Altitude Science, COVID-19, Health, High Altitude, Pandemic

COVID-19 Mortality Data in High Altitudes

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As the COVID-19 pandemic continues and new strains are being discovered every day, there is a rush in the world of science and medicine to uncover how to best prevent and treat those who have been affected. This is a worldwide problem, not solely isolated in one location. However, because the world is not uniform and environments and terrains people live in differ, are there those who live in certain areas better adapted to fighting off COVID compared to others if they were exposed? There have been rumors that those living in high altitudes (2,500m+) have some risk reduction factors associated with less infection and lower COVID-19-related mortality. One example is that people living in high altitudes have physiological traits such as increased erythropoietin production seen within their tissues that decreases the effects of COVID-19 on the human body.

A study was conducted in Ecuador between March 2020 and March 2021 to find a relationship between altitude and COVID-19 mortality rates. This study compared 221 cantons in Ecuador ranging from sea level to above 4,300 meters. Each canton was categorized as either low, moderate, high, or very high altitudes based on their location. During the one year of study, trends based on all-caused deaths and deaths relating to COVID-19 were collected and recorded. At the end of the study, it was shown that there was a 24% higher mortality rate in cantons located below 2,500m of altitude compared to cantons located above 2,500m of altitude. 1 However, when this was broken down into narrower categories, it was found that cantons located at “high altitudes” reported the second highest mortality rates due to COVID-19 compared to cantons located at “moderate and very high altitude” which reported the lowest mortality rates due to COVID-19. These results were confusing and showed conflicting information. In addition, two studies done in America and Peru showed that altitude had no protective factors against COVID-19 mortality rates, while another study in Peru demonstrated that there were “strong protective effects of altitude” against COVID-19. 2,3,4

Mixed results and debates have occurred regarding altitude and COVID-19 mortality rates since studies in this area have been limited. Multiple factors that were not accounted for in different studies could be the reason why. Overestimation, underestimation, unreported, and undiagnosed cases can greatly affect the statistics. Not accounting for underlying illnesses such as diabetes or cancer in relation to COVID-19 deaths is another factor that can contribute to the discrepancies in the research. Not to mention, there were some obvious reasons that may contribute to low mortality rates due to COVID-19, too. Two being that there may be a lower population density in higher altitudes compared to cities/countries near sea level resulting in reduced spread of the virus and that there may be less chronic conditions with people living in higher altitudes that are not exacerbated when they are exposed to COVID-19.

Ultimately, few studies have been conducted relating COVID-19 mortality rates to people living in high altitudes. A variety of theories were proposed as to the reason why people living in higher altitudes have a lower mortality rate when exposed to COVID-19, but the sample size and methods used to conduct the research led to gaps in the study. These gaps were refuted resulting in starting at square one again. Until there is more research done, and more data is collected, we cannot conclusively say that those living in higher altitudes have a lower mortality rate when exposed to COVID-19 compared to those who live at altitudes below 2,500m. The corona virus continues to evolve every day and is still affecting the lives of millions. If the virus continues at this rate, more research could be done to see if people living in high altitudes have protective factors against the virus. However, the main goal is to find a cure against this virus. This area of study can change how people live, and high altitude environments may be the next location people will want to move to.

References

  1. Ortiz-Prado E, Fernandez Naranjo RP, Vasconez E, et al. Analysis of Excess Mortality Data at Different Altitudes During the COVID-19 Outbreak in Ecuador. High Alt Med Biol. 2021;22(4):406-416. doi:10.1089/ham.2021.0070

2. Cardenas L, Valverde-Bruffau V, Gonzales GF. Altitude does not protect against SARS-CoV-2 infections and mortality due to COVID-19. Physiol Rep. 2021;9(11):e14922.             doi:10.14814/phy2.14922

3. Woolcott OO, Bergman RN. Mortality Attributed to COVID-19 in High-Altitude          Populations. High Alt Med Biol. 2020;21(4):409-416. doi:10.1089/ham.2020.0098

4. Thomson TM, Casas F, Guerrero HA, Figueroa-Mujíca R, Villafuerte FC, Machicado C.             Potential Protective Effect from COVID-19 Conferred by Altitude: A Longitudinal Analysis      in Peru During Full Lockdown. High Alt Med Biol. 2021;22(2):209-224.     doi:10.1089/ham.2020.0202

 Alex Fan was born and raised in Southern California. It was his grandmother who led him on the path towards medicine. In his free time, he enjoys going to the beach, trying new food locations, playing volleyball, and catching up with friends and family. He is currently a Drexel PA Student hoping to work with the underserved community in the near future. 

Acclimation, Altitude Science, Doc Talk, Health, High Altitude, Sleep at Altitude

How do you define a good night’s sleep? : An Introduction to the SleepImage Ring, An Interview with Dr. Neale Lange

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Dr. Neale Lange is a leader in sleep medicine who started his medical training in South Africa and now practices Pulmonary and Sleep Medicine for UCHealth in Denver.

Sleep plays a crucial role in cognitive behavior and physical well-being but is often times taken for granted. As Dr. Neale Lange puts it, many people have been taught or trained to devalue sleep in an effort to maximize the time awake to study, get caught up on work, or complete other tasks1. However, research over the years has demonstrated that the toll sleep deprivation plays on the body is significant. Sleep deprivation can lead to impairment in memory, cognition, and emotion, and can lead to chronic medical conditions such as diabetes, heart disease and cancer2. It is also thought that sleep deprivation and hypoxemia are associated with white matter disease in the brain and deep slow wave sleep, is what fixes it4.

Furthermore, Dr. Lange states that sleeping at altitude carries its own risks. Sleeping at altitude, where there is less oxygen in the air, can cause overall poor sleep quality, increased awakenings, frequent arousals, marked nocturnal hypoxia and periodic breathing.. Additionally, sleeping at altitude can negatively impact our sleep architecture, increasing the amount of light sleep and decreasing the amount of deep slow-wave and REM sleep which plays a key role in memory creation, retention and emotional control and personal behavior3.

In hopes to defining a person’s sleep at altitude, Dr. Lange started a sleep lab in Summit County at St. Anthony Summit Hospital, which, as he put it, “opened a can of worms” when he saw how sick and complicated patients sleep apnea cases were. Time and time again, he saw that when patients who were struggling with sleep apnea were given 2L of supplemental oxygen by nasal cannula, the apnea improved. Additionally, those patients with sleep apnea who descended around 4,000 ft to Denver have improved saturations but may still have sleep apnea. His facility study included baseline tests at two hours without oxygen and then two hours with oxygen while a person slept. He found that although the apnea improved in many, improvements in sleep itself did not always follow.

This left him with the question of: How do we measure “good sleep?” Well, as he states, it is not that simple. Though the obvious answer may be to turn to medications to determine good sleep, this can be misleading. Medications have an amnestic effect on people because when they wake up in the morning, if their memory is blank, they feel that they have had a good night’s rest. But in reality, this is subjective. The true data collected during sleep is objective, so to answer his question of measuring sleep, he turns to a tool of cardiopulmonary coupling (CPC). This tool, called a SleepImage Ring, looks similar to an Apple Watch and is worn around a patient’s finger throughout the night. Using Bluetooth technology, data is collected and transferred through a smartphone for analysis, providing the patient with a vast amount of data about their sleep.

The SleepImage System is the only FDA approved medical grade technology with the simplicity of a consumer device on the market for use in both children and adults. It is intended for use by a healthcare professional to establish a patient’s sleep quality and aid in evaluation and clinical diagnosis of sleep disorders and sleep disordered breathing, or SDB. It uses CPC technology which is “based on calculations and spectral analysis of cardiovascular- and respiratory data” collected during sleep using continuous “normal sinus rhythm ECG- or PLETH (Plethysmogram from a PPG sensor) signal as the only input requirement.” The output metrics from the SleepImage System include “sleep duration (SD), total sleep time (TST), wake after sleep onset (WASO) and sleep quality (SQI) and sleep disordered breathing (SDB) related output metrics that include an Oxygen Desaturation Index (ODI), an Apnea Hypopnea Index (sAHI), a Respiratory Disturbance Index (sRDI), Central Sleep Apnea Index and the Sleep Apnea Indicator (SAI) that is derived from Cyclic Variation in Heart Rate (CVHR)6. With a PLETH signal including saturations, the SDB data conforms with the American Academy of Sleep Medicine AHI scoring and severity definitions.” Additionally, we can determine how long a patient spends in various sleep stages, including stable, unstable and REM sleep, determine apnea events, and autonomic nervous system activity. The data is generated and presented on the SleepImage Quality Report (shown below). The ring and report are designed as such where you can do individualized, precise sleep medicine. It is true when Dr. Lange says “the devil is in the details” referring to the vast amount of information that can be analyzed from this device during one night of sleep.

Currently, the gold standard to monitoring and diagnosing sleep disorders is polysomnography, also known as a sleep study, which records certain body functions as you sleep to determine brain activity, oxygen, heart rate, breathing, as well as eye and leg movements5. It can detect types of sleep apnea; however, this comprehensive test is typically done during an overnight stay in a hospital or other sleep center, which presents a disadvantage. The disadvantage to polysomnography is that it takes people out of their natural sleeping environment, is costly, and time consuming, which deter a large portion of people from partaking in sleep studies.

Dr. Neale Lange explains that this device can change the way we look at our sleep and may provide better insight into a person’s sleep on a greater scale due to the ease of wearing the device over multiple nights, compared to spending one night in a sleep lab for a study. A study done on 65,000 users indicated that there is added benefit to multi-night testing as compared to single night testing. Testing for sleep apnea on only one night has been shown to vary from night to night, indicating that single night testing potentially misclassifies 20% of people7. This device provides the ease of multi-night testing for patients, which is a significant advantage and increases accurate diagnosis of sleep disordered breathing. To Dr. Lange, “it is about individualized patient care” and evaluating “the person sitting in front of [him]” which makes this device so valuable. Dr. Lange states that, “living at altitude is a particular challenge, and if people are thinking ahead,” instead of wondering, “how long do I want to live at altitude,” a better question would be, “how can I invest in brain wellness.”

In summary, sleep deprivation, especially at altitude, is an important focus that people should not overlook. At Ebert Family Clinic in Frisco, one of the most important questions asked is, “how did you (or your child) sleep last night?” Now, with the SleepImage Ring, we can objectively evaluate our patient’s sleep which can aid in the diagnosis and management of various conditions.

References

  1. South African Dental Association. (2021, November 25). The sleep disorder spectrum: Mouth breathing to Osa – Dr Neale Lange (WEB126). YouTube. Retrieved December 5, 2021, from https://www.youtube.com/watch?v=agZruGNfFNI
  2. Irish, L. A., Kline, C. E., Gunn, H. E., Buysse, D. J., & Hall, M. H. (2015). The role of sleep hygiene in promoting public health: A review of empirical evidence. Sleep medicine reviews, 22, 23–36. https://doi.org/10.1016/j.smrv.2014.10.001
  3. Wickramasinghe, H., & Anholm, J. D. (1999). Sleep and Breathing at High Altitude. Sleep & breathing = Schlaf & Atmung, 3(3), 89–102. https://doi.org/10.1007/s11325-999-0089-1
  4. Voldsbekk, I., Groote, I., Zak, N., Roelfs, D., Geier, O., Due-Tønnessen, P., Løkken, L. L., Strømstad, M., Blakstvedt, T. Y., Kuiper, Y. S., Elvsåshagen, T., Westlye, L. T., Bjørnerud, A., & Maximov, I. I. (2021). Sleep and sleep deprivation differentially alter white matter microstructure: A mixed model design utilizing advanced diffusion modelling. NeuroImage, 226, 117540. https://doi.org/10.1016/j.neuroimage.2020.117540
  5. Mayo Foundation for Medical Education and Research. (2020, December 1). Polysomnography (Sleep Study). Mayo Clinic. Retrieved December 25, 2021, from https://www.mayoclinic.org/tests-procedures/polysomnography/about/pac-20394877#:~:text=Polysomnography%2C%20also%20called%20a%20sleep,leg%20movements%20during%20the%20study.
  6. MyCardio LLC. (2021, November 24). Introduction to sleepimage®. Retrieved December 10, 2021, from https://sleepimage.com/wp-content/uploads/Introduction-to-SleepImage.pdf
  7. Lechat, B., Naik, G., Reynolds, A., Aishah, A., Scott, H., Loffler, K. A., Vakulin, A., Escourrou, P., McEvoy, R. D., Adams, R. J., Catcheside, P. G., & Eckert, D. J. (2021). Multi-night Prevalence, Variability, and Diagnostic Misclassification of Obstructive Sleep Apnea. American journal of respiratory and critical care medicine, 10.1164/rccm.202107-1761OC. Advance online publication. https://doi.org/10.1164/rccm.202107-1761OC

Catherine Atkinson is a second-year Physician Assistant student at Red Rocks Community College in Arvada, CO. She was born and raised in Colorado where she has lived her entire life. She received her undergraduate degree in integrative physiology from The University of Colorado- Boulder. Prior to PA school, she was an ophthalmic technician at Colorado Retina Associates. In her free time, she loves cooking, skiing, playing golf and spending time with her family and friends. 

Acclimation, Altitude Science, Health, High Altitude, Medicine, Mountaineering

How to Stay Healthy During Your Holidays at High Altitude

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Acute Altitude Illness affects about 7.4% of travelers to mountain resort areas, including Frisco, Colorado which sits at an altitude of about 2800 meters. Dr. Kendrick Adnan, MD, MSPH is an emergency medicine physician associated with Vail Health. Dr. Adnan often sees visitors to Vail and other popular ski and vacation areas in Summit County that are experiencing Acute Altitude Illness. I sat down with Dr. Adnan, and we discussed the treatment of Acute Altitude Illness as well as signs, symptoms, risk factors, and prevention of Acute Altitude Illness.

What causes Acute Altitude Illness?

  • Acute Altitude Illness develops when the body responds to hypoxia, a low level of oxygen in the blood. Areas of high altitude have a lower concentration of oxygen in the air than lower altitudes, which makes your body work harder to put oxygen in your blood. Your body responds to the lower oxygen concentration by increasing how often and how deeply you breathe. This causes a decrease in carbon dioxide and increase in tpH in the blood. Your heart, lungs, blood vessels, and kidneys all respond to the low pH in your blood, which can cause the signs and symptoms of Acute Altitude Illness.
  • Some people will experience severe forms of Acute Altitude Illness called High-Altitude Pulmonary Edema or High-Altitude Cerebral Edema. These are life-threatening conditions that can cause death in both adults and children if not treated promptly by a medical professional.

What are the signs and symptoms of Acute Altitude Illness in adults?

  • Headache
  • Nausea
  • Vomiting
  • Decreased appetite
  • Fatigue
  • Shortness of breath on exertion
  • Decreased exercise tolerance
  • Chest tightness
  • Hypoxia

What are the signs and symptoms of Acute Altitude Illness in children?

  • Fussiness
  • Poor feeding
  • Pale or blue-tinged skin
  • Sleeping too much or too little

What is the treatment for Acute Altitude Illness (AAI)?

The best treatment for AAI is supplemental oxygen through a nasal cannula and descent to a lower elevation. You will need to visit a healthcare provider, clinic, or hospital to get supplemental oxygen if your oxygen level drops below 89%. Visitors to high-altitude areas may be hesitant to abandon their vacation plans in order to descend to a lower altitude. A healthcare provider may be able to prescribe medications to help you recover from AAI. However, if your low oxygen level does not improve with supplemental oxygen and medication, it is important to descend to an area of lower altitude.

Studies show that acetazolamide, dexamethasone, and tadalafil are medications that can potentially treat Acute Altitude Illness and/or High-Altitude Pulmonary Edema. A healthcare provider may prescribe these medications for you if appropriate.

What increases the chance that I will experience Acute Altitude Illness?

  • Traveling by airplane from low altitude to high altitude.
  • Being a resident of low altitude
  • Past episode of Acute Altitude Illness
  • Physical exertion at high altitude, especially in colder temperatures

What can be done to prevent Acute Altitude Illness and High-Altitude Pulmonary Edema?

  • A slower ascent will decrease your risk of AAI. Dr. Adnan recommends spending the night in Denver after air travel if you are planning to visit a high-altitude area.
  • Avoid strenuous exercise like skiing, hiking, and mountain biking for 48-72 hours after arrival to a high-altitude area.
  • Buy a pulse oximeter to check your oxygen level. A level above 89% is normal at high-altitude and does not require treatment.
  • Ask your healthcare provider about taking Diamox (acetazolamide) for 2-3 days before you arrive at a high-altitude destination. You will need a prescription for this medication.
  • Avoid medications that decrease your respiratory rate like opiates, sleeping medications, benzodiazepines, and barbiturates.

References

Schafermeyer, R. W. DynaMed. Acute Altitude Illnesses. EBSCO Information Services. https://www.dynamed.com/condition/acute-altitude-illnesses. Accessed November 19, 2021. Simancas-Racines D, Arevalo-Rodriguez I, Osorio D, Franco JVA, Xu Y, Hidalgo R. Interventions for treating acute high altitude illness. Cochrane Database of Systematic Reviews 2018, Issue 6. Art. No.: CD009567. DOI: 10.1002/14651858.CD009567.pub2. Accessed 03 November 2021.

Sasha Scott is a physician assistant student at Drexel University in Philadelphia, PA. She is originally from Indianapolis, IN and attended Purdue University for undergrad. Sasha enjoys running, cross stitching, cooking, and exploring Philadelphia when she is not studying!

Genetics, Health, High Altitude, Medicine

Carotid Body Tumors at High Altitude

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Carotid body tumors (CBTs) are more common at higher altitudes. It also has been proposed that altitude can play a role in the genetic mutations that cause CBTs to form in the inherited types of CBTs. How might altitude affect the genetics of CBT formation?

The carotid body is a peripheral nervous system sense organ. It is located bilaterally at the bifurcation of the common carotid artery, between the internal and external carotid arteries. The carotid body helps maintain physiologic homeostasis with the help of its sensory chemoreceptors. These sensory chemoreceptors “detect changes in the quality in the composition of arterial blood flow, such as pH, CO2, temperature, and partial pressure of arterial oxygen” (Forbes & Menezes, 2021). The carotid body therefore responds to states of hypoxia, hypercapnia and acidosis.

Carotid body tumors (CBTs) are rare paragangliomas of the head and neck. Sporadic, familial and hyperplastic are the 3 different forms of CBTs.  The hyperplastic form is most prevalent in patients who are in chronic hypoxic states. Chronic hypoxic states are seen in patients with COPD or cyanotic heart disease. However, chronic hypoxic states are also seen in people who live at high altitude. The only known risk factors for developing a carotid body tumor include chronic hypoxia and genetic predisposition. The only treatment for CBTs is surgery, which is a very challenging surgery due to the complex location of CBTs by a main vessel, the carotid artery.

This is an image of an MRI showing carotid body tumors (Burgess et al., 2017)

Risk for CBT’s are related to different altitudes. Prasad et al. (2019) stated the prevalence of CBTs were increased at altitudes exceeding 2000 feet of above sea level where as Chaaban (2021) states CBTs are more common in people living at altitudes exceeding 5000 feet above sea level.  The big question becomes why are CBTs more prevalent at altitude? Forbes & Menezes (2021) found that the Carotid body plays a role in the acclimation to high altitude in regards to ventilation, respiratory rate and oxygen levels. At increasing altitudes, there is less oxygen in the air. This leads to a hypoxic state and causes the respiratory rate to increase. The Carotid body itself is responsible for detecting the low oxygen level at high altitude and then increasing the respiratory rate. There may be a chronic hypoxic state as acclimation to high altitude occurs. There also may be a defect in oxygen sensing by the carotid body, which worsened by moderately high altitudes (Astrom et al., 2003). Hyperplasia of the glomus cells of the Carotid body occurs due to the chronic hypoxia and cellular proliferation can occur due to the defect in oxygen sensing. Hyperplasia and cellular proliferation can then lead to tumor formation. It is even found that patients with multiple tumors, like having bilateral CBT’s (as pictured on the MRI imaging) at first time of diagnosis live at higher altitudes, with longer duration of high altitude residence. (Astrom et al., 2003).

CBTs are rare and some surgeons may only see a few CBTs in their career. According to two ENT surgeons in Lakewood, Colorado at a Level I Trauma center, they have encountered many more CBTs in Colorado in their career than in other places at lower altitude. Peter McGuire, MD has been practicing in Colorado for over 5 years as an ENT surgeon. He has encountered about 5-10 CBTs since being in Colorado (P. McGuire, MD, personal communication, November 9, 2021). He states he has only encountered two at lower altitude. When talking to Erin Roark, FNP, who practices alongside ENT surgeon Christopher Mawn, MD, in the 10 years they have been working together in Colorado they have encountered about 15-20 CBTs. (E. Roark, FNP, personal communication, November 10, 2021).

There is evidence that altitude can affect gene mutations. “It has been proposed that environmental hypoxia modulates genetic predisposition to CBP” (Praasad et al., 2019). It has been found that CBTs that develop at high altitudes have been associated with the penetrance, expressivity, and population genetics of what are considered inherited CBTs. Again, cellular proliferation can occur when there is a defect in oxygen sensing by the carotid body and this defect in oxygen sensing can be worsened by moderately high altitudes. This causes cellular proliferation, increased number of actively dividing cells and increased likelihood of an alteration of the DNA sequence (Astrom et al., 2003). An alteration of the DNA sequence is also called a second-hit somatic mutation. “Therefore, living at higher altitudes is expected to facilitate the development of independent tumor foci that develop clonally following the second-hit mutation” (Astrom et al., 2003).

Many questions remain regarding the increased prevalence of CBT’s at altitude. Research is needed to determine if an existent CBT grows when the patient moves from an area of low altitude to an area of high altitude. Genetic studies looking for underlying predispositions to these tumors and other conditions related to altitude will continue to be fundamental.

For more another article related to genetics and altitude see blog entry from December 2019 on aural atresia.

References

Astrom, K., Cohen, J. E., Willett-Brozick, J. E., Aston, C. E., & Baysal, B. E. (2003). Altitude is a phenotypic modifier in hereditary paraganglioma type 1: Evidence for an oxygen-sensing defect. Human Genetics, 113(3), pp. 228-237. https://doi.org/10.1007/s00439-003-0969-6.

Burgess, A., Calderon, M., Jafif-Cojab, M., Jorge, D., & Balanza, R. (2017). Bilateral carotid body tumor resection in a female patient. International Journal of Surgery Case Reports, 41, 387-391. https://doi.org/10.1016/j.ijscr.2017.11.019

Chaaban, M.R. (2021). Carotid body tumors. Medscape. Retrieved November 7, 2021 from https://emedicine.medscape.com/article/1575155-overview#a8.

Forbes, J. & Menezes, R. (2021). Anatomy, head and neck, carotid bodies. StatPearls Publishing. Retrieved November 7, 2021 from https://www.ncbi.nlm.nih.gov/books/NBK562237/.

Pacheco-Ojeda, L. A., MD. (2017). Carotid body tumors: Surgical experience in 215 cases. Journal of Cranio-Maxillo-Facial Surgery, 45(9), pp. 1472-1477. https://doi.org/10.1016/j.jcms.2017.06.007.

Prasad S., Paties C., Pantalone M., et al. (2019). Carotid body and vagal paragangliomas: Epidemiology, genetics, clinicopathological features, imaging, and surgical management. In: Mariani-Costantini R. (Ed.), Paraganglioma: A Multidisciplinary Approach (ch. 5). Brisbane (AU): Codon Publications. doi: 10.15586/paraganglioma.2019.ch5. Retrieved November 7th, 2021 from https://www.ncbi.nlm.nih.gov/books/NBK543230/.

Katelyn Guagenti is a FNP student at the University of Cincinnati. She graduates December 10, 2021. She lives in Lakewood, CO and she plans to work with Dr. Christopher Mawn and Dr. Peter McGuire at Aspen Ridge ENT clinic after graduation. In her free time she likes to do CrossFit, hike, ski, snowmobile, and any other activity that involves hanging out with her Husband, Vincent, and dog, Judd. Most of all she loves to go to Grand Lake, CO, her favorite place here in beautiful CO. 

Acclimation, Altitude Science, Health, High Altitude, Hyperbaric Therapy, Medicine, Surgery, Technology

Wound Healing at High Altitude: Hyperbaric Therapy, A Patient’s firsthand experience with post-surgical wound healing in Summit County

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The nuances of wound healing at high altitude is a topic that has already been explored on this platform (see Eric Meiklejohn’s “Wound Care at Altitude”). Identifying the impact that impaired oxygen delivery can have on healing time, tissue regeneration, and infection rates offers great insight into the roles health care providers can assume to support our high-altitude patients. For this interview, I was able to speak directly with  a Summit County resident who had firsthand experience with these processes.

I’ve heard a bit about your experiences with wound healing at high altitudes I will ask some preliminary questions,. This entire experience was more of a marathon than a sprint. How long have you been living at this altitude, and how old were you at the time of your procedure? I’d lived at high altitude for over twenty-six years before I was diagnosed with breast cancer. I was Fifty-three when I had my surgery. I was in great shape, exercising regularly, and eating really well.

Tell me about your procedure: Well, the initial procedure was in January 2018 down in Denver. I had a bilateral mastectomy done to remove the cancerous tissue, and bilateral expanders were inserted during that surgery so that down the line I could have implants placed. Within the first week we started noticing some necrotic changes to my incisions, and that they were not healing well. The expanders were inflated with air, and it was thought that my traveling back to high altitude from Denver could have increased the pressure inside them.  By the end of week one I went back in to see my doctor, who deflated my expanders pretty significantly.

Have you ever been diagnosed with a medical condition that could affect wound healing, such as Diabetes or Hypertension? No. Breast Cancer was my first real medical diagnosis.

Had you ever had surgery while living at this altitude before? And if so, what was the outcome? Yes, I’d had surgery for an umbilical hernia and that went very well. No complications at all, everything healed just fine. I’d also had tendon damage in my right hand after a fall, and I recovered really well after that surgery at this same altitude.

Regarding healing after your mastectomies, describe the anticipated wound healing time and wound care directions. The time estimate for  recovery was four weeks. I was to rest for two weeks, increase activity slightly for the second two weeks with minimal physical therapy, then by the end of that fourth week the projection was that I would be mostly recovered. I was given strict precautions against heavy lifting, restricting arm movements, and not driving. For wound care I was doing daily dressing changes, not submerging the area in water, and applying Silvadene cream twice daily.

Following the removal of the expanders, what was the rest of the healing process like? Over the next two months I cared for my wounds at home. They were open and oozing, and over time the daily dressing changes and medication applications became quite taxing, both physically and emotionally. It took a lot out of me, and really interfered with my day-to-day life…not to mention the pain. On March 9th, 2018 I underwent an incision revision and resection procedure for the necrotic tissue. At that point my breast tissue had manifested itself as far as which parts were healthy and which would die, so they went in and resected the areas that were not viable. On the left side I lost most of the top surface of the breast, including the entire nipple area. Two weeks after that, I had a [chemo therapy] port placed in my arm  so I could begin treatments, but that incision also had a difficult time healing. That eventually led to a one month delay in my chemo therapy.

In March and April the incisions on the right breast eventually healed, but because of all the tissue loss and necrosis on the left side those wounds did not heal. There was still a lot of drainage from that breast and it was mostly still open so I had to keep the bandage on. By early May (after this wound had been open for 5 straight months) my doctor and I started seeing more signs of infection to that breast, so around May 12th of 2018 he called me in for an emergency procedure and I had the expander completely removed from my left breast. I continued chemo and eventually that left side began to heal in the absence of the expander.

During this time, from March until I finished chemo in August, the port site never healed. The whole reason behind having the port placed was so it could heal over and I could go back to a normal life between chemo sessions. But instead I walked around with a bandage for those six months because my port site remained open. I had Her2 positive cancer, so after my six months of chemo I needed to continue taking Herceptin for one additional year. I opted to have the port removed after six months and had an IV placed every three weeks for my treatments. It was very hard on my veins, but I felt I had no choice.

In late August, with the port out and the left expander out, the last of my open wounds really started healing. I started looking at what I could do to help my tissue heal even better- my thought was that when this is all done and I am all well healed I would like to have my expanders placed and inflated again, but I don’t want to have to go backwards through this process. I did all this research, and that’s where I learned about hyperbaric therapy. That changed everything for me.

What did you learn about Hyperbaric therapy, and what was your experience with it? I did a lot of independent research online and came up with two options that I wanted to discuss with my doctor. The first was a topical option for applying oxygen directly to the wound, which was a very complicated and involved process -and the second was hyperbaric therapy.

I discussed this with my oncologist who was very familiar with hyperbaric chamber treatment centers in Denver, and who wrote me a referral to be evaluated at the one in Presbyterian St. Luke’s Medical Center. I was evaluated by their team, showed them all the photos I had been taking throughout this entire ordeal, and they seemed hopeful that they would be able to help me. I really wish I’d gone there sooner.

My plan was to use this to help me recuperate a little bit so I could give the expander one more shot on the left side. After having the left expander placed, the second phase of my plan was to get another course of hyperbaric therapy to aid in recovering from that procedure. It was eventually prescribed and accepted by insurance, who approved 27 hyperbaric sessions following my surgery.

I underwent the left expander placement in February of 2019, observed the same restrictions, and had identical at-home wound care as my initial surgery in January 2018, but with the addition of hyperbaric therapy my results were night and day. The day after surgery I started hyperbaric, and in so much less pain. I was off all pain medications within 48hours. I was able to get out, walk, function in my daily life, and the tissue healed really well. It was amazing! I felt great, had tons of energy, and it was just a completely different experience. It was nothing short of miraculous.

What was your hyperbaric chamber treatment like? It was five days a week in Denver. Being there was for me a huge learning experience. There were people there being treated for diabetic wounds, hearing loss, adjunct therapy for various types of cancer, joint and tendon disease, tissue necrosis, concussions, head trauma, and so many other things. I hadn’t known that this therapy could be utilized in all these different areas.

After your successful left expander placement, how was your transition to breast implants? Months after the left expander was reinserted, I did transition to breast implants (summer 2019) but even then, I insisted on post operative hyperbaric therapy. I was only approved for ten sessions that time, but the results were the same. Rapid healing time, noticeable decrease in pain after starting therapy, and the ability to function throughout the day. Of all the factors that played a role in this process for you, what variable would you most want to adjust? Honestly, I just wish I’d started hyperbaric therapy sooner. If there was a way to get providers who work with high altitude dwellers to recommend hyperbaric treatment as a part of their primary or secondary treatment course, that’s the one thing I would change.Well, I am very happy to know that despite the difficulty you experienced in this process, you are now three years post op, well healed, and satisfied with your results. Thank you again for sharing your story. My pleasure. If my sharing can help someone else find hyperbaric therapy or open them up to alternative methods of treatment sooner so as not to have to experience what I went through in those first few months, then it was all worth it.

Janell Malcolm is a second year Physician Assistant student in the Red Rocks PA Program in Arvada, Co. A Jamaica native, she loves the ocean, tropical fruit, and 100 degree weather. You will likely find her spending her free time with family or reading/re-reading Jane Eyre. Her personal and career goals are geared towards providing adequate medical care to underserved communities. Special interests post graduation: Labor & Delivery, General Surgery.

Acclimation, Altitude Science, Genetics, Health, High Altitude, Mountaineering

Effects of High Altitude on Brain Metabolism & Concussion Information

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Changes in altitude have many effects on the physiology of the human body and even metabolism. Some people exposed to high altitude develop acute or chronic mountain sickness due to hypoxia with a spectrum of symptoms including neurocognitive decline of performance and impacting brain function. Head truma at altitude is more likely to lead to brain injury or concussion than those at low altitude.

Imaging with PET/CT using FDG-18 has been used to measure brain metabolism in both human and mice subjects. This type of imaging scans the accumulation of a glucose analog in tissue, specifically the brain in this case. This allows determination of which regions have high or low uptake in metabolism in comparison to a brain at baseline at sea level.

In 2017, mice were studied by being placed in a hypobaric chamber to stimulate hypoxic conditions similar at 5000 meters. Conditions were placed to minimize brown adipose tissue uptake and imaging was performed 45 minutes after an estimated 0.5 mCi FDG injection. After appropriate processing, the results showed an increase in glucose metabolism in the cerebellum and medulla of the mice exposed to high altitude conditions compared to those at baseline. Additionally, certain cortical regions had lower metabolism than baseline mice, and lower cardiac uptake as well. It is thought that the brain’s acclimation response to high altitude.

Images courtesy of Jaiswal S., et al. JNM 2017.

Another study using mice as subjects compared brain metabolism at high altitude after a traumatic brain injury (TBI) to determine if hypoxia alters glucose uptake. A total of 32 mice were imaged at sea level (baseline) and again after 12 weeks exposure at 5000m (hypobaric stimulation), and again after a repetitive closed injury. An SUV (standard uptake value) was compared in each set of images to determine a change in glucose metabolism. 

This study showed a significant increase in FDG uptake in the medulla, cerebellum, and pons, and a decreased uptake in the corpus callosum, cortex, midbrain, and thalamus. A TBI affects glucose metabolism in the brain by decreasing cortical uptake in both high altitude and sea level. This study showed that high altitude affects the brain by making it more susceptible to repeated concussions than mice at sea level.

A third study employed PET/CT imaging to assess regional cerebral glucose metabolism rates in six US Marines before and after a rigorous training period from sea level to high altitude conditions ranging from 10,000-20,000 ft. It was thought that other conditions would be relatively stable as the military has similar regimens for their members. After comparing imaging performed at baseline sea level and after two months of high-altitude exposure, it was clear that brain metabolism changed. There was a decrease in glucose metabolism in three frontal regions, left occipital, and right thalamus. Right and left cerebellum showed an increase in glucose uptake and metabolism.

Red and orange coloring signifies greater FDG-18 uptake which correlates to increased glucose metabolism. The post imaging signifies decreased uptake and hypometabolism of certain brain regions as mentioned previously. Image courtesy of Hochachka PW., et al. AJP, 1999.

The data from these three studies clearly show high altitude exposure with hypoxia changes the way our brain tissue metabolism functions. Studies show Sherpas, native to the Himalayas are the most well adapted high-altitude humans.  Their brain metabolism is the same of that of “low-landers”. Conversely, the Quechuas who are native to the Andes of South America still show small amounts of hypometabolism in their brain. As mentioned previously, it is unknown how long it takes for humans to fully acclimate regarding brain metabolism.

These studies indicate the need for more research regarding brain metabolism and function.  Glucose metabolism is crucial for proper functioning of the brain, its neurons, and other regulatory functions. This brings into question what type of impact high altitude may have on the cognitive functions of the brain in people who move or even live at high altitude. Additionally, the fact that the human brain is more prone to injury or developing a concussion, safety should be a consideration for those involved in high impact sports at high altitude.

References

1.      Jaiswal S, Cramer N, Scott J, Meyer C, Xu X, Whiting K, Hoy A, Galdzicki Z, Dardzinski B.  [18F] FDG PET to study the effect of simulated high altitude on regional brain activity in mice. Journal of Nuclear Medicine May 2017, 58 (supplement 1) 1246.  https://jnm.snmjournals.org/content/58/supplement_1/1246

2.      Jaiswal S, Knutsen A, Pan H, Cramer N, Xu X, Dardzinski B, Galdzicki Z, Allison N, Haight T. FDG PET study showing the effect of high altitude and traumatic brain injury on regional glucose uptake in mice.  Journal of Nuclear Medicine May 2019, 60 (supplement 1) 180. https://jnm.snmjournals.org/content/60/supplement_1/180

3.      Hochachka PW, Clark CM, Matheson GO, et al. Effects on regional brain metabolism of high-altitude hypoxia: a study of six US marines. Am J Physiol. 1999;277(1):R314-R319. doi:10.1152/ajpregu.1999.277.1.R314.  https://pubmed.ncbi.nlm.nih.gov/10409288/

Roberta Grabocka is a second-year physician assistant student at Red Rocks Community College’s PA Program in Arvada, Colorado. Roberta attended Stony Brook University in Long Island, NY for her degree in Health Science and received a post-baccalaureate degree in Nuclear Medicine Technology. She practiced for 3 years as a Nuclear Medicine Technologist in multiple hospitals. This included working in oncological, cardiac, and general nuclear settings performing a variety of studies from PET/CTs, myocardial perfusion imaging, HIDAs, V/Qs, etc. Roberta decided to pursue a career as a Physician Assistant to expand her scope of practice and further her medical knowledge. In her free time, she likes to explore local culture and travel.

Acclimation, Altitude Science, Health, High Altitude

High-Altitude Pregnancy: An Overview of the Research Being Conducted by Dr. Lorna G. Moore and Colleagues

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*All figures and graphs seen in this post came directly from a presentation by Dr. Lorna G Moore from the Department of Obstetrics & Gynecology, University of Colorado School of Medicine on September 15, 2021 at Saint Anthony Summit Hospital

It is well known that women living at high altitudes often give birth to infants of lower birth weight than those living at sea level due in part to intrauterine growth restriction (IUGR). However, causes of fetal growth restriction at high altitude are not well understood. Dr. Lorna G Moore and her colleagues have found high altitude (>8,000ft) such as that of Summit County, Colorado provide a natural laboratory for studying the physiological mechanisms sustaining fetal growth and identifying new therapies for treating pregnancy disorders.1 In this article, I will be reviewing their findings on fetal growth and uteroplacental blood flow at high altitude, whether activation of an enzyme called adenosine monophosphate kinase (AMPK) is protective, and whether hypoxia directly or indirectly reduces fetal growth.

A baby’s birth weight is the single greatest predictor of infant mortality. Preterm birth and low birth weight were the second leading causes of infant mortality in 2018 according to the CDC.2 While infants born at high altitude in Colorado have, on average, lower birth weights, multigenerational populations of Andeans and Tibetans are relatively protected from altitude-associated birth-weight reductions. Studies completed over the last 25 years in regions of the world where populations have lived at high altitude for many millennia (i.e., Andeans, Tibetans, and Ethiopians) provide “evidence for genetic adaptation to high altitude” that have been linked to improved  “distribution of blood flow to vital organs and the efficiency of O2 utilization ”.

Uterine artery blood flow is crucial for reproductive success as it provides the necessary blood flow to the placenta and the fetus to meet their metabolic demands. Uterine artery blood flow increases 60-fold at low altitude but has a lesser increase in high-altitude newcomers in Colorado or elsewhere.1 In contrast, a normal pregnancy rise in uterine artery blood flow occurs in Andeans and Tibetans (Ethiopians have not been studied). 

A major factor responsible for increasing uterine artery blood flow is an increase in the diameter of the main uterine artery. Of 63 genes identified as having been acted upon by natural selection, an allele called “TT” for the gene PRKAA1 which codes for the portion of AMPK involved in that enzyme’s activation is more common in Andeans and is associated both with greater uterine artery diameter and increased birth weight at high altitude.1,4 Activation of AMPK causes the uterine artery to dilate, which Dr. Moore and colleagues hypothesized would increase uterine artery blood flow and thereby help maintain birth weight. At low altitude, one of the key factors responsible for raising uterine artery blood is increased production of the vasodilator, nitric oxide (NO), in the uterine artery. Their studies showed that nitric-oxide induced vasodilation fails to occur at high altitude but, interestingly, uterine artery vasodilation in response to AMPK activation is increased, suggesting that “AMPK activation may be compensatory for the lesser NO-induced vasodilation and helps maintain fetal growth”.4 To test this idea, they used a drug called AICAR to activate AMPK in mice that were kept in simulated sea level (SL) or high altitude (HA) conditions during pregnancy. Mice that were given AICAR at high altitude showed an increase in uterine artery diameter, blood flow, and the percent of cardiac output directed to the uterine circulation (UtA flow/cardiac output).1,6

They also found that AICAR restored approximately half of the altitude-associated reduction in fetal weight.1

Their current studies are trying to figure out how a reduction in uterine artery blood flow reduces fetal growth. Their and other persons’ data suggest that lower blood flow is not solely responsible. Since AMPK is not only a vasodilator but also (and best known as) a “metabolic sensor”, Dr Moore and colleagues think that AMPK may be playing a crucial role in linking blood flow to metabolism factors at high altitude. They are planning to continue studies examining the metabolic factors involved in pregnancy and how they act to affect vasoreactivity and fetal growth.1

References

  1. Moore LG. Using studies at high altitude (HA) to identify the causes and ultimately new treatments for pregnancy disorders. lecture presented at the: September 9, 2021. 
  2. Infant mortality. Centers for Disease Control and Prevention. https://www.cdc.gov/reproductivehealth/maternalinfanthealth/infantmortality.htm. Published September 8, 2021. Accessed September 28, 2021. 
  3. Moore LG. Measuring high-altitude adaptation. J Appl Physiol (1985). 2017;123(5):1371-1385. doi:10.1152/japplphysiol.00321.2017
  4. Skeffington KL, Higgins JS, Mahmoud AD, et al. Hypoxia, AMPK activation and uterine artery vasoreactivity. J Physiol. 2016;594(5):1357-1369. doi:10.1113/JP270995
  5. Lorca RA, Lane SL, Bales ES, et al. High Altitude Reduces NO-Dependent Myometrial Artery Vasodilator Response During Pregnancy. Hypertension. 2019;73(6):1319-1326. doi:10.1161/HYPERTENSIONAHA.119.12641
  6. Lane SL, Houck JA, Doyle AS, et al. AMP-activated protein kinase activator AICAR attenuates hypoxia-induced murine fetal growth restriction in part by improving uterine artery blood flow. J Physiol. 2020;598(18):4093-4105. doi:10.1113/JP279341

Zoe Heller is a second year Physician Assistant student from Red Rocks Community College in Arvada, CO. She was born and raised in colorful Colorado and received her undergraduate degree in biological sciences at the University of Colorado Denver. Prior to PA school she worked as a professional research assistant at the Barbara Davis Center and a medical assistant at Denver Endocrinology, Diabetes and Thyroid Center. When she’s not in clinic or studying, you can find her hiking, skiing, or sitting by a campfire at her mountain property “Coolsville” with her husband and two pups, Timber and Willa.

Altitude Science, Health, High Altitude

Wound Care at Altitude

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Traveling and living at altitude can make many physiologic processes just a little harder. If you have experience in the mountains, you may have noticed that simple cuts and wounds simply take longer to heal than down at sea level. This isn’t your imagination. Wounds can take a significantly longer time to heal while at altitude. This means routine wound care is more important to observe while at altitude.

Normal Wound Healing Process

Wound healing is a well-documented and well-described process. After an injury to the skin, the first step of healing involves creating a blood clot to seal the disrupted vessels. This step involves activation of circulating proteins that promote blood coagulation. Platelets bind together in a strong collection strengthened by coagulation proteins.

The next step of wound healing involves activation of inflammation. While inflammation is generally thought of as a bad thing, it is actually a crucial step in repairing tissues. White blood cells are attracted to the injured area where they can eliminate pathogens that have gotten into the wound. These white blood cells serve other functions as they help to lay down fibrin proteins and activate fibroblasts.

Fibrin and fibroblasts operate in the proliferation stage of wound healing. This stage is when proteins are laid down in the wound to serve as scaffolding for tissues. Blood vessels are then able to heal themselves. Skin cells then start to divide and fill in the area of the wound. After these steps, the collagen that was laid down as a scaffold rearranges itself into a tight matrix that will provide a strong foundation for the healing skin. All in all, the body goes through a few days of inflammation followed by several weeks of regrowing injured tissue.

Changes in Wound Healing at Altitude

Now the question at this point is, how does living at altitude interfere with this whole process? This is an area that is not very well studied, and research is ongoing to discover the impact of altitude on wound healing. What we do know is that wounds tend to take more time healing while at altitude than at sea level. The theory behind this delayed wound healing is due to impaired oxygen delivery at the site of the wound. Individuals with circulation problems like diabetes and arterial stenosis will have similarly delayed healing at wound sites. Furthermore, wounds farthest away from the heart tend to take the longest to heal (think fingers and toes). The coagulation and inflammatory processes will carry on as normal (as these steps don’t require oxygen to function properly); however, proliferation and maturation steps require considerable amounts of oxygen. This can prolong how much time is required in these different steps.

Consequences of Delayed Healing

Prolonged wound healing can lead to some significant consequences. The longer a wound stays open, the greater a chance it has at developing an infection. If a wound becomes infected, it can prolong the healing process even more, lead to more inflammation, result in pain, and even spread of the infection throughout the body. If the maturation phase is interrupted either by an infection or low oxygen state, it can lead to more scar formation and lower tissue strength.

General Wound Care Recommendations

Luckily, the recommendations for caring for a wound do not change while at altitude. It is still important to wash all wounds in clean water. Keep the wound covered with antibiotic jelly such as bacitracin or any over the counter triple-antibiotic ointment. Keep wounds dry and clean and covered with a bandage until it closes. If cuts are deep, they may need to be closed with sutures. Be aware of signs of infection. This would include redness of the wound, warmth, increased pain, purulent discharge, or red streaks radiating away from the wound. While discussing the implications of delayed wound healing at altitude with Dr. Christine Ebert-Santos at Ebert Family Clinic in Frisco, CO, she recommended that sutures closing lacerations remain in for a little longer. For facial lacerations, she recommends leaving them in for 7 days as opposed to the typical 5, and sutures elsewhere can remain in for 10 days. Consult with your regular medical provider if you are concerned with how any wounds are healing.

Sources

Balsa IM, Culp WT. Wound Care. Vet Clin North Am Small Anim Pract. 2015;45(5):1049-1065. doi:10.1016/j.cvsm.2015.04.009

Goodson WH 3rd, Lopez-Sarmiento A, Jensen JA, West J, Granja-Mena L, Chavez-Estrella J. The influence of a brief preoperative illness on postoperative healing. Ann Surg. 1987;205(3):250-255. doi:10.1097/00000658-198703000-00006

Janis JE, Harrison B. Wound healing. Plastic and Reconstructive Surgery. 2016;138. doi:10.1097/prs.0000000000002773

Eric Meiklejohn is a second year Physician Assistant student attending Red Rocks Community College in Arvada, Colorado. He received his undergraduate degree from Colorado State University. Prior to Physician Assistant school, he worked as an EMT both in the Emergency department and on the ambulance. In his free time, he enjoys cooking and spending time with his wife, Nicole, and his dog, Julie.

Acclimation, Altitude Science, Health, High Altitude, Medicine

The Nobel Prize: Hypoxia studies Won in 2019!

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The Nobel prizes are announced this month. Alfred Nobel invented dynamite in 1866. Within 30 years, Nobel made a large fortune from his invention. He demonstrated his passion for literature and science by creating a yearly prize to discoveries most beneficial to humankind. The five prize categories include physics, chemistry, medicine (physiology), literature and peace. The Nobel prize nominations are made by university professors, national assemblies, state governments, and international courts. The prize is awarded yearly to individuals who have discovered a new paradigm or a paradigm shift within their field. The prize recipients are declared on the first Monday of October of every year and the award is presented by the Nobel assembly on November 10th, the anniversary of Alfred Nobel’s death. The Nobel prize consists of a gold medal, a diploma of recognition of achievement, and a cash prize in the amount of $1 million U.S. dollars. 

There is no limit to the number of nominations that can be made or the number of times that an individual can be nominated. There were 400 candidates nominated in the field of medicine in 2019, all of which inspired, challenged, and demonstrated greatness in their field. In 2019 the Nobel Prize in Medicine honored three scientists for their discovery of the human body’s ability to adapt to low oxygen environments. 

Hypoxia is a state of which oxygen supply is insufficient for normal life functions, experienced by the human body at high altitude. Tissues and cells require a range of oxygen in order to survive. Oxygen is required by mitochondria, in all cells, to convert food into useable energy. “Otto Warburg, the recipient of the 1931 Nobel Prize in Physiology or Medicine, revealed that this conversion is an enzymatic process.” At low oxygen environments, as experienced at high altitude, the body must adapt in order to maintain basic cellular function. There are several mechanisms in the human body that increase oxygen concentration including breathing rate, regulated by the carotid body, increased heart rate, stimulated by the vagus nerve, and increased production of red blood cells (RBCs)  through the bone marrow, regulated by the kidney. 

The carotid body is a chemoreceptor near the carotid artery that detects oxygen, carbon dioxide and pH levels in the blood. At low oxygen, the carotid body relays an afferent (ingoing) signal to the the brain via the glossopharyngeal nerve. The medullary center in the brain then sends an efferent (outgoing) signal that increases the respiratory rate to maximize oxygen delivery to the brain. The carotid sinus is a baroreceptor near the aorta of the heart which senses changes in pressure. As pressure increases in the atmosphere, experienced at high altitude, the carotid sinus sends a signal along the vagus nerve to the brain which then increases the heart rate. “The 1938 Nobel Prize in Physiology or Medicine was awarded to Corneille Heymans for discoveries showing how blood oxygen sensing via the carotid body controls our respiratory rate by communicating directly with the brain.”

At low oxygen environments, the kidney increases production of erythropoietin, which stimulates RBC generation in the bone marrow,  called erythropoiesis, resulting in higher oxygen delivery to the brain and skeletal muscles needed at high altitude. Erythropoiesis was discovered in the early 20th century, however oxygen’s role in the process was not completely understood. The cell’s ability to sense and adapt to oxygen availability was discovered and explained by three scientists, William G. Kaelin Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza. 

2019 Nobel Prize, Physiology: 

Thanks to the work of Dr. Gregg L. Semenza and Sir Peter J. Ratcliffe, we now understand that the oxygen sensing mechanism that stimulates erythropoieten is present in all tissues, not just the kidney. Semenza conducted research on liver cells using gene-modified mice and found that a specific protein binds to an individual gene (the EPO gene), dependent upon oxygen availability. Semenza named the binding protein the Hypoxia-Inducible-Factor (HIF). The HIF protein was found to compose two transcription factors, HIF-1alpha and ARNT. In 1995, Semenza published his findings of the HIF protein. His work explained that when the body is at high oxygen environments, there is very little HIF-1alpha present within cells. At high oxygen availability, HIF-1alpha is rapidly degraded by a proteasome within cells. The degradation is signaled by a protein called ubiquitin which binds to HIF-1alpha at high oxygen, flagging HIF-1alpha for degradation by the proteasome. This process was recognized by the 2004 Nobel Prize in Chemistry, Aaron Ciechanover, Avram Hershko and Irwin Rose. 

The mechanism by which ubiquitin binds, causing the degradation of HIF-1alpha at high oxygen environments was explained by the work of William Kaelin, Jr. who conducted research on von Hippel-Lidau’s (VHL) disease. The VHL gene mutation causes an increased risk of cancer. Kaelin showed that the VHL gene encodes a protein that prevents the onset of cancer and was involved in controlling responses to hypoxia. VHL is part of a complex that labels proteins with ubiquitin. Ratcliffe discovered the physical interaction of the VHL gene with HIF-1alpha, causing degradation of the HIF-1alpha at normal oxygen levels. 

At hypoxic environments, HIF-1α is protected from degradation and accumulates in the nucleus, where it associates with ARNT and binds to specific DNA sequences (HRE) in hypoxia-regulated genes (1). At normal oxygen levels, HIF-1α is rapidly degraded by the proteasome (2). Oxygen regulates the degradation process by the addition of hydroxyl groups (OH) to HIF-1α (3). The VHL protein can then recognize and form a complex with HIF-1α leading to its degradation in an oxygen-dependent manner (4). 


At hypoxic environments, HIF-1α is protected from degradation and accumulates in the nucleus, where it associates with ARNT and binds to specific DNA sequences (HRE) in hypoxia-regulated genes (1). At normal oxygen levels, HIF-1α is rapidly degraded by the proteasome (2). Oxygen regulates the degradation process by the addition of hydroxyl groups (OH) to HIF-1α (3). The VHL protein can then recognize and form a complex with HIF-1α leading to its degradation in an oxygen-dependent manner (4).

Kaelin and Ratcliffe’s research identified how oxygen levels regulate the interaction between VHL and HIF-1alpha. Their work demonstrated that at normal oxygen levels, hydroxyl groups are added to specific positions within HIF-1alpha, causing modification of the protein and allowing VHL to recognize and bind to HIF-1alpha, leading to degradation of the protein complex.  At high altitude, cells produce a greater amount of the HIF-1alpha protein which binds to the EPO gene, up-regulating the production of erythropoietin hormone, stimulating RBC production. Together, Semenza, Kaelin, and Ratcliffe explained the oxygen sensing mechanism.

Altitude Science, Exposure, Health, High Altitude

A Hike a Day May Keep the Cardiologist Away

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Cardiovascular disease is one of the leading causes of death worldwide, with approximately 17.9 million people succumbing to the disease annually (World Health Organization, 2021). In the United States, there is an estimated 18.2 million Americans (20 years and older) with coronary artery disease. Of those, an estimated 655,000 Americans die annually from heart disease. Approximately 805,000 experience myocardial infarction (i.e., heart attack); 605,000 of these are first time heart attacks, and the other 200,000 have experienced at least one in their lifetime (Centers for Disease Control, 2020). Prevention and management of myocardial infarctions is constantly evolving, and new innovations are being developed to minimize the long-term, chronic consequences one may deal with. Interestingly, it is possible that life at higher altitudes, such as in the Rocky Mountains, may provide a natural edge over life at sea level. For example, Summit County, Colorado (avg elevation ~11,113 ft) has a life expectancy of 86.83 years (Stebbins, 2019). On the contrary, Lauderdale County, Mississippi (elevation 668 ft) has a life expectancy of 75.2 years (U.S.News, 2021). When looking at data regarding heart attack deaths, Summit County experiences 7.2 per 100,000 and Lauderdale County has 334.1 per 100,000 (Centers for Disease Control, 2017-2019).

Myocardial infarction is defined by cardiac muscle death that results from prolonged ischemia. The ischemia is typically the result of an atherosclerotic plaque that ruptures and occludes an artery supplying an area of heart muscle. This leads to an imbalance between the oxygen supply and demand in the affected tissue. Additional swelling ensues, occluding microcirculation, which results in more regional ischemia (Montecucco, Carbone, & Schindler, 2016). In addition to the lack of oxygen, cardiac cells overload with calcium, which causes excess contraction, cytoskeleton digestion, excess reactive oxygen species (ROS) formation, DNA fragmentation, and the release of cytochrome C from mitochondria, which signals cellular death (Heusch & Gersh, 2017).

How might altitude play a protective role in such a complicated process? There are many hypotheses out there, and some interesting findings have been discovered in animal models. Mentioned earlier, ROS fragment the DNA within cardiac cells, which is a trigger for cellular death. With the DNA damaged, cellular function ceases. ROS exposure is a normal part of life; they result from the oxygen we breath, which form free radicals (lone oxygen atoms), the pollution in the air, and the alcohol one may consume. Surprisingly, there is a reduction of ROS formation when someone is at a high enough altitude. This leads to the cardiac cell’s ability to form new, healthy cells. This suggests that ROS are like the breaks to a car and reduces the cell’s ability to move forward in the process of cell division. By taking the breaks off, it may be possible to regenerate healthy, functional tissue (Nakada, et al., 2017).

Another issue of myocardial infarction is the process of remodeling and scar tissue formation. Depending on the extent of the damage, remodeling can be detrimental and compromise the heart’s ability to pump blood efficiently. The inflammation that results signals neutrophils to the area to form scar tissue to try and repair the damage. Neutrophils also work to prevent adverse remodeling. The goal in managing heart attacks is to minimize any sort of damage that may result, but if we are too aggressive in this process, we can cause the formation of excess ROS. These ROS play a role in prolonging the lifespan of these neutrophils, allowing them to keep working. If we do not get timely resolution of the neutrophil remodeling, then healing may not be optimized (Montecucco, Carbone, & Schindler, 2016).

One study in rats explored how the heart remodels when exposed to intermittent hypoxia. Over the course of this study, rats were gradually exposed to higher simulated altitudes, and returned to baseline elevations for periods of time. The highest elevation they were exposed to was 8000 m, or the summit of Mt. Everest. They discovered that both right and left ventricles did remodel over the course of the experiment, but the left ventricle experienced significant remodeling only at the highest altitude. They also discovered that the functionality of the left ventricle was maintained. The remodeling was explained by reoxygenation that occurred at normal elevations, which resumed the production of ROS. This mechanism was absent at altitude. There are rare adverse effects of living at high altitude, which include stunted body growth, erythrocythemia (excess red blood cell formation), pulmonary hypertension, and myocardial fibrosis (Papoušek, Sedmera, Neckár, Oštádal, & Kolár, 2020).

It is exciting to explore some of the possible benefits of being and living in higher elevations. Going forward, it will be important to see if there are clinical applications, and if these applications can be administered safely and efficiently. Just like scuba divers being treated for the bends in hyperbaric chambers, what if we can develop a hypobaric chamber for those who experienced a recent heart attack? Is it possible to minimize damage by reducing the amount of oxygen entering the body, and how long would one have to be exposed to such treatment? These are very important questions that need further investigation. For now, the best course of action is to eat healthy, stop smoking, and go for a hike. If you happen to be hiking in Colorado, it may help keep the cardiologist away.

References

Centers for Disease Control. (2017-2019). Interactive Atlas of Heart Disease and Stroke. Retrieved from Centers for Disease Control and Prevention: https://nccd.cdc.gov/DHDSPAtlas/reports.aspx?geographyType=county&state=CO&themeId=8&filterIds=9,2,3,4,7&filterOptions=1,1,1,1,1#report

Centers for Disease Control. (2020, September 8). Heart Disease Facts. Retrieved from Centers for Disease Control and Prevention: https://www.cdc.gov/heartdisease/facts.htm

Heusch, G., & Gersh, B. J. (2017). The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge. European Society of Cardiology, 774-784.

Montecucco, F., Carbone, F., & Schindler, T. H. (2016). Pathophysiology of ST-segment elevation myocardial infarction: novel mechanisms and treatments. European Society of Cardiology, 1268-1283.

Nakada, Y., Canseco, D. C., Thet, S., Abdisalaam, S., Asaithamby, A., Santos, C. X., . . . Schiattarella. (2017). Hypoxia induces heart regeneration in adult mice. Nature, 222-226.

Papoušek, F., Sedmera, D., Neckár, J., Oštádal, B., & Kolár, F. (2020). Left ventricular function and remodelling in rats exposed stepwise up to extreme chronic intermittent hypoxia. Respiratory Physiology and Neurobiology.

Stebbins, S. (2019, September 6). 50 counties with high life expectancies: Does yours make the list? Retrieved from USA Today: https://www.usatoday.com/story/money/2019/09/06/the-50-counties-where-people-live-the-longest/40072465/

U.S.News. (2021). Overview of Lauderdale County, MS. Retrieved from U.S.News: https://www.usnews.com/news/healthiest-communities/mississippi/lauderdale-county

World Health Organization. (2021, June 11). Cardiovascular Diseases (CVDs). Retrieved from World Health Organization: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)

Tyler Cole is a second year Physician Assistant student at Midwestern University in Glendale, Arizona. He was born and raised in Glendale, and went to The University of Arizona in Tucson, where he earned his bachelor’s in Physiology and Biochemistry in 2013. From there, he went on to serve the city of Tucson as an Emergency Medical Technician for six years. He was also an EMT instructor at Pima Community College for three years. Outside of medicine, Tyler enjoys watching hockey, fishing, traveling, and spending time with his dog, Louie.

Information and discussion for visitors and residents at high elevations.