Download Heart Failure and Midrange Ejection Fraction

Original Article
Heart Failure and Midrange Ejection Fraction
Implications of Recovered Ejection Fraction for Exercise
Tolerance and Outcomes
Wilson Nadruz, Jr, MD, PhD; Erin West, MSc; Mário Santos, MD; Hicham Skali, MD, MSc;
John D. Groarke, MBBCh, MPH; Daniel E. Forman, MD; Amil M. Shah, MD, MPH
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Background—Evidence-based therapies for heart failure (HF) differ significantly according to left ventricular ejection
fraction (LVEF). However, few data are available on the phenotype and prognosis of patients with HF with midrange
LVEF of 40% to 55%, and the impact of recovered systolic function on the clinical features, functional capacity, and
outcomes of this population is not known.
Methods and Results—We studied 944 patients with HF who underwent clinically indicated cardiopulmonary exercise
testing. The study population was categorized according to LVEF as follows: HF with reduced LVEF (HFrEF; LVEF<40%;
n=620); HF with midrange ejection fraction and no recovered ejection fraction (LVEF was consistent between 40% and
55%; n=107); HF with recovered midrange ejection fraction (LVEF, 40%–55% but previous LVEF<40%; n=170); and
HF with preserved LVEF (HFpEF; LVEF>55%; n=47). HF with midrange ejection fraction and no recovered ejection
fraction and HF with recovered midrange ejection fraction had similar clinical characteristics, which were intermediate
between those of HFrEF and HFpEF, and comparable values of predicted peak oxygen consumption and minuteventilation/carbon dioxide production slope, which were better than HFrEF and similar to HFpEF. After a median of 4.4
(2.9–5.7) years, there were 253 composite events (death, left ventricular assistant device implantation, or transplantation).
In multivariable Cox-regression analysis, HF with recovered midrange ejection fraction had lower risk of composite
events than HFrEF (hazard ratio, 0.25; 95% confidence interval, 0.13–0.47) and HF with midrange ejection fraction
and no recovered ejection fraction (hazard ratio, 0.31; 95% confidence interval, 0.15–0.67), and similar prognosis when
compared with HFpEF. In contrast, HF with midrange ejection fraction and no recovered ejection fraction tended to show
intermediate risk of outcomes in comparison with HFpEF and HFrEF, albeit not reaching statistical significance in fully
adjusted analyses.
Conclusions—Patients with HF with midrange LVEF demonstrate a distinct clinical profile from HFpEF and HFrEF
patients, with objective measures of functional capacity similar to HFpEF. Within the midrange LVEF HF population,
recovered systolic function is a marker of more favorable prognosis. (Circ Heart Fail. 2016;9:e002826. DOI: 10.1161/
CIRCHEARTFAILURE.115.002826.)
Key Words: heart failure
■
oxygen consumption
■
ventricular ejection fraction
H
eart failure (HF) is routinely classified according to left
ventricular ejection fraction (LVEF) as HF with reduced
LVEF (HFrEF) or HF with preserved LVEF (HFpEF), a distinction driven by the important differences in the evidence
base for therapies for HF. Studies of HFrEF have been
restricted to patients with LVEF<40%, whereas diagnostic
guidelines for HFpEF typically include patients with LVEF
>50% to 55%.1–4 As a consequence, few data are available
on the phenotype, natural history, and prognosis of patients
with HF with midrange LVEF of 40% to 55%. Results from
previous reports have suggested that patients with HF with
■
ventricular function, left
See Clinical Perspective
midrange LVEF have clinical features5–7 and mortality rates5
that are intermediate between those of HFrEF and HFpEF.
However, substantial heterogeneity may exist within patients
with HF with midrange LVEF. In particular, this group may
include both patients with de novo HF and patients with HF
with previously reduced LVEF who have recovered their
systolic function.3,8,9 This fact is clinically relevant because
subjects with recovered LVEF have been reported to have
more favorable prognosis among patients with HF.9 However,
Received September 30, 2015; accepted February 18, 2016.
From the Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA (W.N., E.W., H.S., J.D.G., A.M.S.); Department of Internal
Medicine, University of Campinas, Campinas, Brazil (W.N.); Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine of University of
Porto, Porto, Portugal (M.S.); and Department of Medicine, Section of Geriatric Cardiology, University of Pittsburgh Medical Center, PA (D.E.F.).
The Data Supplement is available at http://circheartfailure.ahajournals.org/lookup/suppl/doi:10.1161/CIRCHEARTFAILURE.115.002826/-/DC1.
Correspondence to Amil M. Shah, MD, MPH, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02445.
E-mail [email protected]
© 2016 American Heart Association, Inc.
Circ Heart Fail is available at http://circheartfailure.ahajournals.org
DOI: 10.1161/CIRCHEARTFAILURE.115.002826
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2 Nadruz et al Mid-EF Heart Failure
whether midrange LVEF patients with recovered LVEF have
distinct phenotypic and prognostic features compared with
those without a previous frankly reduced LVEF is not known.
The aim of this study was to compare the clinical features,
cardiopulmonary response to exercise, and long-term clinical outcomes in patients with HF with midrange LVEF either
without previous frankly reduced LVEF (HF with midrange
ejection fraction and no recovered ejection fraction [HFmEF])
or with recovery from previous frankly reduced LVEF (HF
with recovered midrange ejection fraction [HFm-recEF]) in
relation to each other and to HFrEF and HFpEF patients.
Methods
Study Population
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This study included 974 patients with a diagnosis of HF who were
referred for cardiopulmonary exercise testing (CPET) at the Brigham
and Women’s Hospital between July 2007 and June 2013. We excluded participants with missing baseline LVEF data (n=4), who
performed arm ergometer exercise testing (n=1), developed tachyarrhythmias during the CPET (n=2), or had ventricular-paced rhythm
with decreased or similar peak heart rate when compared with resting
heart rate at CPET (n=9), resulting in 958 participants for the analysis. The Partners Human Research Committee approved this study
and waived the requirement for informed consent.
Classification of Patients With HF
LVEF was assessed clinically at the Brigham and Women’s Hospital by
quantitative echocardiography. Baseline LVEF values were obtained
from echocardiography exams that were most contemporaneous to
the CPET dates (median time difference [25th, 75th percentiles]=0
[0, 9] days). The study population was categorized based on LVEF
as follows (Figure 1): (1) HFrEF if the LVEF was <40% (n=620);
(2) HF with midrange LVEF if the LVEF was between 40% and 55%
(n=277); and (3) HFpEF if the LVEF was >55% (n=61). Among patients with midrange LVEF, those who had previously documented
LVEF≥40% (n=100) or a history of recent onset (<3 months) of HF
(n=7) were considered to not have recovered systolic function and
were labeled as HFmEF (n=107), whereas those with a documented
history of LVEF<40% (n=170) were considered to have HFm-recEF.
Sixty-one patients had LVEF>55%, but 17 of them had previously
documented LVEF<40%, and were excluded from the analysis, resulting in 47 participants with HFpEF. Among HFpEF patients, 43
subjects had previous echocardiography documentation of no reduced LVEF and 4 subjects had recent onset (<3 months) of HF. The
median interval time between previously performed echocardiogram
and the echocardiogram that was most contemporaneous to the CPET
dates was similar among the studied groups, with median [25th, 75th
percentiles] as follows: 2.1 [0.5, 7.3] years for HFm-recEF; 3.4 [0.8,
7.7] years for HFmEF; 4.3 [0.4, 7.8] years for HFpEF; P value for
between-group difference=0.47, based on Kruskal–Wallis test. The
distribution of LVEF according to the studied groups is shown in
Figure I in the Data Supplement.
Clinical Variables Definition
Information on patients’ demographics, current medications, pacemaker, implantable cardioverter defibrillator or cardiac resynchronization therapy, body mass index, blood pressure, heart rate,
and gas-exchange variables were collected at the time of CPET.
Additional clinical characteristics and laboratory values most contemporaneous to CPET dates were obtained from chart review. In
HFmEF and HFm-recEF subjects, LVEF data from the latest echocardiogram examination performed after the CPET test were also collected, except if there was an interval event (myocardial infarction,
LV assistant device [LVAD] implantation, and heart transplantation)
between baseline and follow-up echocardiogram.
Symptomatic HF was defined if patients were New York Heart
Association Classification functional class II or greater as determined
by the referring physician, or if the patient had a previous history of
hospitalization for decompensated HF. Antiarrhythmic medications
included amiodarone or digoxin. Glomerular filtration rate was estimated using the Chronic Kidney Disease Epidemiology Collaboration
formula.10 Angiotensin-converting enzyme inhibitors and angiotensin
receptor blockers were coded into a single variable (ACEI/ARB).
Cardiac resynchronization therapy and implantable cardioverter defibrillator were coded as a single variable.
Exercise Protocol
All exercise tests were performed in the Brigham and Women’s
Hospital cardiopulmonary exercise laboratory using an upright cycle
ergometer (Lode, Groningen, The Netherlands; 98% of tests) or a
treadmill (General Electric Healthcare, Waukesha, WI; 2% of tests)
with the subject breathing room-air. Symptom-limited CPET was performed on all subjects. All pharmacological therapy was continued
Figure 1. Study design. *Used arm ergometer
(n=1), developed tachyarrhythmias (n=2), and had
ventricular-paced rhythm with decreased or similar
peak heart rate when compared with resting (n=9)
during CPET. CPET indicates cardiopulmonary
exercise testing; HF, heart failure; HFmEF, HF with
midrange and without recovered LVEF; HFm-recEF,
HF with midrange and recovered LVEF; HFpEF,
heart failure with preserved LVEF; HFrEF, HF with
reduced LVEF; LVAD, left ventricular assistance
device; and LVEF, left ventricular ejection fraction.
3 Nadruz et al Mid-EF Heart Failure
before and through exercise testing. The equipment was calibrated
daily in standard fashion using reference gases. Minute ventilation
(VE), oxygen consumption (VO2), and carbon dioxide production
(VCO2) were acquired breath-by-breath and averaged over a 10-second interval, using a ventilatory expired gas analysis system (MGC
Diagnostics, St. Paul, MN). Peak VO2 was defined as the highest
10-second averaged VO2 during the last stage of the symptom-limited
exercise test. Percentage of predicted peak VO2 was determined based
on the Wasserman formula.11,12 VE/VCO2 slope was taken from rest to
the gas exchange at peak exercise. Rhythm was monitored with a continuous 12-lead ECG. Blood pressure was measured using a standard
cuff sphygmomanometer. Resting and peak heart rate were obtained
from the ECG. Age-predicted maximal heart rate was estimated by
Astrand formula13: 220–age (years). Chronotropic index was calculated as follows: (peak heart rate–resting heart rate)/(age-predicted
maximal heart rate–resting heart rate).14
Outcomes
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All-cause death was determined using the National Death Index with
complete follow-up through December 31, 2014. The composite end
point was defined as the composite outcome of LVAD implantation,
heart transplantation, or all-cause mortality.
Statistical Analysis
Continuous variables are expressed as mean±SD for normally distributed data or median [25th, 75th percentiles] for non-normally distributed data. Categorical variables are expressed as number of subjects
and proportion. Comparisons of baseline features among the studied
groups were performed using 1-way ANOVA followed by Bonferroni
test for normally distributed variables and Kruskal–Wallis test followed by Wilcoxon test for non-normally distributed variables. The
χ2 test was used to compare categorical variables. Bonferroni correction was also applied for pairwise comparison of non-normal and
categorical variables. CPET data are also presented as age-adjusted
mean±SEM with P values estimated from linear regression among
the studied groups.
Univariate and multivariable Cox proportional hazards regression models were used to assess the unadjusted and adjusted association between LVEF categories and all-cause mortality or the
composite outcome of LVAD implantation, heart transplantation,
and all-cause mortality. We tested the proportional hazards assumption for all analyses and no evidence of violation of the proportional-hazards assumption by LVEF categories was observed.
Covariates for multivariable Cox-regression models were selected
using a forward stepwise selection procedure (retention P<0.10)
including clinical and treatment variables that showed significant
differences among the studied groups at baseline as candidate covariates (Tables I and II in the Data Supplement). Two multivariable
Cox-regression models were constructed for each outcome: the first
model included age, gender, and clinical covariates and the second
model further included treatment covariates. When all-cause mortality was considered as the outcome, model 1 was adjusted for age,
sex, glomerular filtration rate, coronary artery disease, postchemotherapy, diabetes mellitus, race, and hemoglobin, whereas model
2 was further adjusted for the use of pacemaker, diuretics, statins,
and ACEI/ARB. When the composite end point was considered as
the outcome, model 1 was adjusted for age, sex, glomerular filtration rate, coronary artery disease, and postchemotherapy, whereas
model 2 was further adjusted for use of diuretics, aldosterone antagonists, anticoagulation, and ACEI/ARB.
In patients with HFmEF and HFm-recEF, baseline and follow-up
LVEF values were compared using Wilcoxon matched-pair signedrank test. Based on the difference between follow-up and baseline
LVEF (∆LVEF), patients were divided into 3 groups: (1) declining
LVEF (∆LVEF <−7%); (2) stable LVEF (∆LVEF between −7% and
+7%), and (3) increasing LVEF (∆LVEF >+7%). The threshold of
7% was chosen because this value corresponds to the inter-reader
variability reported for quantitative assessment of LVEF by echocardiography.15 Furthermore, we calculated the percentage of HFmEF
and HFm-recEF patients who developed frankly reduced LVEF
(LVEF<25%), normal LVEF (LVEF>55%), or remained as midrange
LVEF (LVEF of 40%–55%) at follow-up.
A 2-sided P<0.05 was considered significant. Statistical analysis was performed using Stata software version 12.1 (Stata Corp LP,
College Station, TX).
Results
Population Characteristics
HFmEF had similar clinical features when compared with
HFm-recEF, except for higher LVEF (50% [45%, 55%] versus
45% [40%, 50%], respectively; P=0.003; Table 1). HFmEF
and HFm-recEF had average age and prevalence of hypertension that were more similar to those of HFrEF, whereas the
prevalence of men and ischemic cardiomyopathy tended to be
more similar to those of HFpEF. Compared with both HFpEF
and HFrEF, HFmEF and HFm-recEF were more likely to be
previously exposed to chemotherapy and tended to have lower
prevalence of symptomatic HF, whereas HFm-recEF had
lower prevalence of diabetes mellitus and higher estimated
glomerular filtration rate.
Regarding medical therapies, HFm-recEF and HFrEF
were more likely to use β-blockers and ACEI/ARB and were
less likely to use calcium channel blockers compared with both
HFmEF and HFpEF. The prevalence of aldosterone antagonist
use and of pacemakers or cardiac resynchronization therapy
and implantable cardioverter defibrillator in HFm-recEF
and HFmEF tended to be intermediate between HFpEF and
HFrEF. Both HFm-recEF and HFmEF had a lower prevalence
of diuretic use than HFpEF and HFrEF.
Cardiopulmonary Exercise Performance
CPET variables according to LVEF categories are shown in
Table 2. Mean peak respiratory exchange ratio, a measure
of exercise effort, was >1.1 in all patient groups. HFmEF
and HFm-recEF had comparable ventilatory responses to
exercise, with a higher peak VO2 (both absolute and percent
of predicted) and lower VE/VCO2 slope than HFrEF. HFpEF
tended to show lower absolute levels of peak VO2 than HFmEF
and HFm-recEF, although the percent of predicted peak VO2
values—which accounts for between group differences in
age—were similar between HFpEF and the midrange LVEF
groups. HFmEF and HFm-recEF had similar VE/VCO2 slope
when compared with HFpEF. Resting heart rate of HFmEF
and HFm-recEF was similar to HFpEF but lower than HFrEF
patients. Furthermore, HFm-recEF and HFmEF showed intermediate values of resting systolic blood pressure in comparison with those of HFpEF and HFrEF, but had peak systolic
blood pressure values that were similar to HFpEF and higher
than HFrEF. Finally, age-adjusted CPET findings among
LVEF categories were concordant to the results obtained in
unadjusted analyses (Table III in the Data Supplement).
Outcomes
During a median follow-up of 4.4 [2.9–5.7] years, there
were 184 (19%) deaths, 62 (7%) LVAD implantations, 56
(6%) transplants, and 253 (27%) composite events. Kaplan–
Meier analysis showed that HFrEF had the highest event rates
among the studied groups, HFm-recEF had the lowest rate,
4 Nadruz et al Mid-EF Heart Failure
Table 1. Baseline Clinical and Treatment Features of Study Participants
HFrEF,
n=620 (66%)
HFm-recEF,
n=170 (18%)
Age, y
55.4±13.2
52.2±13.0*
Male, n (%)
452 (73)
104 (61)*
59 (55)*
23 (49)*
White, n (%)
507 (82)
145 (85)
98 (92)*
40 (85)
Body mass index, kg/m2
28.3±5.7
28.7±6.1
29.4±6.6
31.5±8.9*
Ischemic cardiomyopathy, n (%)
188 (30)
18 (11)*
12 (12)*
3 (6)*
20 (12)
17 (16)*
2 (4)
Variables
HFmEF,
n=107 (11%)
HFpEF,
n=47 (5%)
54.4±15.2
63.3±15.5*,†,‡
Clinical
Postchemotherapy, n (%)
38 (6)
NYHA, n (%)
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I
147 (24)
81 (47)*
40 (37)
16 (34)
II
214 (34)
61 (36)
35 (33)
14 (30)
III
210 (34)
27 (16)*
30 (28)
16 (34)†
IV
49 (8)
1 (1)*
2 (2)
1 (2)
Previous HF hospitalization, n (%)
486 (78)
96 (57)*
64 (60)*
41 (87)†,‡
Symptomatic HF, n (%)
560 (90)
128 (75)*
77 (72)*
41 (87)
Hypertension, n (%)
365 (59)
87 (51)
62 (58)
36 (77)†
Diabetes mellitus, n (%)
182 (29)
27 (16)*
22 (21)
15 (32)
Coronary artery disease, n (%)
255 (41)
36 (21)*
28 (26)*
14 (30)
Atrial fibrillation, n (%)
215 (35)
46 (27)
30 (28)
18 (38)
COPD, n (%)
61 (10)
16 (10)
9 (8)
4 (9)
Estimated GFR, mL/min
72±26
82±24*
13.6±1.7
Hemoglobin, g/dL
LVEF, %
25 [19, 30]
75±26
67±26†
13.5±1.7
13.0±2.0*
12.8±2.0†,*
45 [40, 50]*
50 [45, 55]*†
60 [60, 65]*,†,‡
44 (26)*
15 (14)*†
1 (2)*†
47 (28)*
Treatment
CRT/ICD, n (%)
335 (54)
Pacemaker, n (%)
340 (55)
23 (22)*
6 (13)*
β-blockers, n (%)
555 (90)
145 (85)
73 (68)*†
29 (62)*,†
ACEI/ARB, n (%)
510 (82)
146 (86)
58 (54)*†
30 (64)*,†
Aldosterone antagonists, n (%)
220 (36)
38 (22)*
15 (14)*
2 (4)*,†
Diuretics, n (%)
468 (76)
80 (47)*
48 (45)*
34 (72)†,‡
13 (8)*
27 (25)*,†
11 (23)*,†
Calcium channel blockers, n (%)
24 (4)
Anticoagulation, n (%)
244 (39)
43 (25)*
23 (22)*
15 (32)
Antiplatelets, n (%)
350 (57)
68 (40)*
44 (40)*
22 (47)
Antiarrhythmics, n (%)
254 (41)
38 (22)*
Statins, n (%)
322 (52)
72 (43)
6 (6)*,†
41 (38)
4 (9)*
21 (45)
All P values are Bonferroni-adjusted. Data are presented as mean±SD for normally distributed variables and median [25th, 75th percentile] for nonnormally distributed continuous variables. ACEI/ARB indicates angiotensin converting enzyme inhibitor or angiotensin receptor blocker; COPD, chronic
obstructive pulmonary disease; CRT/ICD, cardiac resynchronization therapy and/or implantable cardioverter defibrillator; GFR, glomerular filtration rate;
HF, heart failure; HFmEF, HF with midrange and without recovered LVEF; HFm-recEF, HF with midrange and recovered LVEF; HFpEF, heart failure with
preserved LVEF; HFrEF, HF with reduced LVEF; LVEF, left ventricular ejection fraction; and NYHA, New York Heart Association Classification.
*P<0.05 compared with HFrEF.
†P<0.05 compared with HFm-recEF.
‡P<0.05 compared with HFmEF.
and HFmEF had event rates intermediate between HFrEF
and HFpEF (unadjusted log-rank P<0.001 for the overall difference; Figure 2). Results of univariate and multivariable
Cox-regression analysis are shown in Table 3. In fully adjusted
analysis, HFm-recEF was associated with lower risk of death
(hazard ratio, 0.42; 95% confidence interval, 0.21–0.82;
5 Nadruz et al Mid-EF Heart Failure
Table 2. Baseline Cardiopulmonary Exercise Testing Features of Study Participants
Variables
HFrEF,
n=620 (66%)
HFm-recEF,
n=170 (18%)
HFmEF,
n=107 (11%)
14.4±5.2
18.0±6.3*
17.2±8.8*
HFpEF,
n=47 (5%)
Ventilatory
Peak VO2, mL/min/Kg
14.6±7.9†
% Predicted peak VO2
56.7±18.3
70.6±18.4*
70.0±23.6*
69.0±20.8*
VE/VCO2 slope
34.5±9.2
28.8±5.8*
30.6±6.4*
32.1±7.9
74.2±14.5
69.1±12.7*
69.5±13.7*
69.9±12.1
121.3±28.1
131.8±24.8*
124.4±31.1
114.5±27.3†
0.52±0.28
0.64±0.24*
0.57±0.28
0.51±0.26†
Resting SBP, mm Hg
114.1±18.9
120.7±19.8*
120.1±19.2*
129.2±20.9*,†,‡
Peak SBP, mm Hg
134.9±26.9
151.8±28.0*
151.6±30.4*
156.1±33.5*
Hemodynamic
Resting HR, beats per minute
Peak HR, beats per minute
Chronotropic index
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Resting DBP, mm Hg
73.5±11.1
75.3±11.9
73.8±11.3
74.6±9.8
Peak DBP, mm Hg
74.4±12.5
77.4±11.8*
76.0±12.7
75.6±12.0
Peak RER
1.19±0.13
1.20±0.12
1.20±0.13
1.15±0.12†
All P values are Bonferroni-adjusted. Data are presented as mean±SD. DBP indicates diastolic blood pressure; HF, heart failure; HFmEF, HF with midrange and
without recovered LVEF; HFm-recEF, HF with midrange and recovered LVEF; HFpEF, heart failure with preserved LVEF; HFrEF, HF with reduced LVEF; LVEF, left
ventricular ejection fraction; HR, heart rate; RER, respiratory exchange ratio; SBP, systolic blood pressure; VE/VCO2, minute ventilation–carbon dioxide production
relationship; and VO2, oxygen consumption.
*P<0.05 compared with HFrEF.
†P<0.05 compared with HFm-recEF.
‡P<0.05 compared with HFmEF.
P=0.011) and composite end point (hazard ratio, 0.25; 95%
confidence interval, 0.13–0.47; P<0.001) than HFrEF, but
had similar risk of death and composite end point when compared with HFpEF. HFmEF tended to show intermediate risk
of outcomes in comparison with HFpEF and HFrEF, albeit
not reaching statistical significance in fully adjusted analyses.
Compared with HFmEF, HFm-recEF showed a lower risk
of composite end point (hazard ratio, 0.31; 95% confidence
interval, 0.15–0.67; P=0.003) and a trend toward lower risk of
death (hazard ratio, 0.48; 95% confidence interval, 0.22–1.05;
P=0.067) in analyses adjusted for all potential confounders.
Temporal Change in LVEF Among HFmEF and
HFm-recEF
To further evaluate the natural history of HFmEF and HFmrecEF, we investigated the temporal change in LVEF in these
groups. Follow-up LVEF data were available in 73% (n=78) of
HFmEF patients and in 72% (n=123) of HFm-recEF patients.
The median time between baseline and follow-up echocardiograms was 2.7 [1.8, 3.7] years. Median values of LVEF
showed modest increase in HFmEF (from 50% [44%, 55%] to
52% [45%, 55%]; P=0.03), but did not change in HFm-recEF
(from 48% [40%, 55%] to 50% [44%, 55%]; P=0.42) at follow-up. Conversely, there was no difference in the proportion
of patients who decreased (16% in HFm-recEF and 12% in
HFmEF; P=0.77) or increased (20% in HFm-recEF and 27%
in HFmEF; P=0.24) LVEF at follow-up in both groups. Older
age, higher prevalence of hypertension and lower glomerular filtration rate were associated with reductions in LVEF in
patients with HFm-recEF, whereas no studied variable was
associated with changes in LVEF in HFmEF (Tables IV and
V in the Data Supplement). Among HFm-recEF patients, 71%
remained with LVEF between 40% and 55%, whereas 14%
and 15% developed frankly reduced LVEF (values <25%)
and normal LVEF (values >55%), respectively, at follow-up.
Among HFmEF patients, 66% remained with LVEF between
40% and 55%, whereas 13% and 21% of HFmEF developed frankly reduced and normal LVEF values at follow-up,
respectively.
Discussion
This study of patients with HF with midrange LVEF had 3
major novel findings. First, among patients with HF and midrange LVEF, HFm-recEF had similar clinical characteristics
and measures of exercise tolerance, but better prognosis compared with HFmEF. Second, although their clinical characteristics were distinct from HFpEF and HFrEF, HFmEF and
HFm-recEF had ventilatory responses to exercise that were
better than HFrEF and similar to HFpEF. Third, HFm-recEF
had event rates that were lower than HFrEF and similar to
HFpEF, whereas HFmEF had an intermediate risk of outcomes in comparison with HFpEF and HFrEF. These findings
suggest that, among patients with HF with midrange LVEF,
recovered systolic function is a marker of more favorable
prognosis despite similar clinical characteristics and cardiopulmonary response to exercise.
In the present study, HFm-recEF had lower risk of death,
LVAD implantation, and heart transplantation in comparison
with HFmEF and HFrEF. These findings provide further support to the idea that patients with HF with recovered LVEF
have better prognosis when compared with patients with
lower LVEF but also to patients with similar LVEF levels but
6 Nadruz et al Mid-EF Heart Failure
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Figure 2. Kaplan–Meier curves for death and composite end
point. The composite end point was defined as the composite
outcome of left ventricular assistant device implantation, heart
transplantation or all-cause mortality. HFpEF indicates heart
failure with preserved left ventricular ejection fraction (LVEF);
HFm-recEF, HF with midrange and recovered LVEF; HFmEF, HF
with midrange and without recovered LVEF; and HFrEF, HF with
reduced LVEF.
without previously reduced systolic function.9 In contrast,
HFm-recEF showed similar prognosis as HFpEF, indicating
that HF with midrange LVEF and recovered systolic function
still carries a significant risk of adverse outcomes. These latter findings are clinically relevant because they provide additional basis for maintaining subjects with recovered LVEF on
background medical and device therapy, as previously recommended.8,9,16 The differences in prognosis between HFmEF
and HFm-recEF may also help explain some reported discrepancies on prognosis in the midrange LVEF HF population. In
the Cardiovascular Health Study, survival of midrange LVEF
was intermediate between HFpEF and HFrEF,5 whereas in
the Candesartan in Heart failure Assessment of Reduction in
Mortality and morbidity program, those with midrange LVEF
had mortality rates more similar to HFpEF.6 In the light of our
findings, it can be speculated that midrange LVEF HF populations with higher prevalence of recovered LVEF would have
prognosis more similar to HFpEF, whereas those with lower
prevalence of recovered systolic function would tend to have
an intermediate risk of outcomes in comparison with HFpEF
and HFrEF. However, further studies are needed to confirm
this hypothesis.
Consistent with previous studies in HF, our midrange
LVEF groups had intermediate clinical characteristics (Tables
VI and VII in the Data Supplement)1,5–7,17–19 and tended to have
less clinical manifestations of HF when compared with HFrEF
and HFpEF.4,6 HFmEF and HFm-recEF were also more likely
to have a history of prior exposure to chemotherapy, pointing
toward chemotherapy cardiotoxicity as a potential risk factor
for the development of midrange LVEF. Furthermore, our finding that most of HFmEF and HFm-recEF patients remained
with LVEF between 40% and 55% after a median of 2.8 years
of follow-up indicates that HF with midrange LVEF is not
necessarily a transition step of the progression from normal
LVEF to HFrEF or vice versa. It was noteworthy that a high
proportion (61%) of our midrange LVEF sample had recovered LVEF. Likewise, high rates of improved systolic function
were also reported among HF populations with LVEF>40% or
LVEF>50%,9,20 which implies that the prevalence of recovered
LVEF among HF with midrange LVEF is substantial.
The reasons for the difference in prognosis between
HFmEF and HFm-recEF are not clear. Exercise performance
measures with validated prognostic value, such as peak VO2,
percent of predicted peak VO2 and VE/VCO2 slope,21,22 had
comparable values in both midrange LVEF groups, making
differences in cardiopulmonary capacity unlikely as a cause.
Additionally, the fact that HFm-recEF had lower baseline
LVEF levels than HFmEF suggests that the more favorable prognosis in HFm-recEF is not explained by superior
LV systolic performance of this group. HFm-recEF patients
were more likely to use β-blockers, ACEI/ARB, and cardiac
resynchronization therapy and implantable cardioverter defibrillator than HFmEF patients. Although we were unable to
estimate changes in medical therapy over time, these findings
suggest that differences in treatment regimens may partially
account for the differences in outcomes. However, further
studies are necessary to understand the precise mechanisms
by which HFmEF and HFm-recEF had different outcomes.
Several limitations of this study should be acknowledged.
This is an observational study and therefore unmeasured confounding factors may influence the observed associations. As
noted above, HFm-recEF patients were more likely to use
β-blockers and ACEI/ARB than HFmEF patients, which may
be related to differences in tolerability of these medications and
may have influenced differences in outcomes. Furthermore,
we were unable to evaluate the influence of changes in medical therapy over time on measured outcomes. Skeletal muscle
function and CPET performance can be influenced by duration
of HF and the presence of cachexia, but these data were not
available in our study. Similarly, biomarkers such as N-terminal
of the prohormone brain natriuretic peptide are prognostically
relevant in HF but were not uniformly assessed or available in
our study population. Our sample included patients referred for
CPET from a tertiary medical center and therefore might not
be representative of the overall HF population, potentially limiting the generalizability of our findings. Because physicians
who ordered CPET did not follow any standardized protocol,
it is possible that our findings were influenced by indication
7 Nadruz et al Mid-EF Heart Failure
Table 3. Outcomes of Study Participants
Number
at Risk
No. of
Events
Rate
(95% CI) /100
Person-Year
HR (95% CI)
(Unadjusted)
P Value
HR (95% CI)
(Adjusted*)
P Value
HR (95% CI)
(Adjusted†)
P Value
Death
HFrEF
620
147
5.6 (4.7–6.5)
Ref
HFm-recEF
170
11
1.3 (0.7–2.4)
0.24 (0.13–0.45)
<0.001‡
0.32 (0.17–0.61)
0.001§
0.42 (0.21–0.82)
0.011
HFmEF
107
21
4.6 (3.0–7.1)
0.83 (0.52–1.30)
0.41
0.74 (0.45–1.21)
0.23
0.87 (0.51–1.46)
0.59
HFpEF
47
5
2.6 (1.1–6.3)
0.47 (0.19–1.15)
0.10
0.31 (0.11–0.86)
0.025
0.38 (0.14–1.05)
0.061
HFrEF
620
213
8.8 (7.7–10.1)
Ref
HFm-recEF
170
11
1.3 (0.7–2.4)
0.16 (0.08–0.28)
HFmEF
107
23
5.2 (3.5–7.8)
0.59 (0.39–0.91)
0.016
0.60 (0.38–0.95)
0.029
0.79 (0.49–1.28)
0.34
HFpEF
47
6
3.2 (1.4–7.2)
0.36 (0.16–0.82)
0.014
0.30 (0.12–0.74)
0.009
0.35 (0.14–0.86)
0.023
Ref
Ref
Composite end point
Ref
<0.001║
0.19 (0.10–0.36)
Ref
<0.001‡
0.25 (0.13–0.47)
<0.001‡
Downloaded from http://circheartfailure.ahajournals.org/ by guest on June 12, 2017
The composite end point was defined as the composite outcome of left ventricular assistant device implantation, heart transplantation, or all-cause mortality. CI
indicates confidence interval; HF, heart failure; HFmEF, HF with midrange and without recovered LVEF; HFm-recEF, HF with midrange and recovered LVEF; HFpEF, heart
failure with preserved LVEF; HFrEF, HF with reduced LVEF; LVEF, left ventricular ejection fraction; HR, hazard ratio.
*Adjusted for age, sex, glomerular filtration rate, coronary artery disease, postchemotherapy, diabetes mellitus, race, and hemoglobin with death as outcome and for
age, sex, glomerular filtration rate, coronary artery disease, and postchemotherapy with composite end point as outcome.
†Further adjusted for use of pacemaker, diuretics, statins and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with death as outcome and
for use of diuretics, aldosterone antagonists, anticoagulation, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with composite end point
as outcome.
‡P<0.01, §P<0.05, ║P<0.001, compared with HFmEF.
bias. However, we tried to overcome this potential limitation
by adjusting our Cox-regression models for important clinical characteristics. LVAD and heart transplantation were only
obtained by clinical charts of Brigham and Women’s Hospital,
which might have led to underestimation of these outcomes.
Nevertheless, the frequency that patients with HF get these
treatments at a referral institution different from where they
are being longitudinally followed is usually low.
Conclusion
Patients with HF with midrange LVEF demonstrate a distinct
clinical profile from HFpEF and HFrEF patients, with objective measures of functional capacity similar to HFpEF. Within
the midrange LVEF HF population, recovered systolic function is a marker of more favorable prognosis, suggesting that
identification of recovered LVEF status is important in prognostication and should be systematically assessed.
Sources of Funding
This study was supported by National Heart. Lung, and Blood
Institute grant 1K08HL116792-01A1 (Dr Shah), American Heart
Association grant 14CRP20380422 (Dr Shah) and the Brazilian
National Council for Scientific and Technological Development grant
249481/2013–8 (Dr Nadruz).
Disclosures
Dr Shah reports receiving research support from Novartis, Gilead,
and Actelion. The other author report no conflicts.
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CLINICAL PERSPECTIVE
Few data are available on the phenotype, natural history, and prognosis of patients with heart failure with midrange ejection
fraction (left ventricular ejection fraction [LVEF]) of 40% to 55%. Our study provides novel evidence that, among patients
with heart failure with midrange LVEF, recovered systolic function is associated with more favorable prognosis than midrange without prior reduced LVEF, despite similar clinical characteristics and cardiopulmonary response to exercise. Furthermore, our data suggest that patients with heart failure with midrange LVEF and recovered systolic function have similar
prognosis as compared with patients with preserved LVEF, indicating that heart failure with midrange LVEF and recovered
systolic function still carries a significant risk of adverse outcomes.
Heart Failure and Midrange Ejection Fraction: Implications of Recovered Ejection
Fraction for Exercise Tolerance and Outcomes
Wilson Nadruz, Jr, Erin West, Mário Santos, Hicham Skali, John D. Groarke, Daniel E. Forman
and Amil M. Shah
Downloaded from http://circheartfailure.ahajournals.org/ by guest on June 12, 2017
Circ Heart Fail. 2016;9:e002826
doi: 10.1161/CIRCHEARTFAILURE.115.002826
Circulation: Heart Failure is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX
75231
Copyright © 2016 American Heart Association, Inc. All rights reserved.
Print ISSN: 1941-3289. Online ISSN: 1941-3297
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circheartfailure.ahajournals.org/content/9/4/e002826
Data Supplement (unedited) at:
http://circheartfailure.ahajournals.org/content/suppl/2016/03/23/CIRCHEARTFAILURE.115.002826.DC1
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SUPPLEMENTAL MATERIAL
Heart failure and mid-range ejection fraction: Implications of recovered ejection fraction
for exercise tolerance and outcomes
Short title: Nadruz et al; Mid-EF Heart Failure
Wilson Nadruz Junior, MD, PhD1,2; Erin West, MSc1; Mário Santos, MD3; Hicham Skali, MD,
MSc1; John D. Groarke MBBCh, MPH1; Daniel E. Forman MD4; Amil M. Shah, MD, MPH1
1"
"
Supplemental Table 1. Forward stepwise Cox regression analysis for death including all baseline clinical
and treatment variables that showed significant differences among the studied groups in univariate
analysis.
Variable
Hazard ratio [95% confidence interval]
p
Glomerular filtration rate
0.99 [0.99-0.99]
<0.001
Coronary artery disease
2.05 [1.44-2.94]
<0.001
Diabetes mellitus
1.84 [1.32-2.57]
<0.001
Pacemaker
1.71 [1.23-2.37]
0.001
Post-chemotherapy
2.18 [1.33-3.57]
0.001
Diuretics use
2.06 [1.29-3.29]
0.003
ACEI/ARB use
0.65 [0.45-0.93]
0.017
Hemoglobin
0.89 [0.81-0.97]
0.012
White race
1.79 [1.09-2.92]
0.021
Statins use
0.66 [0.46-2.92]
0.021
Legend. Only variables that showed significant association are shown.
ACEI/ARB – angiotensin converting enzyme inhibitor or angiotensin receptor blocker.
2"
"
Supplemental Table 2. Forward stepwise Cox regression analysis for the composite endpoint including
all baseline clinical and treatment variables that showed significant differences among the studied groups.
Variable
Hazard ratio [95% confidence interval]
p
Glomerular filtration rate
0.99 [0.98-0.99]
<0.001
Diuretics use
2.32 [1.56-3.45]
<0.001
Aldosterone antagonists use
1.61 [1.23-2.09]
<0.001
ACEI/ARB use
0.65 [1.56-3.45]
0.004
Coronary artery disease
1.46 [1.12-1.90]
0.005
Anticoagulation
1.46 [1.12-1.89]
0.005
Post-chemotherapy
1.59 [1.03-2.46]
0.037
Legend. Only variables that showed significant association are shown. The composite endpoint was
defined as the composite outcome of left ventricular assistant device implantation, heart transplantation or
all-cause mortality.
ACEI/ARB – angiotensin converting enzyme inhibitors or angiotensin receptor blockers.
3"
"
Supplemental Table 3: Age-adjusted baseline cardiopulmonary exercise testing features of study
participants.
HFrEF
HFm-recEF
HFmEF
HFpEF
n=620 (66%)
n=170 (18%)
n=107 (11%)
n=47 (5%)
Peak VO2, mL/min/Kg
14.4 ± 0.2
17.5 ± 0.4*
17.1 ± 0.5*
15.9 ± 0.8
VE/VCO2 Slope
34.4 ± 0.3
29.3 ± 0.6*
30.7 ± 0.8*
30.5 ± 1.2*
Resting HR, bpm
74.2 ± 0.6
68.7 ± 1.1*
69.4 ± 1.3*
71.2 ± 2.0
Peak HR, bpm
121.5 ± 1.0
129.2 ± 1.9*
123.8 ± 2.4
121.7 ± 3.7
Chronotropic index
0.52 ± 0.01
0.63 ± 0.02*
0.57 ± 0.03
0.53 ± 0.4†
Resting SBP, mmHg
114.0 ± 0.8
121.6 ± 1.4*
120.3 ± 1.8*
126.9 ± 2.8*‡
Peak SBP, mmHg
134.9 ± 1.1
151.8 ± 2.1*
151.6 ± 2.7*
156.2 ± 4.2*
Resting DBP, mmHg
73.5 ±0.5
75.4 ± 0.9
73.8 ± 1.1
74.5 ± 1.7
Peak DBP, mmHg
74.4 ± 0.5
77.2 ± 0.9*
76.0 ± 1.2
76.1 ± 1.9
Peak RER
1.19 ± 0.01
1.20 ± 0.01
1.20 ± 0.01
1.15 ± 0.02†
Variables
Ventilatory
Hemodynamic
Legend. *p<0.05 compared to HFrEF; † p<0.05 compared to HFm-recEF; ‡ p<0.05 compared to
HFmEF. Data are presented as mean ± standard error of the mean.
HFrEF – HF with reduced LVEF; HFm-recEF – HF with mid-range and recovered LVEF; HFmEF – HF
with mid-range and without recovered LVEF; HFpEF – heart failure with preserved LVEF; LVEF- left
ventricular ejection fraction; DBP – diastolic blood pressure; HR – heart rate; RER - respiratory exchange
ratio; SBP – systolic blood pressure; VE/VCO2 - minute ventilation-carbon dioxide production
relationship; VO2 – oxygen consumption.
4"
"
Supplemental Table 4. Features of heart failure with mid-range and recovered left ventricular ejection
fraction (HFm-recEF) patients according to change in left ventricular ejection fraction
∆LVEF
∆LVEF
∆LVEF
< -7%
-7 to +7%
> +7%
n=20 (16%)
n=78 (64%)
n=25 (20%)
P for trend
Baseline
50 [45, 55]
48 [44, 50]
40 [40, 47]
<0.001
Follow-up
34 [25, 40]
46 [43, 52]
57 [54, 60]
<0.001
57.1 ± 15.1
51.5 ± 12.3
44.6 ± 11.6
0.001
Male gender, n(%)
14 (70)
47 (60)
12 (48)
0.13
White, n(%)
16 (80)
65 (83)
21 (84)
0.74
29.9 ± 5.5
28.66 ± 6.62
28.93 ± 6.97
0.67
Ischemic cardiomyopathy, n(%)
3 (15)
8 (10)
0 (0)
0.07
Post-Chemotherapy, n(%)
2 (10)
8 (10)
4 (16)
0.50
Symptomatic heart failure, n(%)
15 (75)
56 (72)
19 (76)
0.91
Hypertension, n(%)
16 (80)
39 (50)
10 (40)
0.009
Diabetes mellitus, n(%)
5 (25)
14 (18)
4 (16)
0.46
Coronary artery disease, n(%)
5 (25)
13 (17)
4 (16)
0.46
Atrial Fibrillation, n(%)
5 (25)
26 (33)
3 (12)
0.26
COPD, n(%)
3 (15)
8 (10)
0 (0)
0.07
Estimated GFR, mL/min
60.8 ± 29.4
85.9 ± 20.7
89.7 ± 26.0
<0.001
Hemoglobin, g/dL
13.0 ± 1.6
13.8 ± 1.5
13.5 ± 1.7
0.39
CRT/ICD, n(%)
3 (15)
21 (27)
5 (20)
0.77
Pacemaker, n(%)
3 (15)
23 (30)
5 (20)
0.80
Beta-blockers, n(%)
17 (85)
66 (85)
20 (80)
0.63
ACEI/ARB, n(%)
19 (95)
67 (86)
21 (84)
0.30
Aldosterone antagonists, n(%)
5 (25)
18 (23)
3 (12)
0.27
Diuretics, n(%)
13 (65)
37 (47)
12 (48)
0.30
Calcium channel blockers, n(%)
4 (20)
7 (9)
1 (4)
0.08
Anticoagulation, n(%)
5 (25)
21 (27)
3 (12)
0.27
Variables
LVEF, %
Baseline Clinical features
Age, years
Body mass index, kg/m2
Baseline treatment features
5"
"
Antiplatelets, n(%)
11 (55)
27 (35)
7 (28)
0.07
Antiarrhythmics, n(%)
3 (15)
22 (28)
3 (12)
0.69
Statins, n(%)
8 (40)
32 (41)
10 (40)
0.99
Peak VO2, mL/min/Kg
16.7 ± 5.0
18.7 ± 7.1
18.0 ± 4.8
0.56
% Predicted Peak VO2
70.2 ± 18.0
72.0 ± 20.3
70.0 ± 18.7
0.93
VE/VCO2 Slope
28.9 ± 5.5
29.2 ± 6.5
27.0 ± 4.4
0.24
Resting HR, bpm
68.3 ± 12.9
68.5 ± 13.4
69.1 ± 11.4
0.83
Peak HR, bpm
125.8 ± 28.2
132.2 ± 23.9
138.0 ± 24.5
0.10
Chronotropic index
0.61 ± 0.26
0.64 ± 0.23
0.66 ± 0.24
0.50
Resting SBP, mmHg
124.4 ± 17.2
121.0 ± 20.9
118.1 ± 18.5
0.29
Peak SBP, mmHg
154.8 ± 19.6
151.7 ± 29.7
152.5 ± 25.7
0.80
Resting DBP, mmHg
74.9 ± 9.5
75.4 ± 11.5
72.7 ± 13.0
0.48
Peak DBP, mmHg
76.4 ± 8.8
78.2 ± 11.8
78.5 ± 13.7
0.58
Peak RER
1.19 ± 0.12
1.21 ± 0.11
1.24 ± 0.16
0.14
Baseline CPET features
Legend. Data are presented as mean ± standard deviation for normally distributed continuous variables
and median [25th,75th percentile] for non-normally distributed continuous variables.
∆LVEF – change in follow-up LVEF compared to baseline LVEF; ACEI/ARB – angiotensin converting
enzyme inhibitor or angiotensin receptor blocker; COPD – chronic obstructive pulmonary disease;
CRT/ICD - cardiac resynchronization therapy and/or implantable cardioverter defibrillator; GFR –
glomerular filtration rate; LVEF - left ventricular ejection fraction; DBP – diastolic blood pressure; HR –
heart rate; RER - respiratory exchange ratio; SBP – systolic blood pressure; VE/VCO2 - minute
ventilation-carbon dioxide production relationship; VO2 – oxygen consumption.
"
"
6"
"
Supplemental Table 5. Features of heart failure with mid-range and without recovered left ventricular
ejection fraction (HFmEF) patients according to change in left ventricular ejection fraction
∆LVEF
∆LVEF
∆LVEF
< -7%
-7 to +7%
> +7%
n=9 (12%)
n=48 (61%)
n=21 (27%)
P for trend
Baseline
50 [45, 50]
50 [45, 55]
45 [40, 55]
0.09
Follow-up
33 [30, 35]
50 [45, 55]
55 [55, 65]
<0.001
49.4 ± 18.3
53.4 ± 14.8
51.5 ± 16.0
0.92
Male gender, n(%)
4 (44)
25 (52)
12 (57)
0.53
White, n(%)
7 (78)
46 (96)
19 (91)
0.52
28.9 ± 9.7
28.8 ± 6.3
30.5 ± 6.6
0.41
Ischemic cardiomyopathy, n(%)
1 (11)
6 (13)
2 (10)
0.82
Post-Chemotherapy, n(%)
0 (0)
11 (23)
4 (19)
0.42
Symptomatic heart failure, n(%)
7 (78)
31 (65)
16 (76)
0.82
Hypertension, n(%)
4 (44)
26 (54)
12 (57)
0.57
Diabetes mellitus, n(%)
3 (33)
11 (23)
2 (10)
0.11
Coronary artery disease, n(%)
2 (22)
12 (25)
6 (29)
0.69
Atrial Fibrillation, n(%)
3 (33)
11 (23)
5 (24)
0.69
COPD, n (%)
1 (11)
5 (10)
1 (5)
0.48
Estimated GFR, mL/min
79.9 ± 28.0
75.7 ± 23.5
85.9 ± 22.7
0.30
Hemoglobin, g/dL
12.3 ± 2.1
13.4 ± 1.8
13.4 ± 2.3
0.28
CRT/ICD, n(%)
3 (33)
6 (13)
3 (14)
0.34
Pacemaker, n(%)
3 (33)
6 (13)
5 (24)
0.94
Beta-blockers, n(%)
8 (89)
30 (63)
16 (76)
0.90
ACEI/ARB, n(%)
7 (78)
27 (56)
11 (52)
0.27
Aldosterone antagonists, n(%)
1 (11)
6 (13)
2 (10)
0.82
Diuretics, n(%)
4 (44)
16 (33)
11 (52)
0.40
Calcium channel blockers, n(%)
2 (22)
11 (23)
3 (14)
0.50
Anticoagulation, n(%)
3 (33)
9 (19)
3 (14)
0.28
Variables
LVEF, %
Baseline Clinical features
Age, years
Body mass index, kg/m2
Baseline treatment features
7"
"
4 (44.4)
20 (42)
6 (29)
0.32
Antiarrhythmics, n(%)
1 (11)
2 (4)
2 (10)
0.86
Statins, n(%)
2 (22)
16 (33)
7 (33)
0.65
Peak VO2, mL/min/Kg
20.4 ± 13.0
18.6 ± 8.7
16.0 ± 8.9
0.19
% Predicted Peak VO2
76.0 ± 25.7
75.5 ± 24.1
62.3 ± 19.8
0.06
VE/VCO2 Slope
29.4 ± 4.9
30.3 ± 6.4
29.7 ± 4.2
0.94
Resting HR, bpm
65.4 ± 16.4
70.9 ± 14.8
68.8 ± 14.7
0.81
Peak HR, bpm
125.8 ± 34.4
132.0 ± 31.5
121.5 ± 29.2
0.47
Chronotropic index
0.56 ± 0.25
0.65 ± 0.31
0.51 ± 0.22
0.35
Resting SBP, mmHg
121.1 ± 25.4
115.5 ± 17.6
127.0 ± 20.3
0.17
Peak SBP, mmHg
148.9 ± 31.0
152.3 ± 32.3
147.3 ± 29.6
0.75
Resting DBP, mmHg
72.5 ± 9.1
72.2 ± 12.2
76.8 ± 9. 5
0.19
Peak DBP, mmHg
71.7 ± 16.3
75.3 ± 13.0
76.7 ± 10.5
0.39
Peak RER
1.17 ± 0.10
1.21 ± 0.12
1.18 ± 0.13
0.14
Antiplatelets, n(%)
Baseline CPET features
Legend. Data are presented as mean ± standard deviation for normally distributed continuous variables
and median [25th,75th percentile] for non-normally distributed continuous variables.
∆LVEF – change in follow-up LVEF compared to baseline LVEF; ACEI/ARB – angiotensin converting
enzyme inhibitor or angiotensin receptor blocker; COPD – chronic obstructive pulmonary disease;
CRT/ICD - cardiac resynchronization therapy and/or implantable cardioverter defibrillator; GFR –
glomerular filtration rate; LVEF- left ventricular ejection fraction; DBP – diastolic blood pressure; HR –
heart rate; RER - respiratory exchange ratio; SBP – systolic blood pressure; VE/VCO2 - minute
ventilation-carbon dioxide production relationship; VO2 – oxygen consumption.
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Supplemental Table 6. Characteristics of heart failure patients from the Brigham and Women’s Hospital and from other studies that enrolled
chronic heart failure patients."
Cardiovascular Health Study1
CHARM2
HFrEF4 HFmidEF
Variables
HFrEF
HFmidEF
HFpEF
LVEF cut-off
<45%
45–54%
≥55%
≤40%
n
60
39
170
Mean age, years
74
73
Men, %
63
49
He et al3
Brigham and Women’s Hospital
HFpEF
HFrEF
43–52%
>52%
<40%
40–55%
>55%
<40%
40–55%
40–55%
>55%
4576
1295
1500
98
38
128
620
170
107
47
75
65
66
67
62
66
72
55
52
54
63
44
74
68
51
75
79
65
73
61
55
49
24
25
25
28
29
29
32
Mean BMI, kg/m2
Mean HR, bpm
HFmidEF HFpEF HFrEF
HFm-recEF HFmEF HFpEF
74
71
71
77
69
71
74
69
70
70
Mean SBP, mmHg
127
136
138
127
135
138
126
141
139
114
121
120
129
Mean DBP, mmHg
66
68
68
76
78
77
76
79
76
74
75
74
75
Hypertension, %
57
72
59
49
60
70
54
77
88
59
51
58
77
CAD/MI, %
78
69
58
65-75
72
62
51
65
63
41
21
26
30
Diabetes, %
23
36
27
29
27
28
41
48
33
29
16
21
32
10
8
26
35
27
28
38
13.4
14.5
13.5
13.6
13.5
13.0
12.8
50
45
37
64
65
42
49
Atrial fibrillation, %
Hemoglobin, g/dL
ACE inhibitors, %
42
28
25
56
21
17
9"
"
ARB, %
Beta-blockers, %
7
8
17
Aldosterone ant., %
55
57
54
20
11
12
4
23
11
19
21
14
15
39
58
55
90
85
68
62
36
22
14
4
Diuretics, %
78
74
59
88
64
63
67
56
37
76
47
45
72
CCB, %
30
46
31
13
26
37
26
39
57
4
8
25
23
Lipid lowering, %
2
3
5
41
43
40
52
43
38
45
Legend. HFrEF – heart failure (HF) with reduced left ventricular ejection fraction (LVEF); HFmidEF – HF with mid-range LVEF; HFpEF – HF
with preserved LVEF; HFm-recEF – HF with mid-range LVEF and recovered LVEF; HFmEF – HF with mid-range LVEF without recovered
LVEF. CHARM - Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity. BMI – body mass index; HR – heart rate;
SBP – systolic blood pressure; DBP – diastolic blood pressure; CAD – coronary artery disease; MI – myocardial infarction; ACE – angiotensinconverting enzyme; ARB – angiotensin receptor blockers; Aldosterone ant. – aldosterone antagonists; CCB – calcium channel blockers.
1
Gottdiener JS, et al. Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. The Cardiovascular
Health Study. Ann Intern Med 2002;137:631–9. 2 Solomon SD, et al. Influence of ejection fraction on cardiovascular outcomes in a broad
spectrum of heart failure patients. Circulation. 2005;112:3738-44. 3 He KL, et al. Comparison of ventricular structure and function in Chinese
patients with heart failure and ejection fractions >55% versus 40% to 55% versus <40%. Am J Cardiol 2009;103:845–51. 4 Young JB, et al.
Mortality and morbidity reduction with Candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the
CHARM low-left ventricular ejection fraction trials. Circulation. 2004;110:2618-26."
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Supplemental Table 7. Characteristics of heart failure patients from the Brigham and Women’s Hospital and from other studies that enrolled
acutely-decompensated heart failure patients.
OPTMIZE-HF1
ADHERE2
ASCEND-HF3
Brigham and Women’s Hospital
Variables
HFrEF
HFmidEF
HFpEF
LVEF cut-off
<40%
40–50%
>50%
≤40%
40–55%
≥55%
<40%
40–50%
>50%
<40%
40–55%
40–55%
>55%
n
20118
7321
10070
40796
17045
17022
4474
674
539
620
170
107
47
Mean age, years
70
74
76
70
74
74
64
73
76
55
52
54
63
Men, %
62
48
32
61
46
31
71
59
42
73
61
55
49
Mean BMI, kg/m2
39
44
41
28
30
31
28
29
29
32
Mean HR, bpm
89
86
84
Mean SBP, mmHg
135
147
150
136
150
Mean DBP, mmHg
77
77
75
78
79
Hypertension, %
66
74
77
CAD/MI, %
54
49
32
63
60
Diabetes, %
41
48
33
42
29
Atrial fibrillation, %
Hemoglobin, g/dL
eGFR, mL/min/1.73m2
12.5
11.9
11.8
HFrEF* HFmidEF HFpEF HFrEF HFmidEF HFpEF HFrEF HFm-recEF HFmEF HFpEF
83
78
74
74
69
70
70
152
120
130
132
114
121
120
129
77
75
72
70
74
75
74
75
68
82
89
59
51
58
77
47
63
69
60
41
21
26
30
48
44
42
50
51
29
16
21
32
33
32
32
50
55
35
27
28
38
12.8
12.3
11.6
13.6
13.5
13.0
12.8
69
54
51
72
82
75
67
11"
"
ACE inhibitors, %
45
38
34
66
57
51
ARB, %
11
12
14
13
15
16
Beta-blockers, %
56
54
50
67
62
55
Aldosterone ant., %
10
6
Diuretics, %
63
CCB, %
5
Lipid lowering, %
40
†
63
‡
61
‡
60
‡
64
65
42
49
19
21
14
15
59
65
67
90
85
68
62
4
33
21
13
36
22
14
4
59
57
95
97
96
76
47
45
72
†
11
41
37
9
†
36
31
39
4
8
25
23
36
31
52
43
38
45
Pacemaker, %
1
1
1
55
28
22
13
Defibrillator, %
11
4
2
54
26
14
2
Legend. HFrEF – heart failure (HF) with reduced left ventricular ejection fraction (LVEF); HFmidEF – HF with mid-range LVEF; HFpEF – HF
with preserved LVEF; HFm-recEF – HF with mid-range LVEF and recovered LVEF; HFmEF – HF with mid-range LVEF without recovered
LVEF. OPTIMIZE-HF - Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure; ADHERE - Acute
Decompensated Heart Failure Registry; ASCEND-HF – Acute Studies of Nesiritide in Decompensated Heart Failure; BMI – body mass index; HR
– heart rate; SBP – systolic blood pressure; DBP – diastolic blood pressure; CAD – coronary artery disease; MI – myocardial infarction; eGFR –
estimated glomerular filtration rate; ACE – angiotensin-converting enzyme; ARB – angiotensin receptor blockers; Aldosterone ant. – aldosterone
antagonists; CCB – calcium channel blockers. *values are weighted measures adapted from ref. 1. †amlodipine; ‡ACE inhibitor or ARB; 1Fonarow
GC, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the
OPTIMIZE-HF Registry. J Am Coll Cardiol. 2007;50:768-77. 2Sweitzer NK, et al. Comparison of clinical features and outcomes of patients
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hospitalized with heart failure and normal ejection fraction (> or =55%) versus those with mildly reduced (40% to 55%) and moderately to
severely reduced (<40%) fractions. Am J Cardiol. 2008;101:1151-6. 3Toma M, et al. The relationship between left ventricular ejection fraction and
mortality in patients with acute heart failure: insights from the ASCEND-HF Trial. Eur J Heart Fail. 2014;16:334-41.
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Supplemental Figure 1.
Legend: Left ventricular ejection fraction (LVEF) distribution of the studied sample. HFrEF – HF with
reduced LVEF; HFm-recEF – HF with mid-range and recovered LVEF; HFmEF – HF with mid-range
and without recovered LVEF; HFpEF – heart failure with preserved LVEF.
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