Download Left Ventricular Ejection Fraction (EF) of 55% as

ORIGINAL ARTICLE
Circulation Journal
Official Journal of the Japanese Circulation Society
http://www. j-circ.or.jp
Heart Failure
Left Ventricular Ejection Fraction (EF) of 55% as Cutoff for
Late Transition From Heart Failure (HF) With Preserved
EF to HF With Mildly Reduced EF
Tomoya Ueda, MD; Rika Kawakami, MD; Taku Nishida, MD; Kenji Onoue, MD;
Tsunenari Soeda, MD; Satoshi Okayama, MD; Yukiji Takeda, MD; Makoto Watanabe, MD;
Hiroyuki Kawata, MD; Shiro Uemura, MD; Yoshihiko Saito, MD
Background: Heart failure (HF) with preserved (HFpEF) left ventricular ejection fraction (LVEF) is a syndrome with
complex pathophysiology. Little is known about changes in LVEF that occur over time in HFpEF patients. A fundamental clinical question about HFpEF is whether HFpEF is an early manifestation of HF with reduced LVEF (HFrEF).
If so, which patients with HFpEF are likely to show a decline in LVEF to less than 50%? The aim of the present study
was to examine longitudinal changes in LVEF in patients with HFpEF.
Methods and Results: Among 279 consecutive HFpEF patients admitted as emergencies, we examined 100 who
underwent echocardiography at least 1 year after discharge. EF >50% was used as the definition of HFpEF. During
a mean duration from hospitalization to follow-up echocardiography of 31.5 months, 11% of patients had LVEF ≤50%
(mildly reduced LVEF), known as mildly reduced (HFmrEF). The utility of LVEF during hospitalization to predict
HFmrEF was assessed with receiver-operating characteristic curve analysis. A cutoff value of 55% had sensitivity
of 90.9% and specificity of 97.7%. Logistic regression analysis indicated that LVEF ≤55% and ischemic etiology were
strong predictors of progression from HFpEF to HFmrEF (odds ratio [OR] 435, 95% confidence interval [CI] 52.65–
10,614, P<0.0001 and OR 10.9, 95% CI 2.60–74.80, P=0.0007, respectively).
Conclusions: The present study suggests that HFpEF patients with LVEF ≤55% may progress to HFmrEF in the
future. (Circ J 2015; 79: 2209 – 2215)
Key Words: Cutoff value; Echocardiography; Heart failure; Left ventricular ejection fraction
H
eart failure (HF) is an important public health issue
worldwide. Until now, most large clinical studies
have targeted HF with reduced (HFrEF) left ventricular ejection fraction (LVEF).1–4 However, HF with preserved LVEF (HFpEF) has recently gained attention because
many large clinical studies have demonstrated that half of HF
patients have HFpEF5–7 and they have a similar poor prognosis
as those with HFrEF,8–11 even though various lines of evidence
suggest that the pathophysiology of HFpEF is different from
that of HFrEF.
Editorial p 2108
HFpEF is a complex syndrome, of which the molecular
mechanisms and clinical characteristics remain unclear. Recently,
some studies12,13 have reported changes in LVEF that occur
over time in patients with HFpEF; a substantial number of
patients with HFpEF showed a decline to LVEF <50%. However, it is unclear which patients with HFpEF are more likely
to show such a decline. In this context, we performed a longitudinal assessment of LVEF based on echocardiography in
patients with acute decompensated HF (ADHF) in the Nara
Registry and Analyses for Heart Failure 2 (NARA-HF 2
Study) cohort study.
Methods
Study Population and Data Collection
The NARA-HF 2 Study recruited 611 consecutive patients
admitted as emergencies with documented ADHF (either acute
new-onset or acute-on-chronic HF) between January 2007 and
December 2012.14–16 The diagnosis of HF was based on the
Framingham criteria.17 The study population included both
HFrEF and HFpEF patients, but patients with acute myocar-
Received April 15, 2015; revised manuscript received June 20, 2015; accepted June 24, 2015; released online July 29, 2015 Time for
primary review: 5 days
First Department of Internal Medicine (T.U., R.K., T.N., K.O., T.S., S.O., Y.T., M.W., H.K., S.U., Y.S.), Department of Regulatory Medicine for Blood Pressure (Y.S.), Nara Medical University, Kashihara, Japan
Mailing address: Rika Kawakami, MD, First Department of Internal Medicine, Nara Medical University, 840 Shijo, Kashihara 634-8522,
Japan. E-mail: [email protected]
ISSN-1346-9843 doi: 10.1253/circj.CJ-15-0425
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]
Circulation Journal Vol.79, October 2015
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UEDA T et al.
Table 1. Baseline Characteristics of Patients Admitted With Acute Decompensated HF in the NARA-HF 2
Study
Total
(n=100)
50%<LVEF≤55%
(n=13)
LVEF >55%
(n=87)
Age, years
70.3±12.1
69.2±12.8
70.5±12.0
0.8056
Female, %
48.0
38.5
49.4
0.4605
24.2±4.0
25.5±4.3
24.0±3.9
0.2699
Ischemic
35.0
84.6
27.6
<0.0001　Valvular
15.0
7.7
16.1
0.4289
Hypertensive
10.0
0.0
11.5
0.1976
6.0
0.0
6.9
0.3288
P value
Demographic
Body mass index, kg/m2
Etiology of HF, %
Hypertrophic cardiomyopathy
Medical history, %
Hypertension
85.0
84.6
85.1
0.9668
Diabetes mellitus
53.0
61.5
51.7
0.5084
Dyslipidemia
40.0
38.5
40.2
0.8528
Old myocardial infarction
19.0
53.9
13.8
0.0006
Atrial fibrillation
33.0
23.1
34.5
0.4146
23.0
53.9
18.4
0.0046
3.0
0.0
3.5
0.4966
78.0
76.9
78.2
0.9200
121.5±17.0
117.1±11.2
122.2±17.7
0.3563
68.9±9.4
71.2±5.9
68.6±9.8
0.2435
Procedures, %
PCI
CABG
NYHA class on admission, %
III or IV
Vital signs at discharge
SBP, mmHg
Heart rate, beats/min
Laboratory data at discharge
Hemoglobin, g/dl
eGFR, ml/min/1.73 m2*
Sodium, mEq/L
Plasma BNP, pg/ml*
11.0±1.9
10.9±1.4
11.1±2.0
0.8922
32.5 (12.4–58.3)
25.6 (11.0–46.2)
35.4 (12.4–58.4)
0.3822
138.9±3.4　139.1±4.9　139.8±3.5　0.5005
191 (131–348)
347 (206–536)
184 (122–324)
0.0524
Medication at discharge, %
ACE inhibitor or ARB
80.0
69.2
81.6
0.2980
β-blocker
39.0
46.2
37.9
0.5707
MR blocker
20.0
15.4
20.7
0.6466
Diuretic
78.0
76.9
78.2
0.9203
*Data are shown as percentage, mean ± standard deviation, or median (interquartile range). ACE, angiotensinconverting enzyme; ARB, angiotensin-receptor blocker; BNP, B-type natriuretic peptide; CABG, coronary artery
bypass grafting; eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction;
MR, mineralocorticoid receptor; NARA-HF 2 Study, the Nara Registry and Analyses for Heart Failure 2; NYHA, New
York Heart Association; PCI, percutaneous coronary intervention; SBP, systolic blood pressure.
dial infarction (AMI), acute myocarditis, and acute HF with
acute pulmonary embolism were excluded.
The NARA-HF Study 2 included 279 patients with LVEF
>50%. We analyzed data from 100 patients who underwent
follow-up with echocardiography at least 1 year after discharge.
The remaining 179 patients were not enrolled in the present
investigation: 15 patients died in the hospital during the emergency admission, 55 patients died within 1 year of discharge,
7 patients were lost to follow-up, and 102 patients were not
able to undergo follow-up echocardiography in at the study
hospital. None of the 100 patients had severe valvular disease
(aortic or mitral stenosis or regurgitation) or developed newonset AMI during the follow-up period. For each patient,
baseline data included age, sex, body mass index (BMI), HF
etiology, medical history, as well as vital signs, laboratory data,
medications, and echocardiography results during hospitalization and at follow-up.
The study was approved by the Ethics Committee of Nara
Medical University, and written informed consent was given
by all patients according to the Declaration of Helsinki Ethical
Principles for Medical Research Involving Human Subjects.
Definitions
Using echocardiography, we measured LVEF at admission
and at follow-up at least 1 year after discharge. We adopted
the generally accepted criteria of LVEF >50%6,12,18 as the
definition for HFpEF in this study. Receiver-operating characteristic (ROC) curve analysis was performed on LVEF data
obtained during hospitalization to define a cutoff for predicting LVEF ≤50% at follow-up.
Echocardiography
All echocardiography was performed at Nara Medical University Hospital. For each patient, echocardiograms obtained
Circulation Journal Vol.79, October 2015
Longitudinal Changes From HFpEF to HFrEF
2211
during hospitalization and at follow-up (at least 1 year after
discharge) included measurements of LV end-diastolic dimension (LVEDD), LV end-systolic dimension (LVESD), LV
end-diastolic volume (LVEDV), LV end-systolic volume
(LVESV), left atrial dimension (LAD), interventricular septal
(IVS) and LV posterior wall (LVPW) thickness by 2D echocardiography or M-mode. LVEF assessment was based on 2D
echocardiography using the quantitative 2D biplane volumetric Simpson method from 4- and 2-chamber views. LV hypertrophy (LVH) was defined as IVS and LVPW thicknesses
>12 mm. If there echocardiography was performed multiple
times during the hospitalization, we used the data from the
examination performed closest to discharge, because data
immediately after admission might be incorrect because of
tachycardia or inadequate positioning. All measurements were
calculated separately by 1 echocardiologist and 1 expert sonographer. The variation in measurements between the 2 investigators was 3.1% in the present study.
Statistical Analysis
Continuous variables are expressed as mean ± standard deviation or median (interquartile range [IQR]), and between-group
differences were compared using Student’s t-test. Categorical
variables were summarized as percentages and analyzed using
the chi-square test. To evaluate the progression from HFpEF
to HFrEF, results are reported as odds ratio (OR), 95% confidence interval (CI), and P values using logistic regression.
JMP version 10 for Windows (SAS Institute Inc, Cary, NC,
USA) was used for all statistical analyses. P<0.05 was considered statistically significant.
Figure 1. Receiver-operating characteristic curve analysis
for progress to heart failure with mildly reduced ejection fraction (HFmrEF). At the optimal cutoff of left ventricular EF 55%,
sensitivity was 90.9% and specificity was 97.7%. The area
under the curve (AUC) was 0.9893.
with LVEF>55% during hospitalization had a follow-up LVEF
<50%.
Results
Baseline Characteristics of the Study Patients
The mean duration between echocardiography during hospitalization for ADHF and follow-up echocardiography was
31.5 months. During this interval, LVEF fell to <50% in
11.0% (n=11) of patients. The mean age at hospital admission
was 70.3±12.1 years, and 48.0% of the patients were women.
Regarding the etiology of HF, 35.0 % of patients had ischemic
causes, 15.0% had valvular causes, 10.0% had hypertensive
heart disease, and 6.0% had hypertrophic cardiomyopathy.
The New York Heart Association (NYHA) function class on
admission was III or IV in 78.0% of patients. The median
(IQR) plasma B-type natriuretic peptide concentration at discharge was 191 (131–348) pg/ml (Table 1).
Changes in LVEF
The mean LVEF was 67.0±9.2% during hospitalization and
67.4±11.1% at follow-up. During the follow-up period, LVEF
decreased in 50.0% of patients (n=50), increased in 45.0%
(n=45), and did not change in 5.0% (n=5). The median annual
change in LVEF was –0.1%, with 25% and 75% percentiles
of –1.9% and +2.6%, respectively. Among patients with a
decline in LVEF from hospitalization to follow-up, LVEF
decreased to below 50% in 11 patients. Based on ROC curve
analysis for LVEF ≤50% at follow-up, the area under the ROC
curve was 0.9893. The LVEF cutoff value was 55%, with
sensitivity of 90.9% and specificity of 97.7% (Figure 1).
As shown by the distribution of LVEF during hospitalization and follow-up (Figure 2), 10 of 11 patients with LVEF
<50% at follow-up had LVEF between 50% and ≤55% during
hospitalization. Consequently, the proportion of patients with
50%<LVEF≤55% decreased dramatically, from 13.0% during
hospitalization to 4.0% at follow-up. Only 1 of 87 patients
Comparison of Clinical Characteristics of Patients With
50%<LVEF≤55% and LVEF >55%
To identify other clinical predictors of LVEF <50% during
follow-up, we compared the baseline clinical characteristics
of patients with 50%<LVEF≤55% with those with LVEF
>55% (Table 1). Age, BMI, and the proportion of females
were similar in both groups. With regards to HF etiology, the
proportion of patients with ischemic causes was significantly
higher in patients with 50%<LVEF≤55% compared with
patients with LVEF>55%. The prevalence of old MI was
significantly higher in patients with 50%<LVEF≤55% than in
patients with LVEF>55%. There were no significant differences in the prevalence of comorbidities other than old MI
between the 2 groups. NYHA functional class was similar.
Systolic blood pressure and heart rate at discharge were similar in both groups. There were also no significant differences
in laboratory findings or medications at discharge.
Table 2 shows the echocardiographic parameters. The
mean follow-up duration in both groups was similar. There
was a significant difference in the annual change in LVEF
between patients with 50%<LVEF≤55% and LVEF >55%.
LVEDD and LVESD were significantly higher in patients
with 50%<LVEF≤55% than in patients with LVEF >55%
at both measurement points. Regarding LV volume, both
LVEDV and LVESV were significantly larger in patients with
50%<LVEF≤55% than in patients with LVEF >55% during
hospitalization as well as at follow-up. In patients with LVEF
>55%, LVEDV and LVESV were unchanged during hospitalization to follow-up, but LVEDV increased by 10.1% and
LVESV by 28.6% in patients with 50%<LVEF≤55%. LAD
and the prevalence of LVH were similar between the 2 groups
(data not shown).
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UEDA T et al.
Figure 2. Distribution of left ventricular ejection fraction (LVEF) (A) during
hospitalization for acute decompensated heart failure and (B) at followup. Red represents patients with LVEF
<50% at follow-up and the identical
subjects in (A) and (B).
Table 2. Comparison of Echocardiographic Parameters Between HF Patients With 50%<LVEF≤55% or LVEF >55%
Echocardiographic parameter
Total
(n=100)
50%<LVEF≤55%
(n=13)
LVEF >55%
(n=87)
P value
Time to follow-up echocardiography, months
31.5±17.0
37.3±16.6
30.6±17.0
0.1426
LVEF during hosp, %
67.0±9.2
51.9±1.9
69.2±7.5
<0.0001
LVEF at follow-up, %
67.4±11.1
46.0±4.1
70.6±7.7
<0.0001
−0.1 (−1.9 to +2.6)
−4.3 (−6.0 to −1.5)
+0.5 (−1.4 to +2.7)
<0.0001
49.6±7.7
55.4±6.1
48.8±7.5
0.0031
LVEF change per year, %*
LVEDD during hosp, mm
LVEDD at follow-up, mm
49.4±6.5
57.3±6.3
48.3±5.7
<0.0001
0.0 (−1.4 to +1.6)
+0.3 (−0.4 to +2.9)
0.0 (−1.5 to +1.6)
0.1987
LVESD during hosp, mm
33.1±7.2
40.4±5.6
32.0±6.7
<0.0001
LVESD at follow-up, mm
32.4±6.6
42.8±5.6
30.9±5.2
<0.0001
0.0 (−1.6 to +1.2)
0.0 (−1.1 to +2.2)
0.0 (−1.7 to +1.0)
0.2500
LVEDV during hosp, ml
71.9±31.4
100.8±30.7
67.5±29.2
0.0006
LVEDV at follow-up, ml
70.3±34.4
111.4±48.9
64.2±27.2
<0.0001
−0.5 (−5.6 to +8.0)
+3.0 (−7.0 to +10.4)
−0.5 (−5.4 to +8.0)
0.5610
LVESV during hosp, ml
24.9±15.3
49.3±16.1
21.2±11.3
<0.0001
LVESV at follow-up, ml
24.9±20.3
62.1±28.4
19.3±11.0
<0.0001
+0.1 (−2.7 to +2.9)
+3.4 (−2.0 to +8.6)
0.0 (−2.8 to +2.5)
0.0614
LVEDD change per year, ml
LVESD change per year, ml
LVEDV change per year, ml
LVESV change per year, ml
*Data are shown as percentage, mean ± standard deviation or median (interquartile range). LVEF/LVEDV/LVESV change=change between
hosp and follow-up. EDD, end-diastolic dimension; EDV, end-diastolic volume; EF, ejection fraction; ESD, end-systolic dimension; ESV, endsystolic volume; hosp, hospitalization; LV, left ventricular.
Next, we examined which factors were associated with the
transition of LVEF from >55% to ≤55%. As shown in Table 3,
50%<LVEF≤55% during hospitalization and ischemic etiology were strong predictive factors (OR 435, 95% CI 52.65–
10,614, P<0.0001 and OR 10.9, 95% CI 2.60–74.80, P=0.0007,
respectively). Other than these 2 factors, LVEDD, LVESD,
LVEDV and LVESV were significantly associated with pro-
gression to HF with mildly reduced EF (HFmrEF). Regarding
the change in LV volume from baseline to follow-up, the
annual change in LVESV was a predictor (OR 1.12, 95% CI
1.02–1.26, P=0.0232) but the change in LVEDV was not. In
contrast, none of age, sex and medications was associated with
progression to HFmrEF (Table 3).
Circulation Journal Vol.79, October 2015
Longitudinal Changes From HFpEF to HFrEF
2213
Table 3. Predictors of Progression From HF With Preserved EF to HF With Reduced EF
OR
95% CI
P value
50%<LVEF≤55%
435.0
52.65–10,614
<0.0001　Age, years
0.98
0.93–1.03
0.3696
Female sex
0.89
0.24–3.17
0.8577
HF of ischemic etiology
10.9
2.60–74.80
0.0007
LVEDD during hosp, mm
1.14
1.04–1.28
0.0066
LVESD during hosp, mm
1.15
1.05–1.28
0.0018
LVEDV during hosp, ml
1.04
1.01–1.06
0.0007
LVEDV change per year, ml
1.02
0.98–1.06
0.4224
LVESV during hosp, ml
1.16
1.09–1.28
<0.0001　LVESV change per year, ml
1.12
1.02–1.26
0.0232
ACE inhibitor or ARB at discharge
0.63
0.16–3.10
0.5368
β-blocker at discharge
1.35
0.36–4.81
0.6442
MR blocker at discharge
0.88
0.13–3.79
0.8717
Diuretic at discharge
1.35
0.36–4.81
0.6442
LVEDV/LVESV change=change between hosp and follow-up. CI, confidence interval; OR, odds ratio. Other abbreviations as in Tables 1,2.
Discussion
HF is classified simply by LVEF into 2 (HFrEF and HFpEF)
or 3 (HFrEF, HF-borderline EF, and HFpEF) categories.3,12,19,20
As for HFpEF, both the European Society of Cardiology
(ESC) and the American College of Cardiology Foundation
(ACCF)/American Heart Association (AHA) guidelines state
that HFpEF is defined as LVEF >50%,18,21 but large clinical
trials on HFpEF have enrolled patients with LVEF >40% or
45%. Therefore, the definition of HFpEF is not still strictly
fixed, so we used LVEF >50% as the cutoff for HFpEF in the
present study. The present study results indicated that approximately 10% of patients with HFpEF at baseline had a decline
in LVEF to less than 50% but above 40% after a mean followup of 31.5 months. Thus, approximately 10% of patients change
from HFpEF to HFmrEF, or HF-borderline EF. It is unclear
from the present study whether these patients will further
progress to HFrEF over a longer period of time.
The present study found LVEF of 55% as a cutoff for the
transition from HFpEF to HFmrEF with high sensitivity and
specificity based on ROC curve analysis. Although HFpEF is
commonly thought to represent diastolic dysfunction with
normal systolic function, through a more sensitive method,
LV strain, subtle impairment of LV systolic contractility was
recently already demonstrated in some patients with HFpEF.22,23
However, given that normal LVEF as measured is 64.9±4.9%24
by echocardiography and 61% in women and 55% in men by
MRI,25 systolic function with LVEF<55% on echocardiography is moderately reduced rather than normal. The ESC guidelines propose that patients with LVEF in the range of 35–50%
are in a “grey area” and most likely have primary mild systolic
dysfunction.18 However, this “grey area” might be wider.
The clinical syndrome of acute HF diagnosed by Framingham
criteria occurs in patients with any level of LVEF. Earlier
studies have demonstrated that there is a bimodal distribution
of LVEF among patients with acute HF, with a lower proportion of patients with 40%<LVEF≤55%.12,26 Because the
present study enrolled only patients with LVEF >50%, LVEF
at baseline did not show a bimodal distribution, but in the
overall NARA-HF Study 2 there was a similar a bimodal
distribution (Figure S1).
The clinical characteristics of patients with 50%≤LVEF<55%
Figure 3. Change in left ventricular ejection fraction (LVEF)
from hospitalization to follow-up. The median change (interquartile range) was −1.40% (−3.03 to +2.23) in patients with
ischemia and +0.90% (−1.31 to +2.65) in patients with heart
failure of non-ischemic etiology (P=0.0174).
were different from those with LVEF >55%. Consistent
with prior studies,6,12,13 there was a much higher proportion
of patients with ischemic etiology among patients with
50%<LVEF≤55%. Ischemic etiology was a strong predictor
for transition from HFpEF to HFmrEF in the present study, as
reported previously.12,13 In fact, the rate of LVEF decline was
much higher among patients with ischemic etiology than in
those with non-ischemic etiology (Figure 3). In addition, in
patients with 50%<LVEF≤55%, LVEDV and LVESV during
hospitalization were larger than in patients with LVEF >55%,
and the percent increment of LVESV between the 2 echocar-
Circulation Journal Vol.79, October 2015
2214
UEDA T et al.
diography examinations was much greater than that of LVEDV.
Thus, decline of LVEF in patients with 50%<LVEF≤55% was
probably related to the increase in LVESV. These findings all
suggest that there are qualitative differences in the pathophysiology and time course of LV dysfunction between
patients with LVEF >55% and those with LVEF ≤55%.
Patients whose LVEF had fallen to below 50% at follow-up
were not confirmed as having a clinical episode of ischemic
disease during follow-up. Moreover, the proportion of readmission for worsening of HF during follow-up was similar in
patients with LVEF <50% at follow-up and those with LVEF
≥50% at follow-up (45% and 36%, respectively, P=0.5427).
Also, in the univariate logistic regression analysis, readmission for worsening of HF was not a predictor of the decline in
LVEF. Therefore, it is unlikely that additional ischemic events
or worsening of HF during follow-up was the cause of the
decline in LVEF in this study.
Recently, some large randomized clinical trials in HFpEF
patients with various therapeutic agents such as angiotensinreceptor blockers (CHARM-preserved, I-preserved),7,27 and
mineralocorticoid receptor blocker (TOPCAT),28 failed to show
beneficial effects of these drugs in HFpEF, although these
agents have been proven to effectively reduce cardiovascular
events in HFrEF. Of note, the inclusion criteria was LVEF
>40% for the CHARM-preserved study and LVEF >45% for
the I-preserved and TOPCAT studies; because a substantial
number of patients with “grey area” LVEF were included,
further analyses or subanalyses should be conducted with
consideration of this.
Study Limitations
The major limitations are that the sample size was small, the
study was retrospective in nature, and based at a single center.
Approximately half of potentially eligible subjects were
excluded for lack of echocardiography at follow-up, which
might be a potential source of bias. Furthermore, we did not
collect information on medications after discharge that can
potentially affect LVEF. These factors underscore the need for
future prospective studies of greater power, ideally controlled
for medication regimens, that could further elucidate the natural history of HFpEF.
Conclusions
The present study showed that HFpEF patients with LVEF
≤55% were more likely to progress to HFmrEF in the future
than those with LVEF >55%. This finding provides insights to
the pathophysiology of HFpEF and suggests that patients with
ischemic disease, who show 50%≤LVEF<55%, may actually
have HFrEF and not HFpEF. A large-scale prospective study
is necessary to confirm this hypothesis.
Founding Source
This work was supported in part by grants-in-aid from the Ministry of
Health, Labor, and Welfare of Japan, and Takeda Science Foundation.
Conflicts of Interest
Y.S. has conflicts of interest to disclose as follows.
Honoraria: MSD Co, Ltd, Mitsubishi Tanabe Pharma Corporation,
Takeda Pharmaceutical Co, Daiichi Sankyo Company Ltd, Otsuka
Pharmaceutical Co, Ltd, Pfizer Japan Inc.
Research funding: Japan Heart Foundation, The Naito Foundation
Subsidies or Donations: MSD Co, Ltd, Mitsubishi Tanabe Pharma
Corporation, Daiichi Sankyo Company Ltd, Takeda Pharmaceutical Co,
Ltd, Novartis Pharma K.K., Shionogi & Co, Ltd, Astellas Pharma Inc,
AstraZeneca K.K., Ltd, Otsuka Pharmaceutical Co, Ltd, St. Jude Medical
Japan Co, Ltd, Kyowa Hakko Kirin Co Ltd.
Endowed departments by commercial entities: MSD Co, Ltd.
Other authors have no financial conflicts of interest to disclose.
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Supplementary Files
Supplementary File 1
Figure S1. Distribution of left ventricular ejection fraction (LVEF).
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-15-0425
Circulation Journal Vol.79, October 2015