Figure 2
Proposed mechanisms and hypothesised physiopathology at low altitude (<2500 m), high altitude (2500–3500 m) and very high altitude (>3500 m). O2 is the oxygen availability in relationship to sea level. FiO2: angiogenesis occurs at different elevations above sea level but during the hypoxic beneficial window, polycythaemia and red cell as well as platelet adhesiveness are not significant as above 3500 m, thus the protective effect reaches its maximum. Above 3500 m, although angiogenesis is present, the significantly high haematocrit and polycythaemia increase the risk of blood stasis and thrombogenesis. BP, barometric pressure.
Discussion
The results from this review suggest that stroke seems to be more likely to occur in very high-altitude locations (>3500 m) when the exposure is longer than 28 days, especially among younger people (<45 years old). On the other hand, when people live above 1500 m and below 3500 m, it seems like there is a protective effect for stroke, probably triggered by better adaptation to hypoxia, efficient enough to reduce the likelihood of dying when compared with lower altitudes; nevertheless, no information is available about the exact point in which this protective effect becomes a risk factor.
It has been challenging to define how high-altitude exposure can be defined and where the threshold is located in terms of mild or severe hypoxia.37 For instance, Imray et al in 2011 used a classification of high-altitude exposure according to the recommendations from the International Society of Mountain Medicine, a categorisation that seems to be the most pragmatic.38 The authors defined low altitude as everything located below 1500 m, moderate or intermediate altitude between 1500 and 2500 m, high altitude from 2500 to 3500 m, the very high altitude from 3500 to 5800 m, extremely high altitude more than 5800 m and death zone above 8000 m.38
As humans acclimatise to high altitude, adverse and often mild secondary effects can occur in response to hypoxia. Some of these adverse effects are linked to the increased blood viscosity due to polycythaemia, augmented pulmonary arterial pressure and, sometimes, they are linked to a proposed hypercoagulation unbalance.22 24
These consequences might be increasing the risk of forming an atherothrombotic plaque resulting in a stroke or myocardial infarction or venous thrombotic events, resulting in DVT or pulmonary embolism.39–41 Although information about the time of exposure is scarce, the longer the exposure, the higher the risk.21 42
Acute exposure to hypobaric hypoxia produces several compensatory physiological effects that can last for hours, days, months or years. The essential mechanisms are: increasing the heart and respiratory rates, a secondary polycythaemia, haemoconcentration derived from reduced plasma volume caused by respiratory evaporative water loss and polyuria and increased ventilatory response.37 43 44 When acute exposure lasts longer than 28 days, more efficient and prolonged mechanisms take place, including sustained polycythaemia, endothelium changes, reduced vascular resistance, nitric oxide-mediated hypotension and angiogenesis.45–48 Acute exposure to high-altitude hypoxia triggers a series of events that produce a hypercoagulable state.24 This hypercoagulable state is boosted by dehydration, haemoconcentration and polycythaemia. When combined with dehydration (due to tachyphemia and extenuating physical activity) and limited mobilisation (sleeping in tents and secluded spaces), these factors produce the perfect scenario for increasing vascular stasis and thrombosis.22 37 49
When humans are exposed continuously to hypoxia, they develop adaptative mechanisms that are far more efficient than those observed in newcomers.50–53 These long-lasting mechanisms include anatomical (wider chests, shorter and lighter bodies, etc), embryological (smaller fetus and placentas), circulatory (improved maximum flow output and higher pulmonary arterial pressure) and respiratory adaptations (improved hypoxic ventilatory response and oxygen diffusion capacities).52 54–56 Chronic exposure to hypobaric hypoxia leads to the development of more subtle compensatory mechanisms. These factors include long-term erythrocytosis, angiogenesis, capillary remodelling and an improved ventilatory response57–60 (figure 2).
Once the general context of acute or chronic hypobaric hypoxia has been described, the main intrigue is which elevation is enough to generate compensatory mechanisms capable of reducing the risk of developing stroke and when these mechanisms become detrimental. After reviewing the current literature, the information available suggests that a window around 2000–3500 m of elevation might be enough to generate some protective mechanisms (ie, angiogenesis or vascular remodelling) against stroke.21 45 48
In elevations below 2000 m, the degree of compensation might not be enough to ensure a protective effect, while at above 3500 m, the adaptative compensatory mechanisms such as significant polycythaemia and vascular stasis might increase the risk of thrombosis and, therefore, the risk of developing stroke14 22 32 (figure 2).
The information is still contradictory and opposed from one study to another. The few studies available have many limitations, and confounders’ control was low in most of them. Nevertheless, very few studies that are better controlled and designed support some of our statements above. This report was designed to guide clinicians and researchers who are currently working with stroke and wanted to understand the role of elevation and hypobaric hypoxia for developing stroke while we suggest that further analysis and well-controlled studies are needed.
Limitations
Several limitations were found, including scarce information, conflicting results and lack of data when adjusting for confounders. In this sense, more research is needed to obtain a definitive answer; nevertheless, the information provided in this document can be used as an updated guide of the possible role of high-altitude exposure as a risk factor for developing a stroke.
Conclusions
This review suggests that the most robust studies tend to advocate that prolonged living at higher altitudes reduces the risk of developing stroke or dying from it. Increased irrigation due to angiogenesis and increased vascular perfusion might be the reason behind improved survival profiles among those living within this range. In contrast, residing at high-altitude locations, especially above 3500 m, is associated with an apparent increased risk, probably linked to the presence of polycythaemia and other factors such as increased blood viscosity, and the presence of a proposed hypercoagulable state might increase the risk of developing stroke among those exposed to very high altitudes. It seems clear that short-term exposures to very high altitudes are a risk factor for developing a stroke. The available scientific literature suggests that above 3500–4000 m, the risk of developing stroke increases, especially if the exposure is acute among non-adapted populations.
It is important to note that one of the main limitations presented by some of the studies analysed was the lack of analysis of risk factors related to stroke; in addition, the level of education, socioeconomic level or living conditions of the participants were not analysed. We also highlight that certain risk factors such as diabetes, arteriosclerosis, coronary heart disease or hyperlipidaemia have a lower prevalence in people living in high-altitude areas
