Sublingual microcirculatory blood flow and vessel density in Sherpas at high altitude

Gilbert‐Kawai, Edward; Coppel, Jonny; Court, Jo; Kaaij, Jildou Van Der; Vercueil, André; Feelisch, Martin; Levett, Denny; Mythen, Monty; Grocott, Michael P.W.

doi:10.1152/japplphysiol.00970.2016

Cited by 36 publications

(41 citation statements)

References 45 publications

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“…, ; Gilbert‐Kawai et al . ). However, it is unknown whether this increase TVD passively follows changes in cardiac output and arterial blood pressure, or whether it is the result of adaptive response of the microcirculation itself.…”

Section: Introductionmentioning

confidence: 97%

Recruitment of non‐perfused sublingual capillaries increases microcirculatory oxygen extraction capacity throughout ascent to 7126 m

Hilty

Merz

Hefti

et al. 2019

The Journal of Physiology

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Key pointsr A physiological response to increase microcirculatory oxygen extraction capacity at high altitude is to recruit capillaries. r In the present study, we report that high altitude-induced sublingual capillary recruitment is an intrinsic mechanism of the sublingual microcirculation that is independent of changes in cardiac output, arterial blood pressure or systemic vascular hindrance.r Using a topical nitroglycerin challenge to the sublingual microcirculation, we show that high altitude-related capillary recruitment is a functional response of the sublingual microcirculation as opposed to an anatomical response associated with angiogenesis.r The concurrent presence of a low capillary density and high microvascular reactivity to topical nitroglycerin at sea level was found to be associated with a failure to reach the summit, whereas the presence of a high baseline capillary density with the ability to further increase maximum recruitable capillary density upon ascent to an extreme altitude was associated with summit success.Abstract A high altitude (HA) stay is associated with an increase in sublingual capillary total vessel density (TVD), suggesting microvascular recruitment. We hypothesized that microvascular recruitment occurs independent of cardiac output changes, that it relies on haemodynamic changes within the microcirculation as opposed to structural changes and that microcirculatory function is related to individual performance at HA. In 41 healthy subjects, sublingual handheld vital microscopy and echocardiography were performed at sea level (SL), as well as at 6022 m Matthias Peter Hilty has found that, during his education and throughout his board certification in General Internal Medicine and Intensive Care Medicine, his main interests lie in the foundations of human physiology, in addition to their application in clinical practice. Studies of the response of the macro-and microcirculation to critical illness and high altitude environments have lead to his high appreciation of the contrast between witnessing cardiovascular pathophysiology during field studies, in laboratory settings and at the bedside. Hoping to support the upcoming challenge to translate these findings to clinical use, Dr Hilty is applying advanced computational techniques for the objective assessment of a patient's microcirculation. M. P. Hilty and othersJ Physiol 597.10 (C2) and 7042 m (C3), during ascent to 7126 m within 21 days. Sublingual topical nitroglycerin was applied to measure microvascular reactivity and maximum recruitable TVD (TVD NG ). HA exposure decreased resting cardiac output, whereas TVD (mean ± SD) increased from 18.81 ± 3.92 to 20.92 ± 3.66 and 21.25 ± 2.27 mm mm −2 (P < 0.01). The difference between TVD and TVD NG was 2.28 ± 4.59 mm mm −2 at SL (P < 0.01) but remained undetectable at HA. Maximal TVD NG was observed at C3. Those who reached the summit (n = 15) demonstrated higher TVD at SL (P < 0.01), comparable to TVD NG in non-summiters (n = 21) at SL and in both groups at C2. Recruitment of sublingu...

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Section: Introductionmentioning

confidence: 97%

Recruitment of non‐perfused sublingual capillaries increases microcirculatory oxygen extraction capacity throughout ascent to 7126 m

Hilty

Merz

Hefti

et al. 2019

The Journal of Physiology

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“…Anatomically, the microcirculation consists of a network of blood vessels whose primary role is regulation of convective blood flow to match micro-regional oxygen demand (Levick, 2009). In a recent study using incident darkfield imaging, Sherpa highlanders demonstrated significantly greater sublingual microcirculatory blood flow and capillary density when compared with lowlanders at high altitude (Gilbert-Kawai et al, 2017). The authors postulated that this increase could provide both a greater flow per unit tissue volume and a greater flow per unit time, both of which would enhance oxygen delivery.…”

Section: Introductionmentioning

confidence: 99%

Sustained vasomotor control of skin microcirculation in Sherpas versus altitude‐naive lowlanders: Experimental evidence from Xtreme Everest 2

Davies

Gilbert‐Kawai

Wythe

et al. 2018

Experimental Physiology

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Enhanced oxygen delivery, consequent to an increased microvascular perfusion, has been postulated to play a key role in the physiological adaptation of Tibetan highlanders to the hypobaric hypoxia encountered at high altitude. We tested the hypothesis that Sherpas, when exposed to graded hypobaric hypoxia, demonstrate enhanced vasomotor and neurovascular control to maintain microcirculatory flux, and thus tissue oxygenation, when compared with altitude-naive lowlanders. Eighty-three lowlanders [39 men and 44 women, 38.8 (13.1) years old; mean (SD)] and 61 Sherpas [28 men and 33 women, 27.9 (6.9) years old] were studied on ascent to Everest Base Camp over 11 days. Skin blood flux and tissue oxygen saturation were measured simultaneously using combined laser Doppler fluximetry and white light spectroscopy at baseline, 3500 and 5300 m. In both cohorts, ascent resulted in a decline in the sympathetically mediated microvascular constrictor response (P < 0.001), which was more marked in lowlanders than in Sherpas (P < 0.001). The microvascular dilator response evaluated by postocclusive reactive hyperaemia was significantly greater in Sherpas than in lowlanders at all sites (P < 0.002). Spectral analysis of the blood flux signals revealed enhanced myogenic (vasomotion) activity in Sherpas, which was unaffected by ascent to 5300 m. Although skin tissue oxygenation was lower in Sherpas than in lowlanders, the oxygen unloading rate was faster, and deoxyhaemoglobin levels higher, at all altitudes. Together, these data suggest that Sherpas, when exposed to hypobaric hypoxia, demonstrated superior preservation of peripheral microcirculatory perfusion compared with altitude-naive lowlanders. The physiological differences in local microvasculature vasomotor and neurovascular control may play a key role in Sherpa adaptation to high-altitude hypobaric hypoxia by sustaining local perfusion and tissue oxygenation.

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“…Compared to lowlanders, Sherpa highlanders exhibit a significantly higher number of capillaries per square millimeter of muscle cross-section, which would support efficient and effective diffusion of oxygen to muscles [9]. Moreover, a recent study demonstrated that Sherpas exhibit significantly higher sublingual small vessel density, capillary density, and microcirculatory flow per unit time and per unit volume of tissue compared to lowlanders at 5300 m [10]. These findings suggest the notion that peripheral vascular factors at the microcirculatory level play an important role in the process of adaptation to hypoxia in Sherpa highlanders.…”

Section: Discussionmentioning

confidence: 99%

“…Hypoxia-stimulated physiological vasculogenesis and angiogenesis may increase microcirculatory blood flow and capillary density, thus restoring the oxygen supply in tissues to compensate for oxygen insufficiency [8]. Compared to non-Sherpa lowlanders, Sherpa highlanders show significantly greater capillary density in muscle cross-section [9], and higher sublingual microcirculatory blood flow and greater capillary density at high altitude [10]. These findings indicate efficient and effective oxygen transport to tissues in Sherpa highlanders, supporting the notion that microcirculation plays a critical role in the mechanism underlying adaptation to hypoxia [11].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-tolerant vascular endothelial growth factor-A (VEGF-A) and the genetic variations ofVEGFAin Sherpa highlanders

Droma¹,

Kinjo²,

Nozawa³

et al. 2020

Preprint

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24Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, 25 partly by one of the adaptation mechanisms promoting increases of microcirculatory 26 blood flow and capillary density at high altitude for restoring oxygen supply to tissues. 27 Hypoxia stimulates vascular endothelial growth factor (VEGF), which is an important 28 signaling protein involved in hypoxia-stimulated vasculogenesis and angiogenesis. Our 29 present study included 51 Sherpas dwelling in Namche Bazaar village (3440 m) and 76 30 non-Sherpa lowlanders residing in Kathmandu (1300 m) in Nepal. In these participants, 31 we measured plasma VEGF-A concentrations and genotyped five single-nucleotide 32 polymorphisms (SNPs) of VEGFA: rs699947, rs8333061, rs1570360, and rs2010963 in 33 the 5ʹ-untranslated region (5ʹ-UTR); and rs3025039 in the 3ʹ-UTR. The average 34 circulating VEGF-A level in Sherpas did not respond to hypoxia at the high altitude in 35 3440 m, remaining equivalent to the level in non-Sherpa lowlanders at low altitude. Allele 36 discriminations for the analyzed SNPs revealed significant genetic divergences of 37 rs699947, rs8333061, and rs2010963 in Sherpa highlanders compared with non-Sherpa 38 lowlanders, East Asians, South Asians, and the global population; however, consistency 39 with the indigenous Tibetan highlanders from the Tibet Plateau. On the other hand, the 40 SNP rs3025039 in the 3ʹ-UTR presented constant preserved genetic variation among 41 global populations. Our findings indicated that the physiological sea-level VEGF-A 42 concentration in Sherpa highlanders at high altitude was probably linked with the 43 significant variations of VEGFA in Sherpas that regulate the gene expression in a manner 44 of tolerance to hypoxia through production of the optimal biological level of VEGF-A at 45 high altitudes. Precise angiogenesis at high altitude contributes to the adaptive levels of 46 capillary density and microcirculation, providing efficient and effective diffusion of 3 47 oxygen to tissues and representing human adaptation to high-altitude hypoxia 48 environment. 49 Author summary 50 Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, 51 partly by one of the adaptation mechanisms promoting increases of microcirculatory 52 blood flow and capillary density at high altitude for restoring oxygen supply to tissues. 53 Vascular endothelial growth factor (VEGF) is mainly stimulated by hypoxia, and is an 54 important signaling protein involved in hypoxia-stimulated vasculogenesis and 55 angiogenesis. Interestingly, we found that the circulating VEGF-A level in Sherpa 56 highlanders did not respond to hypoxia at high altitude. Furthermore, allele discrimination 57 of the single nucleotide polymorphisms (SNPs) of VEGFA revealed significant 58 divergences of rs699947, rs8333061, and rs2010963 within the VEGFA regulation region 59 in Sherpa highlanders compared to the non-Sherpa lowlanders, East Asians, South Asians, 60 and the global population; however, consistency w...

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Sublingual microcirculatory blood flow and vessel density in Sherpas at high altitude

Cited by 36 publications

References 45 publications

Recruitment of non‐perfused sublingual capillaries increases microcirculatory oxygen extraction capacity throughout ascent to 7126 m

Recruitment of non‐perfused sublingual capillaries increases microcirculatory oxygen extraction capacity throughout ascent to 7126 m

Sustained vasomotor control of skin microcirculation in Sherpas versus altitude‐naive lowlanders: Experimental evidence from Xtreme Everest 2

Hypoxia-tolerant vascular endothelial growth factor-A (VEGF-A) and the genetic variations ofVEGFAin Sherpa highlanders

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