European Heart Journal (2018) 0, 1–11 CURRENT OPINION

doi:10.1093/eurheartj/ehx720

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

Gianfranco Parati1,2*, Piergiuseppe Agostoni3,4, Buddha Basnyat5, Grzegorz Bilo1,2,

Hermann Brugger6,7, Antonio Coca8, Luigi Festi9,10, Guido Giardini11,
Alessandra Lironcurti1, Andrew M. Luks12, Marco Maggiorini13, Pietro A. Modesti14,
Erik R. Swenson12,15, Bryan Williams16, Peter Bärtsch17, and Camilla Torlasco1
1
Department of Cardiovascular, Neural and Metabolic Sciences, Istituto Auxologico Italiano, S. Luca Hospital, Piazzale Brescia, 20, 20149 Milan, Italy; 2Department of Medicine
and Surgery, University of Milano-Bicocca, Piazza dell’Ateneo Nuovo, 1, 20126 Milan, Italy; 3Department of Cardiology, Heart Failure Unit, Centro Cardiologico Monzino, via
Parea 4, 20138 Milan, Italy; 4Department of Clinical Sciences and Community Health, Cardiovascular Section, University of Milano, via Festa del Perdono 7, 20122 Milan, Italy;
5
Nuffield Department of Clinical Medicine, Oxford University Clinical Research Unit-Nepal and Centre for Tropical Medicine and Global Health, University of Oxford, Old Road
campus, Roosevelt Drive, Headington, Oxford OX3 7FZ, UK; 6Institute of Mountain Emergency Medicine at the EURAC Research, viale Druso 1, 39100 Bolzano, Italy; 7Medical
University, Christoph-Probst-Platz 1, Innrain 52 A - 6020 Innsbruck, Austria; 8Hypertension and Vascular Risk Unit, Department of Internal Medicine, Hospital Clı́nic (IDIBAPS),
University of Barcelona, Villarroel 170, 08036 Barcelona, Spain; 9Surgery Department, Ospedale di Circolo Fondazione Macchi, viale Luigi Borri, 57, 21100 Varese, Italy;
10
University of Insubria, via Ravasi 2, 21100 Varese, Italy; 11Department of Neurology, Neurophysiopathology Unit, Valle d’Aosta Regional Hospital, via Ginevra, 3, 11100 Aosta,
Italy; 12Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, 98195 WA, USA; 13Medical Intensive Care Unit,
University Hospital, Rämistrasse 100, 8091 Zürich, Switzerland; 14Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla, 3, 50134 Florence,
Florence, Italy; 15Pulmonary, Critical Care and Sleep Medicine, VA Puget Sound Health Care System, 1660 S Columbian Way, Seattle, 98108 WA, USA; 16University College
London (UCL) and NIHR UCL Hospitals Biomedical Research Centre, NHS Foundation Trust, University College, Gower St, Bloomsbury, London WC1E 6BT, UK; and
17
Department of Internal Medicine, University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany

Received 23 April 2017; revised 24 August 2017; editorial decision 16 November 2017; accepted 15 December 2017

.. The aim of this article is to review the available evidence on the

Introduction ..
.. effects of HA in cardiovascular patients and to address their risk of
..
The travelling options currently available allow an increasingly large .. developing clinically relevant events. This was done through multiple
number of individuals, including sedentary people, the elderly and dis- .. Medline searches on the PubMed database, with the main aim of pro-
..
eased patients, to reach high altitude (HA) locations, defined as loca- .. moting a generally safe access to mountains. Searched terms included
tions higher than 2500 m above sea level (asl),1S i.e. the altitude above .. a combination of either ‘high altitude’ or ‘hypobaric hypoxia’ plus
..
which many of the physiological responses that represent challenges .. each of the following: ‘physiology’, ‘maladaption’, ‘cardiovascular
for the human body start developing. Physiological acclimatization .. response’, ‘systemic hypertension’, ‘pulmonary hypertension’, ‘ischae-
..
mechanisms impose an increased workload on the cardiovascular sys- .. mic heart disease’, ‘cardiac revascularisation’, ‘heart failure’, ‘congeni-
tem, but the actual risk of adverse cardiovascular events associated
.. tal heart disease’, ‘arrhythmias’, ‘implantable cardiac devices’, ‘stroke’,
..
with HA exposure is still a debated issue.1–4 .. ‘cerebral haemorrhage’, ‘exercise’, ‘sleep apnea’. Compared with a
.
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponding author. Tel: þ39 02619112949, Fax: þ39 02619112956, Email: [email protected]
C The Author 2018. Published by Oxford University Press on behalf of the European Society of Cardiology.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/),
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 2 G. Parati et al.

Take-home figure Adapted from Bärtsch and Gibbs2 Physiological response to hypoxia. Life-sustaining oxygen delivery, in spite of a reduction
in the partial pressure of inhaled oxygen between 25% and 60% (respectively at 2500 m and 8000 m), is ensured by an increase in pulmonary ventila-
tion, an increase in cardiac output by increasing heart rate, changes in vascular tone, as well as an increase in haemoglobin concentration. BP, blood
pressure; HR, heart rate; PaCO2, partial pressure of arterial carbon dioxide.

previous review article on this topic,2S we now include the most

.. constitutes 20.94% of total gas molecules in inspired air, which with
..
recent data on hypoxia-induced changes in left ventricular (LV) sys- .. a normal rate of alveolar ventilation leads to an alveolar partial O2
tolic and diastolic function, lung function and ventilation control,
.. pressure of roughly 100 mmHg for a barometric pressure of
..
blood coagulation, and on the effects of pharmacological interven- .. roughly 760 mmHg.5S When breathing at 3000 m altitude asl, the
tions. We also offer an update on the clinical and pathophysiological
.. same percentage of O2 in the inspired air, combined with a lower
..
findings related to the exposure to altitude of patients with pre- .. barometric pressure and higher rate of ventilation, results in an
existing cardiovascular conditions (ischaemic heart disease, heart fail-
.. alveolar partial O2 pressure of roughly 67 mmHg, corresponding to
..
ure, and arterial and pulmonary hypertension). .. what would occur breathing a hypoxic air mixture (fraction of
..
inspired O2 0.14) at sea level (Figure 1).5S A series of physiological
...
.. responses help to maintain adequate tissue O2 delivery and supply
Physics and cardiovascular ..
.. at HA, through a process called ‘acclimatization’. Its efficacy
physiology at high altitude .. depends on the duration of individual’s exposure to altitude, age,
.. sea level partial pressure of oxygen in arterial blood (PaO2) and
..
With increasing altitude, a progressive reduction in barometric pres- .. minute ventilation.2,3,4S,5S These crucial processes include increase
sure, air temperature and air humidity can be observed (Figure 1).1S .. in ventilation, cardiac output, red cell mass and blood O2 carrying
..
For the purpose of this article, we refer to Imray et al.’s1S classification .. capacity, and other metabolic modifications at the microvascular
of altitude ranges. .. and cellular levels (Take home figure). Some of these mechanisms
..
Barometric pressure directly determines the inspired oxygen .. are activated almost immediately, whereas others need hours to
(O2) partial pressure and, in combination with alveolar ventilation,
.. days to attain full expression.2,4–6 A more extensive description of
..
sets the alveolar O2 partial pressure. Its reduction leads to a condi- .. the effects of HA exposure on cardiovascular physiology is pro-
tion known as ‘hypobaric hypoxia’. In practice, at sea level, O2
.. vided in the seminal papers by Bärtsch et al.2

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 Cardiovascular patients at high altitude 3

Figure 1 Altitude classification (Imray et al.1S) (left column); corresponding barometric pressure and fraction in inspired oxygen for different simu-
lated altitudes in a laboratory setting, according to the 1976 US standard Atmosphere by NASA.5S (central two columns); relationship between
altitude2S and environmental characteristics (temperature, humidity, and solar radiation) (box on the right-hand side). We used the 1976 US standard
atmosphere model by NASA to estimate barometric pressure at a given altitude, because the former is a function not only of altitude but also of lati-
tude. For similar altitudes, barometric pressure (and consequently also partial pressure of arterial oxygen) is higher the closer we are to the equator
line.

..
Systemic blood pressure and heart rate .. physically active persons and decreases alveolar diffusing capacity.14
.. Hypoxia-induced hyperventilation leads to hypocapnia and respira-
Acute exposure to hypoxia produces endothelium-dependent and ..
endothelium-independent systemic vasodilation,6S–9S which may ini- .. tory alkalosis, which blunts the initial full hypoxic ventilatory
.. response. The combination of hyperventilation and resulting hypo-
tially induce some degree of blood pressure (BP) reduction. After a ..
few hours, this is counter-balanced, however, by a generalized .. capnia, with increased peripheral chemosensitivity and abnormal
.. loop gain in chemoreflex-induced respiratory regulation7S may lead
altitude-dependent increase in sympathetically mediated vasocon- ..
striction, caused primarily by arterial hypoxaemia through afferent .. to the appearance of nocturnal periodic breathing (PB). This is an
.. abnormal ventilatory pattern, characterized by periods of central
signalling to the cardiovascular control regions of the mid-brain via ..
the arterial peripheral chemoreceptors located in the carotid .. apnoea or hypopnoea alternating with periods of hyperventilation,
.. mainly occurring during sleep.10,16,17,13S,18
bodies.5,6,10S As a result, a significant and persistent arterial BP ..
increase occurs shortly after the arrival at HA, proportional to the .. With exposure over days to weeks, the sensitivity of the peripheral
.. chemoreceptors to hypoxia increases, resulting in a further increase
altitude reached and more evident at night.7 This leads to a reduced ..
degree of the physiological blood pressure fall during sleep,8 which ... in sympathetic activity and enhancement of ventilation, despite the
persists at least over the first 7 days of altitude exposure.9 This is .. progressive increase in arterial blood O2 content and lower partial
.. pressure of arterial carbon dioxide (PaCO ) (‘ventilatory
accompanied by an increase in heart rate (HR) both at rest and dur- .. 2

ing exercise,10,11,11S although maximal HR achieved during exercise .. acclimatization’, see Supplementary material online, Table S1).19,14S
..
at HA is lower compared to sea level (see Supplementary material ..
online, Table S1).2,11–14
..
.. Pulmonary arterial pressure
..
.. Alveolar hypoxia and arterial hypoxaemia (to a lesser degree) induce
Ventilation .. vasoconstriction in the pulmonary circulation, either directly and
..
With acute exposure to altitude, the decrease in PaO2 stimulates .. through sympathetic activation,14,18,19,14S,15S resulting in increased pul-
peripheral chemoreceptors in the carotid bodies leading to sympa-
.. monary vascular resistance and pulmonary artery pressure (hypoxic
..
thetic activation and to an increase in minute ventilation.2,14 .. pulmonary vasoconstriction).14S Hypoxic pulmonary vasoconstriction
Moreover, mild interstitial lung fluid accumulation15 can occur in
.. is a protective mechanism during regional alveolar hypoxia (e.g.

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 4 G. Parati et al.

Table 1 Recommendations for heart failure patients going to high altitude

HF severity level Recommendations Class of Level of References

evidence evidence
....................................................................................................................................................................................................................
All HF patients Carefully evaluate HF co-morbidities (e.g. pulmonary I C
hypertension, anaemia, sleep apnoea)
10,13,20S
Carefully evaluate HF drugs (in particular diuretics, I B
potassium supplementation, and b blockers).
Whenever possible, b1 selective should be
preferred to non-selective beta-blockers
Slow ascent is recommended. Although we do not have I C
precise data on advisable ascent rate, it is prudent not
to exceed that recommended for healthy travellers
(300–500 m/day when above 2500 m)
25
Stable NYHA I-II patients May safely reach high altitude up to 3500 m IIa C
25
Once at altitude, not heavier than moderate physical IIa C
activity is recommended
24
Stable NYHA III patients May safely reach high altitude up to 3000 m, if needed IIa C
23,24
Once at altitude, not heavier than light physical activity IIa C
is recommended
Unstable/NYHA IV patients Avoid high altitude exposure I C

The strength of these recommendations is to be weighted in the light of the limited evidence available.
HF, heart failure; NYHA, New York Heart Association.

..
pneumonia) to shift blood flow to better ventilated lung regions, but .. Recent evidence suggests that hypoxia itself can be the basis for LV
at HA, where the hypoxic stimulus is ubiquitous throughout the lungs, .. alterations. 31P magnetic resonance spectroscopy performed before
..
global alveolar hypoxia leads to general pulmonary hypertension with .. and after ascent to Mt. Everest in healthy individuals revealed a
the risk of pulmonary oedema or right ventricular failure in the .. decrease in the cardiac creatine phosphate/adenosine triphosphate
..
extreme cases (see Supplementary material online, Table S1).16S We .. (PCr/ATP) ratio by 18% (P < 0.01), similarly to what is observed in
found only one study investigating pre-capillary pulmonary .. patients with diseases associated with chronic hypoxia.21 All these
..
hypertension.17S Although the sample size was small (n = 14) and the .. reductions returned to pre-trek levels 6 months after return to the
exposure to simulated HA was short (at rest and after 20 min of mild .. sea level. The authors concluded that a decrease in energy reserve
..
exertion), non-invasive measures of the right heart function demon- .. may be a ‘universal response to periods of sustained low O2 availabil-
strated a predictable rise in pulmonary arterial systolic pressure, not .. ity, underlying hypoxia-induced cardiac dysfunction both in the
..
associated with a deterioration in the right heart function. .. healthy human heart and in patients with cardiopulmonary diseases’.
..
..
.. Other effects
..
Left ventricular function .. Mild dehydration and a hypoxic-mediated diuresis were found to lead
.. to an acute increase in haematocrit and haemoglobin concentration in
The left ventricle undergoes significant changes when exposed to ..
.. the first several days at HA,18S after which the renal production of
HA.11,20,21,17S In particular, a reduction in both diastolic and systolic .. erythropoietin stimulates new red blood cell production to increase
LV volumes and geometrical alterations (increase in the sphericity ..
.. red cell mass, with a further rise in haemoglobin concentration. In the
index) occur, the diastolic function worsens and the LV contractility .. acute exposure phase, this can be associated with increased blood
and LV apex twist increase, the last change being similar to what is ..
.. coagulability.22 Nevertheless, an increased thrombotic risk at HA has
observed in cases of subendocardial LV fibre dysfunction.20 ..
.. never been convincingly demonstrated, and the limited available data
Moreover, after 2 weeks of exposure to very HA, LV mass decreases
.. are conflicting with respect to a hypothetical prothrombotic state.22,23
disproportionately when compared with the concomitant reduction ..
in total body weight (11% vs. 3% reduction for LV mass vs. body ..
..
mass, adjusted for body surface area, P < 0.05).21 Lung impairment via .. Heart failure
cardiopulmonary interaction (with arterial hypoxaemia made worse ..
..
due to mild interstitial oedema), especially during the first 2 weeks, .. Heart failure (HF) is often associated with co-morbidities, such as pul-
and the increased LV inotropic stimulation by an increased sympa- .. monary hypertension, chronic obstructive pulmonary disease, chronic
..
thetic activity are considered to play a role in the development of .. kidney disease, cardiac ischaemia, anaemia, and thrombophilia. This
these changes, but probably they cannot completely explain the
.. condition is also characterized by an increased chemosensitivity.20S
..
extent of the observed findings. . All these conditions are likely to make HF patients more vulnerable

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 Cardiovascular patients at high altitude 5

..
to the HA environment. In spite of this, brief simulated HA exposure ..
..
Ischaemic heart disease
was found to be safe for HF patients,24 even when performing mild
..
physical exercise. Agostoni et al.24 evaluated 38 patients with severe .. It has been suggested that living permanently at moderate altitude
stable HF [New York Heart Association (NYHA) Class III–IV] under- .. might be beneficial, reducing CV mortality.27S Acute exposure to HA,
.. on the other hand, may represent a more challenging condition for the
going cardiopulmonary exercise testing with a progressive reduction ..
in inspired O2 from 21% (sea level) to 18%, 16%, and 14% (the last .. cardiovascular system. Given that total O2 demand is constant for a
..
simulating 3000 m altitude). No episodes of angina, arrhythmias, or .. given workload and that myocardial O2 extraction is already very high
electrocardiographic (ECG) evidence of ischaemia occurred at any .. at sea level, with acute HA exposure cardiac output must increase to
..
simulated altitude. The reduction in maximum work rate achieved at .. maintain O2 delivery despite the reduced blood arterial O2 content.
simulated altitude was progressively greater the more severe the .. In healthy subjects, epicardial coronary blood flow increases due to
..
exercise limitation at sea level. Finally, patients who showed the larg- .. vasodilation during acute HA exposure and thus there may not be any
est increase in the lung diffusion capacity for CO (DLCO) at sea level .. significant impairment during exercise of coronary flow reserve, at least
..
during moderate exercise were those who showed the lowest exer- .. up to 4500 m.27 The actual risk of cardiac ischaemia associated with HA
cise capacity reduction at simulated altitude,20S linking HA exercise .. is indeed unclear. On the one hand, stress testing performed in healthy
..
performance to gas exchange adaptability. .. subjects above a simulated altitude of 8000 m27S did not induce ECG
Schmid et al.25 evaluated stable HF patients (NYHA Class II) exer-
.. alterations; on the other hand, changes in arterial wall properties may
..
cising during a short exposure to HA (3454 m, Jungfraujoch, .. reduce coronary O2 supply in diastole at HA, with possible clinical impli-
Switzerland) and at sea level. During HA exercise, mean peak VO2
.. cations in subjects with silent coronary plaques. Evidence in this regard
..
decreased by 22%, without causing arrhythmias or altering echocar- .. has been obtained through calculation of the subendocardial viability
diographic variables, with the exception of an increase in pulmonary
.. ratio (SEVR), defined as the ratio between diastolic pressure–time index
..
artery systolic pressure (PAPs). Drug therapy of HF may also inter- .. (DPTI, an estimate of myocardial O2 supply based on both coronary
.. artery driving pressure in diastole and diastolic time) and systolic pres-
fere with HA adaptation mechanisms. Critical HF drugs such as beta- ..
blockers and angiotensin-converting enzyme (ACE) inhibitors act on .. sure–time index (SPTI, an estimate of myocardial O2 consumption in
.. systole). Subendocardial viability ratio, therefore, indirectly estimates
the chemoreceptors and on haemodynamic responses through adre- ..
nergic receptors, which are also involved in the alveolar–capillary gas .. the degree of myocardial perfusion and was found to be significantly
.. reduced at 4559 m in healthy volunteers (from 1.63 ± 0.15 to
diffusion control (b2-receptors). Despite their importance in the ..
care of patients with HF which is incontrovertible at sea level, ACE .. 1.18 ± 0.17; P < 0.001).28 The administration of acetazolamide was asso-
.. ciated with a smaller degree of SEVR reduction under hypobaric hypo-
inhibitors and angiotensin receptor blockers (ARBs) do blunt the ..
kidney’s ability to produce erythropoietin and could limit the com- .. xia exposure and with faster recovery after residing for 3 days at HA,
..
pensatory rise in haematocrit and blood O2-carrying capacity that is .. suggesting that acetazolamide may offset the reduction in subendocar-
important at HA.21S,22S HIGHCARE (HIGH altitude CArdiovascular .. dial O2 supply in these conditions.28 Similarly, at HA, also the O2 supply/
..
REsearch) investigators reported that healthy subjects receiving the .. demand ratio (SEVR-CaO2, i.e. SEVR corrected for the arterial O2 con-
non-cardioselective b2 antagonist carvedilol reached lower peak .. tent) displayed significant reductions, which were more pronounced
..
exercise ventilation and lower VO2 peak at HA than those receiving .. with placebo (from 29.6 ± 4.0 to 17.3 ± 3.0; P < 0.001), than with aceta-
the selective b1 receptor blocker nebivolol.13 Carvedilol also .. zolamide (from 32.1 ± 7.0 to 22.3 ± 4.6; P < 0.001), indicating a smaller
..
reduced hyperventilation during exercise, possibly by reducing .. reduction in subendocardial O2 supply/demand ratio with acetazola-
peripheral chemoreceptor sensitivity. This effect may be favourable
.. mide administration. The clinical relevance of a reduced SEVR at HA in
..
in normoxia, because the fall in arterial O2 saturation is quite small at .. patients with an increased cardiovascular risk is suggested by a case
sea level, but can be much greater and unfavourable at HA.20S,23S
.. report of a middle-aged mild hypertensive subject with normal cardio-
..
Moreover, administration of diuretics should be based on the bal- .. pulmonary exercise testing (CPET) at sea level, in whom acute expo-
anced evaluation of signs of early dehydration or fluid gain. Among
.. sure to an altitude of 3340 m was responsible not only for a marked
..
the diuretics, acetazolamide, a carbonic anhydrase inhibitor with mild .. reduction in SEVR and in SEVR-CaO2 but also for the development of
diuretic effect, which is frequently used for mountain sickness pro-
.. angina and ischaemic ECG changes when cardiopulmonary stress test-
..
phylaxis and treatment, should be specifically considered.24S It should .. ing was repeated at HA. This occurred 2 days after a negative stress test
.. at sea level, the only difference being the acute exposure to HA.29
be emphasized that the concomitant administration of acetazolamide ..
and other diuretics may increase the risk of dehydration and electro- .. Patients with coronary artery disease (CAD) may face more diffi-
.. culties with HA exposure, because of the already increased basal cor-
lyte imbalances at HA and should thus be carefully evaluated. ..
A final issue is related to periodic breathing. It can be present in HF .. onary flow at sea level, impairment in arterial elastic properties
.. induced by atheromatous lesions and microvascular dysfunction.
patients at sea level, both during sleep and exercise, but likely it will ..
worsen at HA.12S,25S,26 Whether it should be suppressed with aceta- .. However, there is little evidence available about HA-induced ischae-
..
zolamide remains an issue yet to be clarified. .. mia in CAD patients. Schmid et al.30 did not find signs of ischaemia
Very little is known about the effects of HA in patients who under- .. during CPET performed at 3454 m in 22 low-risk ischaemic patients
..
went heart transplant. Living at moderate altitude seems not to be .. with a normal CPET at sea level. The HA evaluation was performed
harmful, but no data are available on the effects of acute HA .. 6–18 months after revascularization, either by percutaneous stenting
..
exposure.26S Recommendations for HF patients going to be exposed .. or by surgical coronary artery bypass grafting (CABG), and after
to HA are summarized in Table 1. .. wash-out from beta-blockers. The same conclusion was reached by

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 6 G. Parati et al.

Table 2 Recommendation for ischaemic patients ascending to high altitude

Patient risk class Recommendations Class of Level of References

evidence evidence
....................................................................................................................................................................................................................
General recommendations for Patients should continue pre-existing medications at HA. I C
all cardiovascular patients All therapy changes, especially dual anti-antiplatelet
therapy after drug-eluting stent implantation, must be
discussed with a doctor before enacting. Individuals
who do not engage in physical exertion at low altitude
should not engage in physical activity at HA.
28
Acetazolamide administration seems to reduce the risk IIa C
of subendocardial ischaemia at HA in healthy subjects,
and thus use of acetazolamide for AMS prevention
might be helpful. No data are available, however, in
patients with CAD.
5,12,30
After AMI/CABG Patients should wait at least 6 months after uncompli- I C
cated ACS episode as well as after revascularization
before HA exposure.
12,31,33,30S
After stenting Patients should wait at least 6–12 months after coronary IIa C
stenting before HA exposure.
12,31
Low risk (CCS 0-I) May safely ascend to HA, up to 4200 m asl, and practice IIa C
light-to-moderate physical exertion.
22
Moderate risk CAD (CCS II-III) May carefully ascend up to 2500 m, but physical exercise IIa C
heavier than light is contraindicated.
High risk (CCS IV) Should not ascend to HA. I C

The strength of these recommendations is to be weighted in the light of the limited evidence available.
AMI, acute myocardial infarction; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CCS, Canadian Cardiovascular Society; HA, high altitude.

..
De Vries et al.12,31, who evaluated 8 low-risk patients with a history .. for 10 days. ECG, echocardiography, and polysomnography did not
of acute myocardial infarction (MI) and 7 controls during the Dutch .. show any signs of ischaemia or arrhythmia on multiple trips over
..
Heart Expedition 2007 to Aconcagua (4200 m). Furthermore, .. 3 years. On the other hand, Basavarajaiah and O’Sullivan33 reported
Messerli-Burgy et al.5 did not find any increased risk for cardiac .. 2 cases of very late stent thrombosis in patients undergoing intense
..
arrhythmias in post-MI patients at 3546 m. .. physical exertion at moderate altitude (3000 m and 1300 m, 16 and
Heterogeneous definition of ‘low-risk’ individuals, limited informa- .. 48 months after drug-eluting stent implantation, respectively).
..
tion about ongoing treatment, previous performance of any revascu- .. However, no evidence supports a causal link between HA and stent
larization procedure and time since acute MI occurrence reduce the .. thrombosis in these patients. In contrast, intense physical activity has
..
ability to generalize these findings to a wider population. .. been associated with late stent thrombosis at sea level.29S
Evidence for ‘medium-risk’ patients is even more limited. One ..
..
study examined the simulated altitude effects on coronary flow in 8 .. Coronary artery bypass grafting
medium-risk patients undergoing stress testing at a simulated altitude
..
.. In the aforementioned study by Schmidt et al.,30 7 patients underwent
of 2500 m. The results showed an inability of their coronary blood .. CABG. A rapid ascent to HA (3454 m) and submaximal exercise
flow to adapt after an increase in demand.30
..
.. were found to be safe 6 months after CABG.30S
..
.. Recommendations for ischaemic heart disease patients are
Percutaneous revascularization ..
.. reported in Table 2 and Supplementary material online, Table S2.
Only one study and a couple of case reports are available on this ..
topic. In the above-mentioned study by Schmid et al.30, among the 22 ..
..
low-risk, revascularized ischaemic patients, 15 had ST-elevation MI .. Systemic arterial hypertension
and 7 non-ST-elevation MI, undergoing CPET at HA. Among these ..
..
patients, 15 had undergone percutaneous revascularization, and .. As described above, BP increases after a few hours at HA (especially
none showed signs of ischaemia during altitude exercise.30 .. at night) and remains virtually unchanged over the following days.34
..
Moreover, Wu et al.32 described the case of a 49-year-old male engi- .. Hypertensive patients may be more susceptible to HA due to an
neer with a history of CAD treated with 2 drug-eluting stents who,
.. already elevated hypoxic peripheral and central chemoreflex
..
2 years later, went to work on the Qinghai-Tibet railway (4905 m) . sensitivity30S,32S and to alteration in calcium homeostasis.33S,34S

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 Cardiovascular patients at high altitude 7

..
.. When considering the effects of antihypertensive treatment at alti-
.. tude in patients suffering from high blood pressure included in the
..
.. HIGHCARE ANDES study, the combination of a dihydropyridine cal-
.. cium channel blocker and an angiotensin II receptor blocker [nifedi-
..
.. pine GITS (Gastro Intestinal Therapeutic System) and telmisartan]
.. was found to be effective in controlling BP at HA in hypertensive
..
.. patients.35
.. In a large recent study by Keyes et al.,35S 672 trekkers, 60 with a
..
.. prior diagnosis of hypertension, underwent conventional blood
.. pressure measurement at rest at altitudes of 2860, 3400 and
..
.. 4300 m. No significant differences in mean systolic BP (SBP) and
.. diastolic BP (DBP) among altitudes were found either in normoten-
..
.. sive or in hypertensive trekkers, probably because of the large
.. interindividual variability in BP levels at different altitudes obtained
..
Figure 2 Systolic blood pressure profile for 24 h in a healthy vol- .. with the method of BP measurement used in this study. At 3400 m,
unteer at different altitudes. Blue line: sea level; yellow line: Namche
.. 60% of normotensive participants had a BP within 10 mmHg of
..
Bazaar (3400 m); red line: Everest Base Camp 1 (5400 m). .. their BP at 2860 m, while in 21% BP increased above and in 19%
.. decreased below this threshold. Conventional BP decreased with
..
.. altitude exposure in a greater proportion of hypertensive than of
.. normotensives trekkers (36% vs. 21% at 3400 m, P = 0.01 and 30%
..
The HIGHCARE-Himalaya study found that the exposure of .. vs. 15% at 4300 m, P = 0.05). These results should be interpreted
..
healthy volunteers to progressively higher altitudes (up to 5400 m) .. on the background of the acknowledged limitations of conventional
was associated with a progressive, marked increase in systolic .. BP measurements.35S Indeed, conventional BP measurements at
..
and diastolic ambulatory BP, which was more evident than the corre- .. rest have been demonstrated to be poorly sensitive to environ-
sponding increase in conventional BP measurements.7 This increase .. mental influences, in particular when assessing BP response to
..
became evident a few hours after HA was reached, persisted during .. altitude.7,8 This limitation is emphasized by considering additional
the prolonged altitude sojourn (12 days) and was more pronounced .. data reported by Keyes et al., obtained through the few good qual-
..
in older subjects (Figure 2). .. ity 24 h ambulatory BP recordings obtained in a very small sub-
The efficacy of a number of antihypertensive drugs at HA has been .. group of trekkers (2 hypertensive and 4 normotensive individuals).
..
tested in volunteers, also through the various studies performed in the .. Severe hypertension was recorded in five participants, asympto-
frame of the HIGHCARE projects. Non-selective beta-blockade with .. matic, regardless of their conventional BP values. Moreover, an
..
carvedilol in healthy subjects resulted in a significant reduction in the .. increase in nocturnal SBP and DBP in hypertensive but not in nor-
BP response to HA but was associated with reduced arterial haemo- .. motensive participants was reported, although the authors did not
..
globin O2 saturation and exercise tolerance. In contrast, a highly selec- .. show their mean 24 h, daytime, night-time SBP and DBP values.
tive beta-1 adrenergic receptor blocker (nebivolol), while also .. This study further emphasizes the limitations carried by focusing
..
effective in reducing the pressor response to HA, preserved the nor- .. only on conventional BP measurements performed at rest, when
mal nocturnal BP dipping, and was associated with a lesser reduction in
.. exploring the environmental effects on BP at altitude.
..
exercise tolerance at HA.8 Monotherapy with a long-acting ARB (tel- .. Recommendations for hypertensive patients are summarized in Table 3.
misartan) demonstrated an impressive response on both daytime and
..
..
night-time BP, but only up to an altitude of 3400 m. During acute expo- ..
sure to a higher altitude (5400 m), the drug was ineffective, because of
.. Arrhythmias and implantable
..
the concomitant suppression of the renin–angiotensin system.7 The .. devices
mechanisms underlying the increase in BP above an altitude of 5000 m
..
..
are indeed complex in nature, which could explain different responses .. Arrhythmias
..
obtained with different antihypertensive drugs. Interestingly, also aceta- .. The increased sympathetic activity5 and decreased SaO2 characterizing
zolamide was found to antagonize the BP rise induced by HA, as well .. HA exposure, in addition to the increase in right ventricular work and in
..
as the parallel occurrence of central sleep apnoea.9,35 .. cellular transmembrane shifts of potassium, might be a favourable sub-
The effects of altitude exposure on hypertensive patients have also .. strate for arrhythmias. However, to date, an increase in malignant
..
been specifically assessed. Wu et al.36 studied Chinese railroad work- .. arrhythmias at HA has never been systematically demonstrated. Kujanik
ers and reported a greater increase in blood pressure at HA in hyper- .. et al. compared ECG Holter recordings of healthy volunteers obtained
..
tensive compared with healthy individuals. This observation was .. at HA and at sea level. They found increased ventricular and supraven-
confirmed and expanded in the HIGHCARE-Andes Lowlanders .. tricular ectopy already at mild-moderate altitude (1350 m), but these
..
Study,35 where acute exposure of hypertensive patients, permanently .. findings were not correlated with a significant increase in sustained ven-
living at sea level, to an altitude of 3259 m, induced a further signifi- .. tricular arrhythmias.37 Gibelli et al. evaluated microvolt T-wave alternans
..
cant increase in 24 h BP above their already elevated pressures .. (MTWA) and HR variability in eight healthy trained subjects at sea level
observed at sea level, with a mildly steeper rise during night-time .. and after a mountain climbing expedition (Pakistan, 8150 m), both at
..
than during daytime periods. . rest and during exercise. Despite enhanced sympathetic activity,

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 8 G. Parati et al.

Table 3 Clinical and therapeutic recommendations for hypertensive patients planning to go to high altitude

Patients Recommendations Class of Level of References

evidence evidence
....................................................................................................................................................................................................................
7,8,35,36
Patients with moderate–severe Check BP values before and during HA sojourn. IIa B
hypertension and hypertensive
patients with moderate–high car-
diovascular risk
8,35,36
Well-controlled hypertensive May reach very HA (>4000 m) with adequate medical I C
patients/mild hypertensive therapy.
patients
36S
Uncontrolled/severe hypertensive Avoid HA exposure in order to prevent risk of organ I C
patients damage.
....................................................................................................................................................................................................................
Therapy
35
Angiotensin II receptor blockade (tested with Telmisartan) lowers BP in healthy subjects up to I B
3400 m
9
Acetazolamide administration lowers BP at HA while improving SaO2 and mountain sickness I B
symptoms
36
Combination of nifedipine/telmisartan effectively lowers BP in hypertensive patients at an alti- I B
tude of 3300 m
13
Nebivolol effectively controls HA-induced BP increase and preserves nocturnal BP dipping. I C
Selective beta-1 adrenergic receptors blockade is associated with a lesser impairment of
exercise performance when compared with the administration of non-selective beta-blockers
When moderate–severe hypertensive patients and hypertensive patients at moderate–high IIa C
cardiovascular risk plan exposure to HA, adequate modification of their antihypertensive
therapy should be considered in co-operation with their physician

The strength of these recommendations is to be weighted in the light of the limited evidence available.
BP, blood pressure; HA, high altitude.

MTWA testing during exercise at HA was negative in all participants.38

.. pulmonary arterial hypertension. In this study, patients with PAH
..
The authors concluded that there is a low risk of dangerous arrhythmias .. [World Health Organization (WHO) Group 1 with functional class
in healthy trained subjects during exercise under hypobaric hypoxia
.. (FC) III symptoms at diagnosis] on vasodilator treatment did not
..
conditions. The possibility, however, of an increased arrhythmic risk in .. experience any acute deterioration in RV function during simulated
patients with heart diseases favouring arrhythmias, remains an issue yet
.. mild altitude, at rest or following mild exertion.39S
..
to be properly addressed in future studies.37S During sleep at HA, bra- .. The known physiological effects of hypoxia, however, suggest that
..
dycardia, bradyarrhythmias and cycling of heart rate with periodic .. in-flight O2 administration should be considered for patients with
breathing are common findings in young subjects.11S Recommendations .. WHO-FC III and IV pulmonary hypertension and for those with
..
are summarized in Supplementary material online, Table S3. .. PaO2 consistently <60 mmHg.40S–42S Similarly, such patients, as well
.. as patients known to be affected by pulmonary hypertension, should
..
Pacing and implantable cardioverter .. consider the use of supplemental O2 when exposed to
.. altitudes >1500–2000 m.43S Recommendations are summarized in
devices ..
.. Supplementary material online, Table S3.
Little information is available. Brief exposure to a simulated altitude ..
of 4000 m apparently does not affect ventricular stimulation thresh- ..
..
olds39 and a recent observational study showed a low implantable .. Congenital heart disease
cardioverter device (ICD) activation rate (4%) in patients living at ..
..
altitude.38S Recommendations are summarized in Supplementary .. Adults with congenital heart disease should be stratified by specific
material online, Table S3. .. haemodynamic and pathophysiological conditions to assess their fit-
..
.. ness to HA exposure.40
.. Patients with concurrent pulmonary hypertension should be care-
..
Pulmonary hypertension .. ful when going to HA. Indeed, the occurrence of an elevated pulmo-
.. nary pressure due to a pre-existing clinical condition worsens the
..
We found just one very recent study using flight simulation (exposure .. effects of HA exposure. This is exemplified by the fact that corrective
to a simulated altitude of 1700–2500 m) to determine the need
.. surgery for Fontan patients, in whom maintaining low pulmonary
..
for supplemental O2 during prolonged hypoxia in patients with . resistance is essential, has a worse outcome when performed at

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 Cardiovascular patients at high altitude 9

..
HA41,44S, 45S than at sea level. On the other hand, after successful sur- .. at providing practical recommendations for preventive and therapeu-
gical correction, short-term HA exposure (at 3454 m) had no nega- .. tic decision-making.
..
tive impact on pulmonary blood flow and exercise capacity when .. Some general limitations of our article, which apply to all sections,
compared with controls and was clinically well tolerated.41 .. should be acknowledged (see Supplementary material online, Table
..
Patients with cyanotic heart conditions and right to left shunting .. S4). In the field of HA medicine only a limited number of well-
are likely to develop more severe hypoxaemia than healthy individu- .. conducted studies are available, which usually have small sample sizes,
..
als as the increase in pulmonary vascular resistance at HA can worsen .. primarily evaluating young subjects and commonly with lack a ran-
the right-to-left shunt.46S,47S However, reduced blood O2 content is .. domized controlled design. Moreover, studies are often not fully
..
not dangerous by itself, because cardiac output and haematocrit .. comparable because they are performed at different altitude levels
increase sufficiently to maintain adequate systemic O2 delivery. .. and are confounded by a number of different factors, such as the
..
Various trials carried out in a laboratory setting and during short- .. degree of baseline physical conditioning, extent of physical effort at
term exposure to hypobaric hypoxia at altitude suggest that some of .. HA, speed of ascent, climate changes, and latitude. Finally, different
..
those patients are able to maintain O2 delivery even with reductions .. test settings have been used to investigate the cardiovascular effects
in inspired pO2, by increasing their cardiac output along with their .. of altitude exposure, either in the field or in an experimental labora-
..
already higher haematocrit associated with their congenital cardiac .. tory with simulated altitude with either normobaric or hypobaric
abnormalities.42,43,44
.. hypoxia exposure. All these limitations and the lack of a standardized
..
Recommendations are summarized in Supplementary material .. data reporting system make it very difficult to verify the validity and
online, Table S3 and can be applied also for air travel, although specific
.. strength of data from a given trial as well as the consistency of results
..
data in this regard are largely missing. .. among studies and to reproducibly and precisely assign the observed
.. effects to different altitude levels.
..
..
Cerebrovascular conditions ..
..
.. Conclusions
Ischaemic stroke ..
..
Even though evidence is limited, HA exposure seems to pose a risk .. Available studies, although only in a few instances being performed
of cerebral ischaemia for patients who already have suffered an
.. according to a randomized double-blind controlled design, provide
..
ischaemic stroke,29,45,46 both because of the direct effect of hypoxia .. indications that, in spite of their ‘soft’ nature, might nevertheless allow
and due to a reduced cerebrovascular reactivity.47,48S
.. for a safer exposure to hypobaric hypoxia at altitude in patients with
..
Whether the increase in haematocrit and the greater blood viscos- .. a variety of cardiovascular conditions, offering some practical advices
.. and guidance for both patients and physicians. The relative lack of
ity also contribute to a greater stroke risk at HA is unknown. There ..
are, however, data, although somehow controversial,19 suggesting .. highly powered studies, and the type of data summarized in this
.. article, emphasize the need for additional trials of suitable size to bet-
that highlanders and people working at altitude might have a higher ..
risk of stroke compared to those living and working at low .. ter address the cardiovascular implications of both acute and chronic
.. HA exposure.
altitude.48,49 ..
Although presently there is not enough evidence to provide any ..
..
strong recommendation on this issue, it has been suggested only based .. Acknowledgement
on clinical experience that carotid ultrasound imaging, commonly per- ..
.. The authors thank the Department of Innovation, Research and
formed in daily practice to check for the existence of complicated pla- ..
ques or severe carotid stenosis, might help to assess the risk of new .. University of the Autonomous Province of Bozen/Bolzano for cover-
.. ing the Open Access publication costs.
events during HA exposure after atherothrombotic stroke. ..
..
..
Haemorrhagic stroke ..
Arterial blood pressure elevation at HA increases the risk of rupture
.. Supplementary material
..
of cerebral aneurysms and arterial venous malformations as well as ..
the theoretical risk of hypertension-related cerebral haemorrhage.50
.. Supplementary material is available at European Heart Journal online.
..
Nevertheless, there is no evidence on the incidence of intracranial .. Conflict of interest: P.A. reports personal fees from Menarini,
..
haemorrhage in alpine regions. We could not find any systematic .. grants from Daiichi Sankyo, personal fees from Novartis, personal
study evaluating the incidence of intracranial bleeding at HA, nor any .. fees from Boeringer, outside the submitted work. All other authors
..
case report on this topic, although, admittedly, intracranial haemor- .. declared no conflicts of interest in relation to this work.
rhage could be one of the causes of some of the sudden death cases ..
..
reported in this condition. ..
Recommendations for cerebrovascular patients are summarized in .. References
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