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European Heart Journal – Cardiovascular Imaging (2016) 17, 106–113
doi:10.1093/ehjci/jev144
Value of exercise echocardiography in heart
failure with preserved ejection fraction: a substudy
from the KaRen study
Erwan Donal1,2*, Lars H. Lund3, Emmanuel Oger4, Amélie Reynaud2, Frédéric Schnell2,
Hans Persson5, Elodie Drouet6, Cecilia Linde3, and Claude Daubert1,2, on behalf
of the KaRen investigators
1
Cardiologie, CHU Rennes, Rennes, France; 2CIC-IT 804, LTSI INSERM 1099, Université Rennes-1, Hôpital Pontchaillou, rue Henri Le Guillou, F-35000 Rennes, France; 3Pharmacologie
Clinique et CIC-IP 0203, CHU Rennes et Université Rennes-1, Rennes, France; 4Karolinska University Hospital Stockholm, Solna, Sweden; 5Danderyds Hospital, Stockholm, Sweden;
and 6Cellule recherche clinique et registres, Société Française de Cardiologie et URC Paris Est, Paris, France
Received 25 February 2015; accepted after revision 13 May 2015; online publish-ahead-of-print 16 June 2015
Background
KaRen is a multicentre study designed to characterize and follow patients with heart failure and preserved ejection fraction (HFpEF). In a subgroup of patients with clinical signs of congestion but left ventricular ejection fraction (LVEF)
.45%, we sought to describe and analyse the potential prognostic value of echocardiographic parameters recorded
not only at rest but also during a submaximal exercise stress echocardiography. Exercise-induced changes in echo parameters might improve our ability to characterize HFpEF patients.
.....................................................................................................................................................................................
Method
Patients were prospectively recruited in a single tertiary centre following an acute HF episode with NT-pro-BNP
and results
.300 pg/mL (BNP . 100 pg/mL) and LVEF . 45% and reassessed by exercise echo-Doppler after 4 –8 weeks of dedicated treatment. Image acquisitions were standardized, and analysis made at end of follow-up blinded to patients’ clinical
status and outcome. In total, 60 patients having standardized echocardiographic acquisitions were included in the analysis. Twenty-six patients (43%) died or were hospitalized for HF (primary outcome). The mean + SD workload was
45 + 14 watts (W). Mean + SD resting LVEF and LV global longitudinal strain was 57.6 + 9.5% and 214.5 + 4.2%, respectively. Mean + SD resting E/e′ was 11.3 + 4.7 and 13.1 + 5.3 in those patients who did not and those who did experience the primary outcome, respectively (P ¼ 0.03). Tricuspid regurgitation (TR) peak velocity during exercise were
3.3 + 0.5 and 3.7 + 0.5 m/s (P ¼ 0.01). Exercise TR was independently associated with HF-hospitalization or death
after adjustment on baseline clinical and biological characteristics.
.....................................................................................................................................................................................
Conclusion
Exercise echocardiography may contribute to identify HFpEF patients and especially high-risk ones. Our study suggested a prognostic value of TR recorded during an exercise. That was demonstrated independently of the value of
resting E/e′ .
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Heart failure with preserved ejection fraction † Echocardiography † Right ventricle † Strain
Introduction
Heart failure (HF) with preserved ejection fraction (HFpEF) is a
complex pathophysiological entity. Echocardiographic parameters
offer a key tool for syndrome diagnosis as indicated in the new
ESC guidelines.1 HFpEF is defined as an association of typical HF
signs and symptoms, normal or preserved left ventricular ejection
fraction (LVEF) and normal or small LV volumes, pertinent
structural heart disease [LV hypertrophy/left atrial (LA) enlargement], and evidence of diastolic dysfunction.1 Only a few papers
have proposed exercise echocardiography as a relevant diagnostic
tool in HfpEF.2 – 5 The relevance of echocardiographic parameters
that could be recorded during an exercise remains an issue particularly pregnant in this complex HFpEF syndrome. A strong correlation between E/e′ and physical activity has been demonstrated in
a large series of patients including patients with HFpEF.6 We have
* Corresponding author: Tel: +33 2 99 28 25 25; fax: +33 2 99 28 25 10, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
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Exercise echocardiography and heart failure with preserved ejection fraction
previously reported that longitudinal systolic and diastolic LV as well
as right ventricular (RV) functions assessed during a submaximal exercise stress echocardiography can distinguish symptomatic HFPEF
patients from matched normal controls.7 In the present study,
we sought to evaluate the value of submaximal exercise-echocardiographic parameters that are usually recorded at rest and that
one can record during an exercise. The exercise echocardiography
was systematically performed in stable state in the weeks following
an acute HF episode to characterize and potentially predict the
long-term clinical outcome in patients with HFpEF.
of the patient to the exercise. Thus, exercise testing could have been interrupted promptly in the event of typical chest pain, constraining
breathlessness, dizziness, muscular exhaustion, drop in BPs or severe
hypertension (systolic BP ≥ 250 mmHg), or significant ventricular arrhythmia. The test was considered abnormal if the patient presented
one or more of the following criteria: angina, evidence of shortness of
breath at a low workload level (,50 W), dizziness, syncope, or nearsyncope, ≥2 mm ST segment depression compared with baseline,
rise in systolic blood during exercise ,20 mmHg, fall in systolic BP
during exercise, or complex ventricular arrhythmias. Exercise duration
was designed to be 8 – 10 min for every patient. Enough time was set to
record a complete echocardiographic evaluation at each step.
Methods
Two-dimensional and tissue Doppler
echocardiography
8
The design of the KaRen study has been published elsewhere. KaRen
was designed to enrol patients showing HF symptoms who attended
the emergency ward, and to follow them up 4 – 8 weeks after the
acute episode. The inclusion criteria were as follows: (i) acute presentation at hospital admission with clinical HF signs and symptoms,
according to the Framingham criteria; (ii) BNP . 100 pg/mL or
NT-pro-BNP . 300 pg/mL; (3) LVEF . 45% by echocardiography
within the first 72 h.
In this exercise, echocardiography substudy, measurements were carried out in a subgroup of patients after 4–8 weeks following an acute HF
exacerbation. All patients enrolled in Rennes were invited to participate in
the submaximal exercise echo study. After ensuring, they were haemodynamically stable (no functional or clinical signs of acute HF decompensation and no argument for any symptomatic coronary artery disease) and
they had no neurological or orthopaedic limitation, patients who agreed
underwent a semi-supine exercise test. Treatments including betablockers were not modified for the test. All patients had to be in sinus
rhythm at the time of the exercise stress echocardiography but patients
could have been identified as paroxysmal atrial fibrillation patients.
The echo-protocol was always the same, all the exams being performed by the same investigator (E.D.). A particular attention was
brought to get the Doppler recording of the tricuspid regurgitation
(TR) at rest and during exercise. All the parasternal and apical views
were used to get this maximal velocity as a first thing at each step of
the standardized echocardiographic protocol we were and we are using
after our initial experience.7 All the measurements were performed according to the guidelines, offline by a dedicated physician working at the
echo core Lab (CIC-IT 804, Rennes, France). This analysis was done
afterwards, blinded from any clinical consideration. The results of the
exercise echocardiography were not provided to the clinician.
All patients underwent detailed echocardiographic examination at rest
and at the maximal workload sustained during exercise using a Vingmed
VividTM 7 or e9 (GE Healthcare, Horten, Norway). The position of the
patient was constant from baseline to the end on the tilt table and always
the same inclination. LV end-systolic and end-diastolic volumes, as well
as LVEF, were measured using the modified biplane Simpson’s method
from the apical four- and two-chamber views. Left and right atrial
volumes were calculated using the biplane area – length method from
the apical four- and two-chamber views and indexed to the body surface
area.9 The early filling (E) and atrial (A) peak velocities, as well as
the deceleration time of early filling and isovolumic relaxation time,
were measured from transmitral flow. All measurements were averaged
over three beats (3 – 5 according to the homogeneity of the results).
Peak mitral annular myocardial velocity of the LV septal and lateral
walls were recorded (and averaged) using the real-time pulse-wave tissue Doppler method, which allowed for measuring the mean peak systolic (s′ ), early diastolic (e′ ), and late diastolic (a′ ) velocities.10 LV filling
pressure was calculated as the ratio of early mitral diastolic inflow velocity to early diastolic mitral annular velocity (averaged from the septal
and the lateral side of the mitral annulus) (E/e′ ).10 Peak annular RV freewall velocities (RV s′ and RV e′ for peak systolic and early diastolic velocities, respectively) were measured using the same method. Tricuspid
annular peak systolic excursion was calculated using M-mode echocardiography.11 Peak systolic pulmonary arterial pressure (PAP) was estimated using the Bernouilli formula according to the tricuspid maximal
jet velocity. TR maximal velocity was used as a surrogate marker of
PAP according to recommendation.12 That was predefined because
the assessment of right atrial pressure could be challenging at rest but
was supposed even more questionable during the exercise.
Standardized submaximal exercise testing
Speckle tracking
After a clinical examination, arterial blood pressure (BP) measurement
(Dinamap Procare Auscultatory 100), 12-lead electrocardiogram
(ECG), and resting transthoracic echocardiography (Vivid 7, General
Electric Healthcare, Horten, Norway), patients underwent a standard
supine exercise (slightly on the left side) echocardiography on a tilting
table using an electromagnetic cycle ergometer (Ergometrics). Exercise
testing started at an initial workload of 30 W, with increase to 45 (if the
exercise capacity was too weak) and 60 and 90 W every 3 min according to individual patient’s capabilities. The pedalling rate was of 60 rpm.
The ECG was recorded continuously, and BP was measured every 2 min
during both exercise and recovery. BP, ECG, and echocardiographic
images were acquired at rest and at a predefined maximal heart rate
range (HR, 100 – 120/min), with at least three beats recorded. According
to current practice, the physician was standing closed to the patient
performing the images, assessing the clinical, ECG, and BP adaptation
LV longitudinal strains were assessed using the speckle tracking method.13 The apical four-, two-, and three-chamber images were analysed
offline by tracing the endocardium in end-diastole, and the thickness
of the region of interest was adjusted so as to include the entire myocardium. The software automatically tracked myocardial deformation
on the subsequent frame, and the results were displayed graphically.
End-systolic peaks were automatically considered for the measurement
of global longitudinal strain (GLS) and maximal peaks were manually
tracked for the look for mechanical dyssynchrony. The intraobserver
and interobserver variabilities as well as repeatability were previously
reported.7 The GE healthcare EchoPAC BT 12 was used.
Follow-up
After the ‘4 – 8 weeks scheduled visit’, patients were prospectively followed via phone call or by means of correspondence with their
108
E. Donal et al.
physicians every 6 months for at least 18 months. The follow-up was
closed for all patients on 31 October 2012. A dedicated research
team blinded to the initial visit and 4 – 8 week visit (registry unit from
the French Society of Cardiology)8 documented hospitalizations and
cause of hospitalization, death, as well as causes of death.
Definition of cardiovascular events and
primary clinical end-point
The primary clinical endpoint was time to first heart failure hospitalisation or all-cause death. Heart failure had to be defined as primary diagnosis in the patient file for adjudicating hospitalisation as HF related
hospitalisation.
Statistical analysis
Continuous variables were reported using central tendency and dispersion measurements. Qualitative variables were expressed as frequency
and percentage. The primary outcome was defined as either death or
readmission for HF whichever came first (censoring applied at the
date of hospitalization for patients for hospitalized for HF and who subsequently died). We used the Cox proportional hazard model to analyse ‘time to event’ data. The assumption that covariates exhibited a
linear form was checked using the shape of parameter estimate plots
by mid-point quartile intervals, and the pattern of martingale residual
plots as a function of the corresponding covariate. Departure from
the proportional hazards assumption was investigated using timedependent explanatory variables, in addition to a plot of the scaled
Schoenfeld residuals as a function of time.
To develop a prediction model and to test whether some exercise
parameters added some incremental information to parameters measured at rest, we started with selected echo parameters measured at
rest (those associated with the outcome in univariate Cox regression
analysis at a P , 0.10), and then added selected exercise parameters
(those associated with the outcome in univariate Cox regression analysis at a P , 0.10 and not highly correlated with parameters measured
at rest, Spearman coefficient ,0.7). A stepwise backward selection retained parameters associated with outcome at a P-value of ,0.05. We
then adjusted those selected echo parameters on clinical and basic laboratory data (those associated with the outcome in univariate Cox regression analysis at a P-value of ,0.10 among age, gender, medical
history, drug use, creatinine, and NT-pro-BNP levels).
Considering the limited available data and that some echo parameters
had some missing data, we did multiple imputations using the Monte
Carlo Markov Chain method.
All analyses used procedures available in SAS software, version 9.3
(SAS Institute, Cary, NC, USA).
Ethics for the substudy
A specific authorization has been obtained for the KaRen exerciseechocardiographic substudy (authorization 0820-679). A specific
informed consent has been signed by the included patients.
Results
From December 2008 to January 2012, 60 of the 203 patients included at the Rennes University Hospital in the KaRen registry
were enrolled in the substudy. The reason for not participating in
the substudy were significant orthopaedic or neurologic limitation
(n ¼ 45), suboptimal quality of resting echocardiography (missing
data) (n ¼ 33) and refusal to participate (n ¼ 65). There were
some minor differences in baseline clinical characteristics between
patients participating and patients non-participating in the substudy
(that have been reported elsewhere14) with a higher proportion of
males (63.3%, P ¼ 0.0015) and a higher resting SBP (138 +
23 mmHg, P ¼ 0.01) in the substudy population. Mean age was
74.8 + 7.4 years and 28 patients (46.7%) had history of atrial fibrillation or flutter. The workload sustained during exercise was 45 +
14 W (30–90 watts). There was no broad QRS. The exercise time
ranged between 6 and 12 min (Table 1). There was strictly no argument for any coronary artery disease, with no chest pain, no segmental wall motion abnormality observed during the exercise. No
Table 1 Main baseline clinical characteristics of patients included in the ‘KaRen exercise stress echocardiography’
substudy; Comparison with the whole cohort enrolled in Rennes-KaRen centre
Label
Substudy (N 5 60)
KaRen in Rennes (N 5 203)
P-value
Age (years)
Female gender, n (%)
NYHA I/II/III/IV, n
74.8 + 7.4
76.8 + 9.6
0.1782
20 (36.4)
3/47/5/0
76 (50.7)
11/87/35/8
0.0690
0.0067
...............................................................................................................................................................................
Weight (kg)
73.1 + 17.8
78.6 + 19.8
0.0739
BMI (kg/m2)
Overweight/obese, n (%)
27.8 + 5.9
15 (27.8)/20 (37.0)
29.3 + 6.4
46 (31.5)/61 (41.8)
0.1325
0.5029
Diagnosis of HF prior to enrolment, n (%)
24 (43.6)
58 (38.9)
0.5426
History of coronary artery disease, n (%)
History of AF/flutter, n (%)
22 (36.6)
28 (46.7)
38 (25.5)
96 (64.4)
0.7982
0.1279
Arterial hypertension, n (%)
51 (85)
119 (79.9)
0.9831
Type 2 diabetes, n (%)
NT pro-BNP (ng/L), median (p25– p75)
13 (23.6)
2067 [1419–4969]
33 (22.1)
257 [1313– 5216]
0.8214
0.7211
Haemoglobin (g/L)
122.4 + 14.9
119.5 + 18.6
0.2544
Creatinine (mmol/L)
102.5 + 50.1
110.7 + 58.5
0.3544
BMI, body mass index; HF, heart failure.
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Exercise echocardiography and heart failure with preserved ejection fraction
ECG significant change was, as well, observed. The amount of exercise was limited in these elderly patients with HFpEF. Therefore, the
changes observed during the exercise were limited but considered
significant because they appeared after a very short and limited
exercise.
During follow-up (median time of 523 days), 7 patients died
and 21 were hospitalized for decompensated HF. In total, 26 patients (43%) had a primary outcome event when compared with
49% in the whole KaRen cohort.15
Echocardiographic predictors
Table 2 displays demographic data in each group (those with vs.
those without events) and Table 3 the mean values of echo parameters in each group as well as univariate P-values for Cox regression models. E/e′ at rest was associated with the primary endpoint
and remained the only resting echo parameter significantly associated in the multivariable model (Table 4, Figures 1 and 2).
TR maximal velocity was the only parameters recorded during
exercise that remained significantly associated with the primary endpoint in the multivariable model (Table 4). Re-running the final model on raw data (without imputation of missing values) and adjusting
on clinical (history of hypertension and ACE inhibitor use) and biological (creatinine level) parameters showed very similar estimates
(Table 4).
Discussion
E/e′ at rest and estimated PAP by TR maximal velocity measured
during standardized exercise has a predictive value in our HFpEF
population. These two parameters may help to better define the
prognosis of HFpEF individuals. They seem crucial for best characterizing HFpEF patients.
E/e′
E/e′ was a key parameter proposed in the 2007 diagnostic algorithm,10,16 while LVEF and structural heart disease were introduced
in the 2012 ESC guidelines.1 With regard to supposed E/e′ robustness for estimating left heart filling pressures, studies in elderly populations or in dilated or hypertrophic cardiomyopathy patients
have highlighted the necessary prudency in the use of this ratio
for estimating filling pressures.17 – 19 The E/e′ value for estimating filling pressure during exercise also has been challenged.20 However,
studies have found a relationship between exercise E/e′ , exercise
capacity, and invasive left ventricular end-diastolic pressure recorded during exercise.6 To date, E/e′ measured at rest was not
shown to be the best parameter associated with HFpEF prognosis,21,22 whereas the change in E/e′ from rest to exercise was reported to be correlated with prognosis in one study.23 In this
study, 197 patients with Type 2 diabetes mellitus were followed
for 57 months, and the incidence death or hospitalization for heart
failure was 9.1%.
Of note is that E/e′ can be measured during or after exercise.
E/e′ . 14.5 was shown to be an independent predictor of outcome
in a study involving 522 unselected patients referred for exercise
echocardiography.24 Yet, this study was not focused on heart failure
and HFpEF patients. Our study, which used a prospective design and
was part of a large prospective registry, clearly demonstrated the
prognostic value of E/e′ recorded before any exercise.
Table 2 Clinical parameters and medical history according to heart failure or death occurrence during follow-up and
univariate measure of association
Parameters
Patients without event at
the end of follow-up (N 5 34)
Patients hospitalized for
HF or who died (N 5 26)
P-value
...............................................................................................................................................................................
Gender, female, n (%)
14 (41.2)
8 (30.8)
0.3099
Age, years
BMI, n (%)
73.8 + 7.5
76.2 + 7.2
0.3263
0.3836
Normal
Overweight
Obese
7 (21.2)
5 (19.2)
12 (36.4)
14 (42.4)
7 (26.9)
14 (53.8)
Prior diagnosis of HF, n (%)
13 (38.2)
10 (38.5)
History of CAD, n (%)
History of AF/flutter, n (%)
13 (38.2)
14 (41.2)
9 (34.6)
14 (53.8)
0.9433
0.2680
Arterial hypertension, n (%)
26 (76.5)
25 (96.1)
0.0657
Baseline medication, n (%)
Statin
23 (67.6)
22 (84.6)
0.2726
27 (79.4)
17 (65.4)
0.2188
13 (38.2)
2107 [353– 24 975]
16 (61.5)
1994 [305–9352]
0.0795
0.9989
99 + 41
99 + 35
114 + 49
121 + 48
0.0792
0.0038
Beta-blocker
ACE
NT-pro-BNP (ng/L)
Creatinine, mmol/L
At baseline
At 4 –8 weeks
Values for continuous parameters are mean + SD or median [range]; P-values are from univariate Cox regression Wald test.
110
E. Donal et al.
Table 3 Echocardiography parameters (mean + SD): description and univariate association with the risk of heart
failure or death
Parameters
Patients without event at
the end of follow-up (N 5 34)
Patients hospitalized for
HF or who died (N 5 26)
P-value
(raw data)
Missing (%)
0.0169
0.0217
,5
,5
P-value
(imputed data)
...............................................................................................................................................................................
Geometry
SBP
RR
143 + 24
906 + 165
157 + 24
1019 + 200
IVS
11.8 + 2.4
11.7 + 2.7
0.7884
LVED diameter
LVES diameter
50.2 + 6.5
35.6 + 7.3
52.7 + 5.9
37.6 + 7.0
0.1640
0.6030
64.9 + 23.6
58.5 + 9.5
72.3 + 24.1
56.2 + 9.5
0.0575
0.4822
Systolic function
SV
LVEF (%)
s′
7.09 + 1.46
6.50 + 1.52
0.1618
GLS
Septal LS (%)
14.7 + 4.0
13.4 + 4.7
14.2 + 4.4
13.9 + 5.1
0.5193
0.2841
Lateral LS (%)
14.4 + 6.0
16.0 + 7.0
0.4386
Diastolic function
LAVI (mL/m2)
45.5 + 15.7
50.7 + 19.6
0.1080
,2
E-dt (ms)
213 + 92
202 + 70
0.5833
,2
E/e′
e′
11.3 + 4.7
8.5 + 2.8
13.1 + 5.3
7.4 + 2.6
0.0329
0.3727
,5
0.57 + 0.21
85.1 + 21.3
0.50 + 0.10
83.8 + 25.7
0.1173
0.9468
6.66
0.2064
Asynchronism
MIT/RR
LVPEI (ms)
Septo-lateral delay DTI (ms)
Delay IV (ms)
Right ventricle
38.8 + 53.1
45.8 + 52.8
0.8701
211.1 + 23.5
29.5 + 16.5
0.6101
13.3
0.3248
RVPEI (ms)
95.7 + 21.8
89.6 + 21.4
0.2257
13.3
0.2413
RAVI (mL/m2)
TR Vmax (cm/s)
32.1 + 13.4
2.74 + 0.47
40.5 + 19.3
2.99 + 0.72
0.0249
0.0892
8.33
33.3
0.0760
0.0910
RV Sa (cm/s)
11.7 + 2.8
11.6 + 3.3
0.8045
10.0
0.7740
TAPSE (mm)
RV Ea (cm/s)
19.4 + 4.5
10.6 + 4.0
20.1 + 6.7
10.6 + 3.3
0.8019
0.6363
6.66
10.0
0.7366
0.6098
LVES diameter
SV
35.3 + 6.4
62.2 + 23.0
36.3 + 8.2
66.9 + 23.1
0.4894
0.2057
11.7
0.4285
s′
7.07 + 2.06
6.70 + 2.7
0.1883
,2
E/e′
e′
12.6 + 6.4
10.6 + 0.3.8
18.3 + 14.0
8.4 + 3.5
0.0413
0.0867
5
0.0843
Exercise
GLS
15.6 + 4.0
15.9 + 4.2
0.9380
RV Sa (cm/s)
TR Vmax (cm/s)
13.6 + 3.8
3.35 + 0.47
12.6 + 4.1
3.72 + 0.53
0.2052
0.0097
13.3
13.3
0.3086
0.0637
8.33
0.5662
0.4720
SBP
Work load (W)
Reserve
166 + 30
178 + 29
0.1306
45.7 + 13.6
43.8 + 13.4
0.5921
LVEF
20.35 + 7.47
1.65 + 8.13
0.3028
e′
E/e′
21.87 + 2.41
1.72 + 4.77
20.78 + 2.91
3.40 + 12.9
0.1788
0.4971
8.33
s′
0.04 + 2.07
0.05 + 1.80
0.4603
,2
2DS
0.82 + 2.75
1.53 + 3.16
0.3850
LS, longitudinal strain; RV, right ventricular; TR, tricuspid regurgitation; LA, left atrial; E-dt, mitral inflow E-wave deceleration time; RA, right atrial; Vol, volume; RVPEI, right
ventricular pre-ejection interval; LVPEI, left ventricular pre-ejection interval; IV, interventricular; GLS, global longitudinal strain; MIT, mitral inflow duration; RR, cycle length; e′ , early
diastolic pulsed tissue Doppler peak velocity; s′ , systolic pulsed tissue Doppler peak velocity.
Reserve ¼ difference between the measurement made during exercise and the one performed at rest (in other words: reserve ¼ delta exercise 2 rest value).
111
Exercise echocardiography and heart failure with preserved ejection fraction
Table 4 Multivariable estimates for the risk of death or hospitalization for heart failure related on echocardiography
parameters
Model 1
(full model)
P-value
(imputed data)
Model 2
(final model)
P-value
(raw data)
Model 3
(full model)
P-value
(imputed data)
0.0196
0.0078
0.1517
0.0153
0.0128
Model 4
(final model)
P-value
(imputed data)
Model 5 (final model)
P-value
(raw data)
HR
(95% CI)a
0.0020
0.0086
1.76 (1.15–2.68)
0.0016
0.0015
2.07 (1.32–3.25)
........................................
...............................................................................................................................................................................
Resting echo
SBP, mmHg
RR
0.3161
SV
E/e′
0.8708
0.0596
RAVI (mL/m2)
0.1315
TR Vmax (cm/s)
Exercise echo
0.2406
E/e′
0.6618
e′
TR Vmax (cm/s)
0.5642a
0.0056
Model 1 included all resting echo parameters and Model 2 retained only statistically significant parameters at 0.05 level; Model 3 included those selected parameters plus exercise
echo parameters (as E/e′ and e′ were highly correlated, they were not entered simultaneously); Model 4 retained only statistically significant parameters at 0.05 level.
a
HR for 5 units increase of E/e′ and for 0.5 cm/s increase of TR Vmax; adjusted on clinical parameters (history of hypertension, creatinine level and ACE inhibitor use/Model 5) did not
substantial affect estimates.
Figure 2 Graphical presentation of (A) LVEF measured at rest
and during standardized exercise stress echocardiography, (B)
GLS measured under the same conditions, (C ) E/e′ ratio and (D)
TR maximal velocity (Tric Regurg).
Estimated pulmonary artery pressure
using echocardiography
Figure 1 Kaplan– Meier curve for (A) E/e′ ratio measured at rest
and (B) TR maximal velocity recorded during the exercise.
In addition to E/e′ , we showed an independent prognostic value of
TR maximal velocity recorded during exercise emphasizing the
value of exercise stress echocardiography in HFpEF patients. Previous
reports have already demonstrated the test’s diagnostic value2,3,5
and its limits,25 whereas its prognostic value was less obvious. Estimation of PAP during exercise using echocardiography has already
112
been reported to be associated with prognosis, especially in heart
valve diseases.26,27 The prevalence of pulmonary hypertension as
estimated at rest by echocardiography, its impact on functional status, and its impact on prognosis have already been discussed.28 Lam
et al. reported pulmonary hypertension in 83% with a median systolic PAP of 48 mmHg29 in a community study involving 244 HFpEF patients with a mean age of 76 years. The pathophysiological
background of pulmonary hypertension, a reflection of left ventricular increased filling pressures, as well as its rapid and critical increase
during exercise in HFpEF patients, also has been demonstrated.28
Borlaug et al. in HFpEF subjects experienced significantly greater
exercise-induced increases in mean PAP than subjects with noncardiac dyspnoea despite achieving lower peak cardiac outputs.28,30
In the same study, exercise PASP, non-invasively recorded, identified HFpEF with 96% sensitivity and 95% specificity using a cut point
of 45 mmHg. Exercise PASP outperformed resting PASP, natriuretic
peptide levels, and echocardiographic indicators for diagnosing
HFpEF in Borlaug et al. experience.30,31 Thus, high filling pressures
with the propensity for rapid increments during exercise provide
a key prognostic information and potentially a theoretical therapeutic target. But, despite diuretics no specific treatment can currently be recommended in spite of high expectations for sildenafil
that have been frozen by the Relax trial.30,32 – 34
Limitations
Several limitations have to be highlighted. Inviting elderly HFpEF patients to participate in exercise stress echocardiography remains a
challenge. Exercise stress echocardiography may be of interest in
difficult cases, although patients must be fit enough to undergo
the test. Therefore, this testing is unlikely to be considered a key
tool for assessing all HFpEF patients despite its prognostic usefulness, as revealed by our study data. The hand grip would be easier
to perform, but bears its own imperfections, such as lack of standardization and insufficient reproducibility. Dobutamine stress echocardiography could be performed for researching ischaemia but
probably not more as Dobutamine will start by inducing a decrease
in pre and afterload. The workload used during the exercise was low
but stable allowing the images acquisitions. Also, the experience
shows us that when performing an exercise stress echocardiography, the heart maladjustment to changes in loading condition is
most of the time observed at a low level of exercise even in valvular
heart diseases.27
Conclusions
Exercise echocardiography may contribute to identify HFpEF patients and especially high-risk ones. Our study suggested a prognostic value of TR recorded during an exercise. That was demonstrated
independently of the value of resting E/e′ .
Acknowledgements
We also thank the research nurses: Marie Guinoiseau, Rennes University Hospital, Valerie Le Moal, Rennes University Hospital. The
French Cardiac Society: Anissa Bouzamondo, Genevieve Mulak,
and Elodie Drouet.
E. Donal et al.
Conflict of interest: There are no commercial products involved
in this study. However, to the extent that findings in KaRen may affect the use of heart failure drugs or devices, we disclose the following: L.H.L.: research grants and/or speaker and/or consulting
honoraria from AstraZeneca, Novartis, Boston Scientific, and St
Jude Medical; C.L.: principal investigator of REVERSE, a CRT study
sponsored by Medtronic research grants, speaker honoraria, and
consulting fees from Medtronic, speaker honoraria and consulting
fees from St Jude Medical; E.D.: speaker honoraria and consulting
fees from Novartis, Bristol-Myer-Squibb; J-.C.D.: research grants,
speaker honoraria and consulting fees from Medtronic and St Jude
Medical.
Funding
We would like to thank Medtronic Europe, France, and Sweden. Our
thanks also go to the French Federation (FFC), French Society of Cardiology (SFC), and Swedish Society of Cardiology for their dedicated
grants that made the KaRen study feasible.
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