Resting Physiological Correlates of Reduced Exercise Capacity in Smokers with Mild Airway Obstruction

Figures & data

Table 1. Subject characteristics and medications.

	Smokers	Healthy controls	p
	(n = 62)	(n = 32)	values
Male: Female, n	38:24	17:15	0.510
Age, years	65 ± 11	64 ± 9	0.596
Height, cm	168 ± 9	168 ± 9	0.987
Body mass, kg	78 ± 14	75 ± 12	0.249
BMI, kg/m^2	28 ± 5	27 ± 3	0.129
Smoking history, pack-years	42.5 ± 18.9	0.6 ± 1.9	<0.0001
Smoking status, n:
• Current	21	0	—
• Never	0	27	—
• Ex–smoker	42	5	—
BDI focal score (0–12)	8.7 ± 1.6	11.5 ± 0.8	<0.0001
Modified MRC dyspnea scale (0–4)	1.13 ± 0.8	0.06 ± 0.2	<0.0001
CAT score (0–40)	12.6 ± 7.3	3.2 ± 3.3	<0.0001
Oxygen cost diagram (0–100), mm	71 ± 15	91 ± 10	<0.0001
CHAMPS, kcal/week for all activities	3903 ± 3618	6529 ± 4469	<0.0001
SGRQ total score	25.5 ± 16.2	3.7 ± 3.4	<0.0001
Charlson Comorbidity Index	3.4 ± 1.7	2.1 ± 1.1	<0.0001
Noninhaled medications, n (%)
• β-Blocker	8(13)	0(0)	—
• Diuretic	6(10)	1(3)	—
• ACE inhibitor	12(19)	2(6)	—
• Ca channel blocker	7(11)	0(0)	—
• Statin	18(29)	4(13)	—
• Anti–diabetic medications	5(8)	1(3)	—
• Proton pump inhibitor	16(26)	2(6)	—
• Acetyl salicylic acid	6(10)	4(13)	—
• L–thyroxin	9(15)	3(9)	—
Inhaled medications, n (%)
• SABA	19(31)	0(0)	—
• SAMA	3(5)	0(0)	—
• LABA	3(5)	0(0)	—
• LAMA	15(24)	0(0)	—
• ICS	1(2)	0(0)	—
• ICS–LABA	18(29)	0(0)	—

Values are means ± SD.

Abbreviations: BDI = Baseline Dyspnea Index; BMI = body mass index; CAT = COPD Assessment Test; CHAMPS = Community Healthy Activities Model Program for Seniors questionnaire; COPD = chronic obstructive pulmonary disease; MRC = Medical Research Council; SGRQ = St. George's Respiratory Questionnaire. ACE = angiotensin converting enzyme; Ca = calcium; ICS = inhaled corticosteroid; LABA = long-acting β₂-agonist; LAMA = long-acting antimuscarinic; SABA = short-acting β₂-agonist; SAMA = short-acting antimuscarinic; oxygen cost diagram is a visual analog scale (100 mm in length) and that lists activities of daily living according to their levels of oxygen consumption. It is used for quantifying a patient's evaluation of his tolerance to exercise, as a component of health-related quality of life. The BDI score ranges from 0 (very severe impairment) to 4 (no impairment) for each of the following 3 domains (functional impairment, magnitude of task and magnitude of effort); they are summed to determine the BDI focal score (0–12).

Table 2. Resting pulmonary function.

	Smokers	Healthy controls	p values
Post-bronchodilator
FEV1, L	2.54 ± 0.6(90 ± 11)	3.07 ± 0.6(108 ± 12)	0.000(<0.0001)
FEV1 z-score	−0.60 ± 0.72	0.55 ± 0.78	<0.0001
FEV1/FVC, %	65 ± 8	76 ± 5	<0.0001
FEV1/FVC z-score	−1.56 ± 0.87	−0.24 ± 0.68	<0.0001
Pre-bronchodilator
FEV1, L	2.41 ± 0.67(85 ± 12)	2.95 ± 0.67(105 ± 13)	0.000(<0.0001)
FEV1/FVC, %	63 ± 9(80 ± 10)	73 ± 6(94 ± 7)	<0.0001(<0.0001)
FEF25–75%, L/s	1.25 ± 0.78(50 ± 22)	2.23 ± 0.90(94 ± 32)	<0.0001(<0.0001)
SVC, L	3.94 ± 0.8(109 ± 14)	4.23 ± 0.9(118 ± 12)	0.138(0.005)
IC, L	2.83 ± 0.7(104 ± 18)	2.97 ± 0.8(111 ± 18)	0.367(0.098)
FRC, L	3.27 ± 0.8(103 ± 23)	3.11 ± 0.8(98 ± 23)	0.348(0.367)
TLC, L	6.12 ± 1.1(103 ± 13)	6.08 ± 1.1(104 ± 13)	0.876(0.816)
RV, L	2.17 ± 0.6(100 ± 24)	1.86 ± 0.5(86 ± 21)	0.012(0.008)
RV/TLC, %	36 ± 8	31 ± 6	0.003
DLCO, ml/min/mmHg	17.5 ± 5.1(85 ± 22)	21.6 ± 4.9(105 ± 17)	0.000(<0.0001)
DL/VA, ml/min/mmHg/L	3.3 ± 0.7(90 ± 18)	4.1 ± 0.6(110 ± 15)	<0.0001(<0.0001)
VA/TLC	0.85 ± 0.09	0.87 ± 0.06	0.357
sRaw, cmH2O•s	9.2 ± 3.9(217 ± 93)	5.6 ± 1.9(136 ± 50)	<0.0001(<0.0001)
Closing volume, L	0.51 ± 0.3	0.43 ± 0.2	0.151
N2 slope, %/L	4.9 ± 2.1	3.2 ± 1.6	0.000
R5, cmH2O/L/s	4.9 ± 1.6	4.2 ± 1.6	0.051
R5-20, % R5	22.8 ± 10.9	12.9 ± 6.9	<0.0001
AX, cmH2O/L	8.9 ± 8.9	3.4 ± 3.0	0.001
X5, cmH2O/L/s	−1.6 ± 0.9	−1.1 ± 0.5	0.006
Fres, Hz	15.8 ± 5.3	11.9 ± 3.7	0.000

Values are means ± SD, with values in parentheses representing % of predicted normal values.

Abbreviations: AX = reactance area; D_LCO = diffusing capacity of the lung for carbon monoxide; D_L/V_A = D_LCO relative to alveolar volume; FEF_25–75% = forced expiratory flow between 25 and 75% of forced vital capacity; FEV₁ = forced expired volume in 1 second; FVC = forced vital capacity; FEV₁/FVC = ratio between FEV₁ and FVC; FRC = functional residual capacity; Fres = resonant frequency; IC = inspiratory capacity; N₂ = nitrogen; R5 = resistance at 5 Hz during impulse oscillometry; R5-20 = differential change in resistance between 5 and 20 Hz; RV = residual volume; sRaw = specific airway resistance; SVC = slow vital capacity; TLC = total lung capacity; X5 = distal capacitive reactance at 5 Hz.

Figure 1. Measures of small airway dysfunction, pulmonary gas trapping, and lung diffusing capacity in smokers and age-matched healthy controls. (A) R5-20, (B) X5, (C) phase-III N₂ slope, (D) FEF_25–75% (% predicted), (E) RV/TLC (%), and (F) D_LCO (% predicted). Values in box plots represent the median, 10th, 25th, 75th, and 90th percentile. *p < 0.05 smokers vs. healthy controls. Abbreviations: D_LCO = diffusing capacity of the lung for carbon monoxide; FEF_25–75% = maximal mid-expiratory flow; N₂ = nitrogen; R5-20 = change in airway resistance from 5 to 20 Hz during impulse oscillometry (IOS); RV = residual volume; TLC = total lung capacity; X5 = distal capacitive reactance during IOS.

Table 3. Measurements at the peak of symptom-limited incremental cycle exercise.

	Smokers	Healthy controls	p values
Work rate, watts	102 ± 41	156 ± 52	<0.0001
(% predicted)	(69 ± 23)	(107 ± 25)	<0.0001
̇VO2, L/min	1.68 ± 0.60	2.41 ± 0.78	<0.0001
(% predicted)	(79 ± 20)	(116 ± 25)	<0.0001
̇VO2, ml/kg/min	21.5 ± 6.7	31.8 ± 9.1	<0.0001
̇VE, L/min	59.7 ± 21.5	90.7 ± 29.4	<0.0001
(% predicted MVC)	(71 ± 23)	(88 ± 24)	0.001
VT, L	1.73 ± 0.54	2.21 ± 0.58	0.000
Fb, breaths/min	34 ± 6	39.9 ± 6.5	0.000
TI/TTOT	0.46 ± 0.04	0.48 ± 0.02	0.003
IC, L	2.63 ± 0.66	2.98 ± 0.70	0.022
(% predicted)	(96 ± 20)	(112 ± 18)	0.000
Δ IC from rest, L	−0.19 ± 0.47	0.09 ± 0.52	0.006
IRV, L	0.90 ± 0.77	0.77 ± 0.37	0.165
EILV, % TLC	85 ± 8	87 ± 6	0.145
PETCO2, mmHg	33.9 ± 4.3	32.8 ± 4.6	0.269
̇VE/̇VCO2	33.9 ± 4.8	33.9 ± 5.4	0.864
SpO2, %	95.6 ± 1.8	96.0 ± 2.0	0.286
R	1.05 ± 0.1	1.12 ± 0.1	0.003
HR, beats/min	133 ± 24	152 ± 16	0.000
(% predicted)	(79 ± 14)	(91 ± 9)	<0.0001
O2 pulse, mL/beat	12.7 ± 3.8	15.9 ± 4.9	0.001
Dyspnea, Borg units	5.3 ± 2.4	5.1 ± 2.9	0.676
Leg discomfort, Borg units	6.2 ± 2.4	5.8 ± 2.9	0.514

Values are means ± SD.

Abbreviations: EILV = end-inspiratory lung volume; Fb = breathing frequency; HR = heart rate; IC = inspiratory capacity; IRV = inspiratory reserve volume; MVC = maximal ventilatory capacity; O₂ pulse = oxygen pulse; P_ETCO₂ = partial pressure of end-tidal carbon dioxide; R = respiratory exchange ratio; SpO₂ = arterial oxygen saturation measured by pulse oximetry; T_I/T_TOT = inspiratory duty cycle; TLC = total lung capacity; ̇V_E = minute ventilation; ̇V_E/̇VCO₂ = ventilatory equivalent for carbon dioxide; ̇VO₂ = oxygen uptake; V_T = tidal volume.

Figure 2. Selected parameters of responses to incremental cycle exercise plotted against work rate in smokers and age-matched healthy controls. (A) Exertional dyspnea intensity using Borg scale, (B) ̇V_E, (C) ̇V_E/̇VCO₂, (D) PetCO₂, (E) IC, (F) IRV. Values are mean ± SEM. Square symbols represent the points at the highest equivalent work arte of 60 watts. *p < 0.05 smokers vs. healthy controls at rest, standardized work rates or at peak exercise. Abbreviations: IC = inspiratory capacity; IRV = inspiratory reserve volume; PetCO₂ = partial pressure of end-tidal carbon dioxide; TLC = total lung capacity; ̇V_E = minute ventilation; ̇V_E/̇VCO₂ = ventilatory equivalent for carbon dioxide.

Table 4. Correlates of each of the primary outcomes within smokers.

Independent variables	DLCO % predicted	RV/TLC %	X5 cmH2O/L/s	R5-20 % R5	FEV1/FVC %	N2 slope %/L	IC % predicted
Dependent variable: peak ̇VO2 ml/kg/min
r	0.487	−0.389	0.377	−0.341	0.231	−0.182	−0.136
p	<0.0005	0.002	0.003	0.007	0.071	0.161	0.290
^†Model summary: DLCO (% predicted) and RV/TLC (%), R = 0.591, r^2 = 0.350, adjusted r = 0.328, f = 15.85, p < 0.001
Dependent variable: dyspnea/̇VO2 slope
r	−0.352	0.225	−0.290	0.161	−0.210	.330	0.0838
p	0.005	0.079	0.022	0.211	0.102	0.009	0.517
^†Model summary: DLCO (% predicted) and N2 slope, r = 0.447, r^2 = 0.200, adjusted r = 0.172, f = 7.25, p = 0.002
Dependent variable: rest-to-peak change in IC
r	0.298	−0.241	0.515	−0.520	0.352	−0.149	−0.350
p	0.0193	0.0595	<0.0005	<0.0005	0.005	0.253	0.005
^†Model summary: IC (% predicted), R5-20 and X5, r = 0.622, r^2 = 0.388, adjusted r = 0.356, f = 12.23, p < 0.001

Correlation analyses between each of the primary end points and relevant independent variables using Pearson's correlations.

^† Stepwise forward regression analysis showing the best combination of independent variables for each of the primary endpoints.

Abbreviations: D_LCO = diffusing capacity of the lung for carbon monoxide; FEV₁ = forced expired volume in 1 s; FVC = forced vital capacity; IC = inspiratory capacity; N₂ = nitrogen; R5-20 = differential change in resistance between 5 and 20 Hz; RV = residual volume; TLC = total lung capacity; X5 = distal capacitive reactance at 5 Hz; ̇VO₂ = oxygen uptake.

Figure 3. Inter-relationships between D_LCO% predicted, peak ̇VO₂, dyspnea/̇VO₂ slope, and ̇V_E/̇VCO₂ nadir within the smoker group. D_LCO correlated with peak ̇VO₂ (r = 0.487, p < 0.0005), dyspnea/̇VO₂ slope (r = −0.352, p = 0.005), and ̇V_E/̇VCO₂ nadir (r = −0.353, p = 0.005). Abbreviations: D_LCO = diffusing capacity of the lung for carbon monoxide; ̇V_E/̇VCO₂ = ventilatory equivalent for carbon dioxide; ̇VO₂ = oxygen uptake.