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Travel to High Altitudes

If you plan to travel to an elevation higher than 8,000 feet above sea level or higher, you may be at risk for altitude illness, which is caused by low oxygen levels in the air. Below are tips you can follow to prevent altitude illness.

Tips to Avoid Altitude Illness

• Ascend gradually. Avoid traveling from a low elevation to an elevation higher than 9,000 feet (2,750 m) above sea level in one day. If possible, spend a few days at 8,000–9,000 feet before traveling to a higher elevation. This gives your body time to adjust to the lower oxygen levels.
• Once you are above an elevation of 9,000 feet, increase where you will sleep by no more than 1,600 feet per day. For every 3,300 feet you ascend, try to spend an extra day at that elevation without ascending further.
• Do not drink alcohol or do heavy exercise for at least the first 48 hours after you arrive at an elevation above 8,000 feet.
• Traveling to elevations greater than 9,000 ft for 2 nights or more, within 30 days before your trip, can help avoid altitude illness on a longer trip at a high elevation.
• Consider taking day trips to a higher elevation and then returning to a lower elevation to sleep.
• Medicines are available to prevent acute mountain sickness and shorten the time it takes to get used to high elevations. Talk to your doctor about which is best for you given your medical history and trip plans.

If your itinerary does not allow for gradual travel to a higher elevation, talk to your doctor about medicine you can use to prevent or treat altitude illness. Many high-elevation destinations are remote and access to medical care may be difficult. Learn the symptoms of altitude illness so that you can take steps to prevent it.

Altitude Illness

Acute mountain sickness (AMS) is the mildest form of altitude illness. Symptoms include:

• Lack of appetite
• Children who cannot yet talk may just seem fussy

Mild cases can be treated by easing symptoms, for example using pain relievers for a headache. Symptoms should go away on their own within a couple days.

People with altitude illness should not travel to higher elevations until they no longer have symptoms.  A person whose symptoms get worse while resting should travel to a lower elevation to avoid becoming seriously ill or dying.

High-altitude cerebral edema (HACE) is a more serious form of AMS. Symptoms include:

• Extreme fatigue
• Loss of coordination

High-altitude cerebral edema is rare, but it can cause death. If it develops, the person must immediately move, or be moved, to a lower elevation.

A third type of altitude illness, is called high-altitude pulmonary edema (HAPE). It can quickly become life-threatening. Symptoms of high-altitude pulmonary edema include:

• Shortness of breath

A person with these symptoms must immediately move, or be moved, to a lower elevation and will likely need treatment with oxygen.

Preexisting Medical Conditions

People with pre-existing medical conditions should talk with a doctor before traveling to high elevation.

• People with heart or lung disease should talk to a doctor who is familiar with high-altitude medicine before their trip.
• People with diabetes need to be aware that their illness may be difficult to manage at high elevation.
• Pregnant women can make brief trips to high elevations but they should talk with their doctor because they may be advised not to sleep at elevations above 10,000 feet.
• People with some illnesses (e.g., sickle cell anemia, severe pulmonary hypertension) should not travel to high elevations under any circumstances.

More Information

CDC Yellow Book: High Elevation Travel & Altitude Illness

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Is there such thing as reverse altitude sickness?

2 September 2020

Brad Mitchell/Alamy

When creatures accustomed to life at high altitude are brought to sea level, do they experience reverse altitude sickness?

David Muir , Edinburgh, UK

Humans can certainly experience reverse altitude sickness, known as high-altitude de-acclimatisation syndrome (HADAS).

When people who live at low altitude have adjusted to a high-altitude, low-oxygen environment, they can get any of a large number of possible symptoms of HADAS when returning to a lower altitude. Climbers and athletes have documented these physiological effects. HADAS is particularly significant in China, where millions of temporary workers migrate from their homes at low altitude to the high plateaus of Qinghai and Xinjiang.

At the end of their spell of employment, many experience HADAS after descending back to their homes. Scientists in China have shown that high-altitude de-acclimatisation induces oxidative stress, resulting in cell and tissue damage.

Members of populations that have evolved to live at high altitude, such as Tibetans, have also experienced HADAS on moving to sea level.

Because humans who have naturally adapted to live at high altitude may experience HADAS, as well as those who have become temporarily acclimatised, the same is likely to be the case for other mammals. Whether this is true for all vertebrate groups could be a bone of contention.

Chris Daniel , Colwyn Bay, Conwy, UK

Adaptation to altitude has been found to be different in two populations, Tibetans and the Andean peoples.

Tibetans have a level of oxygen-carrying haemoglobin in their blood that is similar to that of lowlanders, but they breathe faster and produce more nitric oxide that promotes vasodilation, or widening of the blood vessels, to carry blood more efficiently around the body.

Andeans, on the other hand, have more haemoglobin and larger lungs, so they can absorb more of the available oxygen from each breath.

One study has found that Tibetans who are genetically adapted to high altitudes but born at lower ones don’t seem to differ from lowlanders in their metabolic response to exercise, although their breathing rate is greater. Another has found that the Quechua Andean people have higher oxygen saturation in their blood than lowlanders regardless of whether they were born at high or low altitude.

Athletes have used the temporary effect of high-altitude adaptation to improve their performance. The most popular method is “live high, train low”, in which athletes sleep at locations up to 2500 metres above sea level, where the lower air density means there is a reduced amount of oxygen.

“Altitude rooms” are another option. These can be used to control oxygen levels to simulate elevated altitudes even up to the height of Everest. Such conditions stimulate the hormone erythropoietin to produce more haemoglobin to restore oxygen to normal levels in the body.

Athletic training, however, takes place at lower altitudes, where the additional oxygen-carrying capacity of the blood enables higher rates of exercise to take place.

This suggests that it isn’t inherently dangerous to adapt to a high altitude and then descend quickly to a low level, as the body will make use of the greater oxygen-carrying capacity of the blood to do more physical activity or lower the breathing rate to reduce the intake of oxygen.

Ruth Garodd , London, UK

Maybe reverse altitude sickness of a sort does exist. When I was trekking in Nepal, I learned that if the Sherpas (born and bred at altitude) play the porters (born and bred in the valleys) at football, then the Sherpas will always win if the match is played at altitude, but the porters will always win in the valleys.

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How does altitude affect the body and why does it affect people differently?

Senior Lecturer (S&C), Murdoch University

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Brendan Scott does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

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Every year, thousands of people travel to high-altitude environments for tourism, adventure-seeking, or to train and compete in various sports. Unfortunately, these trips can be marred by the effects of acute altitude sickness, and the symptoms vary from person to person. To understand why people are affected differently, we have to look at how the body is affected by altitude.

Read more: From Kilimanjaro to Everest: how fit do you have to be to climb a mountain?

How is ‘altitude’ different to sea level?

Air is comprised of different molecules, with nitrogen (79.04%) and oxygen (20.93%) making up the majority of each breath we take. This composition of air remains consistent, whether we are at sea level or at altitude.

However, with altitude, the “partial pressure” of oxygen in this air (how many molecules of oxygen are in a given volume of air) changes. At sea-level, the partial pressure of oxygen is 159 mmHg, whereas at 8,848m above sea level (the summit of Mt Everest), the partial pressure of oxygen is only 53 mmHg.

At high altitudes, oxygen molecules are further apart because there is less pressure to “push” them together. This effectively means there are fewer oxygen molecules in the same volume of air as we inhale. In scientific studies, this is often referred to as “hypoxia”.

What happens in the body in high altitudes?

Within seconds of exposure to altitude, ventilation is increased, meaning we start trying to breathe more, as the body responds to less oxygen in each breath, and attempts to increase oxygen uptake. Despite this response, there’s still less oxygen throughout your circulatory system, meaning less oxygen reaches your muscles. This will obviously limit exercise performance.

Within the first few hours of altitude exposure, water loss also increases, which can result in dehydration. Altitude can also increase your metabolism while suppressing your appetite, meaning you’ll have to eat more than you feel like to maintain a neutral energy balance.

When people are exposed to altitude for several days or weeks, their bodies begin to adjust (called “acclimation”) to the low-oxygen environment. The increase in breathing that was initiated in the first few seconds of altitude exposure remains, and haemoglobin levels (the protein in our blood that carries oxygen) increase, along with the ratio of blood vessels to muscle mass.

Despite these adaptations in the body to compensate for hypoxic conditions, physical performance will always be worse at altitude than for the equivalent activity at sea level. The only exception to this is in very brief and powerful activities such as throwing or hitting a ball, which could be aided by the lack of air resistance.

Read more: Tall tales misrepresent the real story behind Bhutan’s high altitude tigers

Why do only some people get altitude sickness?

Many people who ascend to moderate or high altitudes experience the effects of acute altitude sickness. Symptoms of this sickness typically begin 6-48 hours after the altitude exposure begins, and include headache, nausea, lethargy, dizziness and disturbed sleep.

These symptoms are more prevalent in people who ascend quickly to altitudes of above 2,500m, which is why many hikers are advised to climb slowly, particularly if they’ve not been to altitude before.

It’s difficult to predict who will be adversely affected by altitude exposure. Even in elite athletes, high levels of fitness are not protective for altitude sickness.

There’s some evidence those who experience the worst symptoms have a low ventilatory response to hypoxia. So just as some people aren’t great singers or footballers, some people’s bodies are just less able to cope with the reduction in oxygen in their systems.

There are also disorders that impact on the blood’s oxygen carrying capacity, such as thalassemia, which can increase the risk of symptoms.

But the best predictor of who may suffer from altitude sickness is a history of symptoms when being exposed to altitude previously.

How are high-altitude natives different?

People who reside at altitude are known to have greater capacity for physical work at altitude. For example, the Sherpas who reside in the mountainous regions of Nepal are renowned for their mountaineering prowess.

High-altitude natives exhibit large lung volumes and greater efficiency of oxygen transport to tissues, both at rest and during exercise.

While there is debate over whether these characteristics are genetic, or the result of altitude exposure throughout life, they provide high-altitude natives with a distinct advantage over lowlanders during activities in hypoxia.

So unless you’re a sherpa, it’s best to ascend slowly to give your body more time to adjust to the challenges of a hypoxic environment.

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Safety Precautions for Heart Patients Traveling to High Altitudes

While traveling to high altitudes can put added stress on the heart, there are key steps heart patients can take to ensure a safe trip, based on clinical recommendations recently published in the European Heart Journal .

Written by a team of experts from the European Society of Cardiology and other medical groups, these guidelines addressed the safety of high altitudes for heart patients. Traveling to high elevations can put added stress on the heart, and whether it’s safe for heart patients is largely debated.

To help provide guidance on the issue, experts reviewed existing evidence on high altitude exposure in heart patients. According to authors, there are very few clinical trials on the topic but available evidence should offer practical advice for both patients and providers.

In the new guidelines, experts explain exactly how high altitudes impact our health. According to experts, high altitudes are defined as anywhere more than 2,500 above sea level, where the air is “thinner.” Since the lungs get less oxygen at high elevations, the heart has to work harder to get oxygen-rich blood to the rest of the body. This can cause symptoms like headaches, dizziness and fatigue, even for the healthiest of adults.

In heart patients, however, the effects of high altitudes are more concerning. Changes in altitude can affect factors like blood pressure, potentially worsening existing heart conditions.

For this reason, experts recommend that patients with severe heart conditions —like those with severe heart failure  or uncontrolled very high blood pressure —or patients recovering from heart attack or a stent procedure should avoid traveling to high altitudes. Evidence suggests that it could be dangerous and increase risk of complications and heart events.

For most heart patients, however, simple precautions should do the trick to ensure save travel. For example, experts recommend only light to moderate physical activity while at high altitudes to avoid putting added strain on the heart. Heart patients who are never physically active shouldn’t start being active while at high altitudes. Evidence suggests that heart failure patients should avoid climbing more than 300–500 meters a day when in high-altitude locations, since drastic changes in elevation can worsen symptoms.

Experts also recommend reviewing current medications with a doctor before traveling and carefully taking all medications as prescribed during a trip.

When in doubt, experts recommend discussing any concerns with a doctor before traveling to high altitudes. While most heart patients can travel safely, simple precautions can go a long way in ensuring a safe trip.

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• General Travel Health Advice

Altitude and Travel

Introduction.

• Altitude sickness

Acute Mountain Sickness

Hace and hape.

• Pre-existing medical conditions
• Other considerations at altitude
• Further Information

Travelling to destinations at high altitude can be exciting, challenging and rewarding. However there are risks associated with high altitude including developing altitude sickness, exposure to ultraviolet (UV) light and cold temperatures.

You should have travel insurance that covers you for travelling to altitude.  Your policy should have cover that includes medical evacuation and repatriation home if necessary.

Some destinations at high altitude include:

Altitude Sickness

At altitude the air pressure is lower and this means there is less oxygen available to your body when you breath. We need oxygen for our bodies to work properly. The process of your body adapting to the lower oxygen levels is called acclimatisation and it takes about 3 to 5 days.  If your body does not get enough time to acclimatise to being at high altitude, you can develop altitude sickness (sometimes called mountain sickness). Altitude sickness usually happens at levels above 2,500m.

• Altitude sickness can develop very quickly and can be life threatening.

There are 3 types of altitude sickness:

• Acute Mountain Sickness (AMS)
• High Altitude Pulmonary Oedema (HAPE)
• High Altitude Cerebral Oedema (HACE)

Acute Mountain Sickness (AMS) is more likely to occur if you go to high altitude too quickly and there is not enough time to acclimatise properly.  Even if you are physically fit, you can still suffer from AMS.

Signs and Symptoms of AMS

Symptoms of AMS do not usually happen immediately but start to show a few hours after being at a high altitude.  Symptoms can be mild to begin with, often being likened to having a hangover.  Symptoms you might get can include:

• loss of appetite
• being sick or feeling like you want to be sick
• feeling very tired
• flu like symptoms
• poor sleep and irregular breathing during sleep

If symptoms of AMS are ignored, you can go on to develop more severe and life threatening types of mountain sickness called HAPE or HACE . 

Preventing AMS

The best way to prevent AMS is to give your body enough time to acclimatise to being at a higher altitude. 

You can do this by not travelling too quickly to altitudes above 2,500m

• Take the first 2 to 3 days to acclimatise to being at altitudes below 2500m before going any higher.
• If you can, avoid flying directly to somewhere at high altitude, but if unavoidable acclimatise before any further ascent.
• If you are climbing or trekking, then a slow, gradual ascent is advised.

The major cause of AMS is going too high too quickly.

The Wilderness Medical Society recommend that once you are at an altitude of 2,500m, you should:

• not sleep more than 500m higher than you slept the night before
• have a rest day every 3 to 4 days

It is also important that you:

• you may need to drink 4 to 5 litres of safe water to avoid getting dehydrated
• avoid drinking alcohol
• eat a light but high calorie diet

Treatment of AMS

• be aware of the signs and symptoms of AMS and let someone you are travelling with know that you are beginning to feel unwell
• you should rest at that altitude you are at and not go any higher
• take painkillers to treat any headache e.g. ibuprofen or paracetamol
• if your symptoms of AMS do not improve over a day, then you should descend 500 to 1,000m to a lower altitude
• once your symptoms have gone and you have fully recovered you can ascend again

Medication to prevent AMS

Acetazolamide (Diamox) is a medicine that is sometimes taken to prevent AMS.  It works by speeding up the processes your body goes through to acclimatise to high altitude.  It might be recommended if you have had AMS before or if a gradual ascent is not possible

• Acetazolamide does not replace the need to acclimatise through a gradual assent.

You should speak with a travel health professional who will be able to advise further on using Diamox. 

In South America, Coca tea or Mate de Coca is sometimes suggested for preventing AMS. There is no evidence that this prevents AMS and should not be taken to treat or prevent AMS.

If the signs of AMS are ignored and you continue to go higher, you are at risk of developing life threatening altitude sickness,  High Altitude Cerebral Oedema (HACE) and/or High Altitude Pulmonary Oedema (HAPE).

HACE is due to swelling of the brain.  Symptoms include:

• severe headache
• unsteadiness or not being able to walk in a straight line
• becoming confused or irrational

HAPE is caused by fluid gathering in your lungs. Symptoms include:

• breathlessness even when you are resting
• feeling very weak
• bluish discolouration of the skin (cyanosed)

Both conditions are an emergency and can quickly result in death; descending to a lower altitude must be carried out immediately.

Pre-existing Medical Conditions

If you have certain medical conditions, you should get advice from the health care professional that manages your condition or a travel health professional before travelling to altitude. These conditions include:

• heart conditions
• lung conditions including chronic obstructive pulmonary disease (COPD) and moderate/severe asthma
• sickle cell disease

  It is important to make sure that your underlying condition:

• is as stable as possible
• will not be made worse by travelling to altitude
• is covered by your travel insurance

If you are pregnant and travelling to altitude then you should discuss your travel plans with your midwife or obstetrician before you travel.

Other Considerations at Altitude

Sun protection.

The risk of exposure to Ultra Violet (UV) light is greater at higher altitudes.  The risk of sunburn is increased when UV light is reflected, for example, off snow.

To protect against UV light, you should:

• wear clothing that covers your skin and blocks out UV light
• a facemask or balaclava may be required to protect your face against the cold and sun at very high and extreme altitude
• use a sunscreen that protects against UVA, UVB and UVC light with a high sun protection factor (at least SPF15)
• protect exposed skin such as lips, ears and nose with a high protection sunblock
• wear sunglasses which filter out UV light to protect your eyes

More information on minimising exposure to the sun can be found on our sun safety page.

Cold Protection

Frostbite is a risk in areas at very high altitude due to low temperatures combined with lower oxygen levels in your blood. The risk is even greater if you have poor circulation. To help prevent injuries from the cold you should:

• wear correctly fitting clothes that are approved for cold climates; gloves, hats, socks, boots
• a facemask or balaclava may be required to protect your face against cold and sun at very high and extreme altitude
• keep your hands and feet dry, change wet socks and gloves promptly
• wear goggles to protect your eyes at very high altitudes

Further Information

Altitude Physiology Expeditions British Mountaineering Council Medex: Travel at high altitude booklet Wilderness Medical Society

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• Disease Prevention Advice

Altitude sickness

Altitude sickness can happen when you're at a high altitude. It usually gets better in a few days with rest, but it can sometimes be life-threatening and need treatment.

Check if you're at risk of altitude sickness

You can get altitude sickness if you're in a place that is at a high altitude (usually more than 2,500 metres above sea level).

You're more likely to get it if you travel or climb to a high altitude quickly.

You can get it in places like:

• Mount Everest in Nepal
• Mount Kilimanjaro in Tanzania
• some places in the Alps
• La Paz in Bolivia

You cannot get altitude sickness in the UK.

Check your travel risk

You can check if there's a risk of altitude sickness in a country or place you're travelling to on the TravelHealthPro website

Symptoms of altitude sickness

Symptoms of altitude sickness usually start 6 to 10 hours after being at a high altitude.

The main symptoms include:

• loss of appetite
• feeling or being sick
• feeling tired or exhausted
• difficulty sleeping

Sometimes, the symptoms can develop into more serious symptoms that can be life-threatening.

What to do if you get altitude sickness

If you're at a high altitude and have symptoms of altitude sickness or feel unwell:

• tell someone who you're travelling with that you do not feel well
• rest at the same altitude until you feel better – do not travel or climb to a higher altitude
• you can take anti-sickness medicine or painkillers such as ibuprofen or paracetamol to ease symptoms

Symptoms of altitude sickness usually get better in 1 to 3 days.

If your symptoms have gone and you feel better, you can travel or climb to a higher altitude.

Important: If your symptoms do not get better

If your symptoms get worse or do not improve after 1 day, go to a lower altitude if you can. Try to go around 300 to 1,000 metres lower.

Urgent advice: Get medical help immediately if:

You are at a high altitude and you or someone else:

• have symptoms of altitude sickness and feel very unwell
• are confused
• have problems with balance or coordination
• are seeing or hearing things that are not real (hallucinations)
• feel short of breath, even when resting
• have a cough or are coughing up frothy or bloody spit
• have blue or grey skin, lips, tongue or nails (on brown or black skin this may be easier to see on the palms of the hands or the soles of the feet)
• are very sleepy or difficult to wake

Go to a lower altitude straight away (around 300 to 1,000 metres lower) if you can.

Treatment for altitude sickness

Altitude sickness usually gets better without treatment if you rest.

You may be given medicine to help ease symptoms.

If your symptoms are more serious, you may be given:

• steroid medicine
• medicine to lower your blood pressure
• oxygen through a mask

Rarely, you may need to be treated with oxygen in a special air-tight chamber (hyperbaric chamber) to increase the level of oxygen in your blood.

How to reduce your risk of altitude sickness

There are some things you can do to help reduce your risk of getting altitude sickness.

Do travel or climb to a high altitude slowly to give your body time to get used to lower oxygen levels spend a few days at an altitude below 2,500 metres before going any higher have a rest day at the same altitude every 3 to 4 days (if you're at an altitude of 3,000 metres or more) drink enough water so you do not get dehydrated speak to a GP or travel clinic if you've had altitude sickness before or if you're travelling to a high altitude quickly – they may prescribe medicine to help prevent altitude sickness Don’t

try not to travel from an altitude that's less than 1,200 metres to an altitude that's more than 3,500 metres in 1 day

try not to fly directly to a place with a high altitude – if this is not possible, rest for 1 day before going any higher

try not to sleep more than 500 metres higher than you slept the night before (if you're at an altitude of 3,000 metres or more)

do not drink alcohol while travelling or climbing

Page last reviewed: 31 July 2023 Next review due: 31 July 2026

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Preparing for Safe Travel to High Altitude - Mayo Clinic ASAP Study

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Study name:   Preparing for Safe Travel to High Altitude – Mayo Clinic ASAP Study

Research/study findings:   Altitude Related illnesses (ARI) occurs when someone arrives at a new altitude after the first 3 to 5 days. Common symptoms include headache, gastrointestinal upset, fatigue, dizziness and sleep disruption.

Publication/source/year:   Anderson, M.D., Paul. (2015). Preparing for Safe Travel to High Altitude, Mayo Clinic, ASAP study.

Introduction:

Millions of people travel to high-altitude every year for recreation and for work. Twenty percent of those traveling to altitudes below 5500 m/18,000 ft are affected by some form of altitude illness. This number rises to fifty percent above 18,000 ft. While most cases of altitude illness are mild and self limiting, some cases can become life threatening. If you are planning a trip to altitudes above 1500 m/5000 ft. knowledge is the best prevention for altitude illness. This brief outline serves as merely an introduction to this important topic. Additional resources are highly recommended reading for those traveling to high altitude.

Altitude Related Illnesses

High Altitude Illnesses (HAI) include Acute Mountain Sickness (AMS), High-Altitude Pulmonary Edema (HAPE), and High-Altitude Cerebral Edema (HACE). The symptoms of AMS are typically felt by most people when they arrive at a new altitude, but the symptoms are usually self limiting (e.g. 1st 3-5 days at high altitude).

The exact mechanisms of AMS remain unclear, however symptoms tend to be the most prevalent 1-2 days after arrival at elevation.

The most common symptoms include a headache, gastrointestinal upset, feelings of fatigue, dizziness, and sleep disruption. The more life threatening condition of HAPE includes symptoms of shortness of breath at rest, persistent coughing, exercise intolerance, and possibly the production of pink frothy sputum. HACE is defined as the presence of AMS symptoms with difficulty walking (ataxia), mental status changes, or severe lethargy. If you notice any of these symptoms in yourself or a member of your group, it is critical to stop and evaluate your situation. Descent is usually the first priority when altitude illness occurs.

What is High Altitude?

• High Altitude (1500m-3500m/ 4921-11,483 ft)
• Very High Altitude (3500m-5500m/ 11,483 – 18,045)
• Extreme Altitude (>5500m/ >18,045ft)

What General Health Precautions should I take before traveling to High Altitude?

During decades of research, altitude physiologists have identified fairly reliable prevention strategies for avoiding altitude illnesses. However, individuals who perform well on one outing at a given altitude may become ill on another venture to a similar climate. If you are planning to travel to High Altitude there are certainly some general health precautions that will reduce your chances of experiencing a high-altitude syndrome like AMS, HAPE, or HACE.

Get Organized — Plan your trip itinerary to allow for proper ascent schedules. If you are planning a vacation (e.g. skiing or trekking), allow for an extra day or two during the trip so that members of your group can adjust to the effect of new altitudes. For those planning strenuous alpine ascents, remember that difficult terrain can frustrate attempts to adhere to ascent schedules and terrain and weather can severely limit evacuation options. These factors must be included in your plan. Again, descent forms the primary treatment for most altitude illness, so consider egress routes when planning more challenging ascents. Regardless of your location, give some consideration to what you will do if you or a member of your party becomes ill from altitude.

Get Fit — Being physically fit is not regarded as a preventative factor by most experts in altitude physiology.2 Even the most highly trained athletes suffer the effects of altitude illness. Nevertheless, if you are physically fit you stand a better chance of being more resilient in the midst of any illness. If you are required to participate in your own rescue or the evacuation of another team member, you will likely be much more effective if you are in excellent physical shape.

Get Checked Out — A visit to a medical provider familiar with the demands of altitude travel is helpful before your trip, especially if you have ongoing medical conditions. You should address any acute medical issues such as sinus infections, bronchitis, or chest pain with your doctor before you leave on your trip. Individuals with Heart and Lung disease should be examined carefully as altitude places tremendous strain on the cardiovascular system. Sleep disorders can also pose significant problems at altitude since sleep is significantly disrupted during the acclimatization process. Musculoskeletal conditions can also present problems for traveling efficiently and performing effectively at altitude. A clinician who knows your health conditions and understands the demands of altitude can help you prepare for your trip. Medications useful to you at altitude as well as immunizations for travel to remote areas can also be provided at your pre-trip visit.

Get Hydrated — Dehydration decreases the body’s ability to acclimatize to high altitude. Unfortunately many travelers arrive at their destination dehydrated after long plane-flights, bus trips, or automobile journeys. Excessive caffeine and alcohol ingestion are common during travel and produce a general state of low blood volume. Even before your trip begins, drinking 2-3 liters of water per day can prepare your body for arrival at higher elevations. Keep a 1 liter water bottle with you when traveling and drink as regularly as is feasible, given your mode of transportation. Reducing caffeine and alcohol consumption before your trip will also decrease your chances of arriving at altitude in a dehydrated state.

Get Medications — You should be sure to have an adequate supply of your regular medications when you begin your trip. While most travelers choose to acclimatize to altitude naturally, many people choose to take prescription medications that help the body adjust to high altitudes, such as acetazolamide (Diamox) and dexamethasone. Others suggest supplements such as gingko balboa may be helpful. The specific benefits of these medications/supplements and their side effects are discussed below. Altitude medications are more highly recommended for rapid travel (i.e. by plane) to very high altitude (3500m-5500m/ 11,483 – 18,045 ft) and may not be required for travel to lower elevations.

Get Rested — Domestic and international travel itineraries often disrupt normal sleep schedules and generate feelings of fatigue. Arriving tired and dehydrated at altitude creates room for altitude illness to develop if travelers immediately begin high-exertion activities such as skiing, hiking or climbing. Many travelers find medications such as Zolpidem (Ambien) helpful if they struggle to sleep while traveling to the start of their trip. Alternatively, plan a rest day or two once you arrive at your destination

Get Educated — The best treatment for altitude illnesses is to avoid getting sick in the first place. While there is no flawless way to prevent altitude sickness, most experts agree that knowledgeable travelers are less likely to experience serious conditions such as HAPE and HACE. You should know the symptoms, ascent guidelines, and treatment methods for altitude illnesses. You can also carry with you small books on mountain first aid that have excellent sections on altitude illnesses. Most individuals who have problems at altitude either lack basic knowledge about high-altitude regions, ignore/rationalize away obvious symptoms, or fail to provide the proper treatments for party members who become ill.

What Medications are Effective in Preventing High Altitude Illnesses?

Prevention:

Recent consensus statements on the strength of evidence for various preventive medications are available through the internet.

What follows is a summary drawn from this helpful consensus article. For further reading, health related professionals may wish to investigate the excellent references at the end of the document. http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/07pdf/acs33-05.pdf

1. Acetazolamide: (Diuretic) Fairly effective in preventing many cases of altitude illness. The indications for using Acetazolamide include a) rapid ascent to sleeping elevations > 3000 m, b) significant gains in elevation during an expedition (e.g. moving from 4000 m to 5000 m, and c) previous difficulty during travel to high altitude. Acetazolamide has side effects that many find unpleasant causing some travelers to avoid this medication. Consult with your prescribing physician before taking this medication.

2. Dexamethazone: (Steroid/Anti-inflammatory) Dexamethazone has been shown to be effective in preventing altitude illness in many individuals. Some will take it in conjunction with Acetazolamide, or alone. Consensus statements indicate that this medication should be reserved for individuals who cannot tolerate Acetazolamide.

3. Other medications: Methazolamide, Spironolactone, Nifedipine (useful in treating HAPE, not in preventing AMS) and Sildenafil all seem to have some beneficial effect in some altitude travelers, but scientific research has yet to affirm them as strongly as Acetazolamide and dexamethazone.

Are there any natural supplements that help prevent Altitude Illness?

Gingko Bilboa has been shown to improve circulation and reduce blood pressure in a similar way to Sildenafil (Viagra). Studies have not demonstrated that Gingko is any better than placebo, but some individuals still find this a helpful herbal agent in preventing altitude illness. Other recommendations include high doses of Vitamin C and other anti-oxidant agents which may help reduce the circulating volume of free radicals during acclimatization. Scientific evidence for these interventions is somewhat limited, yet these vitamins may function as excellent support for the irregular diet and lifestyle produced by many travel itineraries. Some substances controlled in the United States may alleviate the symptoms of altitude illness. Coca leaves (coca de mate) are commonly used to make tea or are chewed directly by many high altitude workers and travelers in Central and South America. These remedies are consumed at the travelers own risk. One fine summary of herbal remedies exists at: http://www.denvernaturopathic.com/news/altitude.html

What Guidelines Exist for Safe Travel in High Altitude Regions?

Group Travel: Traveling with a group is an excellent way to reduce the likelihood of altitude illness. Solo travelers may have a more difficult time recognizing AMS symptoms in themselves and may be more likely to rationalize away their symptoms in order to reach a goal. The use of a buddy system (each member of your group has a buddy to watch them throughout the day) is very effective in recognizing AMS symptoms early. While groups increase the number of people who can potentially become ill, they probably decrease the likelihood that serious illness will occur.

Gradual Initial Exposure: Graded ascent to high altitude is preferred over rapid exposure to high altitude. For example, trekking to elevations over 3500 m over a number of days decreases your risk of AMS when compared with flying to the same elevation. Ascend to altitude slowly when possible. If you are rapidly exposed to altitudes > 3500 m (e.g. LaPaz, Bolivia) consider taking Acetazolamide according to accepted therapeutic regimens. Once you arrive at 3500 m, you should take 2-3 days to rest and allow your body to adjust to the new altitude. This involves non-strenuous activities like walking, touring the local town, or sightseeing.

Ongoing Exposure: After 2-3 days spent at altitudes around 3500 m, travelers should increase their sleeping elevation no more than 600 m per day. Gaining more elevation during the day is acceptable so long as overexertion is avoided and the sleeping elevation does not exceed 600m. In addition, an extra night of acclimatization is recommended every 300-900m gain in sleeping elevation. As noted, terrain may frustrate adherence to these schedules, but groups must make their best attempts to approximate these guidelines. 

What Should I do if someone gets Altitude Illness?

Most healthy people will sustain some measure of altitude illness on arrival at altitude, such as a headache, problems sleeping, mild shortness of breath, or fatigue. If these symptoms fail to resolve with a rest day, hydration, and over the counter medications, your group must pay attention, and perhaps initiate treatment.

Treating severe AMS:

1. Discontinue ascent and rest.

2. Acetazolamide 125 mg by mouth every 12 hours until symptom free

3. Dexamethasone 4 mg by mouth every 4-6 hours for two doses. Do not continue ascent until after 18 hours after the last dose and symptom free. This can be used by itself or with Acetazolamide.

4. Give Oxygen, if supplemental oxygen is available.

5. Descend if symptoms persist more than 24-48 hours or if the patient’s condition worsens.

Treating HAPE:

1. IMMEDIATE descent (almost always with assistance) is imperative, and should not be delayed unless descent poses a greater danger to the parties involved (i.e. weather, terrain). Even modest elevation losses can be helpful.

2. In addition to descent, administration of dexamethasone 8 mg IM/PO loading dose followed by 4 mg IM/PO Q 6 hours should be given immediately.

3. Acetazolamide 125 mg PO TID should be given if patient able to tolerate PO.

4. Oxygen supplementation should be given if available.

5. If descent is not possible, place patient in a portable hyperbaric chamber for 4-6 hours. (also called a Gamow bag)

6. Recovery likely to be prolonged with after effects (ataxia) lasting up to weeks. Most who survive evently fully recover neurologically.

Treating HACE:

1. IMMEDIATE descent is imperative (likely with assistance as exertion will worsen symptoms). 500-1000 meters may be all that is required before improvement is observed.

2. Supplemental oxygen.

3. Rest after descent.

4. Nifedipine 20 mg PO followed by 10 mg PO Q 4 hours. If the patient is unable to tolerate PO, empty capsule sublingually.

5. If descent is not possible, place the patient in a portable hyperbaric chamber.

6. Neither supplemental oxygen, hyperbaric therapy, nor any other intervention should delay an opportunity to descend.

7. Both furosemide and acetazolamide can be modestly helpful in improving oxygenation.

Conclusion:

Many of the world’s most fascinating environments exist at high elevations. Whether you plan a leisurely visit or an aggressive wilderness expedition, altitude illness must be a factor in your trip planning. This brief article is merely an introduction to the basic knowledge you will need to recognize and respond correctly to high-altitude illnesses. Remember, most altitude illness is mild and self-limiting, so be prepared for some discomfort and be prepared to recognize when your group members display signs of more serious illness.

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Impact of High Altitude on Cardiovascular Health: Current Perspectives

Robert t mallet.

1 Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, USA

Johannes Burtscher

2 Department of Biomedical Sciences, University of Lausanne, Lausanne, CH-1015, Switzerland

3 Institute of Sport Sciences, University of Lausanne, Lausanne, CH-1015, Switzerland

Jean-Paul Richalet

4 Laboratoire Hypoxie & Poumon, UMR Inserm U1272, Université Sorbonne Paris Nord 13, Bobigny Cedex, F-93017, France

Gregoire P Millet

Martin burtscher.

5 Department of Sport Science, University of Innsbruck, Innsbruck, A-6020, Austria

6 Austrian Society for Alpine and High-Altitude Medicine, Mieming, Austria

Globally, about 400 million people reside at terrestrial altitudes above 1500 m, and more than 100 million lowlanders visit mountainous areas above 2500 m annually. The interactions between the low barometric pressure and partial pressure of O 2 , climate, individual genetic, lifestyle and socio-economic factors, as well as adaptation and acclimatization processes at high elevations are extremely complex. It is challenging to decipher the effects of these myriad factors on the cardiovascular health in high altitude residents, and even more so in those ascending to high altitudes with or without preexisting diseases. This review aims to interpret epidemiological observations in high-altitude populations; present and discuss cardiovascular responses to acute and subacute high-altitude exposure in general and more specifically in people with preexisting cardiovascular diseases; the relations between cardiovascular pathologies and neurodegenerative diseases at altitude; the effects of high-altitude exercise; and the putative cardioprotective mechanisms of hypobaric hypoxia.

Introduction

Worldwide, about 400 million people reside at altitudes above 1500 m (~5000 ft) 1 and more than 100 million lowlanders visit areas above 2500 m (~8000 ft) annually. 2 Altitude ranges are commonly defined as high altitude (1500–3500 m; ~5000–11,500 ft), very high altitude (3500–5500 m; ~11,500–18,000 ft), and extreme altitude (>5500 m; >18,000 ft). 3 Figure 1 shows the altitude ranges of some of the world’s major mountainous regions.

Partial pressure of inspired O 2 (P I O 2 ) is decreased in mountainous regions. Representative cities in major mountain ranges are shown. Notes: The map is courtesy of NASA/JPL-Caltech and adapted from NASA/JPL-Caltech. Aster Global Digital Elevation Map (GDEM) . Available at: https://asterweb.jpl.nasa.gov/images/GDEM-10km-colorized.png . Accessed February 28, 2021. 210

At 5052 m (16,575 ft) above sea level, the world’s highest city is La Rinconada, Peru (population c. 50,000 in 2020). The highest major city, El Alto, Bolivia (population c. 940,000 in 2020) lies at 4150 m (13,615 ft). These and other sizeable cities are in very high-altitude regions ( Figure 1 ).

Whereas highlanders are chronically exposed to altitude and its associated climatic conditions, high-altitude travelers with or without pre-existing diseases, including tourists, climbers and trekkers, mine and road workers, porters and pilgrims, experience less protracted high-altitude exposures of hours to weeks. Climate changes progressively with increasing altitude, characterized by decreasing barometric pressure and partial pressure of inspired O 2 , declining ambient temperature and more intense ultraviolet solar radiation. 4 Although all these conditions may contribute to the development and progression of chronic and acute high-altitude illnesses, the reduced partial pressure of oxygen (hypobaric hypoxia) is considered the primary cause. 5–8 Genetic adaptations enable people to permanently live at altitudes up to 5000 m (~16,400 ft). 9 , 10 The highest altitude tolerable for prolonged sojourns is approximately 6000 m (~19,700 ft), which mine workers on Volcán Aucanquilcha, Chile endured for up to two years (West 1986). Appropriate acclimatization strategies allow short-term stays at altitudes higher than 7000 m (~23,000 ft) even for lowlanders, as demonstrated by many mountaineers. 11

Besides genetic and lifestyle factors, chronic exposure to high-altitude environments may impact cardiovascular health, disease development and life-expectancy. 12–18 While acute ascent to high altitudes may adversely affect cardiovascular health in lowlanders, particularly in those with pre-existing diseases, 19 , 20 acclimatization diminishes this risk and hypoxia conditioning can even benefit and protect the cardiovascular system. 21 , 22 Not surprisingly, the interactions between the high-altitude climate, individual genetic, life-style and socio-economic factors, adaptation and acclimatization processes to various altitudes are extremely complex, restricting straightforward predictions of high-altitude sojourns on health-related outcomes concerning the cardiovascular system. Therefore, this review aims to interpret available epidemiological observations in high-altitude populations, present and discuss cardiovascular responses to acute and subacute high-altitude exposure in general and particularly in people with preexisting cardiovascular diseases, the relations between cardiovascular pathologies and neurodegenerative diseases at altitude, the effects of exercise at altitude and the putative cardioprotective mechanisms of adaptations to acute and chronic hypoxia.

Living at High Altitude: Epidemiological Considerations

Epidemiological data from populations permanently residing at high-altitude strongly indicate that environmental factors differently impact the development of cardiovascular diseases, depending on the altitude. 17 , 18 , 23 , 24 While, for instance, lower mortality from cardiovascular diseases, stroke, cancer, and Alzheimer’s disease was reported in high altitude regions in the Swiss 18 and Austrian 24 Alps and the western United States 17 , 18 , 24 , 25 mortality from pulmonary morbidities (eg, emphysema, COPD) seemed to increase in high altitude residents. 17 , 26 Thus, considering (patho) physiological responses to hypobaric altitude/hypoxia, here we distinguish moderate altitude (1500 to 2500 m) 27 and high altitude from 2500 m to about 5000 m, the highest permanent human residence. 28 Data on the altitude-dependent prevalence of risk factors for cardiovascular diseases, eg, systemic hypertension, dyslipidemia and diabetes mellitus, and cardiovascular disease mortality may provide insights regarding the benefits vs detriments of living at moderate and high altitude, and the underlying mechanisms.

Systemic Hypertension

Reports of the effects of altitude on the prevalence of systemic hypertension, usually defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg, are conflicting. A survey of 1631 Tibet inhabitants living at three different altitude ranges between 2700 and 4505 m revealed a decrease in hypertension prevalence from 40.6% to 20.4% from the lowest to the highest range, associated with decreasing body mass index (BMI). 29 In contrast, systematic review of 8 cross-sectional studies totaling 16,913 individuals identified a close direct correlation between altitude and the prevalence of systemic hypertension in Tibet inhabitants, with a 2% increase in hypertension incidence per 100 m gain in altitude above 3000 m. 30 Concordant with these findings, another meta-analysis of 40,854 Tibetans living at ≥2400 m reported increases in systolic and diastolic blood pressures of 17 and 9.5 mmHg, respectively, per 1000 m gain in elevation. 31 However, in non-Tibetan, primarily Andean highlanders, blood pressure trended downward, albeit not significantly, with increasing altitude. 31

The observed differences between Andean and Tibetan highlanders may represent the vascular consequences of divergent adaptation patterns. 32 In Andean highlanders, chronic mountain sickness and pulmonary artery hypertension are more prevalent, while systemic blood pressure and cerebral blood flow are lower than in Tibetan highlanders. 33 The mechanisms underlying these differences may primarily relate to regulation of gene expression, eg, activation of hypoxia-responsive gene transcription by hypoxia-inducible factors. Notably, a recent study suggested that conventional blood pressure measurement may underestimate hypertension prevalence in Andean highlanders, while ambulatory blood pressure monitoring unmasks hypertension. 34 Collectively these studies identify genetic adaptations, lifestyle and climatic factors as pivotal determinants of blood pressure responses to living at high altitude. Decreased appetite and caloric intake, and increased energy expenditure due to low ambient temperature, likely contribute to lower BMI and reduced risk of hypertension at high altitude. 4 , 29

Dyslipidemia

Studies of residents of Lhasa, Tibet (3660 m) demonstrated high prevalence of hypertriglyceridemia in males and hypercholesterolemia in both sexes, and lower circulating high-density lipoprotein (HDL) cholesterol contents in females. 35 Similar findings were reported from the moderate-altitude (1500–2500 m) Yunnan-Kweichow Plateau in Southwestern China, with a higher prevalence of hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia in males, and slightly lower HDL cholesterol and higher LDL cholesterol values in females. 36 These authors attributed the prevalence of hyperlipidemia mainly to unhealthy living habits associated with obesity. By contrast, highly educated adults living in Riobamba, Ecuador (2754 m) had a lower prevalence of metabolic syndrome, hypercholesterolemia and hyperglycemia than lowlanders living on the Ecuadorian coast, 37 which may have been attributable to reduced appetite and self-reported lower energy intake at altitude. Socio-cultural and socio-economic factors explained inter-individual variation of hypercholesterolemia in the Swiss alpine population, while no specific altitude effects were detected. 38 Again, genetic, life-style, and socio-economic factors are probably more important than altitude-related low temperature and increased energy expenditure.

A cross-sectional study of 284,945 US residents revealed an inverse association (adjusted for multiple confounders) between altitude and diabetes prevalence. 39 Compared to low-altitude (0–499 m) residents, the odds ratio for diabetes was 0.95 (95% CI: 0.90–1.01) between 500 and 1499 m, and 0.88 (0.81–0.96) between 1500 and 3500 m. Notably, the inverse association was only true for men (0.84; 0.76–0.94), not women (1.09; 0.97–1.22). 39 Data from Tibetans living between 2900 and 4800 m suggested that altitude-related hypoxemia and polycythemia were closely associated with glucose intolerance and diabetes mellitus after adjusting for lifestyle. 40 As mentioned above, hyperglycemia was less prevalent in Ecuadorian Altiplano residents (~2770 m) than in lowlanders. 37 As diabetes type 2 is closely associated with obesity, lower obesity prevalence (adjusted for multiple covariates including physical activity) with increasing altitude may largely explain the reduced diabetes risk in highlanders, 41 underscoring the importance of altitude and cold on caloric intake-expenditure balance and BMI.

Chronic Mountain Sickness (CMS)

Chronic mountain sickness (CMS), also known as Monge’s disease, is a syndrome affecting about 5% to 10% of the 140 million people permanently living at high altitude. 42 It seems to be a consequence of progressive loss of ventilatory rate, increasingly observed with aging and resulting in excessive hypoxemia and polycythemia (Hb ≥19 g/dL for women and Hb ≥21 g/dL for men). 43 This syndrome is frequently associated with pulmonary hypertension, and in advanced cases, it may progress to cor pulmonale and congestive heart failure. 43 Periodic travel to lower altitudes is recommended for those with rather mild symptoms, but severe cases should move permanently to lower altitudes. 44

Mortality from Cardiovascular Diseases

In contrast to the inconsistent findings regarding the altitude-dependent prevalence of risk factors for cardiovascular diseases, data on the cardiovascular mortality risk are more consistent, at least for the moderate altitude regions of the Alps. Increasing altitude was associated with lower coronary heart disease and stroke mortality rates for both sexes in Switzerland 18 and lower mortality from coronary artery disease, male colorectal cancer and female breast cancer in Austria. 24 Faeh and colleagues reported respective 22% and 12% reductions in mortality from coronary heart disease and stroke per 1000 m gain in elevation. 18 Adjusted analysis revealed that the decreased mortality probably was not due to reductions in classic cardiovascular risk factors but instead might be explained by geographic factors like altitude/hypoxia and/or the effects of solar radiation on Vitamin D. Accordingly, the Austrian study revealed reductions of coronary artery disease mortality at 1000–2000 m vs <250 m of 28% in men and 31% in women. 24 These findings are concordant with life expectancy increases of 1.2–3.6 years in men and 0.5–2.5 years in women residing in US counties with mean altitudes >1500 m vs residents of counties within 100 m of sea level. 17

Detrimental effects of altitude residence on the risk of heart disease and mortality only rarely have been reported. Virues-Ortega and colleagues demonstrated increased overall mortality at higher altitudes, most pronounced over 3000 m, possibly due to more extreme climate conditions at those altitudes. 5 While risk factors for cardiovascular diseases are not uniformly affected by high altitude conditions, there is agreement on the beneficial effects of moderate if not extreme altitudes on the mortality risk from cardiovascular diseases. It thus seems likely that mild environmental stimuli (eg, hypoxia, cold, ultraviolet radiation) at moderate altitude will promote conditioning associated with favorable outcomes, vs the likely detrimental effects of more intense stimuli at extreme altitudes. 16 However, it is important to mention that altitude-related lifestyle behaviors very likely contribute to the observed beneficial effects of living at “moderate altitudes”, ie, below 2000 m, on the cardiovascular and cerebrovascular systems.

Acute and Subacute Effects of High-Altitude Exposure

Individuals rapidly ascending from low to high altitudes (>2000 m) are at risk to develop acute mountain sickness (AMS), which is characterized by headache as the predominant symptom, commonly accompanied by nausea, lack of appetite, vomiting, insomnia, dizziness, and/or fatigue. 45 The AMS prevalence was shown to increase from 7% at 2200 m to 38% at 3500 m, and to 52% when rapidly ascending to 4559 m in the alpine regions, 45 , 46 and a similar risk has been derived from Chinese highland military medical records. 47 Usually, AMS symptoms resolve during the first days at altitude, but may in rare cases progress to life-threatening diseases such as high-altitude cerebral edema (HACE) and/or high-altitude pulmonary edema (HAPE). A HACE prevalence of 0.98% has been reported in a cohort of 1326 European individuals sojourning to 4000 m, 48 while Wu and colleagues found a prevalence of 0.28% among 14,000 Asian railroad workers who travelled from lowland China to Tibet (3500–5000 m). 49 In a population of unknown HAPE history, the HAPE incidence was 0.2% when climbing to 4500 m within 4 days, but increased to 6% when ascending to this altitude in only 1 to 2 days. 20 Besides hypoxia at high altitude, other risk factors like extreme temperatures must be considered. For instance, while military troops have developed appropriate acclimatization schedules for hypobaric hypoxia, the very low temperature, eg, down to – 55°C during the winter time in the Western Himalayas, still remains an important health challenge, even in young, fit and healthy soldiers. 50 Adverse effects of acute high altitude exposure are largely avoidable by proper acclimatization, ie, low ascent rates, or the use of appropriate pre-acclimatization strategies. 45 A precise understanding of physiological responses to acute high altitude is required to optimize the individual acclimatization process and to avoid potentially associated risks to the cardiovascular system.

Declining partial pressure of oxygen, PO 2 , parallels decreasing barometric pressure (P B ) with increasing altitude. For instance, at 2360 m, the altitude of Addis Ababa, Ethiopia, P B and PO 2 are 75% of those at sea level, and at 5052 m, the altitude of La Rinconada, Peru they are only about 53% of the respective sea level pressures ( Figure 1 ). As PO 2 in the inspired air (P i O 2 ) declines, so does PO 2 in the alveoli (P A O 2 ) and systemic arterial blood (P a O 2 ), as does arterial oxygen saturation (S a O 2 ). Hypoxemia activates peripheral chemoreceptor afferents of the carotid bodies increasing minute ventilation and, via sympathetic activation, heart rate 51 and, thus, cardiac output. Collectively, these ventilatory and cardiac responses partially counteract the diminished oxygen supply at high altitude. 21 , 51–55 Generally, the rising sensitivity of the peripheral chemoreceptors over days at altitude increases ventilation, but ventilatory acclimatization differs among individuals. 56 Hyperventilation improves oxygenation but lowers P a CO 2 producing alkalemia. The resulting decrease of renal tubular H + secretion compensates for the respiratory alkalosis by enhancing urinary excretion of bicarbonate. 57 , 58 Elevated diuresis also causes hemoconcentration, on the one hand reducing plasma volume and lowering stroke volume and, on the other hand, increasing arterial oxygen content and oxygen delivery to tissues at a given cardiac output. 55 , 59 As acclimatization progresses, cardiac output returns to baseline but heart rate remains elevated because of the lower stroke volume ( Figure 2 ). 55

Changes of resting cardiovascular parameters when acutely exposed to high altitude and during acclimatization. Notes: Bbased on data reported in references 55 and 62–65 . From left to right.

Hypoxic pulmonary vasoconstriction, another physiologic hallmark of acute high-altitude ascent, elevates pulmonary artery pressure, and this response reportedly is particularly profound in the elderly. 53 , 62 Systemic blood pressure also increases upon initial ascent to altitude, primarily due to pronounced sympathetic activation, at least in men. 59 , 61 While ventilation and heart rate, pulmonary and systemic blood pressures, and sympathetic activity remain elevated with acclimatization, stroke volume decreases, cardiac output returns to baseline, and arterial oxygen saturation improves ( Figure 2 ). 55 , 59 , 62 Notably, all these responses vary considerably between individuals and do not completely compensate for the reduced P i O 2 , especially at extreme altitudes.

Despite all these changes, in healthy individuals, myocardial oxygen supply and left ventricular function are maintained at rest and even during maximal exercise at high altitude. 55 , 66 Moreover, moderate and high altitude are also well tolerated by healthy elderly subjects, 21 , 67 but may become detrimental in those suffering from cardiovascular diseases. 19 , 60

Cardiovascular Changes in Patients with Preexisting Cardiovascular Diseases

In cardiac patients, hypoxemia might be detrimental even at sea level, although there is very little evidence of aggravated cardiovascular diseases at least at low or moderate altitude. A list of recommendations from the European Society of Cardiology can serve as a basis for clinical practice. 68 However, as yet the biomedical literature provides no clinical evidence regarding the risk of all types of cardiovascular diseases at moderate or high altitude. 19 , 69 , 70 Nevertheless, the basic knowledge of the physiology of hypoxia and of the pathophysiology of cardiac or vascular diseases allows us to propose four simple guidelines to help practitioners make decisions and give appropriate advice to their cardiac patients with regard to altitude sojourns.

• Patients suffering from any diseases that may be aggravated by an overactivation of the adrenergic system (tachyarrhythmias) might be at risk at high altitude.
• Patients suffering from any diseases associated with pulmonary hypertension will be at high risk even at moderate altitude.
• Patients suffering from any diseases presenting, even at sea level, a certain degree of arterial hypoxemia (eg, increased right-to-left shunt) will be at risk at high altitude.
• For a given absolute power output during exercise, the heart rate (and therefore myocardial energy demand) increases with altitude, lowering the ischemic threshold in coronary patients.

The following advice can be given as a function of the preexisting disease.

Arrhythmias

Although rapid ascent to high altitude may increase the frequency of supraventricular and ventricular arrhythmias in patients with underlying heart disease, 60 , 71 , 72 no demonstrable clinical impact has been found. 73 However, it is reasonable to limit the access to altitude above 2500 m for patients with severe arrhythmias associated with underlying heart disease.

Pulmonary Hypertension

Preexisting pulmonary hypertension at sea level may deteriorate at even moderate altitude, regardless of the origin of the hypertension. Patients with congenital or acquired anomalies of the pulmonary circulation are also at high risk. 74 , 75 A transient hypoxic insult to the pulmonary circulation during the first postnatal week leaves a persistent imprint which, when activated by hypobaric hypoxia, predisposes to pulmonary hypertensive responses in adulthood. 76 Nevertheless, a recent pilot study showed that patients with pulmonary hypertension can safely adapt to a moderate altitude of 2048 m. 77

Right-to-Left Shunt

Right-to-left atrium shunting through a patent foramen ovale (PFO) might be aggravated in hypoxic conditions due to increased pressures in the pulmonary artery and the right heart. PFO was found to be present in 56% of patients susceptible to HAPE vs 11% of non-susceptible subjects. 78 , 79 Patients with cyanotic congenital heart diseases may be at heightened risk at even moderate altitude. 80

Coronary Artery Disease

It is reasonable to assume that in patients with a reduced coronary reserve, the decrease in oxygen availability due to altitude exposure will increase the risk of myocardial ischemia. However, the literature shows no evidence of increased incidence of acute myocardial ischemic events at low and moderate altitude. 60 , 72 , 81 , 82 In nine men with coronary artery disease, clinical or electrocardiographic signs of ischemia occurred at lower workloads at 3100 m than at 1600 m, although heart rate and heart rate x systolic blood pressure (rate pressure product, RPP) at the onset of angina were similar at the two altitudes. 72 These findings suggest that patients should limit their activity at high altitude by controlling their heart rate (70–85% of the ischemic threshold rate at lower altitude) rather than their workload. A rapid ascent and submaximal exercise proved to be safe at an altitude of 3454 m for low-risk patients with normal low-altitude exercise stress tests 6 months after revascularization for an acute coronary event. 83 Mortality from coronary heart disease, from 1990 to 2000, in men and women living at 259–1960 m decreased by 22% per 1000 m ascent. The consistently protective effect of living at higher altitude on coronary heart disease and stroke mortality increased after adjustment for potential confounders. 18

Congestive Heart Failure

Very few studies are available about heart failure at high altitude. 69 , 73 , 84 However, in 38 patients with a mean left ventricle ejection fraction of 35%, acute exposure to 3000 m in a hypobaric chamber induced no signs of myocardial ischemia, arrhythmias, or acute heart failure. 84 Altogether, it seems that up to 3000 m, there is no substantial increase in cardiovascular risk for patients with stable, compensated heart failure. 73 , 84 , 85 Corroborating this conclusion, a short-term high-altitude exposure at 3454 m was well tolerated in patients with stable heart failure. 83

The systemic circulation at high altitude is affected by two opposing phenomena: local hypoxia-induced vasodilation and general sympathetic-induced vasoconstriction. The relative impact of these two factors on local perfusion and systemic arterial pressures varies considerably among subjects. 73 , 83 , 86 , 87

In well-controlled hypertensive patients, no significant increase in systemic blood pressure is usually observed and no complications of systemic hypertension at high altitude have been reported. 87 Moreover, in 37 young adult men with stage 1 hypertension, completing a 20-day program of intermittent, normobaric hypoxia (inspired O 2 fraction 0.1; 4–10 daily cycles of 3 min hypoxia and 3 min room air breathing) lowered systolic and diastolic arterial pressures by 22 and 17 mm Hg, respectively. 88 Moreover, the decrease in systemic arterial pressure persisted at least 3 months after the hypoxia program in 85% of the subjects. Concordant with these results, no symptomatic episodes of hypertension were recorded in a cohort of 672 trekkers (60 of them with systemic hypertension), using conventional blood pressure measurements. 89 Therefore, no adverse effects are anticipated when patients with well-controlled hypertension are exposed to high altitude.

In summary, the literature is still sparse concerning cardiac diseases and tolerance to high altitude. However, it seems that patients with cardiac arrhythmias, pulmonary hypertension and right-to-left shunts should avoid an exposure to altitudes above 2500 m. In the case of coronary disease and congestive heart failure, the advice should depend on the functional state of the patient. Patients with well-controlled systemic hypertension are not at higher risk at high altitude.

Relation Between Cardiovascular Pathologies and Neurodegenerative Diseases at Altitude

Cardiovascular risk factors, such as total serum cholesterol or high systolic blood pressure, 90 are major risk factors for cognitive decline, the development of dementia and other age-related neurological diseases. 91–94 The brain’s particular vulnerability to perfusion deficits and its specific blood supply requirements, including increased on-demand perfusion with neuronal activation, highly selective permeability across the blood brain barrier, and vulnerability of the cerebral microvasculature, necessitate a particularly delicate regulation of cerebral blood flow. 95

Diminished oxygen supply to the brain – for example as a consequence of hypoxic conditions in high altitude – jeopardizes brain function and can acutely cause cognitive impairments, 96–101 mood alterations 102 , 103 and altitude-related conditions impacting the brain, such as acute mountain sickness or high altitude cerebral edema. 104 Severe hypoxia may even trigger parkinsonism-like symptoms 105–107 or global amnesia. 108 Brain deoxygenation at altitude reportedly is more pronounced during physical exercise 109 and more persistent than peripheral deoxygenation. 110

Several systemic, brain-specific and cellular physiological adaptations are implemented to mitigate the detrimental consequences of hypoxia on the brain. 111–119 As described above, peripheral chemoreceptor-induced hyperventilation 120 and cardiac output 121 , 122 enhance systemic and brain oxygenation. Metabolic autoregulation and neurovascular coupling 95 , 123 acutely modulate the cerebral blood flow in response to hypoxia. This modulation can vary across different cerebral arteries; thus, Feddersen et al 124 reported increased blood flow velocity in anterior and middle cerebral arteries of ascending mountaineers, while blood flow velocity in the posterior cerebral artery declined. In rats, acute hypoxia exposure only transiently increases cerebral blood flow, 125 while chronic hypoxia triggers erythropoiesis 125 as well as angiogenesis 125 that increases brain capillary densities. 126 , 127 At the cellular level, responses to hypoxia are mediated by numerous biochemical adaptations 111 including downregulation of O 2 -dependent reactions, promotion of glycolysis, 114 protection of mitochondria, 115 boosting of antioxidant defense mechanisms 113 , 116 and attenuation of cell death. 117

These effects of hypoxia exposure suggest its potential application to counteract age-related and pathological alterations of cerebral blood flow and cerebrovascular alterations. The role of aging-related cerebrovascular deterioration and cerebral blood flow dysregulation on cognitive dysfunction has been reviewed by Toth et al 95 and pathological alterations in neurovascular function are proposed to be key mechanisms in the pathogenesis of Alzheimer’s disease. 128

The cardiovascular adaptations to hypoxia, and in particular intermittent application of hypoxia (ie, hypoxia conditioning), improve cerebral blood flow and cerebrovascular function ( Figure 3 ), 90 , 129 in a manner that enhances cerebral oxygenation. 130 , 131 Intermittent hypoxia also increases brain capillary densities, although to a smaller extent than chronic hypoxia. 132 Hypoxia-induced angiogenesis may particularly improve neurovascular coupling. 126 , 133

Hypoxia-evoked adaptations improve cardiovascular determinants of brain oxygenation.

In support of the application of hypoxia to improve brain function, several recent clinical trials have reported improved cognitive function following intermittent hypoxia therapies, for example, in generally healthy older adults 134–136 or those with mild cognitive impairment, 137 , 138 a risk factor for the subsequent development of dementia. Although experimental data on hypoxia conditioning in patients with age-related neurological diseases is limited, the potential of such therapeutic strategies in these diseases is becoming increasingly acknowledged. 119 , 139 , 140 Preclinical studies in rodents further emphasize this potential, for example, in models of Alzheimer’s disease 141 , 142 and Parkinson’s disease. 143

Epidemiological studies on the effect of altitude of residence on brain function are conflicting, due in part to socioeconomic confounders. While reduced memory capacities were reported in young Tibetans living at 3650 m vs low altitude residents 144 and subtle impairments in speed of neurocognitive functions were reported in Andean high vs low altitude residents of different age groups, 145 no adverse cognitive effects were found in adolescent Bolivian high altitude (3700 m) residents. 146 Thielke et al 25 even report reduced Alzheimer’s disease mortality at higher altitudes of residence (up to 1800 m) in California.

More research is required to define the effects of altitude of residence on cognitive functions, particularly in association with neurodegenerative diseases. Nevertheless, controlled hypoxia interventions are promising therapeutic approaches to mitigate age- or disease-related cognitive decline.

Effects of Hypoxia on Aerobic Exercise, and Vice Versa

This section presents a brief description of the effects of hypobaric and normobaric hypoxia on responses to maximal and submaximal exercise, and then discusses some potential benefits and limitations of exercising in hypoxia.

Maximal Responses to Exercise in Altitude

At altitude, the decreased PO 2 and resultant hypoxemia 147 lower maximal oxygen uptake (VO 2max ) by approximately 6–7% per 1000 m increase at altitude. 148 This altered O 2 intake is the main factor limiting aerobic performance at altitude vs sea level. Of interest, the decrement in endurance exercise performance is less severe in normobaric hypoxia imposed by reductions in the inspired fraction of oxygen (F I O 2 ) than equivalent reductions in PO 2 due to decreased barometric pressure, ie, hypobaric hypoxia 149 since the intensity of the normobaric hypoxia stimulus may be lower, although this point is debated. 150 , 151 In either case, maximal cardiac output declines since both maximal stroke volume and heart rate are lower during hypoxia, whether due to decreased barometric pressure or F I O 2 .

Maximal heart rate (HR max ) declines at altitude. 152 , 153 It was argued that this decrease in HR max is only observable above a threshold of 2000–3500m 147 , 154 corresponding to the altitude used in training and/or rehabilitation. However, this decrease was reported already at low altitude (<1000 m). 155 Of clinical interest, the decrease in HR max is lower in normobaric than in hypobaric hypoxia. 156

Submaximal Responses to Exercise at Altitude/in Hypoxia

During submaximal exercise, HR is greater and stroke volume lower at a given exercise intensity in hypoxia vs normoxia. Since resting HR increases while HR max declines with altitude, HR reserve is attenuated, which the HR-based calculations of exercise intensity described below must take into account. The relationships between cardiac output, workload and VO 2 are preserved at all submaximal intensities, but reach their maxima at lower VO 2 and cardiac output 55 implying that altitude does not affect O 2 utilization efficiency. The mechanisms for the increased HR are still debated but sympathetic vasoconstrictor activity and the resultant higher vascular resistance likely predominate.

Therapeutic Exercising in Hypoxia for Cardiovascular Pathologies

Heart rate monitoring is very common and clinically safe for patients. 157 An important aspect when prescribing exercise in cardiovascular patients is the determination of exercise intensity. Generally, the recommended intensity is based on the percentage of HR max 158 , 159 and is estimated as 60–70% of HR max in patients. The hypoxic decrease in HR max described above has clinical implications and requires adjustment of the exercise intensity at altitude since a given percentage of HR max measured in normoxia would overestimate the target exercise intensity at altitude, with the risks of excessive fatigue or decreased adherence to training sessions.

Exercising in hypoxia, even at submaximal intensity, leads to a ‘compensatory’ vasodilatation, relative to the same exercise intensity in normoxia, 160 that, by augmenting blood flow, limits the decrement of oxygen delivery to the active muscles. Nitric oxide (NO) appears as the main vasodilator generated by the endothelium 161 even if several other vasoactive substances are also involved in this compensatory vasodilatation during hypoxic exercise. Of interest, this enhanced exercise hyperemia is greater at high altitude and augmented by increased exercise intensity. 160 , 162 By this mechanism, hypoxia may potentiate exercise-induced vascular adaptations such as vasodilation, 163 potentially benefiting patients with vascular dysfunction as in peripheral artery diseases.

Vasoconstriction in vascular beds of contracting muscles is blunted when exercise is performed in hypoxia, to the extent that vasodilation may prevail. 160 This functional sympatholysis may have additional effect with benefits for hypertensive subjects: the post-exercise hypotensive effect due to a reduction in total peripheral resistance is enhanced in hypoxia suggesting a larger hypotensive effect of exercise in hypoxia than in normoxia, 164 as suggested above.

Altogether, the health benefits of hypoxic exercise in cardiovascular patients are mediated by improved responsiveness of the vascular system, representing the balance of two opposing mechanisms: peripheral vasodilation and sympathetically mediated vasoconstriction. The effects of exercising at altitude in specific patients depend upon several factors, including the patient’s predisposition to exercise, the intensity of the hypoxic dose (altitude, exposure duration, rate of ascent, intermittent pattern) and attainment of adequate exercise intensity (but not limited to moderate intensity). Optimizing the benefits vs risks requires a patient-specific regimen and monitoring.

Cardioprotective Mechanisms of Hypobaric Hypoxia

By generating reactive oxygen species (ROS), intensifying sympathetic stimulation of the heart and lowering intracellular PO 2 , systemic hypoxia mobilizes diverse gene programs expressing myriad cytoprotectants including antioxidant, anti-inflammatory and glycolytic enzymes, anti-apoptotic factors and Ca 2+ transporters, which collectively defend cardiomyocytes from ischemic injury ( Figure 4 ).

Hypobaric hypoxia induces cardioprotective gene expression. Hypoxia elicits cardioprotective adaptations by activating three gene programs: (A) β-adrenergic activation of cyclic nucleotide response element (CRE) binding protein (CREB) promotes transcription of genes encoding sarcoplasmic reticular Ca 2+ ATPase (SERCA) and sarcolemmal Na + /Ca 2+ exchanger (NCX), thereby improving Ca 2+ homeostasis in the face of ischemia-reperfusion. (B) Intracellular hypoxia attenuates O 2 -dependent, prolyl hydroxylase (PHD) mediated degradation of the α subunit of hypoxia-inducible factor-1 (HIF-1), which translocates to the nucleus, binds HIF’s β subunit, and activates hypoxia-response elements (HRE) promoting expression of genes encoding hypoxia-adaptive proteins including erythropoietin, vascular endothelial growth factor (VEGF), nitric oxide (NO) synthase (NOS), endothelin-1, glucose transporters (GLUT) and glycolytic enzymes. Erythropoietin and NO suppress inflammation, VEGF promotes coronary collateral formation, endothelin-1 suppresses apoptosis, and GLUT and glycolytic enzymes support anaerobic ATP and phosphocreatine (PCr) production during ischemia. (C) Cellular hypoxia causes electron (e − ) accumulation in the mitochondrial respiratory complexes. These electrons combine with residual O 2 forming reactive oxygen species (ROS) which oxidize sulfhydryl moieties in Keap1, allowing Nrf2 to activate antioxidant response elements (ARE) in genes encoding antioxidant enzymes, thereby bolstering cellular defenses against ROS overproduction. ROS also augment HIF-1-activated gene expression by blunting HIF-1α degradation. Collectively, these mechanisms increase cardiomyocyte resistance to ischemia-reperfusion induced Ca 2+ overload, inflammation, mitochondrial permeability transition (MPT), ATP depletion and oxidative stress.

Defining hypobaric hypoxia’s cardioprotective mechanisms at the cellular level requires invasive analyses of gene expression, proteins, metabolites and organelles, which are not ethically feasible in humans under most circumstances. Consequently, information on the molecular underpinnings of hypoxia-induced cardioprotection is gleaned from studies in animals, primarily rodents. Many such studies utilize intermittent, not sustained, hypoxia involving brief hypobaric exposures or cyclic exposures to normobaric, hypoxic gas. Although intermittent hypoxia’s cardinal features differ from those of chronic hypoxia, information on intermittent hypoxia’s cytoprotective mechanisms likely applies at least qualitatively to sustained hypoxia, too.

Reactive Oxygen Species Induction of Antioxidant Genes

Hypobaric hypoxia elicits ROS formation in humans. After 48 h at 4300 m altitude, lowlanders showed increased serum and urinary concentrations of the lipid peroxidation products F 2 - and 8-isoprostanes. 165 In men exposed to 5500 m simulated altitude for 4 h, arterial O 2 saturation fell by 45%, serum concentrations of the ROS products malondialdehyde and oxidized protein sulfhydryls increased, 166 and serum [glutathione]/[glutathione disulfide] concentration ratio, a measure of antioxidant capacity, fell. In a recent study in lowlanders spending two weeks at c 3300 m, serum concentrations of total ROS, protein carbonyls and lipid peroxides rose by 38%, 140% and 44%, respectively, while antioxidant capacity fell by 17% and serum pro-inflammatory cytokines tripled. 167

Although intense ROS formation injures cardiomyocytes, moderate ROS formation during controlled hypoxia in rodents activates expression of antioxidant and anti-inflammatory genes, increasing cardiomyocyte resistance to ischemia. Research in hypoxia-conditioned rodents revealed robust antioxidant adaptations that paralleled ischemic tolerance. Jain et al exposed rats to extreme hypobaric hypoxia (9750 m simulated altitude; P I O 2 c 57 mmHg) then grouped the animals according to their hypoxia endurance. 168 The myocardium of the most hypoxia-tolerant rats had greater activities of EPO, GLUT-1 and the antioxidant enzymes catalase, superoxide dismutase and heme oxygenase-1 vs myocardium of the least tolerant animals. Also in rats, two days hypobaric hypoxia (7620 m simulated altitude; P I O 2 c 78 mmHg) induced myocardial lipid peroxidation and protein oxidation and depleted glutathione, but by 5 days, myocardial activities of antioxidant enzymes superoxide dismutase, glutathione S-transferase, glutathione peroxidase, heme oxygenase-1 and metallothionein all increased vs control myocardium. 169 Similarly, a program of 4 cycles of 4-days hypobaric hypoxia (4600 m simulated altitude; P I O 2 c 90 mmHg) and 4-days normoxia elicited mitochondrial ROS formation and increased myocardial catalase, glutathione peroxidase and superoxide dismutase activities. 170 , 171 Hearts isolated from the hypoxia-conditioned rats demonstrated increased left ventricular function and decreased lipid peroxidation following ischemia-reperfusion, vs hearts from normoxic rats. 170 Similarly, hearts isolated from guinea-pigs completing a 28-day intermittent, hypoxia regimen (5000 m simulated altitude for 6 h/d; P I O 2 c 112 mmHg) and subjected to ischemia-reperfusion or H 2 O 2 exposure showed increased superoxide dismutase and catalase activities and improved contractile function which was abolished by the catalase inhibitor aminotriazole. 172

Exposure of mice to 10 h hypobaric (4572 m) hypoxia (P I O 2 = 118 mmHg) activated myocardial expression of genes encoding antioxidant enzymes catalase, glutathione peroxidase, metallothionein and microsomal glutathione S-transferase. 173 The 50% decrease in myocardial glutathione content following hypoxia indicated significant oxidative stress, which likely activated antioxidant gene expression. In dogs completing a 20-day program of cyclic, normobaric hypoxia-reoxygenation 24 h before occlusion-reperfusion of the left anterior descending coronary artery, infarct size was decreased by over 95% and post-ischemic ventricular tachyarrhythmias were sharply attenuated vs sham-conditioned dogs. 174 Oral intake of antioxidant N -acetylcysteine 2 h before each hypoxia session abrogated the cardioprotection, implicating ROS in the cardioprotective mechanism. Although the dogs were conditioned by intermittent, not chronic, hypoxia, these results are concordant with cardioprotection by ROS signaling in chronic hypoxia, too.

Although the molecular mediators of ROS-induced gene expression are not yet established, the ROS-responsive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is the most likely candidate. ROS disrupt the disulfide bonds linking Nrf2 to its repressor, Keap-1, thereby allowing Nrf2 migration from cytosol to nucleus, where its interactions with antioxidant response elements in the promoter regions activate genes encoding a host of antioxidant and anti-inflammatory proteins 175 including catalase, metallothionein, heme oxygenase-1, glutathione peroxidase, glutathione S-transferase and other elements of the cardiomyocyte’s antioxidant armamentarium. 176 The effects of chronic, hypobaric hypoxia on Nrf2 are as yet unknown, and merit investigation.

Hypoxia-Inducible Gene Products

When exposed to chronic hypoxia, cardiomyocytes synthesize proteins that increase their tolerance to reduced O 2 availability. These proteins are products of an extensive gene expression program regulated by hypoxia-inducible factors (HIFs), the best-studied of which is HIF-1, a heterodimer of O 2 -regulated α and constitutive β subunits. During normoxia, prolyl and arginyl hydroxylases hydroxylate HIF-1α, targeting it for proteasomal degradation which limits HIF-1-activated gene expression. 177 HIF-1α hydroxylation declines as cellular O 2 concentration falls, whereupon the subunit translocates to the nucleus and combines with the β subunit forming the transcriptionally active HIF-1 heterodimer. By inactivating prolyl hydroxylase, ROS stabilize HIF-1α and, thereby, augment hypoxia-activation of HIF-1’s gene program. 178–180 HIF-1 activates hypoxia response elements in the promoters of over 100 genes. 181 HIF-1 activates expression of [1] glucose transporters (GLUT) and the entire glycolytic enzyme sequence beyond hexokinase, thereby augmenting glucose catabolism and anaerobic ATP production; [2] vascular endothelial growth factor (VEGF) which, by activating angiogenesis, increases collateral O 2 delivery to ischemic myocardium; [3] nitric oxide synthase (NOS), which generates the anti-inflammatory metabolite nitric oxide, [4] endothelin-1 (ET-1), which activates anti-apoptotic signaling cascades 182 and gene expression; 183 and [5] erythropoietin (EPO), which activates red cell production in erythropoietic tissues, and also exerts anti-inflammatory actions in heart and brain, both of which are capable of synthesizing EPO. 184 , 185 Hypoxia-induction of this diverse gene program 181 increases survival and functional recovery of cardiomyocytes threatened by ischemia-reperfusion.

Chen et al evaluated coronary collateral density in patients with >70% occlusion of one or more conduit coronary arteries. 186 The patients with more extensive coronary collaterals had higher HIF-1α contents in circulating monocytes and leukocytes. The association of greater collateral density and, therefore, myocardial oxygenation with increased HIF-1α content argues that HIF-1α and its gene product VEGF were likely responsible for the increased collaterals.

Sojourns at high altitude elicit EPO production which initiates erythropoiesis to augment the blood’s O 2 -carrying capacity. Accordingly, circulating EPO concentrations increased within one day of ascent in healthy adults ascending from sea level to >3000 m. 187 Analysis of glycosylated EPO glycoforms pinpointed the kidneys as the major source of circulating EPO in human subjects at 3454 m (P I O 2 c 137 mmHg). 188 Whether circulating EPO of renal origin contributes to hypoxia-induced cardioprotection, or if hypobaric hypoxia elicits myocardial EPO formation 184 in humans is unknown.

Sasaki et al studied rats acutely conditioned by 4 h normobaric hypoxia (F I O 2 0.10) and 24 h reoxygenation, followed by permanent coronary artery occlusion. 189 Three weeks later, the hearts of the hypoxia-conditioned rats were found to have greater dobutamine-recruitable contractile reserve, which paralleled increased myocardial capillary and arteriolar density, blood flow and VEGF content vs hearts of non-hypoxic controls. In Jain et al’s study, the myocardium of the most hypoxia-tolerant rats had greater activities of EPO and GLUT-1, as well as the aforementioned antioxidant enzymes, than myocardium of the least tolerant rats. 168 In Singh et al’s study of hypobaric hypoxia conditioned rats, 169 the increased myocardial antioxidant enzymes at 5 d hypoxia were accompanied by increased HIF-1α content and expression of HIF-1’s gene program products EPO, VEGF, GLUT-1 and nitric oxide synthase (NOS). A recent study in mice conditioned by 14 d continuous, normobaric hypoxia (F I O 2 0.07) demonstrated increased myocardial expression of genes encoding VEGF, its receptor VEGF-R2, and RABEP2, a regulator of VEGF-R2 endosomal trafficking, vs normoxic mice. Myocardium of the hypoxic mice also demonstrated increased coronary collateral development and capillary density, and decreased myocardial infarct size following coronary artery occlusion. 190

Hypobaric hypoxia is associated with increased circulating ET-1, as documented in healthy human subjects ascending to 3700–5000 m altitude. 191 , 192 Although a well-recognized vasoconstrictor, ET-1 at moderate concentrations suppresses cardiomyocyte apoptosis 182 , 183 by mobilizing signaling cascades that activate cytoprotective genes. 193 , 194 Human 195 and rat 196 cardiomyocytes synthesize and secrete ET-1 in response to hypoxia. HIF-1 activates cardiac ET-1 gene expression both directly 197 , 198 and via EPO. 199 Unlike moderate hypoxia, severe, deleterious hypoxia provokes ET-1 overproduction which activates cardiomyocyte apoptosis in a manner blunted by endothelin receptor antagonists 200 and likely contributes to the hypertensive response to severe hypoxia. 121

Sympathetic Activity and Myocardial Ca 2+ Management

Ascent to altitude elicits sympathetic activation of the heart. 60 Power spectral analysis of heart rate revealed increased sympathetic and decreased parasympathetic activities in lowlanders during 6-month sojourns at 4500–4800 m altitude. 201 Acute exposure of male lowlanders to 4000 m simulated altitude in a barochamber increased serum catecholamine concentrations. 202 Male lowlanders ascending to >3500 m showed persistently elevated sympathetic tone and serum catecholamines. 203

During hypoxia, β-adrenergic activation increases heart rate and stroke volume to increase cardiac output, thereby maintaining blood pressure and O 2 delivery to the periphery. Cardiomyocytes isolated from rats completing an intermittent, hypobaric hypoxia program showed increased sarcoplasmic reticular Ca 2+ ATPase activity and anti-apoptotic Bcl-2 content, and preserved sarcoplasmic reticular Ca 2+ turnover following in vitro ischemia-reperfusion. 204 In dogs, administration of the β 1 -adrenoceptor antagonist metoprolol during a 20-day intermittent hypoxia regimen prevented the robust reductions of coronary occlusion-reperfusion-induced myocardial infarction and ventricular tachyarrhythmias. 205

Increased cardiomyocyte Ca 2+ turnover mediates the inotropic and lusitropic effects of β-adrenergic activity. Acutely, phosphorylation of molecular targets by cyclic AMP- and Ca 2+ -calmodulin dependent protein kinases increases systolic sarcoplasmic reticular Ca 2+ release to augment Ca 2+ activation of the contractile machinery, and Ca 2+ sequestration to effect diastolic relaxation. β-adrenergic activity induces genes encoding Ca 2+ -transporting proteins ( Figure 4 ) via interaction of cyclic nucleotide response element (CRE) binding protein (CREB) with CRE motifs in gene promoters. 206 Thus, hypoxia-reoxygenation of cardiomyocytes provoked CREB DNA-binding and expression of its target genes. 207 β-Adrenergically activated CREB promotes synthesis of the mitochondrial anti-apoptotic factor, Bcl-2, 208 sarcoplasmic reticular Ca 2+ ATPase, 206 and sarcolemmal Na + /Ca 2+ exchanger. 209 Thus, β-adrenergic activation by hypoxia may elicit gene expression that preserves mitochondrial integrity and Ca 2+ homeostasis under pathological conditions.

Preclinical studies have disclosed complex signaling cascades whereby hypoxia bolsters myocardial resistance to ischemia and reperfusion. β-Adrenergic activity, moderate ROS formation and intracellular hypoxia mobilize CREB, Nrf2 and HIF-1 to activate their respective gene programs. The myriad products of these genes augment anaerobic ATP production and membrane Ca 2+ transport, suppress apoptosis, preserve mitochondrial integrity and confer powerful antioxidant and anti-inflammatory protection to blunt ischemia-reperfusion induced myocardial injury ( Figure 4 ). Defining the extent to which these diverse mechanisms effect cardioprotection in humans is crucial to develop interventions harnessing these mechanisms to treat and prevent ischemic heart disease.

The authors disclose no conflicts of interest in this work.

Mastering Mountain Mystique: How to Prepare for High-Altitude Travel

TL;DR  

• High-altitude travel requires comprehensive preparation to prevent acute mountain sickness .
• Acclimatization, the process of adapting to altitude, is key for a successful journey.
• Engaging in pre-trip training can enhance your body's capability to cope with high altitudes.
• Keeping hydrated and maintaining a balanced diet can help manage altitude sickness.
• Always travel with a well-stocked high-altitude first aid kit.

Understanding Altitude: The Science Behind the Sickness

The higher you climb, the thinner the air becomes. This scarcity of oxygen can send your body into a tailspin. As Dr. Benjamin Levine , a renowned Professor of Internal Medicine at UT Southwestern Medical Center, states, "At high altitudes, the body responds to the decrease in oxygen availability by increasing the respiratory rate and the heart rate. Understanding these physiological responses and preparing accordingly can make the difference between a successful trip and a medical emergency."

Acclimatization: The Body's Natural Defense

Consider acclimatization with your body's built-in altitude toolkit. It takes about two to three weeks for your body to acclimate to high altitudes. During this phase, your body turns into a lean, mean, oxygen-processing machine, enhancing the efficiency of your mitochondria - the cellular powerhouses - and increasing the number of red blood cells, helping ferry more oxygen to your muscles and brain.

High-Altitude Prep: From Couch Potato to Mountain Goat

Pre-trip training.

Before embarking on your journey , focus on improving your aerobic fitness . This involves endurance-based activities like jogging, cycling, and swimming. Strength training, especially exercises targeting your core, can also improve your trekking prowess. Remember, an altitude-ready body is not built overnight, so plan to start your training a few months in advance.

Diet and Hydration

Keeping hydrated can ward off symptoms of altitude sickness. Aim to drink at least 3-4 liters of water a day. Nutritious, easy-to-digest foods like fruits , vegetables, and complex carbohydrates can keep your energy levels stable.

The High-Altitude First Aid Kit

Your high-altitude first aid kit should contain essentials such as medication for altitude sickness (Diamox), pain relief (Ibuprofen), anti-nausea medication, sun protection, and a portable oxygen cylinder.

Conquer the Heights: Em

brace the Journey Once you're physically prepared, it's time to plan your ascent. Pace yourself, ascend gradually, and ensure you spend a day acclimatizing for every 600-900 meters (2,000-3,000 feet) of elevation gained. It's not a race to the top; it's about enjoying the journey while staying safe and healthy.

The Art of "Climb High, Sleep Low"

This mountaineering mantra encourages climbers to ascend to higher altitudes during the day and descend to sleep at night, thereby aiding acclimatization.

The Road Less Travelled: Uncommon Approaches to High-Altitude Travel

Mindfulness and meditation.

Mental preparation is just as crucial as physical preparation. Practicing mindfulness and meditation can help you stay focused, reduce stress, and enhance your overall travel experience. High-altitude travel isn't just about reaching the top, but about connecting with nature and yourself.

Embrace the Local Culture

Engage with local communities, explore regional cuisines, and learn about traditional altitude remedies. It's an enriching way to add more depth to your adventure.

FAQs on High-Altitude Travel

What is the most common mistake high-altitude travelers make.

The most common mistake is ascending too quickly. This does not allow the body time to acclimatize, leading to altitude sickness.

What should I eat while traveling at high altitudes?

Focus on a diet rich in carbohydrates. This provides the body with much-needed energy and aids in digestion, which can be slower at high altitudes.

What is the ideal pace for high-altitude trekking?

The pace varies from person to person. However, the general rule of thumb is to go slow, allowing your body to adjust to the altitude gradually.

Are children more prone to altitude sickness?

Children can acclimatize just as well as adults. However, because they might not be able to communicate their discomfort, caregivers should watch for symptoms of altitude sickness.

Can people with pre-existing medical conditions travel to high altitudes?

People with certain conditions, such as heart and lung diseases, should consult their healthcare provider before planning a high-altitude trip.

What is the ideal time to start preparing for high-altitude travel?

For physical preparation, starting two to three months in advance of your journey is generally recommended. For planning your trip and learning about altitude sickness and acclimatization, the earlier the better.

How will I know if I have altitude sickness?

Symptoms include headaches, nausea, dizziness, fatigue, shortness of breath, and sleep problems. If you experience any of these symptoms, descend to a lower altitude immediately and seek medical help.

Can I still get altitude sickness if I am in good physical shape?

Yes, fitness does not guarantee immunity from altitude sickness. The key is to acclimatize properly, irrespective of physical conditioning.

Is it possible to prevent altitude sickness?

While you cannot fully guarantee prevention, following the guidelines in this guide-such as gradual ascent, hydration, balanced diet, and appropriate rest-can significantly reduce the risk.

Can altitude sickness be life-threatening?

In severe cases, if not treated promptly, altitude sickness can indeed be life-threatening. It's essential to recognize symptoms early and descend to a lower altitude as quickly as possible.

A Final Word

Taking on high altitudes is not just about physical stamina; it’s an all-encompassing endeavor that requires mental fortitude, comprehensive preparation, and a deep respect for nature’s unpredictability. By being mindful of these recommendations , you'll stand a better chance of turning an ambitious high-altitude journey into a triumphant and enriching life experience.

• International Society for Mountain Medicine
• Interview with Dr. Benjamin Levine, UT Southwestern Medical Center
• High Altitude Medicine Guide

5 Types of Altitude in Aviation

Altitude is a critical aspect of aviation, as it refers to the height of an aircraft above sea level. Pilots must understand and use different types of altitude to navigate the skies safely and efficiently.

In this blog post, we will explore the different types of altitude in aviation and their importance for pilots. By the end of this post, you will better understand true altitude,  pressure altitude, density altitude , indicated altitude, flight level, and transition altitude and level.

So, let’s dive in and learn more about the types of altitude in aviation!

What is Altitude?

Altitude is a measure of an aircraft’s height above sea level . It is an important factor in aviation as it determines an aircraft’s position relative to the ground, other aircraft, and obstacles. Pilots use altitude to determine their location, navigate, and avoid collisions. Altitude is typically measured in feet or meters above sea level.

Understanding altitude is crucial for pilots, as it allows them to maintain a safe distance from the ground and other obstacles. It also enables them to navigate different types of airspace where specific altitudes are required for certain operations.

Overall, altitude is a critical component of aviation, and a thorough understanding of the different types of altitude is essential for all pilots. So, let’s explore the different types of altitude in aviation further.

Types of Altitude in Aviation

There are four main types of altitude in aviation: true altitude, pressure altitude, density altitude, and indicated altitude. Each type of altitude is measured and used differently, and pilots need to understand their differences.

True Altitude

True altitude is the vertical distance of an aircraft above mean sea level (MSL). It is  an important reference for navigation  and determines an aircraft’s vertical position on the Earth’s surface. True altitude is measured using altimeters that are calibrated to indicate true altitude.

Pressure Altitude

Pressure altitude is indicated when an altimeter is set to a standard atmospheric pressure of 29.92 inches of mercury (inHg) or 1013.25 millibars (MB). It determines an aircraft’s height above a standard datum plane rather than above mean sea level.  Pressure altitude is important for calculating aircraft performance , as it is not affected by changes in atmospheric pressure.

Density Altitude

Density altitude is relative to the standard sea-level atmosphere conditions. It is calculated by taking pressure altitude and correcting for non-standard temperature and pressure conditions.  Density altitude is essential for aircraft performance, as it affects an aircraft’s lift and thrust capabilities .

Indicated Altitude

Indicated altitude is the altitude shown on an aircraft’s altimeter when it is set to the local barometric pressure at the airport. It is the altitude that the pilot uses for navigating and controlling the aircraft in flight.  Indicated altitude is affected by changes in atmospheric pressure and temperature .

In addition to the four main types of altitude, other related terms are essential for pilots to understand:

Flight Level

Flight level is a type of altitude used in aviation above a certain altitude,  typically 18,000 feet above mean sea level . It is the altitude above the standard datum plane in 100-foot increments. Pilots use flight level instead of true altitude to reduce the number of altitude corrections required for atmospheric pressure changes.

Transition Altitude and Level

Transition altitude and level  are altitude values used to define the boundary between the airspace where aircraft use local barometric pressure and the airspace where they use standard pressure settings. They are essential for avoiding altitude conflicts between aircraft and ensuring safe navigation.

Overall, understanding the different types of altitude in aviation is essential for pilots to navigate safely and efficiently. By knowing how to use and interpret these different altitudes, pilots can maintain situational awareness and make informed decisions in the air.

What is Flight Level in Aviation?

Flight level is a type of altitude used in aviation that is defined as the altitude above the standard datum plane in 100-foot increments. It is typically used above a certain altitude, such as 18,000 feet above mean sea level. Flight level is essential for reducing the number of altitude corrections required for changes in atmospheric pressure, which can be significant at high altitudes.

The  main difference between flight level and altitude  is the reference point used to measure them. Altitude is typically measured in feet or meters above mean sea level, while flight level is measured in 100-foot increments above the standard datum plane. This standardization allows pilots to fly at the same altitude regardless of the local atmospheric pressure, which can vary due to weather conditions.

Another difference between flight level and altitude is the altimeter setting used to measure them. Altitude is measured using local barometric pressure settings, while  flight level is measured using a standard pressure setting of 29.92 inches of mercury or 1013.25 millibars . This standardization helps to reduce the potential for altitude errors and ensures consistent communication between pilots and air traffic control.

In summary, flight level is a type of altitude used in aviation that is standardized and measured above a certain altitude, typically 18,000 feet above mean sea level. It is used to reduce the number of altitude corrections required for changes in atmospheric pressure and is measured using a standard pressure setting. Pilots must understand the differences between flight level and altitude to maintain situational awareness and communicate effectively with air traffic control.

What is Transition Altitude and Level in Aviation?

Transition altitude and level are altitude values used to define the boundary between the airspace where aircraft use local barometric pressure and the airspace where they use standard pressure settings.

Transition altitude is the altitude at which the aircraft switch from the local barometric pressure setting to the standard. It is typically set at 18,000 feet above mean sea level but can vary depending on the location and airspace regulations.

The transition level is the altitude at which the aircraft switch from the standard pressure setting to the local barometric pressure setting on the descent. It is typically set below the transition altitude and varies depending on the location and airspace regulations.

Transition altitude and level are essential for pilots and air traffic control because they ensure safe navigation and avoid altitude conflicts between aircraft. Pilots must change their altimeter settings to ensure they are flying at the correct altitude when transitioning from one type of airspace to another. Failure to make this change can result in altitude errors and potential collisions with other aircraft.

Air traffic control plays a vital role in  managing the transition between different types of airspace  by providing pilots with information on the current altimeter settings and the transition altitude and level. This information helps pilots to make the necessary adjustments to their altimeter settings and maintain safe separation from other aircraft.

In summary, transition altitude and level are altitude values used to define the boundary between airspace where aircraft use local barometric pressure and airspace where they use standard pressure settings. They are essential for ensuring safe navigation and avoiding altitude conflicts between aircraft, and air traffic control plays a critical role in managing the transition between different types of airspace.

How Does The Performance Of An Aircraft Change At Higher Altitudes?

The performance of an aircraft significantly changes at higher altitudes due to the decrease in air density. This reduction in air density, known as high-density altitude, causes thin air and negatively impacts aircraft performance by reducing lift and impairing propeller efficiency. However, planes often cruise at high altitudes because they can burn less fuel and fly faster in less dense air. Despite this, the decreased air density also reduces engine performance, even though it improves fuel efficiency.

High altitude coupled with high temperatures and humidity can further reduce aircraft performance. When operating under these conditions, pilots must adapt their takeoff plans accordingly as these factors can affect takeoff distance, available power, and climb rate. The optimum altitude for flight is not constant and changes based on atmospheric conditions and the weight of the aircraft.

How Do Altitudes Vary In Different Regions Of The World?

Altitudes across the globe vary significantly due to geographical features and location. The highest point is Mount Everest in the Himalayas, while regions like the Tibetan Plateau in Asia and the Andean Altiplano in South America have landscapes over 10,000 feet above sea level.

Countries’ average topographical elevation can be influenced by mountain ranges or plateaus, with each continent having its highest and lowest points, such as Mount Kilimanjaro and Lake Assal in Africa, and Mount Everest and the Dead Sea in Asia. These altitudinal differences also impact regional climates, with temperature generally decreasing as altitude increases, leading to diverse weather patterns and ecosystems.

Learn More About the Types of Altitudes in Aviation at California Aeronautical University Today

We have explored the different types of altitudes in aviation, including true altitude,  pressure altitude, density altitude , indicated altitude, flight level, and transition altitude and level. Each type of altitude is measured and used in different ways, and pilots need to understand the differences between them to navigate safely and efficiently.

We also discussed the importance of altitude in aviation and how it affects aircraft performance, navigation, and collision avoidance.

By understanding the different types of altitude in aviation, you can become a more informed and skilled pilot and ensure the safety of yourself and others in the skies.

If you are interested in learning more about the types of altitude in aviation, we encourage you to explore the resources available at  California Aeronautical University . CAU offers a comprehensive curriculum covering all aviation aspects, including altitude and its importance in flight operations.

By  pursuing a degree  in aviation at CAU, you can gain the knowledge and skills necessary to become a successful pilot and advance your career in the aviation industry.  Contact us  today to learn more.

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Mr. Matthew A. Johnston has over 23 years of experience serving various roles in education and is currently serving as the President of California Aeronautical University. He maintains memberships and is a supporting participant with several aviation promoting and advocacy associations including University Aviation Association (UAA), Regional Airline Association (RAA), AOPA, NBAA, and EAA with the Young Eagles program.  He is proud of his collaboration with airlines, aviation businesses and individual aviation professionals who are working with him to develop California Aeronautical University as a leader in educating aviation professionals.

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