Journal of Cardiac Failure Vol. 25 No. 4 2019

Diastolic IntraLeft Ventricular Pressure Difference During
Exercise: Strong Determinant and Predictor of Exercise Capacity
in Patients With Heart Failure
SHINGO TSUJINAGA, MD,1 HIROYUKI IWANO, MD, PhD,1 MIWA SARASHINA, MD,1 TAICHI HAYASHI, MD, PhD,1
MICHITO MURAYAMA, MS,2 AYAKO ICHIKAWA,3 MASAHIRO NAKABACHI, MS,3 HISAO NISHINO,3SHINOBU YOKOYAMA,3 ARATA FUKUSHIMA, MD, PhD,1 TAKASHI YOKOTA, MD, PhD,1 KAZUNORI OKADA, PhD,4
SANAE KAGA, PhD,4 PAVLOS P. VLACHOS, PhD,5 AND TOSHIHISA ANZAI, MD, PhD1
Sapporo, Japan; and West Lafayette, USA

ABSTRACT
Background: Although the enhancement of early-diastolic intraleft ventricular pressure difference(IVPD) during exercise is considered to maintain exercise capacity, little is known about their relationshipin heart failure (HF).
Methods and Results: Cardiopulmonary exercise testing and exercise-stress echocardiography were performed in 50 HF patients (left ventricular [LV] ejection fraction 39 § 15%). Echocardiographic images
were obtained at rest and submaximal and peak exercise. Color M-mode Doppler images of LV inflow
were used to determine IVPD. Thirty-five patients had preserved exercise capacity (peak oxygen consumption [VO2] 14 mL¢kg¡1¢min¡1; group 1) and 15 patients had reduced exercise capacity (group 2). During
exercise, IVPD increased only in group 1 (group 1: 1.9 § 0.9 mm Hg at rest, 4.1 § 2.0 mm Hg at submaximum, 4.7 § 2.1 mm Hg at peak; group 2: 1.9 § 0.8 mm Hg at rest, 2.1 § 0.9 mm Hg at submaximum,
2.1 § 0.9 mm Hg at peak). Submaximal IVPD (r = 0.54) and peak IVPD (r = 0.69) were significantly correlated with peak VO2. Peak IVPD determined peak VO2 independently of LV ejection fraction. Moreover,submaximal IVPD could well predict the reduced exercise capacity.
Conclusion: Early-diastolic IVPD during exercise was closely associated with exercise capacity in HF. In
addition, submaximal IVPD could be a useful predictor of exercise capacity without peak exercise in HF
patients. (J Cardiac Fail 2019;25:268277)
Key Words: Heart failure, exercise capacity, exercise-stress echocardiography, intraleft ventricularpressure difference.

Limited exercise capacity is a major symptom and causeof disability in patients with chronic heart failure (HF).
Moreover, exercise intolerance has been reported to be
associated with poor prognosis in HF patients.1,2 The

exercise capacity is known to be maintained by the increaseof cardiac output during exercise in HF regardless of left
ventricular (LV) ejection fraction (EF).3 In normal conditions, during exercise LV suction augments the pressure fallin the LV cavity in early diastole, and the generated earlydiastolic intraleft ventricular pressure difference (IVPD)
pulls blood from left atrium to the LV apex, which maintains or even increases diastolic filling despite the shortening of the filling time.4 Therefore, early-diastolic IVPD
during exercise has been considered to be associated with
exercise capacity.
The IVPD can be estimated noninvasively by integrating
the Euler equation from echocardiographic color M-mode
Doppler (CMMD) data.5 By applying this method to exercise-stress echocardiography, a previous study demonstrated that augmentation of early-diastolic IVPD by
exercise was blunted and that its changes during exercise
were strongly associated with exercise capacity in patientswith HF with reduced EF.6 However, the impact of theearly-diastolic IVPD on exercise capacity in HF with preserved EF has not been elucidated. In addition, peak

From the 1Department of Cardiovascular Medicine, Faculty of Medicine
and Graduate School of Medicine, Hokkaido University, Sapporo, Japan;
2
Diagnostic Center for Sonography, Hokkaido University Hospital, Sapporo, Japan; 3Division of Clinical Laboratory and Transfusion Medicine,
Hokkaido University Hospital, Sapporo, Japan; 4Faculty of Health Sciences, Hokkaido University, Sapporo, Japan and 5School of MechanicalEngineering, Purdue University, West Lafayette, Indiana, USA.
Manuscript received September 25, 2018; revised manuscript received
January 21, 2019; revised manuscript accepted February 5, 2019.
Reprint requests: Hiroyuki Iwano, MD, PhD, Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine,
Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan.
Tel: +81-11-706-6974; Fax: +81-11-706-7874.
E-mail: h-iwano@med.hokudai.ac.jp
Funding: This study was supported in part by a Kimura Memorial Heart
Foundation research grant for 2015.
See page 277 for disclosure information.
1071-9164/$ - see front matter© 2019 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.cardfail.2019.02.005

268
Downloaded for Anonymous User (n/a) at Hokkaido Ono Memorial Hospital from ClinicalKey.jp by Elsevier on May 26,
2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.

Intra-LV pressure differences during exercise in HF  Tsujinaga et al
exercise places excessive load on the patients with severe
symptomatic HF, which is preferred to be avoided. Accordingly, the aim of the present study was to confirm thatearly-diastolic IVPD during exercise could be associatedwith exercise capacity in chronic HF patients with various
LV EF, and moreover, that the IVPD at submaximal exercise could predict exercise capacity without excessive
workload.
Methods
Study Population and Protocol

The screening process in this study is shown in Supplemental Fig. 1. The present study prospectively enrolled
160 consecutive HF patients who were admitted to ourdepartment for the management of HF and referred forclinically indicated cardiopulmonary exercise testing(CPX) from July 2016 to January 2018. All patients werediagnosed as stage B or C chronic HF according to theguidelines.7 From the 160 patients, we excluded thosewith atrial fibrillation or flutter, inducible myocardialischemia, significant left-sided valvular disease with the
exception of secondary mitral regurgitation (MR) (moderate or severe aortic regurgitation, aortic stenosis, mitral
stenosis, or primary MR assessed with the use of Doppler
echocardiography according to guidelines),8 prosthetic
valve replacement, obstructive hypertrophic cardiomyopathy, peripheral artery disease, obvious anemia defined byhemoglobin <10 g/dL, congenital heart disease, respiratory disease, pericardial disease, or left ventricular assist
device implantation. Accordingly, 55 patients with HF
who denied the exclusion criteria were eligible for thepresent analysis. After the confirmation that HF was in stable condition, CPX and exercise-stress echocardiography
were performed without discontinuing b-blockers if thepatient was taking them. The study protocol was approvedby the Institutional Review Board of the Hokkaido University Hospital, and written informed consents were obtained
from all of the patients.
Cardiopulmonary Exercise Testing

A symptom-limited CPX was performed with the use of
an upright electromechanical bicycle ergometer (Aerobike
75XLII; Combi Wellness, Tokyo, Japan) using a ramp protocol as previously described.9 Peak oxygen consumption(VO2), defined as the maximal VO2 attained during exercise, was measured by means of simultaneous respiratory
gas analysis with the use of a breathing apparatus (Aeromonitor AE-300S; Minato Medical Science, Osaka, Japan).
The maximal work, peak respiratory exchange, and anaerobic threshold (AT) determined by means of the V-slope
method10 were also measured.
Exercise-Stress Echocardiography

Exercise-stress echocardiography with the use of asupine bicycle ergometer (Angio V2; Lode, Groningen,

269

The Netherlands) and iE33 ultrasound system with S5-1
transducer (Philips Ultrasound, Bothell Washington) was
performed within 7 days after CPX. To adjust the workload
during the stress echocardiography among the patients, we
determined the submaximal workload as the level of AT
and peak workload as 80% of the CPX peak workload. The
protocol of exercise stress was as follows: the workload
was increased to the level of AT in 3 minutes and echocardiographic images at submaximal exercise were acquired
within 5 minutes, and then the workload was further
increased to 80% of the CPX peak workload in the following 3 minutes and the images at peak exercise wereacquired within 5 minutes. Echocardiographic images
including 2-dimensional, Doppler, and CMMD images
were acquired at rest and submaximal and peak exercise.
LV end-diastolic volume, end-systolic volume, and EF
were measured by means of the method of disks. LV mass
was calculated according to the Devereux formula. The
Doppler image of LV outflow was recorded in the apicallong-axis view, and time-velocity integral was measured
for the estimation of stroke volume. Cardiac output was calculated as stroke volume £ heart rate. Transmitral Doppler
flow was recorded and peak early (E) and late diastolicvelocity (A) measured. Septal and lateral peak systolicannular velocities (s0 ) as well as early-diastolic peak of
mitral annular velocities (e0 ) were measured from the apical
4-chamber view with the use of pulsed-wave tissue Doppler
imaging, and average of the septal and lateral velocities
were used for the subsequent analysis. The ratio of E toe0 (E/e0 ) was calculated. CMMD images were recorded withthe cursor parallel to LV inflow in the apical 4-chamber
view.
Estimation of Arterial and End-Systolic ElastanceEnd-systolic pressure was estimated as 0.9 £ brachialsystolic blood pressure,11 and the arterial elastance (Ea)
was derived as the ratio of end-systolic pressure to strokevolume as assessed by echocardiography.12 The endsystolic elastance (Ees) was derived as the ratio of endsystolic pressure to LV end-systolic volume.12
Definition of Exercise Intolerance

Patients were divided into 2 groups according to peakVO2: group 1 (preserved exercise capacity, defined by peakVO2 14 mL¢kg¡1¢min¡1) and group 2 (reduced exercise
capacity defined by peak VO2 <14 mL¢kg¡1¢min¡1).13
Analysis of the IVPD With the Use of CMMD Images

CMMD images were analyzed with the use of an automated analysis algorithm based in Matlab (The Mathworks,
Natic, Massachusetts).14 Briefly, the early-diastolic IVPD
from the mitral annulus to the LV apex was determinedwith the use of CMMD data to integrate the Euler equation
as previously described.14 From the temporal profile of the
IVPD, the early-diastolic peak IVPD from the mitral

Downloaded for Anonymous User (n/a) at Hokkaido Ono Memorial Hospital from ClinicalKey.jp by Elsevier on May 26,
2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.

270

Journal of Cardiac Failure Vol. 25 No. 4 April 2019

annulus to the LV apex was calculated. This method has
been validated by comparison with direct measurementswith micromanometers.5
Reproducibility Analysis

The test-retest reproducibility of IVPD measurement wasassessed in 15 of the study subjects. The same CMMD
images at rest and peak exercise were analyzed on 2 separate days and compared. The absolute differences between
repeated measurements of IVPD at rest and at peak exercise
were 0.36 § 0.33 mm Hg (20%) and 0.50 § 0.40 mm Hg(13%), respectively.
Statistical Analysis

Quantitative variables were expressed as mean § SD if
normally distributed, and as median (interquartile range) if
nonnormally distributed. Qualitative variables werereported as frequency and percentage. Parametric unpairedt test or nonparametric Wilcoxon test was used to compare
quantitative variables. The chi-square test was used to compare qualitative variables. A mixed-effects measures analysis of variance was used in which one factor was abetween-subjects variable and the other was a withinsubjects variable, incorporating rest and submaximal andpeak exercise responses. Tukey-Kramer test was used forpost hoc analysis. Pearson correlation coefficient was used
to examine the relationship between continuous variables.
A linear regression analysis determined cofactors associated with peak VO2, and a multiple linear regression analysis was performed establishing 4 models in which variables
were selected based on significant cofactors in univariable
analysis and determinants of peak VO2 established in previous reports.1517 To test the correlations between IVPD andthe parameters obtained during exercise-stress echocardiography, the datasets at rest and submaximal and peak exercise were used for the linear regression analyses. A linear
regression analysis to clarify the factors associated withpeak VO2 and a receiver operating characteristic (ROC)
analysis were performed to evaluate the utility of the IVPD
at submaximal exercise for the prediction of reduced exercise capacity. The incremental value of the IVPD at submaximal exercise over clinical and echocardiographic
characteristics to predict reduced exercise capacity wasinvestigated by the significance of the increase in global
chi-square. For all tests, a P value of <0.05 was considered
to be statistically significant. Statistical analyses were performed with the use of JMP Pro 13.1.0 (SAS Institute,Cary, North Carolina).
Results
Patient Characteristics

Among the 55 eligible patients with HF, 5 were excluded
owing to insufficient echocardiographic image quality
obtained during exercise. Therefore, the final study population consisted of 50 patients. The baseline characteristics ofthe studied patients are presented in Table 1. Almost half ofthe patients had moderate HF symptom, and 18 (36%) had
dilated cardiomyopathy. Prevalences of the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin
receptor blockers (ARB) and of b-blockers were high, andloop diuretics were administered in roughly half of thepatients. Plasma B-type natriuretic peptide (BNP) level wasmodestly increased, and the average LV EF was 39% overall.
In addition, the study population included 22 patients (44%)
with relatively preserved LV EF (40%).
Comparisons Between Patients With and Without
Exercise Intolerance

Among the 50 patients with HF, 35 had preserved exercise capacity, defined by peak VO2 14 mL¢kg¡1¢min¡1(group 1), and 15 had reduced exercise capacity (group 2;
Table 1). There were some tendencies that dilated cardiomyopathy was more frequent and ischemic heart diseaseless frequent in group 1. Patients in group 2 were more
likely to have diabetes mellitus and to be treated with loop
diuretics, mineral corticoid receptor antagonist, and tolvaptan than those in group 1. However, b-blockers and ACE
inhibitors or ARBs were administered similarly in bothgroups.
Hemoglobin was significantly higher and creatinine aswell as plasma BNP level were lower in group 1 than ingroup 2. There were some tendencies that LV mass index,
LV end-diastolic volume, and LV end-systolic volume
were larger and LV EF lower in group 2. Respiratoryexchange ratio was similar between the groups, with anaverage >1.15, suggesting that adequate stress could beachieved in both groups.
Responses to Exercise During Stress Echocardiography

The time from CPX to exercise-stress echocardiography
was 3 § 2 days. Changes in hemodynamic and echocardiographic parameters during the exercise-stress echocardiography are summarized in Table 2. Excise duration was
similar between the groups. Although heart rate wasincreased in groups 1 and 2, it achieved higher values ingroup 1. Stroke volume did not change in both groups,
although patients in group 1 had greater stroke volume atsubmaximal and peak exercise. As a result, cardiac output
was significantly increased only in group 1. LV EF did notchange in both groups, although the patients in group 1
showed a tendency to its increase and s0 significantly
increased only in group 1. Increase in MR was more frequently observed in group 2 than in group 1. As shown in
Fig. 1A, IVPD was significantly increased at submaximal
and peak exercise overall. However, the increase wasobserved only in group 1, and in group 2 it remained at thesame value as at rest during exercise (Fig. 1B). As a result,
IVPD during exercise was significantly higher in group 1
than in group 2 (Fig. 2). The patients who showed increasein MR to more than moderate during exercise did not show
an increase in IVPD during exercise (at rest 1.8 § 0.8 mm

Downloaded for Anonymous User (n/a) at Hokkaido Ono Memorial Hospital from ClinicalKey.jp by Elsevier on May 26,
2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.

Intra-LV pressure differences during exercise in HF  Tsujinaga et al

271

Table 1. Baseline Clinical Characteristics
Variable

Overall (n = 50)

Group 1 (n = 35)

Group 2 (n = 15)

P Value

Age, yMale, n (%)
Body surface area, m2
Systolic BP, mm Hg
Diastolic BP, mm Hg
Heart rate, beats/min
NYHA functional class
I
II
III
Cardiac disease
Dilated cardiomyopathy
Ischemic heart disease
Hypertensive heart disease
Hypertrophic cardiomyopathy
Other
Comorbidity
Hypertension
Dyslipidemia
Diabetes mellitus
Medication
ACE inhibitors or ARBs
b-Blockers
Calcium antagonists
Loop diuretics
Mineral corticoid receptor antagonists
Tolvaptan
StatinAspirinLaboratory data
Hemoglobin, g/dL
Total protein, g/dL
Albumin, g/dL
Total bilirubin, mg/dL
Creatinine, mg/dL
Triglyceride, mg/dL
HDL cholesterol, mg/dL
LDL cholesterol, mg/dL
HbA1c, %BNP, pg/mL
Echocardiographic data
LV mass index, g/m2
LV EDV, mL
LV ESV, mL
LV EF, %LV EF <40%
LA volume index, mL/m2
Mitral regurgitation, n (%)
None or trivial
Mild
Moderate
Severe
CPX data
Peak VO2, mL¢kg¡1¢min¡1
AT, mL¢kg¡1¢min¡1
Peak RER

59 § 1630 (60)1.65 § 0.21
106 § 1863 § 1168 § 1157 § 1622 (63)
1.68 § 0.22
109 § 1666 § 1067 § 1063 § 13
8 (53)
1.59 § 0.19
98 § 2255 § 1269 § 15

.19
.53
.16
.06
<.01
.63
<.001

9 (18)
18 (36)23 (46)9 (26)
17 (49)9 (26)0 (0)1 (7)14 (93)18 (36)8 (16)
6 (12)
5 (10)
13 (26)

14 (40)4 (11)
4 (11)
4 (11)
9 (26)

4 (27)
4 (27)
2 (13)
1 (7)
4 (27)

21 (42)24 (48)10 (20)15 (43)14 (40)3 (9)6 (40)
10 (67)7 (47)

.85
.08
<.01

43 (86)40 (80)6 (12)
28 (56)22 (44)12 (24)21 (42)10 (20)31 (89)27 (77)3 (9)15 (43)
11 (31)5 (14)
13 (37)5 (14)

12 (80)13 (87)
3 (20)
13 (87)
11 (73)7 (47)
8 (53)
5 (33)

.42
.70
.35
<.01
<.01
.03
.29
.14

13.4 § 2.0
6.9 § 0.5
4.1 § 0.4
0.7 § 0.3
0.9 § 0.3
110 (83155)
54 § 17111 § 33
6.0 § 0.6
138 (57345)

13.8 § 1.9
6.9 § 0.5
4.2 § 0.4
0.7 § 0.3
0.8 § 0.2
107 (86179)
54 § 15113 § 35
5.9 § 0.4
119 (29248)

12.3 § 2.0
7.0 § 0.6
4.1 § 0.4
0.7 § 0.3
1.2 § 0.4
114 (77155)
55 § 22109 § 29
6.2 § 1.0364 (96575)

.02
.42
.57
.99
<.001
.58
.92
.70
.29
.01

117 (90151)
99 (80186)
68 (42129)
39 § 1528 (56)47 § 21110 (89146)
99 (77181)
62 (38123)
42 § 1416 (46)42 § 18

128 (99154)
127 (80199)
88 (44161)
32 § 13
12 (80)60 § 21

.35
.46
.22
.07
.03
<.01
.04

24 (48)17 (34)9 (18)0 (0)20 (57)
11 (31)4 (11)0 (0)4 (27)
6 (40)
5 (33)0 (0)17.7 § 5.2
11.1 § 3.4
1.2 § 0.1

20.2 § 4.0
11.9 § 3.3
1.2 § 0.1

11.8 § 1.6
9.0 § 2.6
1.2 § 0.1

.68

<.001
<.01
.11

Data are expressed as mean § SD if normally distributed, median (interquartile range) if nonnormally distributed, or n (%). P values are for the comparisons between patients with preserved exercise capacity (group 1) and those with reduced exercise capacity (group 2). BP, blood pressure; NYHA, NewYork Heart Association; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; HDL, high-density lipoprotein; LDL, low-density
lipoprotein; HbA1c, hemoglobin A1c; BNP, B-type natriuretic peptide; LV, left ventricular; EDV, end-diastolic volume; ESV, end-systolic volume; EF,ejection fraction; LA, left atrial; CPX, cardiopulmonary exercise testing; VO2, oxygen consumption; AT, anaerobic threshold; RER, respiratory exchange
ratio.

Hg, at submaximal exercise 2.2 § 0.6 mm Hg, at peak exercise 2.3 § 0.8 mm Hg; P = NS), which was the same findingin group 2 patients without increase in MR during exercise(at rest 2.0 § 0.9 mm Hg, at submaximal exercise 2.1 §1.0 mm Hg, at peak exercise 2.3 § 1.0 mm Hg; P = NS).

Determinants of Exercise Capacity

The results of the univariable and multivariable regression analyses to determine peak VO2 are presented in Supplemental Table 1. Among the clinical parameters as well

Downloaded for Anonymous User (n/a) at Hokkaido Ono Memorial Hospital from ClinicalKey.jp by Elsevier on May 26,
2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.

272

Journal of Cardiac Failure Vol. 25 No. 4 April 2019
Table 2. Exercise-Stress Echocardiographic Measurements Except IVPD

Variable

OverallGroup 1

Group 2

P Value

Exercise duration, minHeart rate, beats/min
Rest
Submaximal exercise
Peak exercise
Systolic BP, mm Hg
Rest
Submaximal exercise
Peak exercise
Stroke volume, mL
Rest
Submaximal exercise
Peak exercise
Cardiac output, L/min
Rest
Submaximal exercise
Peak exercise
LV EF, %Rest
Submaximal exercise
Peak exercise
s0 , cm/s
Rest
Submaximal exercise
Peak exercise
E-wave velocity, cm/s
Rest
Submaximal exercise
Peak exercise
e0 , cm/s
Rest
Submaximal exercise
Peak exercise
E/e0
Rest
Submaximal exercise
Peak exercise
TR pressure gradient, mm Hg
Rest
Submaximal exercise
Peak exercise
Increase in mitral regurgitation to more than moderate

12.1 § 3.1

12.5 § 3.1

11.3 § 2.9.23

67 § 1194 § 17*104 § 20*67 § 1097 § 16*111 § 17*67 § 1386 § 17*88 § 18*

1.00
.26
<.001

110 § 17134 § 25*155 § 28*114 § 16139 § 22*162 § 27*

101 § 19123 § 28138 § 25*

.51
.31
.02

58 § 1763 § 2165 § 2162 § 1669 § 1872 § 1748 § 1748 § 2147 § 22

.18
<.01
<.001

3.8 § 1.0
6.0 § 2.4*
6.9 § 2.9*

4.1 § 1.0
6.8 § 2.2*
8.0 § 2.4*

3.1 § 0.8
3.9 § 1.2
3.8 § 1.4

.53
<.001
<.001

39 § 1543 § 1745 § 2042 § 1447 § 1850 § 2032 § 1332 § 1234 § 15

.07
.06
.04

5.4 § 1.6
6.4 § 2.1*
6.9 § 2.5*

5.6 § 1.7
7.0 § 2.1*
7.6 § 2.5*

4.7 § 0.9
4.8 § 1.1
5.2 § 1.1

.64
<.01
<.01

69 § 20100 § 24*
108 § 28*65 § 1898 § 23*105 § 29*78 § 21106 § 25*
115 § 23*

.40
.91
.79

5.4 § 2.2
7.2 § 3.0*
7.6 § 3.7*

5.9 § 2.3
7.9 § 3.0*
8.6 § 3.8*

4.5 § 1.7
5.2 § 2.0
5.1 § 1.8

.62
.04
<.01

14.2 § 5.9
16.6 § 7.8
17.5 § 10.4

12.4 § 5.3
14.4 § 6.9
14.7 § 9.1

18.5 § 5.1
21.8 § 7.4
25.0 § 10.0*

<.001
<.001
<.001

21 § 930 § 8*37 § 14*
7 (14)

19 § 628 § 7*32 § 12*1 (3)25 § 1333 § 10*45 § 14*
6 (40)

<.01
.04
<.001
<.001

Data are expressed as mean § SD or n (%). P values are for the comparisons between patients with preserved exercise capacity and those with reduced
exercise capacity. s0 , average of the peak systolic myocardial velocity from septal and lateral sites of the mitral annulus; E, peak early-diastolic filling velocity;0e , average of the peak early-diastolic myocardial velocity from septal and lateral sites of the mitral annulus; TR, tricuspid regurgitation. Other abbreviations
as in Table 1.
*P<.05 versus rest within the groups.

as hemodynamic and echocardiographic parameters at
peak exercise, age, plasma BNP level, heart rate, e0 , E/e0 ,LV EF, stroke volume, and cardiac output were significantly correlated with peak VO2. Although IVPD at rest
did not correlate with peak VO2, IVPD at peak exercise
and its change during exercise were significantly correlated with peak VO2 (Fig. 3), which was consistent withthe previous report.6 In addition, similar correlations wereobserved even in patients with preserved LV EF (r = 0.64;
P < .01) as well as in those with reduced EF (r = 0.65;
P < .01; Fig. 4). Multivariable analysis showed that IVPD
at peak exercise was an independent determinant of peakVO2 in all of the constructed models (Supplemental
Table 1). Notably, IVPD remained a significant determinant independently from LV EF.

Determinants of IVPD

Overall, s0 , e0 , LV end-diastolic volume, LV end-systolicvolume, and Ees were significantly correlated with IVPD,
whereas Ea was not (Supplemental Table 2). When the correlations were tested in patients with reduced LV EF(<40%) and preserved LV EF (40%), only Ees significantly correlated with IVPD in patients with reduced LV
EF. In contrast, in those with preserved LV EF, s0 and e0 in
addition to Ees were significantly correlated with the IVPD.
IVPD at Submaximal Exercise as a Predictor of Reduced
Exercise Capacity

The results of the regression analyses to clarify the factors associated with peak VO2 and ROC analyses to predict

Downloaded for Anonymous User (n/a) at Hokkaido Ono Memorial Hospital from ClinicalKey.jp by Elsevier on May 26,
2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.

Intra-LV pressure differences during exercise in HF  Tsujinaga et al273

Fig. 1. (A) Changes in early-diastolic intraleft ventricular pressure difference (IVPD) during exercise in all patients. (B) Changes inearly-diastolic IVPD during exercise in patients with preserved exercise capacity and reduced exercise capacity. VO2, oxygen consumption;
P values were derived from a mixed-effects analysis of variance. *P < .05 versus rest within the groups; yP < .05 versus patients with
reduced exercise capacity.

reduced exercise capacity with the use of the stress echocardiographic parameters at submaximal exercise are presented in Supplemental Table 3. Interestingly, althoughheart rate at submaximal exercise had modest predictive
values, with an area under the ROC curve of 0.67 (95%
confidence interval [CI] 0.470.82; P = .05), IVPD and cardiac output at the submaximal stage could well predict the
reduced exercise capacity: the area under the ROC curve,

sensitivity, and specificity were, respectively, 0.81 (95%
CI 0.660.91; P < .001), 87%, and 71% for IVPD (cutoff
value 3.0 mm Hg), and 0.87 (95% CI 0.730.94;
P < .001), 92%, and 70% for cardiac output (cutoff value
5.5 L/min). Furthermore, an incremental value of the IVPD
at submaximal exercise on clinical parameters, E/e0 , andcardiac output at submaximal exercise for the prediction of
reduced exercise capacity was observed (Fig. 5).

Fig. 2. Temporal profiles of intraleft ventricular pressure difference (IVPD) and corresponding color M-mode Doppler images obtained
from (A) a patient with preserved exercise capacity and (B) a patient with reduced exercise capacity. It is noteworthy that IVPD wasincreased by exercise only in the patient with preserved exercise capacity.

Downloaded for Anonymous User (n/a) at Hokkaido Ono Memorial Hospital from ClinicalKey.jp by Elsevier on May 26,
2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.

274

Journal of Cardiac Failure Vol. 25 No. 4 April 2019

Fig. 3. Correlations between IVPD and peak VO2 in overall patients. Abbreviations as in Fig. 1.

Discussion
In this study, we demonstrated that early-diastolic IVPD
was a powerful determinant of exercise capacity in HF
patients with various LV EF. Importantly, IVPD remained
determinant even after adjustment for LV EF. Furthermore,
IVPD at submaximal exercise could predict reduced exercise capacity with the cutoff value of 3.0 mm Hg having an
incremental value on cardiac output, which directly determines VO2 together with peripheral factors. This result canbe interpreted that “gentle” exercise-stress echocardiographic IVPD could be a useful predictor of exercise capacity, reducing the physical burden associated with the stresstest in HF patients.
Impact of the IVPD on Exercise Capacity in HF

To function as an effective pump, the LV needs to fill
without an elevation of left atrial pressure. During exercise,in the normal situation, LV suction augments the early-diastolic IVPD, which contributes to the maintenance or evenenhancement of LV filling and subsequent ejection without
overt elevation of left atrial pressure despite the shorteningof the filling time.4 Given the formula “VO2 = cardiac output £ arteriovenous oxygen content difference,” LV suction
during exercise should be an important contributor for the
exercise capacity through the increase in cardiac output
resulting from the maintenance of stroke volume despite
the increased heart rate.4
However, the impact of LV suction on exercise capacity
has not been well investigated in HF patients despite thefact that exercise intolerance is a major symptom, andmoreover a predictor of the outcome, in HF patients.1,13
Only one previous study observed that augmentation of
IVPD assessed by means of the same method as ours wasdiminished in HF patients. Rovner et al tested the CMMDderived IVPD in HF patients with LV systolic dysfunction

Downloaded for Anonymous User (n/a) at Hokkaido Ono Memorial Hospital from ClinicalKey.jp by Elsevier on May 26,
2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.

Intra-LV pressure differences during exercise in HF  Tsujinaga et al275

Fig. 4. Correlations between IVPD and peak VO2 in patients with reduced left ventricular (LV) ejection fraction (EF) and those with preserved LV EF. Abbreviations as in Fig. 1.

Fig. 5. Incremental value of intraleft ventricular pressure difference (IVPD) at submaximal exercise over conventional parameters to predict reduced exercise capacity. The figure illustrates the global chi-square values of logistic regression models for the prediction of reduced
exercise capacity defined by peak oxygen consumption <14 mL¢kg¡1¢min¡1, incorporating age, plasma B-type natriuretic peptide (BNP)level, submaximal E/e0 , submaximal cardiac output (CO), and submaximal IVPD. Notably, the addition of submaximal IVPD as an explanatory variable to the other parameters significantly increased the global chi-square value.

Downloaded for Anonymous User (n/a) at Hokkaido Ono Memorial Hospital from ClinicalKey.jp by Elsevier on May 26,
2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.

276

Journal of Cardiac Failure Vol. 25 No. 4 April 2019

(LV EF 25.9 § 13.3%) and found that the augmentation of
IVPD by exercise was reduced in HF patients comparedwith the normal control subjects and that this augmentation
was positively associated with peak VO2.6 They therefore
concluded that impaired myocardial relaxation was associated with reduced diastolic suction force during exercise inpatients with HF with severe systolic dysfunction. Our
study confirmed their observations and further extended theresults for patients with preserved LV EF, which could be
associated with reduced LV longitudinal function. This has
not been previously demonstrated but could be expected
because the relation of LV suction, ejection, and VO2 isconsistent regardless of LV EF. Although the mechanismsof the reduced LV suction might be different between HF
with reduced LV EF and HF with preserved LV EF, as
described in the next section, the present results provide anovel insight for the understanding of the mechanisms of
exercise intolerance in HF patients with various LV EF.
Despite the usefulness of the early-diastolic IVPD, tounderstand the pathophysiology of exercise intolerance in
HF, as of this moment, we need special software for its calculation. We hope that this method could become widely
available in routine practice in the near future.
Determinants of the IVPD

Certain part of the LV suction is considered to be a resultof elastic recoil of intramyocardial and extracellular components which were compressed and storing the energy ofcontraction during systole.18 Therefore, the early-diastolic
IVPD should be determined by the parameters of LV deformation during systole as well as early diastole, and in fact,
previous studies have shown the relationships between
IVPD and the parameters of LV systolic and diastolic function.19 Intriguingly, when the determinants were tested inpatients with reduced LV EF and with preserved LV EF inthis study, we found differences in the results. Although
Ees significantly correlated with IVPD in both groups, s0
and e0 correlated with IVPD only in patients with preserved
LV EF. These results could be interpreted that LV contractility would determine the LV suction regardless of LV EF
and that LV contractility would be mainly determined bylongitudinal function in patients with preserved LV EF but
not in those with reduced LV EF. These are consistent withthe concept that decreased longitudinal LV function is amajor contributor to the reduced LV diastolic function in
HF with preserved LV EF.20
IVPD as a Predictor of Exercise Intolerance

Because reduced exercise capacity is an important prognostic factor of HF,1,13 an objective assessment of exercise
capacity is a critical issue in the management of HF. Peak
VO2 measured by means of CPX is an established marker
of exercise capacity, and a predictor of peak VO2 obtained
without peak exercise might be preferred, especially inpatients with advanced HF, to reduce the physical burden
even though the safety of CPX in HF has been confirmed

in many clinical studies.21 Based on the strong relationshipbetween IVPD at peak exercise and peak VO2, we presumed that IVPD at submaximal exercise could predict
exercise capacity. As expected, we could demonstrate thatsubmaximal IVPD allowed a noninvasive evaluation of
reduced exercise capacity (Supplemental Table 3). Importantly, the submaximal IVPD improved the predictive ability of the parameters consisting of clinical information andsubmaximal cardiac output (Fig. 5), suggesting that theadditional measurement of IVPD during submaximal exercise-stress echocardiography could offer more accurate estimation of exercise capacity in HF patients without
peak exercise. From the additive predictive value of IVPD
on cardiac output despite the sequence of LV filling generated by IVPD and following ejection, IVPD might reflect
intrinsic LV diastolic mechanics that can not be fully
expressed by cardiac output. Further study is needed to elucidate the physiologic background of IVPD during exercise.

Study LimitationsFirst, as a single-center study, the present results sufferfrom the limitation of a small sample size, and further studies are needed to confirm our conclusions. Second, we
excluded 105 out of 160 patients according to the exclusion
criteria because of the diversity of HF in a clinical practice,which narrows the population to which we can apply ourconclusions. On the other hand, this strict selection could
exclude potential confounding factors that would affect therelationship between IVPD and exercise capacity in HF
patients. Third, we did not consider peripheral determinantsof exercise capacity, such as deconditioning, skeletal muscle atrophy, and oxygen metabolism. However, the relationship between IVPD during exercise and peak VO2 isconsistent regardless of the limiting factors of the exercise.
Therefore, we think that the usefulness of IVPD for the prediction of exercise capacity could be solid regardless of thecausal relationships between IVPD and peripheral factors.
Fourth, we evaluated IVPD only along a single scan linefrom the mitral annulus to LV apex. Therefore, we could
not evaluate IVPD outside of that scan line. Fifth, exercise
stress was performed separately in CPX and stress echocardiography to adjust the workload with the use of the CPX
data in stress echocardiography among the patients. Therefore, the difference in posture and the time between the tests
would have weakened the relationship between peak VO2and IVPD during exercise.

Conclusion
Early-diastolic IVPD as a parameter of LV suction during exercise was closely associated with exercise capacityin chronic HF patients regardless of LV EF. In addition,
IVPD at submaximal exercise could predict exercise capacity without peak exercise.

Downloaded for Anonymous User (n/a) at Hokkaido Ono Memorial Hospital from ClinicalKey.jp by Elsevier on May 26,
2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.

Intra-LV pressure differences during exercise in HF  Tsujinaga et al
Disclosures
None.
Supplementary Materials
Supplementary material associated with this article canbe found in the online version at doi:10.1016/j.card
fail.2019.02.005.
References
1. Szlachcic J, Massie BM, Kramer BL, Topic N, Tubau J. Correlates and prognostic implication of exercise capacity in chronic
congestive heart failure. Am J Cardiol 1985;55:1037–42.
2. Likoff MJ, Chandler SL, Kay HR. Clinical determinants ofmortality in chronic congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy. Am J Cardiol
1987;59:634–8.
3. Lang CC, Agostoni P, Mancini DM. Prognostic significanceand measurement of exercise-derived hemodynamic variables
in patients with heart failure. J Card Fail 2007;13:672–9.
4. Cheng CP, Igarashi Y, Little WC. Mechanism of augmented
rate of left ventricular filling during exercise. Circ Res
1992;70:9–19.
5. Greenberg NL, Vandervoort PM, Firstenberg MS, Garcia MJ,
Thomas JD. Estimation of diastolic intraventricular pressure
gradients by Doppler M-mode echocardiography. Am J Physiol Heart Circ Physiol 2001;280:H2507–15.
6. Rovner A, Greenberg NL, Thomas JD, Garcia MJ. Relationship of diastolic intraventricular pressure gradients andaerobic capacity in patients with diastolic heart failure. Am
J Physiol Heart Circ Physiol 2005;289:H2081–8.
7. Writing Committee M, Yancy CW, Jessup M, Bozkurt B, Butler J, Casey Jr DE, et al. 2013 ACCF/AHA guideline for the
management of heart failure: a report of the American College
of Cardiology Foundation/American Heart Association Task
Force on Practice Guidelines. Circulation 2013;128:e240–327.
8. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin
3rd JP, Guyton RA, et al. 2014 AHA/ACC guideline for the
management of patients with valvular heart disease: a reportof the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol
2014;63:e57–185.
9. Yokota T, Kinugawa S, Yamato M, Hirabayashi K, Suga T,
Takada S, et al. Systemic oxidative stress is associated with277

lower aerobic capacity and impaired skeletal muscle energy
metabolism in patients with metabolic syndrome. Diabetes
Care 2013;36:1341–6.
10. Beaver WL, Wasserman K, Whipp BJ. A new method for
detecting anaerobic threshold by gas exchange. J Appl Physiol
1986;60:2020–7.
11. Chen C-H, Fetics B, Nevo E, Rochitte CE, Chiou K-R, Ding
P-A, et al. Noninvasive single-beat determination of left ventricular end-systolic elastance in humans. J Am Coll Cardiol
2001;38:2028–34.
12. Antonini-Canterin F, Poli S, Vriz O, Pavan D, Bello VD, Nicolosi GL. The ventricular-arterial coupling: from basic pathophysiology to clinical application in the echocardiographylaboratory. J Cardiovasc Echogr 2013;23:91–5.
13. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds Jr LH,
Wilson JR. Value of peak exercise oxygen consumption for
optimal timing of cardiac transplantation in ambulatory
patients with heart failure. Circulation 1991;83:778–86.
14. Stewart KC, Kumar R, Charonko JJ, Ohara T, Vlachos PP,
Little WC. Evaluation of LV diastolic function from color
M-mode echocardiography. JACC Cardiovasc Imaging
2011;4:37–46.
15. Burgess MI, Jenkins C, Sharman JE, Marwick TH. Diastolic
stress echocardiography: hemodynamic validation and clinicalsignificance of estimation of ventricular filling pressure with
exercise. J Am Coll Cardiol 2006;47:1891–900.
16. Podolec P, Rubis P, Tomkiewicz-Pajak L, Kopec G, Tracz W.
Usefulness of the evaluation of left ventricular diastolic function changes during stress echocardiography in predicting
exercise capacity in patients with ischemic heart failure. J Am
Soc Echocardiogr 2008;21:834–40.
17. Borlaug BA, Reddy YN. Determinants and correlates of exercise capacity in heart failure. JACC Heart Fail 2015;3:815–7.
18. Bell SP, Nyland L, Tischler MD, McNabb M, Granzier H,
LeWinter MM. Alterations in the determinants of diastolic
suction during pacing tachycardia. Circ Res 2000;87:235–40.
19. Firstenberg MS, Greenberg NL, Garcia MJ, Thomas JD. Relationship between ventricular contractility and early-diastolic
intraventricular pressure gradients: a diastolic link to systolic
function. J Am Soc Echocardiogr 2008;21:501–6.
20. Wang J, Khoury DS, Yue Y, Torre-Amione G, Nagueh SF.
Preserved left ventricular twist and circumferential deformation, but depressed longitudinal and radial deformation inpatients with diastolic heart failure. Eur Heart J 2008;29:
1283–9.
21. Skalski J, Allison TG, Miller TD. The safety of cardiopulmonary exercise testing in a population with high-risk cardiovascular diseases. Circulation 2012;126:2465–72.

Downloaded for Anonymous User (n/a) at Hokkaido Ono Memorial Hospital from ClinicalKey.jp by Elsevier on May 26,
2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.