Micro- and macrovascular function in the highest city in the world: a cross sectional study

Abstract

Background: Since vascular responses to hypoxia in both healthy high-altitude natives and chronic mountain sickness (a maladaptive high-altitude pathology characterised by excessive erythrocytosis and the presence of symptoms-CMS) remain unclear, the role of inflammation and oxidative/nitrosative stress on the endothelium-dependent and -independent responses in both the micro- and macrocirculation, in healthy Andeans at different altitudes and in CMS patients, was examined.

Methods: 94 men were included: 18 lowlanders (LL), 38 healthy highlanders permanently living at 3800 m (n = 21-HL-3800) or in La Rinconada, the highest city in the world (5100-5300 m) (n = 17-HL-5100/No CMS). Moreover, 14 participants with mild (Mild CMS) and 24 with moderate to severe CMS (Mod/Sev CMS) were recruited. All undertook two reactivity tests: i) local thermal hyperaemia (microcirculation) and ii) flow-mediated dilation (macrocirculation). Endothelium-independent function (glyceryl trinitrate) was also assessed only in La Rinconada.

Findings: Conductance and skin blood flow velocity during the microcirculation test, as well as macrocirculation progressively decreased with altitude (LL > HL-3800 > HL-5100/No CMS). CMS also induced a decrease in macrocirculation (HL-5100/No CMS > Mild CMS = Mod/Sev CMS), while glyceryl trinitrate restored vascular function. Both oxidative stress and nitric oxide metabolites increased with altitude only. Principal component analysis revealed that increasing inflammation with altitude was associated with a progressive decline in both micro- and macrovascular function in healthy highlanders.

Interpretation: Both micro and macrovascular function are affected by chronic exposure to hypoxia, the latter being further compounded by CMS.

Funding: The "Fonds de dotation AGIR pour les maladies chroniques", the "Air Liquide Foundation", and the "French National Research Agency".

Keywords: Altitude; Chronic mountain sickness; Flow-mediated dilation; Inflammation; Microcirculation.

Fig. 1

Effect of altitude on micro- and macrovascular function. Effect of the altitude of residence in healthy subjects on cutaneous vascular conductance during the initial peak (panel A) and plateau (panel B) of local thermal hyperemia, as well as on flow-mediated dilation (panel C) and shear rate area under the curve (panel D). List of abbreviations: CVC, cutaneous vascular conductance; FMD, flow-mediated dilation; SR_AUC, shear rate area under the curve; LL, lowlanders living at sea level (0 m); HL-3800, healthy highlanders living at 3800 m; HL-5100/No CMS, healthy highlanders living at 5100 m. Data are expressed as Mean ± SD. An analysis of variance was used to detect any effect of altitude. These analyses were conducted on raw macrovascular data and on natural logarithm-transformed data for the microvascular function. Bonferroni corrected post-hoc analyses were used where required and indicated on the figure as follows: ^∗, P < 0.05 vs. LL; $, P < 0.05 vs. HL-3800.

Fig. 2

Effect of CMS on micro- and macrovascular function. Effect of CMS in subjects living at 5,100 m on cutaneous vascular conductance during the Initial peak (panel A) and plateau (panel B) of local thermal hyperaemia, as well as on flow-mediated dilation (panel C) and shear rate area under the curve (panel D). List of abbreviations: CVC, cutaneous vascular conductance; FMD, flow-mediated dilation; SR_AUC, shear rate area under the curve; CMS, Chronic Mountain Sickness; HL-5100/No CMS, healthy highlanders living at 5100 m; Mild CMS, highlanders with mild CMS at 5100 m; Mod/Sev CMS, highlanders with moderate to severe CMS at 5100 m. Data are expressed as Mean ± SD. An analysis of variance was used to detect any effect of CMS. These analyses were conducted on raw macrovascular data and on natural logarithm-transformed data for the microvascular function. Bonferroni corrected post-hoc analyses were used where required and indicated on the figure as follows: £: P < 0.05 vs. HL-5100/No CMS.

Fig. 3

Principal component analysis. PCA explaining the role of inflammation on the microcirculation (panel A) and macrocirculation (panel B). IL-6/7/8 (interleukin 6/7/8) MCP-1 (Monocyte chemoattractant protein 1), MIP-1β (Macrophage inflammatory protein-1) and TNF-α (Tumor necrosis factor α) were highlighted as the main inflammatory components. Peak and plateau CVC (cutaneous vascular conductance) make up the microvascular parameters, while FMD% (flow-mediated dilation) is the chosen macrovascular parameter. LL, lowlanders living at sea level (0 m); HL-3800, healthy highlanders living at 3800 m; HL-5100/No CMS, healthy highlanders living at 5100 m.