heart failure: a single or two syndromes? Listing of arguments favouring heart failure to be a single or two distinct syndromes.
also be more prominent in DHF. Finally, in clinical outcome of pulmonary oedema. In the outpatient setting, however, trials with pharmacological intervention, patients with DHF complaints of breathlessness are frequently reported have not responded as convincingly as patients with without detectable signs of congestion. ‘Presence of signs SHF,8,82 which suggests that different pathophysiological or symptoms of congestive heart failure' as the first criter- mechanisms may be operative.
ium for the diagnosis of HFNEF is therefore preferable to For clarity, the terms HFNEF and HFREF will be used ‘presence of signs and symptoms of congestive heart throughout the remaining part of this manuscript and, failure'. The latter criterion is used by the National Heart, respectively, replace the terms DHF and SHF. This use of Lung, and Blood Institute's Framingham Heart Study.93 HFNEF and HFREF does not imply that the issue of heartfailure presenting as one or two syndromes is resolved.
Normal or mildly abnormal systolicleft ventricular function Three obligatory conditions for heart failure The presence of normal or mildly abnormal systolic LV func- with normal left ventricular ejection fraction tion constitutes the second criterion for the diagnosis of Three obligatory conditions need to be satisfied for the diag- HFNEF. Since LVEF of heart failure patients presents as a nosis of HFNEF (Figure 2): (i) presence of signs or symptoms unimodal distribution, the choice of a specific cut-off of congestive heart failure; (ii) presence of normal or mildly value remains arbitrary.33 The National Heart, Lung, and abnormal LV systolic function, and (iii) evidence of diastolic Blood Institute's Framingham Heart Study93 used an LVEF .
LV dysfunction.
50% as cut-off for normal or mildly abnormal systolic LVfunction and this cut-off value has meanwhile been usedor proposed by other investigators.60,94 In the present Signs or symptoms of congestive heart failure consensus document, an LVEF . 50% is also considered Signs or symptoms of congestive heart failure include lung consistent with the presence of normal or mildly abnormal crepitations, pulmonary oedema, ankle swelling, hepatome- systolic LV function. LVEF needs to be assessed in accordance galy, dyspnoea on exertion, and fatigue. Different modes of to the recent recommendations for cardiac chamber quanti- presentation of dyspnea (i.e. effort related or nocturnal) fication of the American Society of Echocardiography and need to be distinguished.83 In HFNEF, breathlessness is the European Association of Echocardiography.95 It is of frequently the earliest symptom due to pulmonary conges- importance to note that in HFNEF reduced long-axis shorten- tion,84 whereas muscle fatigue is more prominent in HFREF ing is frequently compensated for by increased short-axis due to reduced cardiac output, impairment of vasodilator capacity, and abnormalities of skeletal muscle metabolism.
As already demonstrated by Frank, Starling, and Wiggers Breathlessness is especially difficult to interpret in elderly and later re-appraised,96 LV relaxation depends on end- and in obese, who represent a large proportion of the systolic load and volume.97–101 The criterion of ‘presence HFNEF population. Objective evidence of reduced exercise of normal or mildly abnormal LV function' therefore needs performance can be provided by metabolic exercise to be implemented with measures of LV volumes. To exclude significant LV enlargement,95 LVEDVI and LV consumption (VO2max)85–89 (reduced VO2max , 25 mL/kg/ end-systolic volume index cannot exceed 97 mL/m2 and min; low VO2max , 14 mL/kg/min) or by the 6 min walking 49 mL/m2, respectively.
test90–92 (marked limitation ,300 m). In the hospital Another concern related to establishing normal or mildly setting, signs and symptoms of congestive heart failure are abnormal LV function deals with the time elapsed between usually simultaneously present as many patients are the clinical heart failure episode and the procurement of hospitalized for decompensated heart failure or episodes the LV systolic function data. According to the criteria of

W.J. Paulus et al.
Diagnostic flowchart on ‘How to diagnose HFNEF' in a patient suspected of HFNEF. LVEDVI, left ventricular end-diastolic volume index; mPCW, mean pulmonary capillary wedge pressure; LVEDP, left ventricular end-diastolic pressure; t, time constant of left ventricular relaxation; b, constant of left ventricularchamber stiffness; TD, tissue Doppler; E, early mitral valve flow velocity; E0, early TD lengthening velocity; NT-proBNP, N-terminal-pro brain natriuretic peptide;BNP, brain natriuretic peptide; E/A, ratio of early (E) to late (A) mitral valve flow velocity; DT, deceleration time; LVMI, left ventricular mass index; LAVI, leftatrial volume index; Ard, duration of reverse pulmonary vein atrial systole flow; Ad, duration of mitral valve atrial wave flow.
the National Heart, Lung, and Blood Institute's Framingham hypothesis that measurement of diastolic LV dysfunction Heart Study, a definite or probable diagnosis of HFNEF was not required to make the diagnosis of HFNEF was requires the information on LV systolic function to be tested.60 Ninety-two per cent of patients with a history of obtained within 72 h following the heart failure episode.93 heart failure, an LVEF . 50%, and evidence of LV concentric This requirement may be obsolete because Doppler echocar- remodelling had an elevated LV end-diastolic pressure and diographic examinations of patients with hypertensive all of them had at least one haemodynamic or Doppler echo- pulmonary oedema performed sequentially at the time of cardiographic index of abnormal LV relaxation, filling, or hospital admission and following stabilization revealed iden- diastolic stiffness. In this group of patients, acquisition of tical LVEF and LV end-diastolic volume without evidence of data on diastolic LV dysfunction therefore provided no improvement of LV systolic function in the days following additional diagnostic information and was therefore only hospital admission.102 of confirmatory significance. As this study looked at patientswith a well-established history of heart failure, these resultscannot be extrapolated to patients presenting solely with Evidence of abnormal left ventricular relaxation, symptoms of breathlessness without a history or physical filling, diastolic distensibility, and diastolic stiffness signs suggestive of congestive heart failure. Nevertheless, Do we need evidence of left ventricular dysfunction this study among others,19,58–61 clearly demonstrates that during relaxation or diastole? evidence of concentric LV remodelling has important impli- The need to obtain positive evidence of abnormal LV relax- cations for the diagnosis of HFNEF and is a potential surro- ation, filling, diastolic distensibility, and diastolic stiffness, gate for direct evidence of diastolic LV dysfunction.94 The as proposed in the original guidelines of the European present consensus document (Figure 2) therefore considers Study Group,1 has been challenged.60 Recognizing the diffi- an LV wall mass index .122 g/m2 (C) or an LV wall mass culties in the assessment of diastolic LV dysfunction, the index .149 g/m2 (F) sufficient evidence95 for the diagnosis How to diagnose diastolic heart failure of HFNEF when TD yields non-conclusive results or when by observations in hypertensives, in which the combined plasma levels of natriuretic peptides are elevated.
use of these variables provided a semiquantitative estimateof LV end-diastolic pressure.120 Both studies measuredduration of reversed pulmonary vein atrial systole flow Invasive assessment of left ventricular dysfunction (Ard) and duration of mitral A wave flow (Ad) and used during relaxation or diastole their difference (Ard2Ad . 30 ms) to diagnose diastolic LV Evidence of abnormal LV relaxation, filling, diastolic disten- sibility, and diastolic stiffness can be acquired invasively Because of the absence of pseudonormalization on TD during cardiac catheterization. Invasively acquired evidence lengthening velocity measurements, the use of blood flow of diastolic LV dysfunction continues to be considered as pro- Doppler measures of diastolic LV function is no longer rec- viding definite evidence of HFNEF.1,19,93,94 Such evidence ommended as a first-line diagnostic approach to diastolic consists of a time constant of LV relaxation (t) .48 ms, an LV dysfunction. Only when TD lengthening velocities are LV end-diastolic pressure .16 mmHg or a mean pulmonary suggestive but non-diagnostic or when plasma levels of capillary wedge pressure .12 mmHg103–106 (Figure 2). The natriuretic peptides are elevated does the simultaneous pre- mathematics involved in deriving the time constant of LV sence of a low E/A ratio and a prolonged DT or a prolonged relaxation is explained in the appendix (Supplementary Ard2Ad index provide diagnostic evidence of diastolic LV material online). When LV end-diastolic pressure or pulmon- dysfunction (Figure 2).
ary capillary wedge pressure is elevated in the presence of anormal LVEDVI, LV end-diastolic distensibility is considered Tissue Doppler assessment of left ventricular dysfunction to be reduced. LV diastolic distensibility refers to the posi- during relaxation or diastole tion on a pressure–volume plot of the LV diastolic TD measures tissue velocity relative to the transducer with pressure–volume relation107 in contrast to LV stiffness, high spatial (mm) and temporal resolution (.100 s21).
which refers to a change in diastolic LV pressure relative The most frequently used modality of TD is measurement to diastolic LV volume (dP/dV ) and equals the slope of the of LV basal (‘annular'), longitudinal myocardial shortening, diastolic LV pressure–volume relation. A diastolic LV stiffness or lengthening velocity. Measurements can be obtained modulus .0.27 also provides diagnostic evidence of dias- either at the septal or at the lateral side of the mitral tolic LV dysfunction (see Supplementary material online, annulus. As explained in the appendix (Supplementary Appendix). The inverse of LV stiffness is LV compliance material online), the peak systolic (S) shortening velocity (dV/dP). Muscle stiffness (E) is the slope of the myocardial and the early diastolic (E0) lengthening velocities are con- stress–strain relation and represents the resistance to sidered to be sensitive measures of LV systolic or diastolic stretch when the myocardium is subjected to stress. Calcu- lation of stress (s) requires a geometric model of the LV and Especially, the ratio of early mitral valve flow velocity (E) calculation of strain (e) an assumption of an unstressed LV divided by E0 correlates closely with LV filling pressures.
dimension. Although muscle stiffness is generally considered E depends on left atrial driving pressure, LV relaxation to reflect the material properties of the myocardium and kinetics, and age but E0 depends mostly on LV relaxation therefore be insensitive to acute neurohumoral changes, kinetics and age. Hence, in the ratio E/E0, effects of LV recent clinical and experimental studies provided clear evi- relaxation kinetics and age are eliminated and the ratio dence for altered muscle stiffness following administration becomes a measure of left atrial driving pressure or LV of nitric oxide,108 endothelin-1,109 or angiotensin II.110 The filling pressure. E0 can also be conceptualized as the mathematics involved in deriving an LV or myocardial stiff- amount of blood entering the LV during early filling, ness modulus is outlined in the appendix (Supplementary whereas E represents the gradient necessary to make this material online).
blood enter the LV. A high E/E0 thus represents a highgradient for a low shift in volume. Information on LV filling Blood flow Doppler assessment of left ventricular pressures can also be derived from the time interval dysfunction during relaxation or diastole between the onset of E and the onset of E0 (TE2E0).133,134 Isovolumic LV relaxation time (IVRT), ratio of peak early (E) When the ratio E/E0 exceeds 15, LV filling pressures are to peak atrial (A) Doppler mitral valve flow velocity, decel- elevated and when the ratio is lower than 8, LV filling press- eration time (DT) of early Doppler mitral valve flow velocity, ures are low.135 E/E0 is a powerful predictor of survival after and ratio of pulmonary vein systolic (S) and diastolic (D) flow myocardial infarction and E/E0 . 15 is superior as predictor velocities were originally considered to be indicative of dias- of prognosis than clinical or other echocardiographic vari- tolic LV dysfunction if they exceeded specific cut-off values ables.136 The close correlation between E/E0 and LV filling indexed for age groups.1 These blood flow Doppler-derived pressures has been confirmed in heart failure patients with indices of diastolic LV dysfunction were subject of immedi- depressed (,50%) or preserved LV ejection fraction137 and ate critique111 and subsequently more carefully scrutinized in patients with slow relaxation or pseudonormal early in numerous studies.112–117 These studies are summarized mitral valve flow velocity filling patterns.138 In the diagnos- in the appendix (Supplementary material online) and tic flow charts shown in Figures 2 and 3, the ratio E/E0 is showed a variable outcome of blood flow Doppler-derived therefore considered diagnostic evidence of presence of indices in terms of their predictive value for HFNEF.
diastolic LV dysfunction if E/E0 . 15, and diagnostic When combining mitral valve blood flow Doppler with evidence of absence of HFNEF if E/E0 , 8. An E/E0 ratio pulmonary vein blood flow Doppler,118 93% of patients ranging from 8 to 15 is considered suggestive but non- suspected of HFNEF showed evidence of diastolic LV dysfunc- diagnostic evidence of diastolic LV dysfunction and needs tion.119 The strength of a combined use of mitral flow to be implemented with other non-invasive investigations velocity and pulmonary vein flow velocity is also supported to confirm the diagnosis of HFNEF (Figure 2). The proposed

W.J. Paulus et al.
Diagnostic flow chart on ‘How to exclude HFNEF' in a patient presenting with breathlessness and no signs of fluid overload. S, TD shortening velocity.
E/E0 cut-off values are based on pulsed Doppler measure- Left atrial volume measurements ments and on averaged velocities of lateral and septal A left atrial volume indexed to body surface area (¼ left atrial mitral annulus.
volume index) .32 mL/m2 was first recognized in the elderlyas a strong predictor (P ¼ 0.003) of a cardiovascular eventwith a higher predictive value than other echocardiographi- Strain and strain rate imaging cally derived indices such as LV mass index (P ¼ 0.014) or LV TD-derived strain rate and strain measurements are new diastolic dysfunction (P ¼ 0.029).140 In a population-based quantitative indices of regional intrinsic cardiac defor- study, left atrial volume index was also strongly associated mation139 and are presumed to be independent of transla- with the severity and duration of diastolic LV dysfunction: the left atrial volume index progressively increased from a Assessment of regional deformation obviously implies that value of 23 + 6 mL/m2 in normals to 25 + 8 mL/m2 in mild all myocardial segments are to be investigated to rule out diastolic LV dysfunction, to 31 + 8 mL/m2 in moderate dias- diastolic LV dysfunction. In contrast, TD E/E0 interrogates tolic LV dysfunction, and finally to 48 + 12 mL/m2 in severe global LV performance and is therefore preferred over diastolic LV dysfunction.141 Left atrial volume index was strain and strain rate measurements in the diagnostic flow- therefore proposed as a biomarker of both diastolic LV dys- charts of HFNEF (Figures 2 and 3). Potential future use of function and cardiovascular risk.142,143 A raised left atrial strain and strain rate imaging for the assessment of diastolic volume index (.26 mL/m2) has recently been recognized as LV dysfunction is further highlighted in the appendix a relatively load-independent marker of LV filling pressures (Supplementary material online).
and of LV diastolic dysfunction in patients with suspectedheart failure and normal LVEF.116 In these patients, left How to diagnose diastolic heart failure atrial volume index is a more robust marker than left atrial predictive value was aimed for when choosing the cut-off area or left atrial diameter.144,145 For these reasons, the values of NT-proBNP (220 pg/mL; Roche Diagnostics) and of present consensus document considers a left atrial volume BNP (200 pg/mL; Triage Biosite). For the exclusion of index .40 mL/m2 to provide sufficient evidence of diastolic HFNEF (Figure 3), a high negative predictive value was LV dysfunction when the E/E0 ratio is non-conclusive (i.e.
aimed for and the respective cut-off values of NT-proBNP 15 . E/E0 . 8) or when plasma levels of natriuretic peptides (120 pg/mL) and of BNP (100 pg/mL) were adjusted accord- are elevated (Figure 2). Similarly, a left atrial volume index ingly. NT-proBNP values of 120 and 220 pg/mL yielded, ,29 mL/m2 is proposed as a prerequisite to exclude respectively, a negative predictive value of 93% and a HFNEF (Figure 3). Left atrial volume index values of 29 and positive predictive value of 80%.146 BNP values of 100 40 mL/m2 correspond, respectively, to the lower cut-off and 200 pg/mL yielded, respectively, a negative predictive values of mildly abnormal and severely abnormal LA size in value of 96% and a positive predictive value of 83%.160 the recent recommendations for cardiac chamber quantifi- Cut-off values of NT-proBNP were derived from ROC analysis cation of the American Society of Echocardiography and the performed in HFNEF patients presenting with exertional dys- European Association of Echocardiography.95 The conduit, pnoea.146 An ROC analysis for BNP in HFNEF patients pre- reservoir, and pump functions of the left atrium in normal senting with exertional dyspnoea has not been reported.
and pathophysiological conditions are further explained in Cut-off values of BNP were therefore derived from ROC the appendix (Supplementary material online).
analysis performed in HFNEF patients presenting in theemergency room with acute heart failure.160 As cut-off Heart failure biomarkers: the natriuretic peptides values of NT-proBNP and BNP were derived from different Atrial natriuretic peptide (ANP) and brain natriuretic HFNEF subgroups, their respective magnitudes and ranges peptide (BNP) are produced by atrial and ventricular myo- cannot be compared. To achieve satisfactory positive pre- cardium in response to an increase of atrial or ventricular dictive values, the diagnostic cut-offs of NT-proBNP and diastolic stretch and their secretion results in natriuresis, BNP had to be raised to a level, at which sensitivity drops vasodilation, and improved LV relaxation. Cardiac myocytes below 80%. This results from the overlap of NT-proBNP and produce pro-BNP, which is subsequently cleaved in the blood BNP values between controls and HFNEF patients, especially into NT-proBNP and BNP.
when the HFNEF patients present with exertional dys- In patients with HFNEF,146,147 NT-proBNP values correlate pnoea.117 Natriuretic peptides are therefore recommended with early diastolic LV relaxation indices, such as the time mainly for exclusion of HFNEF and not for diagnosis of constant of LV relaxation (t), late diastolic LV relaxation HFNEF. Furthermore, when used for diagnostic purposes, indices, such as LV end-diastolic pressure, and the LV stiff- natriuretic peptides do not provide diagnostic stand-alone ness modulus. BNP and NT-proBNP values also vary with evidence of HFNEF and always need to be implemented the degree of LV diastolic dysfunction: progressively higher with other non-invasive investigations.
values were observed in patients with a mitral valve flowvelocity pattern of impaired LV relaxation, pseudonormali- Cardiac magnetic resonance zation, or restriction.117,148 The area under the receiver The specific advantage of cardiac magnetic resonance (CMR) operating characteristics (ROC) curve of NT-proBNP (0.83) over echocardiography is the possibility to acquire images in equalled the area observed for LV end-diastolic pressure any selected plane or along any selected axis. This makes (0.84) and exceeded the area observed for an abnormal TD CMR the gold standard for LV volume, LA volume, and LV E0/A0 ratio (0.81).146 Combining NT-proBNP with the E/E0 mass measurements.161,162 A routine CMR exam in the ratio increased the area under the ROC curve from 83 setting of heart failure will acquire the following images: to 95%.146 In contrast to its usefulness in symptomatic iso- cine images (same slice over the cardiac cycle) with a set lated diastolic LV dysfunction, natriuretic peptides were a of contiguous short-axis slices, covering the entire heart suboptimal screening test for preclinical diastolic LV from base to apex and a set of long-axis slices (two, three, and four chamber). CMR can provide a whole range of LV In normal individuals, the concentration of NT-proBNP filling parameters which are identical or nearly identical to rises with age and is higher in women than in men.150 BNP those obtained with echocardiography. As such, CMR is a and NT-proBNP levels can be influenced by comorbidities valid alternative for those patients who do not have an ade- such as sepsis,151 liver failure,152 or kidney failure.153,154 quate echocardiographic image quality to reliably obtain Plasma levels of BNP rise independently of LV filling press- these parameters. Moreover, CMR constitutes not only a ures once glomerular filtration rate falls below 60 mL/min.
valid alternative to echocardiography but could also be Furthermore, BNP and NT-proBNP plasma levels do not the first-choice technique if small changes in LA or LV exclusively reflect left atrial distension but can also rise as volumes and in LV mass are expected (e.g. when evaluating a result of right atrial distension. The latter is especially progression of disease or reaction to therapy). Finally, important when pulmonary hypertension occurs as a result several morphological and functional parameters such as of chronic obstructive pulmonary disease,155 pulmonary tissue characterization or LV diastolic untwisting can only embolism,156 or mechanical ventilation.157 Finally, obesity be assessed by CMR. These parameters contain important lowers BNP levels158,159 and lower cut-off values have to novel information for the identification of ischaemic, inflam- be used once body mass index exceeds 35 kg/m2.
matory, or infiltrative myocardial disease and for the evalu- The flowcharts for the diagnosis or exclusion of HFNEF ation of diastolic LV dysfunction. Further details on the use (Figures 2 and 3) do not consider an elevated BNP or of CMR are available in the appendix (Supplementary NT-proBNP to provide sufficient evidence for diastolic LV material online).
dysfunction and require additional non-invasive examina- Because of limited availability of CMR facilities, CMR is tions. For the diagnosis of HFNEF (Figure 2), a high positive currently considered to be a research tool and therefore W.J. Paulus et al.
not included in the diagnostic flowcharts of HFNEF. As the becomes the most likely cause of breathlessness. If an echo- clinical use of CMR is expanding and starting to address dias- cardiogram confirms the absence of valvular or pericardial tolic LV dysfunction,163 indices of diastolic LV dysfunction disease, LV volumes and LVEF should be measured in accord- derived from CMR will probably have to be included in ance to the recent recommendations of the American future diagnostic strategies of HFNEF.
Society of Echocardiography and the European Associationof Echocardiography.95 If LVEF exceeds 50%, if LVEDVI is,76 mL/m2, and if the patient has no atrial fibrillation, How to diagnose heart failure with normal atrial dilatation, LV hypertrophy, low TD S or high TD E/E0, left ventricular ejection fraction the diagnosis of HFNEF is ruled out.
This consensus statement on ‘How to diagnose DHF?' retainsa diagnostic strategy of three requirements that need to be satisfied to diagnose HFNEF (Figure 2). These requirementsare: (i) signs or symptoms of congestive heart failure; As HFNEF currently accounts for more than 50% of all heart (ii) normal or mildly abnormal systolic LV function, and (iii) failure patients and as the prevalence of HFNEF in the heart evidence of diastolic LV dysfunction. Since many patients failure population rises by 1% a year,8 an updated set of with HFNEF present with breathlessness and no signs of diagnostic criteria for HFNEF is required. The diagnostic fluid overload, symptoms are considered sufficient clinical flowcharts on HFNEF proposed in this consensus statement evidence to suggest the presence of congestive heart provide a strategy on ‘How to diagnose HFNEF' (Figure 2) failure. A LVEF of 50% is proposed as cut-off value of and on ‘How to exclude HFNEF' (Figure 3). The diagnostic mildly abnormal LV systolic function and an LVEDVI of strategy on ‘How to diagnose HFNEF' is specifically intended 97 mL/m2 as cut-off value of the absence of significant LV for patients suspected of having HFNEF and is primarily enlargement. Invasive diagnostic evidence of diastolic LV based on the positive predictive value of successive dysfunction can be obtained by measuring the time constant examinations. The diagnostic strategy on ‘How to exclude of LV relaxation, LV end-diastolic pressure, pulmonary HFNEF' is proposed for patients presenting with breathless- capillary wedge pressure, or the LV stiffness modulus. Non- ness and no physical signs of fluid overload and is mainly invasive diagnostic evidence of diastolic LV dysfunction based on the negative predictive value of successive is preferably derived from myocardial TD (E/E0 . 15). If examinations. These updated strategies for the diagnosis myocardial TD yields values suggestive but non-diagnostic of HFNEF should be helpful not only for individual patient for diastolic LV dysfunction (15 . E/E0 . 8), TD needs to be management but also for patient selection of future clinical implemented with other non-invasive investigations to trials looking at treatments for HFNEF.
provide diagnostic evidence of diastolic LV dysfunction.
These non-invasive investigations can consist of: (i) a Supplementary material blood flow Doppler of mitral valve flow velocity (E/A ratioand DT combined), or of pulmonary vein flow velocity Supplementary material is available at European Heart (Ard2Ad index); (ii) an echocardiographic measure of LV Journal online.
mass index or of left atrial volume index; (iii) an electrocar-diogram with evidence of atrial fibrillation; and (iv) a determination of plasma BNP or NT-proBNP. If plasmaNT-proBNP . 220 pg/mL or BNP . 200 pg/mL, diagnostic The authors gratefully acknowledge the thoughtful comments of the evidence of diastolic LV dysfunction also requires additional members of the board of the Heart Failure and Echocardiography non-invasive investigations, which can consist of: (i) TD (E/E0 Associations of the European Society of Cardiology.
ratio); (ii) a blood flow Doppler (E/A ratio and DT combined;Ard2Ad index); (iii) echo measures of LV mass index or left Conflict of interest: none declared.
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