D1. Altitude- detailed

Question 1

Headings pneumonic

Answer 1

MVGAHOHTMD

Question 2

Headings (list)

Answer 2

Introduction

Mechanisms of acclimatisation

Ventilatory acclimatisation

Genetics of high altitude

AMS

HACE

Oedema formation in HACE

HAPE

Treatment of HAPE

Monge’s disease/ CMS

Difficulties in research and future

Conclusion

Question 3

Introduction subheadings (list)

Answer 3

Acclimatisation

HACE and HAPE

Question 4

(Intro) Acclimatisation

Answer 4

● Each year it is estimated that over 100million people travel to high altitudes [<2500m]; in order to survive at this altitude, the body must acclimatise in order to cope with the physiological challenge of hypoxia.

● This is facilitated through changes driven by the HIF-alpha system that occur over several weeks, including erythropoiesis, pulmonary arteriolar vasoconstriction and ventilatory acclimatisation.

● However, whilst humans are able to acclimatise to high altitude, this rarely results in the same level of physical/mental fitness seen at sea level.

Question 5

(Intro) HACE and HAPE

Answer 5

● It has been suggested by various epidemiological studies, that the incidence of high-altitude pulmonary oedema (HAPE) can be as high as 0.6-6% at 4500m, whilst the incidence of high-altitude cerebral oedema (HACE) is estimated to be 0.5-1% at similar altitudes.

● These statistics highlight the importance of understanding both HACE and HAPE. It is important to note that these conditions often do not exist in isolation, and up to 15% of individuals diagnosed with HAPE also develop HACE.

● Whilst a broad understanding of the physiological processes that underlie HAPE and HACE, hypoxic pulmonary vasoconstriction and cerebral vasodilation respectively, many of the molecular details behind oedema formation remain poorly understood.

Question 6

Mechanisms of acclimatisation subheadings (list)

Answer 6

Erthyropoiesis

Hypoxic pulmonary vasocontriction

Chuvash polycythaemia

Question 7

(Mechanisms)
Erthyropoiesis

Answer 7

● In response to the hypoxic conditions at high altitudes, cellular [HIF-1] is increased specifically, as demonstrated by Ratcliffe, Kaelin & Semenza, for which they were awarded the Nobel Prize in Physiology/Medicine 2019).

● This then alters the transcription of over 1000 genes within the genome, including increasing the transcription of the gene encoding erythropoietin [EPO].

● Figure 1

● EPO is then released by peritubular interstitial fibroblasts in renal mesangial cells and drives erythropoiesis, by stimulating proerythroblast production in bone marrow and accelerating their development into erythrocytes.

Question 8

(Mechanisms) Hypoxic pulmonary vasocontriction

Answer 8

● Another adaptation that occurs as the body attempts to acclimatise to altitude is hypoxic pulmonary vasoconstriction (HPV).

● Whilst local HPV is beneficial, as it diverts blood flow from hypoxic areas of the lung to areas with better oxygenation to ensure V/Q matching, at high altitudes the low PiO2 causes global HPV.

● Euler & Liljestrand (1946) from HAPE section

● This can acutely lead to high altitude pulmonary oedema, in which fluid accumulates between the interstitial space and alveoli, impairing gas exchange and resulting in rapidly progressive dyspnoea, tachycardia, respiratory failure and can be fatal.

Question 9

(Mechanisms) Chuvash polycythaemia

Answer 9

● Now thought that they = attributed to HIF system (refer to Figure 1).

● Evidence for this comes from patients with Chuvash polycythaemia, who have elevated levels of EPAS1/HIF-2α due to homozygosity for hypomorphic alleles for VHL and display higher resting PAP and RV dysfunction.

● Thus suggests that HIF system -> pulmonary vascular remodelling.

● Nevertheless, this experiment supports my argument that humans are, in general, a sea-level design, as acclimatisation may be maladaptive and can have deleterious effects.

Question 10

Ventilatory acclimatisation subheadings (list)

Answer 10

Triphasic response- Figure 2

Renal compensation is insufficient

Hodson 2015

Question 11

(Ventilatory acclimatisation) Triphasic response- Figure 2

Answer 11

● Another of the major changes the body undergoes in order to acclimatise to altitude chronically is ventilatory acclimatisation.

● This is triphasic, yet ultimately results in a progressive rise in ventilation and fall in PCO2 within a number of days this increased respiratory minute volume facilitates sufficient oxygen delivery to tissues and thus enables survival.

● Figure 2

Question 12

(Ventilatory acclimatisation) Renal compensation is insufficient

Answer 12

● However, whilst the core theory explaining ventilatory acclimatisation is that it is mediated through pH effects, recent evidence suggests that renal compensation is insufficient to fully restore arterial pH, and that the CSF remains acidic.

● Instead, it is possible that ventilatory acclimatisation occurs as a direct response to hypoxia at the carotid bodies, through HIF-related mechanisms.

● This thus supports my argument that humans are, in general, a sea-level design, as they are unable to function at maximal capacity at high altitudes, barring certain populations such as the Tibetans that have undergone natural selection and evolved to survive at high altitudes.

Question 13

(Ventilatory acclimatisation) Hodson 2015

Answer 13

● Method: Used plethysmography to measure tidal volume and respiratory rate in response to hypoxia in conditionally inactivated PHD/HIF-1/HIF-2α mice, using Cre-recombinase mediated excision.

● Results: Found that inactivation of PHD using tamoxifen resulted in enhanced hypoxic ventilatory responses, however, this could be compensated for by inactivating HIF-2α [but not HIF-1α].

● Furthermore, inactivation of HIF-2α strikingly impaired ventilatory acclimatisation to chronic hypoxia, as well as carotid body proliferation.

● Limitation: Use of animal model- limits translatability.

Question 14

Genetics of high altitude subheadings (list)

Answer 14

Tibetans

Groves 1993 and genomic comparisons

Yi 2010- Han Chinese and Danish populations and EPAS1

Question 15

(Genetics) Tibetans

Answer 15

● The Tibetan population is commonly used to study the genetic adaptations to high altitude.

● This population, unlike the closely related Han Chinese population, have been altitude-dwellers for centuries.

● This has enabled genetic adaptation to this high altitude.

● The Tibetan phenotype is typically associated with protection against Chronic mountain sickness, particularly when compared with Peruvian populations.

Question 16

(Genetics) Groves 1993 and genomic comparisons

Answer 16

● Groves et al in 1993 studied the hypoxic pulmonary vasoconstrictor response in five Tibetan volunteers.

● The authors performed pulmonary artery catheterisation in these volunteers to measure pulmonary artery pressure.

● Baseline values showed that at 3600m the Tibetan population had pulmonary artery pressures within sea-level standards.

● Furthermore, when the Tibetans breathed a hypoxic gas mixture, the authors observed little change in pulmonary arterial pressure and vascular resistance.

Question 17

(Genetics) Yi 2010- Han Chinese and Danish populations and EPAS1

Answer 17

● Yi et al in 2010 sequenced 50 Tibetan exomes and compared the sequencing data with Han Chinese and Danish populations to identify changes in allelic frequencies consistent with genetic adaptation in Tibetans.

● Using population branch statistics (PBS), they identified EPAS1 as the strongest candidate gene for natural selection.

● In addition, the most differentiated (in terms of allelic frequency) EPAS1 variant was correlated with erythrocyte count within a larger Tibetan cohort.

● This was an intronic EPAS1 SNP, which was captured by this exome-targeted approach and was found at 87% frequency in Tibetans compared with 9% in Han Chinese.

Question 18

AMS subheadings (list)

Answer 18

Consequences and link with HACE

Paul Bert 1878

Question 19

(AMS) Consequences and link with HACE

Answer 19

● A common feature of acute altitude illness is rapid ascent by otherwise fit individuals to altitudes above 3000 m without sufficient time to acclimatise.

● Acute Mountain Sickness (AMS) is generally mild and occurs in those who ascend quickly above 2,500 m without proper acclimatisation.

● Its hallmark symptom is high altitude headache, often accompanied by fatigue, dizziness, gastrointestinal discomfort, and sleep issues.

● AMS may result from dilation of cerebral vessels triggering the trigeminal vascular system, with symptom escalation linked to inflammatory responses and hypoxic sleep.

Question 20

(AMS) Paul Bert 1878

Answer 20

● Method: Placed a bird inside a pressure chamber & subjected it to hypobaric & normobaric hypoxia

● Results: Bird lost consciousness at same PO2 regardless of barometric pressure

● Replicated the results in himself in larger version of the chamber

● Conclusion: AMS = driven by hypoxia

Question 21

HACE subheadings (list)

Answer 21

Charles Houston 1975

Severinghaus 1966 and CBF

Physiological process underlying oedema

Question 22

(HACE) Charles Houston 1975

Answer 22

● Charles Houston in 1975 produced a series of twelve case reports detailing neurological symptoms experienced at high altitude based on his experience of climbing some of the highest mountains in the Himalayas.

● These neurological symptoms he described were thought to be attributable to cerebral oedema, and now come under the bracket of HACE.

● Both HACE and HAPE are consequences of evolutionarily-favourable responses to hypoxia at low altitude.

● Hypoxia has long been known to increase cerebral blood flow by vasodilation in hypoxic conditions.

Question 23

(HACE) Severinghaus 1966 and CBF

Answer 23

● Hypoxia has long been known to increase cerebral blood flow by vasodilation in hypoxic conditions.

● Following exposure to hypoxia, vasodilation of the arterioles supplying the brain occurs to increase cerebral blood flow (CBF)

● Method: Measured CBF in 7 male volunteers 6-8hrs after rapid ascent to 3810m using inert N2O tracer with arterial and jugular venous blood sampling

● Results: Saw 24% increase in CBF

Question 24

(HACE) Physiological process underlying oedema

Answer 24

● The mechanisms underpinning CBF regulation during changes in O2 content are multifactorial, involving deoxyhemoglobin-mediated release of nitric oxide metabolites and ATP.

● Deoxyhemoglobin nitrite reductase activity is thought to mediate vasodilation through potential mechanisms including nitric oxide, adenosine, prostaglandins, and expoxyeicosatrienoic acids.

● HACE is associated with an increase in intracranial pressure.

● Invasive ICP monitoring is the gold standard, but is difficult to perform in the field at altitude, both on a practical and an ethical basis.

Question 25

Oedema formation in HACE subheadings (list)

Answer 25

Aetiology- vasogenic or cytotoxic Hackett 2019 and consequences of oedema Fischer 2001- dexamethasone preserving BBB integrity Acetazolamide

Question 26

(Oedema in HACE) Aetiology- vasogenic or cytotoxic

Answer 26

● The aetiology of oedema formation in HACE has been contentious, with both vasogenic or cytotoxic oedema being suggested as potential causes of HACE. ● Vasogenic oedema is characterised by cerebral fluid accumulation including plasma proteins as a result of vascular injury and disruption to the blood brain barrier (BBB). ● Cytotoxic oedema involves the passage of fluid into cells resulting in an expansion of the intracellular space. ● This in turn establishes an osmotic gradient for ionic oedema to form.

Question 27

(Oedema in HACE) Hackett 2019 and consequences of oedema

Answer 27

● HACE is a medical emergency that requires rapid descent from altitude, and failure to do so can be fatal. ● One of the main consequences of HACE is the development of microbleeds in the brains. ● Hackett et al in 2019 performed a retrospective study using 8 patients treated for HACE, and observed their MRIs over a period of time. ● Finding that over time the microhaemorrhages didn’t worsen during the hospitalisation process, but remained visible for a period of up to ten years and began to coalesce over time.

Question 28

(Oedema in HACE) Fischer 2001- dexamethasone preserving BBB integrity

Answer 28

● Dexamethasone is recommended for patients with high altitude cerebral oedema and it is thought to work by preserving blood-brain barrier integrity. ● Method: Cultured monolayers of porcine capillary endothelial cells in normoxic and hypoxic conditions, and measured permeability of the monolayers through measuring radioactive insulin accumulation ● Results: Cells in hypoxic conditions = found to be hyperpermeable – this = attenuated by addition of dexamethasone ● Furthermore, dexamethasone reduced hypoxia-induced expression of VEGF, which = known contributor to formation of vasogenic oedema

Question 29

(Oedema in HACE) Acetazolamide

Answer 29

● Acetazolamide is also indicated as a potential treatment for individuals with HACE. ● Carbonic anhydrase in the lumen of the proximal tubule of the kidney converts carbonic acid to water and carbon dioxide. ● Water and carbonic dioxide enter the intracellular space via diffusion. ● The intracellular carbonic anhydrase enzyme converts water and carbon dioxide back to carbonic acid, which dissociates into H+ and bicarbonate.

Question 30

HAPE subheadings (list)

Answer 30

Physiological processes underlying oedema Mechanisms Operation Everest II study 1980s and exercise Heterogeneous vasoconstriction Inflammation and impaired alveolar fluid clearance

Question 31

(HAPE) Physiological processes underlying oedema

Answer 31

● HAPE is non-cardiogenic pulmonary oedema occurring in rapidly ascending non-acclimatized healthy individuals. ● HAPE mostly occurs in rapidly ascending non-acclimatised individuals, typically within 2-5 days of reaching high altitude. ● Hypoxia in the pulmonary circuit causes vasoconstriction aiding with ventilation-perfusion matching. ● However, this can become deleterious at altitude by causing pulmonary hypertension and increasing pulmonary capillary pressure

Question 32

(HAPE) Mechanisms

Answer 32

● Intrapulmonary arteries constrict in response to alveolar hypoxia, diverting blood to better-oxygenated lung segments, thereby optimizing ventilation/perfusion matching and systemic oxygen delivery. ● In response to alveolar hypoxia, a mitochondrial sensor dynamically changes reactive oxygen species and redox couples in pulmonary artery smooth muscle cells (PASMC). ● This inhibits potassium channels, depolarizes PASMC, activates voltage-gated calcium channels, and increases cytosolic calcium, causing vasoconstriction. ● Sustained hypoxia activates rho kinase, reinforcing vasoconstriction, and hypoxia-inducible factor (HIF)-1α, leading to adverse pulmonary vascular remodeling and pulmonary hypertension (PH).

Question 33

(HAPE) Operation Everest II study 1980s and exercise

Answer 33

● Exercise at high altitude has also been shown to increase pulmonary hypertension and exacerbate the risk of HAPE. ● The Operation Everest II study in the 1980s, assessed the response to exercise of a number of volunteers during a simulated climb to Everest in an altitude chamber. ● Pulmonary artery pressure was measured using cardiac catheterisation, and it was found that using an exercise ergometer, there was significantly increased pulmonary arterial pressure when exercising at altitude, and this was correlated with the intensity of the exercise. ● However, the study lasted 40 days, and therefore doesn’t mimic the rapid ascent that typically causes the onset of HAPE.

Question 34

(HAPE) Heterogeneous vasoconstriction

Answer 34

● Hypoxic pulmonary vasoconstriction alone would not account for the dramatic rise in pulmonary capillary pressure seen in HAPE patients, and certainly not the patchy appearance on radiographic scans. ● Thus, a number of theories have been suggested that account for the rise in pulmonary capillary pressure. ● The most compelling evidence currently points towards heterogeneous vasoconstriction leading to regional overperfusion. However, there is also evidence for pulmonary venoconstriction increasing capillary pressure. ● The onset of fluid extravasation from pulmonary capillaries has been the subject of much debate.

Question 35

(HAPE) Inflammation and impaired alveolar fluid clearance

Answer 35

● It is thus possible that inflammation may not be a causative agent in initial HAPE, but inflammation in response to alveolar leakage and capillary damage may exacerbate fluid leakage. ● It is possible that oedema in HAPE may be compounded by impaired alveolar fluid clearance. ● Alveolar fluid reabsorption occurs in the manner shown, and sodium transport across cultured cells has been shown to be impaired in hypoxia. ● Beta-2 adrenoreceptor agonists such as salmeterol can improve reabsorption, which may underlie their therapeutic effects in HAPE.

Question 36

Treatment of HAPE subheadings (list)

Answer 36

Nifedipine and dexamethasone Smith & Talbot 2009 and iron

Question 37

(Treatment) Nifedipine and dexamethasone

Answer 37

● The importance of this vasoconstriction in causing HAPE can be supported by the efficacy of nifedipine, an L-type calcium ion channel blocking vasodilator, in treating HAPE. ● Nifedipine itself may not just be used as treatment but also as prophylactic. ● Dexamethosone may also work to prevent HAPE by increasing the expression of endothelial nitric oxide synthase. When given before ascent, dexamethasone works by activating gene expression in a non-transcriptional fashion. ● Identifying those that = susceptible to HAPE may help us target prophylactic therapies to those who most need it

Question 38

(Treatment) Smith & Talbot 2009 and iron

Answer 38

● Iron has also been proposed to be an effective pharmacological intervention for those suffering from HAPE and other high-altitude conditions. ● This was examined by Smith & Talbot in 2009 in Peru who took unacclimatised sea level residents in Peru up to the town of Cerro de Pasco in an ascent of over 4400m in 8 hours. ● Repeated measurements of pulmonary arterial pressure were made using Doppler echocardiography, and participants were either infused with iron sucrose solution or a placebo. ● There was a significant increase in the pulmonary arterial pressure upon ascent to altitude across both groups, that was largely reversed by the infusion of iron on day 3 after the ascent.

Question 39

Monge’s disease/ CMS subheadings (list)

Answer 39

Pathophysiology Tibetans and EPAS1

Question 40

(Monge’s/ CMS) Pathophysiology

Answer 40

● Increasing the haematocrit (>60%) increases the viscosity, systemic vascular resistance and risk of vascular thrombosis. ● When exceeding 80%, the symptoms of Monge’s disease (chronic mountain sickness) become apparent. ● This condition can cause hypoxaemia, heart failure and neurological symptoms such as headaches, fatigue and tinnitus. ● This condition is typically treated by phlebotomy or alternatively by descent to altitude, which will both decrease the viscosity of the blood.

Question 41

(Monge’s/ CMS) Tibetans and EPAS1

Answer 41

● However, there are populations, such as the Tibetans, who have lived at high altitudes for generations, that do not display raised haematocrit levels, thus evading chronic mountain sickness. ● This is attributed to a mutation in EPAS1, which encodes HIF2alpha and alters the setpoint of activation of HIF pathway to avoid polycythaemia- Yi 2010 ● However, individuals living at low altitudes with gain of function mutations in EPAS1 and individuals with Chuvash Polycythaemia, in which homozygosity for hypomorphic alleles for VHL leads to elevated levels of EPAS1/HIF2alpha & HIF1alpha. ● Both cause excessive erythrocytosis and excess risk of thrombolytic events, and these disorders are strikingly similar to the phenotype of CMS, and thus supports the natural selection of EPAS1 SNPs in Tibetans in order to reduce the incidence of CMS.

Question 42

Difficulties in research and future subheadings (list)

Answer 42

Limited technology and recruiting volunteers Demographic of travellers Butscher 2008 and prevention

Question 43

(Difficulties) Limited technology and recruiting volunteers

Answer 43

● High altitude conditions such as HAPE and HACE are difficult to research given the limited medical facilities at high altitude. ● However, it is difficult to study more molecular details at this altitude due to a lack of high-resolution microscopes and other necessary equipment. ● Furthermore, altitude sickness may also limit the effectiveness of researchers when at high-altitude laboratories. ● As such, much of the molecular work for HACE and HAPE is performed in rats and mice in hypoxic chambers.

Question 44

(Difficulties) Demographic of travellers

Answer 44

● This often necessitates the use of mountaineers who have already experienced HAPE and are susceptible to the condition, or those travelling to high altitude for other reasons. ● The demographic of this population is relatively narrow, given many mountaineers and high-altitude skiers are males in the 20-40 age range. ● Therefore, it is difficult to extrapolate conclusions on HAPE and HACE in this group, to other ethnicities, genders, age groups and those with pre-existing medical conditions.

Question 45

(Difficulties) Butscher 2008 and prevention

Answer 45

● The future of high-altitude pathophysiology will likely involve prevention of high-altitude illness, as opposed to improved treatment of the condition. ● The potential for this was showcased by a systematic review from Butscher et al in 2008, who found that arterial oxygen saturation after 30 minutes of exposure to a simulated rapid ascent to >2500m was a strong predictor of the development of AMS on higher climbs. ● Furthermore, researchers suggested that signs of sympathetic activation may also act as future indicators of AMS. ● Better education for climbers on the importance of slow ascents may also reduce the frequency of AMS, HACE and HAPE incidents.

Question 46

Conclusion

Answer 46

● In conclusion, HACE and HAPE are both undesirable consequences of homeostatic mechanisms, in place to preserve oxygen delivery to the brain and match ventilation and perfusion respectively. ● Whilst we understand these processes relatively well, there is more debate surrounding the aetiology of oedema formation in the conditions. ● HACE is typically thought of as vasogenic oedema resulting from vascular injury, whilst HAPE is the result of stress failure of pulmonary capillaries. ● Barriers to understanding more about these conditions are the limited access to medical equipment such as MRI machines at altitude, and the difficulty in recruiting volunteers for studies.