Scientific Research

Fabiola León-Velarde: Uncovering the Mysteries of Chronic Mountain Sickness

by David Warmflash, MD, Bonnie Denmark, M.A./M.S.

What do rodents, birds, pulmonary hypertension, sleep disturbances, congestive heart failure, and native Andean mountain dwellers have in common? They’re all part of the research of one Peruvian physiologist, Dr. Fabiola León-Velarde Servetto (hereafter, León-Velarde; Figure 1). The list does not amount to a string of unrelated research topics. Rather, all the topics tie into one particular medical condition: chronic mountain sickness (CMS), which can occur in people spending long periods of time at altitudes higher than 2,500 meters, and affects more than 15 percent of people who live higher than 3,200 meters. That means millions of people in parts of South America and Southeast Asia.

Leon-Velarde
Figure 1: Dr. Fabiola León-Velarde speaking at the 2009 Annual Conference of Executives (CADE) with the Peruvian Institute of Business Administration (IPAE). image © CADE Peru

Since the 1970s, understanding of what happens to the body at high altitude has expanded considerably. This is due not only to studies examining humans at high altitudes but also to studies on numerous other species. Scientists have had to look carefully at the physiology the lungs, heart, and blood of birds, both those that fly high and those that stay on the ground, such as chickens. As with many other medical topics, experiments on rodents, such as mice and rats, also have been vital; plus healthy and ill humans have also been at the center of research.

Today, few of the scientists studying mountain physiology and medicine are women, but one of those women is one of the world’s foremost authorities in the field. Thus, in celebration of International Women’s Day on March 8, 2016, the Council of the Order of Merit of Women of Cayetano Heredia University in Lima, Peru, awarded the Medal of Honor of Merit to León-Velarde. She is the university’s first woman rector, and the award recognized a scientific career that, as of the writing of this profile, included roughly 150 research articles. It’s not the culmination of her career, though; she’ll be contributing to high altitude physiology for years to come.

High altitude physiology

León-Velarde grew up in Lima, Peru, the daughter of a Peruvian veterinarian father and an Uruguayan mother whose parents had fled Europe during World War II. As a child, Fabiola had to be dragged away from her studies to participate in other activities, though she enjoyed volleyball and playing guitar. She was always extremely interested in how humans and other animals functioned and thus wanted to study physiology even before she had heard the word.

Lima is located in Peru’s coastal region, where the land reaches only modest elevations. But by her college years, León-Velarde was fascinated by the question of how people of the Sierra region – the Andean mountains (Figure 2) – could live with less oxygen. In obtaining her Various other towns in the mountain region have fewer people, but are located at still higher elevations, where the pressure of oxygen in the air is much lower than it is at sea level. The human body physiology changes in low oxygen pressure environments so that the blood can deliver enough oxygen to body tissues to maintain life. This has major implications for people who visit high altitude locals for short periods, but also for people living throughout the Andes range and in other mountain environments, such as those of Nepal and Tibet.

Peru map
Figure 2: Map of Peru with the Andean Mountains indicated. image © CDC

Insight from aviators and mountain climbers

By the time of León-Velarde’s birth on June 18, 1956, scientists and physicians were well aware that physiology of the human body changes dramatically during rapid ascent to high altitude. Mountain climbers Tenzing Norgay and Edmund Hillary had reached the peak of Mount Everest (elevation 8,848 m; 29,029 ft) in 1953. This was after 150 years of research that had begun when early 19th century balloon aeronauts had started ascending to altitudes in excess of 7,000 meters.

In 1862, English aeronauts (balloon pilots) Henry Coxwell and James Glaisher reached 11,300 meters, causing Glaisher to lose consciousness (Figure 3). Before fainting himself, Coxwell was able to pull a cord with his teeth, opening a valve, causing the balloon to descend.

Glaisher and Coxwell
Figure 3: Illustration from Travels in the Air (1871) by James Glaisher, showing his companion, Henry Coxwell, attempting to open the valve so that the balloon could descend.

That close call taught scientists that humans could not ascend to such heights without breathing pure oxygen from tanks, so when airplanes came along and flew higher and higher in the 1920s, 30s, and 40s, all kinds of new equipment developed. Aircrews wore advanced oxygen masks and pressure suits, and pressurized cabins came into use, but physiologists also looked into the details of what happened to the lungs, blood, brain, and eyes when people were exposed to low oxygen pressure (hypoxia) and low air pressure (hypobaria) without protection of masks and suits. This knowledge and the new technology of oxygen tanks and masks were vital to the Norgay-Hillary success in climbing Everest in 1953 (Figure 4).

But not all mountain climbers were as well-equipped as the 1953 Everest team. Prior to 1953 and after, several climbers died trying to reach the peak of Everest and other high mountains, or more often they died trying to get down. The reason was a condition that physicians came to call altitude sickness or mountain sickness. They learned it was different from balloon and airplane flight, where ascent took a matter of minutes. Mountain climbers took days to reach altitudes that denied the lungs of significant amounts of oxygen. Physiologists found that climbers’ bodies adapted gradually to the increasing altitude. This is called acclimation (or acclimatization). It protected them from some of the problems that caused pilots to suffer at high altitude, but it created other problems. Some of the problems, altitude headache for example, were minor and not life-threatening. However, reaching high elevations also could produce life-threatening swelling in the lungs and swelling in the brain that might not kill a climber directly, but took away the climber’s judgment and coordination as if the climber were drunk. This turned out to be the reason why descending mountains often proved more dangerous than going up, since reaching the pinnacle put the climbers into that drunken-like state.

Scientists and physicians found that certain drugs, including an important drug called acetazolamide, could prevent many aspects of mountain sickness. They also found that slowing one’s ascent, or descending to lower elevations to sleep before ascending the next day, could be helpful, and by the late 1970s, the medical intervention to prevent and treat mountain sickness was fairly advanced.

Scientists also knew that people who were native to high elevations were different from people who ascended for just brief periods. They had extremely high numbers of red blood cells (RBCs) in their blood, much higher than the normal number found in healthy people. The condition is called polycythemia (Greek for ‘many cells’), and it can result from many causes other than living at high altitude. Scientists realized that polycythemia in mountain dwellers compensated for the hypoxia of the environment by enabling body tissues to receive almost the normal amount oxygen that they would receive at sea level.

Comprehension Checkpoint

_____ is when the bodies of mountain climbers adapt to increasing altitude.

Polycythemia is a double-edged sword

Polycythemia (a high number of red blood cells) developing from exposure to hypoxia (low oxygen) could be helpful to those living on mountaintops as well as those wishing to climb high. By spending gradually longer periods at gradually higher altitudes, ambitious mountain climbers in the 1970s found that they could train their bodies to reach increasingly higher levels without using supplemental oxygen. This allowed climbers Reinhold Messner and Peter Habeler to reach the top of Everest without carrying oxygen in 1978.

Hillary and Tenzing
Figure 4: Jamling Tenzing Norgay and Edmund Hillary, the first people to reach the summit of Mount Everest, shown with their supplemental oxygen gear. image © Jamling Tenzing Norgay

The achievement amazed altitude researchers around the world, both those who worked directly with mountain climbers and those who studied the health of people who lived their entire lives in mountain environments. The latter group of researchers included Dr. Carlos Monge Cassinelli (1921-2006), for whom León-Velarde was working as an undergraduate research protégé. León-Velarde had met Dr. Monge in her first year of college through his son, who was also a freshman. Monge’s work so fascinated her that she was inspired to follow in his footsteps and later referred to him as her “scientific father.”

Climbers Messner and Habeler had shown modest increases in their RBC counts, but Monge had been studying Andean natives since the 1940s. During his lifetime, he defined so many characteristics of the illness affecting mountain dwellers that “Monge disease” is one of two terms by which the condition is known today. Monge found that many of the Andean residents had RBC counts much higher than the two Everest heroes. If a modest increase in RBCs could enable non-mountain dwellers to scale Everest without carrying oxygen, it seemed reasonable to think that mountain natives should be perfectly adapted to hypoxia.

Monge knew well that the polycythemia did help the Andeans, but by the time he was mentoring León-Velarde it also was becoming clear that the adaptation was a double-edged sword. Though polycythemia helped Andeans cope with hypoxia, some of them also became ill, because of effects of altitude on the lungs, heart, and other organs. Scientists suspected that these effects could have resulted from the extra RBCs making the blood abnormally thick. This meant that illness connected with living long-term at high altitudes was fundamentally different from the illness observed in climbers who ascended and remained on mountains for only several days. Researchers separated mountain sickness into two different conditions: acute mountain sickness (AMS) and chronic mountain sickness (CMS). The latter term is synonymous with Monge disease, and this was the state of altitude medicine when León-Velarde entered the field as a graduate student, continuing to work with Monge.

Comprehension Checkpoint

People who live high in the mountains have _____ red blood cells than those who live at lower altitudes.

Working to understand a complex condition

Since graduate school in the 1980s to the present time, León-Velarde has studied human subjects and a variety of non-human animals to obtain a broad idea of what happens physiologically to any animal that spends long periods of time in high altitude conditions. Over the course of her career she has conducted numerous experiments:

  • Investigating levels of RBCs and various hormones in rats and correlated those measurements with the animals’ lung function.
  • Studying how a phenomenon called the Bohr effect, which modulates how hemoglobin binds oxygen in the blood, differs in embryos of birds that are native to high elevations compared with humans.
  • Examining the effects of different altitudes on the permeability of oxygen through avian (bird) eggshells.
  • Comparing the passage of oxygen and carbon dioxide through air cells of avian eggs to the passage of those gases through the membranes that separate the air sacks of human lungs to the blood vessels where the air exchange occurs.
  • Conducting studies on cells taken from liver and various other organs of mice to see how altitude and oxygen pressure affect metabolism.
  • In short, she has utilized all available laboratory animal and cell-based approaches to come at high altitude physiology from every which angle. But she has spent the greatest amount of her research time working directly with human subjects.

    León-Velarde has been a leader of research of CMS, including the epidemiology (who and how many people CMS affects and what factors put people at risk), the pathophysiology (disruptions in cell chemical pathways and body system mechanisms that cause symptoms and harm the overall health of those living at high elevations), the symptoms and physical changes in patients that help doctors arrive at a diagnosis, and the testing of potential treatments and preventive measures. In the 1990s, she traveled to Andean populations documenting symptoms and CMS cases, particularly in a Peruvian mining city called Cerro de Pasco, which sits at an elevation of 4,300 meters. She found CMS in 15.6 percent of the residents of the town, with evidence of the same incidence in other towns of that elevation and higher, not just in Peru but throughout the Andes in Ecuador, Colombia, Venezuela, Bolivia, Colombia, and Chile.

    Comprehension Checkpoint

    All of her research has focused on humans.

    Reasons for Chronic Mountain Sickness

    It was noted earlier that CMS symptoms are connected with polycythemia (abnormally high numbers of RBCs) that develops in people living at high altitude. A lot of the CMS symptoms relate to the lungs and control of breathing. The extra thick blood flows sluggishly through pulmonary blood vessels and the brain. Blood pressure in the lungs increases. This is called pulmonary hypertension, and in many cases that’s enough to trigger a series of events leading to death. If the affected person does not die from their lung disease directly, the lungs can weaken gradually, causing them to suffer for many years. Or, the high pressure in the lungs can cause blood pressure inside the heart to increase. This causes the heart to enlarge while organs such as the liver swell up with a backlogging of blood and other fluids. This is called congestive heart failure, and it can lead to several other conditions that ultimately kill the person.

    León-Velarde and her colleagues found that the risk of developing CMS was increased in those who were old, and especially those who were obese, or who had other lung conditions or exposure to indoor air pollution, namely tobacco smoke. Working together with her mentor Monge, she also found that the quantity of hemoglobin, the protein that carries oxygen in RBCs (Figure 5), was higher overall in people throughout the high elevation Andean towns compared with people living at lower elevations, whether or not they suffered from CMS.

    Hemoglobin
    Figure 5: Red blood cells contain hemoglobin molecules, a type of protein that transports oxygen from the lungs (via the heme) and carbon dioxide back to the lungs. image © ttsz/iStockphoto

    In addition to blood, lung, and heart effects that are particular to CMS, people with CMS also experience symptoms that happen in AMS, such as difficulty sleeping, headaches, loss of appetite, confusion, and inability to concentrate. This was a clue that CMS resulted not only from the body’s producing extra hemoglobin and RBCs to compensate for hypoxia, but also from changes in the control of breathing that occur in some cases of AMS. By the early 2000s, this led León-Velarde to figure out that there really were two pathways leading to CMS, one involving polycythemia, the other accompanied by high altitude pulmonary hypertension (HAPH; high blood pressure in lung blood vessels in people at high altitude) – not necessarily caused by polycythemia as researchers had suspected earlier, but instead by hypoventilation (when a person’s breathing rate is abnormally slow), resulting from an inadequate response to hypoxia. This was similar to what researchers were discovering in connection with AMS, and knowing about it contributed to an increasingly systematic understanding of altitude illnesses and how to diagnose and manage patients afflicted with them.

    In 2008, León-Velarde and several colleagues, led by Jean-Paul Richalet of the University of Paris, published results of study confirming that acetazolamide – the mainstay drug used in treatment and prevention of AMS – also works with similar reliability and safety when it comes to CMS. She has also helped to test and confirm the utility of several other medications that are now used for treating the polycythemia of CMS and very dangerous aspects of altitude pulmonary hypertension.

    Comprehension Checkpoint

    When people at high altitudes have thick blood,

    Looking for genetic clues

    Like so many key leaders in many areas of biomedicine, León-Velarde has been delving into the field of genetics to uncover more clues. Early in her career, she found CMS and increased hemoglobin and RBC numbers to be far less common in natives of Tibetan mountains compared with Andean dwellers. This led to various genetic studies over the years, each taking advantage of the dramatically expanding genetic technology that has characterized biology and medicine in recent decades. León-Velarde has taught the world so much in this area, but also taught us that there is still so much to learn, because the more she has uncovered about CMS, the more complex the disruption in cell biology has turned out to be.

    At the time of writing of this profile, León-Velarde and a growing team that Professor Monge and she built in Lima at the same university where she did all of her studies has been working to understand the role of fetal hemoglobin in the development of CMS. Babies are born with a high proportion of a fetal form of hemoglobin, which is replaced gradually by adult hemoglobin, usually during the first year of life. With some people, fetal hemoglobin persists for many years and this provides protection against certain genetic blood diseases, such as thalassemia and sickle cell anemia. For several years, observations of blood characteristics of people with CMS have led researchers to suspect that the persistence of fetal hemoglobin must explain why certain mountain dwellers suffered from CMS and others did not. León-Velarde and other experts have wondered whether persistence of fetal hemoglobin to adulthood in Tibetans, for instance, might underlie the lower incidence of CMS in Tibet compared with the Andes. But in March 2016, several of her colleagues released a study showing that difference in CMS susceptibility between Tibet and the Andes is not due to fetal hemoglobin, but rather to variations in a gene called SENP1.

    On account of this finding and others from studies that she and her team continue to publish at full speed, there is no way to wrap up the story of Fabiola León-Velarde’s science career at present. Her research over the last three and a half decades has revealed the details of high altitude on human physiology to be more complex than initially thought. Exposing such complexity has led to improved diagnostic capability and medications that are saving lives, but it may take the same amount of time for her to tie it all together.

    Promoting STEM

    León-Velarde consciously sets an example not only for women who are traditionally underrepresented in altitude research, but for all Peruvians. She actively promotes Science, Technology, Engineering, and Mathematics (STEM) education in her country (Figure 6), where 75 percent of the careers are non-scientific. Science plays a notably smaller role in universities and general culture in Perú, not only compared with the United States and Europe, but also compared with neighboring countries such as Chile and Brazil, she noted in an interview for Peruvian television. She believes that expansion of STEM careers can result from improved basic education and more scholarships for scientific study.

    Leon-Velarde UN
    Figure 6: León-Velarde presenting UN Women Executive Director Michelle Bachelet an honorary doctorate from Universidad Peruana Cayetano Heredia in 2012. image © UN Women/Anibal Solimano

    She is particularly appreciative of the need for scholarship support because a scholarship saved her when her family suffered economic hardship during political turmoil in the early 1980s. León-Velarde almost had to leave the university, but for Dr. Monge, who arranged for a scholarship that allowed her to stay and complete her master’s degree and doctorate. Never in her wildest imagination back then would she have envisioned herself as becoming the first female rector at the same university. But now that her academic career has reached heights competing with the Andes and Himalayas, she’s more eager than ever to pay back society.

    Summary

    The air has less oxygen at high altitudes, and the physiology of the body changes dramatically as a result. This module profiles the work of Peruvian physiologist Fabiola León-Velarde, who has significantly advanced the world’s understanding of mountain sickness. The module traces Leon-Velarde’s research and accomplishments while educating readers on changes to the body at high altitudes. Several health effects of high altitude are explored in detail.

    • References
    • Bigham, A.W., Wilson, M.J., Julian, C.G., Kiyamu, M., Vargas, E., Leon-Velarde, F. ,… & Shriver, M.D. (2013). Andean and Tibetan patterns of adaptation to high altitude. Am J Hum Biol, 25(2), 190-7.

    • Cayetano Heredia University Overseas Alumni: Peruvian American Endowment. (2012). “La vida universitaria es un momento para darse la libertad de soñar,” interview with Fabiola León-Velarde. http://www.cayetano-pae.com/wp-content/uploads/2012/09/67-Dra-Leon-Velarde.pdf
    • Frappell, P.B., León-Velarde, F., & Rivera-Ch., M. (2007). Oxygen transport at high altitude: an integrated perspective. Introduction. Respir Physiol Neurobiol, 158(2-3), 115-20.
    • Hsieh, M.M., Callacondo, D., Rojas-Camayo, J., Quesada-Olarte, J., Wang, X., Uchida, N.,… & Tisdale, J.F. (2016). SENP1 but not fetal hemoglobin differentiates chronic mountain sickness from healthy Andean highlanders. Exp Hematol, S0301-472X(16), 30001-7.
    • León-Velarde, F., de Muizon, C., Palacios, J.A., Clark, D., & Monge, C. (1996). Hemoglobin affinity and structure in high-altitude and sea-level carnivores from Peru. Comp Biochem Physiol A, 113(4), 407-11.
    • León-Velarde, F., Gamboa, A., Chuquiza, J.A., Esteba, W.A., Rivera-Chira, M., Monge, C. (2000). Hematological parameters in high altitude residents living at 4,355, 4,660, and 5,500 meters above sea level. High Alt Med Biol, 1(2), 97-104. 
    • León-Velarde, F., & Mejía, O. (2008). Gene expression in chronic high altitude diseases. High Alt Med Biol, 9(2), 130-9.
    • León-Velarde, F., & Monge-C., C. (2004). Avian embryos in hypoxic environments. Respir Physiol Neurobiol, 141(3), 331-43.
    • León-Velarde, F., & Richalet, J.P. (2007). Carlos Monge Cassinelli: portrait. Adv Exp Med Biol, 618, 291-7.
    • León-Velarde, F., Vargas, M., Monge, C., Torrance, R.W., & Robbins, P.A. (1996). Alveolar Pco2 and Po2 of high-altitude natives living at sea level. J Appl Physiol, 81(4), 1605-9.
    • León-Velarde, F., Villafuerte, F.C., & Richalet, J.P. (2010). Chronic mountain sickness and the heart. Prog Cardiovasc Dis, 52(6), 540-9.
    • Monge, C., & León-Velarde, F. (1994). Similarity of PO2 and PCO2 values in the air cell of eggs of birds and in the alveolar gas of humans at sea level and at high altitude. J Comp Physiol B, 164(2), 156-8.
    • Richalet, J.P., Rivera-Ch., M., Maignan, M., Privat, C., Pham, I., Macarlupu, J.L.,… & León-Velarde, F. (2008). Acetazolamide for Monge's disease: efficiency and tolerance of 6-month treatment. Am J Respir Crit Care Med, 177(12), 1370-6.
    • TV Peru (October 10, 2011). Fabiola León-Velarde interview. https://vimeo.com/32935525
    • Universidad Peruana Cayetano Heredia. (2016). En el Día Internacional de la Mujer Rectora recibe Medalla de Honor al Mérito. http://www.upch.edu.pe/portal/ver-mas/item/2405-en-el-dia-internacional-de-la-mujer-rectora-recibe-medalla-de-honor-al-merito.html

    David Warmflash, MD, Bonnie Denmark, M.A./M.S. “Fabiola León-Velarde” Visionlearning Vol. SCIRE-2 (9), 2016.