Study of disease- full

Question 1

Headings pneumonic (list)

Answer 1

CCHIVCAHOHTMD

Question 2

Headings (list)

Answer 2

Introduction

Choice of topics

CPVT and heart failure (calcium/ pacemaking)

HCN mutations and sick sinus syndrome (pacemaking)

Inherited arrhythmia syndromes- SCD

Ventricular arrhythmias- SCD

Chuvash polycythaemia and HIF system (altitude)

AMS (altitude)

HACE (altitude)

Oedema formation in HACE (altitude)

HAPE (altitude)

Treatment of HAPE (altitude)

Monge’s disease/ CMS (altitude)

Difficulties in research and future (altitude)

Conclusion

Question 3

Introduction subheadings (list)

Answer 3

Argument

Inferences are not straightforward

Question 4

(Intro) Argument

Answer 4

● Studying disease is a common way to elucidate normal biological function, especially when experimentation in healthy organisms would be unfeasible or unethical.
● This may occur through identifying underlying genetic causes, observing functional losses or insights derived from drug therapies.
● Argument: to a large extent, studying disease allows us to identify the molecular and genetic causes of disease, the processes of which can then be extrapolated to determine normal function in healthy organisms.
● Also many studies of disease are based on animal models - which arguably do not fully replicate the complexity of human disease, and therefore may not accurately reflect normal function
● We should not rely solely on insights gained from disease to determine normal function - should develop more robust methods of studying function in healthy organisms through imaging, genome sequencing etc.

Question 5

(Intro) Inferences are not straightforward

Answer 5

● Inferences of function are not as straightforward in certain diseases such as:
● Chronic heart failure, where RyR2 channels are modulated by intracellular kinases like PKA, making it challenging to distinguish whether pathological phenotypes result from altered phosphorylation, disease progression itself, or compensatory mechanisms.
● Chuvash polycythaemia, where elevated HIF activity promotes erythrocytosis and vascular remodeling, but the same pathway is also crucial for normal hypoxic adaptation, making it difficult to disentangle pathological from protective roles.

Question 6

Choice of topics subheadings (list)

Answer 6

Cardiovascular disease is a systemic stress test of physiology

Altitude physiology as a natural stress model

Bidirectional insights

Question 7

(Topics) Cardiovascular disease is a systemic stress test of physiology

Answer 7

● Cardiovascular disease helps pinpoint what precise molecular interactions and feedback systems are essential for maintaining cardiac function, often before technology can detect them in healthy systems.
● The cardiovascular system integrates hemodynamics, electrophysiology, metabolism, and endocrine signaling, so its failure often reveals the importance of homeostatic mechanisms that are otherwise invisible in health.
● For example, CPVT highlights how subtle changes in calcium handling (RyR2 mutations) can destabilize excitation-contraction coupling, helping us understand the fine balance required for normal cardiac rhythm.
● Similarly, chronic heart failure and studies on RyR2 hyperphosphorylation demonstrate how dynamic modulation (e.g., by PKA) of channel activity is essential to physiological adaptability- and how loss of that control contributes to disease.

Question 8

(Topics) Altitude physiology as a natural stress model

Answer 8

● Altitude reveals the boundaries of adaptive physiology, and disease states help define when beneficial responses become harmful, sharpening our understanding of human limits
● Altitude represents a controlled environmental perturbation- mainly hypoxia- that allows researchers to probe how the body compensates via ventilation, hematopoiesis, and vascular remodeling.
● Disease states like Chuvash polycythaemia or Monge’s disease (chronic mountain sickness) illustrate what happens when these adaptive mechanisms go too far, such as excessive HIF activity leading to pathological erythrocytosis.
● By studying how maladaptive responses evolve in altitude disease, we better understand where the physiological “sweet spot” lies- for example, how much erythropoiesis is adaptive vs. thrombogenic.

Question 9

(Topics) Bidirectional insights

Answer 9

● In both topics, studying disease states doesn’t just illuminate pathology- it feeds back into normal physiology:
● Heart failure and CPVT have taught us about normal calcium cycling and the role of sympathetic activation.
● Altitude sickness has revealed new insights into cerebral blood flow regulation, BBB integrity, and pulmonary vascular responses that apply broadly, even at sea level.

Question 10

CPVT and heart failure (calcium/ pacemaking) subheadings (list)

Answer 10

Mutations to RYRs apparatus including calsequestrin and triadin

Jiang 2004

RyR2 mutations and flecainide

Hilliard 2010 and flecainide

Shan 2010 and ryanodine receptor in chronic heart failure

Question 11

(CPVT and HF) Mutations to RYRs apparatus including calsequestrin and triadin

Answer 11

● CPTV is an inherited condition that causes cardiac arrhythmias.
● The disease is caused by a variety of different mutations in the ryanodine receptor apparatus, including calsequestrin and triadin.
● However, the most common mutation that causes CPVT1 is to the RyR2 channel itself.

Question 12

(CPVT and HF) Jiang 2004

Answer 12

● Jiang et al in 2004 showed that these RyR2 mutations were gain of function.
● The authors transfected either wild-type or CPVT-mutant RyR2s into HEK293 cell lines and loaded them with fluo3-AM.
● Under confocal line-scan microscopy, the occurrence of Ca2+ sparks was significantly higher in HEK cells transfected with CPVT-mutant RyR2 channels.
● However, the use of the embryonic kidney line raises questions as to the validity of these results in myocytes.
● Nonetheless, these findings have been supported by more recent studies in isolated ventricular myocytes from both humans and mouse models.

Question 13

(CPVT and HF) RyR2 mutations and flecainide

Answer 13

● RyR2 mutations can increase the sensitivity of the ryanodine receptor to calcium concentrations on the cytosolic side of the SR membrane.
● The unifying feature of CPVT mutations is that their deleterious effects are only present upon sympathetic nervous system activation, often during exercise, and resulting in sudden cardiac death.
● One of the most promising new drugs in the treatment of CPVT is the class 1c anti-dysrhythmic, flecainide.
● Several clinical trials have shown that combination therapy of flecainide with beta blockers is effective at reducing the recurrence of tachycardias, particularly during exercise.

Question 14

(CPVT and HF) Hilliard 2010 and flecainide

Answer 14

● The mechanism of action for flecainide was initially controversial, given that the drug is traditionally thought to blockade voltage gated sodium channels.
● However, Hilliard et al in 2010 identified another potential mechanism of action by comparing Wistar rats with Casq2-/- models of CPVT.
● Flecainide reduced the amplitude and intensity of the calcium sparks in the CPVT model.
● This was sufficient to prevent arrhythmogenic calcium waves. ● These findings were supported by Kryshtal et al in 2021 who used a similar experimental design in the presence of the voltage-gated sodium channel (VGSC) blocker tetrodotoxin (TTX).
● Flecainide administration had the same effect on calcium sparks in the presence or absence of TTX.
● Furthermore, using a modified version of flecainide (NM-FL) that was unable to block RyR2 channels did not improve symptoms in the CPVT mice model.
● These results together suggest that RyR2 blockade and inhibition of Ca2+ is the primary mechanism of action for flecainide.
● However, this must be treated with caution given that the two studies described, used only one mouse model of one of the many mutations capable of causing CPVT.

Question 15

(CPVT and HF) Shan 2010 and ryanodine receptor in chronic heart failure

Answer 15

● The ryanodine receptor is not just affected by genetic aberrations in CPVT, instead there can be modulation by intracellular kinases.
● This can occur particularly in prolonged conditions such as chronic heart failure.
● Shan et al in 2010 used a mice model of a constitutively hyperphosphorylated RyR2.
● The authors developed a RyR2 S2808D knockin mice model.
● The authors found that mimicking chronic PKA phosphorylation with isoproterenol caused cardiomyopathy with significantly reduced ejection fraction in the knockin mice.
● When these channels were isolated and recorded in the presence of 150nM calcium, the single channel patch clamp recordings in lipid bilayers showed that these channels had a greater open probability.
● After myocardial infarction, these mice were more pre-disposed to ventricular tachycardia and death following the LAD ligation model of MI.
● Together, these findings demonstrate that the chronic hyperphosphorylation of RyR2 in heart failure predisposes to the development of arrhythmia due to increased open probability of the RyR2 channel.
● It would have been interesting for the authors to study calcium transients with calcium dyes in myocytes isolated from the canine models, to determine the frequency of arrhythmogenic events.

Question 16

HCN mutations and sick sinus syndrome (pacemaking) subheadings (list)

Answer 16

Mutations and sick sinus syndrome

HCN channels, stem cells and connexin-43 proteins

Qu 2003

Question 17

(HCN and sick sinus) Mutations and sick sinus syndrome

Answer 17

● Mutations in both membrane and calcium-handling proteins can have deleterious effects on SAN pacemaking.
● For instance, mutations in HCN proteins are commonly associated with sick sinus syndrome. Patients with this condition typically present with varied atrial arrhythmias, syncope, and fatigue.

Question 18

(HCN and sick sinus) HCN channels, stem cells and connexin-43 proteins

Answer 18

● Despite conflicting reports as to the necessity of HCN channels for pacemaking activity, these ion channels have been described as a potential therapeutic option for delivery of a biological pacemaker.
● Other biological pacemaker avenues of research have focused on transplantation of pacemaker-like cells developed from embryonic stem cells into the SAN.
● Furthermore, it may not be essential for cells to express all pacemaker currents, if these cells can be made to couple with existing pacemaker cells with connexin-43 proteins.

Question 19

(HCN and sick sinus) Qu 2003

Answer 19

● Qu et al in 2003 were the first to use the HCN2 channel as a target for gene therapy.
● This channel has intermediate kinetics when compared with the HCN4 and HCN1 channels expressed in the HCN.
● The authors developed adenoviral vectors to express the HCN2 channel and GFP in the left atrium of an adult canine model, where there was direct injection of the vector.
● Electrodes were implanted to artificially stimulate vagal tone to the SAN to block endogenous pacemaker activity, whilst ECG recorded the electrical activity in the induced pacemaker region of the left atrium.
● The authors observed pacemaker firing in the left atrium, and study of dissociated isolated myocytes under patch clamp showed funny current when cAMP was present in the patch pipette.
● However, these studies were only performed 3-4 days after direct cardiac injection, which is no indication of the longevity of the treatment.

Question 20

Inherited arrhythmia syndromes (SCD) subheadings (list)

Answer 20

Table 1

Sanguinetti 1996 and long QT syndrome

Kyndt 2001 and Brugada Syndrome

Question 21

(Arrhythmia syndromes) Table 1- syndromes, pattern of inheritance, and gene

Answer 21

Long QT syndrome, Autosomal dominant, KCNQ1, KCNH2, SCN5A

Brugada syndrome, Autosomal dominant, SCN5A

Catecholaminergic polymorphic ventricular tachycardia, Autosomal dominant/ recessive, RYR2/ CASQ2

Question 22

(Arrhythmia syndromes) Sanguinetti 1996 and long QT syndrome

Answer 22

● Sanguinetti et al in 1996 built on work that had previously identified KvLQT1 as the ion channel mutated in LQT1.
● This channel is now known as KCNQ1.
● The authors transfected Chinese hamster ovary cells with cDNA for the channel, and showed the unique Iks-like properties of the channel under voltage clamp conditions.
● The authors then co-transfected the minK cDNA, and showed that coasembly of these proteins was sufficient to replicate the Iks channel properties, whereby depolarising stimuli were followed by a brief delay then a repolarising outward potassium current.
● It would have been interesting for the authors to perform site-directed mutagenesis to visualise whether mutations in this gene were sufficient to reduce the repolarising current.

Question 23

(Arrhythmia syndromes) Kyndt 2001 and Brugada Syndrome

Answer 23

● Kyndt et al studied the implications of mutations on the current flow through these channels in 2001.
● The authors first identified a family of patients with Brugada syndrome, and performed exome sequencing of the SCN5A gene, before identifying a novel G1406R mutation in the gene.
● The authors then cloned the wild-type and mutant SCN5A genes before transfecting them in COS-7 cells.
● This enabled whole-cell patch clamping of the cells, in response to depolarising steps.
● The authors observed significantly reduced current through the SCN5A channels, demonstrating the loss of function.
● If this experiment were to be repeated, it would be more sensible to make hiPSCs from the skin of these Brugada syndrome patients, and measure whole cell currents under these situations.

Question 24

Ventricular arrhythmias (SCD) subheadings (list)

Answer 24

Fowler 2020 and NCX exchange

Bögelholz 2016 and NCX mediated calcium extrusion

Question 25

(Ventricular arrhythmias) Fowler 2020 and NCX exchange

Answer 25

● Fowler et al in 2020, where they used myocytes isolated from rabbit models of heart failure with reduced ejection. ● The heart failure myocytes had increased occurrence of these late calcium events. ● Current clamp recordings showed that there was a prolongation of the cardiac action potential relative to control rabbits. ● Whilst these results would appear to show that late calcium sparks during the cardiac action potential contribute to EADs, it is important to note that the coronary ligation model used in the rabbits is not representative of the broad spectrum of clinical heart failure. ● Spontaneous Ca2+ release from the SR elevates intracellular Ca2+ concentration which can activate Na+-Ca2+ exchange. ● The activation of Na+-Ca2+ exchange can cause afterdepolarisations, due to the electrogenic nature of the protein, if this occurs in late systole this can result in EADs.

Question 26

(Ventricular arrhythmias) Bögelholz 2016 and NCX mediated calcium extrusion

Answer 26

● The potential for NCX to initiate these DADs relevant to arrhythmias was described by Bögelholz et al in 2016 who artificially over-expressed the NCX protein in mice and subjected the atrial cardiomyocytes to atrial pacing designed to induce fibrillation. ● Patch clamp experiments in the current clamp mode showed no significant increase in DADs. ● However, the number of spontaneous action potentials triggered by DADs was increased nearly 20-fold compared to wild-type mice. ● Whilst these results show that NCX mediated calcium extrusion may be sufficient to cause arrhythmogenesis, it is important to note that the model of overexpression is unlikely to represent normal physiology. ● Further experiments could test whether cardiospecific knockouts of NCX in atrial myocytes prevented any DADs. ● Figure 1

Question 27

Chuvash polycythaemia and HIF system (altitude)

Answer 27

● 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 28

AMS (altitude) subheadings (list)

Answer 28

Consequences and link with HACE Paul Bert 1878

Question 29

(AMS) Consequences and link with HACE

Answer 29

● 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. ● Increased intracranial blood volume from vasodilation reduces compliance and may raise intracranial pressure, particularly during sleep. ● Similar cerebral vasodilation is seen in High Altitude Cerebral Edema (HACE), suggesting AMS could be an early stage of this more severe condition. ● Obstructed venous outflow and hypoxia-related breathing patterns during sleep may form a mechanistic bridge between AMS and HACE.

Question 30

(AMS) Paul Bert 1878

Answer 30

● 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 ● Limitation: Did not control PCO2, which can also affect the respiratory & CV systems therefore may have been responsible for results

Question 31

HACE (altitude) subheadings (list)

Answer 31

Charles Houston 1975 Severinghaus 1966 and CBF Physiological process underlying oedema

Question 32

(HACE) Charles Houston 1975

Answer 32

● 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 33

(HACE) Severinghaus 1966 and CBF

Answer 33

Severinghaus 1966 and CBF: ● 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 ● Limitation: Suggestions that N2O tracer can affect NO metabolism and hence cerebral vasodilation ● However, other studies have since used different methods such as using radioactively labelled xenon and found similar increases in CBF

Question 34

(HACE) Physiological process underlying oedema

Answer 34

● 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. ● There are other, more indirect measurements of intracranial pressure, including measurement of optic nerve sheath diameter and tympanic membrane displacement. ● However, these non-invasive methods suffer from decreased reliability. ● This might explain the past difficulties in establishing a causal link between intracranial pressure.

Question 35

Oedema formation in HACE (altitude) subheadings (list)

Answer 35

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

Question 36

(Oedema formation) Aetiology- vasogenic or cytotoxic

Answer 36

● 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. ● It has been proposed that the initial oedema formation in HACE may be attributable to ionic oedema.

Question 37

(Oedema formation) Hackett 2019 and consequences of oedema

Answer 37

● 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. ● One of the major difficulties with understanding the formation of these microbleeds is the difficulty in doing MRI scans at altitude during the development of HACE, as such, many of the MRI scans are done during the hospitalisation process, by which time the microbleeds have formed.

Question 38

(Oedema formation) Fischer 2001- dexamethasone preserving BBB integrity

Answer 38

● 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 ● Conclusion: Evidence for effectiveness of dexamethasone in preserving BBB and preventing vasogenic oedema ● Limitations: Use of porcine cells may limit translatability – ideally use human cells instead [human iPSC-derived endothelial cells]

Question 39

(Oedema formation) Acetazolamide

Answer 39

● 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. ● By inhibition of the enzyme, CAI medications result in the inhibition of the resorption of bicarbonate by the tubular cells, leading to retention of bicarbonate in the tubular lumen.

Question 40

HAPE (altitude) subheadings (list)

Answer 40

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

Question 41

(HAPE) Physiological processes underlying oedema

Answer 41

● 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 ● Grove 1985 (from HPV section) ● HAPE can have a fatality rate of up to 50% if left untreated, as it typically progresses to severe hypoxaemia. ● Cyanosis, tachypnoea and tachycardia are all common in advanced cases of HAPE.

Question 42

(HAPE) Mechanisms

Answer 42

● 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). ● Weaker hypoxic ventilatory response in mountaineers has also been associated with HACE. ● Insufficient ventilation causes hypoxia, providing a greater stimulus for hypoxic pulmonary vasoconstriction.

Question 43

(HAPE) Operation Everest II study 1980s and exercise

Answer 43

● 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 44

(HAPE) Heterogeneous vasoconstriction

Answer 44

● 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. ● West proposed the concept of stress failure in 1991, whereby high pressure in alveolar capillaries induces endothelial-cell disruption and damage to the extracellular matrix, thus enabling both protein and fluid into the alveolar space. ● Previous theories explaining fluid extravasation in HAPE focused on the potential for inflammation-induced disruption to the endothelial cell layer.

Question 45

(HAPE) Inflammation and impaired alveolar fluid clearance

Answer 45

● 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. ● Figure 3

Question 46

Treatment of HAPE (altitude) subheadings (list)

Answer 46

Nifedipine and dexamethosone Smith & Talbot 2009 and iron

Question 47

(Treatment) Nifedipine and dexamethosone

Answer 47

● 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 ● Genomic studies = essential in this e.g. Butscher 2008 in future section

Question 48

(Treatment) Smith & Talbot 2009 and iron

Answer 48

● 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 49

Monge’s disease/ CMS (altitude) subheadings (list)

Answer 49

Pathophysiology Tibetans and EPAS1

Question 50

(Monge's/ CMS) Pathophysiology

Answer 50

● 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. ● The pathophysiology of this condition is similar to Chuvash polycythaemia, a rare genetic condition characterised by excessive production of red blood cells.

Question 51

(Monge's/ CMS) Tibetans and EPAS1

Answer 51

● 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 52

Difficulties in research and future (altitude) subheadings (list)

Answer 52

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

Question 53

(Difficulties) Limited technology and recruiting volunteers

Answer 53

● 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. ● Recruiting volunteers for high-altitude studies can be a major obstacle to many prospective studies into HACE and HAPE. ● Given the severity of these conditions it would be unethical to let inexperienced volunteers develop HAPE and HACE without proper medical care in place.

Question 54

(Difficulties) Demographic of travellers

Answer 54

● 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 55

(Difficulties) Butscher 2008 and prevention

Answer 55

● 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. ● Informing mountaineers on early signs of these conditions will also enable climbers to seek medical attention and descend earlier on in the development of the disease. ● Furthermore, understanding the molecular pathophysiology of HACE and HAPE will enable development of pharmacological interventions to treat these altitude conditions.