Monthly Archives: January 2023

Acclimation, Altitude Science, Exposure, Genetics, Health, High Altitude, Sleep at Altitude

Are Epigenetics the Bridge to Permanent Physiologic Adaptations in Organisms Living at High Altitude?

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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. 

References 

1. Centers for Disease Control and Prevention. What is Epigenetics. https://www.cdc.gov/genomics/disease/epigenetics.htm. Accessed December 30th, 2022.

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

A woman in a white coat with long, dark, straight hair below her shoulders smiles.

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.

Acclimation, Altitude Science, Athletic Training, Backpacking, Exposure, Health, High Altitude, High Altitude Training & Fitness, Mountaineering

When Altitude gets High, does Stroke get higher?

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Does altitude increase or decrease risk of strokes? As one review put it, “Due to limited literature, lack of large series, and controlled studies, the understanding of stroke at high altitude is still sketchy and incomplete”. What is clear is that stroke at high altitude can often be misdiagnosed (or underdiagnosed), due to the similarity of initial presentation with high altitude cerebral edema (HACE). Both conditions present with imbalance or ataxia, and both can present with focal neurological deficits.  There are few large urban populations at high altitude (Addis Ababa in Ethiopia is 7,726 ft), so medical providers have fewer resources.  Without the ability to perform neuroimaging with a CT scan or MRI in a timely manner a diagnosis of HACE vs. stroke could be uncertain. HACE often causes global cerebral dysfunction, differentiating it from an early stroke before the onset of focal symptoms can and often does prove challenging. 

While the prevalence of strictly hemorrhagic and ischemic strokes at high altitude remains murky, it is known that exposure to high altitude can result in conditions such as TIA, cerebral venous thrombosis (CVT), seizures, and cranial nerve palsies. Most of the research that has been done on strokes is focused on “moderate” and “high” altitudes, as opposed to “very high” or “extremely high” altitudes. As such, there is very little research on populations living at 3500m or higher. There was at least one tangible piece of evidence indicating that the higher the elevation, the earlier the mean onset of stroke – Dhiman et al. (2018) found that at an elevation of 2,000m, the mean age of onset of stroke was 62 years. The age decreased to a mean of 57.9 years at 2,200m in another study (Mahajan et al. (2004)). Yet another study (Razdan et al. (1989)) found 10.9% of the patients in their sample suffered strokes aged < 40, though this was at an altitude of only 1,530m. Some reports suggest higher stroke prevalence at higher altitudes, and at a strikingly young age – between age 20 and age 45.

Student presentation on stroke at altitude at Colorado Medical Society meeting 2022

There have been mixed results on the effect that altitude has on strokes. One systematic review study found 10 studies displaying an increase in stroke prevalence with higher altitude, 5 other studies showing that altitude was actually protective against stroke, and 2 studies in which the results were ambiguous. This study and other sources alluded to the fact that poorer stroke outcomes at higher altitude may be due to polycythemia and increased viscosity of blood. Specifically, Ortiz-Prado et. al noted that “living in high-altitude regions (>2500m) increases the risk of developing thrombosis through hypoxia-driven polycythaemia which leads to a hypercoagulation unbalance”, which was associated with increased risk for stroke. Ortiz-Prado et. al noted that most of their info came from “very few cross-sectional analyses”. These analyses did find “a significant association between living in high-altitude regions and having a greater risk of developing stroke, especially among younger populations”. When the effects of altitude on stroke were broken down by race (Gerken, Huber, Barron, & Zapata, 2022) it was found to be protective in some populations (Whites, African Americans), but detrimental in other populations (Hispanics, Asian-Pacific, and American-Indian). Going back to the work of Ortiz-Prado et. al, altitude increased the risk of stroke at elevations above 3500m, when the time spent at this elevation was at least 28 days, and more so in younger persons (below the age of 45). At lower elevations, between 1500m and 3500m, increased / easier acclimatization and adaptation to hypoxia seemed to offer protective effects against the risk of stroke. Chronic exposure to hypoxia at high altitude triggers adaptive / compensatory mechanisms, such as higher pulmonary arterial flow and improved oxygen diffusing capacity. Ortiz-Prado et. al concluded that a window of ideal elevation seems to exist – below an altitude of 2000m the adaptive mechanisms do not seem to be sufficient to yield a protective effect – however, above 3500m, adaptive mechanisms may actually become maladaptive (excessive polycythemia & blood stasis), yielding a higher risk for stroke. A lack of any adaptation (i.e. in altitude naïve persons) was even more detrimental at such high altitudes, with the authors concluding that “above 3500–4000m, the risk of developing stroke increases, especially if the exposure is acute among non-adapted populations” (Ortiz-Prado et. al, 2022).

Strokes are more common in males compared to females, and this held true at altitudes of 3380m, 4000m, and 4572m. In addition to the standard vascular risk factors such as hypertension, smoking, and diabetes, the higher incidence of polycythemia in persons living at high altitude is thought to play a role. One study (Jha et al. (2002)) found that 75% of the patients in their sample who had suffered strokes had some form of polycythemia – this was at an altitude of 4270m. (Dr. Christine Ebert-Santos of Ebert Family Clinic in Frisco, Colorado at 2743m suspects everyone who lives at altitude has polyerythrocythemia as more accurately described by Dr. Gustavo Zubieta-Calleja of La Paz, Bolivia at 3625m.)

Only about 2% of the world’s population resides at what is considered “high altitude”. Given the current world population (over 8 billion, 5 million), that is still over 160,100,000 people. The sheer number of people that may be at increased risk of stroke is all the more reason for us to act, and act soon, to get more research done. This is further exemplified by the fact that “cerebrovascular events or stroke is the second leading cause of death worldwide, affecting more than 16 million people each year” (Ortiz-Prado et. al). Guidelines need to be implemented to assist in the diagnosis and treatment of stroke at high altitude, to help differentiate it from related conditions such as HACE, giving patients the standard of care that they need and deserve. While a fascinating topic, stroke seems to be delegated to the sidelines in the mountains, cast aside by culprits such as HAPE, HACE, altitude sickness, and hypoxia. More research, more resources, and more funding need to be funneled into understanding stroke at higher altitudes. Overall, it is clear living at or even exposure to higher altitudes can result in a multitude of neurological symptoms, and that a higher incidence of stroke may yet be one of them.

References

Maryam J. Syed, Ismail A. Khatri, Wasim Alamgir, and Mohammad Wasay. Stroke at Moderate and High Altitude. High Altitude Medicine & Biology.Mar 2022.1-7. http://doi.org.mwu.idm.oclc.org/10.1089/ham.2021.0043

Current World Population – https://www.worldometers.info/world-population/ 

Ortiz-Prado E, Cordovez SP, Vasconez E, Viscor G, Roderick P. Chronic high-altitude exposure and the epidemiology of ischaemic stroke: a systematic review. BMJ Open. 2022;12(4):e051777. Published 2022 Apr 29. doi:10.1136/bmjopen-2021-051777

Gerken, Jacob (MS), Huber, Nathan (MS), Barron, Ileana (MD, MPH-S), Zapata, Isain (PhD). “Influence of Elevation of Stroke and Cardiovascular Outcomes”. Poster presented at a conference in Colorado, in 2022.

Links

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9058702/ https://www-liebertpub-com.mwu.idm.oclc.org/doi/full/10.1089/ham.2021.0043

Born in Salt Lake City, Utah, Piotr Poczwardowski has also lived in Upstate New York, Florida, and Colorado (where he spent the 13 years prior to moving to Glendale for PA school). While attending the University of Denver, he volunteered at a nearby hospital Emergency Department, and also participated in a study abroad program in Italy. After earning a degree in Psychology, he worked as both a Primary Care Medical Scribe and Neurology MA. His main hobbies include skiing, watching movies, hiking, swimming, playing video games, reading, and playing ping pong. Piotr has also volunteered at the Sky Ridge Medical Center Emergency Department and secured a job as a Primary Care Medical Scribe after graduating from the University of Denver in 2018. Piotr is now attending Midwestern University’s PA program in Glendale, AZ.