Pulmonary Vascular Reserve and Exercise Capacity at Sea Level and at High Altitude

Abstract

Pavelescu, Adriana, Vitalie Faoro, Herve Guenard, Claire de Bisschop, Jean-Benoit Martinot, Christian Melot, Robert Naeije. Pulmonary vascular reserve and exercise capacity at sea level and at high altitude. High Alt. Med. Biol. 14:19–26, 2013.—It has been suggested that increased pulmonary vascular reserve, as defined by reduced pulmonary vascular resistance (PVR) and increased pulmonary transit of agitated contrast measured by echocardiography, might be associated with increased exercise capacity. Thus, at altitude, where PVR is increased because of hypoxic vasoconstriction, a reduced pulmonary vascular reserve could contribute to reduced exercise capacity. Furthermore, a lower PVR could be associated with higher capillary blood volume and an increased lung diffusing capacity. We reviewed echocardiographic estimates of PVR and measurements of lung diffusing capacity for nitric oxide (DL_NO) and for carbon monoxide (DL_CO) at rest, and incremental cardiopulmonary exercise tests in 64 healthy subjects at sea level and during 4 different medical expeditions at altitudes around 5000 m. Altitude exposure was associated with a decrease in maximum oxygen uptake (Vo₂max), from 42±10 to 32±8 mL/min/kg and increases in PVR, ventilatory equivalents for CO₂ (V_E/Vco₂), DL_NO, and DL_CO. By univariate linear regression Vo₂max at sea level and at altitude was associated with V_E/Vco₂ (p<0.001), mean pulmonary artery pressure (mPpa, p<0.05), stroke volume index (SVI, p<0.05), DL_NO (p<0.02), and DL_CO (p=0.05). By multivariable analysis, Vo₂max at sea level and at altitude was associated with V_E/Vco₂, mPpa, SVI, and DL_NO. The multivariable analysis also showed that the altitude-related decrease in Vo₂max was associated with increased PVR and V_E/Vco₂. These results suggest that pulmonary vascular reserve, defined by a combination of decreased PVR and increased DL_NO, allows for superior aerobic exercise capacity at a lower ventilatory cost, at sea level and at high altitude.

Introduction

Aerobic exercise capacity measured by a maximum oxygen uptake (Vo₂max) has been shown to be greater in healthy subjects with lower pulmonary vascular resistance (PVR) (La Gerche et al., 2010, Lalande et al., 2012). Subjects with the highest exercise capacity also had an increased pulmonary transit of agitated saline, which may be explained by greater capillary distension leading to decreased PVR (Lalande et al., 2012). At high altitude, there has been a report of improved Vo₂max after the intake of endothelin receptor blockers to decrease PVR (Naeije et al., 2010). In these studies, there was an inverse correlation between pulmonary artery pressures (Ppa) at rest and Vo₂max (Naeije et al., 2010) and a direct correlation between lung diffusing capacities for nitric oxide (DL_NO) and carbon monoxide (DL_CO) at rest and Vo₂max, at sea level as well as at high altitude (de Bischop et al., 2012). This latter result was not entirely expected, as several studies have shown DL_NO more than DL_CO to be better associated with Vo₂max in healthy subjects, particularly in those with excessively increased body weight or smoking habits (Tzani et al., 2008; Zavorsky et al., 2010).

The measurement of lung diffusing capacity is usually done with CO as tracer gas. The Roughton and Forster equation states that 1/DL_CO=1/Dm+1/θVc where Dm is the membrane component of the alveolo-capillary transfer of CO, θ the rate of combination of CO with blood, and Vc the capillary blood volume (Roughton and Forster, 1957). Provided θ for CO at the appropriate Po₂ is known, the simultaneous measurements of CO and of nitric oxide (NO) transfer allows for the calculation of Dm and Vc (Guenard et al., 1987). The reaction of NO with hemoglobin is quasi-instantaneous so that θNO can be assumed to be infinite and the transfer factor for NO with correction for the NO/CO ratio of diffusivity can be used for the calculation of Dm, and hence Vc (Guenard et al., 1987). It has recently been pointed at that θNO has actually a finite value, introducing uncertainty about previously reported Dm and Vc calculations (Borland et al., 2012). However, a simple DL_NO/DL_CO ratio identifies relative changes in the components of lung diffusion (Glenet et al., 2007, Hughes and Pride, 2012).

We therefore reviewed Doppler echocardiographic studies of the pulmonary circulation and measurements of lung diffusing capacity, as well cardiopulmonary exercise tests of 64 healthy subjects evaluated at sea level and subsequent exposure to high altitudes during four different expeditions. We tested the hypothesis that a low PVR could be related to pulmonary vascular distension and possibly also recruitment including the pulmonary capillaries, and that therefore both a low PVR and a high lung diffusing capacity would be related to exercise capacity. Altitude exposure-induced hypoxic pulmonary vasoconstriction would allow examination of the effects of increased PVR. This could lead to a decreased pulmonary vascular distension because of decreased resistive vessel compliance (Groepenhoff et al., 2012) or, alternatively, increased pulmonary vascular distension because of higher pulmonary capillary pressures (Maggiorini et al., 2001). We reasoned that it would also be of interest to examine the effects of associated changes in ventilatory responses expressed as ventilation (V_E) at any given rate of carbon dioxide production (Vco₂) in normoxia and in hypoxia. It has indeed been previously suggested that increased lung diffusing capacity at high altitudes allows for preserved gas exchange at lower levels of ventilation and O₂ cost of breathing (Dempsey et al., 1971). On the other hand, pulmonary hypertension is associated with increased V_E/Vco₂ in proportion to disease severity (Sun et al., 2001; Deboeck et al., 2012). Thus, excessive hypoxia-induced increase in PVR could increase ventilatory responses at high altitudes, increase the O₂ cost of breathing, and thereby decrease Vo₂max.

Materials and Methods

Study population

Sixty-four healthy European lowlanders, 33 men and 31 women, aged 20 to 61 years, mean 32 years, gave a written informed consent to the study, which was approved by the Ethical Committee of the Erasme University Hospital (Brussels), approval number P2010/164, reference Eudract/CCB B40620108839. All of them had an unremarkable previous medical history and normal clinical examination, chest X-ray film, and normal electrocardiogram. Only three of them were light smokers.

Experimental protocol

All the subjects underwent a clinical examination with measurements of blood pressure (BP), heart rate (HR), and trans-cutaneous ear pulse oximetry oxygen saturation (Spo₂) followed by an echocardiographic examination and lung diffusing capacity measurements at rest, and then a cardiopulmonary exercise test (CPET). This sequence of measurements was obtained at sea level, in Brussels (Belgium) and again during the first 10 (mean 5, range 3–12) days of arrival at high altitude. The high altitude locations were the Whymper hut (5000 m) on Mount Chimborazo in Ecuador (n=9 subjects), the Huyana Potosi hut (4850 m) in Bolivia (n=10), the Pyramid International Laboratory Observatory (5050 m) in Khumbu area of Sagamartha National Park in Nepal (n=20), or the Cerro de Pasco (4350 m) in Peru (n=25). The adaptation to high altitude was checked before each series of measurements using a self-reported acute mountain sickness questionnaire (Lake Louise score) (Roach et al., 1993).

Echocardiography

The echocardiographic measurements were performed with a Vivid 7 ultrasound system at sea level and with its Vivid i portable version at altitude in Nepal and Peru (GE Ultrasound Horten Norway) or a Cypress Acusson portable ultrasound system (Siemens, Erlangen, Germany) in Ecuador and Bolivia. Recordings were stored on optical disks and analyzed by cardiologists experienced in echocardiography. Cardiac output (Q) was estimated from the left ventricular outflow tract cross-sectional area and pulsed-wave Doppler velocity-time integral (LVOT_VTI), systolic Ppa (sPpa) was calculated from the maximum velocity of the continuous-Doppler tricuspid regurgitation jet (TRV), and mean Ppa (mPpa) from the acceleration time (AcT) of right ventricular outflow tract flow velocity as previously reported (Naeije et al., 2010). Mean Ppa was calculated from sPpa as mPpa=0.6×sPpa+2 (Naeije et al., 2010). All measurements were made in triplicate and results are presented as means. Total pulmonary vascular resistance (TPVR) was calculated as the ratio between mPpa and Q, and stroke volume (SV) as Q/HR. TPVR and SV were indexed to the body surface area (TPVRI, SVI). As hypoxic exposure does not increase left atrial pressure or wedged Ppa in normal subjects at rest (Maggiorini et al., 2001), TPVR was thought to provide a reasonable estimation of PVR. Therefore, PVR is used instead of TPVR in subsequent sections of this report.

Cardiopulmonary exercise test

Exercise capacity was estimated by a standard incremental cardiopulmonary exercise test (CPET) performed in an upright position on an electronically braked cycle ergometer (Monark, Ergomedic 818E, Vansbro, Sweden). The work rate was increased by 15–30 watts/min (according to previously known exercise capacity and predicted decrease by 35% at high altitude) so that the test would last 10–12 min until exhaustion. Maximal oxygen uptake (Vo₂max) and the ratio of ventilation to CO₂ production (V_E/Vco₂) at the anaerobic threshold were measured as previously described (Naeije et al., 2010), using a cardiopulmonary exercise system (Oxycon Mobile Jaeger, Hoechberg, Germany or Medisoft, Dinant, Belgium). Vo₂max was determined on the basis of an identifiable plateau of the Vo₂-workload relationship at maximum exercise capacity or, in case of doubt, by a Vo₂ measured at exhaustion with a heart rate equal to predicted and a respiratory exchange ratio>1.15. The anaerobic threshold was determined by the V-slope method (Naeije et al., 2010).

Lung diffusion measurements

DL_NO and DL_CO were measured in the sitting position with corrections for hemoglobin and inspired partial pressure of oxygen, using an automated device for calibrations, mixing of gases, and online calculations (Hyp'Air compact, Medisoft, Dinant, Belgium) as previously reported (Glenet S et al, 2007; de Bisschop C et al., 2012), with a breath holding time of 4 sec, concentrations of inspired gases 40 ppm of NO, 1600 ppm of CO, 8% of helium, and 19% of O₂ in nitrogen, and first 0.8 L of expired gas discarded. Measurements were repeated two to three times, with the aim to obtain DL_CO values within 5% and DL_NO values within 10% of each other. The coefficient relating DL_NO and Dm was set at 1.97 according to the solubility and molecular weights of both gases (Aguilaniu B et al., 2008). Assuming linearity between 1/θ_CO and Po₂, we used an equation proposed by Forster (1987) expressing the blood conductance of CO (θ_CO) as a function of capillary Po₂: \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland, xspace}\usepackage{amsmath, amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document} \begin{align*}1 / \theta_{\rm {CO}} = 1.3 + 0.0041 \ * \ {\rm Pcapo}_2\end{align*} \end{document}

where Pcapo₂ is the capillary partial pressure of O₂ estimated as: alveolar Po₂ – Vo₂/(DL_CO *1.23) with partial pressures in mmHg, Vo₂ in mL/min, and DL_CO in mL/min/mmHg. Alveolar PO₂ was calculated from the local barometric pressure and the expired fraction of O₂. Oxygen uptake was calculated by taking the mass balance of oxygen between inspiration and expiration during the manoeuvre. The fraction of oxygen in the residual volume preceding the inspiration was supposed to be similar to that found in the expired sample (mean 16.4%). We used DL_CO x 1.23 as a surrogate for DL_O2 (Roughton and Forster, 1957). Hemoglobin concentrations were measured from venous blood samples, and Vc and DL_CO values corrected accordingly for an inspired Po₂ of 150 mmHg and for standard concentrations of hemoglobin of 14.6 g/dL for men and 13.4 g/dL for women (Macintyre et al., 2005). To compare sea level and altitude DL_CO, Vc and Dm values derived from the measurement at altitude using the hypoxic θ_CO value were used to calculate DL_CO as if the subjects were at the sea level by replacing the hypoxic θ_CO value by the normoxic one. Ambient CO or carboxyhemoglobin were not measured, so that potentially confounding effects of pollution in the mining city of Cerro de Pasco were not taken into consideration.

Statistical analysis

Continuous variables were presented as mean±SD after checking for normality of distributions. A univariate linear regression was performed to determine the significant variables associated with Vo₂max in normoxia (sea level) and hypoxia (high altitude) or ΔVo₂max from normoxia to hypoxia, followed by a multivariable linear regression using the backward elimination technique to find the independent variables associated with Vo₂max in normoxia and hypoxia or ΔVo₂max from normoxia to hypoxia. A p<0.05 was considered significant. Linear correlations were calculated between Vo₂max and its independent variables, and between PVR and lung diffusing capacity measurements.

Results

Effects of altitude on clinical state, echocardiography (Table 1), CPET (Table 2), and lung diffusion (Table 3)

Altitude exposure was well tolerated, with transient mild degrees of headache, fatigue, weakness, dyspnea and lethargy, but, at time of the measurements, Lake Louise scores were at 4±1, corresponding to no or only mild acute mountain sickness. No subject felt that mild acute mountain sickness could have affected exercise capacity. There were a decrease in rest and end-exercise Spo₂ and increases in rest HR, hemoglobin and (slightly) BP.

Table 1.

Rest Clinical Data and Hemodynamic Variables

	Sea level	High altitude	p
Clinical findings
HR, bpm	67±13	74±15	<0.001
SBP, mmHg	121±13	126±11	0.05
DBP, mmHg	74±8	82±10	0.02
Spo₂, %	99±1	86±6	<0.001
Hemoglobin, g/dl	13.8±1.6	15.0±2.9	<0.05
Echocardiography-derived hemodynamic measurements
mPpa, mmHg^*	17±6	30±8	<0.001
mPpa, mmHg^**	16±3	27±11	<0.001
Q, L/min	5.4±1.3	5.6±1.3	0.06
SV, mL	82.2±22.0	79.3±23.3	0.2
PVR, Wood units	3.2±1.2	5.6±1.9	<0.001

Values are mean±SD.

HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure, Spo₂, pulse oximetry oxygen saturation, mPpa, mean pulmonary artery pressure; Q, cardiac output; SV, stroke volume; PVR, total pulmonary vascular resistance.

estimated from the right ventricle outflow acceleration time; ^**estimated from the tricuspid regurgitation jet velocity.

Table 2.

Cardiopulmonary Exercise Test (CPET) Data

Variable	Sea level	High altitude	p
Maximal workload, W	245±74	161±47	<0.001
Vo₂max, mL/min/kg	42.4±9.6	32.0±7.5	<0.001
V_E max, L/min	117±33	125±39	0.009
RER max	1.25±0.08	1.16±0.11	<0.001
O₂ pulse, mL/beat	16±5	13±4	<0.001
V_E/Vco₂ max	32±4	53±7	<0.001
V_E/Vo₂ max	40±6	62±9	<0.001
Vo₂ at AT, mL/min/kg	27.8±8.1	20.3±4.4	<0.001
V_E/Vco₂ at AT	28±4	42±8	<0.001
HR max, beats/min	180±16	158±20	<0.001
SBP at maximal workload, mmHg	174±39	168±24	NS
DBP at maximal workload, mmHg	81±16	86±14	NS
Spo₂ at maximal workload, %	96±3	77±6	<0.001

Values are mean±SD.

HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure, SpO₂, pulse oximetry oxygen saturation, VO₂max, maximum oxygen uptake; V_E/VCO₂ at AT, ventilatory equivalent for carbon dioxide at anaerobic threshold; V_E/VCO₂ max, ventilatory equivalent for carbon dioxide at maximum workload; V_E/VO₂ max, ventilatory equivalent for oxygen at maximum workload; V_E, ventilation; RER, respiratory exchange ratio.

Table 3.

Rest Lung Diffusion Measurements

Variable	Sea level	High altitude	p
DL_NO, mL/min/mmHg	151±35	168±40	<0.001
DL_CO, mL/min/mmHg	33.5±7.8	39.0±9.2	<0.001
DL_NO/DL_CO	4.5±0.4	4.3±0.4	<0.001

DL_NO, lung diffusing capacity for nitric oxide; DL_CO, lung diffusing capacity for carbon monoxide.

Altitude was associated with increased TRV and decreased AcT. Sufficient quality TRV signals could be obtained in only 58 of the 64 subjects, so that only AcT were used for the calculation of mPpa. There was no significant difference between the Ppa estimated by the two methods in the subjects in whom quality signals were available (Table 1). Maximal oxygen uptake, Vo₂ at anaerobic threshold, and O₂ pulse were decreased, and V_E/Vco₂ at maximum workload, as well as at anaerobic threshold, and V_E/Vo₂ max markedly increased, by respectively 25%, 27%, 19%, 40%, 50%, and 55%. Altitude exposure was associated as well with decreases in maximum workload (34%), HR (14%), respiratory exchange ratio (7%), and increases in V_E (7%).

DL_CO and DL_NO were increased by 16% and 11%, respectively, so that DL_NO/DL_CO decreased by 4%. VA increased from 6±1.2 L at sea level to 6.5±1.2 L at high altitude (p<0.001).

Univariate and multivariable analysis of variables associated with Vo₂max

At sea level, the univariate analysis showed that Vo₂max was weakly but significantly associated with lower V_E/Vco₂ (Fig. 1), mPpa (not shown, r=0.25, p<0.05), mPpa/SVI (Fig. 2), and PVRI (not shown, r=0.24, p<0.05), or higher SVI (not shown, r=0.31, p<0.05), DL_NO (Fig. 3) and DL_CO (not shown, r=0.21, p=0.05).

FIG. 1.

Vo₂max as a function of V_E/Vco₂ at sea level and at altitude. Decrease in V_E/Vco₂ is associated with proportionally increase in Vo₂max.

FIG. 2.

Vo₂max as a function of mPpa/SVI at sea level and at altitude. Decrease in mPpa/SVI is associated with proportionally increase in Vo₂max.

FIG. 3.

Vo₂max as a function of DL_NO at sea level and at altitude. Increase in DL_NO is associated with proportionally increase in Vo₂max.

At sea level, the multivariable analysis showed that only lower V_E/Vco₂ (p<0.001), mPpa (p<0.05), or mPpa/SVI (p<0.05), and higher SVI (p<0.05) and DL_NO (p<0.05) were significantly associated with Vo₂max (adjusted r² of the model 0.68, SEE 7.2).

At high altitude, the univariate analysis showed that Vo₂max was weakly but significantly associated with lower PVRI (not shown, r=0.30, p<0.05), mPpa/SVI (Fig. 2), and V_E/Vco₂ (Fig. 3), and higher DL_NO (Fig. 1) and DL_CO (not shown, r=0.21, p=0.05).

At high altitude, the multivariable analysis showed that only lower V_E/Vco₂ (p<0.001), mPpa/SVI (p<0.05), PVRI (p<0.05), and higher DL_NO (p<0.01) were independently associated with Vo₂max (adjusted r² of the model 0.54, SEE 5.3). The magnitude of the decrease in Vo₂max at high altitude was independently associated with increases in PVRI and in V_E/Vco₂ (adjusted r² of the model 0.63, SEE 0.64). Linear correlations between changes in Vo₂max and changes in PVRI and in V_E/Vco₂ from sea level to high altitude are shown in Figures 4 and 5.

FIG. 4.

Change in Vo₂max as a function of change in PVRI from sea level to altitude. The magnitude of the decrease in Vo₂max at high altitude is correlated with the change in PVRI from sea level to high altitude.

FIG. 5.

Change in Vo₂max as a function of change in V_E/Vco₂ from sea level to altitude. The magnitude of the decrease in Vo₂max at high altitude was correlated with changes in V_E/Vco₂ from sea level to high altitude.

Discussion

The present results show for the first time that in healthy subjects, Vo₂max is independently associated with a higher DL_NO, a lower ventilation at any given metabolic rate, and a lower pulmonary vascular resistance, both at sea level and at high altitude. These data are in keeping with the hypothesis that a lower pulmonary vascular resistance associated with more distensible resistive vessels and capillaries, or higher pulmonary vascular reserve, allows for a higher exercise capacity at a lower ventilatory cost, both in normoxia and in hypoxia.

In the present study, lung diffusing capacity was measured by the transfer of both NO and CO. The NO/CO transfer method was initially introduced with the rationale that the infinite affinity of NO for hemoglobin (θNO) would allow to calculate the membrane component of DL_CO (Guenard et al., 1987). The Roughton and Forster equation states that 1/DL_CO=1/Dm+1/θVc, where Dm and Vc are the membrane and capillary blood volume components of DL_CO respectively (Roughton and Forster, 1957). With θVc equal to the infinite, a DL_NO measurement would exclusively be determined by the membrane component of the alveolo-capillary gas transfer. Recent work has demonstrated that θNO has a finite value, introducing uncertainty about previously reported Dm and Vc calculations (Borland et al., 2012). Furthermore, the assumption of the linearity of 1/θ-Po₂ relationship at low Po₂ may not be sufficiently robust, introducing an additional uncertainty about the DL_CO measurements at high altitude. The doubt on linearity is related to the value of θ_CO at 0 mmHg Po₂. For this Po_2, the Forster equation gives a θ_CO value of 0.77 mmHg⁻¹min⁻¹. Recent data derived from the experiments on vesicles containing deoxygenated Hb confirm this range of values. At concentrations of Hb similar to human red cells and similar shape, the ratio of NO to CO rates of transfer to the vesicles was 7.7. Using the Borland θ_NO value of 4.5 mmHg⁻¹min⁻¹, θ_CO would be 0.59 in the range of Forster values (Sakai et al., 2008). Reduction in Po₂ might itself increase DL_CO due to less competition by O₂ for the hemoglobin binding site, however the rate-limiting step for CO binding is the internal bond with the heme formation (Olson et al. 2003). A recalculation of DL_CO in a previous study at the Po₂ of the altitude of 5000 m decreased DL_CO at rest by an average of 2 mL/min/mmHg at rest (de Bisschop et al, 2012), which offers only a partial explanation for the global average increase of 6 mL/min/mmHg found in the present meta-analysis.

The DL_NO/DL_CO ratio slightly decreased at high altitude, suggesting a predominant effect of increased Vc (Glenet et al, 2007, Hughes and Pride, 2012). This could be explained by capillary distension in addition to recruitment related to increased pulmonary prefusion pressure caused by hypoxic pulmonary vasoconstriction and, possibly, increased effective capillary pressure related to a venous component of hypoxic vasoconstriction (Maggiorini et al, 2001). However, the small size of the effect and the many assumptions on which the estimation is based make this result incompletely convincing. Furthermore, the DL_NO/DL_CO ratio did not change when DL_CO was recalculated with Po₂-corrected θ_CO values.

During exercise at various intensities, DL_CO and DL_NO have been shown to increase in proportion to workload, with no change in the DL_NO/DL_CO ratio, which was stable at 4.52±0.24 (Zavorsky et al., 2004). In the present study, DL_NO/DL_CO was at the same mean value of 4.5 at sea level. Altitude exposure was associated with an increase in both DL_NO and DL_CO, confirming previous report in acclimatized subjects (Agostoni et al, 2011) or altitude exposure without strenuous exercise (Groepenhoff et al., 2012). However, the DL_NO/DL_CO, ratio slightly decreased. This is probably explained by capillary distension in addition to recruitment related to increased pulmonary perfusion pressure caused by hypoxic pulmonary vasoconstriction and, possibly, increased effective capillary pressure related to a venous component of hypoxic vasoconstriction (Maggiorini et al, 2001). However, DL_NO/DL_CO ratio did not change when DL_CO was recalculated with sea level θ values.

In the present study, a univariate analysis revealed that Vo₂max was associated with both DL_CO and DL_NO at sea level and at altitude. However, the multivariable analysis disclosed that only DL_NO was associated with Vo₂max, at sea level and at altitude. We previously showed that DL_NO and DL_CO were correlated to Vo₂max with only a p<0.1 level of significance at sea level, but a p<0.05 level of significance at altitude (de Bisschop et al., 2011). DL_CO has been shown to be associated with aerobic exercise capacity in patients with chronic heart failure (Puri et al., 1995; Agostoni et al., 2006), lung diseases (Wehr and Johnson, 1976), and in normal subjects (Tzani et al., 2008; Zavorsky et al., 2010). In healthy subjects, DL_NO has been shown to be superior to DL_CO in estimating Vo₂max, particularly in the less fit and overweight (Zavorsky et al., 2010) or in those with smoking habits (Tzani et al., 2008). In the present study on a larger number of subjects, DL_NO was clearly shown, by a rigorous multivariable analysis, to be superior to DL_CO in being associated to Vo₂max in both normoxic and hypoxic conditions. This observation together with the inverse correlation to PVRI or mPpa/SVI suggests a decreased capillary contribution to PVR, probably through capillary distension to aerobic exercise capacity.

The observation of a lower PVR associated with a higher exercise capacity at altitude is in keeping with previous reports (Ghofrani et al., 2004; Faoro et al., 2009; Fischler et al., 2009; Naeije et al., 2010; Naeije, 2011). In the present study, a lower mPpa and a higher SVI were both independently associated with a higher Vo₂max at sea level as well as at high altitude. Accordingly, a lower mPpa/SVI was associated to a higher Vo₂max in both conditions as well. However, PVRI is associated with Vo₂max only at high altitude. The reason of this apparent discrepancy is probably in the HR-dependency of the calculation of cardiac output from the LVOT velocity time integral (Christie et al., 1987). Fitter subjects have a lower HR, which might lead to an underestimation of cardiac output at rest. This is why the mPpa/SVI ratio may be more adequate for the noninvasive estimation of a higher aerobic exercise capacity. A higher SVI in a more distensible pulmonary capillary bed is a likely contributor to the observed improvement in lung diffusing capacity.

Invasive, as well as more recent noninvasive studies, show that the response of the pulmonary circulation to exercise at progressively increased workload is characterized by variable slopes of mPpa-Q relationships, from 1 to 2.5 mmHg/L/min, with maximum mPpa between 40 and 50 mmHg at the highest flows (Reeves et al., 1999; La Gerche et al. 2010; Argiento et al., 2012, Lalande et al., 2012). There may be a maximum possible Ppa with which a healthy right ventricle can cope to maintain flow output adapted to peripheral demand, and this will be reached at higher maximal Q in subjects with lower PVR (La Gerche et al., 2010; Argiento et al., 2012). Positive pulmonary transit of agitated saline in healthy subjects at high levels of exercise and cardiac output probably reflects both arteriolar and capillary distension (La Gerche et al., 2010, Lalande et al., 2012). Another factor to consider is exercise-induced increase in left atrial pressure, which occurs at high levels of exercise (Stickland et al., 2006), and is transmitted upstream to mPpa in a close to one to one ratio (Reeves et al., 1999). This increase in left atrial pressure is delayed to higher levels of exercise in very fit subjects (Stickland et al., 2006) in relation to a decreased left ventricular diastolic compliance (Levine et al., 1991). The present demonstration that DL_NO is associated with Vo₂max is in keeping with the notion that a lower PVR allowing for higher levels of exercise is related to increased distension of the pulmonary capillary segment in response to increased flow and left atrial pressure.

The combination of higher DL_NO related to lower PVR being associated with higher aerobic exercise capacity was equally identified in normoxia and in hypoxia. Hypoxic pulmonary vasoconstriction in humans is usually mild and variable (Grover et al., 1983), but with a capillary-venous component (Maggiorini et al., 2001). This may explain why pulmonary vasodilating interventions decrease PVR and improve Vo₂max (Faoro et al., 2009; Fischler et al., 2009; Naeije et al., 2010) and limit post-exercise decrease in DL_NO (de Bisschop et al., 2011; Naeije, 2011).

The effects of short-term altitude exposure on lung diffusing capacity has been reported variably (reviewed in de Bischop et al., 2011) but with a strong tendency to improvement when time is taken for optimal acclimatization (Agostoni et al., 2011). In the present study, altitude exposure was associated with moderate but significant increases in both DL_NO and DL_CO. Long-term to life-long exposure to high altitudes is associated with a marked increase in lung diffusing capacity, as well as with a decreased ventilatory response to exercise (Dempsey et al., 1971). It has been assumed that increased lung diffusion would be a favorable adaptation by allowing for maintained gas exchange at a lower level of ventilation (Dempsey et al., 1971). In the present study, V_E/Vco₂ was independently associated with Vo₂max, and also inversely correlated to DL_NO. However, pulmonary hypertension may be a cause of increased V_E/Vco₂ (Sun et al., 2001), in proportion to disease severity (Deboeck et al., 2012). It is therefore not excluded that a lower PVR in healthy subjects might have contributed to lower ventilatory responses to exercise, particularly at high altitude where hypoxia induces pulmonary vasoconstriction. We wondered if part of the observed correlations and associations could be body size-dependent. Larger size individuals have higher Vo₂max, stroke volumes, and lung diffusing capacities. Vco₂max and cardiac output were corrected for body weight and body surface area, respectively. Diffusing capacities could have been corrected for alveolar volume, but altitude is associated with increased lung volumes (Agostoni et al., 2011), so that this would be a confounding factor. Another possible correction could have been in the expression of all the measurements in % predicted, but this might have produced disproportionate changes in different variables, and a statistical analysis is preferably done on source numbers. This is why, in the present study, we limited the corrections for body dimensions to Vco₂max, flow and stroke volume measurements.

In conclusion, aerobic capacity at sea level, as well as at high altitude, tends to be higher in subjects with more pulmonary vascular reserve defined by a combination of lower pulmonary vascular resistance and higher lung diffusing capacity, along with a lower level of ventilation at any metabolic rate.

Footnotes

Acknowledgments

AP and RN drafted the report; AP performed part of the echocardiographic measurements, VF the CPET, and HG, CDB and JBM the lung diffusion measurements; CM advised and performed the statistical analysis; RN directed the expeditions, designed the studies, participated to the measurements, and is the guarantor of the paper, taking responsibility of the integrity of the work as a whole, from inception to published article. All the authors contributed to successive drafts of the report by comments and suggestions, and approved the final submitted version.

The authors thank S Huez, K Retailleau, R Bastin, M Moreels, M Mulè. and P Argiento for contribution to the echocardiographic examinations, M Lamotte, G Deboeck, M van der Plas, M Groepenhoff, S Beloka and M Overbeek for contribution to the CPET's, and C Scoditti, M Overbeek and G Leurquin-Stercq for contribution to lung diffusion measurements.

The expedition to Nepal was funded by the Ev-K2-CNR Project in collaboration with the Nepal Academy of Science and Technology as foreseen by the Memorandum of Understanding between Nepal and Italy, and thanks to contributions from the Italian National Research Council. The expeditions to Nepal and Peru were supported by grants from Pfizer. The expedition to Peru was made possible by the Instituto de Investigaciones de la Altura Universidad Peruana Cayetano Heredia, allowing for the use of the Cerro de Pasco Facilities. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author Disclosure Statement

No competing financial interests exist.

References

Agostoni

, Bussotti

, Cattadori

et al. 2006. Gas diffusion and alveolar-capillary unit in chronic heart failure. Eur Heart J, 27:2538–2541.

Agostoni

, Swenson

, Bussotti

et al. HIGHCARE Investigators. 2011. High altitude exposure of three weeks duration increases lung diffusing capacity in humans. J App Physiol, 110:1564–1571.

Aguilaniu

, Maitre

, Glenet

, Gegout-Petit

, Guenard

. 2008. European reference equations for CO and NO lung transfer. Eur Respir J, 31:1091–1097.

Argiento

, Vanderpool

, Mule

et al. 2012. Exercise stress echocardiography of the pulmonary circulation. Limits of normal and gender differences. Chest, 142:1158–1165.

Borland

, Dunningham

, Bottrill

et al. 2010. Significant blood resistance to nitric oxide transfer in the lung. J Appl Physiol, 108:1052–1060.

Christie

, Sheldal

, Tristani

, Sagar

, Pitacin

, Wann

. 1987. Determination of stroke volume and cardiac output during exercise: Comparison of two-dimensional and Doppler echocardiography, Fick oximetry, and thermodilution. Circulation, 76:539–547.

de Bisschop

, Martinot

, Leurquin-Sterk

, Faoro

, Guenard

, Naeije

. 2012. Improvement in lung diffusion by endothelin A receptor blockade at high altitude. J Appl Physiol, 112:20–25.

Deboeck

, Scoditti

, Huez

et al. 2012. Exercise testing to predict outcome in idiopathic vs associated pulmonary arterial hypertension. Eur Respir J, 40:1410–1419.

Dempsey

, Reddan

, Birnbaum

, Forster

, Thoden

, Grover

, Rankin

. 1971. Effects of acute through life-long hypoxic exposure on exercise pulmonary gas exchange. Respir Physiol, 13:62–89.

10.

Faoro

, Boldingh

, Moreels

et al. 2009. Bosentan decreases pulmonary vascular resistance and improves exercise capacity in acute hypoxia. Chest, 135:1215–1222.

11.

Fischler

, Maggiorini

, Dorschner

et al. 2009. Dexamethasone but not tadalafil improves exercise capacity in adults prone to high altitude pulmonary edema. Am J Respir Crit Care Med, 180:346–352.

12.

Forster

. 1987. Diffusion of gases across the alveolar membrane. Handbook of Physiology. The Respiratory System. Gas Exchange. Bethesda, MD: American Physiological Society, 71–88.

13.

Ghofrani

, Reichenberger

, Kohstall

et al. 2004. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: A randomized, double-blind, placebo-controlled crossover trial. Ann Intern Med, 141:169–177.

14.

Glenet

, De Bisschop

, Vargas

, Guenard

. 2007. Deciphering the nitric oxide to carbon monoxide lung transfer ratio: Physiological implications. J Physiol, 582:767.

15.

Groepenhoff

, Overbeek

, Mulè

et al. 2012. Exercise pathophysiology in patients with chronic mountain sickness. Chest 2012, 142:877–884.

16.

Grover

, McMurtry

, Reeves

. 1983. Pulmonary circulation. Handbook of Physiology, the Cardiovascular System, Peripheral Circulation and Organ Blood Flow, ed. Bethesda MD: Am Physiol Soc sect 2, 103–136.

17.

Guenard

, Varene

, Vaida

. 1987. Determination of lung capillary blood volume and membrane diffusing capacity in man by the measurements of NO and CO transfer. Respir Physiol, 70:113–120.

18.

Hughes

, Pride

. 2012. Examination of the carbon monoxide diffusing capacity (DLCO) in relation to its KCO and VA components. Am J Respir Crit Care Med, 186:132–139.

19.

La Gerche

, MacIsaac

, Burns

et al. 2010. Pulmonary transit of agitated contrast is associated with enhanced pulmonary vascular reserve and right ventricular function during exercise. J Appl Physiol, 109:1307–1317.

20.

Lalande

, Yerly

, Faoro

, Naeije

. 2012. Pulmonary vascular distensibility predicts aerobic capacity in healthy individuals. J Physiol, 590:4279–4288.

21.

Levine

, Lane

, Buckey

, Friedman

, Blomqvist

. 1991. Left ventricular pressure-volume and Frank-Starling relation in endurance athletes. Implications for orthostatic tolerance and exercise performance. Circulation, 84:1016–1023.

22.

Macintyre

, Crapo

, Viegi

et al. 2005. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J, 26:720–735.

23.

Maggiorini

, Mélot

, Pierre

et al. 2001. High altitude pulmonary edema is initially caused by an increased capillary pressure. Circulation, 103:2078–2083.

24.

Naeije

. 2011. Pro: Hypoxic pulmonary vasoconstriction is a limiting factor of exercise at altitude. High Alt Med Biol, 12:309–312.

25.

Naeije

, Huez

, Lamotte

et al. 2010. Pulmonary artery pressure limits exercise capacity at high altitude. Eur Respir J, 36:1049–1055.

26.

Olson

, Foley

, Maillett

, Paster

. 2003. Measurement of rate constants for reactions of O2, CO, and NO with hemoglobin. Methods Mol Med, 82:65–91.

27.

Puri

, Baker

, Dutka

, Oakley

, Hughes

, Cleland

. 1995. Reduced alveolo-capillary membrane diffusing capacity in chronic heart failure. Its pathophysiological relevance and relationship to exercise performance. Circulation, 91:2769–2774.

28.

Reeves

, Dempsey

, Grover

. 1999. Pulmonary circulation during exercise. Pulmonary Vascular Physiology and Physiopathology. Weir

, Reeves

. New York: Marcel Dekker, 107–133.

29.

Roach

, Bartsch

, Hackett

, Oelz

. 1993. The Lake Louise Acute mountain sickness scoring system. Hypoxia and Mountain Medicine. Sutton

, Houston

, Coates

. Burlington, VT: Queen City, 327–330.

30.

Roughton

FJW

, Forster

. 1957. Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in the human lung, with special reference to true diffusing capacity of pulmonary membrane and volume of blood in the lung capillaries. J Appl Physiol, 11:290–302.

31.

Sakai

, Sato

, Masuda

, Takeoka

, Tsuchida

. 2008. Encapsulation of concentrated hemoglobin solution in phospholipid vesicles retards the reaction with NO, but not CO, by intracellular diffusion barrier. J Biol Chem, 283:1508–1517.

32.

Stickland

, Welsh

, Petersen

et al. 2006. Does fitness level modulate the cardiovascular hemodynamic response to exercise? J Appl Physiol, 100:1895–1901.

33.

Sun

, Hansen

, Oudiz

, Wasserman

. 2001. Exercise pathophysiology in patients with primary pulmonary hypertension. Circulation, 104:429–435.

34.

Tzani

, Aiello

, Colella

et al. 2008. Lung diffusing capacity can predict maximal exercise in apparently healthy smokers. J Sports Sci Med, 7:229–234.

35.

Wehr

, Johnson

. 1976. Maximal oxygen consumption in patients with lung diseases. J Clin Invest, 58:880–890.

36.

Zavorsky

, Quiron

, Massarelli

, Lands

. 2004. The relationship between single-breath diffusion capacity of the lung for nitric oxide and carbon monoxide during various exercise intensities. Chest, 125:1019–1027.

37.

Zavorsky

, Wilson

, Harris

, Kim

, Carli

, Mayo

. 2010. Pulmonary diffusion and aerobic capacity: Is there a relation? Does obesity matter? Acta Physiol, 98:499–507.

Pulmonary Vascular Reserve and Exercise Capacity at Sea Level and at High Altitude

Abstract

Abstract

Introduction

Materials and Methods

Study population

Experimental protocol

Echocardiography

Cardiopulmonary exercise test

Lung diffusion measurements

Statistical analysis

Results

Effects of altitude on clinical state, echocardiography (Table 1), CPET (Table 2), and lung diffusion (Table 3)

Univariate and multivariable analysis of variables associated with Vo2max

Discussion

Footnotes

Acknowledgments

Author Disclosure Statement

References

Univariate and multivariable analysis of variables associated with Vo₂max