A systematic review of diastolic stress tests in heart failure with preserved ejection fraction, with proposals from the EU-FP7 MEDIA study group

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1 European Journal of Heart Failure (2014) 16, doi: /ejhf.184 A systematic review of diastolic stress tests in heart failure with preserved ejection fraction, with proposals from the EU-FP7 MEDIA study group Tamás Erdei 1, Otto A. Smiseth 2, Paolo Marino 3, and Alan G. Fraser 1 * 1 Wales Heart Research Institute, Cardiff University, Cardiff, UK; 2 Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; and 3 Cardiology Clinic, Universita Piemonte Orientale, Novara, Italy Received 2 May 2014; revised 22 September 2014; accepted 25 September 2014; online publish-ahead-of-print 12 November 2014 Aims Cardiac function should be assessed during stress in patients with suspected heart failure with preserved ejection fraction (HFPEF), but it is unclear how to define impaired diastolic reserve.... Methods and results We conducted a systematic review to identify which pathophysiological changes serve as appropriate targets for diagnostic imaging. We identified 38 studies of 1111 patients with HFPEF (mean age 65 years), 744 control patients without HFPEF, and 458 healthy subjects. Qualifying EF was >45 55%; diastolic dysfunction at rest was a required criterion in 45% of studies. The initial workload during bicycle exercise (25 studies) varied from 12.5 to 30 W (mean 23.1 ± 4.6), with increments of 10 25W (mean 19.9 ± 6) and stage duration 1 5 min (mean 2.5 ± 1); targets were submaximal (n = 8) or maximal (n = 17). Other protocols used treadmill exercise, handgrip, dobutamine, lower body negative pressure, nitroprusside, fluid challenge, leg raising, or atrial pacing. Reproducibility of echocardiographic variables during stress and validation against independent reference criteria were assessed in few studies. Change in E/e was the most frequent measurement, but there is insufficient evidence to establish this or other tests for routine use when evaluating patients with HFPEF.... Conclusions To meet the clinical requirements of performing stress testing in elderly subjects, we propose a ramped exercise protocol on a semi-supine bicycle, starting at 15 W, with increments of 5 W/min to a submaximal target (heart rate b.p.m., or symptoms). Measurements during submaximal and recovery stages should include changes from baseline in LV long-axis function and indirect echocardiographic indices of LV diastolic pressure.... Keywords Diastolic stress test Exercise test Heart failure with preserved ejection fraction Functional reserve Echocardiography Introduction In patients with impaired cardiac functional reserve as an explanation for suspected heart failure with preserved ejection fraction (HFPEF), both symptoms and abnormal echocardiographic signs may be detected only during exercise. Multiple mechanisms, including but not confined to abnormal diastolic function, may account for poor exercise capacity during stress, so each should be assessed... when a stress test is performed. In elderly patients, other diseases that can reduce exercise capacity and cause breathlessness on exertion include anaemia, COPD, asthma, exercise-induced bronchospasm, heart valve disease, dynamic LV outflow tract obstruction, myocardial ischaemia, and dynamic mitral regurgitation. We report a systematic review and analysis of published studies of diastolic stress testing, which we performed in order to *Corresponding author: Wales Heart Research Institute, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. Tel: , Fax: , fraserag@cf.ac.uk

2 1346 T. Erdei et al. identify which measurements of diastolic functional reserve have been validated against independent reference criteria or demonstrated to correlate with outcomes. Based on current evidence, we propose a new stress echocardiographic protocol, and we summarize research that is needed before diastolic stress testing can be implemented more widely. Methods Search strategy All studies reported up to December 2012 using dynamic or non-dynamic diastolic stress protocols in patients with known or suspected HFPEF were identified by a Medline search, restricted to human studies published in English. Multiple searches were performed with one term from each of two groups: ( heart failure with normal ejection fraction or heart failure with preserved ejection fraction or diastolic heart failure ) AND ( stress echocardiography or exercise echocardiography or exercise test or stress test or diastolic stress test or bicycle or treadmill or handgrip or isometric exercise test or leg raising or pharmacologic stress or pharmacological stress or dobutamine or nitroprusside or lower body negative pressure or atrial pacing or saline infusion ). Using the terms heart failure with normal ejection fraction or heart failure with preserved ejection fraction or diastolic heart failure, we identified 282, 109, and 750 published manuscripts, respectively, which were screened for eligibility. Studies were included in this review if subjects had a preserved LVEF ( 45%) and signs or symptoms of heart failure, and underwent a diastolic stress protocol. Two additional studies of stress testing in patients without symptoms at rest but with risk factors for HFPEF were included. 1,2 The reference lists of the selected papers were screened for other relevant studies. Studies were not included if diastolic function was assessed during stress in patients diagnosed to have heart failure with reduced ejection fraction (HFREF), or if investigations were performed in mixed groups of patients undergoing elective coronary arteriography without signs or symptoms of heart failure; examples are discussed 3,4 but not included in the summary tables in this review. Data from control patients with normal EF and from healthy subjects were included in many studies, and these are summarized. Studies were not included if their primary focus was the diagnosis of myocardial ischaemia. Results Thirty-eight studies 1,2,5 40 were selected (Tables 1 and 2). These included 1111 patients with HFPEF; 458 healthy controls (enrolled in 45% of the studies, and usually matched for age); and 744 patients with normal EF used as controls who had hypertension, diabetes mellitus (with or without breathlessness), non-cardiac causes of dyspnoea (attributed to obesity, obstructive airways disease, restrictive airways disease), chest discomfort without symptoms of heart failure (before scheduled angiography to exclude coronary disease), atypical chest pain without coronary disease but with invasive evidence of normal diastolic function, or fatigue or dyspnoea but without diastolic dysfunction. One study used an upper limit of age for inclusion of 85 years, 26 and four selected patients older than 65 years; 2,11,12,14 all other studies reported no age restriction. The mean age of patients with HFPEF was 65 years; 630/1111 (56.7%) were female.... Definition of heart failure with preserved ejection fraction According to consensus recommendations, HFPEF can be diagnosed when three requirements are met simultaneously: signs or symptoms of heart failure; preserved LV global systolic function (EF by echocardiography >50% and LV end-diastolic volume index <97 ml/m 2 ); and evidence of LV diastolic dysfunction. 41 In the selected studies, the definition of HFPEF was very heterogeneous. Signs or symptoms of heart failure were essential in all studies, frequently specified as exertional dyspnoea or NYHA class II III or positive Framingham heart failure criteria. 42 Preserved EF was defined as >45% in five studies, >50% in 31 studies, and >55% in one study; it was not defined in one study. Diastolic dysfunction on invasive or non-invasive investigation was essential for diagnosing HFPEF in 17/38 (45%) studies; it was defined in many different ways (see footnotes to Tables 1 and 2). Twenty-six studies were performed after publication of the HFPEF consensus, 41 but only three studies applied elements of its diagnostic criteria. For example, prolonged retrograde pulmonary venous flow during atrial contraction was never reported. Indications Most of the studies included in this analysis (35/38) were simple cross-sectional observations in which the authors tried to answer some pathophysiological questions about mechanisms and indicators of diastolic dysfunction during dynamic or non-dynamic stress. These investigations often involved subjects or patients who were already suspected or diagnosed to have HFPEF. In three studies, 1,13,19 the purpose of the investigation was the diagnosis of early HFPEF in a patient with normal resting haemodynamics. In seven studies, 5,9,19,23,30,38,40 both HFPEF subjects and patients with hypertension but without HFPEF underwent stress testing (see footnotes to Tables 1 and 2). None of the included studies attempted to use diastolic stress testing to stratify risk, estimate prognosis, or predict responses to therapy, in subjects confirmed to have HFPEF. Exclusion criteria Exclusion criteria included atrial fibrillation (AF) in 15 studies and any arrhythmia (presumably including AF) in another 8 studies. Patients with ischaemic heart disease were excluded from 22/38 studies. Other exclusion criteria included moderate or severe heart valve disease, prosthetic heart valves, congenital heart disease, cardiomyopathy, cardiac amyloidosis, myocarditis, pericardial disease, constrictive pericarditis, atrioventricular block, bradycardia, bundle branch block, pacemaker or implanted cardiac defibrillator, aortic aneurysm, severe COPD, pulmonary embolism, cor pulmonale, idiopathic pulmonary hypertension, hepatic disease, renal failure, active malignancy, anaemia, contraindication to dobutamine, inability to exercise on an upright bicycle, low exercise capacity, poor echocardiographic windows, severe arthritis, and inability to measure E/e at rest or on exercise.

3 A systematic review of diastolic stress tests in HFPEF 1347 Table 1 Non-dynamic stress protocols used for diastolic stress testing in heart failure with preserved ejection fraction. First author, year of publication Definition of HFPEF No. of subjects Patients on BB (%) EF (%) HF signs/ symptoms * Evidence of DD Other criteria Patients Healthy controls BB stopped before exercise Modalities during stress Echocardiography manufacturer and system Specific protocol Comments... Isometric exercise: handgrip Kawaguchi, > a,b 8 a,b 40 c No Invasive Sustained handgrip exercise for 2 5min Westermann, > and 12 d 0 49 NS Invasive Handgrip exercise with raised arms as long as possible Penicka, > and 10 e 0 50 NS Invasive, echo (dynamic MR) NS Sustained handgrip exercise (duration not defined) Pharmacological stress: dobutamine infusion Penicka, > and 10 e 0 50 NS Invasive Dobutamine in 3 min stages: 5, 10, and 20 μg/kg/min Chattopadhyay, > and 29 f 0 71 Yes Echo GE Vingmed, Vivid Dobutamine in 3 min stages: 5, Five 10, 20, 30, and 40 μg/kg/min. Atropine given if target heart rate not reached Lee, > and 34 g NS Echo GE, Vivid 7 Dobutamine in 3 min stages: 5, 10, 20, 30, and 40 μg/kg/min. Atropine given if target heart rate not reached Norman, > Yes Echo Siemens Dobutamine 2, 4, 8, amd 16 μg/kg/min, 2.5 min stages. Data acquired in last 1.5 min Interventions to change preload Reduce preload: lower body negative pressure Prasad, >50 + 2a 2b Yes Invasive, echo Bhella, >50 + 2a 2b and 12 h 55 Yes Invasive, echo ATL HDI 5000CV or Philips ie33 ATL HDI 5000CV or Philips ie33 After 30 min rest, 5 min at 15 mmhg and 5 min 30 mmhg k After 30 min rest, 5 min at 15 mmhg and 5 min 30 mmhg Reduce preload: nitroprusside infusion l Penicka, > and 10 e 0 50 NS Invasive Nitroprusside from 0.5 μg/kg/min to decrease BP by 20 mmhg Increase preload: rapid intravenous infusion Prasad, >50 + 2a 2b Yes Invasive, echo ATL HDI 5000CV or Philips ie33 Warm saline ( ml/min; 37 C). Measurements after 10 and 20 ml/kg infusion Pressure volume data were acquired before patients discontinued exercise Pressure volume loops were recorded at the end of handgrip exercise Target heart rate: 0.85 (220 ageinyears) Target heart rate: 0.85 (220 ageinyears)

4 1348 T. Erdei et al. Table 1 Continued First author, year of publication Definition of HFPEF No. of subjects Patients on BB (%) EF (%) HF signs/ symptoms * Evidence of DD Other criteria Patients Healthy controls BB stopped before exercise Modalities during stress Echocardiography manufacturer and system Specific protocol Comments... Bhella, >50 + 2a 2b and 12 h 55 Yes Invasive, echo ATL HDI 5000CV or Philips ie33 Warm saline ( ml/min; 37 C). Measurements after and ml/kg Increase preload: leg raising Penicka, > and 10 e 0 50 NS Invasive Leg lifting (no detailed protocol given) Borlaug, > and 20 m 0 44 No Invasive Passive elevation of legs before ergometry Bhella, >50 + 4a 4b Yes 31 Phosphate magnetic resonance spectroscopy Static leg lifts within the MRI scanner to achieve a pre-determined exercise-induced metabolic state Combined intervention: atrial pacing Westermann, > and 20 i 0 49 NS Invasive Atrial pacing at 120 b.p.m. for at least 5 min Wachter, > and7 j 0 71 No Atrial pacing at 100 and 120 b.p.m. Smaller volumes generally used in the HFPEF patients to keep the PCWP <25 mm Hg and to avoid inducing pulmonary oedema BB, beta-blocker; BP, blood pressure; DD, diastolic dysfunction; HF, heart failure; HFPEF, heart failure with preserved ejection fraction; MRI, magnetic resonance imaging; NS, not stated a From a total of 14 subjects (6 HFPEF and 8 controls), handgrip exercise was performed in 11 subjects (not stated how many patients and controls) and supine bicycle exercise in 3 subjects. b Total study population was larger [10 HFPEF and 25 hypertensive controls, 9 age-matched normotensive and 14 young (<50) normotensives]. c On beta-blocker or calcium channel blocker. d A subset of patients: 25 HFPEF and 12 controls from total of 70 HFPEF and 20 controls. e 20 patients with invasively diagnosed HFPEF and 10 breathless controls. f 41 HFPEF and 29 breathless controls (due to obesity, obstructive airways disease, restrictive airways disease, or undetermined cause). g 47 hypertensive subjects with HFPEF and 34 patients with hypertension but without HFPEF. h 24 old (>65 years) healthy controls and 12 young (<50 years) healthy controls. i 70 HFPEF and 20 controls (with chest discomfort but no symptoms of heart failure, scheduled for angiography to exclude coronary artery disease) j 17 HFPEF and 7 control subjects with atypical chest pain but without coronary artery disease and without invasive diagnosis of diastolic dysfunction. k Due to large body habitus, 2 patients with HFPEF could not use the lower body negative pressure apparatus, so had head-up tilt at (20 and 40 or 60 ) instead. l Nitroprusside also decreases afterload. m 22 HFPEF and 20 non-cardiac dyspnoea subjects. Definitions of HFPEF * Sometimes stated: exertional dyspnoea or NYHA II III or Framingham criteria. 1 Invasively measured LV end-diastolic pressure >16 mmhg at rest or during haemodynamic interventions. 2a All HFPEF patients were required to have either an elevated BNP level, documented pulmonary congestion by chest radiography, or evidence of elevated left-sided filling pressures by right heart catheterization at the time of their index hospitalization 2b All patients selected were >65 years old. 3 Normal resting haemodynamics (PCWP <25 mmhg) but PCWP on exercise 25 mmhg. If PCWP <25 mmhg, subjects were classified as having non-cardiac dyspnoea. 4a Index hospitalization with evidence of pulmonary congestion, an elevated PCWP, or an elevated BNP within 6 months of enrolment. 4b All patients selected were >65 years old. 5 Invasive diagnosis of diastolic dysfunction according to the Heart Failure Association of of the European Society of Cardiology consensus statement

5 A systematic review of diastolic stress tests in HFPEF 1349 Table 2 Dynamic exercise protocols used for diastolic stress testing in heart failure with preserved ejection fraction First author, year of publication Definition of HFPEF No. of subjects Patients on BB (%) EF (%) HF signs/ Evidence symptoms * of DD Other criteria Patients Healthy controls BB stopped before exercise Modalities during or after exercise Echo vendor, machine type Initial workload (W) Incremental workload (W)... Supine bicycle protocols Ha, > NS Echo Sequoia, Acuson Pedal rate (r.p.m.) Stage length (min) Exercise target 25 25? 3 Maximal Tschope, > NS Yes Invasive Submaximal Talreja, > NS Yes Echo, invasive NS Maximal Ha, > and 117 a 0 24 Yes Echo NS 25 25? 3 Maximal Plehn, > Yes Radionuclide, invasive 25 25? 5 Maximal Borlaug, > and 20 b 0 44 No Invasive Maximal Maeder, > No Echo, invasive NS 0.3 ± 0.1 W/kg 1.0 ± 0.2 W/kg?? Maximal (only two stages) Borlaug, > c 0 50 No Echo NS Maximal (transmitral flow), invasive Semi-supine bicycle protocols Ennezat, > and 25 d 0 56 Yes Echo Philips SONOS ? 3 Maximal Tan, > No Echo GE Vivid 7???? Submaximal (symptomlimited to max. HR 100, for optimal frame rate) Phan, > No Radionuclide??? >3 Submaximal ( Semi-erect exercise at 50% of heart rate reserve) Tan, > e No Echo GE Vivid 7? 25?? Submaximal (images acquired from onset of symptoms with sustained workload) Sahlen, > f 0 48 Yes Echo, tonometry GE Vivid E9 0 10? 1 Submaximal (data acquired when HR >110/min, cycling stopped after imaging) Donal, > No Echo GE Vivid Submaximal to HR 120 b.p.m. Tartiere, > No Echo, tonometry GE, NS 30?? Submaximal (after HR stabilized and before E/A fused; one stage only) Upright bicycle protocols Guazzi, > g 0 30 NS CPEX???? Maximal (individualized ramp protocol) Borlaug, > and19 h 0 65 NS Radionuclide, CPEX Wachter, > and7 i 0 71 No CPEX (only in HFPEF) 25 25? 3 Maximal 20 20? 2 Maximal

6 1350 T. Erdei et al. Table 2 Continued First author, year of publication Definition of HFPEF No. of subjects Patients on BB (%) EF (%) HF signs/ Evidence symptoms * of DD Other criteria Patients Healthy controls BB stopped before exercise Modalities during or after exercise Echo vendor, machine type Initial workload (W) Incremental workload (W)... Maeder, of > No CPEX? 5 15? 1 Maximal Penicka, > and 0 50 NS Confirmation 25 25? 2 Maximal 10 j symptoms Borlaug, > , 19, and 10 k 0 57 Yes CPEX, echo (VAC), peripheral artery tonometry Haykowsky, > Yes CPEX, echo (LV volumes) Pedal rate (r.p.m.) Stage length (min) Exercise target GE Vivid ? 3 Maximal HP Sonos ? 3 Maximal Holland, > Yes Echo, tonometry GE Vivid 7?? 50? Submaximal (steady state for 1 min at 60% of maximal HR ) Meluzin, > and NS Echo after 54 l exercise GE Vivid 7 and E ? 2 Maximal Takaya, > NS CPEX 15 15? 1 Maximal Treadmill protocols Mottram, > No Echo GE Vivid 5 Bruce NA Maximal Guazzi, > g 0 30 CPEX NS Individualized ramp protocol NA Maximal Witte, > m NS CPEX Modified Bruce NA Maximal Farr, > No CPEX Modified Naughton NA Maximal Tan, > (7) No CPEX Modified Bruce NA Maximal Phan, > No CPEX Incremental ramp NA Maximal Tan, > e No CPEX Modified Bruce NA Maximal Phan, Normal + 18a 18b 41 and Incremental ramp protocol NA Maximal 16 n (chronotropic 41 0 q NA CPEX response, HRR) Holland, > and NS Echo Philips 7500 or IE 33 Standard NA Maximal Holland, > Yes Echo, tonometry GE Vivid 7 Graded treadmill protocol NA Maximal Bhella, > a 20b Yes CPEX, CO by Modified Astrand Saltin NA Maximal ( 5 min modification steady-state exercise of acetylene at 30% then 5min rebreathing at 60% of peak VO 2, technique and maximal exercise) Wang, > and 0 73 NS Echo Philips Sonos 30 p 7500 Other protocols Borlaug, > and3 b 0 44 No Invasive <6 min on Bruce protocol, then echo NA Submaximal Arm exercise: adduction with lifting weights, if femoral access had been obtained. Repetition frequency was gradually increased to subjective fatigue.

7 A systematic review of diastolic stress tests in HFPEF 1351 Table 2 Continued First author, year of publication Definition of HFPEF No. of subjects Patients on BB (%) EF (%) HF signs/ Evidence symptoms * of DD Other criteria Patients Healthy controls BB stopped before exercise Modalities during or after exercise Echo vendor, machine type Initial workload (W) Incremental workload (W)... Borlaug, > c 0 50 No Echo (transmitral flow), invasive Pedal rate (r.p.m.) NS Arm exercise: adduction with lifting weights Stage length (min) Exercise target BB, beta-blocker; CO, cardiac output; CPEX, cardiopulmonary exercise testing; DD, diastolic dysfunction; echo, echocardiography; HF, heart failure; HFPEF, heart failure with preserved ejection fraction; HR, heart rate; HRR, heart rate reserve; NA, not applicable; NS, not stated; VAC, ventricular-arterial coupling. a 24 HFPEF with exertional dyspnoea and 117 without exertional dyspnoea [LV functional reserve assessment in patients with hypertension (61) and diabetes mellitus (24)]. b 22 HFPEF and 20 non-cardiac dyspnoea (NCD) subjects exercised on supine bicycle, 10 HFPEF and 3 NCD had arm exercise (where femoral access were used); altogether 32 HFPEF and 3 NCD subjects. c 20 HFPEF (11 exercised on supine bicycle, 9 had arm exercise). d 25 HFPEF and 25 hypertensive controls. e 30 patients with hypertension and shortness of breath on exertion and normal EF but without evidence of diastolic dysfunction. f 21 elderly (>65 years), female, hypertensive subjects with normal EF (>55%) but without evidence of diastolic dysfunction. g 46 patients of HFPEF with EF >50% (and some more subjects with lower EF). h 17HFPEFand19 non-hfpef controls. i 17 HFPEF and 7 control subjects with atypical chest pain but without coronary artery disease and without invasive diagnosis of diastolic dysfunction. j 20 patients with invasively diagnosed HFPEF and 10 breathless controls. k 21 HFPEF and 19 patients with hypertension without heart failure and 10 control subjects without cardiovascular disease. l 30 HFPEF and 54 patiens with shortness of breath on exertion without diastolic dsyfunction. m Patients with preserved systolic function (EF >45%) and diastolic dysfunction. n 41 HFPEF and 16 subjects with hypertension without HFPEF. o 148 HFPEF patients and 288 subjects referred for exercise echo for investigation of fatigue or dyspnoea but without diastolic dysfunction (non-hfpef controls). p 70 HFPEF (43 with systolic dyssynchrony) and 30 controls with hypertension and EF >50% (without DD). q Patients with HfPEF on BB were excluded to assess chronotropic response and HR recovery accurately. r Patients were free of medications that could influence haemodynamic measurements. Definitions of HFPEF: * Sometimes stated: exertional dyspnoea or NYHA II III or Framingham criteria. 1 Nearly normal resting but increased filling pressure at exercise; evidence of abnormal LV relaxation, filling, and/or diastolic distensibility according to consensus statement from 1998: during LV angiography, slow isovolumic LV relaxation was indicated by an increase in change in pressure with respect to time (dp/dtmin; 1100 mmhg/s) and/or a prolongation of the time constant of LV pressure decay (tau, 48 ms) as derived from LV pressure recordings and/or during echocardiographyby a prolongation of isovolumic relaxation time (IVRT, ms). Slow early LV filling was indicated by a reduction of the ratio of E /A 1 and/or of the E wave deceleration time ( ms). Reduction of the e /a ratio (<1) confirmed diastolic dysfunction. An E/e ratio <8 was accepted as normal. Reduced LV diastolic distensibility was indicated by an increase in LV end-diastolic pressure (LVEDP 16 mmhg) as derived from LV pressure recordings and/or by PCWP that was measured by right heart catheterization at rest ( 12 mmhg) or during exercise ( 20 mmhg). 2 Abnormal LV relaxation, defined as the presence of a mitral E/A <0.75 and/or deceleration time (DT) >240 ms. 3 Normal resting systolic and diastolic function by echocardiography (E/A >1, DT<220 ms, Valsalva negative) and invasive measurements (LVEDP <16 mmhg PCWP < 12 mmhg) but abnormal increase in PCWP (>12 mmhg during peak exercise). 4 Normal resting haemodynamics (PCWP <25 mmhg) but PCWP on exercise 25 mm Hg. If PCWP < 25 mmhg, subjects were classified as having non-cardiac dyspnoea (NCD). 5 Invasive evidence of diastolic dysfunction: prolonged LV relaxation at rest (tau >48 ms) and/or elevated filling pressures (LVEDP >15 mmhg at rest or >22 mmhg with exercise). 6 Radiographic (pulmonary vascular redistribution/interstitial oedema/pleural effusion) evidence of heart failure. 7 The criteria of Vasan and Levy for probable diastolic heart failure: the cause of HF in patients with a normal LVEF is probably LV diastolic dysfunction once mitral valve disease, cor pulmonale, primary volume overload conditions, and non-cardiac causes of symptoms are excluded (objective evidence of LV diastolic dysfunction is not needed). 8 Objective evidence of exercise limitation on cardiopulmonary exercise testing: a maximal oxygen uptake (VO2 max) <80% of age- and sex-predicted values. 9 Hypertensive subjects with (A) normal baseline echo (including EF >50%) and (B) history of exertional dyspnoea. 10 Elderly (>65 years), female, hypertensive subjects with EF >55%. 11 NT-proBNP >300 pg/ml. 12 Hospitalization for pulmonary oedema due to heart failure. 13 Invasive diagnosis of diastolic dysfunction according to the Heart Failure Association consensus statement Invasively measured LVEDP >16 mmhg at rest or during haemodynamic interventions. 15 Clear evidence of diastolic dysfunction at rest (i.e. E/e >15) or non-conclusive E/e (8 15), with supplementary criteria suggesting raised LV filling pressure as per guidelines; 41 however, no details about supplementary criteria. 16 Impaired LV relaxation defined by the combination of E/A ratio <1 and E-wave DT >250 ms. 17 Diastolic dysfunction defined: at least one of the following: E:A wave reversal on transmitral Doppler (<0.5), a prolonged DT of transmitral E wave (>280 ms), or an increased IVRT (>105 ms). 18a LV hypertrophy and/or evidence of diastolic dysfunction on echocardiographic Doppler (not defined). 18b Objective evidence of exercise limitation on cardiopulmonary exercise testing: a maximal oxygen uptake (VO2 max) <80% of age- and sex-predicted values. 19 Evidence of DD (according to Heart Failure Association consensus statement 2007, but not all supplementary criteria were used): resting E/e >15; in patients with non-conclusive E/e (8 15), further echocardiographic assessment was made on the basis of AF, left atrial (LA) size (LA volume index >40 ml/m 2 or LA area >20 cm 2 if LA volume was unobtainable), LVmass index >122 g/m 2 (men) or >149 g/m 2 (women), or E/A ratio <0.5 and deceleration time >280 ms. 20a Index hospitalization with evidence of pulmonary congestion, an elevated PCWP, or an elevated BNP within 6 months of enrolment. 20b All patients selected were >65 years old. 21 Presence of diastolic dysfunction (mean of septal and lateral mitral annular early diastolic velocity: Ea <8).

8 1352 T. Erdei et al. Stress protocols Dynamic exercise tests (Table 2) employed supine (n = 8) or semi-supine (n = 7) bicycle ergometry with imaging during exercise, or sitting upright bicycle (n = 10) or treadmill exercise (n = 12) mainly with imaging immediately afterwards. The initial workload during bicycle exercise (supine/semi-supine/upright) varied from 12.5 to 30 W (mean 23.1 ± 4.6), with increments from 10 to 25 W (mean 19.9 ± 6) and stage duration from 1 to 5 min (mean 2.5 ± 1 min); targets were submaximal (n = 8) or maximal (n = 17). In 9/25 studies of bicycle exercise (36%), beta-blockade was suspended beforehand, while in six studies (24%) the policy was not stated. Most treadmill protocols (11/12) used maximal targets; Bruce or modified Bruce (n = 5) or incremental ramp protocols (n = 3) were the most common. Beta-blockers were stopped before treadmill exercise in 2/12 studies (16%); no policy was stated in four other studies (32%). Cardiopulmonary exercise testing (CPEX) with measurements of gas exchange was performed during upright bicycle exercise in six studies, during treadmill testing in seven studies, and during either method in different centres in one other study. Only a few studies reported the feasibility of performing dynamic exercise tests. Inability to exercise was an exclusion criterion in five studies. 1,2,24,29,30 In two reports from the same group, 6 out of and6outof48subjects 1 were unable to perform any exercise. In other studies, 56 patients from a total of 239 subjects (23%) were excluded because they could not exercise at a workload of >25 W, 19 and 30 of 102 subjects were excluded because they could not exercise beyond stage one. 36 Elsewhere, patients were excluded if they were unable to perform a maximal CPEX test. 28,34 Ennezat and colleagues reported that all 25 patients in their study (aged 74 ± 9 years) were able to to exercise on a semi-recumbent bicycle. 23 Ha and colleagues reported difficulties with interpretation of data in 10% of subjects because of sinus tachycardia or exercise-induced atrial tachyarrhythmia at low levels of exercise; 16 in another of their studies, premature tachycardia made the analysis uninterpretable in 42 out of 239 patients (18%). 19 In the study by Holland and colleagues, 25 of 531 patients (5%) were excluded from the analysis because E/e could not be measured either at rest or during exercise. 39 Isometric stress protocols (n = 3) involved handgrip exercise for 2.5 min, as long as possible, or an unreported duration. Pressure volume loops were acquired before or immediately after patients discontinued exercise. Pharmacological stress with dobutamine was evaluated in four studies two 8,9 using standard doses (5, 10, 20, 30, 40 μg/kg/min in 3 min stages) with atropine if the target heart rate [0.85 (220 age in years)] was not reached, and two 7,10 using lower doses (5, 10, 20 μg/kg/min in 3 min stages; or 2, 4, 8, 16 μg/kg/min in 2.5 min stages). Diastolic function has been monitored after interventions to change loading conditions. In two studies, preload was reduced by lower body negative pressure for 5 min at 15 mmhg followed by 5 min at 30 mmhg (compared with initial measurements after resting supine for 30 min); the subjects were placed in a cylindrical... metal tank sealed at the level of the iliac crest, with suction from a vacuum pump controlled by a regulator calibrated against a mercury manometer. In another study, 7 preload was reduced by nitroprusside (from 0.5 μg/kg/min, until systolic pressure decreased by 20 mmhg). In two studies, 11,12 preload was increased by rapid i.v. infusion of warm saline (37 C, at ml/min, with measurements after 10 and 20 ml/kg), and in three studies it was increased by leg raising (no detailed protocols given). Atrial pacing, which alters both contractile function and loading, was used in two studies,at 120 b.p.m. for >5min, orat100 and 120 b.p.m. (duration not stated). Variables tested The variables tested during studies of diastolic stress testing in HFPEF are summarized in Table 3. The invasive measurements most often used as comparators for non-invasive indices were LV end-diastolic pressure (LVEDP), PCWP, and the relaxation time constant during isovolumic relaxation (tau). Less common but more detailed measurements included LV diastolic elastance, minimal rate of LV pressure change (dp/dt min ), LV diastolic stiffness (b; dp/dv), LV diastolic stiffness constant (β), end-diastolic stiffness, end-systolic elastance, end-systolic wall stress, and peak systolic and mean pulmonary arterial pressure. The main diagnostic target used in 15/38 studies (39%) was the estimation of LV filling pressure by the E/e ratio. Only one study estimated filling pressure from the ratio of the early diastolic velocity of mitral inflow to the flow propagation velocity (E/Vp). Two studies departed from convention and validation by deriving e from stored loops of colour myocardial velocity imaging (MVI). Diastolic functional reserve index (DFRI), based on change in e velocity on exercise, was reported in four studies; two used pulsed MVI and defined DFRI as Δe e rest 19 or as Δe (1 1/e rest ), 26 and two used colour MVI data [with the formula Δe (1 1/e rest )]. 1,24 Most studies assessed mitral inflow by pulsed-wave Doppler. More informative measurements included Vp (four studies): during semi-supine bicycle exercise HFPEF patients had lower suctional reserve (ability to increase Vp on exercise) compared with controls (ΔVp 11 ± 13vs.22± 14cm/s;P = 0.001). 25 In another study, however, Vp was higher in 11 patients with HFPEF than in 13 controls at both lower (39.4 ± 12.6 cm/s vs ± 8.6 cm/s; P = 0.038) and higher filling pressures (50.8 ± 10.8 cm/s vs ± 8.8 cm/s; P = 0.043). 11 Isovolumic relaxation time (IVRT) was assessed in four studies, and early diastolic untwisting in two: diastolic peak apical rotational velocity was used as a surrogate of untwisting rate. In the same studies, peak apical rotation, and the percentage reductions of apical rotation in early, mid, and late diastole, and LV twist, were reported when feasible. LV diastolic strain rate and diastolic dyssynchrony were reported in single studies. Since patients with HFPEF may have reduced LV longitudinal shortening, myocardial systolic velocities were measured by pulsed MVI in five studies and by colour MVI in five studies. Systolic functional reserve index (SFRI) based on the change of s velocity on exercise, was reported in three studies, using different definitions

9 A systematic review of diastolic stress tests in HFPEF 1353 Table 3 Variables measured during stress in studies of diastolic stress testing in heart failure with preserved ejection fraction Variables References... I. Invasive studies Left ventricular end-diastolic pressure 5, 6, 7, 13, 15, 17, 22 Pulmonary capillary wedge pressure 11, 12, 13, 17, 18, 20, 21 LV diastolic elastance 22 Minimal rate of LV pressure change (dp/dt min ) 6, 7, 15 LV diastolic stiffness (b; dp/dv) 6 LV diastolic stiffness constant (β) 6, 15 Tau (relaxation time constant, during isovolumic relaxation) 5, 6, 7, 15, 22 End-diastolic stiffness 7 End-systolic elastance 7 End-systolic wall stress 20 Pulmonary artery mean pressure 13, 20, 21 Pulmonary artery systolic pressure 13 II. Non-invasive studies 1. Echocardiography (variables of diastolic function and selected variables of systolic function) A. Traditional Doppler/colour M-mode Early diastolic velocity of mitral inflow (E) 1, 2, 8, 11, 12, 16, 18, 19, 21, 22, 24, 27, 32, 33, 35 Late diastolic velocity of mitral inflow (A) 1, 8, 11, 16, 19, 27, 32, 33, 35 E/A 1, 2, 8, 11, 16, 19, 27, 32, 33, 35 Deceleration time (DT) 1, 8,16, 18, 19, 22, 33 Flow propagation velocity (Vp) 1, 11, 12, 24 Isovolumic relaxation time (IVRT) 1, 8,11, 22 Estimated filling pressure (E/Vp) 12 Presence of dynamic mitral regurgitation 7 B. Pulsed myocardial velocity imaging (MVI) Systolic annular velocity by pulsed MVI (s ) 26, 32, 33, 35, 40 Early diastolic annular velocity by pulsed MVI (e ) 11, 12, 16, 18, 19, 21, 26, 32, 33, 35 Late diastolic annular velocity by pulsed MVI (a ) 32, 33, 35 E/e 1, 10, 12, 16, 18, 19, 21, 24, 26, 32, 33, 35, 39 Diastolic functional reserve index (pulsed MVI) 19, 26 Systolic functional reserve index (pulsed MVI) 26 Electromechanical delay from QRS onset to peak s (Ts) between the septum and the 40 lateral segment C. Colour MVI (cmvi), off-line analysis Longitudinal systolic myocardial velocity (s cmvi) 1, 2,8,9,24 Longitudinal early diastolic myocardial velocitiy (e cmvi) 1, 2,8,9,24,27 Longitudinal late diastolic myocardial velocitiy (a cmvi) 1, 8,24 E/e (cmvi) 8, 27 Diastolic functional reserve index 1, 24 Systolic functional reserve index 1, 24 LV systolic and diastolic dyssynchrony (Ts SD, Te SD) (time to peak myocardial 9 systolic velocity and time to peak early diastolic velocity) D. Speckle tracking echocardiography Longitudinal displacement (Siemens VVI, velocity vector imaging) 10 Longitudinal systolic (s sp) velocity by speckle tracking (Siemens VVI) 10 Longitudinal early diastolic (e sp) velocity by speckle tracking (Siemens VVI) 10 Longitudinal systolic strain rate (Siemens VVI) 10 Longitudinal diastolic strain rate (Siemens VVI) 10 Radial velocities (Siemens VVI) 10 Radial displacement (Siemens VVI) 10 GLS (average of 12 segments of septal, lateral, inferior, and anterior walls) 1, 24 Global four-chamber longitudinal strain 26 Global two-chamber longitudinal strain 26 Global three-chamber longitudinal strain 26 Global radial strain (short axis mid ventricular or papillary muscle level) 1, 24, 26

10 1354 T. Erdei et al. Table 3 Continued Variables References... Global circumferential strain 26 2D strain systolic reserve (=ΔGLS 4 chamber [1 (1/GLS 4 chamber at rest)] 26 Peak apical rotation 1, 24 Diastolic peak rotational velocity (surrogate of untwisting rate) 1, 24 The percentage of LV apical untwist in early diastole [25% of untwist (from peak rotation to peak untwist) 1, 24 duration] The percentage of LV apical untwist in mid diastole (50%) 1, 24 The percentage of LV apical untwist in late diastole (75%) 1, 24 LV twist (if basal rotation also available: 45 out of 56 patients at rest, 20 out of 56 patients on exercise) Arterial functional parameters A. Ventricular arterial interaction Arterial elastance 2, 9, 22, 23, 24, 26, 27, 29, 30 Ventricular elastance (end-systolic elastance) 2, 24, 26, 27 Ventricular arterial coupling ratio 2, 26, 27, 30 LV diastolic elastance 19 Arterial compliance 27 Peripheral vascular resistance 27 B. Central (aortic) stiffness Central systolic blood pressure 2, 27, 32 Central diastolic blood pressure 2, 27, 32 Central end-systolic pressure 2, 32 Central augmented pressure 2, 27, 32 Augmentation index 2, 32 CTr, timing of the reflected wave 32 ΔE W, wasted LV pressure energy 32 Aortic pulse wave velocity 27 C. Local arterial stiffness Carotid Peterson modulus (Ep) 27 GLS, global longitudinal strain and modalities (pulsed or colour MVI). Longitudinal myocardial systolic velocity by colour MVI on exercise correlated with Vp (r = 0.47, P = 0.005), compatible with a mechanistic link between systole and diastolic suction. 24 Other variables of LV systolic function measured in single studies included longitudinal displacement, global longitudinal strain, global longitudinal strain systolic reserve, and longitudinal systolic strain rate by two-dimensional speckle tracking echocardiography. Systolic dyssynchrony was analysed in two studies. Variables of central aortic stiffness including central blood pressure, augmentation index, and pulse wave velocity were measured in three studies. The local arterial stiffness of the right common carotid artery was evaluated in one study. Ventricular arterial coupling was reported as the ratio of elastances in four studies (Table 3). Reproducibility Inter- and/or intra-observer variability of measurements during stress were reported in 8/38 studies (21%), more often for myocardial velocities by pulsed or colour MVI than for blood-pool Doppler measurements. Tan and colleagues reported interclass correlation coefficients (ICCs) for interobserver variability of pulsed and colour MVI from to 0.96 at rest and 0.67 to 0.99 during semi-supine bicycle exercise; intraobserver variability was at rest and onexercise. 1,24 In another study, the intraobserver variability of systolic, early- and late-diastolic mitral annular velocities by colour MVI was <10% at rest ( %, %, and %, respectively) and <13% during dobutamine infusion ( %, %, and %, respectively). 8 The intraobserver reproducibility of E/e was good, with small mean differences and high ICCs for measurements both at rest (0.0 ± 0.3; ICC = 0.996, P < 0.001) and after treadmill exercise (0.0 ± 0.3; ICC = 0.975, P < 0.001). 39 Interobserver variability was also low, with small mean differences between observers at rest ( 0.2 ± 1.1) and after exercise (0.1 ± 1.3). The interobserver ICC for resting E/e (0.953, Pp < 0.001) was higher than the ICC for exercise E/e (0.873, P < 0.001; P = 0.04 for Fisher s z-score). 39 Validation against independent reference criteria Some stress protocols compared non-invasive measurements of diastolic function with invasive measurements made during cardiac catheterization, or with CPEX. In 14/38 studies neither was performed, and so non-invasive measurements during stress could not be compared with any independent reference criteria. In 9/38

11 A systematic review of diastolic stress tests in HFPEF 1355 studies, either invasive testing or CPEX was performed but without comparison with echocardiography. In six studies both invasive and non-invasive measurements (echocardiographic in five studies 11,12,18,21,22 and radionuclide in one study 20 ) were performed during stress. Correlations between diastolic function on exercise by echocardiography and CPEX were reported in two studies. 1,24 Talreja et al. reported that E/e (11.7 ± 0.5 to 14.4 ± 0.6, P < 0.01) and PCWP (14 ± 4to23± 10 mmhg, P < 0.001) both increased during supine bicycle exercise; the sensitivity of E/e 15 to predict a normal PCWP during exercise was 89%, and E/e >15 during exercise was associated with PCWP >20 mmhg. 18 However, they studied only 12 patients, and individual slopes of PCWP vs. E/e were very variable. In another small study (of 14 patients), E/e decreased during supine bicycle exercise (13.2 ± 4.1 to 11.1 ± 3.4, P < 0.05) in spite of an increase in PCWP (10 ± 4 to 23 ± 6 mmhg, P < 0.05). 21 There were no correlations between PCWP and septal (r = 0.19; P = 0.39), lateral (r = 0.04; P = 0.87), or mean E/e (r = 0.12; P = 0.59) at rest, or during peak exercise (septal E/e vs. PCWP r = 0.22, P = 0.33). In 47 subjects (including 11 with HFPEF), Bhella and colleagues manipulated PCWP from 0.8 to 28.8 mmhg during right heart catheterization with simultaneous transthoracic echocardiography. 12 Based on 267 paired measurements, they confirmed a weak but significant relationship between E/e and PCWP (PCWP = 0.58 E/e ; P < 0.001). In HFPEF, the relationship remained significant (60 paired measurements, P = 0.04), but individual linear regression slopes varied from 1.44 to 4.42 and r 2 from 0.01 to 0.82; changes in E/e and PCWP were discordant in three and concordant in eight patients. In the same study, changes in E/Vp correlated with changes in PCWP in the whole group (P = 0.005) but not in HFPEF patients with only 59 paired measurements (P = 0.16). Within individual subjects with HFPEF, neither E/e nor E/Vp tracked changes in left-sided filling pressures reliably. 12 In 56 patients with HFPEF, the echocardiographic measurements during exercise that correlated with peak oxygen consumption were s by colour MVI (r = 0.61, P = 0.003), e by colour MVI (r = 0.42, P = 0.038), apical rotation (r = 0.44, P = 0.026), E/e (r = 0.34, P = 0.04), Vp (r = 0.35, P = 0.03), and early diastolic untwisting (r = 0.53, P = 0.007). 24 Correlations were higher in 30 patients with treated hypertension but without HFPEF (s, r = 0.66, P < 0.001; e, r = 0.65, P < 0.001; apical rotation, r = 0.61, P < 0.001; Vp, r = 0.59, P < 0.001; early untwist, r = 0.52, P = 0.007). 1 In 20 HFPEF subjects, mean LVEDP increased during dynamic exercise from 19 to 30 mmhg (P < ), but limited echocardiographic correlates were reported; the mean deceleration time of early mitral inflow decreased from 196 to 129 ms (P = 0.003). 22 Meluzin and colleagues reported that NT-proBNP was a good predictor of HFPEF [area under the curve (AUC) 0.83, P < 0.001; optimal cut-off 200 pg/ml with sensitivity 77%, specificity 87%]. 33 NT-proBNP (AUC 0.90) 17 and peak exercise BNP (AUC 0.81) 35 accurately identified elevated LV filling pressures during exercise that were confirmed by invasive measurement. There were weak correlations between resting log NT-proBNP and PCWP (R = 0.37; P = 0.051) orlvedp(r = 0.39; P = 0.04), and a strong association between log NT-proBNP and PCWP during exercise (R = 0.78; P <0.001) Only four studies 17,32,33,35 compared non-invasive measurements of diastolic function with BNP or NT-proBNP concentrations. Tschöpe and colleagues found no significant correlation at rest between log NT-proBNP and tau, dp/dt min,e/a,e /a,e/e ratio, or mitral deceleration time. 17 In another study, of 15 HFPEF patients and 15 controls, change in E/e on exercise was associated with change in BNP (r = 0.60; P = 0.04). 32 Mottram and colleagues reported a modest increase in BNP on exercise, from 48 ± 57 to 74 ± 97 pg/ml, P = 0.007).35 Peak transmitral E velocity (r = 0.41, P < 0.05) and s, e, and a (P < 0.01) all correlated with the increment of BNP, but there was no correlation between the peak exercise E/e ratio and peak exercise BNP (r = 0.08, P = 0.71). A peak exercise BNP cut-off of 38 pg/ml was 88% sensitive and 71% specific for a peak exercise E/e ratio >10, but the confidence intervals for a positive test result were reported to be too wide to provide useful information. Discussion This review has shown an almost complete lack of consensus concerning the specific diagnostic objectives of diastolic stress tests, the optimal diagnostic targets, and the methods that should be employed. There is no agreement concerning diagnostic criteria that could correlate with responses to targeted treatment. It is important to have age-related reference values for different variables of diastolic functional reserve to establish what is normal, but these are not available. In general, published studies have not recruited typical patients with HFPEF who are elderly, have many co-morbidities including ischaemic heart disease, and may be in AF. Stress intervention Cardiovascular responses differ between supine and upright exercise. Conventional treadmill and upright bicycle exercise tests, with echocardiographic imaging at the end of the test, are useful for diagnosing LV systolic dysfunction and ischaemia, but are of limited value for detecting exercise-induced diastolic dysfunction. 33,43 At higher workloads, increased upper body motion and respiratory rate limit image quality. When posture during exercise echocardiography was changed from supine to upright in controls and patients who had a myocardial infarction, e decreased and E/e increased, due to the preload dependence of e. 43 The E/e ratio has been validated only during supine or semi-supine bicycle exercise, 3,44 which also allow continuous imaging during stress. Consensus recommendations state that in patients with impaired myocardial relaxation E/e increases on exercise because e goes up less than mitral E velocity goes up, and that E remains increased for a few minutes after exercise whereas e is still low. 45 In order to obtain E and e velocities after exercise, recording may be delayed until cross-sectional images have been acquired for analysis of wall motion since this avoids the merging of E and A velocities that occurs at faster heart rates. 45 However, systemic vascular resistance and cardiac loading change rapidly within the first 2 min after stopping exercise, as physiological adaptations such as splanchnic vasoconstriction are reversed. 47 Measuring changes

12 1356 T. Erdei et al. in LV diastolic function immediately after dynamic exercise on a treadmill or upright bicycle may be unreliable. Waiting for an unspecified period while the heart rate slows is unpredictable. Early diastolic relaxation In healthy subjects, the onset of untwisting and myocardial relaxation in LV apical segments ( regional diastole) precedes aortic valve closure (and the start of global diastole). Measuring the delay in peak untwisting is a promising technique, but it has several limitations and it has been insufficiently evaluated during stress, especially in obese subjects with limited acoustic windows. Speckle tracking needs good-quality echocardiographic images which are difficult to acquire during exercise. Measuring basal rotation is technically demanding and unreliable during exercise due to increased through-plane motion; in one study, basal short-axis images could be obtained in only 80% of subjects at rest and in 36% on exercise. 24 Changes in LV twist (defined as the difference between apical and basal rotation) have been estimated from measurements of apical rotation alone, because it is the dominant component of total LV twist. 24 In subjects in whom twist could be calculated, apical rotation and total LV torsion were correlated both at rest (r = 0.74, P < 0.001) and on exercise (r = 0.53, P = 0.016). Other echocardiographic indices of early diastolic filling such as Vp and IVRT have also not been widely evaluated during stress. In hypertensive patients without HFPEF, suctional reserve was lowerthanincontrols(δvp = 10.6 ± 10.9 vs ± 12.2 cm/s; P < 0.001). 1 There may be a mechanistic link between systolic shortening and diastolic suction. 24 Baseline IVRT was shorter in HFPEF than in controls (96 ± 35 vs. 146 ± 19ms;P < 0.001), across all levels of preload. 11 Left ventricular compliance and filling pressure Left ventricular filling pressure, as a common final pathway of all processes affecting LV diastolic function, is considered to be an important diagnostic target that should be measured or estimated at rest and during exertion during any diastolic stress test. It is important to differentiate LV diastolic dysfunction from normal physiological variations in LV filling during exercise, particularly in patients who have exertional dyspnoea and normal LV systolic function. The measurement that has been used most often during stress studies is the E/e ratio, which was first validated as a marker of mean PCWP. 48 The E/e ratio has been little validated in HFPEF at rest, 44 and some studies have suggested low sensitivity and specificity. 8 More recently, its accuracy has been questioned in HFPEF 12 as well as in HFREF. 48 There are technical challenges in measuring E and e when heart rate increases and early and atrial filling phases become fused. The E/e ratio is used as an indicator of mean filling pressure, although it is composed of early diastolic velocities; it is not used to discriminate between impaired (early-diastolic) relaxation and reduced (end-diastolic) compliance. Borlaug 13 found higher resting E/e ratios in HFPEF than in patients with non-cardiac dyspnoea, but there was substantial... overlap and only 9% of patients with HFPEF had E/e ratios >15. Receiver operating characteristic analysis showed that E/e did not adequately identify HFPEF verified by catheterization studies. Burgess found moderate correlations between E/e and mean LV diastolic pressure in a non-hfpef population (37 unselected patients undergoing clinically indicated left heart catheterization, of whom 84% had EF >45%), both at rest (r = 0.67) and on exercise (r = 0.59). 3 In another study, of 37 non-hfpef patients who consented to a stress test after diagnostic coronary angiography (EF = 56 ± 12%; 28% had CAD; 19% had hypertension), E/e >13 during stress had 67% sensitivity and 95% specificity for identifying a mean LV diastolic pressure >15 mmhg. 5 Other comparisons of E/e against invasive measurements of LV diastolic pressure during stress have given conflicting results. 18,21 An increase of E/e during exercise is not specific for HFPEF since it may be caused by ischaemia 49 or other pathological processes that affect cardiac function. 50 It is also not very sensitive, because it did not change during submaximal exercise in HFPEF patients who developed marked abnormalities of LV rotation, untwisting rate, and suction. 24 A recent randomized trial 51 in patients with HFPEF, however, demonstrated a 58% reduction of the exercise-induced increase in estimated LV filling pressure after short-term treatment with ivabradine, compared with placebo; this was determined by the E/e ratio (+3.1 ± 2.7 vs ± 2.0, P = 0.004). Treatment increased exercise capacity by 36% and peak oxygen uptake by 21%, and changes in E/e correlated with changes in exercise capacity (β = 0.30, P = 0.02). Among 436 patients investigated for breathlessness, only 36% of 148 subjects who met recommended criteria for HFPEF 41 at rest, with an E/e >15 or E/e 8 15 with other abnormalities, also had a raised E/e (>13) during treadmill exercise; and among 288 subjects with normal diastolic function at rest who were therefore not suspected to have HFPEF, 14% developed an E/e >13onexercise. 39 Thus, the emphasis on E/e by the studies in this review seems misplaced. Over-reliance on any single measurement during diastolic stress testing is inappropriate. There are other non-invasive indices of left atrial (LA) filling pressure such as E/Vp, but Bhella and colleagues found in a small study that it does not track changes in PCWP reliably in HFPEF. 12 The difference in duration between antegrade and retrograde flow during atrial contraction is an excellent echocardiographic index of LVEDP 52 but it is hard to obtain during stress, and impossible in patients in AF. Although LA volume correlates with chronic elevations of filling pressure, acute changes during stress have not been reported. Left ventricular functional reserve It is possible that changes in longitudinal myocardial function during early diastole on exercise might be useful for diagnosing HFPEF, but the rationale for the indices that have been suggested is not clear. The suggested formulae 1,19,24,26 do not discriminate between excellent functional reserve in a subject with reduced resting function (such as an elderly subject with suspected but not confirmed HFPEF) and poor or moderate functional reserve in a younger subject with good resting function. In this context,

13 A systematic review of diastolic stress tests in HFPEF 1357 it is unsurprising that a low diastolic functional reserve index, calculated as the product of Δe and baseline e, and defined as <13.5, was very sensitive but poorly specific for detecting exercise-induced diastolic dysfunction in a non-hfpef population. 4 In the study by Ha and colleagues, 19 the variance in peak oxygen consumption explained by their index is very small (r 2 = 0.08). In our opinion, a much simpler measurement should be assessed such as the percentage change in function from rest to peak exercise. Optimal protocol Ideally, there should be a standard diastolic stress test that can be used in the majority of patients. It should be physiological and therefore based on exercise rather than pharmacological stress. Upright exercise would be preferred if it could be combined with imaging during stress, but, since that is almost impossible, a compromise can be accepted so that patients exercise in a semi-recumbent posture, as long as control data are developed from healthy age-matched subjects. Since the mean age of patients with HFPEF is years, the initial workload of the exercise protocol should not be too high and the increments in workload should not be too strenuous. The stages need to be short enough so that subjects can maintain their effort for long enough to be able to reach at least medium workloads, but exercise should be sustained in a steady state for long enough so that diastolic function can be studied non-invasively before the early and atrial phases of diastolic function become fused. The test should be simple, reproducible, and feasible in older subjects in routine clinical practice. Submaximal exercise is likely to be more feasible and more equivalent to usual daily activities. Less breathlessness during the examination may make it possible to acquire better-quality images. A heart rate < b.p.m. will avoid fusion of myocardial and mitral, early and atrial phase velocities, and a slower heart rate is better for the frame rate limitations of speckle tracking. We propose a new protocol (Cardiff-MEDIA protocol) for assessing diastolic function by echocardiography during exercise on a semi-supine bicycle (Figure 1). This incorporates the following features: A ramped stress protocol, starting at 15W,with5Wincrements every minute. An initial target heart rate of b.p.m. (or less if the patient becomes symptomatic before reaching this heart rate; arateof100 b.p.m. represents 62% and 74% of the age-related maximal target heart rates of 60-year-old and 85-year-old subjects, respectively). When the heart rate of b.p.m. is reached, then the workload at that time should be maintained constant (with no further increase) for 3 min while echocardiographic imaging is performed. If the patient is asymptomatic and able to continue after this stage, the workload can be increased by the same increments (+5 W every minute) until symptoms develop or the maximal target heart rate is reached, in order to assess if the patient has ischaemia.... Figure 1 Exercise protocol recommended for diastolic stress testing, which is being evaluated in the MEDIA study. HR, heart rate. A pedalling rate of r.p.m. Standardized imaging performed during at least three (and optionally four) stages: baseline; at the heart rate of b.p.m. or whenever symptoms develop (whichever occurs first); and at 2 min into the recovery period or when the diastolic velocities are no longer fused. If the patient can reach his or her maximal target heart rate, then apical four-chamber, two-chamber, and long-axis images should be acquired to assess regional wall motion. Variablestobemeasured The echocardiographic variables to be recorded should have been validated against invasive measurements during exercise. We recommend that both early diastolic LV relaxation and end-diastolic LV compliance or pressures are assessed, using measurements such as those listed in Table 4. Further research is needed to determine which of these tests will be most useful; until then, this proposal lists measurements that can assess different components of diastolic function, since treatment of HFPEF may vary if the problem is related to increased LV stiffness (diuretics, nitrovasodilators) or to impaired early diastolic relaxation (beta-blockade). 53,54 In the final column of Table 4, we indicate some measurements which may be easily applied. The increase in early diastolic myocardial velocity on exercise compared with rest is an indicator of myocardial relaxation, but e is also influenced by preload. It may be a useful target but normal reference ranges from stress tests in age-matched healthy controls are not yet available. The clinical example shown in Figure 2 suggests that E/e may be of limited value, compared with simple changes in mitral inflow and in LV long-axis function. Diastolic stress tests should estimate changes in LV filling pressure, as a consequence of all the processes affecting diastolic function, but alternative methods need to be developed. Estimation of LV suction by Vp has high variability. 25 Since reduced systolic longitudinal shortening is a typical feature of HFPEF, changes in systolic function may also be informative. This could be measured from

14 1358 T. Erdei et al. Table 4 Possible mechanisms for diastolic dysfunction on exercise, related to diagnostic targets on echocardiography Possible mechanism Diagnostic imaging target by echocardiography... Delayed and reduced untwisting Timing and amplitude and rate of untwisting Impaired suction Reduced flow propagation velocity (Vp) Slow relaxation, reduced early diastolic myocardial functional reserve Reduced increment in e (e exercise /e rest ) * Prolonged isovolumic relaxation time (IVRT) Prolonged deceleration time (DT) of mitral inflow Reduced LV compliance during stress (increased regional myocardial Comparison of antegrade mitral flow and retrograde flow in pulmonary veins stiffness) during atrial contraction (Ar d A d ) Increased LV mean filling pressure Increased rise in E/e (E/e exercise )/(E/e rest ) * Changes in E/Vp Reduced longitudinal systolic myocardial functional reserve Reduced increment in s (s exercise /s rest ) * * Recommended by the EU-FP7 MEDIA study group. Figure 2 Change of E/e during exercise in a patient with heart failure with preserved ejection fraction (HFPEF) and in an age-matched normal subject. The traces show velocity profiles of mitral inflow measured by pulsed-wave Doppler echocardiography and mitral annular velocities measured by pulsed-wave myocardial velocity imaging, in a normal subject (upper panels) and in a patient with HFPEF (lower panels), at rest (on the left) and during submaximal exercise at similar heart rates (on the right). E, peak early diastolic velocity of mitral inflow; e, early diastolic myocardial velocity; sept, septal site; lat, lateral site; E/e, calculated ratio of E and the mean e velocity (average of both sites). Note that during submaximal exercise in the normal subject both E and e velocities increase substantially, while in the patient both increments are damped, and so the E/e ratio does not change significantly in either test. Note also that there are similar changes in the systolic myocardial velocities, and an increase in the integral of mitral flow during atrial contraction in the patient.