PRESENTED BY
GIANFRANCO PARATI

Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Gianfranco Parati

High altitude (HA) locations are defined as sites situated at an elevation of at least 2500m above sea level. Contemporary transportation options provide easy access to HA locations, making them conveniently available to a large number of individuals including the elderly, sedentary, and diseased persons. With increasing altitude, a progressive reduction in barometric pressure, air temperature, and air humidity develop. Physiological acclimatization mechanisms impose a significantly increased workload on the cardiovascular and renal systems. The effects of HA exposure are observed on numerous occasions, including ascending to mountain areas for leisure or work, on long-haul flights, and intermittent hypoxia exposure in miners working in HA conditions and residing at sea level. In all these cases, and especially for individuals with cardiovascular and renal problems, as well as patients with arterial hypertension, there is a need for clear instruction on safe exposure to HA conditions. Responding to this requirement, several years ago, a group of authors summarized the available information on this subject to provide recommendations and instructions for individuals with pre-existing clinical conditions, such as heart failure, arterial hypertension, arrhythmias, pulmonary and renal disease, planning to explore mountains for different reasons (1).

Physics and physiology of HA exposure
Ascending to HA exposes one to a gradual decline of barometric pressure, which determines the amount of inspired oxygen (O2), its partial pressure, and, in combination with alveolar ventilation, sets the alveolar O2 partial pressure (Figure 1). Its reduction leads to a condition known as ‘hypobaric hypoxia’. Alveolar hypoxia and arterial hypoxemia induce vasoconstriction in the pulmonary circulation, both directly and through sympathetic activation, resulting in increased pulmonary vascular resistance and pulmonary artery pressure (hypoxic pulmonary vasoconstriction) (1). However, hypoxemia is not the only factor affecting one’s health at HA. It is accompanied by other environmental parameters, such as low temperature, high UV radiation, and reduced humidity (Figure 1).

Figure 1. The relationship between the altitude, barometric pressure and fraction of inspired oxygen (FiO2), (1)

In a condition of acute hypoxia, a series of physiological responses help to maintain adequate O2 delivery and supply to the tissues. Acute exposure to hypoxia produces endothelium-dependent and endothelium-independent systemic vasodilation, which may initially induce a certain degree of blood pressure (BP) reduction. After a few hours, however, the initial vasodilation is replaced by systemic vasoconstriction, due to sympathetic activation reflexly induced by hypoxemia through peripheral chemoreceptor stimulation. Life-sustaining O2 delivery, in spite reduced pCO2, is in fact ensured by an increase in pulmonary ventilation, and sympathetic activation, leading to adjustments in cardiac output, BP, heart rate, and vascular tone, as well as increased hemoglobin concentration, and changes in renal function, i.e. water and sodium renal excretion (Figure 2), (1).

Figure 2. Physiological response to hypoxia (1)

The main effects of acute HA exposure
HIGHCARE (High Altitude Cardiovascular Research) program is a multidisciplinary scientific project which yielded a series of studies conducted in different HA regions, including the European Alps, Himalaya (Mount Everest), and the Andes in the last 20 years. The research aimed to explore the changes and adaptation mechanisms of cardiovascular and respiratory systems occurring in individuals exposed to HA hypobaric hypoxia. The observed effects of hypobaric hypoxia included hyperventilation and interstitial pulmonary edema; an increase of heart rate, cardiac output, and BP, accompanied by direct pulmonary vasoconstriction, and cerebral vasodilatation. There was an increased hemoglobin affinity for O2 accompanied by a rise of hematocrit. Furthermore, a rise in ANP and ADH levels were noted, as well as increased sodium bicarbonate renal excretion as a response to hypocapnia and respiratory alkalosis. Other changes included sleep disturbances and metabolic changes similar to metabolic syndrome (1). The observed changes were dependant on the duration of an individual’s exposure to altitude, age, the partial pressure of O2 in arterial blood, and minute ventilation. Some of these mechanisms activated almost immediately, whereas others needed hours to days to attain full expression.

The effects of HA on BP have also been monitored, considering that renin-angiotensin system activity changes with altitude. Conventional and ambulatory BP was measured at baseline and on-treatment with an angiotensin receptor blocker in healthy voluteers : after 8 weeks at sea level, and under acute exposure to 3400 and 5400 m altitude, the latter upon arrival and after 12 days (Mt. Everest base camp). The results showed a progressive increase of ambulatory BP with increasing altitude, which remained elevated after 3 weeks (2). The antihypertensive effects of the angiotensin receptor blocker were evident at sea level and at 3400m, but disappeared during the first week at 5400m due to suppression of renin-angiotensin-aldosterone system during acute exposure to such a very high altitude.

The effects of altitude on BP were explored also in hypertensive patients living in Peru at sea level and brought to an altitude of 3260 m for a few days. In the Peruvian Study, one hundred subjects with mild, untreated hypertension were randomized to double-blind placebo and angiotensin receptor blocker ̶ calcium channel blocker combination. Twenty-four-hour ambulatory BP monitoring was performed off-treatment, after 6 weeks of treatment at sea level, on treatment during acute exposure to HA (3260m), and immediately after return to sea level. 24-hour BP increased significantly during acute HA exposure in hypertensive subjects, however, the treatment with angiotensin receptor blocker ̶ calcium channel blocker combination provided effective protection in these circumstances (3).

Another study evaluated the effects of HA on diuresis and related mechanisms. Cardiovascular, endocrine, and renal responses to stepwise acute exposure to simulated altitude (6,000m) were compared in ten acclimatized recumbent mountaineers after descending from Himalayan altitudes of at least 4,000m and ten non-acclimatized recumbent volunteers for a mean of 24 days. The results showed that natriuresis and diuresis typified the renal responses to altitude exposure of both the acclimatized, as well as non-acclimatized subjects. This led to the conclusion that the renal effects were mediated by atrial natriuretic peptide release and slight suppression of arginine-vasopressin (AVP) secretion. Increased urine flow at altitude offset the cardiac (volume) overload, resulting from hypoxic stimulation of the arterial chemoreceptors. Enhanced AVP secretion, as found in the non-acclimatized subjects at and above 4000 m, coincided with inadequate altitude adjustment (4).

The effects of chronic HA exposure
Regarding chronic altitude exposure, the HIGHCARE Andes Study investigated differences between individuals residing in Cerro de Pasco, a mining town at 4550 m of altitude in the Peruvian Andes, and individuals living in Lima, at sea level. The prevalence of hypertension was low but not negligible among Andean HA dwellers. Higher rates of hypertension were observed with ambulatory as compared to office BP measurements. Relevant differences were observed in factors associated with daytime vs. night-time and diastolic vs. systolic hypertension. Polycythemia and chronic mountain sickness appeared to be strongly associated with ambulatory hypertension among highlanders (1).

High altitude hypoxic conditions exhibit several effects on the kidney depicted as High-Altitude Renal Syndrome. This condition is characterized by polycythemia, hyperuricemia, microalbuminuria, and increasing BP. ACE inhibitors appear effective at reducing proteinuria and lowering hemoglobin levels in these patients (5).

Recommendations for patients exposed to HA conditions
Based on the gathered evidence of the effects of HA on the human organism and system functions, we should increase awareness of altitude effects in persons with pre-existing cardiovascular and renal conditions. They should be advised on the importance of adequate preparation for the ascent, which should incorporate physical training and health status checks. If necessary, their chronic therapy should be revised and adjusted to expected conditions. The journey should be well planned, with a pre-determined speed of ascent, degree of physical activity, and altitudes at which to sleep to avoid possible adverse events.

Gianfranco Parati MD, FESC
University of Milano-Bicocca.
IRCCS, Istituto Auxologico Italiano, S.Luca Hospital; Cardiology Unit and Dept of Cardiovascular, Neural and Metabolic Sciences.
e-mail  gianfranco.parati@unimib.it; dir.sci@auxologico.it
Orcid: http://orcid.org/0000-0001-9402-7439

References

1. Parati G, Agostoni P, Basnyat B, et al. Clinical recommendations for high altitude exposure of individuals with pre-existing cardiovascular conditions: A joint statement by the European Society of Cardiology, the Council on Hypertension of the European Society of Cardiology, the European Society of Hypertension, the International Society of Mountain Medicine, the Italian Society of Hypertension and the Italian Society of Mountain Medicine. Eur Heart J. 2018;39(17):1546-1554. doi:10.1093/eurheartj/ehx720

2. Parati G, Bilo G, Faini A, et al. Changes in 24 h ambulatory blood pressure and effects of angiotensin II receptor blockade during acute and prolonged high-altitude exposure: a randomized clinical trial. Eur Heart J. 2014;35(44):3113-3122. doi:10.1093/eurheartj/ehu275

3. Bilo G, Villafuerte FC, Faini A, et al. Ambulatory blood pressure in untreated and treated hypertensive patients at high altitude: the High Altitude Cardiovascular Research-Andes study. Hypertension. 2015;65(6):1266-1272. doi:10.1161/HYPERTENSIONAHA.114.05003

4. Koller EA, Bührer A, Felder L, Schopen M, Vallotton MB. Altitude diuresis: endocrine and renal responses to acute hypoxia of acclimatized and non-acclimatized subjects. Eur J Appl Physiol Occup Physiol. 1991;62(3):228-234. doi:10.1007/BF00643747

5. Arestegui AH, Fuquay R, Sirota J, et al. High altitude renal syndrome (HARS). J Am Soc Nephrol. 2011;22(11):1963-1968. doi:10.1681/ASN.2010121316

6. Parati G. High Altitude Medicine. Presented at the 57th European Renal Association – European Dialysis Transplantation Association Congress (fully virtual), June 8, 2020. Available on the Virtual Meeting

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