Online Appendix
Individual cases
Using the combined cardio-pulmonary and echo stress protocol we were able to recognize individual etiologies for effort intolerance.
The patient shown in figure 2 had HFpEF combined with severe chrontropic incompetence and markedly reduced LV compliance. Because of
the low compliance E wave deceleration time was markedly short, and even at peak exercise mitral inflow E and A waves where not fused,
resulting in "wasted diastolic filling time" at peak exercise. Diminution of calcium blockers resulted in faster peak heart rate, optimal diastolic
time duration, resulting in partial fusion of E and A waves at peak exercise, and improved cardiac output and peak VO2.
The patient in figure 3 had severe systolic dysfunction at rest, effort dyspnea, and was referred to the combined test before consideration of left
ventricular assist device. Stroke volume improved noticeably during exercise related to an increase in end diastolic volume and ejection fraction.
However, the calculated A-VO2 difference was found to be low at peak exercise (0.1) although RER was normal (1.1) suggesting possible
reduced extraction of oxygen at peripheral muscles due to impaired fitness. The patient underwent cardiac rehabilitation for 12 weeks (two
sessions a week) with improvement of symptoms and effort capacity.
Online Figure 1. (A) Normal mitral inflow E wave and A waves at rest (a) and E' (b) in a control patient at baseline and at peak exercise (c,d).
Note that E/E' ratio remains below 8 throughout exercise, and the normal fused E and A waves during peak exercise. (B) A patient with HFpEF
presented with effort dyspnea. At baseline E/A was 3, deceleration time was 146msec (a) and E' was 3 (b) all suggestive of severe diastolic
dysfunction and markedly disturbed LV compliance at rest (restrictive physiology). At peak exercise heart rate increased only to 95 (58% of
predicted), O2 pulse was 7 cc/beat (44% of predicted), VO2/kg was 8.4 cc/kg/min (25% of predicted) and VO2/cardiac output was 0.14 (normal).
Mitral inflow at peak exercise (c) showed that even at peak exercise mitral inflow E and A waves where not fused, E wave deceleration time was
markedly short (119msec) and the diastasis period (arrow) was prolonged, suggesting "wasted diastolic time" at peak exercise, and that even
with faster heart rate, and shorter diastolic period, LV filling will not worsen. E' velocity did not change (d) resulting in high E/E' ratio at peak
exercise suggesting markedly elevated LV end diastolic pressure. Calcium blockers were weaned and the exam was repeated a week later. At
the second exam peak exercise heart rate increased to 120 (73% of predicted), O2 pulse increased to 9 cc/beat (56% of predicted), VO2/kg
increased to 13.7 cc/kg/min (41% of predicted) and symptoms improved considerably. Mitral inflow at peak exercise (e) after weaning the
calcium blockers showed partial fusion of E and A waves with no "wasted diastolic filling time (persistence of diastasis at peak exercise). E' at
peak exercise increased to 5 suggesting improvement in active relaxation and LV end diastolic pressure at peak exercise (f).
E: Mitral Inflow E wave; A: Mitral Inflow A wave; E': Tissue Doppler Early Diastolic velocity of Septal Annulus; A': Tissue Doppler End
Diastolic velocity of Septal Annulus; F: Fused Mitral Inflow E and A wave; F': Tissue Doppler Early and Late Fused Diastolic velocity of Septal
Annulus.
Online Figure 1a
Online Figure 1b.
Online Figure 2. A patient with HFrEF (ejection fraction 30%) presented with effort dyspnea. At peak exercise heart rate increased to 145 (87%
of predicted), O2 pulse was 13 cc/beat (75% of predicted), peak VO2 was 1950 cc/min (83% of predicted), saturation was normal throughout the
exam (97%), hemoglobin was normal (14.1 mg/dL). Upper right panel) The pattern of increase in VO2 (liters/minute) and VCO2 as related to
increasing work rate in the first exam shows that effort capacity is impaired but there is no flattening in the curve of VO2 related to increasing
work rate. Lower left panel) Left ventricular outflow track flow integral at rest shows markedly low stroke volume (46cc). Upper right panel)
Left ventricular outflow track flow integral at unloaded exercise shows marked improvement in stroke volume (98cc). The doubling of stroke
volume with minimal exercise was related to the excellent compliance enabling the Frank-Starling mechanism to increase the end diastolic
volume, ejection fraction and stroke volume during exercise.Although his rest ejection fraction was low, cardiac function improved significantly
at exercise and was not the main cause of effort intolerance. The A-VO2 difference was calculated and found to be low at peak exercise (0.1)
although RER was normal (1.1) suggesting impaired peripheral oxygen extraction (low fitness). The patient underwent cardiac rehabilitation for
12 weeks (two sessions a week) with discontinuation of symptoms. He repeated the protocol which showed normalization of effort capacity
(lower right panel). Note that the pattern of increase in VO2 (liters/minute) and VCO2 as related to increasing work rate in the second exam
shows normalization of effort capacity despite the low rest ejection fraction.
Online Figure 2.
Online Table 1. Multivariate analyses to explore the contribution of the different rest and unloaded effort parameters on maximal effort capacity
(VO2 max)
Age, years
LAVI, cc/m2
Cardiac output rest
EDV for E/e' rest
S' rest
EF rest
E/e' ratio rest
SV stress
HR, stress
EDV for E/e' stress
SVR stress
S' stress
EF, stress
MR volume, stress
VO2/CO stress
P value
R2 *
VO2 by rest
VO2 by unloaded
Regression Coefficient; P‐Value
−0.006; P=0.05
P=0.9
P=0.2
0.04; P<0.0001
0.21; P<0.0001
P=0.2
P=0.3
Regression Coefficient; P‐Value
P=0.2
P=0.2
0.15; P=0.0006
P=0.4
P=0.7
0.04;P<0.0001
P=0.8
P=0.9
P=0.4
<0.0001
0.71
<0.0001
0.87
Online Table 2. "HFpEF Borderline" Characteristics
Variable
Age, years
Gender, male n (%)
Ejection fraction, %
Diastolic dimension, mm
Systolic dimension, mm
End diastolic volume, cc
End diastolic volume index, cc/ m2
End systolic volume, cc
End systolic volume index, cc/ m2
LV mass index gram/ m2
Relative Wall Thickness
LAVI, cc/m2
Stroke volume cc/beat
Cardiac output liter/minute
Cardiac index liter/minute/ m2
Mitral inflow E wave m/sec
Mitral inflow A wave m/sec
Mitral inflow DT, ms
E' cm/sec
E/e' ratio
S' cm/sec
Right ventricle systolic pressure, mm Hg
FVC liter
FVC, %Predicted
FEV1 liter/sec
Borderline (n=8)
60.7±5
5(62)
48.9±5.8*‡
57.0±7.7*‡
43.8±10*‡
174±63*‡
92.6±29*
89.7±36*‡
47.5±16*‡
123±40
0.33±0.1*
46.9±22
81.3±17‡
5.8±1.6‡
3.1±1.1‡
0.79±0.23
0.52±0.28
185±49
5.1±1.5
16.6±7.8
4.0±0.9
38.5±9.1
2.8±0.9
90.3±14
2.9±0.9
FEV, %Predicted
FEV1/FVC ratio
FEV1/FVC ratio, %Predicted
VO2 @AT liter/minute
VE/VCO2 ratio @AT
Work Load Watts
O2 pulse max mL/beat
VO2 max liter/minute
VO2 max, %Predicted
VO2/kg max mL/minute/kg
VO2/kg, %Predicted
RER ratio
‡P<0.05 compared to HFrEF
92.3±16
84.6±10
110.3±15
0.88±0.4
35.2±4.8
104.3±52
11.3±4.1
1.28±0.5
62.0±10
15.7±5.6
61.5±8.2
1.05±0.1
Online Table 3. Baseline, unloaded, anaerobic threshold (AT), and maximal exercise cardio-pulmonary stress and echo characteristics of the
HFpEF, "HFpEF borderline", HFrEF and control
Measurement
Baseline
Unloaded
Effort
Anaerobic
Threshold
Maximal
Effort
End
diastolic
volume,
mL
End
systolic
volume,
mL
Ejection
Fraction
(%)
Normal
HFpEF
HFrEF
Intermediate
Normal
HFpEF
HFrEF
Intermediate
Normal
HFpEF
HFrEF
Intermediate
Normal
HFpEF
HFrEF
Intermediate
Normal
HFpEF
123.4±20
122.6±18
230.6±40
174.7±63
44.0±13
41.1±11
169.6±42
89.3±36
64.7±7
66.5±7
27.3±6
48.6±4.8
7.1±1.4
4.9±1.2
3.4±1.0
4.1±0.9
8.0±2.5
5.8±1.7
138.8±19
128.6±22
237.0±43
220.6±73
37.6±10
39.7±12
164.8±43
109.7±41
73.1±6
69.2±6
31.0±10
50.3±8
8.7±2.3
5.9±1.7
4.0±1.8
5.3±1.5
9.9±2.4
6.9±2.5
158.3±22
127.4±18
234.1±48
202.7±72
41.2±16
35.0±15
152.0±41
88.9±48
74.1±9
72.8±10
35.1±11
59.1±13
10.3±1.9
7.7±2.9
4.9±2.3
5.9±1.9
14.7±4.3
8.1±4.4
133.3±23
118.1±18
223.8±57
198.2±44
36.7±16
33.4±17
146.1±54
90.6±35
73.0±10
72.1±11
34.6±14
53.5±11
10.4±2.3
8.0±2.8
5.4±3.1
7.3±3.1
17.8±4.4
9.5±5.0
P value
for each
group
<0.0001
0.12
0.8
0.03
0.09
0.09
0.08
0.06
0.001
0.06
0.2
0.4
0.01
0.01
0.05
0.02
<0.0001
0.03
HFrEF
Intermediate
Normal
HFpEF
HFrEF
Intermediate
Normal
HFpEF
HFrEF
Intermediate
Normal
HFpEF
HFrEF
Intermediate
Normal
HFpEF
HFrEF
Intermediate
Normal
HFpEF
3.7±1.9
5.4±1.5
9.3±3.9
14.6±5.1
25.2±13.5
17.6±7.8
77.3±10
78.8±17
50.8±4.1
81.8±16
4.5±1.1
4.8±1.2
4.7±1.1
4.9±1.2
80.2±9
76.6±14
77.6±8.4
70.6±9
6.2±1.1
6.0±1.5
4.6±2.0
6.0±1.8
9.6±3.6
16.3±5.8
20.7±5.8
23.4±16
92.1±15
91.0±20
58.5±20
76.5±13
6.5±1.2
6.7±1.7
5.7±1.9
6.3±1.6
87.1±11
85.6±15
93.5±19
81.8±15
8.0±1.8
7.7±2.0
6.1±2.7
7.3±2.8
8.7±3.0
18.3±10.3
17.9±8.6
21.1±15
105.0±16
94.5±24
71.2±34
83.7±20
10.3±2.8
8.9±2.6
8.3±1.8
9.3±3.6
120.7±20
98.7±22
103.1±15
93.2±17
12.6±2.6
9.4±3.5
6.6±3.9
7.9±3.7
7.6±2.3
17.8±9.5
23.1±9.3
19.9±8.7
98.6±13
86.7±19
66.3±34
80.2±30
12.7±3.8
11.3±3.6
10.0±3.8
11.4±4.1
156.0±20
109.3±31
120.3±15
105.2±22
14.5±2.9
9.6±4.2
0.1
0.3
0.02
0.08
0.4
0.6
<0.0001
0.007
0.02
0.2
<0.0001
<0.0001
0.03
0.02
<0.0001
<0.0001
0.04
0.004
<0.0001
0.007
Tissue
Doppler
S',
cm/sec
Tissue
Doppler
e',
cm/sec
E/e'
Ratio
Stroke
Volume,
mL
O2
pulse,
cc/beat
Heart
Rate,
BPM
Cardiac
Output,
Within
Group
Between
Groups
Time*Group
Interaction
<0.0001
<0.0001
0.004
0.003
<0.0001
0.03
<0.0001
<0.0001
0.3
<0.0001
0.003
0.3
<0.0001
<0.0001
0.001
0.8
0.004
0.03
<0.0001
0.002
0.01
<0.0001
0.5
0.3
<0.0001
0.002
0.0001
<0.0001
0.0001
0.003
L/min
HFrEF
4.0±0.5
4.8±1.2
6.5±3.3
7.1±4.9
0.6