Download abnormal peripheral muscle oxygenation during submaximal

ABNORMAL PERIPHERAL MUSCLE OXYGENATION DURING SUBMAXIMAL EXERCISE IN
PULMONARY ARTERIAL HYPERTENSION
PDF version available to : www.hypertensionarteriellepulmonaire.ca
Simon Malenfant BSc1,Vincent Mainguy MSc1, François Potus MSc1, Anne-Sophie Neyron BSc1, François Maltais MD1, Sébastien Bonnet PhD1, Didier Saey PhD1 and Steeve Provencher MD MSc1
de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, Canada
Abstract
Objectives
INTRODUCTION Pulmonary arterial hypertension (PAH) is a vascular remodeling disease
characterized by a progressive increase in pulmonary vascular resistance leading to right
ventricular failure. Despite therapies, most patients display persistent and significant exercise
intolerance. Many observations suggest that exercise limitation in PAH is not simply due to
pulmonary hemodynamic impairment but that other determinants intrinsic to the skeletal muscle
are involved. Importantly, cardiac output at rest and during exercise poorly correlates with the
disproportionate decrease in VO2max seen in this disease. A decrease in VO2max could also result
from a lower amount of muscle capillaries, impairing the O2 delivery to skeletal muscles. We
hypothesized that O2 delivery to skeletal muscles during exercise would be impaired in PAH
independently of cardiac output and arterial oxygen saturation.
1.  Comparing peripheral muscle microcirculation oxygenation at rest
and at submaximal exercise between PAH patients and healthy
controls.
2.  Exploring the possible link between the peripheral muscle
microcirculation oxygenation and cardiac output, systemic saturation
in O2 and exercise capacity.
METHOD 5 PAH patients were paired according to age, height, weight and sex with 5 healthy
controls. On day 1, we assessed maximum voluntary and involuntary muscle strength using
femoral nerve stimulation, muscle endurance and peak exercise capacity on an electrically
braked ergometer. On day 2, PAH patients performed 2 submaximal exercises at 70% of their
peak workload, with and without supplemental O2. Concentration of deoxyhemoglobin ([HHb]) in
the microcirculation of the dominant quadriceps was continuously measured using near-infrared
spectroscopy (NIRS). Non invasive cardiac output (CO) using the BMEYE Nexfin and systemic
oxygen saturation (SpO2) were also assessed. Healthy control carried out the sequence of
exercise to the same workload as the PAH patients with whom they were paired.
Methods
Pulmonary arterial hypertension (PAH) is a vascular remodeling disease
characterized by a progressive increase in pulmonary vascular resistance
leading to right ventricular failure. Despite therapies, most patients display
persistent and significant exercise intolerance1. Many observations suggest
that exercise limitation in PAH is not simply due to pulmonary hemodynamic
impairment2 but that other determinants intrinsic to the skeletal muscle are
involved3,4. Importantly, cardiac output at rest and during exercise poorly
correlates with the disproportionate decrease in VO2max seen in this disease5.
A decrease in VO2max could also result from a lower amount of muscle
capillaries, impairing the O2 delivery to skeletal muscles. We hypothesized that
O2 delivery to skeletal muscles during exercise would be impaired in PAH
independently of cardiac output and arterial oxygen saturation
Muscle deoxyhemoglobin ([HHb]) by near infrared
spectroscopy (NIRS)
Cardiac output (CO) by BMEYE Nexfin
Systemic pulse oxymetry (SpO2) by portable
telemetric system
Day 2
Blood
sampling
MVC
Twq
Submaximal
exercise*
MVC
Twq
Nexfin + NIRS on the dominant
quadriceps continuously monitored
Without O2 supplementation
VO2 max in
supine position
Endurance
Resting
period
(60 min)
MVC
Twq
Submaximal
exercise*
40
40
1010
30
=0.81
0.81
2R == 0.81
RR
0.01
0.01
ppp<<<
0.01
2
2
20
20
10
10
00
-10
-10
20
20
30
40
30
40
VO2 max (mLO2/Kg/min)
88
66
4
PAH : Ÿ
Controls : Δ
4
22
00
Increase in [HHb] (%)
40
30
2020
20
1010
10
00
0
pp== 0.78
0.78
pp== 0.62
0.62
10
55
5
00
0
00
0
-5-5
-5
-10
-10
-10
-15
-15
p = 0.03
p = 0.03
Healthy
controls
n=5
[HHb]
with O2
pp<< 0.01
0.01
15
1010
-2-2
[HHb]
without O2
pp<< 0.01
0.01
3030
1515
CO (L/min)
0.52
< 0.01
0.01
< 0.01
< 0.01
0.46
0.09
< 0.01
< 0.01
0.03
0.75
0.78
0.04
0.08
0.04
4040
Individual differences in Δ [HHb]
during submaximal exercise
in PAH patients and
healthy controls
Correlation between [HHb]
without O2 supplementation
and exercise capacity
30
Without O2 supplementation With O2 supplementation
p-value*
Δ SpO2 (%)
Recent syncope
WHO functional class IV
6MWT distance < 300 m
Total lung capacity < 80% of predicted
FEV1/FVC < 70%
Left ventricle ejection fraction < 40%
Study design
MVC
Twq
BMI
Peak workload (W)
Peak heart rate (bpm)
VO2 peak (mLO2/min)
VO2 peak (mLO2/kg/min)
RER
VE (L/min)
VE/VCO2
O2 pulse (mL/batt.)
SpO2 @ peak power (%)
Borg scale – leg fatigue
Borg scale – dyspnea
Maximum voluntary strength (Kg)
Maximum involuntary strength (Kg)
Endurance (N⋅m)
Healthy controls
(n = 5)
24.8 (3.9)
116 (21)
166 (25)
1729 (354)
26.7 (5.1)
1.25 (0.08)
71 (16)
33 (4)
10.3 (1.3)
98 (1)
6 (3)
7 (2)
30.2 (6.0)
9.6 (1.3)
2000 (543)
Submaximal exercise*
*Analyzed by unpaired t-test, values are mean (sd)
Study measurements
Background
PAH
(n = 5)
22.9 (5.0)
55 (22)
126 (16)
845 (266)
14.1 (2.0)
1.21 (0.11)
55 (12)
47 (8)
6.7 (1.9)
87 (9)
5 (3)
6 (2)
22.0 (4.5)
8.1 (1.0)
1244 (411)
(Kg/m2)
> 25 mmHg au repos
WHO functional class II-III
Stable condition
Exclusions criteria
Day 1
Physiological parameters (n = 10)
Δ [HHb] (μmol/s)
RESULTS PAH patients had a lower peak workload (55 (22) vs 116 (21) W, p<0.01), heart rate (126
(16) vs 166 (25) bpm, p=0.01), relative VO2 max (14.1 (2.0) vs 26.7 (5.1) mlO2/Kg/min, p<0.01), O2
pulse (6.7 (1.9) vs 10.3 (1.3) mL/beat, p<0.01), maximal voluntary contraction (22.0 (4.5) vs 30.2
(6.0) Kg, p=0.04) and muscular endurance (1244 (411) vs 2000 (543) Nm, p=0.04 ) compared to
healthy controls, whereas ventilatory equivalent for CO2 was higher (47 (8) vs 33 (4), p<0.01). At
submaximal exercise (mean Wpeak @ 70% = 39 (15) W) without O2 supplementation, PAH patients
showed an increase [HHb] in dominant quadriceps that was significantly higher compared to
controls (+28 (+5) vs +7 (+6) %, p<0.01) despite similar CO at the end of exercise (9,6 (3,8) vs 9,0
(1,8) L/min, p=0.78). The variation of the SpO2 between rest and submaximal exercise showed a
significant difference for PAH patients (-7,0 (-5,4) vs. -0,4 (-0,9) %, p=0.03) compared to healthy
controls. The increased [HHb] during submaximal exercise strongly correlated with exercise
capacity (R2=0,81, p <0.01). The addition of supplemental O2 did not significantly influence the
increase of quadriceps [HHb] during exercise (+27 (+7) vs +11 (+8)%, p<0.01) for PAH patients.
CONCLUSION These preliminary results suggest that PAH patients exhibit an inadequate muscle O2
supply during submaximal exercise that is not related to cardiac output. Impaired O2 delivery may
contribute to exercise intolerance of PAH subjects.
PAH patients’ characteristics
Results
Increase in [HHb] (%)
1Centre
PAH
patients
n=5
pp== 0.03
0.03
-15
Healthy
controls
n=5
PAH
patients
n=5
*Analyzed by unpaired t-test, values are mean (sd)
MVC
Twq
Nexfin + NIRS on the dominant
quadriceps continuously monitored
Conclusion
With O2 supplementation!
PAH patients seem to have an insufficient muscle oxygen supply, independently from the central component and independently from exercise
intensity, as reflected by an O2 extraction at a capillary level more important compared to healthy controls. O2 extraction is not significantly
modified by O2 supplementation, suggesting peripheral microcirculation abnormalities. Those abnormalities are correlating with the patient’s
exercise capacity. Thus, abnormal peripheral muscle microcirculation could contribute to exercise intolerance of PAH patients.
* 70% peak workload for PAH patients. Controls exercised at the same workload as their matched PAH patients
References
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2. 
3. 
Galiè N et al., Eur Heart J, 2009, 30(20), pp 2493-2537.
Provencher S et al., Eur Respir J, 2008, 32(2), pp 393-398.
Harrington D et al., JACC, 1997, 30(7), pp 1758-1764.
4. 
5. 
Mainguy V et al., Thorax, 2010, 65(2), pp 113-117.
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