Exercise capacity in COPD patients with exercise-induced pulmonary hypertension

Figures & data

Table 1 Patient characteristics and echocardiographic data for 93 patients with COPD divided into three groups by mPAP at rest and ΔmPAP/ΔCO slope

Variable	mPAPrest <25 mmHg		mPAPrest ≥25 mmHg	p-value
	ΔmPAP/ΔCO slope ≤3 mmHg/L/min	ΔmPAP/ΔCO slope >3 mmHg/L/min
	n=29	n=42	n=22
Gender, female %	31	62*	59	0.03
Age, years^¤	62 (5)	66 (6)*	61 (8)#	0.03
Height, cm^¤	173 (8)	167 (9)*	169 (11)	0.02
BMI kg/m^2	27 (4)	23 (4)*	25 (6)	0.004
Hemoglobin, g/dL	14.7 (1.4)	14.3 (1.0)	14.3 (1.1)	0.38
FEV1 % pred.	51 (15)	45 (17)	29 (9)*,#	<0.001
FVC % pred.	79 (20)	75 (21)	59 (16)*,#	0.001
FEV1/FVC %	53 (9)	48 (11)	41 (11)*	0.001
TLC % pred.	114 (14)	129 (21)	136 (26)*	0.001
RV % pred.^¤	171 (41)	209 (65)*	253 (57)*,#	<0.001
RV/TLC %^¤	54 (11)	62 (10)*	69 (9)*,#	<0.001
DLCO % pred.	63 (16)	52 (20)*	30 (14)*,#	<0.001
LV EF, %	58 (3)	57 (5)	58 (4)	0.63
LV E/A ratio (no unit)	1.08 (0.26)	1.05 (0.29)	1.06 (0.27)	0.89
LV E/E’ ratio (no unit)	9.0 (2.2)	8.6 (2.2)	10.1 (2.0)#	0.03
LA volume, mL/m^2	24 (5)	23 (5)	21 (6)	0.09
TAPSE, mm	22.9 (2.7)	21.3 (2.9)	18.8 (3.8)*,#	<0.001
RV FAC, %	0.38 (0.08)	0.39 (0.07)	0.33 (0.08)#	0.02

Notes: ANOVA was performed for variables with normal distribution, otherwise ¤non-parametric Kruskal–Wallis test was performed. Values are presented as mean (standard deviation) or %. For TLC and RV, n=90. For DLCO, n=83.

* p<0.05, significantly different from mPAP_rest <25 mmHg and ΔmPAP/ΔCO slope ≤3 mmHg/L/min.

# p<0.05, significantly different from mPAP_rest <25 mmHg and ΔmPAP/ΔCO slope >3 mmHg/L/min.

Abbreviations: mPAP, mean pulmonary artery pressure; CO, cardiac output; BMI, body mass index; FEV₁, forced expiratory volume in 1 second; pred., predicted; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume; DLCO, diffusion capacity of the lung for carbon monoxide; LV, left ventricular; EF, ejection fraction; E, transmitral early diastolic velocity; A, late diastolic velocity; E’, septal mitral annular early diastolic tissue velocity; LA, left atrial; TAPSE, tricuspid annulus plane systolic excursion; RV, right ventricular; FAC, fractional area change.

Table 2 Hemodynamic data by right heart catheterization at rest and peak exercise in 93 patients with COPD divided into three groups by mPAP at rest and ΔmPAP/ΔCO slope

Variable	mPAPrest <25 mmHg		mPAPrest ≥25 mmHg	p-value
	ΔmPAP/ΔCO slope ≤3 mmHg/L/min	ΔmPAP/ΔCO slope >3 mmHg/L/min
	n=29	n=42	n=22
mPAP rest, mmHg	17.9 (3.9)	18.1 (3.2)	28.7 (4.6)*,#	<0.001
mPAP peak, mmHg	33.6 (7.0)	39.1 (7.1)*	48.6 (6.7)*,#	<0.001
PAWP rest, mmHg	9.0 (3.2)	7.8 (3.4)	10.7 (2.8)#	0.01
PAWP peak, mmHg	16.7 (4.2)	16.7 (4.1)	15.8 (3.7)	0.69
CO rest, L/min	5.3 (0.8)	4.9 (1.0)	5.5 (1.2)	0.07
CO peak, L/min	12.3 (1.4)	9.0 (2.1)*	9.0 (2.6)*	<0.001
CI rest, L/min/m^2	2.8 (0.4)	2.9 (0.4)	3.1 (0.5)*	0.04
CI peak, L/min/m^2	6.4 (0.8)	5.2 (1.1)*	5.0 (1.0)*	<0.001
PVR rest, WU	1.67 (0.57)	2.19 (0.97)	3.43 (1.51)*,#	<0.001
PVR peak, WU	1.38 (0.37)	2.65 (1.04)*	3.97 (1.56)*,#	<0.001
TPR rest, WU	3.4 (0.8)	3.8 (1.0)	5.5 (1.6)*,#	<0.001
TPR peak, WU	2.7 (0.5)	4.6 (1.3)*	5.8 (1.8)*,#	<0.001
mRAP rest, mmHg	5.5 (3.3)	4.7 (3.2)	6.9 (3.0)#	0.03
mRAP peak, mmHg	9.3 (4.2)	9.6 (2.4)	10.7 (3.3)	0.27
ΔmPAP/ΔCO slope, mmHg/L/min	2.3 (0.6)	6.2 (3.5)*	7.3 (5.0)*	<0.001

Notes: ANOVA between the three groups. Values are presented as mean (standard deviation).

* p<0.05, significantly different from mPAP_rest <25 mmHg and ΔmPAP/ΔCO slope ≤3 mmHg/L/min.

# p<0.05, significantly different from mPAP_rest <25 mmHg and ΔmPAP/ΔCO slope >3 mmHg/L/min.

Abbreviations: mPAP, mean pulmonary artery pressure; CO, cardiac output; PAWP, pulmonary arterial wedge pressure; CI, cardiac index; PVR, pulmonary vascular resistance; TPR, total pulmonary resistance; mRAP, mean right atrial pressure.

Table 3 Cardiopulmonary exercise test characteristics at rest and during exercise in 93 patients with COPD divided into three groups by mPAP at rest and ΔmPAP/ΔCO slope

Variable	mPAPrest <25 mmHg		mPAPrest ≥25 mmHg	p-value
	ΔmPAP/ΔCO slope ≤3 mmHg/L/min	ΔmPAP/ΔCO slope >3 mmHg/L/min
	n=29	n=42	n=22
Peak load, watt	89 (23)	60 (31)*	40 (21)*,#	<0.001
${\dot{\mathrm{V}}\text{O}}_2$ peak, mL/kg/min	18.3 (4.8)	17.1 (3.9)	13.9 (3.0)*,#	0.001
${\dot{\mathrm{V}}\text{O}}_2$ peak/kg % pred.	57 (16)	59 (14)	46 (13)*,#	0.003
MVV rest, L/min¤	67 (25)	47 (21)*	34 (12)*,#	<0.001
Ventilation peak, L/min¤	53 (15)	42 (15)*	35 (12)*	<0.001
Ventilation peak % pred.	58 (17)	55 (20)	43 (15)*	0.01
Ventilatory reserve, %	16 (25)	5 (19)	−7 (19)*	0.001
$\dot{\mathrm{V}}\text{E}/{\dot{\mathrm{V}}\text{CO}}_2$ nadir	36 (7)	37 (6)	41 (8)*	0.05
$\dot{\mathrm{V}}\text{E}/{\dot{\mathrm{V}}\text{CO}}_2$ slope	35 (9)	34 (8)	32 (9)	0.53
Heart rate rest, beats/min	87 (18)	90 (16)	96 (18)	0.16
Heart rate peak, beats/min	134 (18)	134 (17)	130 (19)	0.68
O2-pulse peak mL/beat	10.9 (2.7)	8.3 (2.5)*	7.5 (2.1)*	<0.001
O2-pulse peak % pred.	72 (14)	64 (20)	55 (12)*	0.003
Systemic MAP rest, mmHg	95 (12)	95 (16)	93 (10)	0.77
Systemic MAP peak, mmHg	133 (21)	136 (28)	129 (23)	0.55
RER peak	0.96 (0.13)	0.95 (0.13)	0.90 (0.12)	0.20
PaO2 rest, mmHg	77 (11)	72 (8)	61 (11)*,#	<0.001
PaO2 peak, mmHg	74 (12)	68 (12)	50 (8)*,#	<0.001
PaCO2 rest, mmHg	39 (3)	41 (5)	44 (5)*	0.008
PaCO2 peak, mmHg	41 (5)	43 (7)	48 (8)*,#	<0.001
SaO2 rest, %¤	96 (2)	95 (2)*	92 (5)*,#	<0.001
SaO2 peak, %¤	94 (3)	93 (4)	84 (8)*,#	<0.001
pH peak	7.36 (0.03)	7.36 (0.03)	7.35 (0.04)	0.86
Lactate peak, mmol/L¤	5.6 (2.2)	5.6 (2.9)	4.1 (2.4)*,#	0.03
Lactate peak % pred.¤	75 (31)	81 (42)	57 (39)*,#	0.02

Notes: ANOVA was performed for variables with normal distribution, otherwise

¤ non-parametric Kruskal–Wallis test was performed. Values are presented as mean (standard deviation).

* p<0.05, significantly different from mPAP_rest <25 mmHg and ΔmPAP/ΔCO slope ≤3 mmHg/L/min.

# p<0.05, significantly different from mPAP_rest <25 mmHg and ΔmPAP/ΔCO slope >3 mmHg/L/min.

Abbreviations: mPAP, mean pulmonary artery pressure; CO, cardiac output; ${\dot{\mathrm{V}}\text{O}}_2$, oxygen uptake; pred., predicted; $\dot{\mathrm{V}}\text{E}$, ventilation; ${\dot{\mathrm{V}}\text{CO}}_2$, carbon dioxide production; O₂-pulse, oxygen pulse; MAP, mean arterial pressure; RER, respiratory exchange ratio; PaO₂, arterial oxygen tension; PaCO₂, arterial carbon dioxide tension; SaO₂, oxygen saturation; MVV, maximal voluntary ventilation.

Figure 1 (A) First horizontal panel shows the number of COPD patients able to exercise at a specific load; from left to right the graphs present patients with normal hemodynamic response, patients with exercise-induced pulmonary hypertension, patients with pulmonary hypertension and all patients. The next panels show the development of variables during exercise for each patients, as well as the mean values represented by light blue lines for COPD-normal, red lines for COPD-EIPH, and dark blue lines for COPD-PH. With increasing load, fewer patients are represented in the presentation of the mean. (B) Development of arterial blood gases, lactate, and pH during exercise.

Abbreviations: EIPH, exercise-induced pulmonary hypertension; PaO₂, arterial oxygen tension; PaCO₂, arterial carbon dioxide tension; PH, pulmonary hypertension; SaO₂, oxygen saturation; ${\dot{\mathrm{V}}\text{O}}_2$, oxygen uptake.

Table 4 Estimated differences between COPD patients with normal exercise responses, exercise-induced pulmonary hypertension, and pulmonary hypertension at rest in a linear mixed model that includes measurements at rest and each level of exercise, adjusted for gender, age, and FEV₁

Variable		Estimate (95% CI)	Difference (95% CI)	p-value
$\dot{\mathbf{V}}{\mathbf{O}}_2$, mL/kg/min	Level/intercept
	COPD-EIPH (n=29)	2.5 (−0.5, 5.5)		0.10
	COPD-normal (n=42)		−0.3 (−0.8, 0.3)	0.34
	COPD-PH (n=22)		−0.1 (−0.8, 0.7)	0.82
	Slope
	COPD-EIPH	1.9 (1.7, 2.1)		<0.001
	COPD-normal		−0.5 (−0.8, −0.3)	<0.001
	COPD-PH		0.2 (−0.2, 0.6)	0.20
Ventilation, L/min	Level/intercept
	COPD-EIPH	1.5 (−7.7, 10.7)		0.75
	COPD-normal		1.2 (−0.7, 3.1)	0.20
	COPD-PH		3.3 (1.7, 5.6)	0.04
	Slope
	COPD-EIPH	4.6 (4.2, 5.0)		<0.001
	COPD-normal		−0.5 (−1.1, 0.0)	0.05
	COPD-PH		0.4 (−0.4, 1.1)	0.31
Respiratory frequency, breaths/min	Level/intercept
	COPD-EIPH	14 (2, 26)		0.02
	COPD-normal		1 (−1, 4)	0.27
	COPD-PH		3 (0.3, 6)	<0.001
	Slope
	COPD-EIPH	2.3 (1.9, 2.6)		<0.001
	COPD-normal		−0.6 (−1.1, −0.2)	0.004
	COPD-PH		0.0 (−0.6, 0.6)	0.91
Heart rate, beats/min	Level/intercept
	COPD-EIPH	111 (73, 149)		<0.001
	COPD-normal		5 (−5, 14)	0.32
	COPD-PH		−1 (−12, 9)	0.83
	Slope
	COPD-EIPH	7.7 (6.8, 8.7)		<0.001
	COPD-normal		−2.6 (−4.1, −1.1)	<0.001
	COPD-PH		1.1 (−0.7, 2.9)	0.23
O2-pulse, mL/beat	Level/intercept
	COPD-EIPH	2.5 (−0.01, 5.1)		0.05
	COPD-normal		0.3 (−0.2, 0.9)	0.24
	COPD-PH		0.2 (−0.4, 0.9)	0.48
	Slope
	COPD-EIPH	0.65 (0.57, 0.73)		<0.001
	COPD-normal		−0.01 (−0.12, 0.11)	0.90
	COPD-PH		−0.15 (−0.003, 0.33)	0.11
PaO2, mmHg	Level/intercept
	COPD-EIPH	61 (42, 80)		<0.001
	COPD-normal		−0.4 (−5, 4)	0.87
	COPD-PH		−6 (−11, −2)	0.01
	Slope
	COPD-EIPH	−0.6 (−1.1, −0.1)		0.03
	COPD-normal		0.3 (−0.5, 1.1)	0.41
	COPD-PH		−2.0 (−3.1, −1.0)	<0.001
PaCO2, mmHg	Level/intercept
	COPD-EIPH	48 (38, 62)		<0.001
	COPD-normal		−0.8 (−3.0, 1.5)	0.50
	COPD-PH		0.8 (−2.3, 3.0)	0.65
	Slope
	COPD-EIPH	0.5 (0.2, 0.7)		0.002
	COPD-normal		−0.2 (−0.7, 0.1)	0.15
	COPD-PH		0.9 (0.5, 1.4)	<0.001
Lactate, mmol/L	Level/intercept
	COPD-EIPH	−0.2 (−2.2, 1.8)		0.85
	COPD-normal		0.1 (−0.3, 0.5)	0.73
	COPD-PH		0.1 (−0.6, 0.5)	0.83
	Slope
	COPD-EIPH	0.8 (0.6, 0.9)		<0.001
	COPD-normal		−0.3 (−0.4, 0.1)	0.002
	COPD-PH		0.1 (−0.1, 0.3)	0.52
pH	Level/intercept
	COPD-EIPH	7.34 (7.31, 7.41)		<0.001
	COPD-normal		0.003 (−0.008, 0.138)	0.60
	COPD-PH		0.006 (−0.006, 0.019)	0.31
	Slope
	COPD-EIPH	−0.01 (−0.01, −0.01)		<0.001
	COPD-normal		0.004 (0.001, 0.006)	0.005
	COPD-PH		−0.006 (−0.01, −0.00)	0.002

Notes: COPD-EIPH: mPAP_rest <25 mmHg and ΔmPAP/ΔCO slope >3 mmHg/L/min. COPD-normal: mPAP_rest <25 mmHg and ΔmPAP/ΔCO slope ≤3 mmHg/L/min. COPD-PH: mPAP_rest ≥25 mmHg. Reference group: COPD-EIPH. Significant differences between groups are shown in bold.

Abbreviations: mPAP, mean pulmonary artery pressure; CO, cardiac output; VO₂, oxygen uptake; O₂-pulse, oxygen pulse; PaO₂, arterial oxygen tension; PaCO₂, arterial carbon dioxide tension; SaO₂, oxygen saturation; EIPH, exercise-induced pulmonary hypertension; PH, pulmonary hypertension.