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Clinical perspectives and evidence of diastolic stress test in heart failure with preserved ejection fraction
The Egyptian Heart Journal (2015) xxx, xxx–xxx
H O S T E D BY
Egyptian Society of Cardiology
The Egyptian Heart Journal www.elsevier.com/locate/ehj www.sciencedirect.com
ORIGINAL ARTICLE
Clinical perspectives and evidence of diastolic stress test in heart failure with preserved ejection fraction Evgeny Belyavskiy a,*, Daniel A. Morris a, Elisabeth Kraigher-Krainer a, Martin Kropf a,c, Aravind K. Radha Krishnan a, Albrecht Schmidt d, Burkert Pieske a,b a
Department of Internal Medicine and Cardiology, Charite´ University Medicine Berlin - Campus Virchow Klinikum, Berlin, Germany Department of Internal Medicine and Cardiology, German Heart Center Berlin, Berlin, Germany c AIT Austrian Institute of Technology, Graz, Austria d Medical University of Graz, Graz, Austria b
Received 16 April 2015; accepted 6 June 2015
KEYWORDS Diastolic stress test; Heart failure with preserved ejection fraction; Echocardiography; Exercise test
Abstract The diagnosis of heart failure with preserved ejection fraction (HFPEF) remains on the basis of echocardiographic analyses at rest. However, some patients with HFPEF have symptoms such as dyspnea only during exercise. Accordingly, echocardiographic analyses at rest could be insufficiently sensitive to identify these patients. In line, recent studies demonstrated that in some patients with HFPEF left ventricular diastolic abnormalities occur only during exercise. This review discusses and analyzes the clinical relevance and evidence of using diastolic stress test echocardiography in patients with HFPEF. ª 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of Egyptian Society of Cardiology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
1. Introduction The diagnosis of heart failure with preserved ejection fraction (HFPEF) remains on the basis of echocardiographic analyses at rest.1 However, some patients with HFPEF have symptoms such as dyspnea only during exercise.2–4 Accordingly, noninvasive echocardiographic analyses at rest could be insufficiently sensitive to identify these patients.5–9 In line, recent * Corresponding author at: Department of Internal Medicine and Cardiology, Charite´ University Medicine Berlin - Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany. Tel.: +49 30450565494; fax: +49 304507565494. E-mail address: [email protected] (E. Belyavskiy). Peer review under responsibility of Egyptian Society of Cardiology.
studies demonstrated that in some patients with HFPEF left ventricular diastolic abnormalities occur only during exercise.10–12 This review discusses and analyzes the clinical relevance and evidence of using diastolic stress test echocardiography in patients with HFPEF. 2. Pathophysiological diastolic processes in HFPEF Left ventricle (LV) diastolic dysfunction plays a key role in the pathophysiology of HFPEF, which is principally characterized by delayed myocardial relaxation and increased ventricular stiffness.13–15 However, it remains poorly understood why some patients with diastolic dysfunction have symptoms of HF such as dyspnea, while others remain asymptomatic.
http://dx.doi.org/10.1016/j.ehj.2015.06.002 1110-2608 ª 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of Egyptian Society of Cardiology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Belyavskiy E et al. Clinical perspectives and evidence of diastolic stress test in heart failure with preserved ejection fraction, The Egypt Heart J (2015), http://dx.doi.org/10.1016/j.ehj.2015.06.002
2 Recent studies using invasive cardiac catheterization suggested that, unlike asymptomatic subjects, HFPEF patients have a significant increase of LV filling during exercise which leads to a rise of pulmonary capillary pressures and thereby, to the development of dyspnea.10,16,17 Moreover, invasive exercise testing substantially improves prediction of long-term mortality in such patients.18 Hence, one could expect that if in patients with HFPEF these important pathophysiological hemodynamic measurements could be reproducible during exercise using non-invasive techniques such as diastolic echocardiographic analyses (diastolic stress test), and it would be of great clinical and diagnostic relevance in the management of these patients.19–21 3. Echocardiography at rest in HFPEF Echocardiography at rest remains an important method to characterize the underlying functional and structural changes in HFPEF. Tissue-Doppler derived E/e0 ratio stays as one of the cornerstones in the non-invasive evaluation of diastolic function at rest in these patients.1,23 The E/e0 ratio P15 if using e0 of septal site of the mitral annulus or P13 if using average values of septal and lateral site indicates accurately increased left ventricle end-diastolic pressure (LVEDP), whereas an E/e0 value <8 indicates normal filling pressures.1,22,23 It has been shown that E/e0 > 15 may be able to provide stand-alone evidence of diastolic LV dysfunction without further need of serial noninvasive tests in HFPEF patients.2,22 However, many patients with signs and symptoms of HFPEF fall into the ‘‘grey zone’’ of key echocardiographic diagnostic parameters, such as E/e0 = 8–15, and thus, other echocardiographic indices should be used.1,23 Hence, a technique that may accurately categorize these border-line patients with E/e0 8–15 as truth HFPEF could be great importance in the clinical practice.24 4. Echocardiography during exercise – diastolic stress test in HFPEF At the moment the diagnosis of HFPEF remains on the basis of echocardiographic analyses at rest.1 However, some patients with HFPEF have symptoms such as dyspnea only during exercise.2–4 Accordingly, non-invasive echocardiographic analyses at rest could be insufficiently sensitive to identify these patients.5–9 In line, several studies demonstrated that in some patients with HFPEF LV diastolic abnormalities occur only during exercise.10–12 In addition, Kitzman et al. showed that symptoms of primary diastolic dysfunction occur only during exertion because diastolic filling pressure is normal at rest and increases only with exertion.25 Furthermore, Ha et al. in 45 patients with normal LVEF referred for evaluation of exertional dyspnea highlighted the importance of the diastolic stress test.4 In this regard, the authors confirmed that diastolic stress echocardiography using supine bicycle exercise is technically feasible for demonstrating changes of E/e0 ratio during exercise as a result of changes in exercise-induced diastolic filling pressures.4 In agreement, Burgess et al. demonstrated that E/e0 ratio correlates with invasively measured left ventricle diastolic pressure (LVDP) during exercise and approximately one-quarter of the patients manifested an elevated LV filling pressure only during exercise.20 Moreover, it was found that
E. Belyavskiy et al. even despite normal echocardiographic analyses at rest, patients with early-stage HFPEF may display hemodynamic abnormalities (elevated filling pressures) exclusively during exercise stress-test.10 In such patients diastolic stress test can provide additional useful information (using the non-invasive estimation of LVEDP by the E/e0 ratio) that might clarify the diagnosis of early-stage HFPEF6,20,21,26,27 (Table 1 shows invasive diastolic stress-test studies in HFPEF). Measurement of E/e0 during exercise is feasible and had been invasively validated for the estimation of raised LVEDP, with E/e0 > 13 accurately identifying raised LVEDP (>15 mmHg).19 (Table 2 shows non-invasive diastolic stresstest studies in HFPEF.) It means that exercise echocardiography focusing on the evaluation of diastolic function may be the basic step for the diagnosis of HFPEF manifested only during exercise.28 Several studies showed that the pathophysiology of HFPEF is a complex process involving not only worsening of relaxation and an increase in myocardial stiffness but also abnormalities in longitudinal systolic function.11,12,29 Therefore in last years there is growing evidence that the diastolic stress test with myocardial deformation analysis can provide important diagnostic findings that can be helpful in the management of patients presenting with dyspnea of an unclear etiology or suspected HFPEF.11,30 In this regard, Tan et al. demonstrated that HFPEF patients have a combination of systolic and diastolic abnormalities of ventricular function that is more obvious on exercise than at rest and that includes reduced myocardial systolic strain, rotation, LV suction, longitudinal (annular) function, and delayed untwisting.11 5. Future considerations concerning to diastolic stress test in HFPEF At the moment there is no defined protocol how the stress-test should be performed. The methodological approach during diastolic stress test is less standardized and issues remain on feasibility, accuracy and prognostic value.24 Recently, Erdei et al. have shown a lack of consensus concerning the specific diagnostic objectives of diastolic stress test, the optimal diagnostic targets, and the methods that should be employed.32 In addition, the authors evidenced that there is no agreement concerning diagnostic criteria that could correlate with responses to targeted treatment.32 Therefore, we consider that in order to establish the usefulness of diastolic stress test in HFPEF, new expert consensus or guidelines should standardize the protocol of diastolic stress test in these patients. 6. Clinical perspectives and conclusion The diagnostic of HFPEF remains considered on echocardiographic resting examinations. However, some patients with HFPEF have symptoms such as dyspnea only during exercise. Accordingly, LV echocardiographic analyses at rest could be insufficiently sensitive to identify these patients. In line, recent studies demonstrated that LV diastolic abnormalities and elevation of LV filling pressures with consequent dyspnea occur only during exercise in some patients with HFPEF. Noninvasive diastolic stress test showing LV diastolic changes only during exercise has demonstrated to be of great importance in diagnosis and management of these patients. Nonetheless,
Please cite this article in press as: Belyavskiy E et al. Clinical perspectives and evidence of diastolic stress test in heart failure with preserved ejection fraction, The Egypt Heart J (2015), http://dx.doi.org/10.1016/j.ehj.2015.06.002
1
Invasive diastolic stress-test studies in HFPEF.
Author
Patient‘s characteristic
Modalities during exercise
Healthy controls
Changes of exercise hemodynamics
Max workload
Conclusion/results
Tscho¨pe 200533
15 HFPEF Pts
Invasive
15 Pts with excluded CAD
15 HFPEF Pts
87 ± 27 W HFPEF
PCWP:
PCWP:
‘‘Basal NT-proBNP correlated strongly with filling pressures during maximal exercise’’
6 ± 2 fi 14 ± 5 mmHg
7 ± 2 fi 24 ± 8 mmHg
134 ± 26 W controls
No
Mean LVDP:
88 ± 10 W
‘‘E/e ratio correlates with invasively measured LVDP during exercise’’
n.d, symptomlimited
‘‘E/e0 ratio of greater than 15 during exercise is associated with a significantly elevated PAWP of greater than 20 mmHg’’
88 ± 28 W HFPEF
‘‘Important number of HFNEF patients cannot be identified by their baseline pattern of ventricular filling or direct measurement of the left ventricular pressure at rest. Diastolic stress-test should be performed with accurate non-invasive methods as a primary approach’’
IC: preserved LVEF, HF symptoms EC: AF, COPD or VHD 2
Burgess, 200620
37 Pts:
Invasive Echo
8.3 ± 4.2 mmHg fi 9.1 ± 4.3 mmHg E/e0 : no increased 9.8 ± 2.4 fi 10.3 ± 2.1 8.9 ± 5.3 mmHg fi 21.5 ± 7.0 mmHg E/e0 : significantly increased 11.8 ± 4.7 fi 16.1 ± 6.7 20.8 ± 3.4 mmHg fi 20.4 ± 5.4 mmHg E/e0 : significantly increased 16.3 ± 4.9 fi 18.1 ± 8.6
(1) LVDP normal (n = 20)
(2) LVDP high only with exercise (n = 9) (3) LVDP high at rest (n = 8) IC: SR, indication for LV catheterization EC: unstable coronary syndromes, severe VHD or valve surgery CAD: 70% 3
Talreja, 200719
12 Pts
Invasive Echo
No
IC: LVEF > 50%, NYHA II-III EC: more than moderate VHD, COPD, known or suggested primary Pulmonary hypertension or pulmonary embolism CAD: n.d. 4
Plehn, 200934
28 HFPEF Pts IC: HTN (>3 years), exertional dyspnea, LVEF P 50%, PAP < 15 mmHg, PCWP > 12 mmHg during peak exercise EC:LBBB, VHD, LVH (>14 mm), COPD, diabetes CAD: no
12 HFPEF Pts, PAWP significantly increased: 14 ± 4 fi 22 ± 10 mmHg
Invasive
10 healthy
28 HFPEF Pts
PCWP: increased
PCWP: significantly increased
7.5 ± 2 fi 10 ± 2 mmHg
7.4 ± 2 fi 19 ± 9 mmHg
98 ± 27 W controls
Clinical perspectives and evidence of diastolic stress test in heart failure
(continued on next page)
3
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Table 1
4
5
6
7
Author
Patient‘s characteristic
Modalities during exercise
Healthy controls
Changes of exercise hemodynamics
Max workload
Conclusion/results
Maeder, 201035
14 HFPEF Pts
Invasive Echo
8 controls
14 HFPEF Pts
n.d, symptomlimited
PCWP:
PCWP:
10 ± 4 fi 20 ± 7* mmHg
10 ± 4 fi 23 ± 6* mmHg
‘‘Invasive hemodynamic studies with exercise are required to formally establish the pathophysiologic profile in patients with suspected HFNEF and to evaluate the effects of novel therapies’’
*p = 0.31 between exercise PCWP in controls and HFPEF 23 non-cardiac dyspnea (NCD) Pts
*p = 0.31 between exercise PCWP in controls and HFPEF n.d, symptomlimited
LVEDP: no changes: 12 ± 3 fi 14 ± 4 mmHg
LVEDP: significantly increased: 13 ± 2 fi 34 ± 6 mmHg
‘‘Euvolemic patients with exertional dyspnea, normal brain natriuretic peptide, and normal cardiac filling pressures at rest may have markedly abnormal hemodynamic responses during exercise, suggesting that chronic symptoms are related to heart failure. Invasive exercise hemodynamic testing may enhance diagnosis of HFPEF in this expanding population of patients with exertional dyspnea of unknown etiology’’
10 controls with LVEDP < 16 mmHg or/ and no increase during exercise
20 HFPEF Pts
54 ± 19 W HFPEF
‘‘A significant proportion of stable outpatients with unexplained chronic dyspnea may have HFPEF. Because the majority of these outpatients do not fulfill the diagnostic criteria for heart failure and noninvasive tests do not show overt pathology, a correct diagnosis of HFPEF represents a challenge’’
Borlaug, 201010
Penicka, 201016
IC: HF symptoms, LVEF > 50%, (NYHA II-II) + impaired exercise capacity, SR EC:LBBB, CMP, more than mild valvular heart disease, COPD CAD: all have negative stress-echo, myocardial perfusion scan or exercise ECG 32 HFPEF Pts IC: EF > 50%, exertional dyspnea, normal brain natriuretic peptide assay, normal resting hemodynamics CAD: no Pts with peak exercise PCWP > 25 mmHg were classified as having HFPEF (n = 32), and those with values < 25 mmHg were classified as having noncardiac dyspnea (NCD) (n = 23) 20 HFPEF Pts
IC: LVEF > 50%, dyspnea (NYHA II-III), SR, LVEDP > 16 mmHg at rest or significantly increase significantly during hemodynamic interventions. EC: COPD, AF, significant CAD (stenosis > 50%), cardiac surgery, VHD, CMP, recent ACS (66 months) CAD:23% (1) Hand grip
Invasive Echo
Invasive
32 HFPEF Pts
91 ± 24 W controls
(1) LVEDP: significantly increased 11 ± 1.5 fi 13 ± 1.6 mmHg
(1) LVEDP: significantly increased 21 ± 6.3 fi 28 ± 5.4 mmHg
E. Belyavskiy et al.
Please cite this article in press as: Belyavskiy E et al. Clinical perspectives and evidence of diastolic stress test in heart failure with preserved ejection fraction, The Egypt Heart J (2015), http://dx.doi.org/10.1016/j.ehj.2015.06.002
Table 1 (continued)
(3) Nitroprusside infusion
(4) Dobutamine infusion
8
9
Borlaug, 201116
Dorfs, 201318
20 HFPEF Pts
Invasive
IC: preserved EF, exertional dyspnea CAD: no
Echo
355 HFPEF Pts IC: unexplained dyspnea (suspected HFPEF) EC: LVEF 6 50%, significant CAD, VHD, prior cardiac surgery, PM, cardiac shunt, constrictive pericarditis, CMP, pulmonary artery hypertension
Invasive Echo
(2) LVEDP: significantly increased 11 ± 1.5 fi 14 ± 1.0 mmHg (3) LVEDP: significantly decreased 21 ± 6.3 fi 8 ± 2.6 mmHg (4) LVEDP: significantly decreased 21 ± 6.3 fi 8 ± 2.6 mmHg
(2) LVEDP: no changes 21 ± 6.3 fi 24 ± 4.3 mmHg
No
Mean LVDP: significantly increased:
(3) LVEDP: significantly decreased 21 ± 6.3 fi 13 ± 5.3 mmHg (4) LVEDP: significantly decreased 21 ± 6.3 fi 16 ± 8.4 mmHg n.d, symptomlimited
Patients with early HFPEF develop increased LV diastolic filling pressures during supine exercise
74.1 + 32.6 W
‘‘Hemodynamic stress testing should be considered in particular if measurements at rest are normal, because it provides not only the unique opportunity to rule out a cardiac cause of dyspnea in uncertain cases, but also to identify patients at risk. An excessive rise of PCWP during exercise despite normal PCWP at rest is associated with increased mortality and may be considered as early HFPEF’’
14 (10–16) fi 20 (16–27) mmHg
No
355 HFPEF Pts PCWP: significantly increased 9.4 ± 4.1 fi 22.9 ± 7.4 mmHg
Differences were considered statistically significant when P < 0.05. E/e0 : ratio of early transmitral flow velocity to early diastolic mitral annulus velocity, HFPEF: heart failure preserved ejection fraction, HFNEF: heart failure normal ejection fraction, IC: inclusion criteria, EC: exclusion criteria, Pts: patients, CAD: coronary artery disease, n.d: no date, PAWP: pulmonary artery wedge pressure, PCWP: pulmonary capillary wedge pressure, COPD: chronic obstructive lung disease, LV: left ventricle, LVDP: left ventricle diastolic pressure, LVDEP: left ventricle end-diastolic pressure, SR: sinus rhythm, HF: heart failure, LVEF: left ventricle ejection fraction, CMP: cardiomyopathies, VHD: valvular heart disease, HTN: hypertension, PAP: pulmonary artery pressure, PM: pacemaker, ACS: acute coronary syndrome, NCD: noncardiac dyspnea.
Clinical perspectives and evidence of diastolic stress test in heart failure 5
Please cite this article in press as: Belyavskiy E et al. Clinical perspectives and evidence of diastolic stress test in heart failure with preserved ejection fraction, The Egypt Heart J (2015), http://dx.doi.org/10.1016/j.ehj.2015.06.002
(2) Leg lifting
6
1
Non-invasive diastolic stress-test studies in HFPEF.
Author
Patient‘s characteristic
Modalities during exercise
Healthy controls
Changes of E/e0 in HFPEF group during/ after exercise (stress-test)
Max workload
Conclusion/results
Mottram, 200436
26 HFPEF Pts:
Echo
No
26 HFPEF Pts:
n.d, symptomlimited
‘‘In patients with limited capacity due to suspected DHF, BNP increases during exercise and is higher in those patients who likely have elevated filling pressures at maximal exercise. This increase in BNP with exercise is associated with enhanced myocardial function.’’
IC: well-treated HTN, LVEF > 50%, exertional dyspnea, diastolic dysfunction EC: angina, myocardial infarction, COPD, VHD, LVEF 6 50% 2
Ha, 20054
45 HFPEF Pts: (1A) E/e0 at rest < 10 without increase E/e0 during exercise (n = 17) (1B) E/e0 at rest < 10 with increase E/ e0 during exercise (n = 9) (2) E/e0 at rest > 10 (n = 19)
Echo
No
IC: exertional dyspnea
3
Burgess, 200620
EC: Pts with echocardiographic or electrocardiographic evidence of myocardial ischemia were excluded 166 Pts (1) Exercise E/e0 6 13 (n = 126)
4
Talreja, 200719
IC: Pts with EF > 50%, exertional dyspnea (NYHA II-III) EC: more than moderate valvular heart disease; COPD; known or suggested primary pulmonary hypertension or pulmonary embolism CAD: n.d.
75 W
‘‘Diastolic stress echocardiography using supine bicycle exercise is technically feasible for demonstrating changes of E/e0 = ratio and tricuspid regurgitant velocity during exercise as a result of changes in exercise-induced diastolic filling pressures’’
(2) Significantly increased: 9.2 ± 0.8 fi 13.5 ± 3.4 (3) No increase: 16.0 ± 4.1 fi 13.5 ± 4.5
75 W
166 Pts
n.d, symptomlimited
‘‘The findings of this study validate exercise E/e0 as a marker of ventricular filling pressure, and suggest that its measurement may explain functional impairment in patients with normal or mildly abnormal diastolic parameters at rest’’
n.d, symptomlimited
‘‘Noninvasively obtained Doppler of mitral and mitral annulus velocities provides a reliable estimation of PAWP not only at baseline, but also with exercise. Specifically, an E/e0 ratio of greater than 15 during exercise is associated with a significantly elevated PAWP of greater than 20 mmHg.’’
Echo, invasive
No
(1) No increase: 9.9 ± 2.4 fi 9.2 ± 2.1 (2) Significantly increased 15.1 ± 5.2 fi 16.9 ± 4.8
Echo, invasive
No
12 HFPEF Pts
(2) Exercise E/e0 P 13 (n = 40) IC: SR, indication for LV catheterization EC: unstable coronary syndromes, severe valvular disease or valve surgery CAD: in 70% of Pts 12 HFPEF Pts
E/e0 lateral significantly increased: 7.7 ± 2.0 fi 10.0 ± 4.8 E/e0 septal significantly increased: 9.1 ± 2.2 fi 11.6 ± 3.6 45 HFPEF Pts: (1) No increase: 8.7 ± 1.9 fi 6.4 ± 2.6
significantly increased 11.7 ± 0.5 fi 14.5 ± 0.6
75 W
E. Belyavskiy et al.
Please cite this article in press as: Belyavskiy E et al. Clinical perspectives and evidence of diastolic stress test in heart failure with preserved ejection fraction, The Egypt Heart J (2015), http://dx.doi.org/10.1016/j.ehj.2015.06.002
Table 2
6
7
Ennezat, 200837
25 HFPEF Pts IC: EF > 50%, decompensated HF hospitalization.
Ha, 200921
EC: ACS, arrhythmias, primary valvular disease, CMP or constrictive pericarditis CAD: no 141 Pts (1) DFRI < 13.5 (n = 64)
Tan, 200911
(2) DFRI P 13.5 (n = 77) None had echocardiographic or electrocardiographic evidence of myocardial ischemia at rest 56 HFPEF Pts IC: EF > 50%, NYHA II and more
Echo
Echo
25 hypertensive as controls: significantly increased 8 ± 3 fi 10 ± 2* *E/e0 was measured only in 5 Pts during the test
No
25 HFPEF Pts: significantly increased 13 ± 4 fi 15 ± 2#
45 W Pts,
#E/e0 was measured only in 5 Pts during the test
65 W controls
141 Pts (1) Significantly increased 12.5 ± 4.0 fi 15.2 ± 4.4 (2) No changes: 11.4 ± 3.6 fi 11.1 ± 2.9
50 W
50 W
9
10
Maeder, 201035
Tan, 201038
Holland, 201139
14 HFPEF Pts IC: HF symptoms, LVEF > 50%, (NYHA II-II)+impaired exercise capacity, SR EC:LBBB,CMP, more than mild VHD, COPD CAD: all have negative stress-echo, myocardial perfusion scan or exercise ECG 30 Pts IC: hypertension, EF > 50%, exertional dyspnea EC: uncontrolled BP, the presence of LVH or evidence of PH on echo, COPD, VHD, arrhythmia (including AF), PM or ICD, CAD 15 HFPEF Pts: IC: LVEF > 50%, exertional dyspnea, diastolic dysfunction (E/ e0 > 15) EC: history of angina or CAD, VHD, LVEF 6 50%, arrhythmia
‘‘Patients with preserved LV systolic function and impaired myocardial relaxation at rest exhibit a wide spectrum of alterations in diastolic function during exercise’’
Echo
27 healthy as controls: No changes: 8.2 ± 2.0 fi 8.8 ± 1.8
56 HFPEF Pts No changes: 11.4 ± 4.3 fi 11.4 ± 4.5
n.d, symptomlimited (to max HR = 100/min)
‘‘HFNEF patients have a combination of systolic and diastolic abnormalities of ventricular function that is more obvious on exercise than at rest’’
Echo, invasive
8 controls, increased 9.5 ± 3.4* fi 11.1 ± 3.4 *p = 0.04 between resting E/e0 in HFPEF and controls
14 HFPEF Pts
n.d, symptomlimited
‘‘E/e0 septal doesn‘t reflect hemodynamic changes during exercise in HFPEF patients’’
n.d, symptomlimited
‘‘Patients with treated hypertension with normal resting echocardiography can have exercise limitation associated with widespread systolic and diastolic left ventricular dysfunction on exercise’’
n.d, submaximal (steady state for P 1 min at 60% of maximal HR)
‘‘Patients with HFPEF have increased E/e00 with exercise compared with age-matched and sexmatched controls. This response to exercise is clearly evident at low workloads similar to those experienced during activities of daily living, when symptoms are present, and is associated with indices of abnormal central, but not peripheral BP’’
EC: COPD, VHD, PM or ICD, CAD 8
‘‘When compared with patients with similar comorbidities but without history or evidence of heart failure, patients with HFPEF experience greater arterial stiffening and thereby a deterioration of global LV systolic performance during dynamic exercise’’
significantly decreased:
13.2 ± 4.1 fi 9.4 ± 3.4#
Echo
Echo
22 healthy as controls: No changes:
#p = 0.28 between peak exercise E/e0 in HFPEF and controls 30 Pts No changes:
8.4 ± 2.1 fi 9.3 ± 2.2
9.4 ± 2.6 fi 10.1 ± 2.1
15 healthy as controls Submax exercise:
15 HFPEF Pts: Submax exercise:
E/e0 significantly decreased: 10.7 ± 3.5 fi 11.9 ± 3.0 Maximal exercise: E/e0 significantly decreased:
E/e0 significantly increased: 13.8 ± 3.5 fi 17.6 ± 6.8* Maximal exercise: E/e0 significantly increased:
Clinical perspectives and evidence of diastolic stress test in heart failure
(continued on next page)
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5
8
Author
11
Meluzin 201131
Patient‘s characteristic
84 Pts:
Modalities during exercise
Echo
IC: LVEF P 50%, exertional dyspnea, diastolic dysfunction (E/ e0 > 15) EC: significantly CAD (stenosis > 40%), history of MI, VHD, CMP, liver, renal, lung disease, anemia (1) HFPEF Pts (n = 30), were selected according to current HFPEF recommendations (+11 patients had the exercise-induced E/ e0 > 15 or E/e0 septal > 13 (2) Pts with NCD (n = 54) 12
Donal, 201212
21 HFPEF Pts
Tartie`reKesri, 201240
23 HFPEF Pts IC: LVEF > 45%, SR, stable hemodynamic conditions, CAD: 10%
Changes of E/e0 in HFPEF group during/ after exercise (stress-test)
10.7 ± 3.5 fi 8.6 ± 2.5* *p > 0.05 between E/e0 at submax and max level in controls 14 healthy as controls
13.8 ± 3.5 fi 16.3 ± 4.3* *p = 0.433 between E/e0 at submax and max level in HFPEF 84 Pts:
E/e0 no changes: 7.3 ± 0.4 fi 7.3 ± 0.4
E/e0 no changes: 9.3 ± 0.3 fi 9.1 ± 0.3
Max workload
Conclusion/results
n.d, symptomlimited
‘‘A significant proportion of patients require exercise to diagnose HFNEF. The prevalence of isolated, only exercise-induced HFNEF must be viewed cautiously due to a relatively small number of patients included.’’
45–60 W
‘‘In patients recently hospitalized for treatment of HF with HFPEF (EF P 45%) subtle abnormalities of systolic and diastolic functions were present at rest and increased by a submaximal exercise stress echocardiography’’
76 ± 27 W HFPEF 143 ± 55 W controls
‘‘In HFPEF patients, moderate exercise leads to a steep increase in proximal afterload that is underestimated at rest and is associated with unfavorable ventriculo arterial coupling and exercise intolerance’’
30 HFPEF Pts 10.8 ± 0.4 fi 11.3 ± 0.5
54 PTs with NCD 8.5 ± 0.3 fi 8.0 ± 0.2 Echo
IC: LVEF P 45%, acute HF hospitalization. CAD: 23% 13
Healthy controls
Echo
15 hypertensive as controls: significantly increased 8 ± 2.5 fi 16 ± 6* *p = ns (Pts vs. controls during exercise) 15 hypertensive as controls: no changes: 11 (9–12) fi 11(10–13)
21 HFPEF Pts significantly increased 13 ± 6 fi 15 ± 6* * p = ns (Pts vs. controls during exercise) 23 HFPEF Pts: no changes: 20 (17–23) fi 22 (18–28)
Differences were considered statistically significant when P < 0.05. E/e0 : ratio of early transmitral flow velocity to early diastolic mitral annulus velocity, HFPEF: heart failure preserved ejection fraction, HFNEF: heart failure normal ejection fraction, IC: inclusion criteria, EC: exclusion criteria, Pts: patients, CAD: coronary artery disease, n.d: no date, PAWP: pulmonary artery wedge pressure, COPD: chronic obstructive lung disease, LV: left ventricle, SR: sinus rhythm, LVDP: left ventricle diastolic pressure, LBBB: left bundle branch block, ECG: electrocardiogram, PCWP: pulmonary capillary wedge pressure, ACS: acute coronary syndrome, CMP: cardiomyopathies, VHD: valvular heart disease, PM: pacemaker, ICD: implantable cardiac defibrillators, LVH: left ventricle hypertrophy, BP: blood pressure, AF: atrial fibrillation, HR: heart rate, MI: myocardial infarction, NCD: noncardiac dyspnea.
E. Belyavskiy et al.
Please cite this article in press as: Belyavskiy E et al. Clinical perspectives and evidence of diastolic stress test in heart failure with preserved ejection fraction, The Egypt Heart J (2015), http://dx.doi.org/10.1016/j.ehj.2015.06.002
Table 2 (continued)
Clinical perspectives and evidence of diastolic stress test in heart failure large studies are needed to validate the role of diastolic stress test in HFPEF. 19.
Conflict of interest All authors have no conflicts of interest to declare.
20.
References 21. 1. Paulus WJ, Tscho¨pe C, Sanderson JE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007;28:2539–50. 2. Borlaug B, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 2011;32:670–9. 3. Sanderson JE. Exercise echocardiography and the diagnosis of heart failure with a normal ejection fraction. Heart 2010;96:997–8. 4. Ha JW, Oh JK, Pellikka PA, et al. Diastolic stress echocardiography: a novel noninvasive diagnostic test for diastolic dysfunction using supine bicycle exercise doppler echocardiography. J Am Soc Echo 2005;18:63–8. 5. Skaluba SJ, Litwin SE. Mechanisms of exercise intolerance: insights from tissue doppler imaging. Circulation 2004;109:972–7. 6. Holland DJ, Prasad SB, Marwick TH. Contribution of exercise echocardiography to the diagnosis of heart failure with preserved ejection fraction (HFPEF). Heart 2010;96:1024–8. 7. Park JH, Marwick TH. Use and limitations of E/e’ to assess left ventricular filling pressure by echocardiography. J Cardiovasc Ultrasound 2011;19:169–73. 8. Tscho¨pe C, Lam CS. Diastolic heart failure: what we still don’t know. Looking for new concepts, diagnostic approaches, and the role of comorbidities. Herz 2012;37:875–9. 9. Bhella PS, Pacini EL, Prasad A, et al. Echocardiographic indices do not reliably track changes in left-sided filling pressure in healthy subjects or patients with heart failure with preserved ejection fraction. Circ Cardiovasc Imag 2011;4:482–9. 10. Borlaug BA, Nishimura RA, Sorajja P, et al. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail 2010;3:588–95. 11. Tan YT, Wenzelburger F, Lee E, et al. The pathophysiology of heart failure with normal ejection fraction. J Am Coll Cardiol 2009;54:36–46. 12. Donal E, Thebault C, Lund LH, et al. Heart failure with a preserved ejection fraction additive value of an exercise stress echocardiography. Eur Heart J Cardiovasc Imaging 2012;13: 656–65. 13. Van Heerebeek L, Paulus WJ. Impact of comorbidities on myocardial remodeling and dysfunction in heart failure with preserved ejection fraction. SOJ Pharm Pharm Sci 2014;1:1–20. 14. Zile MR, Baicu C, Gaasch WH. Diastolic heart failure: abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med 2004;19:1953–9. 15. Fontes-Carvalho R, Leite-Moreira A. Heart failure with preserved ejection fraction: fighting misconceptions for a new approach. Arq Bras Cardiol 2011;96:504–14. 16. Borlaug BA, Jaber WA, Ommen SR, et al. Diastolic relaxation and compliance reserve during dynamic exercise in heart failure with preserved ejection fraction. Heart 2011;97:964–9. 17. Penicka M, Bartunek J, Trakalova H, et al. Heart failure with preserved ejection fraction in outpatients with unexplained dyspnea: a pressure-volume loop analysis. J Am Coll Cardiol 2010;55:1701–10. 18. Dorfs S, Zeh W, Hochholzer W, et al. Pulmonary capillary wedge pressure during exercise and long-term mortality in patients with
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suspected heart failure with preserved ejection fraction. Eur Heart J 2014;35:3103–12. Talreja DR, Nishimura RA, Oh JK. Estimation of left ventricular filling exercise by Doppler echocardiography in patients with normal systolic a simultaneous echocardiographic-cardiac catheterization Study. J Am Echocardiogr 2007;20:477–9. Burgess MI, Jenkins C, Sharman JE, Marwick TH. Diastolic stress echocardiography: hemodynamic validation and clinical significance of estimation of left ventricular filling pressure with exercise. J Am Coll Cardiol 2006;47:1891–900. Ha JW, Choi D, Park S, et al. Left ventricular diastolic functional reserve during exercise in patients with impaired myocardial relaxation at rest. Heart 2009;95:399–404. Ommen SR, Nishimura RA, Appleton CP, et al. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures. A comparative simultaneous Doppler-catheterization study. Circulation 2000;102: 1788–94. Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 2009;22:107–33. Picano E. Stress Echocardiography. 5th ed. Springer Verlag: Berlin, Heidelberg; 2009, 612 . Kitzman DW, Higginbotham MB, Cobb FR, et al. Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17:1065–72. Kane GC, Oh JK. Diastolic stress test for the evaluation of exertional dyspnea. Curr Cardiol Rep 2012;14:359–65. Holland DJ, Prasad SB, Marwick TH. Prognostic implications of left ventricular filling pressure with exercise. Circ Cardiovasc Imag 2010;3:149–56. Oh JK, Kane GC. Diastolic stress echocardiography: the time has come for its integration into clinical practice. J Am Soc Echo 2014;27:1060–3. Kraigher-Krainer E, Shah AM, Gupta DK, et al. PARAMOUNT Investigators Impared systolic function by strain imaging in heart failure with preserved ejection fraction. Am Coll Cardiol 2014;63:447–56. Wang J, Fang F, Wai-Kwok Yip G, et al. Changes of ventricular and peripheral performance in patients with heart failure and normal ejection fraction: insights from ergometry stress echocardiography. Eur J Heart Fail 2014;16:888–97. Meluzı´ n J, Sitar J, Krı´ stek J, et al. The role of exercise echocardiography in the diagnostics of heart failure with normal left ventricular ejection fraction. Eur J Echocardiogr 2011;12: 591–602. Erdei T, Smiseth OA, Marino P, Fraser AG. A systematic review of diastolic stress test in heart failure with preserved ejection fraction, with proposals from EU-FP7 MEDIA study group. Eur J Heart Fail 2014;16:1345–61. Tscho¨pe C, Kasner M, Westermann D, et al. Elevated NTProBNP levels in patients with increased left ventricular filling pressure during exercise despite preserved systolic function. J Card Fail 2005;11:S28–33. Plehn G, Vormbrock J, Christ M, et al. Masked diastolic dysfunction caused by exercise testing in hypertensive heart failure patients with normal ejection fraction and normal or mildly increased LV mass. Acta Cardiol 2009;64:617–26. Maeder MT, Thompson BR, Brunner-La Rocca HP, Kaye DM. Hemodynamic basis of exercise limitation in patients with heart failure and normal ejection fraction. J Am Coll Cardiol 2010;56:855–63. Mottram PM, Haluska BA, Marwick TH. Response of B-type natriuretic peptide to exercise in hypertensive patients with suspected diastolic heart failure: correlation with cardiac function, hemodynamics, and workload. Am Heart J 2004;148:365–70.
Please cite this article in press as: Belyavskiy E et al. Clinical perspectives and evidence of diastolic stress test in heart failure with preserved ejection fraction, The Egypt Heart J (2015), http://dx.doi.org/10.1016/j.ehj.2015.06.002
10 37. Ennezat PV, Lefetz Y, Mare´chaux S, et al. Left ventricular abnormal response during dynamic exercise in patients with heart failure and preserved left ventricular ejection fraction at rest. J Card Fail 2008;14:475–80. 38. Tan YT, Wenzelburger F, Lee E, et al. Abnormal left ventricular function occurs on exercise in well-treated hypertensive subjects with normal resting echocardiography. Heart 2010;96: 948–55.
E. Belyavskiy et al. 39. Holland DJ, Sacre JW, Leano RL. Contribution of abnormal central blood pressure to left ventricular filling pressure during exercise in patients with heart failure and preserved ejection fraction. J Hypertens 2011;29:1422–30. 40. Tartie`re-Kesri L, Tartie`re JM, Logeart D, et al. Increased proximal arterial stiffness and cardiac response with moderate exercise in patients with heart failure and preserved ejection fraction. J Am Coll Cardiol 2012;59:455–61.
Please cite this article in press as: Belyavskiy E et al. Clinical perspectives and evidence of diastolic stress test in heart failure with preserved ejection fraction, The Egypt Heart J (2015), http://dx.doi.org/10.1016/j.ehj.2015.06.002
H O S T E D BY
Egyptian Society of Cardiology
The Egyptian Heart Journal www.elsevier.com/locate/ehj www.sciencedirect.com
ORIGINAL ARTICLE
Clinical perspectives and evidence of diastolic stress test in heart failure with preserved ejection fraction Evgeny Belyavskiy a,*, Daniel A. Morris a, Elisabeth Kraigher-Krainer a, Martin Kropf a,c, Aravind K. Radha Krishnan a, Albrecht Schmidt d, Burkert Pieske a,b a
Department of Internal Medicine and Cardiology, Charite´ University Medicine Berlin - Campus Virchow Klinikum, Berlin, Germany Department of Internal Medicine and Cardiology, German Heart Center Berlin, Berlin, Germany c AIT Austrian Institute of Technology, Graz, Austria d Medical University of Graz, Graz, Austria b
Received 16 April 2015; accepted 6 June 2015
KEYWORDS Diastolic stress test; Heart failure with preserved ejection fraction; Echocardiography; Exercise test
Abstract The diagnosis of heart failure with preserved ejection fraction (HFPEF) remains on the basis of echocardiographic analyses at rest. However, some patients with HFPEF have symptoms such as dyspnea only during exercise. Accordingly, echocardiographic analyses at rest could be insufficiently sensitive to identify these patients. In line, recent studies demonstrated that in some patients with HFPEF left ventricular diastolic abnormalities occur only during exercise. This review discusses and analyzes the clinical relevance and evidence of using diastolic stress test echocardiography in patients with HFPEF. ª 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of Egyptian Society of Cardiology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
1. Introduction The diagnosis of heart failure with preserved ejection fraction (HFPEF) remains on the basis of echocardiographic analyses at rest.1 However, some patients with HFPEF have symptoms such as dyspnea only during exercise.2–4 Accordingly, noninvasive echocardiographic analyses at rest could be insufficiently sensitive to identify these patients.5–9 In line, recent * Corresponding author at: Department of Internal Medicine and Cardiology, Charite´ University Medicine Berlin - Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany. Tel.: +49 30450565494; fax: +49 304507565494. E-mail address: [email protected] (E. Belyavskiy). Peer review under responsibility of Egyptian Society of Cardiology.
studies demonstrated that in some patients with HFPEF left ventricular diastolic abnormalities occur only during exercise.10–12 This review discusses and analyzes the clinical relevance and evidence of using diastolic stress test echocardiography in patients with HFPEF. 2. Pathophysiological diastolic processes in HFPEF Left ventricle (LV) diastolic dysfunction plays a key role in the pathophysiology of HFPEF, which is principally characterized by delayed myocardial relaxation and increased ventricular stiffness.13–15 However, it remains poorly understood why some patients with diastolic dysfunction have symptoms of HF such as dyspnea, while others remain asymptomatic.
http://dx.doi.org/10.1016/j.ehj.2015.06.002 1110-2608 ª 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of Egyptian Society of Cardiology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Belyavskiy E et al. Clinical perspectives and evidence of diastolic stress test in heart failure with preserved ejection fraction, The Egypt Heart J (2015), http://dx.doi.org/10.1016/j.ehj.2015.06.002
2 Recent studies using invasive cardiac catheterization suggested that, unlike asymptomatic subjects, HFPEF patients have a significant increase of LV filling during exercise which leads to a rise of pulmonary capillary pressures and thereby, to the development of dyspnea.10,16,17 Moreover, invasive exercise testing substantially improves prediction of long-term mortality in such patients.18 Hence, one could expect that if in patients with HFPEF these important pathophysiological hemodynamic measurements could be reproducible during exercise using non-invasive techniques such as diastolic echocardiographic analyses (diastolic stress test), and it would be of great clinical and diagnostic relevance in the management of these patients.19–21 3. Echocardiography at rest in HFPEF Echocardiography at rest remains an important method to characterize the underlying functional and structural changes in HFPEF. Tissue-Doppler derived E/e0 ratio stays as one of the cornerstones in the non-invasive evaluation of diastolic function at rest in these patients.1,23 The E/e0 ratio P15 if using e0 of septal site of the mitral annulus or P13 if using average values of septal and lateral site indicates accurately increased left ventricle end-diastolic pressure (LVEDP), whereas an E/e0 value <8 indicates normal filling pressures.1,22,23 It has been shown that E/e0 > 15 may be able to provide stand-alone evidence of diastolic LV dysfunction without further need of serial noninvasive tests in HFPEF patients.2,22 However, many patients with signs and symptoms of HFPEF fall into the ‘‘grey zone’’ of key echocardiographic diagnostic parameters, such as E/e0 = 8–15, and thus, other echocardiographic indices should be used.1,23 Hence, a technique that may accurately categorize these border-line patients with E/e0 8–15 as truth HFPEF could be great importance in the clinical practice.24 4. Echocardiography during exercise – diastolic stress test in HFPEF At the moment the diagnosis of HFPEF remains on the basis of echocardiographic analyses at rest.1 However, some patients with HFPEF have symptoms such as dyspnea only during exercise.2–4 Accordingly, non-invasive echocardiographic analyses at rest could be insufficiently sensitive to identify these patients.5–9 In line, several studies demonstrated that in some patients with HFPEF LV diastolic abnormalities occur only during exercise.10–12 In addition, Kitzman et al. showed that symptoms of primary diastolic dysfunction occur only during exertion because diastolic filling pressure is normal at rest and increases only with exertion.25 Furthermore, Ha et al. in 45 patients with normal LVEF referred for evaluation of exertional dyspnea highlighted the importance of the diastolic stress test.4 In this regard, the authors confirmed that diastolic stress echocardiography using supine bicycle exercise is technically feasible for demonstrating changes of E/e0 ratio during exercise as a result of changes in exercise-induced diastolic filling pressures.4 In agreement, Burgess et al. demonstrated that E/e0 ratio correlates with invasively measured left ventricle diastolic pressure (LVDP) during exercise and approximately one-quarter of the patients manifested an elevated LV filling pressure only during exercise.20 Moreover, it was found that
E. Belyavskiy et al. even despite normal echocardiographic analyses at rest, patients with early-stage HFPEF may display hemodynamic abnormalities (elevated filling pressures) exclusively during exercise stress-test.10 In such patients diastolic stress test can provide additional useful information (using the non-invasive estimation of LVEDP by the E/e0 ratio) that might clarify the diagnosis of early-stage HFPEF6,20,21,26,27 (Table 1 shows invasive diastolic stress-test studies in HFPEF). Measurement of E/e0 during exercise is feasible and had been invasively validated for the estimation of raised LVEDP, with E/e0 > 13 accurately identifying raised LVEDP (>15 mmHg).19 (Table 2 shows non-invasive diastolic stresstest studies in HFPEF.) It means that exercise echocardiography focusing on the evaluation of diastolic function may be the basic step for the diagnosis of HFPEF manifested only during exercise.28 Several studies showed that the pathophysiology of HFPEF is a complex process involving not only worsening of relaxation and an increase in myocardial stiffness but also abnormalities in longitudinal systolic function.11,12,29 Therefore in last years there is growing evidence that the diastolic stress test with myocardial deformation analysis can provide important diagnostic findings that can be helpful in the management of patients presenting with dyspnea of an unclear etiology or suspected HFPEF.11,30 In this regard, Tan et al. demonstrated that HFPEF patients have a combination of systolic and diastolic abnormalities of ventricular function that is more obvious on exercise than at rest and that includes reduced myocardial systolic strain, rotation, LV suction, longitudinal (annular) function, and delayed untwisting.11 5. Future considerations concerning to diastolic stress test in HFPEF At the moment there is no defined protocol how the stress-test should be performed. The methodological approach during diastolic stress test is less standardized and issues remain on feasibility, accuracy and prognostic value.24 Recently, Erdei et al. have shown a lack of consensus concerning the specific diagnostic objectives of diastolic stress test, the optimal diagnostic targets, and the methods that should be employed.32 In addition, the authors evidenced that there is no agreement concerning diagnostic criteria that could correlate with responses to targeted treatment.32 Therefore, we consider that in order to establish the usefulness of diastolic stress test in HFPEF, new expert consensus or guidelines should standardize the protocol of diastolic stress test in these patients. 6. Clinical perspectives and conclusion The diagnostic of HFPEF remains considered on echocardiographic resting examinations. However, some patients with HFPEF have symptoms such as dyspnea only during exercise. Accordingly, LV echocardiographic analyses at rest could be insufficiently sensitive to identify these patients. In line, recent studies demonstrated that LV diastolic abnormalities and elevation of LV filling pressures with consequent dyspnea occur only during exercise in some patients with HFPEF. Noninvasive diastolic stress test showing LV diastolic changes only during exercise has demonstrated to be of great importance in diagnosis and management of these patients. Nonetheless,
Please cite this article in press as: Belyavskiy E et al. Clinical perspectives and evidence of diastolic stress test in heart failure with preserved ejection fraction, The Egypt Heart J (2015), http://dx.doi.org/10.1016/j.ehj.2015.06.002
1
Invasive diastolic stress-test studies in HFPEF.
Author
Patient‘s characteristic
Modalities during exercise
Healthy controls
Changes of exercise hemodynamics
Max workload
Conclusion/results
Tscho¨pe 200533
15 HFPEF Pts
Invasive
15 Pts with excluded CAD
15 HFPEF Pts
87 ± 27 W HFPEF
PCWP:
PCWP:
‘‘Basal NT-proBNP correlated strongly with filling pressures during maximal exercise’’
6 ± 2 fi 14 ± 5 mmHg
7 ± 2 fi 24 ± 8 mmHg
134 ± 26 W controls
No
Mean LVDP:
88 ± 10 W
‘‘E/e ratio correlates with invasively measured LVDP during exercise’’
n.d, symptomlimited
‘‘E/e0 ratio of greater than 15 during exercise is associated with a significantly elevated PAWP of greater than 20 mmHg’’
88 ± 28 W HFPEF
‘‘Important number of HFNEF patients cannot be identified by their baseline pattern of ventricular filling or direct measurement of the left ventricular pressure at rest. Diastolic stress-test should be performed with accurate non-invasive methods as a primary approach’’
IC: preserved LVEF, HF symptoms EC: AF, COPD or VHD 2
Burgess, 200620
37 Pts:
Invasive Echo
8.3 ± 4.2 mmHg fi 9.1 ± 4.3 mmHg E/e0 : no increased 9.8 ± 2.4 fi 10.3 ± 2.1 8.9 ± 5.3 mmHg fi 21.5 ± 7.0 mmHg E/e0 : significantly increased 11.8 ± 4.7 fi 16.1 ± 6.7 20.8 ± 3.4 mmHg fi 20.4 ± 5.4 mmHg E/e0 : significantly increased 16.3 ± 4.9 fi 18.1 ± 8.6
(1) LVDP normal (n = 20)
(2) LVDP high only with exercise (n = 9) (3) LVDP high at rest (n = 8) IC: SR, indication for LV catheterization EC: unstable coronary syndromes, severe VHD or valve surgery CAD: 70% 3
Talreja, 200719
12 Pts
Invasive Echo
No
IC: LVEF > 50%, NYHA II-III EC: more than moderate VHD, COPD, known or suggested primary Pulmonary hypertension or pulmonary embolism CAD: n.d. 4
Plehn, 200934
28 HFPEF Pts IC: HTN (>3 years), exertional dyspnea, LVEF P 50%, PAP < 15 mmHg, PCWP > 12 mmHg during peak exercise EC:LBBB, VHD, LVH (>14 mm), COPD, diabetes CAD: no
12 HFPEF Pts, PAWP significantly increased: 14 ± 4 fi 22 ± 10 mmHg
Invasive
10 healthy
28 HFPEF Pts
PCWP: increased
PCWP: significantly increased
7.5 ± 2 fi 10 ± 2 mmHg
7.4 ± 2 fi 19 ± 9 mmHg
98 ± 27 W controls
Clinical perspectives and evidence of diastolic stress test in heart failure
(continued on next page)
3
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Table 1
4
5
6
7
Author
Patient‘s characteristic
Modalities during exercise
Healthy controls
Changes of exercise hemodynamics
Max workload
Conclusion/results
Maeder, 201035
14 HFPEF Pts
Invasive Echo
8 controls
14 HFPEF Pts
n.d, symptomlimited
PCWP:
PCWP:
10 ± 4 fi 20 ± 7* mmHg
10 ± 4 fi 23 ± 6* mmHg
‘‘Invasive hemodynamic studies with exercise are required to formally establish the pathophysiologic profile in patients with suspected HFNEF and to evaluate the effects of novel therapies’’
*p = 0.31 between exercise PCWP in controls and HFPEF 23 non-cardiac dyspnea (NCD) Pts
*p = 0.31 between exercise PCWP in controls and HFPEF n.d, symptomlimited
LVEDP: no changes: 12 ± 3 fi 14 ± 4 mmHg
LVEDP: significantly increased: 13 ± 2 fi 34 ± 6 mmHg
‘‘Euvolemic patients with exertional dyspnea, normal brain natriuretic peptide, and normal cardiac filling pressures at rest may have markedly abnormal hemodynamic responses during exercise, suggesting that chronic symptoms are related to heart failure. Invasive exercise hemodynamic testing may enhance diagnosis of HFPEF in this expanding population of patients with exertional dyspnea of unknown etiology’’
10 controls with LVEDP < 16 mmHg or/ and no increase during exercise
20 HFPEF Pts
54 ± 19 W HFPEF
‘‘A significant proportion of stable outpatients with unexplained chronic dyspnea may have HFPEF. Because the majority of these outpatients do not fulfill the diagnostic criteria for heart failure and noninvasive tests do not show overt pathology, a correct diagnosis of HFPEF represents a challenge’’
Borlaug, 201010
Penicka, 201016
IC: HF symptoms, LVEF > 50%, (NYHA II-II) + impaired exercise capacity, SR EC:LBBB, CMP, more than mild valvular heart disease, COPD CAD: all have negative stress-echo, myocardial perfusion scan or exercise ECG 32 HFPEF Pts IC: EF > 50%, exertional dyspnea, normal brain natriuretic peptide assay, normal resting hemodynamics CAD: no Pts with peak exercise PCWP > 25 mmHg were classified as having HFPEF (n = 32), and those with values < 25 mmHg were classified as having noncardiac dyspnea (NCD) (n = 23) 20 HFPEF Pts
IC: LVEF > 50%, dyspnea (NYHA II-III), SR, LVEDP > 16 mmHg at rest or significantly increase significantly during hemodynamic interventions. EC: COPD, AF, significant CAD (stenosis > 50%), cardiac surgery, VHD, CMP, recent ACS (66 months) CAD:23% (1) Hand grip
Invasive Echo
Invasive
32 HFPEF Pts
91 ± 24 W controls
(1) LVEDP: significantly increased 11 ± 1.5 fi 13 ± 1.6 mmHg
(1) LVEDP: significantly increased 21 ± 6.3 fi 28 ± 5.4 mmHg
E. Belyavskiy et al.
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Table 1 (continued)
(3) Nitroprusside infusion
(4) Dobutamine infusion
8
9
Borlaug, 201116
Dorfs, 201318
20 HFPEF Pts
Invasive
IC: preserved EF, exertional dyspnea CAD: no
Echo
355 HFPEF Pts IC: unexplained dyspnea (suspected HFPEF) EC: LVEF 6 50%, significant CAD, VHD, prior cardiac surgery, PM, cardiac shunt, constrictive pericarditis, CMP, pulmonary artery hypertension
Invasive Echo
(2) LVEDP: significantly increased 11 ± 1.5 fi 14 ± 1.0 mmHg (3) LVEDP: significantly decreased 21 ± 6.3 fi 8 ± 2.6 mmHg (4) LVEDP: significantly decreased 21 ± 6.3 fi 8 ± 2.6 mmHg
(2) LVEDP: no changes 21 ± 6.3 fi 24 ± 4.3 mmHg
No
Mean LVDP: significantly increased:
(3) LVEDP: significantly decreased 21 ± 6.3 fi 13 ± 5.3 mmHg (4) LVEDP: significantly decreased 21 ± 6.3 fi 16 ± 8.4 mmHg n.d, symptomlimited
Patients with early HFPEF develop increased LV diastolic filling pressures during supine exercise
74.1 + 32.6 W
‘‘Hemodynamic stress testing should be considered in particular if measurements at rest are normal, because it provides not only the unique opportunity to rule out a cardiac cause of dyspnea in uncertain cases, but also to identify patients at risk. An excessive rise of PCWP during exercise despite normal PCWP at rest is associated with increased mortality and may be considered as early HFPEF’’
14 (10–16) fi 20 (16–27) mmHg
No
355 HFPEF Pts PCWP: significantly increased 9.4 ± 4.1 fi 22.9 ± 7.4 mmHg
Differences were considered statistically significant when P < 0.05. E/e0 : ratio of early transmitral flow velocity to early diastolic mitral annulus velocity, HFPEF: heart failure preserved ejection fraction, HFNEF: heart failure normal ejection fraction, IC: inclusion criteria, EC: exclusion criteria, Pts: patients, CAD: coronary artery disease, n.d: no date, PAWP: pulmonary artery wedge pressure, PCWP: pulmonary capillary wedge pressure, COPD: chronic obstructive lung disease, LV: left ventricle, LVDP: left ventricle diastolic pressure, LVDEP: left ventricle end-diastolic pressure, SR: sinus rhythm, HF: heart failure, LVEF: left ventricle ejection fraction, CMP: cardiomyopathies, VHD: valvular heart disease, HTN: hypertension, PAP: pulmonary artery pressure, PM: pacemaker, ACS: acute coronary syndrome, NCD: noncardiac dyspnea.
Clinical perspectives and evidence of diastolic stress test in heart failure 5
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(2) Leg lifting
6
1
Non-invasive diastolic stress-test studies in HFPEF.
Author
Patient‘s characteristic
Modalities during exercise
Healthy controls
Changes of E/e0 in HFPEF group during/ after exercise (stress-test)
Max workload
Conclusion/results
Mottram, 200436
26 HFPEF Pts:
Echo
No
26 HFPEF Pts:
n.d, symptomlimited
‘‘In patients with limited capacity due to suspected DHF, BNP increases during exercise and is higher in those patients who likely have elevated filling pressures at maximal exercise. This increase in BNP with exercise is associated with enhanced myocardial function.’’
IC: well-treated HTN, LVEF > 50%, exertional dyspnea, diastolic dysfunction EC: angina, myocardial infarction, COPD, VHD, LVEF 6 50% 2
Ha, 20054
45 HFPEF Pts: (1A) E/e0 at rest < 10 without increase E/e0 during exercise (n = 17) (1B) E/e0 at rest < 10 with increase E/ e0 during exercise (n = 9) (2) E/e0 at rest > 10 (n = 19)
Echo
No
IC: exertional dyspnea
3
Burgess, 200620
EC: Pts with echocardiographic or electrocardiographic evidence of myocardial ischemia were excluded 166 Pts (1) Exercise E/e0 6 13 (n = 126)
4
Talreja, 200719
IC: Pts with EF > 50%, exertional dyspnea (NYHA II-III) EC: more than moderate valvular heart disease; COPD; known or suggested primary pulmonary hypertension or pulmonary embolism CAD: n.d.
75 W
‘‘Diastolic stress echocardiography using supine bicycle exercise is technically feasible for demonstrating changes of E/e0 = ratio and tricuspid regurgitant velocity during exercise as a result of changes in exercise-induced diastolic filling pressures’’
(2) Significantly increased: 9.2 ± 0.8 fi 13.5 ± 3.4 (3) No increase: 16.0 ± 4.1 fi 13.5 ± 4.5
75 W
166 Pts
n.d, symptomlimited
‘‘The findings of this study validate exercise E/e0 as a marker of ventricular filling pressure, and suggest that its measurement may explain functional impairment in patients with normal or mildly abnormal diastolic parameters at rest’’
n.d, symptomlimited
‘‘Noninvasively obtained Doppler of mitral and mitral annulus velocities provides a reliable estimation of PAWP not only at baseline, but also with exercise. Specifically, an E/e0 ratio of greater than 15 during exercise is associated with a significantly elevated PAWP of greater than 20 mmHg.’’
Echo, invasive
No
(1) No increase: 9.9 ± 2.4 fi 9.2 ± 2.1 (2) Significantly increased 15.1 ± 5.2 fi 16.9 ± 4.8
Echo, invasive
No
12 HFPEF Pts
(2) Exercise E/e0 P 13 (n = 40) IC: SR, indication for LV catheterization EC: unstable coronary syndromes, severe valvular disease or valve surgery CAD: in 70% of Pts 12 HFPEF Pts
E/e0 lateral significantly increased: 7.7 ± 2.0 fi 10.0 ± 4.8 E/e0 septal significantly increased: 9.1 ± 2.2 fi 11.6 ± 3.6 45 HFPEF Pts: (1) No increase: 8.7 ± 1.9 fi 6.4 ± 2.6
significantly increased 11.7 ± 0.5 fi 14.5 ± 0.6
75 W
E. Belyavskiy et al.
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Table 2
6
7
Ennezat, 200837
25 HFPEF Pts IC: EF > 50%, decompensated HF hospitalization.
Ha, 200921
EC: ACS, arrhythmias, primary valvular disease, CMP or constrictive pericarditis CAD: no 141 Pts (1) DFRI < 13.5 (n = 64)
Tan, 200911
(2) DFRI P 13.5 (n = 77) None had echocardiographic or electrocardiographic evidence of myocardial ischemia at rest 56 HFPEF Pts IC: EF > 50%, NYHA II and more
Echo
Echo
25 hypertensive as controls: significantly increased 8 ± 3 fi 10 ± 2* *E/e0 was measured only in 5 Pts during the test
No
25 HFPEF Pts: significantly increased 13 ± 4 fi 15 ± 2#
45 W Pts,
#E/e0 was measured only in 5 Pts during the test
65 W controls
141 Pts (1) Significantly increased 12.5 ± 4.0 fi 15.2 ± 4.4 (2) No changes: 11.4 ± 3.6 fi 11.1 ± 2.9
50 W
50 W
9
10
Maeder, 201035
Tan, 201038
Holland, 201139
14 HFPEF Pts IC: HF symptoms, LVEF > 50%, (NYHA II-II)+impaired exercise capacity, SR EC:LBBB,CMP, more than mild VHD, COPD CAD: all have negative stress-echo, myocardial perfusion scan or exercise ECG 30 Pts IC: hypertension, EF > 50%, exertional dyspnea EC: uncontrolled BP, the presence of LVH or evidence of PH on echo, COPD, VHD, arrhythmia (including AF), PM or ICD, CAD 15 HFPEF Pts: IC: LVEF > 50%, exertional dyspnea, diastolic dysfunction (E/ e0 > 15) EC: history of angina or CAD, VHD, LVEF 6 50%, arrhythmia
‘‘Patients with preserved LV systolic function and impaired myocardial relaxation at rest exhibit a wide spectrum of alterations in diastolic function during exercise’’
Echo
27 healthy as controls: No changes: 8.2 ± 2.0 fi 8.8 ± 1.8
56 HFPEF Pts No changes: 11.4 ± 4.3 fi 11.4 ± 4.5
n.d, symptomlimited (to max HR = 100/min)
‘‘HFNEF patients have a combination of systolic and diastolic abnormalities of ventricular function that is more obvious on exercise than at rest’’
Echo, invasive
8 controls, increased 9.5 ± 3.4* fi 11.1 ± 3.4 *p = 0.04 between resting E/e0 in HFPEF and controls
14 HFPEF Pts
n.d, symptomlimited
‘‘E/e0 septal doesn‘t reflect hemodynamic changes during exercise in HFPEF patients’’
n.d, symptomlimited
‘‘Patients with treated hypertension with normal resting echocardiography can have exercise limitation associated with widespread systolic and diastolic left ventricular dysfunction on exercise’’
n.d, submaximal (steady state for P 1 min at 60% of maximal HR)
‘‘Patients with HFPEF have increased E/e00 with exercise compared with age-matched and sexmatched controls. This response to exercise is clearly evident at low workloads similar to those experienced during activities of daily living, when symptoms are present, and is associated with indices of abnormal central, but not peripheral BP’’
EC: COPD, VHD, PM or ICD, CAD 8
‘‘When compared with patients with similar comorbidities but without history or evidence of heart failure, patients with HFPEF experience greater arterial stiffening and thereby a deterioration of global LV systolic performance during dynamic exercise’’
significantly decreased:
13.2 ± 4.1 fi 9.4 ± 3.4#
Echo
Echo
22 healthy as controls: No changes:
#p = 0.28 between peak exercise E/e0 in HFPEF and controls 30 Pts No changes:
8.4 ± 2.1 fi 9.3 ± 2.2
9.4 ± 2.6 fi 10.1 ± 2.1
15 healthy as controls Submax exercise:
15 HFPEF Pts: Submax exercise:
E/e0 significantly decreased: 10.7 ± 3.5 fi 11.9 ± 3.0 Maximal exercise: E/e0 significantly decreased:
E/e0 significantly increased: 13.8 ± 3.5 fi 17.6 ± 6.8* Maximal exercise: E/e0 significantly increased:
Clinical perspectives and evidence of diastolic stress test in heart failure
(continued on next page)
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Please cite this article in press as: Belyavskiy E et al. Clinical perspectives and evidence of diastolic stress test in heart failure with preserved ejection fraction, The Egypt Heart J (2015), http://dx.doi.org/10.1016/j.ehj.2015.06.002
5
8
Author
11
Meluzin 201131
Patient‘s characteristic
84 Pts:
Modalities during exercise
Echo
IC: LVEF P 50%, exertional dyspnea, diastolic dysfunction (E/ e0 > 15) EC: significantly CAD (stenosis > 40%), history of MI, VHD, CMP, liver, renal, lung disease, anemia (1) HFPEF Pts (n = 30), were selected according to current HFPEF recommendations (+11 patients had the exercise-induced E/ e0 > 15 or E/e0 septal > 13 (2) Pts with NCD (n = 54) 12
Donal, 201212
21 HFPEF Pts
Tartie`reKesri, 201240
23 HFPEF Pts IC: LVEF > 45%, SR, stable hemodynamic conditions, CAD: 10%
Changes of E/e0 in HFPEF group during/ after exercise (stress-test)
10.7 ± 3.5 fi 8.6 ± 2.5* *p > 0.05 between E/e0 at submax and max level in controls 14 healthy as controls
13.8 ± 3.5 fi 16.3 ± 4.3* *p = 0.433 between E/e0 at submax and max level in HFPEF 84 Pts:
E/e0 no changes: 7.3 ± 0.4 fi 7.3 ± 0.4
E/e0 no changes: 9.3 ± 0.3 fi 9.1 ± 0.3
Max workload
Conclusion/results
n.d, symptomlimited
‘‘A significant proportion of patients require exercise to diagnose HFNEF. The prevalence of isolated, only exercise-induced HFNEF must be viewed cautiously due to a relatively small number of patients included.’’
45–60 W
‘‘In patients recently hospitalized for treatment of HF with HFPEF (EF P 45%) subtle abnormalities of systolic and diastolic functions were present at rest and increased by a submaximal exercise stress echocardiography’’
76 ± 27 W HFPEF 143 ± 55 W controls
‘‘In HFPEF patients, moderate exercise leads to a steep increase in proximal afterload that is underestimated at rest and is associated with unfavorable ventriculo arterial coupling and exercise intolerance’’
30 HFPEF Pts 10.8 ± 0.4 fi 11.3 ± 0.5
54 PTs with NCD 8.5 ± 0.3 fi 8.0 ± 0.2 Echo
IC: LVEF P 45%, acute HF hospitalization. CAD: 23% 13
Healthy controls
Echo
15 hypertensive as controls: significantly increased 8 ± 2.5 fi 16 ± 6* *p = ns (Pts vs. controls during exercise) 15 hypertensive as controls: no changes: 11 (9–12) fi 11(10–13)
21 HFPEF Pts significantly increased 13 ± 6 fi 15 ± 6* * p = ns (Pts vs. controls during exercise) 23 HFPEF Pts: no changes: 20 (17–23) fi 22 (18–28)
Differences were considered statistically significant when P < 0.05. E/e0 : ratio of early transmitral flow velocity to early diastolic mitral annulus velocity, HFPEF: heart failure preserved ejection fraction, HFNEF: heart failure normal ejection fraction, IC: inclusion criteria, EC: exclusion criteria, Pts: patients, CAD: coronary artery disease, n.d: no date, PAWP: pulmonary artery wedge pressure, COPD: chronic obstructive lung disease, LV: left ventricle, SR: sinus rhythm, LVDP: left ventricle diastolic pressure, LBBB: left bundle branch block, ECG: electrocardiogram, PCWP: pulmonary capillary wedge pressure, ACS: acute coronary syndrome, CMP: cardiomyopathies, VHD: valvular heart disease, PM: pacemaker, ICD: implantable cardiac defibrillators, LVH: left ventricle hypertrophy, BP: blood pressure, AF: atrial fibrillation, HR: heart rate, MI: myocardial infarction, NCD: noncardiac dyspnea.
E. Belyavskiy et al.
Please cite this article in press as: Belyavskiy E et al. Clinical perspectives and evidence of diastolic stress test in heart failure with preserved ejection fraction, The Egypt Heart J (2015), http://dx.doi.org/10.1016/j.ehj.2015.06.002
Table 2 (continued)
Clinical perspectives and evidence of diastolic stress test in heart failure large studies are needed to validate the role of diastolic stress test in HFPEF. 19.
Conflict of interest All authors have no conflicts of interest to declare.
20.
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Please cite this article in press as: Belyavskiy E et al. Clinical perspectives and evidence of diastolic stress test in heart failure with preserved ejection fraction, The Egypt Heart J (2015), http://dx.doi.org/10.1016/j.ehj.2015.06.002