Monthly Archives: October 2021

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.