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. 2014 Feb 12;592(Pt 6):1397–1409. doi: 10.1113/jphysiol.2013.266593

Resting pulmonary haemodynamics and shunting: a comparison of sea-level inhabitants to high altitude Sherpas

Glen E Foster 1,✉, Philip N Ainslie 1, Mike Stembridge 2, Trevor A Day 3, Akke Bakker 4, Samuel J E Lucas 5,6, Nia C S Lewis 1, David B MacLeod 7, Andrew T Lovering 8
PMCID: PMC3961095  PMID: 24396057

Abstract

The incidence of blood flow through intracardiac shunt and intrapulmonary arteriovenous anastomoses (IPAVA) may differ between Sherpas permanently residing at high altitude (HA) and sea-level (SL) inhabitants as a result of evolutionary pressure to improve gas exchange and/or resting pulmonary haemodynamics. To test this hypothesis we compared sea-level inhabitants at SL (SL-SL; n = 17), during acute isocapnic hypoxia (SL-HX; n = 7) and following 3 weeks at 5050 m (SL-HA; n = 8 non-PFO subjects) to Sherpas at 5050 m (n = 14). Inline graphic, heart rate, pulmonary artery systolic pressure (PASP) and cardiac index (Qi) were measured during 5 min of room air breathing at SL and HA, during 20 min of isocapnic hypoxia (SL-HX; Inline graphic = 47 mmHg) and during 5 min of hyperoxia (Inline graphic = 1.0; Sherpas only). Intracardiac shunt and IPAVA blood flow was evaluated by agitated saline contrast echocardiography. Although PASP was similar between groups at HA (Sherpas: 30.0 ± 6.0 mmHg; SL-HA: 32.7 ± 4.2 mmHg; P = 0.27), it was greater than SL-SL (19.4 ± 2.1 mmHg; P < 0.001). The proportion of subjects with intracardiac shunt was similar between groups (SL-SL: 41%; Sherpas: 50%). In the remaining subjects, IPAVA blood flow was found in 100% of subjects during acute isocapnic hypoxia at SL, but in only 4 of 7 Sherpas and 1 of 8 SL-HA subjects at rest. In conclusion, differences in resting pulmonary vascular regulation, intracardiac shunt and IPAVA blood flow do not appear to account for any adaptation to HA in Sherpas. Despite elevated pulmonary pressures and profound hypoxaemia, IPAVA blood flow in all subjects at HA was lower than expected compared to acute normobaric hypoxia.

Introduction

The resting pulmonary haemodynamic response when individuals from lowland areas are exposed to high altitude (HA) is reasonably well characterized (Reeves, 1973; Swenson, 2013). For example, hypoxic pulmonary vasoconstriction (HPV) is stimulated largely by alveolar partial pressure of oxygen (Inline graphic) and ventilation–perfusion relationships leading to increases in pulmonary artery pressure (Marshall & Marshall, 1983). At sea level (SL), this response to regional alveolar hypoxia might be considered adaptive, as its teleological role is to decrease perfusion of poorly ventilated alveoli and assist in the matching of ventilation and perfusion throughout the lung (Marshall et al. 1981; Orchard et al. 1983). However, when the whole lung is hypoxic, such as with chronic exposure to HA, HPV may in fact be a maladaptive response leading to high perfusion pressure, capillary damage and an increased risk of HA pulmonary oedema. HA residents from the Andes are prone to chronic mountain sickness, and greater hypoxaemia, pulmonary vasoconstriction and increased haematocrit contribute to their increased pulmonary arterial vascular pressure (Penaloza & Arias-Stella, 2007; Stuber & Scherrer, 2010). However, not all HA ethnic groups are prone to elevated pulmonary artery pressures and chronic mountain sickness, which suggests that some individuals and populations of HA residents have different phenotypes for life in environments with low Inline graphic. Tibetans and Sherpas, for example, are thought to be well adapted to HA owing partly to their relatively low pulmonary artery pressures, minimal polycythemia, elevated resting ventilation and a high lung diffusing capacity (Groves et al. 1993; Hoit, 2005; Hoit et al. 2011; Faoro et al. 2013). Although we do not contest that Tibetans and Sherpas are well adapted to their HA environment, the direct evidence for low resting pulmonary artery pressures with alveolar hypoxia in this HA population is based on investigations with small sample sizes that lack adequate control groups. To shed light on resting pulmonary haemodynamics in Sherpas, it would be most appropriate to study resting pulmonary haemodynamics in HA Sherpas and in SL inhabitants at SL and following acclimatization to HA.

The circulatory system has two pathways that could help to alleviate pulmonary pressure by providing a low resistance pathway for blood. However, these pathways also prevent some blood from passing through the blood–gas interface within the lung, which could impair pulmonary gas exchange efficiency. These pathways include intracardiac shunt, of which the most notable is the patent foramen ovale (PFO), and intrapulmonary arteriovenous anastomoses (IPAVA). A PFO is detected in 35–38% of the general population (Woods, 2010; Marriott et al. 2013; Elliott et al. 2013). By contrast, blood flow through IPAVA is detected at rest in approximately 30% of healthy humans at SL (Woods, 2010; Elliott et al. 2013) and increases to near 100% in healthy male and female humans during exercise (Eldridge et al. 2004; Stickland et al. 2007; Kennedy et al. 2012) and with exposure to hypoxia (Imray et al. 2008; Lovering et al. 2008a; Laurie et al. 2010). At lower altitudes, e.g. <3000 m, the presence of a right-to-left shunt pathway, such as a PFO or IPAVA, could potentially worsen systemic arterial hypoxaemia and over time lead to greater pulmonary hypertension, suggesting blood flow through these pathways could be detrimental (Levine et al. 1991; Swenson & Bärtsch, 2012). However, with increasing altitude, the impact of blood flow through IPAVA and/or PFO on pulmonary gas exchange efficiency will decrease as Inline graphic approaches Inline graphic. Accordingly, at altitudes > 3000 m, blood flow through these pathways may provide a beneficial effect by allowing for lower pulmonary vascular pressure without having a significant impact on gas exchange. Based on this rationale, there is reasonable ground to investigate whether Sherpas, a group of well-adapted HA residents living in the Himalayas, may have adapted to utilize large diameter right-to-left shunt pathways when hypoxaemic to divert blood flow away from the conventional pulmonary circulation in an attempt to reduce pulmonary vascular pressure for a given level of HPV.

With this rationale in mind, we aimed to measure pulmonary haemodynamics and Inline graphic and to characterize the occurrence of intracardiac shunt and blood flow through IPAVA in Sherpas who permanently reside at HA compared to SL inhabitants at SL and following ∼3 weeks of acclimatization to 5050 m. To provide a reasonable comparison to acute hypoxia studies investigating pulmonary haemodynamics and right-to-left shunt (Laurie et al. 2010), we studied the pulmonary haemodynamic response in a subset of SL subjects during exposure to acute isocapnic hypoxia. Based on the results of previous investigations (Groves et al. 1993; Hoit, 2005; Schwab et al. 2008; Stuber & Scherrer, 2010; Hoit et al. 2011; Groepenhoff et al. 2012; Faoro et al. 2013) we hypothesized that Sherpas at HA would have low pulmonary vascular pressure similar to SL inhabitants at SL and would have decreased pulmonary vascular pressure compared to SL inhabitants following acclimatization to HA. Secondly, we hypothesized that the lower pulmonary artery vascular pressure in Sherpas at altitude would be explained by more blood flow through right-to-left shunt pathways compared to SL inhabitants. Such differences might help to explain the previously reported reduced pulmonary pressure and total pulmonary resistance in Sherpas compared to SL inhabitants.

Methods

Ethical approval

All experimental procedures and protocols were submitted to and approved by the Clinical Research Ethics Board at the University of British Columbia and the Nepal Health Medical Research Council, and conformed to the latest revision of the Declaration of Helsinki. All participants provided written informed consent prior to participation in this study.

Subjects

We studied a group of SL subjects in Kelowna, British Columbia, Canada, near SL (SL-SL; n = 17; elevation = 344 m). From this group, a subset of subjects were identified as PFO negative (PFO−) and were subsequently studied for pulmonary haemodynamics and blood flow through IPAVA at SL during acute isocapnic hypoxia (n = 7) and at HA following 3 weeks of acclimatization at the EV-K2-CNR Laboratory, Nepal (SL-HA; n = 8; elevation = 5050 m). Three weeks of exposure to HA was selected to ensure a reasonable length of time for acclimatization. Previous work by Lundby et al. (2004) has demonstrated that there is little difference in arterial oxyhaemoglobin saturation (Inline graphic) and haematocrit between 2 and 8 weeks of acclimatization to 4100 m. Due to logistical barriers one subject in the SL-HA group was not studied during acute isocapnic hypoxia at SL. SL subjects were excluded if they were born above 1200 m in elevation or if they had travelled to HA (>2500 m) in the past 6 months. Finally, a group of HA residents of Sherpa ancestry were recruited from HA regions of the Khumbu Valley and were studied at HA (n = 14; elevation = 5050 m). Sherpas were excluded if they were not permanent residents above 2800 m, if they were born below an altitude of 2800 m and if they did not self-identify as a Sherpa. No Sherpas had travelled below 2800 m within 2 months of this study.

Experimental protocol

At both SL and HA, all subjects were first measured for height and weight and then instrumented with an intravenous catheter at the antecubital fossa. Following 5 min of supine rest, three consecutive blood pressure measurements were obtained from the right upper arm by using a manual sphygmomanometer and stethoscope for auscultation of Korotkoff sounds. Also at this time, Inline graphic (Model 3100, WristOx, Nonin Medical Inc., Plymouth, MN, USA) was measured by pulse oximetry of the right index finger. While in the supine position, collapse of the inferior vena cava (IVC) during a rapid inspiration was imaged by ultrasound to estimate right atrial pressure (Yildirimturk et al. 2011). The subject was then positioned laterally on their left side and echocardiographic images were recorded to determine stroke volume (SV) and pulmonary artery systolic pressure (PASP). Heart rate (HR) was measured using a standard three-lead electrocardiograph. Next, an apical four-chamber view of the heart was acquired and the presence or absence of intracardiac shunt or blood flow through IPAVA was determined using agitated saline contrast echocardiography (Kennedy et al. 2012; Elliott et al. 2013). This was repeated during the release of a Valsalva manoeuvre as a provocative stimulus to ensure the patency of the foramen ovale was identified appropriately. At SL, subjects identified as PFO− were subsequently exposed to 20 min of isocapnic hypoxia to determine pulmonary haemodynamics and blood flow through IPAVA during an acute hypoxic exposure. Pulmonary haemodynamics and blood flow through IPAVA were measured during the last 5 min of hypoxia. In Sherpas only, at HA the above measurements were repeated after breathing hyperoxia (Inline graphic = 1.0) for 5 min to determine the impact of hypoxia relief. Agitated contrast studies were repeated if there was any doubt in the classification of the shunt to intracardiac or intrapulmonary.

Pulmonary haemodynamics

All echocardiography measurements were performed using the same commercially available ultrasound system (Vivid Q, 3.5 MHz transducer, GE Healthcare, Piscataway, NJ, USA) by the same trained sonographer (M.S.). First, the diameter of the left ventricular outflow tract at the level of the aortic annulus was determined from the parasternal long axis view. Measurements were taken at the end of systole and the average of three cardiac cycles was taken as the diameter of the aorta. Then, the velocity time integral (VTI) of the left ventricular outflow tract was obtained from an apical five-chamber view by placing a pulsed wave Doppler sample volume just within the aortic valve. SV was calculated as the product of the VTI and aortic area, and cardiac output (Q) was obtained by multiplication with HR. These methods have been previously described and validated against thermodilution and direct Fick (Christie et al. 1987). Cardiac index (Qi) was determined by indexing Q with body surface area to facilitate comparisons between groups. Tricuspid regurgitation peak velocity was measured by continuous-wave Doppler ultrasound using colour flow imaging from the apical four-chamber view. The pulmonary artery pressure gradient could then be estimated from the simplified Bernoulli equation and PASP could be estimated by addition of right atrial pressure. IVC diameter was measured from subcostal longitudinal images approximately 2 cm distal to the right atrial junction. The collapsibility index was calculated as the percentage difference between maximal and minimal size of IVC. Right atrial pressure was predicted using the collapsibility index as recommended by the American Society of Echocardiography (Lang et al. 2005). This method has been validated against right atrial pressure obtained directly by right heart catheterization (Yildirimturk et al. 2011). All pulmonary haemodynamic measurements were made on three cardiac cycles and averaged to provide a single value. Total pulmonary resistance was estimated by indexing PASP against Q (i.e. PASP/Q; mmHg l−1). This non-invasive estimate of total pulmonary resistance correlates well with invasive measurements (Abbas et al. 2003; Roule et al. 2010).

Agitated saline contrast echocardiography

The presence of intracardiac shunt (i.e. PFO) was determined under resting conditions and during a provocative stimulus (i.e. release from Valsalva) using agitated saline contrast echocardiography (Marriott et al. 2013). Two, 5 ml syringes were connected by three-way stopcocks and connected to the 22-guage cannula placed in the antecubital vein. One syringe contained 4 ml of sterile saline and the other contained 0.5 ml of air. The two syringes were flushed back and forth forcefully to agitate the mixture prior to rapid injection. The agitated contrast was visualized travelling through the heart from an apical four-chamber view of the heart. If a negative test was identified, a provocative manoeuvre was used to further assess the patency of the foramen ovale. In this case, subjects were instructed to Valsalva at the end of a normal expiration. Agitated contrast was subsequently injected and, once visualized in the right atrium, the subjects were asked to relax and breathe quietly. A PFO was identified if contrast appeared in the left ventricle within fewer than five cardiac cycles after the contrast cloud filled the right atrium (Marriott et al. 2013). After all contrast injections, a minimum of 20 cardiac cycles was recorded. In the event that a subject was identified as being PFO negative they were then studied for resting blood flow through IPAVA. An IPAVA was defined when contrast appeared in the left ventricle six or more cardiac cycles after the contrast appeared in the right atrium. Therefore, all subjects were identified as PFO+ or PFO− and IPAVA positive or negative. A PFO+ subject could also have blood flow through an IPAVA, but this technique cannot distinguish between the two. As a result, blood flow through IPAVA can only be studied in subjects identified as PFO−. This technique has been used to investigate blood flow through IPAVA in subjects during rest and exercise at SL breathing room air and during acute normobaric hypoxia (Stickland et al. 2004; Imray et al. 2008; Kennedy et al. 2012; Laurie et al. 2012; Elliott et al. 2013). A scoring system was used to determine the severity of blood flow through IPAVA based on the greatest density and spatial distribution of microbubbles in the left ventricle of a single cardiac cycle during the subsequent 20 cardiac cycles (Lovering et al. 2008b). This 0–5 scoring system assigns a ‘0’ for no microbubbles; ‘1’ for 1–3 microbubbles; ‘2’ for 4–12 microbubbles; ‘3’ for more than 12 microbubbles bolus; ‘4’ for greater than 12 microbubbles heterogeneously distributed; and ‘5’ for more than 12 microbubbles homogeneously distributed. All echocardiograms were conducted and analysed by the same un-blinded investigator (M.S.). Previous work by members of our group has shown good agreement between scorers who have been blinded to the experimental conditions (Laurie et al. 2010).

Isocapnic hypoxia

Respiratory parameters were acquired at 200 Hz using an analog-to-digital converter (PL3504, ADInstruments, Colorado Springs, CO, USA) interfaced to a personal computer and analysed using commercially available software (LabChart, ADInstruments). During the isocapnic hypoxia protocol subjects breathed through a mouthpiece and two-way non-rebreathing valve, and a nose clip was applied to obstruct the nasal passage. Respired gas pressures were sampled at the mouth and analysed for Inline graphic and Inline graphic (ML206, ADInstruments). Respiratory flow was measured at the mouth using a pneumotachograph (HR 800L, Hans Rudolph, Shawnee, KS, USA). Inline graphic, Inline graphic, and inspiratory and expiratory tidal volume were determined for each breath online using custom designed software (LabView, National Instruments, Austin, TX, USA). Inline graphic was measured continuously by pulse oximetry (ML320/F, ADInstruments). Inline graphic was maintained at 45 mmHg and Inline graphic was maintained at resting levels by using a portable end-tidal forcing system (AirForce, G. E. Foster, Vancouver, Canada; Querido et al. 2013; Bain et al. 2013). This system uses independent gas solenoid valves for O2, CO2 and N2 and controls the volume of each gas being delivered to an inspiratory reservoir through a mixing and humidification chamber. Using feedback information regarding Inline graphic, Inline graphic, inspired and expired tidal volumes, and estimates of O2 consumption and CO2 production the system prospectively targets the inspirate using the alveolar gas equation to bring end-tidal gas levels to the desired level. Gas control fine-tuning is accomplished using a complex feedback control and error reduction algorithm. Pulmonary haemodynamics and blood flow through IPAVA were determined during 5 min of baseline breathing and during the last 5 min of isocapnic hypoxia.

Statistical analysis

Statistical comparisons and calculations were made using statistical software (Statistica v.7.0, Statsoft Inc., Tulsa, OK, USA). Subject resting characteristics were compared between the three groups by one-way analysis of variance (ANOVA). Pulmonary haemodynamics were compared between groups by a one-way ANOVA. For all analyses, when significant F-ratios were detected, Tukey's HSD test was applied and corrected for unequal sample sizes where appropriate to determine where the differences lay. Differences between haemodynamic parameters were compared within each group for PFO+ and PFO− subjects using an un-paired t test. Fisher's exact test was used to compare the frequency of intracardiac shunt and IPAVA between groups. Shunt score was compared between groups by Friedman's test, with Dunn's post-test if appropriate. All data are presented as mean ± SD (unless otherwise noted) and statistical significance was set at P < 0.05 for all comparisons.

Results

Subject characteristics and resting haemodynamic data are presented in Table 1. Groups were similar in age, but only SL-SL was taller than Sherpas (P < 0.05). Body mass for all three SL groups was similar, but only SL-HX and SL-HA were significantly heavier than Sherpas (P < 0.05). Body mass index (BMI) was similar between groups but body surface area was greater in SL-SL, SL-HX and SL-HA compared to Sherpas. Inline graphic was lowered similarly during acute hypoxia and HA (P < 0.001), and was similar between SL-HA and Sherpas. Likewise, HR was elevated during acute hypoxia and HA (P < 0.001) but was similar between groups exposed to hypoxia. Both mean arterial pressure (MAP) and Qi were not appreciably different between the four groups. Table 2 displays the geographical locations and altitude of where Sherpas were born.

Table 1.

Subject characteristics and resting haemodynamics between SL inhabitants at SL (SL-SL), during acute isocapnic hypoxia (SL-HX), following 3 weeks of HA acclimatization (SL-HA), and in Sherpas at HA (5050 m). Subjects are further separated into groups based on their intracardiac shunt status (i.e. PFO+/PFO−)

SL-SL
 Sherpas
PFO− PFO+ Both SL-HX PFO− only SL-HA PFO− only PFO− PFO+ Both
n 10 7 17 7 8 7 7 14
Age (years) 32.6 ± 7.4 27.3 ± 6.0 30.4 ± 7.2 30.9 ± 5.3 30.0 ± 5.5 41.6 ± 17.3 25.6 ± 5.3* 33.7 ± 15.0
Sex (M:F) 9:1 4:3 13:4 6:1 7:1 7:0 7:0 14:0
Height (cm) 176 ± 6 177 ± 7 178 ± 6* 176 ± 7 177 ± 7 167 ± 7 168 ± 7 168 ± 7
Body mass (kg) 80.8 ± 12.4 70.7 ± 13.0 76.6 ± 13.3 84.8 ± 13* 80.7 ± 13.4* 62.7 ± 7.5 68.6 ± 12.4 65.7 ± 10.3
BMI (kg m−2) 26.1 ± 3.6 22.6 ± 3.1 24.6 ± 3.7 27.3 ± 3.4 26.4 ± 4.0 22.3 ± 1.2 24.3 ± 4.0 23.3 ± 3.0
BSA (m2) 1.98 ± 0.17 1.86 ± 0.19 1.93 ± 0.18* 2.03 ± 0.18* 2.01 ± 0.18* 1.71 ± 0.14 1.78 ± 0.07 1.75 ± 0.16
Birth altitude (m) 275 ± 387 122 ± 162 185 ± 277† 141.7 ± 185† 125 ± 178† 3979 ± 247 3884 ± 571 3931 ± 425
Inline graphic (%) 97.7 ± 1.3 97.9 ± 1.4 97.8 ± 1.3† 77.6 ± 3.9 81.2 ± 1.7 80.9 ± 3.8 83.9 ± 2.0 82.4 ± 3.3
HR (b.p.m.) 56.7 ± 7.1 58.7 ± 11.9 57.5 ± 9.1† 66.3 ± 13.2 70.3 ± 11.3 73.9 ± 14.3 77.9 ± 13.5 75.9 ± 13.5
MAP (mmHg) 89.8 ± 7.9 92.8 ± 8.0 91.1 ± 7.8 93.6 ± 7.0 99.3 ± 9.7 89.9 ± 7.0 94.4 ± 7.9 92.1 ± 7.5
Qi (l min–1 m−2) 2.05 ± 0.27 2.41 ± 0.47 2.21 ± 0.40 2.70 ± 0.73 1.91 ± 0.17 2.40 ± 0.53 2.06 ± 0.41 2.24 ± 0.49
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Values are mean ± SD.

*

Significantly different from Sherpa or different from PFO− within each group (P < 0.05);

†

significantly different from Sherpa (P < 0.001). BMI, body mass index; BSA, body surface area; Inline graphic, oxyhaemoglobin saturation; HR, heart rate; MAP, mean arterial pressure; Qi, cardiac index.

Table 2.

Distribution of geographical locations and altitudes where Sherpas were born

Location Elevation (m) Frequency (n)
Dingboche 4410 2
Khumjung 3780 1
Khunde 3840 3
Lukla 2840 1
Namche Bazaar 3440 1
Pangboche 3930 1
Pheriche 4240 4
Thame 3750 1
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Figure 1A displays PASP for all groups, including SL subjects during acute hypoxia and Sherpas during hyperoxia breathing. Acute hypoxia and HA increased PASP in SL-HX and SL-HA to a level similar to that of Sherpas. Hyperoxia decreased PASP in Sherpas (P < 0.01); however, PASP was still greater than that observed in the SL-SL group (P < 0.01). Figure 1B displays total pulmonary resistance as estimated by PASP/Q. Total pulmonary resistance was elevated at HA in the SL-HA group, but was not significantly different from Sherpas. Hyperoxia had no effect on total pulmonary resistance in Sherpas. Total pulmonary resistance was not significantly elevated during acute hypoxia owing to a small (albeit statistically insignificant) increase in Qi.

Figure 1.

Figure 1

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Pulmonary artery systolic pressure (PASP, A) and total pulmonary resistance (PASP/Q, B) in SL inhabitants at SL during rest (SL-SL; n = 17), during acute hypoxia (SL-HX; n = 7) and at HA (SL-HA; n = 8), and in Sherpas at HA (Sherpa; n = 14) and during 5 min of breathing 100% oxygen (Sherpa O2; n = 14). Where appropriate, groups are divided into their status of intracardiac shunt (i.e. PFO−/PFO+). Values are mean ± SD. *P < 0.01 compared to SL-SL and †P < 0.01 compared to SL-HA and Sherpa. Within each group there are no significant differences between PFO− and PFO+ status.

Figure 2 shows a contrast echocardiogram for one Sherpa at 5050 m who was identified as having a resting intracardiac shunt. Figure 3A displays the percentage of subjects positive for intracardiac shunt in Sherpas and SL-SL. In Sherpas, 7 of 14 subjects were positive for intracardiac shunt, which was not statistically different from SL-SL where 7 of 17 subjects were positive for intracardiac shunt. There were no significant differences between PFO+ and PFO− subjects in either SL subjects or Sherpas (Table 1 and Fig. 1).

Figure 2.

Figure 2

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The sequence of images shows pre-injection where no microbubbles are visible (A) followed by the appearance of the microbubble cloud in the right ventricle and the appearance of microbubbles in the left ventricle within three cardiac cycles (B, labelled with circles).

Figure 3.

Figure 3

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A, percentage of subjects positive for intracardiac shunt in SL inhabitants at SL (SL-SL) and in Sherpas at HA. B, percentage of subjects positive for IPAVA in SL inhabitants during acute hypoxia (SL-HX) and at HA (SL-HA), and in Sherpas at HA who were negative for intracardiac shunt (Sherpa).

In both SL-SL and Sherpas, 5 of 7 intracardiac shunts were identified in the resting state without Valsalva. Eight subjects studied at SL were negative for both intracardiac shunt and resting blood flow through IPAVA and were subsequently studied during acute isocapnic hypoxia (n = 7 only) and at 5050 m (i.e. SL-HA) to determine the presence of hypoxia-induced blood flow through IPAVA. Similarly, seven Sherpas were negative for intracardiac shunt and were subsequently studied for resting blood flow through IPAVA at 5050 m. Figure 3B shows the percentage of subjects identified for resting blood flow through IPAVA during acute hypoxia and at HA. During acute isocapnic hypoxia exposure, 100% of subjects displayed blood flow through IPAVA. At HA the proportions were much less and not statistically different between Sherpas and SL-HA. Nonetheless, 4 of 7 Sherpas and 1 of 8 SL-HA subjects were identified as having a resting IPAVA at HA. In addition, blood flow through IPAVA remained in 3 of 4 Sherpas breathing 100% O2. Figure 4 shows two contrast echocardiograms in one Sherpa who had a resting blood flow through IPAVA at 5050 m (Fig. 4A) and while breathing 100% O2 (Fig. 4B).

Figure 4.

Figure 4

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Note that microbubbles are present in the left ventricle in each image (labelled with circles). Both A and B were assigned microbubble scores of 1.

The magnitude of blood flow through IPAVA for all subjects at HA was low. At 5050 m all subjects who were positive for blood flow through IPAVA at rest had a microbubble score of ‘1’ while breathing ambient air. While breathing hyperoxia, one Sherpa had a microbubble score of ‘2’ with the remaining two Sherpas having a score of ‘1’ (i.e. 1 subject increased their score with hyperoxia while 1 subject normalized their response). We did not observe a microbubble score for blood flow through IPAVA greater than ‘2’ in any subject during any experimental conditions.

Discussion

This is the first study to simultaneously examine pulmonary haemodynamics, presence of intracardiac shunt and blood flow through IPAVA between Sherpas and acclimatized SL inhabitants at HA. The major findings from this study indicate that (1) there are no differences in resting pulmonary haemodynamics between acclimatized SL inhabitants and Sherpas, and (2) blood flow through shunt pathways does not appear to contribute to HA adaptation in Sherpas. Principally, we found that pulmonary arterial pressure and total pulmonary resistance were similar between Sherpas at HA and SL inhabitants following 3 weeks of acclimatization. In addition, we found a similar number of subjects with intracardiac shunt and blood flow through IPAVA between Sherpas and SL inhabitants. Despite elevated pulmonary pressures and profound hypoxaemia at HA, the number of subjects with blood flow through IPAVA and the magnitude of blood flow through IPAVA for a given level of hypoxaemia in all subjects was lower than expected based on: (1) acute isocapnic hypoxia testing at SL in a subset of our SL subjects, and (2) the results of previous investigations involving acute normobaric hypoxia (Laurie et al. 2010; Elliott et al. 2011). The lack of difference in cardiac output between HA and SL measurements may be one explanation for the lower than expected blood flow through IPAVA. Another explanation may relate to pulmonary vascular remodelling to HA in both SL inhabitants and Sherpas. Relevant methodological considerations and evidence to support these conclusions will now be discussed.

Pulmonary haemodynamics and adaptation to HA

In humans, there are several populations of life-long HA residents including the residents of Leadville, Colorado, in North America (Reeves & Grover, 1975), the Andean natives of South America (Banchero et al. 1966; Schwab et al. 2008; Groepenhoff et al. 2012), the Amhara highlanders in Ethiopia (Hoit et al. 2011) and the Tibetans from the Himalayas (Groves et al. 1993; Hoit, 2005) who have been studied for pulmonary adaptations to HA environments. Of this group of HA residents, the Tibetans have been reported to have the lowest mean pulmonary pressure at rest and display no rise in pulmonary vascular resistance (Groves et al. 1993; Hoit, 2005). Tibetans have been reported to exhibit little hypoxic pulmonary vasoconstriction, as evidenced by no change in pulmonary vascular resistance with hyperoxia breathing (Groves et al. 1993). However, the operation Everest II studies also demonstrated in healthy lowlanders that elevated pulmonary resistance with HA exposure was not immediately reversed by hyperoxia (Groves et al. 1987).

Sherpas are another group of HA natives from the Himalayan plateau who share recent ancestry with the Tibetan highlanders (Hochachka, 1998). Pulmonary haemodynamics have previously been assessed directly in five Tibetan highlanders by right heart catheterization and studied during rest at 3658 m and with further hypoxic stress (14% O2) (Groves et al. 1993). Mean pulmonary pressure, cardiac output and pulmonary vascular resistance were reported to be unchanged with exposure to hypoxia and not different from SL norms. A closer assessment of individual subject data indicates that a limitation in statistical power may have prevented the detection of hypoxia-induced pulmonary vasoconstriction. Specifically, three of five subjects increased pulmonary vascular resistance markedly (range of difference = −0.2 to +2.2 woods units). However, it is difficult to compare our data to this study (Groves et al. 1993) due to differences in techniques (i.e. right heart catheterization vs. echocardiography). Instead, the direct comparison of our group of Sherpas to the group of Tibetans studied by Hoit (2005) is more valid as similar techniques and methodology were used (albeit at slightly different altitudes). Specifically, we found similar PASP (mean ± SE: 30.0 ± 1.6 vs. 31.5 ± 1.0 mmHg), Qi (2.2 ± 0.1 vs. 2.7 ± 0.8 l min–1 cm–2), and total pulmonary resistance (8.2 ± 0.6 vs. 8.5 ± 0.4) between our Sherpas and the Tibetans of Hoit (2005), respectively. Recently, Faoro et al. (2013) assessed pulmonary haemodynamics and gas exchange at rest and during exercise in Sherpas. They estimated mean pulmonary artery pressure using a prediction equation from the measurement of PASP and subsequently calculated pulmonary vascular resistance. In that study, the authors compared their measurements made in Sherpas to measurements made in a control group of SL inhabitants within 2 days of arrival at 5050 m. In our experience, 40–50% of subjects will have symptoms of acute mountain sickness during this time-point and be in the very early stages of acclimatization (i.e. more hypoxaemic with little renal compensation for the respiratory alkalosis) (Fan et al. 2010; Lucas et al. 2011; Willie et al. 2013); therefore, comparison with Sherpas at this time-point seems problematic. Here, we compared our findings in Sherpas to a group of SL inhabitants both at SL and following ∼3 weeks of acclimatization to HA and our subjects were free of acute mountain sickness symptoms and therefore we believe this to be a more appropriate comparison. Our data showed that while PASP and total pulmonary resistance in the Sherpas were significantly elevated compared to SL inhabitants at SL, following acclimatization SL inhabitants and Sherpas did not differ in terms of PASP and total pulmonary resistance (see Fig. 1). Based on these results and direct comparisons, we suggest that Sherpas and Tibetans have similar pulmonary haemodynamics at HA and they do not differ substantially from SL inhabitants following acclimatization to HA.

Intracardiac shunt

Agitated saline contrast echocardiography is a highly sensitive technique useful in identifying intracardiac shunts (Marriott et al. 2013). The prevalence of intracardiac shunting in the general population (sample sizes ranging from 104 to 1162 subjects) has been estimated to be 35–38% (Woods, 2010; Elliott et al. 2013; Marriott et al. 2013). In the current investigation, we characterized the occurrence of intracardiac shunt in a relatively small sample of subjects at SL and Sherpas at HA. The observed occurrence of intracardiac shunt in our groups of subjects is consistent with previous reports (Woods, 2010; Elliott et al. 2013; Marriott et al. 2013). We detected intracardiac shunt in 41% of SL inhabitants; this was not statistically different from our Sherpa population, where intracardiac shunt was detected in 50% of subjects (see Fig. 3). Although Valsalva was used as a provocative manoeuvre to verify the patency of the foramen ovale, intracardiac shunts were detected in the majority of subjects (∼83%) at rest without requiring a provocative manoeuvre. This indicates that the majority of PFO+ subjects had an intracardiac shunt in the resting state while at HA. Despite this, the amount of blood flow through the PFO did not lead to a measureable effect on Inline graphic and pulmonary vascular pressure between PFO+ and negative subjects at altitude. Therefore, at least in this population, the prevalence of intracardiac shunt is similar between Sherpas and SL inhabitants and the amount of right-to-left shunt was small enough that there was no appreciable impact on saturation or pulmonary vascular pressure at 5050 m. Of note, in subjects breathing an Inline graphic between 0.10 and 0.12, which is equivalent to-an altitude of 5050 m, we have previously calculated that the total venous admixture would need to be >25% to account for all of the pulmonary gas exchange efficiency that occurs with this level of hypoxia (Laurie et al. 2010). Thus, at 5050m, a significantly large amount of shunt would be required to have an impact on saturation and/or pulmonary gas exchange efficiency. However, this does not preclude that the presence of a PFO would have a larger impact on saturation and gas exchange at lower altitudes where shunt fractions on the order of 5–8% would have a significant effect on pulmonary gas exchange efficiency (Laurie et al. 2010).

Blood flow through IPAVA

Agitated saline contrast echocardiography is the only non-invasive means of assessing blood flow through IPAVA in PFO− subjects. Using this technique, blood flow through IPAVA at rest is detectable in 30% of healthy humans who are PFO− (Elliott et al. 2013), but the prevalence increases to nearly 100% in healthy humans during exercise (Eldridge et al. 2004; Stickland et al. 2007; Kennedy et al. 2012) and with exposure to acute normobaric hypoxia (Lovering et al. 2008a; Laurie et al. 2010). In the current study, we also found that 100% of subjects exposed to 20 min of isocapnic hypoxia had blood flow through IPAVA (see Fig. 2B). Several mechanisms could be responsible for the opening of IPAVA, including: (1) the hypoxic stimulus, (2) increases in pulmonary vascular pressure or (3) increases in cardiac output. Laurie et al. (2010) found that the number of subjects with blood flow through IPAVA increased with reductions in Inline graphic. For example, it was noted that 100% of subjects had blood flow through IPAVA while breathing a 10% oxygen mixture for 30 min. In addition, the magnitude of blood flow through IPAVA (i.e. microbubble score) increased with reductions in Inline graphic and was related to changes in Inline graphic and PASP. The result from their study provides correlational evidence to indicate that blood flow through IPAVA contributes to the total venous admixture. In direct contrast to these results, we found very little evidence of blood flow through IPAVA in SL inhabitants after living at HA for 3 weeks, nor in Sherpas permanently living at HA (see Fig. 3B). In those subjects who demonstrated blood flow through IPAVA, the magnitude estimated by microbubble score was small (i.e. <2) and therefore seems unlikely to have contributed appreciably to the total venous admixture. The discrepancies between studies are potentially explained by differences in normobaric versus hypobaric hypoxia, the impact of acclimatization on cardiac output and/or vascular remodelling. Interestingly, 100% of subjects exposed to acute isocapnic hypoxia at SL were found to have blood flow through IPAVA and they had a larger rise in cardiac output compared to subjects at HA. This indicates that increases in cardiac output may be a stimulus for blood flow through IPAVA.

An increase in right heart cardiac output and the associated pulmonary vascular shear stress has been suggested as a stimulus capable of increasing blood flow through IPAVA; when cardiac output is increased by dobutamine, dopamine, or adrenaline there is a predictable increase in microbubble score (Laurie et al. 2012; Bryan et al. 2012). In our investigation, the lack of detectable blood flow through IPAVA in Sherpas and SL inhabitants at HA could be explained by the fact that cardiac output did not differ from our SL inhabitants measured at SL. Bryan et al. (2012) intravenously delivered dobutamine in increasing doses to increase cardiac output. They found that the microbubble score, PASP and physiological shunt fraction (Qs/Qt) increased in relation to cardiac output. Therefore, blood flow through IPAVA with both acute hypoxia and exercise could potentially be explained by an increase in cardiac output.

An alternative explanation for the lack of blood flow through IPAVA with chronic hypoxia could relate to remodelling of the pulmonary vasculature. While it is not clear to what extent vascular remodelling will affect IPAVA, small pulmonary arteries, which normally have very little smooth muscle, increase the expression of α-smooth muscle actin, and larger pulmonary arteries develop thickened media and adventitia (Stenmark et al. 2006). Interestingly, the time course of pulmonary vascular remodelling is surprisingly quick upon exposure to HA, with adventitial fibroblasts and medial smooth muscle cells increasing DNA synthesis after about 3–6 days of HA exposure (Stenmark et al. 2006). In addition, mRNA levels for procollagens and fibronectin are significantly elevated in lung parenchyma tissue of rats following exposure to as little as 3 days of hypoxia (Berg et al. 1998). Whether IPAVA increase the number of smooth muscle cells or the thickness of their adventitia or media with chronic hypoxia is unknown. One intriguing hypothesis suggests that IPAVA act as pressure relief valves to protect the delicate pulmonary capillaries. In line with this hypothesis, IPAVA may provide a low resistance pathway for blood to travel and thus prevent capillary damage caused by high pulmonary vascular pressure. With chronic hypoxia, as vascular remodelling ensues and the pulmonary vasculature's ability to handle high pulmonary pressure is improved, the need for blood flow through IPAVA may be substantially reduced to augment the amount of blood flow through the lung's gas exchange surfaces.

Limitations

We found that 3 of 4 Sherpas had resting blood flow through IPAVA at HA breathing 100% O2. It has been previously shown that breathing 100% O2 prevents blood flow through IPAVA during exercise (Lovering et al. 2008b; Elliott et al. 2011) and in 80% of resting subjects who demonstrate blood flow through IPAVA (Elliott et al. 2013). In Elliott et al. (2013), we also reported that a subset of healthy young asymptomatic subjects (6/31 or 20%) with blood flow through IPAVA at rest (near SL) continue to have blood flow through IPAVA despite breathing 100% O2. Although one explanation may be that these subjects had pulmonary arteriovenous malformations (PAVMs) that allowed blood to flow through them despite the fact that these subjects were breathing 100% O2, it is currently unknown whether hyperoxia acts only to prevent blood through IPAVA and not PAVMs. Because PAVMs are considered to be rare and associated with diseases such as hereditary haemorrhagic telangiectasia, it is unlikely that these healthy asymptomatic young subjects had PAVMs but may simply have blood flow through IPAVA despite breathing 100% O2, for reasons that are currently unexplainable. Of note, at 5050 m, alveolar Inline graphic would be approximately half of that in subjects breathing 100% O2 at SL, so it is possible that the alveolar Inline graphic may not be sufficient to close the IPAVA in Sherpas at this altitude. We acknowledge the possibility that some of our Sherpas may have PAVMs that are non-reactive to changes in Inline graphic. Therefore, it is possible that we measured blood flow through PAVMs rather than IPAVA and Sherpas could potentially be free from IPAVA. However, based on our work in young asymptomatic subjects, it is also entirely plausible that our Sherpas may have IPAVA that are unresponsive to hyperoxia. This is supported by the fact that Sherpas and SL inhabitants during acclimatization to HA had similar microbubble scores during rest at HA. Future research could study Sherpas during exercise to determine if such a provocative stimulus could open up IPAVA to a greater degree than during rest at HA.

Statistical power can be a problem in many HA field studies and this increases the risk of a type-II error. While we are confident that the proportion of our subjects who were identified as having a PFO (41% of SL subjects and 50% of Sherpas) is a good reflection of the prevalence in the general population, we are less confident in the proportions of subjects with resting blood flow through IPAVA. This is because after removal of the subjects with PFOs, our sample size is decreased by half. Although we conclude that the number of subjects with resting blood flow through IPAVA at HA (1 of 8 SL-HA subjects and 4 of 7 Sherpas) is similar, we recommend that future research is required to reconcile these similarities in a larger sample. The strength of our study lies in determining the differences between PASP in Sherpas and low-landers. As we are able to compare measurements in Sherpas with measurements made in SL inhabitants at SL and after acclimatization to HA, it is unlikely that a type-I error was made.

Acute hypoxia at SL was performed under isocapnic conditions. Although a poikilocapnic response test may have been a more appropriate comparison, we do not anticipate that this difference in protocol would have a negative impact on our results. Microbubble scores obtained with isocapnic hypoxia are not significantly different from microbubble scores obtained previously using a poikilocapnic hypoxia protocol (Laurie et al. 2010). Rather, the purpose of this acute hypoxia protocol provides confidence that the data obtained from our SL subjects are similar to other published reports in SL subjects and help to improve interpretation of the lack of blood flow through IPAVA detected while at HA.

Finally, total pulmonary resistance could be affected by the relationship between haematocrit and blood viscosity. For example, a 10% increase in haematocrit (45–55%) would lead to approximately a 20% increase in relative viscosity (Hoffman, 2011). To determine the impact of changes in haematocrit on our total pulmonary resistance measurements, we compared resting haematocrit values from our SL-HX (46.7 ± 0.6%; mean ± SEM) and SL-HA groups (49.4 ± 1.1%). Unfortunately, direct comparisons to our Sherpa group cannot be made as blood samples were not taken from this group. Instead, we have selected haematocrit values from Sherpas from previously published literature (Winslow et al. 1989) and from an unpublished data set from a previous expedition to the EV-K2-CNR laboratory in 2008. During this expedition, arterial blood samples were taken from eight Sherpas (including four who participated in the current study) and analysed for haematocrit. Mean haematocrit from Winslow et al. (1989) was 48.4 ± 0.8% (at an altitude of 3700 m) and from our unpublished data set was 53.9 ± 2.0% (at an altitude of 5050 m). Based on these data, the relative error in our measurement of total pulmonary resistance is less than ∼10% between HA and SL measurements. This value is based on the curvilinear relationship between haematocrit and relative blood viscosity (and standardized to a blood haematocrit of 45%), as described previously (Hoffman, 2011). As a result, it is unlikely that differences in haematocrit between Sherpas and SL inhabitants can account for the similarity in total pulmonary resistance at HA and can only account for less than ∼10% of the rise in total pulmonary resistance between SL measurements. The effect haematocrit has on blood flow through IPAVA is presently unknown.

Conclusion

Pulmonary vascular pressure in Sherpas is elevated by comparison to SL inhabitants at SL but not different from SL inhabitants following 3 weeks at HA. We found a similar proportion of subjects with intracardiac shunt and blood flow through IPAVA in Sherpas compared to SL inhabitants. At HA the effect of right-to-left shunting on Inline graphic may be negligible and therefore is not a strong stimulus for selective adaptation for success in the HA environment. Alternatively, chronic hypoxaemia (i.e. weeks to lifelong), unlike acute hypoxaemia (i.e. minutes to hours), may lead to remodelling of the pulmonary vasculature such that blood flow through IPAVA is reduced compared to acute hypoxia. Or perhaps more simply, the lack of a significant difference in cardiac output after acclimatization while at HA could be responsible for the lack of blood flow through IPAVA. These hypotheses are supported by the fact that both SL inhabitants and Sherpas had significantly less blood flow through IPAVA by comparison to either our acute hypoxia exposure or based on published studies of acute normobaric hypoxia, where cardiac output often increases and time for pulmonary vascular remodelling would not be sufficient. Taken together, blood flow through PFO and IPAVA do not appear to contribute to resting cardiopulmonary haemodynamics in well-adapted Sherpas at HA.

Key points

  • Evolutionary pressure to improve gas exchange and/or resting pulmonary haemodynamics in hypoxic environments may have led to differences in the amount of blood that flows through right-to-left shunt pathways between Sherpas and sea-level inhabitants.

  • We studied sea-level inhabitants during rest at sea level and acute isocapnic hypoxia and during rest at high altitude following 3 weeks of acclimatization and compared their responses to those of Sherpas during rest at high altitude.

  • Contrary to some previous literature, we found similar resting pulmonary pressure and total pulmonary resistance between acclimatized sea-level inhabitants and Sherpas at high altitude.

  • We also found a similar number of subjects from each group with intracardiac shunt and intrapulmonary shunt at high altitude.

  • These results help us better understand resting cardiopulmonary adaptations to high altitude by comparing life-long high altitude residents with sea-level inhabitants acclimatized to high altitude.

Acknowledgments

This study was carried out within the framework of the Ev-K2-CNR Project in collaboration with the Nepal Academy of Science and Technology as foreseen in the Memorandum of Understanding between Nepal and Italy, and thanks to a contribution from the Italian National Research Council.

Glossary

Inline graphic

fraction of inspired oxygen

HA

high altitude

HPV

hypoxic pulmonary vasoconstriction

IPAVA

intrapulmonary arteriovenous anastomoses

HR

heart rate

IVC

inferior vena cava

SL

sea level

SL-HA

sea level group at high altitude

SL-HX

sea level group during acute hypoxia

SL-SL

sea level group at sea level

Inline graphic

oxyhaemoglobin saturation

SV

stroke volume

PASP

pulmonary artery systolic pressure

PAVM

pulmonary arteriovenous malformation

PFO

patent foramen ovale

Q

cardiac output

Qi

cardiac index

VTI

velocity time integral

Additional Information

Competing interests

The authors have no conflict of interest.

Author contributions

(1) Conception and design of the experiments: G.E.F., P.N.A. and A.T.L.; (2) collection, analysis and interpretation of data: G.E.F., P.N.A., M.S., T.A.D., A.B., S.J.E.L., N.C.S.L., D.B.M. and A.T.L.; (3) drafting the article or revising it critically for important intellectual content: G.E.F., P.N.A., M.S., T.A.D., A.B., S.J.E.L., N.C.S.L., D.B.M. and A.T.L.

Funding

This study was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the American Physiological Society Giles F. Filley Memorial Award for Excellence in Respiratory Physiology and Medicine (A.T.L.).

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