Download Galectin-3 in patients with heart failure with preserved ejection

European Journal of Heart Failure (2015) 17, 214–223
doi:10.1002/ejhf.203
Galectin-3 in patients with heart failure
with preserved ejection fraction: results
from the Aldo-DHF trial
Frank Edelmann1,2*, Volker Holzendorf3, Rolf Wachter1,2, Kathleen Nolte1,
Albrecht G. Schmidt4, Elisabeth Kraigher-Krainer4,5, André Duvinage6, Ines
Unkelbach1, Hans-Dirk Düngen7, Carsten Tschöpe8, Christoph
Herrmann-Lingen2,9, Martin Halle6, Gerd Hasenfuss1,2, Götz Gelbrich10, Wendy
Gattis Stough11, and Burkert M. Pieske4,5,7
1 Department
of Cardiology and Pneumology, Heart Center, University of Göttingen, Göttingen, Germany; 2 German Center for Cardiovascular Research (DZHK), University of
Göttingen, Göttingen, Germany; 3 Clinical Trial Center, University of Leipzig, Leipzig, Germany; 4 Department of Cardiology, Medical University Graz, Graz, Austria;
5 Ludwig-Boltzmann Institute for Translational Heart Failure Research (LBI), Graz, Austria; 6 Department of Preventive and Rehabilitative Sports Medicine, Technical University
Munich, Munich, Germany; 7 Department of Internal Medicine-Cardiology, Charite-Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin, Germany; 8 Department of
Cardiology and Pneumology, Charité-Campus Benjamin Franklin, Universitätsmedizin Berlin, Berlin, Germany; 9 Department of Psychosomatic Medicine and Psychotherapy,
University of Göttingen, Göttingen, Germany; 10 Institute of Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany; and 11 Departments of Pharmacy
Practice and Clinical Research, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC, USA
Received 22 July 2014; revised 8 October 2014; accepted 10 October 2014 ; online publish-ahead-of-print 24 November 2014
Aims
...................
Galectin-3 is a marker of myocardial fibrosis and mediates aldosterone-induced cardiovascular inflammation and
fibrosis. Characteristics of galectin-3 and its response to spironolactone have not been evaluated in heart failure with
preserved ejection fraction (HFpEF). The aim of this study was to determine the association between galectin-3 levels
and patient characteristics in HFpEF; to evaluate the interaction between spironolactone and galectin-3 levels; and to
assess the association between galectin-3 and clinical outcomes.
.....................................................................................................................................................................
Methods
Aldo-DHF investigated spironolactone 25 mg once daily vs. placebo for 12 months in patients with NYHA class II–III,
and results
LVEF ≥50%, grade ≥ I diastolic dysfunction, and peakVO2 ≤ 25 mL/kg/min. Galectin-3 levels were obtained at baseline,
and at 6 and 12 months. The association between baseline galectin-3, change in galectin-3, and all-cause death or
hospitalization was evaluated, and the interaction between galectin-3 and treatment was assessed. Median baseline
galectin-3 was 12.1 ng/mL. After multivariable adjustment, baseline galectin-3 inversely correlated with peak VO2
(P = 0.021), 6 min walk distance (P = 0.002), and Short Form 36 (SF-36) physical functioning (P = 0.001), and directly
correlated with NYHA class (P = 0.007). Baseline NT-proBNP correlated with E/e’ velocity ratio (P ≤ 0.001), left atrial
volume index (P < 0.001), and LV mass index (P = 0.009). Increasing galectin-3 at 6 or 12 months was associated with
all-cause death or hospitalization independent of treatment arm [hazard ratio (HR) 3.319, 95% confidence interval
(CI) 1.214–9.07, P = 0.019] and NT-proBNP (HR 3.127, 95% CI 1.144–8.549, P = 0.026). Spironolactone did not
influence galectin-3 levels.
.....................................................................................................................................................................
Conclusion
Galectin-3 levels are modestly elevated in patients with stable HFpEF and relate to functional performance and quality
of life. Increasing galectin-3 was associated with worse outcome, independent of treatment or NT-proBNP.
..........................................................................................................
Keywords
Galectin-3 •
Heart failure •
Diastolic •
Mortality •
Morbidity •
Spironolactone
*Corresponding author. Department of Cardiology, University of Göttingen, Rober-Koch-Str. 40, D-37075 Göttingen, Germany. Tel: +49 551 399258, Fax: +49 551 39 10567,
Email: [email protected]
© 2014 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and
distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
215
Introduction
Heart failure with preserved ejection fraction (HFpEF) is a
heterogenous syndrome with many potential pathophysiological contributors. Myocardial fibrosis is a major component of
HFpEF pathophysiology, and it is a manifestation of collagen
synthesis (or decreased collagen degradation), inflammation, and
oxidative stress.1 – 5 Galectin-3 belongs to the family of soluble beta-galactoside-binding lectins. It is secreted by activated
macrophages and promotes myofibroblast proliferation.6 – 11 It is a
marker of myocardial fibrosis7 and mediates aldosterone-induced
vascular inflammation and fibrosis.12 Overexpression of galectin-3
results in cardiac fibrosis in rats,8 and it correlates with markers of
cardiac extracellular matrix turnover in patients with heart failure
with reduced ejection fraction (HFrEF).13 Initial observations in
humans relate increased galectin-3 plasma levels to poorer outcome, and galectin-3 was shown to be an independent predictor
of mortality in patients with HFrEF.11,14 – 19
To date, most published studies of galectin-3 in heart failure
were performed in patients with chronic or acute HFrEF, but
few data are available in patients with HFpEF. An analysis of the
Framingham Offspring Cohort showed that baseline galectin-3 levels were not different among patients who developed incident
HFpEF or HFrEF over a mean follow-up of 11.2 years.20 One
study including both HFrEF and HFpEF patients acutely hospitalized for heart failure found that higher circulating galectin-3 was
a stronger predictor of death or subsequent heart failure hospitalization in the HFpEF patients than in the HFrEF patients.14
The Aldosterone Receptor Blockade in Diastolic Heart Failure
(Aldo-DHF) study was a randomized, controlled trial investigating the effects of chronic aldosterone receptor blockade in 422
ambulatory, stable HFpEF patients.21 It is the largest collection of
prospective data in a well-defined HFpEF population. The objective
of the present analysis was to (i) describe galectin-3 plasma levels in
this HFPEF population and the association of galectin-3 levels with
demographic, clinical, and echocardiographic characteristics; (ii)
evaluate the association and interaction between spironolactone
treatment and galectin-3 concentrations over time; and (iii) assess
the association between changes in galectin-3 over time and clinical
outcomes.
Methods
The Aldo-DHF trial was a multicentre, randomized, placebocontrolled, double-blind study. The study design and the primary
results of the Aldo-DHF trial have been previously published.21,22
Briefly, eligible patients were enrolled and randomized to spironolactone 25 mg once daily or matching placebo. Patients with NYHA class
II or III heart failure symptoms, LVEF ≥50% at rest, echocardiographic
evidence of grade ≥ I diastolic dysfunction22 or present AF, and peak
VO2 ≤ 25 mL/kg/min were eligible for participation. Major exclusion
criteria included: prior documented LVEF ≤40%, significant CAD,
myocardial infarction or coronary artery bypass graft surgery within 3
months, definite or probable pulmonary disease [vital capacity <80%
or forced expiratory volume in 1 s (FEV1 ) <80% of reference values
on spirometry], body mass index ≥36 kg/m2 , or serum creatinine
>1.8 mg/dL. The study protocol was reviewed and approved by the
..................................................................................................................................................................................
Galectin-3 in patients with HFpEF
institutional review board of each participating centre, and all patients
provided written informed consent prior to enrolment. Aldo-DHF
was conducted in accordance with national laws, guidelines for good
clinical practice, and the Declaration of Helsinki.
Galectin-3 assay
Plasma collections for galectin-3 assessments were performed at baseline, and at 6 and 12 months after randomization in the entire study
cohort. According to a pre-specified standard, peripheral venous blood
was drawn into EDTA-containing tubes, centrifuged immediately, and
stored at −80 ∘ C. Frozen samples from the trial sites were sent to
the biomarker core laboratory (University of Göttingen) for analysis
using shipping containers prepared by the co-ordinating centre. Analysis of galectin-3 was performed using an enzyme-linked immunosorbent
assay (ELISA) developed by BG Medicine (BG Medicine, Inc., Waltham,
MA, USA). The lower limit of detection for this assay is 1.13 ng/mL, and
it does not cross-react with collagens, other members of the galectin
family, or common heart failure medications.23 Personnel at the core
laboratory were blinded to the patients’ clinical data.
Statistical analysis
The population for this analysis included all patients with galectin-3
values at baseline, and at 6 and 12 months (n = 377). The study population was dichotomized based on the median baseline galectin value
(≤12.1 ng/mL and >12.1 ng/mL). Statistical analyses were performed
using IBM SPSS Statistics 20.0.0 software (Armonk, New York, USA).
A P-value <0.05 was considered statistically significant, and all statistical
tests were two-sided.
Baseline characteristics are reported as percentages for categorical
variables, and mean ± standard deviation (SD) for continuous variables; some values were additionally reported as median (interquartile
range). The clinical variables that correlated with elevated galectin-3 at
baseline were determined using a bivariate correlation (model 1), and
were correlated as partial correlation coefficient corrected for sex
and age only (model 2), and as partial correlation coefficient corrected
for sex, age, AF, mean arterial pressure, estimated glomerular filtration
rate (eGFR), haemoglobin, and NT-proBNP (model 3a). The same
procedure was also conducted with the log-transformed values of
NT-proBNP only (bivariate correlation, model 1), partial correlation
coefficient for sex and age only (model 2), and for sex, age, AF, mean
arterial pressure, eGFR (mL/min/1.73 m2 ), haemoglobin (g/dL), and
galectin-3 (model 3b).
Galectin-3 levels were analysed over 12 months of follow-up. We
calculated differences between values at baseline and 12 months, and
from 6 to 12 months by treatment group. P-values for the interaction
term of galectin-3 with treatment were calculated using a univariate
analysis of variance (ANOVA) model with repeated measurements.
These analyses were also adjusted as described before (models 1, 2,
and 3a).
Aldo-DHF was designed to evaluate the effect of spironolactone
therapy vs. placebo on the co-primary endpoints of change in peak VO2
and change in E/e’ from baseline to 12 months. To evaluate the association between baseline galectin-3 and spironolactone treatment effect
on these endpoints, an analysis of covariance (ANCOVA) was used
with treatment group as the dependent variable, baseline galectin-3 as
the independent variable (model 1), adjusted for covariates sex and
age (model 2), or adjusted for covariates sex, age, AF, mean arterial
pressure, eGFR, and haemoglobin (model 3).
© 2014 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
216
F. Edelman et al.
A Cox proportional hazards model was used to evaluate the
association between baseline galectin-3 and the composite of all-cause
death or hospitalization within 12 months. The association between
change in galectin-3 and all-cause death or hospitalization was also
evaluated. The three Cox regression models described above were
used to evaluate possible associations between the change in galectin-3
and the composite endpoint of all-cause death or hospitalization. In
addition, every model was additionally adjusted by treatment group
and NT-proBNP.
Results
A total of 422 patients were enrolled in Aldo-DHF from March
2007 to April 2011. After 12 months, mean E/e’ decreased in the
spironolactone group compared with the placebo group, but no
between-group difference was observed in peak VO2 .21 Of the 422
randomized patients, 377 patients had absolute values of galectin-3
reported at each time point (baseline, 6 and 12 months) and were
included in this analysis (Figure 1).
Baseline values of galectin-3 were normally distributed
[12.51 ± 3.83 ng/mL (mean ± SD); 12.11 ng/mL (median)], and
the concentrations were similar in the spironolactone and
placebo arms [12.5 ng/mL ± 3.7 ng/mL (mean ± SD); 12.15 ng/mL
(median), spironolactone vs. 12.5 ng/mL ± 3.9 ng/mL (mean ± SD);
12.10 ng/mL (median), placebo]. Patients with galectin-3 levels
above the median were older, more often had a history of hypertension, AF, NYHA class III symptoms, and oedema, and were
treated more frequently with beta-blockers or diuretics (Table 1).
The median baseline NT-proBNP level in the overall cohort
was 159 pg/mL, reflecting a stable, well-compensated population.
NT-proBNP was higher in patients with baseline galectin-3 values
...........................................................................................
Figure 1 Participant flow diagram. Disposition of patients through the study. BL, baseline; FU, follow-up.
>12.1 ng/mL [Pearson’s r = 0.301, 95% confidence interval (CI)
0.209–0.388], and eGFR was lower in these patients (Pearson’s
r = −0.416, 95% CI (−0.493 to −0.332) (Table 1). The maximum
work load, maximum duration of exercise, and peak VO2 were
lower and the VE/VCO2 slope was higher in patients with baseline
galectin-3 levels above the median. The 6 min walk distance was
also shorter for patients with galectin-3 > 12.1 ng/mL compared
with patients with galectin ≤12.1 ng/mL. Left atrial (LA) size was
larger and E/e’ higher in patients with galectin-3 > 12.1 ng/mL at
baseline. The Minnesota Living With Heart Failure Questionnaire
(MLWHFQ) scores did not differ across the galectin-3 subsets, but
the the Short Form 36 (SF-36) physical function baseline scores
were higher in the group with galectin-3 > 12.1 ng/mL.
After full adjustment for sex, age, AF, mean arterial pressure, eGFR, haemoglobin, and NT-proBNP (model 3a), baseline
galectin-3 levels were inversely correlated with peak VO2 , 6 min
walk distance, and the SF-36 physical functioning scale score,
and directly correlated with NYHA class (Table 2). After full
adjustment, baseline galectin-3 lost its significant association with
E/e’ and LA volume index. Of note, (log) NT-proBNP levels did
not, independent of other factors (model 3b), correlate with peak
VO2 , 6 min walk distance, SF-36 physical functioning scale score,
NYHA class, or LVEF, but they were significantly associated with
E/e’, LA volume index, and LV mass index.
Over the course of 12 months, galectin-3 levels significantly
increased in the overall study cohort (Figure 2). Galectin-3
increased more quickly (by 6 months) in patients treated with
spironactolone than in placebo group patients. This observation
remained stable after adjustment for sex and age (model 2) but was
lost in the full adjusted model. After 12 months, galectin-3 levels
were not significantly different between the groups (Figure 3).
© 2014 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
217
Galectin-3 in patients with HFpEF
Table 1 Baseline characteristics
Demographics
Gender (female)
Age, years
Clinical characteristics
Body mass index, kg/m2
LVEF, %
Systolic blood pressure, mmHg
Diastolic blood pressure, mmHg
Mean arterial pressure, mmHg
Laboratory data
Sodium, mmol/L
NT-proBNP, pg/mL, median (IQR)
Potassium, mEq/L
Haemoglobin, g/dL
Estimated glomerular filtration rate, mL/min
Co-morbidities, n (%)
Hospitalized within last 12 months
Coronary artery disease
History of myocardial infarction
CABG
Atrial fibrillation
Hypertension
Hyperlipidaemia
Diabetes mellitus
Cerebrovascular diseases
Peripheral arterial occlusive disease
COPD
Depression
Signs and symptoms, n (%)
NYHA class II
NYHA class III
Oedema
Paroxysmal nocturnal dyspnoea
Nocturnal cough
Fatigue
Baseline medications, n (%)
ACE inhibitor orARB
Beta-blocker
Diuretics
Calcium channel blocker
Antiplatelet
Anticoagulation
Lipid-lowering drug
Exercise testing
Maximum work load, W
Maximum exercise duration, s
Peak VO2 , mL/min/kg
Anaerobic threshold, W
ATVO2 , mL/min; kg
VE /VCO2 slope
Borg score
RERmax
Walk distance, m
Total
(n = 415)
Galectin-3 ≤ 12.1 ng/mL
(n = 208)
Galectin-3 > 12.1 ng/mL
(n = 207)
P-value
217 (52.3)
67 (8)
100 (48.1)
65 (7)
117 (56.5)
68 (8)
0.085
<0.001
29.0 (3.6)
67.4 (7.8)
135.2 (18.1)
79.3 (11.1)
97.9 (11.8)
28.7 (3.5)
67.0 (7.7)
136.7 (17.4)
81.1 (10.2)
99.6 (10.9)
29.3 (3.6)
67.8 (7.9)
133.8 (18.8)
77.5 (11.6)
96.3 (12.4)
0.085
0.268
0.112
0.001
0.004
140.3 (3.0)
159 (84–299)
4.2 (0.4)
13.8 (1.2)
78.7 (18.7)
140.3 (3.2)
140 (75–225)
4.2 (.4)
14.0 (1.1)
84.7 (17.2)
140.4 (2.7)
192 (93–377)
4.2 (.4)
13.7 (1.3)
72.5 (18.2)
0.868
<0.001
0.505
0.012
<0.001
153 (36.9)
167 (40.2)
67 (16.1)
30 (7.2)
21 (5.1)
382 (92.0)
269 (64.8)
69 (16.6)
43 (10.4)
16 (3.9)
14 (3.4)
47 (11.3)
83 (39.9)
81 (38.9)
30 (14.4)
12 (5.8)
3 (1.4)
186 (89.4)
132 (63.5)
28 (13.5)
16 (7.7)
4 (1.9)
6 (2.9)
20 (9.6)
70 (33.8)
86 (41.5)
37 (17.9)
18 (8.7)
18 (8.7)
196 (94.7)
137 (66.2)
41 (19.8)
27 (13.0)
12 (5.8)
8 (3.9)
27 (13.0)
0.199
0.589
0.339
0.250
0.001
0.048
0.562
0.083
0.074
0.040
0.580
0.271
357 (86.0)
58 (14.0)
164 (39.5)
67 (16.1)
61 (14.7)
244 (58.8)
188 (90.4)
20 (9.6)
68 (32.7)
29 (13.9)
24 (11.5)
126 (60.6)
169 (81.6)
38 (18.4)
96 (46.4)
38 (18.4)
37 (17.9)
118 (57.0)
0.010
0.010
0.004
0.222
0.068
0.460
321 (77.3)
299 (72.0)
226 (54.5)
102 (24.6)
219 (52.8)
57 (13.7)
228 (54.9)
153 (73.6)
135 (64.9)
94 (45.2)
43 (20.7)
106 (51.0)
18 (8.7)
107 (51.4)
168 (81.2)
164 (79.2)
132 (63.8)
59 (28.5)
113 (54.6)
39 (18.8)
121 (58.5)
0.064
0.001
<0.001
0.064
0.459
0.003
0.151
100.1 (29.2)
541 (175)
16.3 (3.5)
64.0 (25.0)
11.6 (3.2)
30.3 (5.2)
5.4 (3.7)
1.1 (0.1)
530 (87)
104.2 (29.0)
571 (175)
16.9 (3.2)
67.7 (25.8)
12.1 (3.3)
29.7 (5.3)
5.5 (4.8)
1.1 (.1)
546 (83)
95.9 (28.9)
510 (170)
15.8 (3.6)
60.2 (23.7)
11.1 (3.1)
31.0 (5.1)
5.2 (1.9)
1.1 (.1)
514 (88)
0.004
<0.001
0.001
0.002
0.002
0.016
0.511
0.095
<0.001
© 2014 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
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F. Edelman et al.
Table 1 Continued
Total
Galectin-3 ≤ 12.1 ng/mL
Galectin-3 > 12.1 ng/mL
P-value
(n = 415)
(n = 208)
(n = 207)
...........................................................................................................................................
Echocardiographic parameters
LVD(ED) (mm)
LVD(ES) (mm)
LVMI, g/m2
LVMImale , g/m2
LVMIfemale , g/m2
LAES (mm)
Left atrial volume index, mL/m2
Deceleration time (ms)
Medial e’ wave velocity, cm/s
Medial a’ wave velocity, cm/s
E/e’
Health-related quality of life scores
Total score MLWHFQ
SF-36 physical function score
PHQ-Sum
46.6 (6.2)
25.5 (6.5)
108.8 (28.1)
117.2 (31.0)
101.1 (22.7)
44.3 (5.7)
28.1 (8.5)
242.8 (62.2)
5.9 (1.3)
9.2 (1.8)
12.8 (4.1)
46.9 (6.5)
25.4 (7.0)
110.9 (31.1)
120.4 (33.8)
100.6 (24.1)
43.9 (5.7)
27.1 (7.4)
245.1 (61.1)
6.0 (1.2)
9.4 (1.7)
12.3 (3.6)
46.3 (6.0)
25.5 (5.9)
106.7 (24.7)
113.4 (27.0)
101.5 (21.5)
44.6 (5.6)
29.1 (9.3)
240.6 (63.3)
5.9 (1.4)
9.0 (1.9)
13.2 (4.4)
0.328
0.776
0.126
0.112
0.770
0.247
0.022
0.468
0.426
0.013
0.023
21.8 (15.7)
62.7 (22.2)
5.6 (4.1)
20.5 (15.3)
65.6 (20.8)
5.7 (4.1)
23.1 (15.9)
59.7 (23.1)
5.6 (4.1)
0.106
0.009
0.828
In the main Aldo-DHF study, the effects of spironolactone on
E/e’ and peak VO2 were similar across pre-specified subgroups.21
We performed an exploratory analysis to determine if baseline
galectin-3 level interacted with the effect of spironolactone on
E/e’ or peak VO2 in these pre-specified subgroups. No significant
interactions were detected between galectin-3 and the effect of
spironolactone on E/e’ or peak VO2 for any subgroup.
A total of 111 patients died or were hospitalized for any cause
during 12 months of follow-up in the overall cohort [1 death
(1 spironolactone, 0 placebo); 110 patients hospitalized for any
cause (60 spironolactone, 50 placebo); 36 of whom were hospitalized for cardiac causes (21 spironolactone, 15 placebo)].21 Baseline galectin-3 levels were not associated with all-cause death or
hospitalization within 12 months after adjustment for treatment
group (P = 0.259) (Figure 4A), but changes in galectin-3 plasma levels over time were associated with clinical outcomes. An increase
in galectin-3 levels from baseline at either 6 or 12 months was associated with the composite of all-cause mortality and hospitalization
after adjustment for treatment group (Figure 4B) and after adjustment for age, sex, AF, mean arterial pressure, eGFR, haemoglobin,
treatment group, and log2 NT-proBNP (Table 3).
Discussion
This is a post-hoc analysis of 377 out of 422 patients with stable,
compensated HFpEF who were randomized into the prospective
Aldo-DHF trial. All patients in this analysis had baseline and
follow-up measurements of galectin-3. Galectin-3 levels were
modestly elevated at baseline and further increased over 12
.........................................................................................
Values are n (%) for categorical variables and mean (SD) for continuous variables.
ATVO2 , oxygen consumption at anaerobic threshold; CABG, coronary artery bypass graft; IQR, interquartile range; LAES , left atrial end-systolic diameter; LVD(ED), left
ventricular dimensions (end-diastolic); LVD(ES), left ventricular dimensions end-systolic; LVMI, left ventricular mass index; MLWHFQ, Minnesota Living with Heart Failure
Questionnaire; peak VO2 , maximum oxygen uptake; PHQ-Sum, Patient Health Questionnaire sum score; RER, respiratory exchange ratio; SF-36, Short Form 36; VE /VCO2 ,
ventilatory equivalent of carbon dioxide.
months of follow-up. Higher galectin-3 levels at baseline were
associated with a sicker patient population, and an increase in
galectin-3 over time was associated with an increased risk of death
or hospitalization (predominantly hospitalization) after adjustment
for known prognostic markers, including NT-proBNP. Galectin-3
plasma levels at baseline were not associated with spironolactone
treatment effects, and spironolactone did not modulate changes
in galectin-3 plasma levels over time.
Earlier reports suggest that galectin-3, a marker of cardiac fibrosis, correlates with several cardiovascular risk factors, predicts incident heart failure with reduced and preserved LVEF, and predicts
mortality in the general population.15,20 Galectin-3 is elevated in
both chronic and acute HFrEF, and it is an independent predictor
of mortality in these patients.9,11,18,24,25
Most of the galectin-3 heart failure literature focuses on patients
with HFrEF, although some studies have reported data relevant
to HFpEF. Galectin-3 levels correlated with echocardiographic
measures of higher filling pressure (higher E/Ea ratio), abnormalities of diastolic relaxation (lower Ea velocity), and valvular
regurgitation in an analysis of data from the Pro-BNP Investigation
of Dyspnoea in the Emergency Department (PRIDE) study.26 The
highest levels of galectin-3 were associated with a higher risk of
4-year mortality, independent of LV dimensions and function in
this analysis of the PRIDE study.26 Galectin-3 was an independent
predictor of all-cause mortality or heart failure hospitalization
during 18 months of follow-up in 592 patients with NYHA class
II–IV heart failure enrolled in the Advising and Counseling in Heart
Failure (COACH) trial [hazard ratio (HR) 1.38, 95% CI 1.07–1.78,
P = 0.015 adjusted for age, gender, BNP, eGFR, and diabetes].
An interaction was observed between LVEF and galectin-3, such
© 2014 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
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Galectin-3 in patients with HFpEF
Table 2 Correlations of galectin-3 and N-terminal pro brain natriuretic peptide (log) with functional variables at
baseline
Variable
Correlation coefficient (P-value)
.........................................................................................................
Galectin-3
Log NT-proBNP
..............................................
................................................
*
†
‡
Bivariate
Partial
Partial
Bivariate*
Partial†
Partial‡
...........................................................................................................................................
Peak VO2
Six minute walk distance§
SF-36 physical functioning scale§
NYHA class§
LVEF
E/e’ (medial) velocity ratio§
LA volume index§
LV mass index§
−0.18
(<0.001)
−0.26
(<0.001)
−0.25
(<0.001)
0.18
(<0.001)
0.07
(0.14)
0.12
(0.012)
0.14
(0.004)
−0.06
(0.20)
−0.11
(0.023)
−0.18
(<0.001)
−0.22
(<0.001)
0.13
(0.009)
0.04
(0.45)
0.06
(0.2)
0.11
(0.033)
−0.07
(0.13)
−0.10
(0.06)
−0.15
(0.003)
−0.16
(0.002)
0.12
(0.022)
0.03
(0.49)
0.04
(0.45)
0.05
(0.33)
−0.04
(0.40)
−0.16
(0.002)
−0.09
(0.08)
−0.10
(0.06)
−0.02
(0.67)
0.00
(0.97)
0.31
(<0.001)
0.43
(<0.001)
0.11
(0.032)
−0.08
(0.09)
0.03
(0.5)
−0.07
(0.17)
−0.10
(0.06)
−0.05
(0.37)
0.26
(<0.001)
0.39
(<0.001)
0.09
(0.07)
−0.04
(0.39)
0.07
(0.15)
0.00
(0.94)
−0.12
(0.023)
−0.06
(0.25)
0.27
(<0.001)
0.30
(<0.001)
0.12
(0.023)
Figure 2 Galectin-3 levels at baseline, and at 6 and 12 months.
Median values and 95% confidence intervals (CIs) for galectin-3
at baseline and during follow-up.
that increasing quartiles of baseline galectin-3 levels were associated with a greater risk for all-cause mortality or heart failure
hospitalization in patients with HFpEF (defined as LVEF >40%,
n = 107) than in patients with HFrEF (n = 485).14 Longitudinal
measurements of galectin-3 did not add to its predictive value in
..............................................................................
LA, left atrial; peak VO2 , maximum oxygen uptake; SF-36, Short Form 36.
* Pearson’s correlation coefficient without adjustment for covariables .
† Partial correlation coefficient. controlling for sex and age.
‡ Partial correlation coefficient, controlling for sex, age, AF, mean arterial pressure, estimated glomerular filtration rate, haemoglobin, and log NT-proBNP or log galectin-3,
respectively.
§ The two corresponding correlation coefficients of this functional variable with galectin-3 and NT-proBNP are significantly different from each other (P < 0.05).
this study, but the levels were already high at baseline and were
generally stable over 6 months,14 which is different from our study
where galectin-3 was modestly elevated at baseline and increased
significantly over 12 months. Significant correlations between
plasma concentrations of galectin-3 and inflammatory cytokines
(vascular endothelial growth factor, interleukin-6, and C-reactive
protein) were also detected in this analysis.14 Galectin-3 above a
median of 13.8 ng/mL independently predicted all-cause mortality
in a study of 419 patients hospitalized with heart failure and
LVEF >45%.27
In Aldo-DHF, baseline galectin-3 was not associated with subsequent clinical outcomes, but the overall study event rate was
relatively low and a substantial part of the hospitalizations were
due to non-cardiac causes, as is typical for a HFpEF population.21
Additionally, galectin-3 levels at baseline were only modestly elevated at a median value of 12.1 ng/mL. In comparison, the median
galectin-3 concentration in the HF-ACTION study addressing
outpatients with reduced EF was 14 ng/mL,16 and 75% of hospitalized patients in the COACH study had galectin-3 concentrations
>15.2 ng/mL.14 The Carrasco-Sanchez study reported a median
galectin-3 level of 13.8 ng/mL.27 The clinically available assay categorizes heart failure patients with galectin-3 levels >17.8 ng/mL at
high risk of all-cause death or all-cause hospitalization.28 Galectin-3
also predicted all-cause mortality in patients enrolled in the PREVEND study with a median concentration of 10.9 ng/mL, but the
patients were followed for a median of 10 years.15 However, data
© 2014 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
220
F. Edelman et al.
on galectin-3 measurements in well-defined HFpEF patient populations are sparse, and lower plasma levels and cut-off values may
be associated with clinical events as suggested from our present
results. Also, increasing galectin-3 over time was associated with
12-month all-cause mortality or hospitalization even after multiple
adjustments, including NT-proBNP. This new finding may bear
clinical relevance and needs validation, but it could be a new
approach towards detecting pathophysiological progression of the
disease (i.e. progression of fibrosis) and improving risk stratification of HFpEF patients. The increase in galectin-3 from baseline
to 12 months was modest (from 12.5 ng/mL to 13.3 ng/mL in the
placebo group and to 13.8 ng/mL in the spironolactone group),
suggesting that relatively small increases in galectin-3 levels may be
important. In an analysis of the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) (n = 1329, HFrEF, mean
LVEF 32%) and a subset of patients enrolled in COACH with acute
decompensated heart failure (n = 324, HFrEF, mean LVEF 33%),
increasing galectin-3 levels (above the threshold of 17.8 ng/mL)
over 3 or 6 months were associated with an increasing incidence
of death or heart failure hospitalization.29 The study investigators
also evaluated the magnitude of change in galectin-3 levels and
found that an increase of ≥15% in galectin-3 levels from baseline
translated to a 50% increase in the risk of all-cause mortality or
heart failure hospitalization (HR 1.5, 95% CI 1.173–1.917).29
Whether thresholds of change in galectin-3 that are useful for risk
stratification will be similar in HFpEF and HFrEF deserves further
study.
Several possibilities may be considered to explain spironolactone’s lack of effect on galectin-3 concentrations in this study.
.....................................................................................
Figure 3 Change of galectin-3 levels by treatment group (for baseline to F6, baseline to F12, and F6 to F12). Mean values and 95% confidence
intervals (CIs) for change of galectin-3 in the spironolactone and placebo group. Adjustment 1: adjusted for sex and age (model 2). Adjustment
2: adjusted for sex and age, AF, mean arterial pressure, estimated glomerular filtration rate (mL/min/1.73 m2 ), haemoglobin (g/dL), and log2
NT-proBNP.
Mineralocorticoid receptor (MR) antagonism with eplerenone and
oxprenoate potassium inhibited aldosterone-induced increases in
galectin-3 in primary rat aortic vascular smooth muscle cells, but
these compounds had no effect on galectin-3 concentrations in the
absence of aldosterone.30 It is possible that plasma aldosterone
was not substantially elevated in the stable population represented
by Aldo-DHF, thereby minimizing the potential for an MR antagonist (MRA) to influence galectin-3 levels. This hypothesis requires
further study.
Plasma aldosterone levels increase after chronic administration of an MRA.31 Aldosterone stimulates galectin-3 expression
through the MR.30 It is plausible that incomplete MR blockade
might still allow for aldosterone-mediated galectin-3 stimulation.
The doses necessary to produce complete MR blockade in this
population are not known, and it is uncertain if agents with greater
MR selectivity would produce different results. These possibilities
are speculative, and further research is needed to understand fully
the observations of this study. Finally, post-hoc analyses are subject
to type II error and the influence of unmeasured or unrecognized
confounders, which perhaps is the most likely explanation given
the incongruent observation that spironolactone improved some
parameters representative of remodelling but failed to influence
galectin-3 concentrations during follow-up.
These findings should be interpreted in the context of several limitations. As stated, this was a post-hoc analysis. Covariates
unaccounted for in the analysis could have influenced the findings.
The number of clinical events was relatively low and driven by
heart failure hospitalization, limiting the ability to draw definitive
conclusions from these data. Additionally, the number of patients
© 2014 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
221
Galectin-3 in patients with HFpEF
Figure 4 (A) Association between baseline galectin-3 levels and all-cause mortality and all-cause hospitalization. * P-value for galectin-3 only;
with an increased galectin-3 level was small; therefore, the association between change in galectin-3 and subsequent clinical outcome
requires confirmation in larger data sets. Finally, it is not possible to
determine whether galectin-3 increased first or the clinical event
occurred first. Thus, only associations between galectin-3 and clinical outcomes can be detected; the independent prognostic value
of increases in galectin-3 cannot be determined from these data.
Despite these limitations, this exploratory analysis from Aldo-DHF
adds to the small existing body of literature describing galectin-3
in patients with HFpEF. It is the first to examine the association
between the MRA spironolactone and galectin-3 levels over 12
months of follow-up in a HFpEF population. The observations from
....................................
†P-value adjusted for sex, age, AF, mean arterial pressure, estimated glomerular filtration rate (eGFR; mL/min/1.73 m2 ), haemoglobin (g/dL),
treatment group, and log2 NT-proBNP. (B) Association between change in galectin-3 levels and all-cause mortality and all-cause hospitalization.
*
P-value for galectin-3 only; †P-value adjusted for sex, age, AF, mean arterial pressure, eGFR (mL/min/1.73 m2 ), haemoglobin (g/dL), treatment
group, and log2 NT-proBNP.
this analysis of Aldo-DHF are important to consider as new studies
are designed and to advance knowledge in this field.
Conclusion
Galectin-3 concentrations are modestly elevated in patients with
well-compensated HFpEF and predominantly mild symptoms, and
they are related to different measures of functional performance.
Galectin-3 levels increase over time in these patients, and this
increase is associated with subsequent hospitalization. There was
no evidence from this study that spironolactone modulates the
observed increase in galectin-3 over time, although spironolactone
© 2014 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
222
F. Edelman et al.
Table 3 Association of galectin-3 with all-cause mortality and hospitalization
Model 1*
P-value
Model 2†
P-value
Model 3‡
P-value
...........................................................................................................................................
Galectin-3 at median
(12.11 ng/mL)
Galectin-3 at median
(12.11 ng/mL) by armd
Galectin-3 at median
(12.11 ng/mL) by NT-proBNP¶
Galectin-3 increased (at 6 and 12
months)
Galectin-3 increased (at 6 and 12
months) by armd
Galectin-3 increased (at 6 and 12
months) by NT-proBNP¶
1.242 (0.852–1.811)
0.259
1.197 (0.812–1.767)
0.364
1.170 (0.773–1.772)
0.457
1.240 (0.851–1.808)
0.263
1.196 (0.811–1.764)
0.367
1.170 (0.773–1.772)
0.457
1.126 (0.755–1.680)
0.561
1.111 (0.740–1.669)
0.611
1.104 (0.721–1.689)
0.650
3.475 (1.277–9.451)
0.015
3.480 (1.277–9.484)
0.015
3.319 (1.214–9.073)
0.019
3.445 (1.265–9.388)
0.016
3.453 (1.265–9.427)
0.016
3.319 (1.214–9.073)
0.019
3.304 (1.214–8.996)
0.019
3.291 (1.206–8.975)
0.02
3.127 (1.144–8.549)
0.026
did improve echocardiographic measures reflective of diastolic
filling and ventricular remodelling. These findings provide the
foundation for future studies to evaluate further the contribution
of galectin-3 to HFpEF pathophysiology and to determine if it is a
viable target for therapeutic intervention.
Funding
This work was supported the German–Austrian Heart Failure
Study Group and the German Competence Network of Heart
Failure. Aldo-DHF was funded by the Federal Ministry of Education and Research, grant no. 01GI0205 [Clinical trial program
Aldo-DHF (FKZ 01KG0506)].
Conflict of interest: F.E. reports having been an investigator, consultant, or speaker for Berlin Chemie, Novartis, Pfizer,
Servier, Bayer, Gilead, CVRx, Relypsa, Sanofi, Abbott, BG Medicine,
and Astra-Zeneca. R.W. reports having been, since 2003, an
investigator, consultant, or speaker for Bayer, Berlin Chemie,
Boehringer Ingelheim, Boston Scientific, CVRx, Gilead, Johnson &
Johnson, Medtronic, Novartis, Pfizer, Relypsa, Sanofi, and Servier.
C.H.-L. reports receiving speaker’s honoraria from Pfizer, Servier,
and Berlin-Chemie. He has received royalties from Verlag Hans
Huber and Deutscher Ärzteverlag, and participates in institutional
research co-operation with KKH-Allianz. M.H. reports receiving
speaker’s honoraria from Berlin-Chemie, Merck Sharpe & Dohme,
Bristol-Myers Squibb, and Sanofi-Aventis, and receiving honoraria
as a board member (Sanofi-Aventis), for expert testimony (Health
Insurance Company, TK Germany), and as a consultant (BMW).
G.H. reports receiving honoraria for presentations from CVRx,
Impulse Dynamics, and Servier, and serving as a consultant for
Novartis and Servier. G.G. reports receiving remuneration from
Robert Bosch Health Care for board membership. B.P. reports
receiving speaker honoraria from Bayer Healthcare, Boehringer
Ingelheim, Servier, Medtronic, Bristol-Myers-Squibb, and Menarini,
.................................................................................................................................
The results are given as the hazard ratio (95% confidence interval).
* Model 1: biomarker group only.
† Model 2: galectin-3 adjusted by sex and age.
‡ Model 3: galectin-3 adjusted by sex, age, AF, mean arterial pressure, estimated glomerular filtration rate (mL/min/1.73 m2 ), and haemoglobin (g/dL).
¶ Every model additionally adjusted by treatment group.
d Every model additionally adjusted by NT-proBNP.
and serving as a consultant and/or steering committee member
for Bayer Healthcare, Menarini, and Novartis. He participated in
research co-operations (institutional) with Bayer Healthcare and
Medtronic. W.G.S. reports having been consultant for the University of Göttingen; but has no relationships with industry. All other
investigators have no conflicts of interest to declare.
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