Chronotropic incompetence can limit exercise tolerance in COPD patients with lung hyperinflation

Figures & data

Figure 1 Relationship between dynamic inspiratory capacity (IC_dyn) changes from rest to peak with chronotropic-metabolic index and percentage of age-predicted maximum heart rate (HR_max), (A and B), respectively.

Notes: Global Initiative for Chronic Obstructive Lung Disease stages (stage 1: half-full dots; stage 2: empty squares; stage 3 and 4: filled triangles). The broken-line trend is represented by the black solid lines.

Table 1 Subject characteristics

GOLD stage	Stage I	Stage II	Stage III–IV	P-value
Sample size	n=6	n=26	n=15
Age, years	53.5 (49; 56)	60 (54; 64)‡	49 (44; 56)‡	0.031
BMI, kg·m^−2	26.0 (23.8; 26.4)	27.8 (22.8; 30.7)	21.9 (18.9; 29.1)	0.224
Gender, M/F	4/2	22/4	7/8	0.028
Smoking status, % current	50	40	20	0.238
Smoking, pack-year	30 (30; 40)	27.5 (16.5; 40)	42.5 (25; 61)	0.279
Lung function test
FEV1 L	3.2 (3.0; 3.4)*,#	2.1 (1.8; 2.6)*,‡	1.4 (1.2; 1.7)#,‡	<0.001
FEV1 % predicted	0.88 (0.83; 0.94)*,#	0.66 (0.59; 0.72)*,‡	0.45 (0.34; 0.48)#,‡	<0.001
FVC, L	4.9 (4.4; 5.7)*,#	3.8 (3.1; 4.3)*,‡	3.1 (2.7; 3.6)#,‡	<0.001
FEV1/FVC, %	67.2 (64.8; 68.4)*,#	58.8 (54.1; 63.7)*,‡	47.8 (32.6; 54.5)#,‡	<0.001
IC, L	3.2 (3.0; 4.4)#	2.8 (2.4; 3.3)‡	2.1 (1.9; 2.7)#,‡	0.001
TLC, L	7.4 (6.7; 8.1)	6.1 (5.6; 7.3)	6.5 (5.8; 7.5)	0.187
FRC, L	3.7 (3.6; 3.9)	3.5 (3.0; 4.6)	4.5 (3.5; 4.8)	0.248
IC/TLC	45.7 (40.8; 53.8)#	41.5 (38.8; 47.1)‡	35.6 (29.4; 39.9)#,‡	<0.001
RV, L	2.4 (2.3; 2.9)#	2.8 (1.8; 3.4)	3.4 (2.7; 4.0)#	0.012
RV/TLC, %	98 (86; 100)*,#	114.5 (104; 123)*,‡	145 (136; 160)#,‡	<0.001
DL,CO, mL·min^−1·mmHg^−1	23.0 (15.2; 26.7)	19.8 (14.4; 24.3)	11.6 (9.6; 15.5)	0.032
DL,CO % predicted	81.5 (59; 88)	75 (51; 85)	48 (38; 62)	0.033

Notes: Data are presented as median (interquartile range).

*,#,‡ Significant difference between groups. Bold values represent the significant results.

Abbreviations: GOLD, Global Initiative for Chronic Obstructive Lung Disease; BMI, body mass index; FEV₁, forced expiratory volume in the first second; FVC, forced expiratory vital capacity; IC, inspiratory capacity; TLC, total lung capacity; FRC, functional residual capacity; RV, residual volume; D_L,CO, diffusing capacity of the lung for carbon monoxide; M, male; F, female.

Table 2 Cardiopulmonary exercise testing (peak values, except AT)

GOLD stage	Stage I	Stage II	Stage III–IV	P-value
Sample size	n=6	n=26	n=15
Workload, W	97.5 (95; 150)#	90 (80; 100)‡	65 (60; 85)#,‡	<0.001
V’O2, mL·kg^−1·min^−1	24.3 (23.6; 25.2)#	18.5 (15.5; 21.8)	17.5 (15.4; 19.1)#	0.035
V’O2, % predicted	77.4 (62.8; 80.9)	70.0 (55.0; 80.0)	64.0 (61.0; 68.0)	0.215
AT V’O2, mL·kg^−1·min^−1	16.0 (15.0; 16.6)*,#	12.1 (10.6; 14.1)*	12.0 (11.0; 13.4)#	0.033
RER	1.2 (1.0; 1.3)	1.2 (1.1; 1.2)	1.2 (1.1; 1.2)	0.859
Arterial lactate, mmol·L^−1	7.6 (5.7; 9.2)	5.7 (4.8; 7.3)	5.5 (4.3; 6.4)	0.036
Borg dyspnea score	4 (3; 7)	4 (3; 5)	3 (3; 5)	0.865
Borg leg effort score	4 (4; 7)	4 (3; 5)	3 (2; 5)	0.314

Notes: Data are presented as median (interquartile range).

*,#,‡ Significant difference between groups. Bold values represent the significant results.

Abbreviations: AT, anaerobic threshold; GOLD, Global Initiative for Chronic Obstructive Lung Disease; V’O₂, oxygen uptake; RER, respiratory exchange ratio.

Table 3 Ventilatory response during submaximal exercise (peak values, except V_T/V’_E inflexion point)

GOLD stage	Stage I	Stage II	Stage III–IV	P-value
Sample size	n=6	n=26	n=15
fR, breaths·min^−1	31 (23; 41)	31 (27; 38)	34 (30; 38)	0.655
VT, L	2.3 (1.8; 3.3)#	1.8 (1.6; 2.0)‡	1.5 (1.1; 1.6)#,‡	0.001
VT/FEV1, %	74.9 (59.5; 91.0)#	83.6 (74.6; 91.0)‡	105.0 (85.6; 117.2)#,‡	0.003
VT/FVC, %	49.5 (40.7; 57.3)	48.4 (45.2; 51.1)	46.3 (38.5; 50.2)	0.649
V’E, L·min^−1	76.5 (64; 88)*,#	54.5 (48; 64)*,‡	48 (37; 53)#,‡	<0.001
V’E reserve, % predicted	33.9 (11.7; 44.9)#	28.0 (21.8; 34.4)‡	2.7 (−10.5; 16.6)#,‡	<0.001
VT/V’E inflection point, % peak V’E	52.5 (46; 61)*,#	40 (32; 50)*,‡	30 (26; 32)#,‡	<0.001
ICdyn, L	−0.08 (−0.14; 0.11)#	220.38 (−0.52; 0)‡	−0.67 (−0.95; −0.35)#,‡	<0.001
EELV/TLC, %	53 (49; 58)#	61 (54; 70)‡	70 (68; 79)#,‡	<0.001
Gas exchange
VD/VT, %	32 (31; 35)#	37 (31; 40)‡	45 (38; 51)#,‡	0.004
Pa,O2, mmHg	99.8 (98; 101)	93.5 (80.7; 99)	86 (60; 93)	0.065
Pa,CO2, mmHg	33.1 (27.0; 35.0)*,#	38.5 (36.0; 40.6)*,‡	41.4 (40.7; 45.0)#,‡	<0.001

Notes: Data are presented as median (interquartile range).

*,#,‡ Significant difference between groups. Bold values represent the significant results.

Abbreviations: GOLD, Global Initiative for Chronic Obstructive Lung Disease; f_R, breathing frequency; V_T, tidal volume; FEV₁, forced expiratory volume in the first second; FVC, forced expiratory vital capacity; V’_E, minute ventilation; IC_dyn, dynamic inspiratory capacity; EELV, end-expiratory lung volume; TLC, total lung capacity; V_D, dead volume; Pa,O₂, arterial partial pressure of oxygen; Pa,CO₂, arterial partial pressure of carbon dioxide.

Table 4 Cardiovascular response during submaximal exercise (peak values, except recovery)

GOLD stage	Stage I	Stage II	Stage III–IV	P-value
Sample size	n=6	n=26	n=15
HR, beat·min^−1	149 (142; 162)	130 (113; 150)	133 (122; 140)	0.074
HR peak-rest, beat·min^−1	60 (54; 71)	42.5 (32; 67)	42 (28; 61)	0.102
HRmax, %	88.2 (83.3; 94.7)#	79.2 (73.4; 90.6)	78.8 (70.7; 83.2)#	0.042
HR reserve use, %	76.3 (67.5; 87.3)#	55.0 (41.3; 80.6)	52.5 (42.6; 63.8)#	0.032
Chronotropic-metabolic index	0.68 (0.61; 0.73)#	0.58 (0.47; 0.75)	0.47 (0.39; 0.60)#	0.027
O2 pulse, mL·beat^−1	11.7 (10.5; 12.4)#	10.8 (10.1; 13.9)‡	8.3 (7.3; 9.7)#,‡	<0.001
O2 pulse, % predicted	95.5 (88.0; 104.0)#	86.0 (74.0; 99.0)‡	77.0 (65.0; 82.0)#,‡	0.005
OUES, mL·min^−1	1 548 (1 344; 1 988)	1 701 (1 467; 1 988)	1 321 (1 138; 1 937)	0.188
V’E/V’CO2 slope	26.1 (23.8; 30.3)	30.2 (26.9; 33.5)	32.0 (29.0; 37.4)	0.079
Mean arterial pressure, mmHg	125.3 (120.0; 133.0)	123.7 (103.5; 135.2)	117.0 (111.7; 125.0)	0.537
Double product, mmHg·beat·min^−1	29 523 (28 120; 31 266)#	25 619 (23 471; 29 539)‡	20 295 (19 380; 24 024)#,‡	<0.001
Post-exercise heart rate recovery
HR recovery at 1 min, beat·min^−1	17.5 (13; 18)	10 (3; 19)	13 (6; 20)	0.636
HR recovery at 3 min, beat·min^−1	41 (31; 49)	28.5 (20; 35)	27 (19; 36)	0.262

Notes: Data are presented as median (interquartile range).

#,‡ Significant difference between groups. Bold values represent the significant results.

Abbreviations: GOLD, Global Initiative for Chronic Obstructive Lung Disease; HR, heart rate; HR_max, age predicated maximum heart rate; min, minute; O₂, oxygen; OUES, oxygen uptake efficiency slope; V’_E, minute ventilation; V’CO₂, carbon dioxide output.

Table 5 Relationships between dynamic hyperinflation, GOLD stage and chronotropic incompetence

Group patients	No hyperinflation*	Hyperinflation*	P-value**
GOLD			0.019
I–II	18	14
III–IV	3	12
Chronotropic incompetence, %	14.3	76.9	<0.0001

Notes:

* Defined by an IC_dyn <−0.34 L;

** P-values obtained by Fisher exact test. Bold values represent the significant results.

Abbreviations: GOLD, Global Initiative for Chronic Obstructive Lung Disease; IC_dyn, dynamic inspiratory capacity.

Table 6 Multivariate analysis of chronotropic incompetence

Variables	OR (95% confidence interval)
Dynamic hyperinflation status	25 (3.5–191.6)*
Age	1.094 (1.008–1.187)*
BMI	0.952 (0.826–1.098)
TLC	0.676 (0.342–1.336)
IC/TLC	0.956 (0.849–1.076)
RV/TLC	1.004 (0.970–1.039)
GOLD stage	1.056 (0.088–12.634)

Notes:

* P-values <0.05. Bold values represent the significant results.

Abbreviations: OR, odds ratio; BMI, body mass index; TLC, total lung capacity; IC, inspiratory capacity; RV, residual volume; GOLD, Global Initiative for Chronic Obstructive Lung Disease.