Impact of High Altitude on Cardiovascular Health: Current Perspectives

Abstract

Globally, about 400 million people reside at terrestrial altitudes above 1500 m, and more than 100 million lowlanders visit mountainous areas above 2500 m annually. The interactions between the low barometric pressure and partial pressure of O₂, climate, individual genetic, lifestyle and socio-economic factors, as well as adaptation and acclimatization processes at high elevations are extremely complex. It is challenging to decipher the effects of these myriad factors on the cardiovascular health in high altitude residents, and even more so in those ascending to high altitudes with or without preexisting diseases. This review aims to interpret epidemiological observations in high-altitude populations; present and discuss cardiovascular responses to acute and subacute high-altitude exposure in general and more specifically in people with preexisting cardiovascular diseases; the relations between cardiovascular pathologies and neurodegenerative diseases at altitude; the effects of high-altitude exercise; and the putative cardioprotective mechanisms of hypobaric hypoxia.

Keywords: acclimatization; adaptation; conditioning; exercise; hypobaria; hypoxia.

Figure 1

Partial pressure of inspired O₂ (P_IO₂) is decreased in mountainous regions. Representative cities in major mountain ranges are shown. Notes: The map is courtesy of NASA/JPL-Caltech and adapted from NASA/JPL-Caltech. Aster Global Digital Elevation Map (GDEM) . Available at: https://asterweb.jpl.nasa.gov/images/GDEM-10km-colorized.png. Accessed February 28, 2021.

Figure 2

Changes of resting cardiovascular parameters when acutely exposed to high altitude and during acclimatization. Notes: Bbased on data reported in references and . From left to right.

Figure 3

Hypoxia-evoked adaptations improve cardiovascular determinants of brain oxygenation.

Figure 4

Hypobaric hypoxia induces cardioprotective gene expression. Hypoxia elicits cardioprotective adaptations by activating three gene programs: (A) β-adrenergic activation of cyclic nucleotide response element (CRE) binding protein (CREB) promotes transcription of genes encoding sarcoplasmic reticular Ca²⁺ ATPase (SERCA) and sarcolemmal Na⁺/Ca²⁺ exchanger (NCX), thereby improving Ca²⁺ homeostasis in the face of ischemia-reperfusion. (B) Intracellular hypoxia attenuates O₂-dependent, prolyl hydroxylase (PHD) mediated degradation of the α subunit of hypoxia-inducible factor-1 (HIF-1), which translocates to the nucleus, binds HIF’s β subunit, and activates hypoxia-response elements (HRE) promoting expression of genes encoding hypoxia-adaptive proteins including erythropoietin, vascular endothelial growth factor (VEGF), nitric oxide (NO) synthase (NOS), endothelin-1, glucose transporters (GLUT) and glycolytic enzymes. Erythropoietin and NO suppress inflammation, VEGF promotes coronary collateral formation, endothelin-1 suppresses apoptosis, and GLUT and glycolytic enzymes support anaerobic ATP and phosphocreatine (PCr) production during ischemia. (C) Cellular hypoxia causes electron (e⁻) accumulation in the mitochondrial respiratory complexes. These electrons combine with residual O₂ forming reactive oxygen species (ROS) which oxidize sulfhydryl moieties in Keap1, allowing Nrf2 to activate antioxidant response elements (ARE) in genes encoding antioxidant enzymes, thereby bolstering cellular defenses against ROS overproduction. ROS also augment HIF-1-activated gene expression by blunting HIF-1α degradation. Collectively, these mechanisms increase cardiomyocyte resistance to ischemia-reperfusion induced Ca²⁺ overload, inflammation, mitochondrial permeability transition (MPT), ATP depletion and oxidative stress.