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SUPPLEMENTAL MATERIAL- ONLINE APPENDIX
Without IGFBP7
With IGFBP7
(N = 55)
(N = 161)
p Value
Age (yrs), median (IQR)
71 (62, 80)
68 (62, 76)
0.18
Male (%)
33/55 (60.0)
79/161 (49.1)
0.16
White race (%)
48/55 (87.3)
149/161 (92.5)
0.23
Ischemic etiology (%)
23/55 (41.8)
61/161 (37.9)
0.61
Hypertension (%)
48/55 (87.3)
135/161 (83.9)
0.54
Presence of atrial fibrillation/flutter (%)
32/55 (58.2)
79/161 (49.1)
0.24
Chronic obstructive pulmonary disease
13/55 (23.6)
29/161 (18.0)
0.37
Diabetes mellitus (%)
27/55 (49.1)
66/161 (41.0)
0.30
Hospitalization for heart failure in last year (%)
28/55 (50.9)
51/161 (31.7)
0.01
Anemia (%)
27/54 (50.0)
49/161 (30.4)
0.009
33.6 (27.9, 40.9)
32.9 (28.4, 38.6)
0.67
Systolic blood pressure (mm Hg), median (IQR)
130 (113, 141)
125 (113, 137)
0.10
Diastolic blood pressure (mm Hg), median (IQR)
70 (62, 78)
70 (63, 79)
0.53
Heart rate (bpm), median (IQR)
70 (60, 77)
68 (62, 79)
0.56
Characteristic
Body mass index (kg/m2), median (IQR)
1
Online Table 1. Comparison between subjects with
available IGFBP7 and those without available
measurements
Jugular venous pressure ≥8 cm H2O (%)
31/54 (57.4)
64/155 (41.3)
0.04
4/55 (7.3)
10/161 (6.2)
0.78
Moderate or worse peripheral edema (%)
12/55 (21.8)
32/161 (19.9)
0.76
NYHA functional class >II (%)
32/55 (58.2)
83/161 (51.6)
0.40
Orthopnea (%)
41/52 (78.8)
89/150 (59.3)
0.01
ACE inhibitor or angiotensin receptor blocker (%)
41/55 (74.5)
111/161 (68.9)
0.43
Beta blocker (%)
45/55 (81.8)
119/161 (73.9)
0.24
5/55 (9.1)
18/161 (11.2)
0.66
Calcium channel blocker (%)
18/55 (32.7)
48/161 (29.8)
0.69
Statin (%)
34/55 (61.8)
104/161 (64.6)
0.71
Daily diuretic use at randomization (%)
52/55 (94.5)
134/161 (83.2)
0.04
44.5 (23.0, 58.0)
43 (30, 63)
0.57
22 (13, 32)
22 (16, 30)
0.68
Walk distance (m), median (IQR)
244 (177, 320)
328 (253, 392)
<0.001
Creatinine (mg/dl), median (IQR)
1.29 (0.88, 1.68)
1.08 (0.84, 1.31)
0.005
Cystatin C (mg/l), median (IQR)
1.57 (1.22, 1.90)
1.22 (1.03, 1.69)
0.003
eGFR (ml/min/1.73 m2), median (IQR)
56.8 (35.2, 70.8)
66.9 (49.0, 83.4)
0.02
NT-pro-BNP (pg/ml), (IQR)
1,331 (508, 2059)
619 (211, 1288)
0.001
Pro-collagen III NTP (μg/L), median (IQR)
8.1 (6.5, 10.1)
7.62 (5.80, 9.49)
0.26
High-sensitivity troponin I (pg/ml), median (IQR)
11.9 (6.8, 36.3)
8.4 (4.8, 16.4)
0.02
Rales (%)
Aldosterone antagonist (%)
MLWHF total score (%)
MLWHF physical dimension score (%)
2
ACE = angiotensin converting enzyme, eGFR =
estimated glomerular filtration rate, IQR = interquartile
range, bpm=beats per minute, MLWHF= Minnesota Living with Heart Failure, NT-proBNP = amino-terminal pro-B-type natriuretic peptide, NTP = amino-terminal peptide,
NYHA = New York Heart Association.
Galectin 3 (ng/ml), median (IQR)
14.1 (12.1, 19.5)
13.7 (11.0, 16.9)
3
0.32
OnlineTable 2. Baseline diastology parameters and correlation with NT-proBNP and galectin-3
NT-proBNP
N
Galectin-3
Spearman
Correlation
Wilcoxon
With
Spearman
<Median >Median Rank Sum Baseline Correlation
(619)
(619)
p Value
(ρ)
p Value
N
<Median
(13.75)
Spearman
Correlation
Wilcoxon
With
Spearman
>Median Rank Sum Baseline Correlation
(13.75)
p Value
(ρ)
p Value
Baseline
echocardiography
MV inflow: E velocity
at leaf tip (m/s)
150 0.9 (0.7,
1.1)
MV inflow: A velocity
at leaf tip (m/s)
111
0.7 (0.5,
0.9)
E/A ratio
111
LV relaxation septal
(medial) - E' (m/s)
1.0 (0.9,
1.3)
0.017
0.3529
<0.0001
146
0.9 (0.8,
1.1)
1.0 (0.8,
1.25)
0.07
0.1320
0.11
0.5 (0.3,
0.8)
0.006
−0.2483
0.009
110
0.6 (0.4,
0.8)
0.8 (0.5,
1.0)
0.10
0.1501
0.11
1.20
(0.92,
1.75)
2.00
(1.13,
3.67)
<0.001
0.4542
<0.0001
110
1.5 (1.0,
2.0)
1.5 (0.89,
2.0)
0.84
−0.0384
0.69
145
0.06
(0.05,
0.08)
0.06
(0.04,
0.08)
0.30
−0.1632
0.05
142 0.06 (0.05, 0.06 (0.04,
0.08)
0.08)
0.48
−0.0757
0.37
Filling pressure septal
(medial) - E/E' (m/s)
142
14 (10,
20)
17.5
(12.9,
25)
0.016
0.3666
<0.0001
139 14.6 (11.2, 16.7 (11.7,
20.0)
25.0)
0.12
0.1470
0.08
LA volume index
112
40.5
(31.2,
49.8)
52.2
(39.8,
59.4)
0.004
0.4454
<0.0001
110 40.9 (31.7, 44.5 (37.8,
55.4)
59.1)
0.13
0.1974
0.04
4
RVSP (mm Hg)
102
36.4
(32.0,
47.7)
43.6
(35.0,
51.2)
0.04
0.2842
0.004
99
40.5 (32.0, 43.4 (34.2,
51.0)
48.6)
0.44
0.0114
0.91
Echo LV mass index
116
71.5
(60.1,
85.3)
78 (63,
101)
0.11
0.1350
0.15
113 73.6 (62.9, 79.5 (59.4,
88.1)
98.0)
0.87
−0.0019
0.98
LV hypertrophy
116
0.48
0.078
0.41
113
0.16
0.128
0.18
Echo LV end-diastolic
volume index
78
50.6
(46.2,
65.2)
48.1
(42.6,
56.7)
0.06
−0.1271
0.27
77
50.1 (44.0, 50.8 (44.1,
60.4)
65.2)
0.55
0.0938
0.42
Echo LV end-systolic
volume index
78
21.6
(16.4,
29.9)
18.5
(15.3,
23.1)
0.15
−0.0763
0.51
77
21.3 (16.2, 20.0 (16.0,
25.7)
32.1)
0.51
0.0833
0.47
Echo LVEF (%)
158
61 (58,
68)
60 (55,
65)
0.12
−0.0903
0.26
154
60.5 (57, 60 (56, 66)
67)
0.40
−0.0877
0.28
LV stroke volume
141
84 (72,
103)
68 (57,
85.9)
0.0002
−0.2641
0.002
138 78.7 (64.6, 81.9 (65.2,
90.6)
93.5)
0.70
0.0266
0.76
Cardiac index
133
2754
(2201,
3114)
2282
(2024,
2751)
0.003
−0.2060
0.02
131
0.39
0.0379
0.67
Aortic distensibility
60
1.26
(0.67,
2.44)
0.95
(0.57,
1.20)
0.20
−0.2373
0.07
60
1.19 (0.66, 1.04 (0.61,
2.52)
1.73)
0.41
−0.0419
0.75
MRI LV mass (g)
87
137 (100, 136 (100,
169)
186)
0.45
0.0752
0.49
87
138 (101,
181)
129 (94,
161)
0.29
−0.0855
0.43
MRI EDV (ml)
87
105 (93,
135)
0.30
0.0847
0.44
87
117 (94,
137)
104 (93,
132)
0.38
−0.0176
0.87
29 (45.3) 27 (51.9)
26 (43.3)
30 (56.6)
Baseline cardiac MRI
122 (94,
132)
2414
(2064,
2843)
2528
(2162,
3066)
5
MRI ESV (ml)
87
36.0
(28.3,
52.7)
44.6
(27.5,
57.6)
0.16
0.1004
0.35
87
41.4 (31.2, 35.7 (25.5,
57.7)
51.0)
0.11
−0.0698
0.52
MRI LVEF (%)
87
67.0
(59.9,
70.7)
62.8
(51.8,
72.3)
0.23
-0.0794
0.46
87
63.2 (57.3, 68.0 (64.4,
69.4)
72.5)
0.08
0.1163
0.28
6
EDV = end-diastolic volume, ESV = endsystolic volume, LA = left atrium, LV = left
ventricle, LVEF = left ventricular ejection
fraction, MRI = magnetic resonance
imaging, MV = mitral valve, RVSP =
estimated right ventricular systolic pressure.
OnlineTable 3. Change in LV diastology measures with change in biomarker values at 24 weeks
NT-proBNP
Galectin-3
Spearman
Correlation Spearman
With
Correlation Adjusted p
N Change (ρ) p Value
Value
N
Spearman
Correlatio
n With Spearman
Change Correlation
(ρ)
p Value
Adjusted p
Value
Echocardiography change
from baseline to week 24
MV inflow: E velocity at leaf
tip (m/s)
143
0.21737
0.009
<.0001
139
−0.12792
0.13
0.20
MV inflow: A velocity at leaf
tip (m/s)
101 −0.16857
0.09
0.09
101
0.09448
0.35
0.08
E/A ratio
101
0.22015
0.03
0.0007
101
−0.00971
0.92
0.24
LV relaxation septal (medial) E' (m/s)
134 −0.01248
0.89
0.05
131
−0.08822
0.32
0.26
Filling pressure septal (medial)
- E/E' (m/s)
132
0.15375
0.08
<.0001
129
0.02135
0.81
0.51
LA volume index
99
0.05035
0.62
0.48
96
−0.21106
0.04
0.07
RVSP (mm Hg)
87
0.36574
0.0005
<.0001
84
0.00937
0.93
0.55
7
NT-proBNP
Galectin-3
Spearman
Correlation Spearman
With
Correlation Adjusted p
N Change (ρ) p Value
Value
N
Spearman
Correlatio
n With Spearman
Change Correlation
(ρ)
p Value
Adjusted p
Value
MRI change from baseline to
week 24
LV stroke volume
132
0.06044
0.49
0.55
129
−0.00875
0.92
0.68
Cardiac index
120
0.09514
0.30
0.52
118
−0.04523
0.63
0.72
Aortic distensibility
46
0.23030
0.12
0.19
45
0.03604
0.81
0.36
EDV = end-diastolic volume, ESV = end-systolic volume, LA = left atrium, LV = left ventricle, LVEF = left ventricular ejection fraction, MRI = magnetic resonance imaging, MV
= mitral valve, RVSP = right ventricular systolic pressure.
8
OnlineTable 4. Median IGFBP7 concentration in those receiving sildenafil compared with placebo at baseline and 24 weeks
IGFBP7 Measure
N
Sildenafil
Placebo
p Value for
Wilcoxon
IGFBP7
(N = 79)
(N = 81)
Rank
Change From
Median (25th, Median (25th,
Sum p
Linear
75th Percentile) 75th Percentile) Value
Regression
Baseline
160
240 (188, 289)
215 (180, 268)
0.17
-
Week 24
160
226 (189, 287)
230 (189, 269)
0.90
-
Change from baseline to week
24
159 −1.5 (−19, 13.6) 13.6 (−5.0, 31.2)
<0.001
0.001
9