Roberto Santos is an avid outdoorsman, prolific reader, writer and web developer currently stationed in the Colorado high country. Originally from the Northern Mariana Islands, his work, study and adventures have taken him from surfing across the Pacific, to climbing the highest peaks in Japan and Colorado.
Acute mountain sickness (AMS) is a condition that can occur when individuals ascend to high altitudes rapidly, typically above 2,500 meters (8,200 feet). The symptoms of AMS are due to the body’s struggle to adapt to the decreased oxygen levels at higher elevations. More specifically, the symptoms are caused by cerebral vasodilation that occurs in response to hypoxia, in an attempt to maintain cerebral perfusion.1
The typical symptoms of AMS include headache, nausea, vomiting, anorexia, and fatigue. In children the symptoms are less specific including increased fussiness, crying, poor feeding, disrupted sleep, and vomiting. Symptom onset is usually 6-12 hours after arrival to altitude but this can vary.
AMS affects children, adults, males and females equally, with a slight increased incidence in females. It is difficult to believe, but physical fitness does not offer protection against AMS. However, people who are obese, live at low elevation, or undergo intense activities upon arrival to elevation are at increased risk.1
Treatments for Acute Mountain Sickness
Descending
Descending and decreasing altitude is a vital treatment for people with severe symptoms of AMS. By decreasing altitude there will be more oxygen in the air and symptoms will not be as severe..2
Oxygen
Since the main cause of AMS is hypoxia, oxygen supplementation is an effective treatment when descent is not wanted or possible. Supplemental oxygen even at .5L to 1L per hour can be effective in reducing symptoms.1 It can be prescribed for short periods of time or to be used only during sleep In the central Colorado Rockies, this may be a practical solution for “out of towners” who have traveled up to the town of Leadville (10,158’/3096m) for vacation, but in an austere environment supplemental oxygen may not be a reasonable treatment option. There should be symptomatic improvement within one hour.
Acetazolamide
Acetazolamide is a carbonic anhydrase inhibitor which causes increased secretion of sodium, potassium, bicarb, and water. This mechanism of actions lends beneficial to the treatment of AMS because it decreases the carbonic anhydrase in the brain. 3There is evidence to support the use of acetazolamide in the prevention of AMS, but minimal evidence pointing towards it’s role in treatment. Dosing is inconsistent but is usually prescribed at 125-250mg BID.
Hyperbaric Therapy
Many people consider hyperbaric chambers to be large structures in hospitals, however there are portable and lightweight hyperbaric chambers that can be used in austere environments or during expeditions. The mechanism of action of hyperbaric therapy is a simulated decrease in elevation, of approximately 2500 meters. These chambers will remove symptoms within approximately one hour of use but symptoms are likely to return. They are useful in the field but not frequently required in a hospital setting.1
Lynde Tucker is a third year medical student who grew up in Lake Tahoe California, and moved to Colorado for medical school. She is grateful for the opportunity to be back living in the mountains and working in a mountain community.
The fundamentals of vitality include food, water, air, shelter, and sleep. Sleep, though often underappreciated, can influence our physical and mental health, complex and easily impacted by outside factors. Living at a high altitude may be wonderful but what is gained in beauty and adventure, is compromised with reduced quality sleep. With increasing elevation comes more nighttime awakenings, brief arousals, nocturnal hypoxemia, and periodic breathing. Light sleep increases and slow-wave and REM sleep decrease.
The current gold standard for diagnosis of suspected sleep disorders includes polysomnography: seven or more streams of data at a hospital or sleep center. The SleepImage System allows for more flexibility with children, adolescents, and adults. Currently, Dr. Chris Ebert-Santos of Ebert Family Clinic in Frisco, Colorado, USA (9000′) is using this technology primarily to assess some of the most common forms of Sleep Breathing Disorders and secondly, to analyze the percentage of oxygen desaturation of her patients while in their homes.
The SleepImage System measures several variables that construct a summary for each individual. Sleep quality is generated using Sleep Quality Index (SQI) biomarkers. Pathology markers measure sleep duration, efficiency, and latency. Central Sleep Apnea (CSA) and Obstructive Sleep Apnea (OSA) are assessed together as Sleep Apnea Hypoxia Index (sAHI). Periodic and fragmented sleep pathology are reported and can be used to assess disease management long-term.
Recently, the clinic analyzed Patient X’s sleeping patterns without and with supplemental oxygen. The theory: adding a steady flow of oxygen to the nightly sleep regimen reduced the total amount of time desaturating and severity of sleep breathing disorders. On the night preceding treatment, Patient X experienced an SQI of 17 (expected >55) and efficiency at 95% (expected >85%) for overall sleep quality. Sleep opportunity demonstrated a 0h:02m latency (expected <30m), and duration of 5h:47m (expected 7-9h); sAHI was marked as severe for both 4% and 3% desaturation with values at 34 and 61, respectively (severe= >30.0 in adults). Fragmented sleep was at 55% (expected <15%) and periodicity at 22% (expected <2%). Lastly, Patient X spent 25% of his night’s sleep under 90% SpO2, 18% under 88% Spo2, and 4% under 80% SpO2. Ideally, a healthy night’s sleep should aim to remain above 90% SpO2 for the majority of the time in bed.
When oxygen supplementation was introduced, improvements were observed. Sleep quality showed a slight change, SQI increased to 31 (previously 17, expected >55), and efficiency decreased to 87% (previously 95%; expected >85%) while remaining at a target value. Sleep opportunity showed a slight increase during latency to 0h:12m while remaining within the expected value of <30mins; duration jumped to 8h:14m but that could be attributed to an early bedtime. Fragmented sleep remained in the severe range but decreased by 5%; periodicity improved to 0%, removing it from both the severe and moderate range. The most notable improvement was observed with sAHI, both the 3% and 4% desaturation categories improved to the moderate range with values of 9 and 14, respectively. Time under 90% SpO2 also improved to only 4% throughout the night and 0% below 88% SpO2.
Since data is collected while patients sleep, skewed results from the placebo effect can be reduced or eliminated. Increased duration could be attributed to longer time in bed, as mentioned above, and should be examined more in-depth longitudinally. Latency for sleep increased with oxygen treatment but that could be attributed to discomfort from the nasal cannula or greater tiredness one day over the other. Similarly, latency should be examined longitudinally.
The results seen with this patient are common in our population. Many people report they slept significantly better their first night on oxygen. Many patients studied on and off oxygen show the same dramatic decrease in their sleep apnea index. The gold standard for treating sleep apnea involves a mask to increase the pressure in the airway and prevent the collapse and narrowing that occurs during relaxation and sleep. Does the supplemental 2 liters per minute of oxygen cause enough increased airway pressure to prevent airway narrowing? Supplemental oxygen would not be considered for an intervention or treatment in other locations where sleep studies are conducted because they are not usually showing significant hypoxia. Does the improvement in oxygen, even if it is the difference between oxygen saturations in the high 80’s and low 90’s increasing to the mid 90’s affect the balance of oxygen and carbon dioxide in a way that changes the incidence of apnea and drive to breathe during sleep?
Long-term, this easy-to-use SleepImage System can assess sleep disorders across all age groups and contribute to long-term management for many people living at altitude. Oxygen, a simple intervention that is widely available and relatively inexpensive, requiring no special visits to fit and adjust, has the potential to improve symptoms and sleep greatly.
References
Introduction to SleepImage https://sleepimage.com/wp-content/uploads/Introduction-to-SleepImage.pdf
Diagnosis and treatment of obstructive sleep apnea in adult https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714700/
Sleep and Breathing at High Altitude https://pubmed.ncbi.nlm.nih.gov/11898114/#:~:text=Sleep%20at%20high%20altitude%2 0is,REM%20sleep%20have%20been%20demonstrated.measure
Ashley Cevallos is a second-year Physician Assistant student at Red Rocks Community College in Arvada, CO. She received her undergraduate degree from University of Maryland, Baltimore County. Before PA school, she worked as a vestibular technician and research coordinator for Johns Hopkins department of Otolaryngology. She was born in Ecuador and raised in Maryland. In her free time, she enjoys hiking, yoga, discovering new plants/animals and picnics.
This comprehensive review of the biology, history and physiology of high elevation starts with a fatal hot air balloon ride that happened in 1875. The passengers went past 8,000 meters, or over 26,000 feet and lost consciousness. The balloon failed and fell to the ground but not until after the altitude related hypoxia killed two out of the three passengers. Currently the legal limit in many parts of the world for how high a hot air balloon can fly is around 3,000 feet.
The pressure the atmosphere exerts on our bodies, the barometric pressure, that is the pressure of all gasses including oxygen, decreases as we go higher in altitude. As seen in the graph below, the higher you go, the less barometric pressure. This leads to a decrease in the partial pressure of oxygen. The percentage of air that contains oxygen is 21% at any height. However, the oxygen molecules are less dense higher up so with every breath our bloodstream gets less oxygen which is called hypoxemia. Our tissues then get less oxygen as well which is called hypoxia.
Our bodies go through a process called acclimatization to help us adjust to these changes at altitude. The first change we see is increased ventilation. The decrease in oxygen stimulates chemoreceptors in our aorta and carotid which then regulate the depth and rate of our breathing, making our breaths deeper and faster to try and get more oxygen in. This involuntary action is called the hypoxic ventilatory response (HVR). There is an inverse relationship between carbon dioxide and oxygen in the alveoli of our lungs. Since we breathe deeper and faster at altitude we breathe out more carbon dioxide, hence increasing the partial pressure of oxygen. Discussions about carbon dioxide, how it affects the kidneys, what happens to hemoglobin, cardiac output, are very helpful for a deeper understanding of what happens in the body at altitude.
There are three major illnesses that can occur when our bodies do not go through acclimatization properly: acute mountain sickness (AMS), high altitude cerebral edema (HACE), and high altitude pulmonary edema (HAPE). AMS is the most common. It is seen within 4-12 hours of ascending to altitudes higher than 2500 meters. A headache is needed to diagnose AMS in most scoring systems used for diagnosis, other symptoms include GI symptoms, dizziness, fatigue, and sleep disturbances. HACE is a progression of these symptoms. It is dangerous since as the name implies it is cerebral edema or swelling. There may be signs of altered mental status, ataxia, and can progress to coma and death within 24 hours. According to the blog there is not much understanding/consensus of which part of the acclimatization process goes wrong to cause these potentially fatal outcomes, nor is there a clear answer about whether you can have one without the other. The onset of HAPE is slower, occurring between 1-5 days, rarely after a week. There are more pulmonary symptoms as the name suggests such as excessive shortness of breath, chest tightness, cough, sputum production. The podcast discusses in detail theories about the causes of HAPE.
The history of altitude sickness goes back to Ancient Chinese, Greek and Roman medical texts. “The ancients also observed that the rarity of the air on the summit of Olympus was such that those who ascended it were obligated to carry sponges moistened with vinegar and water and to apply them now and then to their nostrils as the air was not dense enough for their respiration.” This suggested they believed there was no water vapor in the air at high altitudes making it difficult to breathe. Some other texts mentioned “headache mountains” suggesting the naming of mountains based on side effects they experienced at these high altitudes.
The podcast hosts reviewed landmark experiments showing the effects of hypoxia on people and animals. Robert Boyle and Robert Hooke’s experiments using an air pump to investigate an animal’s response to different air pressures. Results showed that survival was shortened at lower pressures. Hook also created a decompression chamber so humans could test low pressure effects. He personally sat in there for 15 minutes at 570 torr, the equivalent of 7,800 ft (2400 m), and experienced some hearing loss. Anton Lavoisier performed another experiment, he compared blood that passed through the lungs with fresh air with venous blood. Freshly ventilated blood was bright red and venous blood was darker red, suggesting something changes in our blood when having contact with fresh air. Another scientist, Mayow, put a mouse on a stool inside of a bowl of water then covered it with a glass bell, creating a sealed environment. The same thing was done with a candle.
Results were that the water levels inside the bell rose as the animal breathed or as the candle burned, suggesting the mouse or the flame was consuming some part of the air which the water came in to fill. He demonstrated there must be at least two different components in air, one of them being necessary for both animal respiration and combustion. Later on he also suggested this “component” is taken up by the lungs and passed into the blood where it is involved during heat production and muscle movement, explaining why breathing increases during exercise, as we need more of this substance in the air to move.
Mountaineering and hot air balloons led to further understanding during the 1700 and 1800s. Paul Bert used animals in hypobaric chambers, simulating the low pressure of high altitude. He found that illness and death always occurred at a certain level of blood oxygen. The same thing happened when air pressure was kept at sea level but the overall oxygen concentration was lowered. Bert also suspected that people and animals at high altitude produce more red blood cells for increased oxygen absorption. Now we know this is true. Plasma volume drops 15-25% which causes a rise in the concentration of hemoglobin. This occurs within around 1-2 days of ascent to altitude. This triggers erythropoietin which stimulates red blood cell production. However, this occurs over days or weeks. So if you are at high altitude for less time your body will not get to this step. (Read “Red Flags At Altitude blog about lab values seen in the patient portal).
To understand altitude effects many researchers now study small animals. The highest mammal is the yellow-rumped leaf-eared mouse, at 21,000 ft, studied by Jay Storz and colleagues. North American deer mice are the only mammals above tree line in the Rocky Mountains. University of Denver Assistant Professor of Biology Jon Velotta does studies comparing these high dwellers to their lower altitude cousins. With colleagues Catie Ivy andGraham Scott they were able to show that the breathing rate, red blood cells and hemoglobin increase proportionately to decreasing partial pressures of oxygen.
Anyone interested in the nitty gritty of altitude will learn from this podcast, as well as many other medical topics covered by Colorado-based hosts Erin Allmann Updike MD, PhD and epidemiologist and Erin Welsh PhD disease ecologist and epidemiologist. Each podcast is accompanied by original recipes for a themed cocktail and nonalcoholic drink.
Claudia Ismerai Reyes is a PA student at Red Rocks Community College in Arvada, Colorado. She grew up in Phoenix, Arizona and went to Arizona State University to get her bachelor’s degree in biology. The first in her family to graduate college. She moved to Colorado a little over five years ago and worked as a CNA at Denver Health for over two years before getting into PA school. In her free time, she likes to watch movies with her husband, trying new places to eat, or playing board games at home.
My love for hiking developed during my childhood explorations of the breathtaking landscapes of the Sierra Nevada. As I ventured into the rugged mountains and hiked along scenic trails, I couldn’t help but feel a deep connection with nature. However, my passion for hiking was not without its moments of caution. On several occasions, I witnessed the awe-inspiring yet intimidating power of lightning storms dancing across the vast mountain skies. These encounters instilled in me a profound curiosity about the risks associated with lightning strikes in high-altitude regions.
When I moved to Colorado for PA school, my awareness of the dangers posed by lightning strikes grew even stronger. The dramatic topography and frequent thunderstorms in Colorado amplify the risk for individuals exploring high-altitude areas. It was during my last clinical rotation at a burn unit that I had the opportunity to care for several patients who had been struck by lightning. Witnessing the effects firsthand fueled my determination to educate the public about the actionable steps they can take to stay safe during lightning storms.
Lightning strikes
Lightning possesses an immense amount of energy, with a voltage of over 10 million volts (in comparison, most car batteries measure 12.6 V).1 Additionally, a lightning bolt reaches incredibly high temperatures, reportedly up to 30,000 Kelvin (53540.33 F).1 Lightning injuries occur in different ways, including as direct strikes, side splash, contact injuries, or ground current.
Direct strikes are uncommon, accounting for only 5% of cases, and happen when a person is directly struck by lightning.2
Contact injuries occur when a person touches an object that is struck by lightning. 2
Side splash injuries occur when the current jumps or “splashes” from a nearby object and then follows the path of least resistance to reach the individual. These injuries make up about 1/3 of all lightning related injuries. 2
Ground current is the most prevalent cause of injury, accounting for half of all cases, and occurs when lightning strikes an object or the ground near a person and subsequently travels through the ground to reach the individual. 2
In Colorado, an average of 500,000 lightning flashes hit the ground each year. Based on data since 1980, lightning causes 2 fatalities and 12 injuries per year throughout the state.3According to data since 1980, lightning causes an average of 2 fatalities and 12 injuries annually throughout the state.3 Colorado ranked third in the United States for the number of lightning fatalities between 2005 and 2014, as depicted in Figure 1.
Fig. 1. Lightning fatalities by state. 3
The high number of injuries attributed to lightning in Colorado can be influenced by several factors. One of these factors is the easy access to high elevation terrain, such as 14ers (mountains with a peak elevation of at least 14,000 feet). This accessibility allows inexperienced outdoor enthusiasts to venture into potentially dangerous situations due to their lack of knowledge and preparation.
For instance, individuals who are not familiar with summer weather patterns may embark on a hike above the tree line late in the day, underestimating the risk of a storm forming. This lack of understanding puts them in an exposed and perilous position should adverse weather conditions arise.
Even with thorough preparation and extensive knowledge of weather patterns, it is still possible to find oneself in a situation where you have to weather a storm. Given that a significant proportion of Colorado’s hiking trails are located above the tree line, where appropriate shelter is sparse, hikers are more susceptible to lightning strikes in these exposed areas.
Pathophysiology of Lightning Strike Injuries
The overall ratio of lightning injuries to deaths is 10:1 and there is a 90% chance of sequelae in survivors.4 The primary mechanism of injury in lightning strikes is the passage of electrical current through the body. The high voltage and current can cause tissue damage through several mechanisms, including thermal injury, electrical burns, and mechanical disruption of tissues. The severity of the injury depends on factors such as the voltage and current of the lightning bolt, the duration of contact, and the pathway the current takes through the body.
Lightning strikes can cause various types of injuries, with cardiac and respiratory arrest being the most common fatal complications.5 The path of least resistance determines the flow of electricity through different organs in the body, with nerves being the most conductive, followed by blood, muscles, skin, fat, and bone. 5 When lightning strikes, the electrical surge can induce cardiac arrest and cessation of breathing by affecting the medullary respiratory center. As a result, most patients initially present with asystole and may progress to different types of arrhythmias, commonly ventricular fibrillation. 5
Interestingly, there have been case reports documenting successful resuscitation of lightning strike victims who were initially apneic and pulseless for as long as 15 to 30 minutes. 5This has led to the recommendation that in the immediate aftermath of a lightning strike, individuals who appear to be dead should be prioritized for treatment.
Superficial skin burns are experienced by around 90% of lightning strike victims, but deep burns are less common, occurring in less than 5% of cases. A characteristic skin manifestation of a lightning strike is the Lichtenberg figure, which is considered pathognomonic. Neurological symptoms can also occur, including keraunoparalysis, which is a transient paralysis affecting the lower limbs more than the upper limbs. This paralysis is often accompanied by sensory loss, paleness, vasoconstriction, and hypertension, and is thought to result from overstimulation of the autonomic nervous system, leading to vascular spasm. In most cases, this paralysis resolves within several hours, but in some instances, it may last up to 24 hours or cause permanent neurological damage. 5
Additionally, it is common for lightning strike victims to have a perforated tympanic membrane (eardrum) or develop cataracts immediately following the incident. These injuries to the ear and eyes are associated with the intense energy of the lightning discharge.6
What can hikers do to stay safe?
Preparation
Monitor weather forecasts: Stay updated on weather conditions before engaging in outdoor activities, especially in areas prone to thunderstorms. Pay attention to thunderstorm warnings or watches issued by local authorities. Having a mobile or handheld NOAA Weather Radio All-Hazards (NWR) can also be helpful as it can transmit life-saving weather information at a moment’s notice.
In Colorado most thunderstorms develop after 11 am, so it is best to plan your trip so that you are descending by late morning.7Fig. 2 shows number of lightning fatalities by time of day in Colorado between 1980 and 2020. The vast majority take place after the 11 am threshold.
Fig. 2 Lightning fatalities in Colorado by time of day3
What to Do If Caught in a Storm
If you can hear thunder, you are close enough to be struck by lightning. Lightning can strike up to 25 miles away from the storm. 7 Once you hear thunder, if possible quickly move to a sturdy shelter (substantial building with electricity or plumbing or an enclosed, metal-topped vehicle with windows up). Avoid small shelters, such as picnic pavilions, tents, or sheds. Stay sheltered until at least 30 minutes after you hear the last clap of thunder.
Fig 3. Areas to avoid when sheltering from lightning.
If you are outdoors and cannot reach a suitable shelter, avoid open areas, hilltops, and high places that are more exposed to lightning strikes. Seek lower ground and stay away from tall objects, such as trees, poles, or metal structures. Bodies of water, including lakes, rivers, pools, and even wet ground, are conductive and increase the risk of a lightning strike. Move away from these areas during thunderstorms. Separate group members by at least 20 ft as lightning can jump up to 15 feet between objects.
If a strike is eminent (static electricity causes hair or skin to stand on end, a smell of ozone is detected, a crackling sound is heard nearby), the current recommendation is to assume “lightning position”, pictured in Fig. 4.
Fig. 4. Lightning position8
To potentially reduce the risk of ground current injury from an imminent lightning strike, another strategy is to insulate oneself from the ground. This can be done by sitting on a pack or a rolled foam sleeping pad. However, it’s important to note that this and the lightning position should be considered a strategy of last resort and not relied upon as the primary means of prevention. Maintaining this position for an extended period can be challenging, and it’s crucial to prioritize seeking proper shelter and following established lightning safety guidelines to minimize the overall risk of injury. 5
Case Study
25 YO F presents to the Burn Unit as a transfer from Cheyenne Regional Medical Center s/p lighting strike. Patient (pt) was caught in a thunderstorm on a hike and sheltered under a tall tree. Suddenly, she felt like she was being lifted up into the air and then dropped. Pt had a brief (<5 sec) loss of consciousness (LOC). When she woke up, she was completely numb and couldn’t move any of her extremities. Witness (friend) states the lightning splashed from the tree to the pt. Pt denies hitting her head with the fall. She denies taking blood thinners. She has no past medical history (PMHx) or past surgical history (PSHx).
Physical exam
Neuro: AOX4, No CN deficit on exam, LE paralysis resolved, LE paresthesia improving but still present
HEENT: L ruptured tympanic membrane, hearing loss on L side
CBC, CMP, troponin were all WNL. Serum hCG negative. CK mildly elevated (222)
EKG showed NSR.
CXR, CT brain, and c-spine neg for acute injury
She was admitted to the UC Health burn center for observation with tele. Her lab work and vitals remained stable throughout her hospitalization. She was evaluated by the trauma team with a negative trauma work up. The day of discharge, she was tolerating a regular diet, ambulating and sating well on room air. She was deemed appropriate for discharge home without patient audiology and ophthalmology follow up.
References
1. US Department of Commerce N. Understanding lightning science. National Weather Service. April 16, 2018. Accessed July 8, 2023. https://www.weather.gov/safety/lightning-science-overview.
2. Cooper MA, Holle RL. Mechanisms of lightning injury should affect lightning safety messages. 21st International Lightning Detection Conference. April 19-20, 2010; Orlando, FL.
3. US Department of Commerce N. Colorado Lightning statistics as compared to other states. National Weather Service. March 4, 2020. Accessed July 7, 2023.https://www.weather.gov/pub/Colorado_ltg_ranking.
4. US Department of Commerce N. How dangerous is lightning? National Weather Service. March 12, 2019. Accessed July 8, 2023. https://www.weather.gov/safety/lightning-odds.
5. Chris Davis, MD; Anna Engeln, MD; Eric L. Johnson, MD; Scott E. McIntosh, MD, MPH; Ken Zafren, MD; Arthur A. Islas, MD, MPH; Christopher McStay, MD; William R. Smith, MD; Tracy Cushing, MD, MPH. Wilderness Medical Society Practice Guidelines for the Prevention and Treatment of Lightning Injuries: 2014 Update. WILDERNESS & ENVIRONMENTAL MEDICINE. 2014; 25, S86–S95
6. Flaherty G, Daly J. When lightning strikes: reducing the risk of injury to high-altitude trekkers during thunderstorms. Academic.oup.com. Accessed July 8, 2023. https://academic.oup.com/jtm/article/23/1/tav007/2635599.
7. NWS Colorado Offices – Boulder G. Colorado Lightning Awareness Week june 19-25, 2022. ArcGIS StoryMaps. June 25, 2022. Accessed July 8, 2023. https://storymaps.arcgis.com/stories/11d021f1b800429a869ead2dc32c0f96.
8. McKay B and K. How to survive A lightning strike: An illustrated guide. The Art of Manliness. April 25, 2022. Accessed July 8, 2023. https://www.artofmanliness.com/skills/outdoor-survival/how-to-survive-a-lightning-strike-an-illustrated-guide/.
Sophia Ruef is a Physician Assistant student at Red Rocks Community College in Arvada, CO. She grew up on the central coast of California and earned her Bachelor of Science degree inBiology with a concentration in anatomy and physiology from Cal Poly San Luis Obispo. She worked as an EMT and a tech in the Bay Area after her undergraduate education. In her free time, she enjoys hiking, backpacking, canyoneering, and spending time with family and friends.
During my last week of a clinical rotation at Ebert Family Clinic in Frisco, Colorado, at 9000 feet, I was thrilled to have the opportunity to interview high altitude resident Karen Terrell with physician Dr. Chris Ebert-Santos. During this time, we were able to discuss high altitude pulmonary hypertension, also known as NAPH. This is a condition that Karen has been living with since 2015. NAPH is condition that can affect people that live above 8,200 feet, more than 140 million people live at this altitude worldwide, including the population of Summit County, where the town of Frisco, Colorado is. Pulmonary hypertension is a group of disorders that will typically be diagnosed during a heart catheterization measuring the mean arterial pressure of the right side of the heart. These disorders are broken down into five groups. High altitude pulmonary hypertension is in group three. The primary symptoms that people first notice is extreme fatigue, difficulty getting air upon exertion, and difficulty engaging in their normal exercise routines.
How long have you lived in Summit County [Colorado], and where did you move from originally?
Karen: I grew up in Nebraska, I moved to New York City as soon as I was old enough to leave home. I went to Boulder for school, and then moved to Denver for work. I went to an Outward-Bound Experience, and I fell in love with this area. I have lived in Summit County over 37 years. My kids were born and raised here; they are now in their 30s.
What are some of the things that you love to do in area?
Karen: I downhill ski, I uphill ski, and I cross country ski. Mountain biking is my passion. I downhill bike, that is where you take the gondola to the top of the mountain and then ride your bike down.
When did you start to have symptoms?
Karen: 2015
What were the symptoms that you noticed first?
Karen: Extreme fatigue and erratic pulse, with or without exertion. By the end of a run, I would be so exhausted that I was practically crawling home.
Do have to go on oxygen at any point?
Karen: In 2018 I started using oxygen at night. I still use oxygen at night. In 2020 I started riding and skiing with portable oxygen. When my oxygen columns fail, so do I. It was also during this time I began to work on nasal breathing night and day. I have been doing research on the importance of nasal breathing and retraining the body on how to take in oxygen. Practicing nasal breathing is especially important when you are using a nasal cannula to get oxygen when you are being active.
https://oxygo.life/oxygo-fit
Dr. Chris Ebert-Santos: The standard is “if you’re 50 and you’ve lived here 10 years and you want to live here for another 10 years you should be sleeping on oxygen.”
Between 2015 and 2018 did you have any other symptoms or worsening concerns?
Karen: In 2017 I applied for life insurance. I was denied as I had what I now know is chronic proteinuria. The nephrologist was perplexed as to why someone who is as active as I am and takes no medication is having this condition. The insurance company essentially told me that they would not touch me with a 10-foot pole. This was the “canary in the mine” that made me think something was not right. In 2018, I had a cardiac ablation. The cardiac ablation corrected the erratic heart rate and relieved my extreme fatigue. However, it did nothing for my oxygen saturation.
You mentioned in 2020 that you started to ski and ride your bike with portable oxygen. Did something happen in 2020, besides COVID?
Karen: You know, with everything that I have going on health wise I have been so cautious that I have not ever had COVID. In 2020, I was at an office visit with my PA. I mentioned that biking and skiing at higher elevation with exertion, that I felt flattened and near-dead. My pulse oximeter showed oxygen saturation of low 70’s. My PA freaked out and thought I had Pulmonary Hypertension (as opposed to HAPH) and sent me to a Denver Pulmonary specialist.
What did the pulmonary specialist tell you?
Karen: When I went to the pulmonary specialist, they said my oxygen numbers were fine at Denver’s elevation. The Pulmonologist advised moving to lower elevation but said there is no knowing how low until I experiment. I have lived in Summit County and raised my children here; my children still live here. Moving was not an option. I started riding and skiing with portable oxygen. When 02 columns fail, so do I. I do have periodic episodes of extreme joint pain resulting from excessive stress/time at desk (10-hr days). However, I try to eliminate the pain by remaining active using oxygen when I need it. If I don’t use oxygen to sleep, I feel half dead the next day and it is difficult to wake up the next day. I worry about the long-term effects of the hypoxia, however I continue to monitor. I am hoping to see more research done in the area of high-altitude pulmonary hypertension.
Jennifer Wolfe is in her final semester of Nurse Practitioner school at Georgetown University. She was born and raised in Missouri and attended The University of Missouri where she graduated with a bachelor’s degree in psychology. After attending Mizzou she married her husband who was active duty in the US Navy. They traveled to many bases and had two boys before calling Denver their home in 2011. Jennifer received her BSN from Denver College of Nursing. Jennifer has spent 7 years as a nurse in the emergency department of several level II trauma centers before starting at Georgetown as a part of the Family Nurse Practitioner program. Jennifer enjoys spending her free time with her family and their three dogs.
Every newborn I have managed while rotating at Ebert Family Clinic in Frisco, Colorado at 9000′ has needed oxygen supplementation. It is known that at high altitudes, there is a lower oxygen concentration in the air, which poses challenges to our bodies. What exactly happens, and what are the consequences of chronic high-altitude exposure? There are approximately 140 million people that live at high altitudes, defined as at least 2500 meters above sea level, who are affected by chronic hypoxic conditions.1 In this article, I will focus on how hypoxia — low levels of oxygen in the blood — affects pregnant women, alters fetal to newborn transition and development, and whether cardiorespiratory exercise by mothers during pregnancy can prevent diseases such as high-altitude pulmonary hypertension (HAPH) development in offspring.
Pulmonary hypertension (PH) is abnormally high blood pressure in the pulmonary arteries. PH is classified into 5 groups based on the cause. High-altitude pulmonary hypertension (HAPH) is Group III PH and defined as mean pulmonary arterial pressure (PAP) ≥25 mm Hg. Chronic high-altitude hypoxia can lead to the development of HAPH, which has adverse effects on the heart from right ventricular wall thickening to reduced cardiac output, and eventual right heart failure and death. HAPH can occur in utero, so it’s imperative to understand how hypoxia affects mothers and their fetuses during and after birth.2
During pregnancy, the fetus doesn’t breathe air and the lungs are not used. The fetus receives all its oxygen and nutrition needs from the mother’s blood, which flows through the blood vessels in the umbilical cord to the placenta and then to the baby.3 Circulating blood bypasses the lungs by flowing in different pathways through openings called shunts that close at birth to allow for adult circulation. In utero, the baby’s lungs fill with a special fluid that helps the lungs grow.4 The fluid in the lungs, in combination with naturally thicker pulmonary vascular and pulmonary vessel vasoconstriction from low PO2, causes higher vascular resistance in pulmonary circulation that allows for the diversion of blood away from the lungs through the shunts.2 At low altitudes, in the first few days after birth, the high PAP in the lungs drops. The sharp drop in PAP is due to “expansion of the lungs, pulmonary vasodilation from higher PO2, a gradual receding of fluid, a thinning of pulmonary vascular smooth muscle, and… closing of the [shunts]”. This process is known as cardiopulmonary transition. However, at altitude, perinatal hypoxia negatively affects cardiopulmonary transition. The elevated pressures in the pulmonary arteries and vascular resistance persist into early childhood delaying cardiopulmonary transition, which can have developmental consequences such as HAPH and right heart failure, as discussed.
It was discovered that cardiopulmonary transition delay is linked to a high-altitude hypoxia-induced proinflammatory state within the pulmonary vasculature that leads to pulmonary artery remodeling and HAPH. Hypoxia activates or upregulates transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NK-kB), that signals for inflammatory mediators such as hypoxia-inducible factors (HIF). HIF-1a inhibits mammalian target of rapamycin (mTOR). mTOR signaling has an important role in cell metabolism, cell proliferation, and survival, thus inhibiting mTOR prevents “non-proliferative branching and elongation of conducting airways and fluid removal from the lungs,” which contributes to increases in pulmonary vascular resistance and lung development during the cardiopulmonary transition and the onset of newborn gas exchange. 2,5 HIF also contributes to the uncontrolled proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMC) which is also a crucial contributing factor to pulmonary vessel wall thickening, pulmonary vascular remodeling, and vascular resistance. 5 Metabolic studies showed that chronic hypoxia not only increased the expression of these proinflammatory molecules and mediators but also reduced anti-inflammatory products like omega-3 fatty acids.2
Studies have shown that cardiorespiratory exercise reduces proinflammatory markers and increases anti-inflammatory stimulus in healthy and HAPH populations.2 However, exercise training is not sufficient to reverse PAH, so we need to prevent HAPH from developing in utero with maternal exercise. The American College of Obstetrics and Gynecologists (ACOG) recommends resistance training twice a week and moderate-intensity cardiorespiratory training daily for a total of 150 minutes a week. Studies showed that pregnant women who followed this recommendation had a 25% reduced risk of developing conditions like gestational diabetes and hypertension that contribute to compromised uterine blood flow and fetal hypoxic conditions. At low altitudes, exercise by pregnant mothers leads to benefits such as decreased fat mass, leptin, oxidative stress, pulmonary valve defects, aortic valve defects and inflammation, and increased neurogenesis in the fetus. Some animal studies at high altitudes showed that offspring of physically active pregnant rodents also received similar benefits from maternal exercise. The offspring were protected against proinflammatory stressors evidenced by low levels of inflammatory mediators, which protected them against the inflammatory processes that drive pulmonary artery remodeling and pressures that lead to HAPH. Further animal studies should be conducted to further explore the possibilities that maternal exercise can counteract the inflammatory changes and prevent HAPH development in fetus and newborns.
Resources
Mirrakhimov AE, Strohl KP. High-altitude Pulmonary Hypertension: an Update on Disease Pathogenesis and Management. The Open Cardiovascular Medicine Journal. 2016; 10: 19-27. doi: 10.2174/1874192401610010019
Leslie E, Gibson AL, Gonzalez Bosc LV, Mermier C, Wilson SM, Deyhle MR. Can Maternal Exercise Prevent High-Altitude Pulmonary Hypertension in Children?. High Altitude Medicine & Biology. 2023; 24: 1-6. https://doi.org/10.1089/ham.2022.0098
He S, Zhu T, Fang Z. The Role and Regulation of Pulmonary Artery Smooth Muscle Cell in Pulmonary Hypertension. International Journal of Hypertension. 2020; 2020: 1478291. doi: 10.1155/2020/1478291
Several students from Summit High School’s Track & Field team attended the Colorado State Track and Field Championships in Lakewood in May, where they competed with top runners across the state. The boys team placed 20th out of 39 teams, and the girls team tied for 9th place out of 40 teams in Class 4A rankings. Throughout the season, many students set new personal records and broke previous school records.
I had the pleasure of speaking with Summit High School hurdles coach, Jay Peltier, about training young athletes in high altitude. Jay has coached Track & Field for 15 years and has even helped lead some high schools to win state titles. He has trained student athletes in cities close to sea level as well as ones in higher elevation, like Colorado Springs. This is his second season coaching in Summit County.
Exercising at high altitude can be a challenge due to the decreased oxygen concentration at higher elevations. Because of this, there is reduced oxygen availability to muscles, causing fatigue to occur sooner at lower working rates. Given his experiences coaching at different altitudes, I asked Jay how he has adjusted his training to being at 9,000 ft. He notes that with elevation as high as this, it’s difficult to train hard for long periods. His workouts at high altitude include longer rest times between reps and less volume per workout. For example, one of Jay’s staple workouts for sprinters when he was training at lower elevation included running twelve 200 meter sprints, totaling up to a volume of 2,400 meters. At high altitude, he would decrease the volume to about 1,800 meters.
I also asked Jay about how competing at track meets at a lower elevation affects athletes that have been living and training at high altitude. Generally, athletes that run events greater than 400 meters should be faster running at lower elevations because there is increased oxygen availability. This is because distance running is a form of aerobic exercise in which the body uses oxygen as the primary source for energy. Sprinters, on the other hand, may not see the same benefit competing at lower elevation because sprinting is a form of anaerobic exercise, where the body relies on burning carbohydrates for energy. Despite this, Jay recognizes that there are many other variables that can affect these high altitude athletes competing at lower elevations, including weather. Jay notes that competing in lower areas, like Denver or Grand Junction, can also be 20 degrees warmer compared to Summit County. Increased temperatures can lead to exhaustion faster, especially for distance runners.
Jay and his fellow coaches try to tell their athletes after every practice to “Eat right. Sleep right. Drink right.” in order to maximize their workout. This includes getting a good balance of carbs, protein, fruits, and vegetables in their diet to properly fuel their body. He recommends his athletes get at least 9 hours of sleep at night. He notes that sleep deprivation can significantly impact how one trains, especially at altitude. Lastly, he emphasizes to his athletes the importance of staying hydrated. While this is essential for all athletes, the risk of dehydration is higher at altitude. He recommends they drink half their bodyweight in ounces, plus an extra 10 ounces for being at elevation.
Resources
Jones, Cody. “State Champion Again: Summit’s Ella Hagen Wins 1,600-Meter State Title at Final Day of the Colorado State Track and Field Meet.” SummitDaily.Com, 24 May 2023, www.summitdaily.com/news/state-champion-again-summits-ella-hagen-wins-1600-meter-state-title-at-final-day-of-the-colorado-state-track-and-field-meet/.
Mancera-Soto, Erica M., et al. “Effect of Hypobaric Hypoxia on Hematological Parameters Related to Oxygen Transport, Blood Volume and Oxygen Consumption in Adolescent Endurance-Training Athletes.” Journal of Exercise Science & Fitness, vol. 20, no. 4, 18 Oct. 2022, pp. 391–399, https://doi.org/10.1016/j.jesf.2022.10.003.
Myasthenia Gravis (MG) is a condition caused by the production of antibodies that block acetylcholine receptors. This blockade of neuromuscular signaling results in rapid muscular fatigue and weakness. Increased activity tends to worsen muscular issues which usually resolve with rest. Prominent symptoms of MG include drooping eyelids, double vision — OMG (ocular myasthenia gravis)– difficulty swallowing, slurred speech, and shortness of breath. Generally, muscles in the face and throat are considered to be the most commonly impacted by Myasthenia Gravis. However, this condition can affect any muscle group throughout the body (1). Gastrointestinal (GI) manifestations such as abdominal pain, recurrent vomiting, and constipation have been reported by individuals with MG. A case presenting to the Summit Medical Center located at 9,100 feet illustrates an unusually severe manifestation:
St. Anthony Summit Medical Center on Peak One Drive in Frisco, Summit County, Colorado, at the foot of Peak One of the Ten Mile Range, enshrouded in snowy mist.
A 70 year old woman was brought to the emergency department (ED) with severe abdominal and chest pain, concerned that she had a dissecting aortic aneurysm. She reported three previous episodes of severe pain in the 2 weeks leading up to the ED visit, all starting in the afternoon, increasing to prostration by 5 pm and resolving with bed rest. Past medical history was significant for myasthenia gravis for which she took azathioprine 100 mg BID (twice daily). Two months previously she had a flare with ptosis and double vision, treated with prednisone 40 mg daily.
Laboratory tests were normal. Imaging showed distended loops of bowel consistent with ileus. She was treated with pain medication and symptoms resolved.
The patient continued to have episodes once or twice a month, including another ED visit, precipitated by treatment with duoneb, which has anticholinergic activity, a tonic water drink, and guaifenesin, both antimuscarinic substances that interact with the cholinergic receptors in the viscera.. Taking pyridostigmine, a cholinesterase inhibitor, led to resolution within 2 hours, marked by “sparkly” sensations in her arms and legs and reactivation of bowel sounds with flatus.
CT scan of patient with intestines diffusely distended with bowel gas.
Until recently, GI symptoms were considered rare in myasthenia gravis. Then a case study in 2001 demonstrated that gastric dysmotility was a common feature among individuals with Myasthenia Gravis (2). Among all the motility dysfunction reported, gastroparesis was found to be a common autonomic feature in MG patients (2). Gastroparesis is the slowing or stopping of movement in the GI tract resulting in delayed gastric emptying. Further research demonstrated that intestinal pseudo-obstruction was considered to be one of the most common GI manifestations of individuals with MG(3,4,5).
In 2007 it was demonstrated that receptors in gut muscles were structurally similar to skeletal muscle receptors, indicating that GI motility could be highly impacted by the presence or lack of acetylcholine (6). Considering that antibody production in Myasthenia Gravis Individuals can decrease acetylcholine binding to receptors, the presence of GI symptoms among other autonomic dysfunction symptoms suggests inadequate treatment which can result in a poor prognosis for these individuals (7).
What was previously considered a rare symptom within a rare condition, is now being proposed as an early identification tool. Taking into account receptor similarity, GI symptoms can be used as early indicators of myasthenia gravis, specifically gastrointestinal dysmotility (8). The case study showed that MG developed less than a decade after the initial onset of gastrointestinal dysmotility symptoms (8). There is a clear need to identify GI symptoms earlier in MG individuals. This will allow for better treatment and improved long-term health outcomes for these individuals.
At altitude, the low barometric pressure causes gaseous distension in normal individuals producing increased flatus (see blog on HAFE). Combined with MG, GI manifestations can be even more severe. Medical providers treating residents of high altitude communities should consider MG in the differential of patients with abdominal complaints and treat recognized MG patients with anticholinesterase medications to control symptoms. None of this patient’s providers were aware of this manifestation of MG, including the neurologist who specializes in MG, the gastroenterologist who performed an upper endoscopy and colonoscopy, the ED staff, the radiologist and the primary care provider. Patients with MG and their providers need to be aware of medications that interact with the cholinergic receptors in all parts of the body and screen for these as possible precipitators of symptoms outside the classic description of the disease.
2. Vernino S, et al. Myasthenia gravis with autoimmune autonomic neuropathy. Auton Neurosci. 2001;88(3):187–192.
3. Pande R, Leis AA. Myasthenia gravis, thymoma, intestinal pseudo-obstruction, and neuronal nicotinic acetylcholine receptor antibody. Muscle Nerve 1999;22:1600-1602
4. Musthafa CP, Moosa A, Chandrashekharan PA, Nandakumar R, Narayanan AV, Balakrishnan V. Intestinal pseudo-obstruction as initial presentation of thymoma. Indian J Gastroenterol 2006;25:264-265.
5. Seretis C, Seretis F, Gemenetzis G, Gourgiotis S, Lagoudianakis E, Pappas A, Keramidaris D, Salemis N. Adhesive ileus complicating recurrent intestinal pseudo-obstruction in a patient with myasthenia gravis. Case Rep Gastroenterol. 2012
6. Mandl, P, Kiss, JP. Role of presynaptic nicotinic acetylcholine receptors in the regulation of gastrointestinal motility. Brain Res Bull. 2007;72:194–200
7. Putri Aaliyah. Autonomic Dysfunciton. Gastroparesis as autonomic manifestation of myasthenia Gravis: A rare case report. Clinical Neurophysiology. 132: 94-95, 2021 8. Alnajjar, S., Idiaquez Rios, J., Fathi, D., Liu, G., & Bril, V. (2022). Gastrointestinal Dysmotility as the First Manifestation of Myasthenia Gravis. Canadian Journal of Neurological Sciences, 1-2.
8. Alnajjar, S., Idiaquez Rios, J., Fathi, D., Liu, G., & Bril, V. (2022). Gastrointestinal Dysmotility as the First Manifestation of Myasthenia Gravis. Canadian Journal of Neurological Sciences, 1-2.
There are three types of High Altitude Pulmonary Edema (HAPE) recognized in visitors and people living at high altitudes. These include classic HAPE (C-HAPE), which involves an individual that lives at low altitude traveling to high altitude. Re-entry HAPE (RE-HAPE) is seen in an individual that lives at high altitude who travels to low altitude and then returns to high altitude. And high-altitude resident pulmonary edema (HARPE) which occurs in an individual that lives at high altitude and does not change altitude (Ebert-Santos, Wiley). While these have been extensively studied and are subtypes that people are warned of, a fourth unexpected type of HAPE has been recently described by pediatric pulmonologist Santiago Ucros in Bogota, Columbia at the Universidad de los Andes. (Ucros)
Highlanders HAPE (HL-HAPE) occurs in people that live at high altitude who then travel to higher altitudes. Though most people who live at high altitudes for long periods of time assume they are immune to HAPE, the recognition of HL-HAPE shows this is not the case. One man had a run-in with HL-HAPE during his long-awaited trip to Mt. Kilimanjaro.
A resident of Summit County, Colorado, Jonathan Huffman set out to climb Mt. Kilimanjaro with his wife Katie when he was 37 years old. He is originally from Texas, but has been living in Breckenridge, Colorado, elevation 9,600 ft, for 15 years. In preparation for the climb, he spent the summer hiking multiple fourteen thousand foot peaks in Colorado, trail running at 9,000-12,000 ft, and mountain biking.
The elevation of Mt. Kilimanjaro is 19,341 feet and the summit generally takes each group anywhere from 5 to 9 days, depending on the route taken. In September, Jonathan and Katie traveled to Tanzania where they spent two days adjusting to jet lag and preparing for their climb. They had chosen to follow the Lemosho Route which is 42 miles long with an elevation gain of 16,000 to 17,000 feet.
On the first day, Jonathan and his party started at the Lemosho trailhead (7,742 feet) and hiked up 9,498 feet to the first camp. He noticed that his throat felt dry and he found himself having to clear it often. He attributed this symptom to the dusty environment.
On the second day, he felt as though his body was fighting the dust, which had found its way into his eyes, sinuses, and throat. He also felt extremely fatigued and stated that every action felt more difficult. Though he could tell his body was struggling to adapt, Jonathan continued to push forward with full force. He made it to the second camp at 11,500 feet.
“Day three, we went from 11,500 feet to 13,800 feet,” Jonathan recounts. “After we arrived to this camp, our guides offered to allow us to take a break then hike even higher. This was [an] optional acclimatization test … but I actually skipped it. I was so tired when I got to camp on this day, I decided to just nap in the tent until dinner time.”
On the fourth day, Jonathan’s group hiked up an overpass to Lava Tower located at 15,190 feet. This was also an altitude test, and he passed. He stated that this was the highest he had ever climbed, but that he was beginning to feel more like his normal self. The group stopped for lunch at the tower, but he did not have much of an appetite. He ate the food anyways at the insistence of the guides.
“Then after lunch, we descended down to Barranco Camp [from 15,190 feet to 13,044 feet] and this is where I realized I had HAPE.”
As they were nearing the camp, he felt fluid building in his lungs that was easy to cough up. By the evening, however, he felt as though he was drowning and was unable to lay down. While the guides encouraged him to immediately hike down, he did not want to hike in the dark. He spent the night propped up on duffle bags or sitting in a kitchen chair, with his oxygen reaching as low as 67% at one point.
In the morning, he received 30 minutes of oxygen treatment before beginning his 8-hour descent. His symptoms improved when he reached 6,500 feet. He was picked up in a rescue vehicle and received further treatment at a hospital in Moshi. While he made a full recovery, he stated that he still felt the effects of HAPE while exercising in Colorado at times, up to months after the experience. While Jonathan was only about 2 days away from the summit, he knew that turning back was the best choice. He plans to re-attempt the climb in a few years.
Jonathan’s story serves as an important reminder to those living at altitude that HAPE can affect anyone. Jonathan’s wife Katie along with everyone else in the group also experienced mild symptoms of altitude sickness including headaches. Research still needs to be conducted on the cause and prevention of this condition in all types. While this shouldn’t stop hikers and climbers from climbing mountains, they should be aware of the signs and symptoms of HAPE, when to seek treatment, and the best ways to prevent it from occurring.
Epigenetics slide from speaker at Hypoxia conference in La Paz Bolivia, 2022
The CDC defines epigenetics as “the study of how your behaviors and environment can cause changes that affect the way your genes work… epigenetic changes are reversible and do not change your DNA sequence, but they can change how your body reads a sequence.”1 Examples of epigenetic changes include methylation, histone modifications, and non-coding RNAs. Researchers have postulated the involvement of epigenetics in an organism’s adaptations to hypoxic high-altitude environments. After looking into this topic, I questioned if epigenetics may be the bridge to the permanent physiologic alterations in organisms living at high altitudes.
Hypoxia Inducible Factor-1 (HIF-1) is a nuclear transcription factor activated in hypoxia states, and regulates several oxygen-related genes. The role of epigenetics, specifically methylation of HIF-1 in the expression of the erythropoietin gene, in states of hypoxia was researched. Erythropoietin was chosen due to it being a widely known protein that stimulates erythropoiesis in states of hypoxia. It was confirmed that HIF-1 binds to a HIF-1 binding site (HBS) on the erythropoietin enhancer and will induce transcription of erythropoietin.2 CpG methylation in the HBS interferes with HIF-1 binding, thus inhibiting the activation of transcription of erythropoietin.2 They also found that there were several other oxygen-related genes that were susceptible to similar epigenetic changes.2 Another study investigating HIF-1 and its binding to HIF-1 response element (HRE) upstream to a target gene confirmed the potential for epigenetic changes, specifically methylation. They found that this HIF-1 binding site has a CpG dinucleotide, making it inherently susceptible to methylation.3 To clarify, the most notable epigenetic change is the methylation of cytosine located 5’ to guanine, known as CpG dinucleotides.3 Again, they reported that methylation of the CpG island in the HIF-1 binding site upstream of the target gene, erythropoietin, was negatively correlated with its expression.3
Furthermore, research on epigenetic changes in rats exposed to long and short-term intermittent hypoxic environments and their room air recovery treatments suggests there is a long-term effect in rats exposed to long-term intermittent hypoxia.4 Rats were exposed to short-term (10 days) and long-term (30 days) intermittent hypoxia resembling obstructive sleep apnea oxygen profiles.4 The short-term hypoxic rats treated for 10 days at room air reversed their altered carotid body reflexes including hypertension, irregular breathing, and increased sympathetic tone. While the long-term hypoxia rats treated for 30 days at room air did not have a reversal of altered carotid body reflexes.4 There were similar results in reactive oxygen species (ROS) and antioxidant enzyme (AOE) levels. The long-term hypoxia rats had increased levels of ROS and decreased AOEs in their recovery periods compared to the short-term hypoxia rats.4
Erythropoietin is not the only oxygen-related gene that is affected. For example, a study looked at the methylation profiles of Tibetan and Yorkshire pigs under high-altitude hypoxia. IGF1R and AKT3 were two notable differentially methylated genes found to have high expression and low methylation levels in Tibetan pigs that suggest a role in adaptation to hypoxic environments.5 Both genes are responsible for cell proliferation and survival.5 Tibetan pigs are known to have become physiologically adapted to their high-altitude hypoxic environment over generations and epigenetic changes were verified in the genome-wide sequence ran in this study.5 This study alludes that epigenetics is not only a bridge but may be a part of the permanent physiologically selected adaptations to ensure survival at high altitudes.
In conclusion, research demonstrates a variety of epigenetic changes that are taking place in these high-altitude hypoxic environments. The research suggests that they may likely be tissue-specific as well. There are definite knowledge gaps in the exact roles that epigenetics may play in hypoxic environments and gene expression. There is room for more research and identifying alterations to epigenetics to improve human physiologic adaptations to hypoxia.
2. Wenger, R.H., Kvietikova, I., Rolfs, A., Camenisch, G. and Gassmann, M. (1998), Oxygen-regulated erythropoietin gene expression is dependent on a CpG methylation-free hypoxia-inducible factor-1 DNA-binding site. European Journal of Biochemistry, 253: 771-777. https://doi.org/10.1046/j.1432-1327.1998.2530771.x
3. Yin H, Blanchard KL. DNA methylation represses the expression of the human erythropoietin gene by two different mechanisms [published correction appears in Blood 2000 Feb 15;95(4):1137]. Blood. 2000;95(1):111-119.
4. Nanduri J, Semenza GL, Prabhakar NR. Epigenetic changes by DNA methylation in chronic and intermittent hypoxia. Am J Physiol Lung Cell Mol Physiol. 2017;313(6):L1096-L1100. doi:10.1152/ajplung.00325.2017
5. Zhang B, Ban D, Gou X, et al. Genome-wide DNA methylation profiles in Tibetan and Yorkshire pigs under high-altitude hypoxia. J Anim Sci Biotechnol. 2019;10:25. Published 2019 Feb 5. doi:10.1186/s40104-019-0316-y
Emily Paz is a third-year medical student at Rocky Vista University College of Osteopathic Medicine and is looking forward to pursuing a career in orthopedics. She is from the central coast of California and earned her Bachelor of Science degree in General Biology from the University of California San Diego. She worked in an emergency department as an EMT after her undergraduate education which reaffirmed her passion and curiosity for medicine. In her free time, she enjoys snowboarding, practicing Muay Thai, cooking, and spending time with family and friends.
