(Circulation. 1997;96:1224-1232.)
© 1997 American Heart Association, Inc.
Articles |
Effect of High-Altitude Exposure in the Elderly
The Tenth Mountain Division Study
From The Institute for Exercise and Environmental Medicine, Presbyterian Hospital of Dallas (B.D.L., J.H.Z.), and the Department of Internal Medicine/Division of Cardiology, University of Texas Southwestern Medical Center at Dallas (B.D.L., C.R.deF.).
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Abstract |
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Background More than 5 million people/year over age 60 visit high altitude, which may exacerbate underlying cardiac or pulmonary disease. We hypothesized that the elderly would exhibit an impaired functional capacity at altitude, with increased myocardial ischemia compared with sea level (SL).
Methods and Results Twenty veterans (68±3 years)
were studied at (1) SL, (2) acute simulated altitude to 2500 m,
and (3) after 5 days of acclimatization to 2500 m. With acute
altitude, PaO2 and oxyhemoglobin saturation
decreased and pulmonary artery pressure increased 43%,
associated with sympathetic activation.
O2peak decreased 12% acutely but
normalized after acclimatization. The best predictor of
O2peak with acute altitude was
O2peak at SL (r=.94). The
double product that induced 1-mm ST depression during exercise with
acute altitude was 5% less than SL but normalized after
acclimatization. One patient with severe coronary disease
sustained a myocardial infarction after an exercise test.
Conclusions Moderate altitude exposure in the elderly is associated with hypoxemia, sympathetic activation, and pulmonary hypertension resulting in a reduced exercise capacity that is predictable based on exercise performance at SL. Patients with coronary artery disease who are well compensated at SL do well at moderate altitude, although acutely ischemia may be provoked at modestly lower myocardial and systemic work rates. The elderly acclimatize well with normalization of SL performance after 5 days. A prudent policy would be for elderly individuals, particularly those with coronary artery disease, to limit their activity during the first few days at altitude to allow this acclimatization process to occur.
Key Words: aging • coronary disease • exercise • hypoxia • physiology
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Introduction |
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One of the most significant issues facing the aged is the maintenance of independence and functional capacity. The factors that limit physical performance may be functions of aging itself (senescence) or the development of comorbid conditions such as coronary artery disease. In this study, we chose to examine high altitude as a common occupational and recreational stimulus that affects oxygen transport and that could provide insight into the functional capacity of the elderly.
Exposure to high altitude results in significant arterial
hypoxemia that may exacerbate preexisting cardiac or pulmonary
disease. In fact, the "Levy test," which was popular in the
1940s, used hypoxia equivalent to an altitude of 
5500 m
(18 000 ft) as a means of diagnosing coronary artery disease
by provoking myocardial ischemia.1 In recent
years, the number of persons going to high altitude has increased
substantially, with estimates of 35 million visitors per year to
Western state areas of >2500 m.2 Nearly 60% of
individuals going to altitude are >age 40, and 15% are elderly
(>age 60).3 The elderly in Western societies have a
prevalence of clinically apparent coronary artery disease of
10%,4 with up to 60% of elderly individuals having
significant coronary lesions as documented by autopsy
studies.5 In addition, the elderly have reductions in
ventilatory capacity and efficiency6 and hypoxic
ventilatory drive7 that may impair the normal adaptive
response to altitude.
Despite extensive past research into the pathophysiology of high-altitude exposure, there are remarkably few data available regarding the effects of altitude on the elderly, with or without significant comorbidity.8 A recent open debate in the medical literature among four prominent physicians in the field of high-altitude medicine serves to emphasize the lack of data on which to base clinical decisions regarding the safety of travel to altitude in this population.9 10 11 The purpose of this study was therefore to investigate the cardiopulmonary response to moderate high altitude in the elderly, both acutely and after acclimatization. We hypothesized that the elderly would exhibit an impaired functional capacity at moderate altitude, with an associated risk of increased myocardial ischemia and cardiac arrhythmias compared with exercise at sea level.
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Methods |
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Subjects
Subjects were all veterans or spouses of the United States Army Tenth Mountain Division who were planning to attend their 50th reunion in Vail, Colo, at an altitude of 2500 m. Some of these individuals volunteered to participate in a series of medical studies organized by the Colorado Altitude Research Institute.12 A subset of this population consisting of 254 members and spouses who reside in the southwest United States were solicited to undergo a more extensive battery of tests at sea level and simulated altitude in Dallas, Tex, and then again after acclimatization to altitude in Vail. Subjects were excluded if they could not perform treadmill exercise (wheelchair bound, stroke, orthopedic illness, etc) or had a recent (<4 weeks) myocardial infarction, episode of unstable angina, decompensated heart failure, life-threatening arrhythmias, known symptomatic aortic outflow obstruction, or severe other systemic noncardiac disease. The first 20 without exclusion criteria to respond to the solicitation comprised our study population.
Subjects were also characterized in general terms according to the
presence or absence of known coronary artery disease, defined
as angiographically proven coronary artery disease (at least
one lesion in a major coronary artery of 
70% narrowing of
cross-sectional diameter), a documented history of myocardial
infarction, or an ECG with Q waves confirmed by the presence of a focal
wall motion abnormality on echocardiogram. Subjects without known heart
disease were further divided into those at "high risk" for
coronary artery disease defined as at least two known risk
factors in addition to age: male gender, cigarette smoking,
hypertension, diabetes, hypercholesterolemia
with repeat total cholesterol values >260 mg/dL, or
a first-degree relative with documented coronary artery disease
before the age of 45. All subjects provided informed consent to a
protocol approved by the Institutional Review Board of the University
of Texas Southwestern Medical Center and Presbyterian Hospital of
Dallas.
Study Protocol
All subjects were brought to Dallas 1 to 4 weeks before
attending the reunion in Vail and admitted to the General Clinical
Research Center at the University of Texas Southwestern Medical Center.
Comprehensive physiological evaluation occurred
over 3 separate days in Dallas as follows: day 1, medical history and
physical examination, familiarization with laboratory equipment,
biochemistry evaluation (blood and urine), and basic pulmonary
function testing as described below; day 2, sea level maximal exercise
testing; and day 3, acute simulated high-altitude testing. The order
between sea level and altitude testing was not randomized for safety
reasons, so as not to perform maximal hypoxic exercise in an elderly
subject with severe silent ischemia. All simulated altitude
testing took place in a hypobaric chamber that was decompressed to a
simulated altitude of 2500 m (barometric pressure, 560
mm Hg). Temperature was controlled between 20° and 22°C with
humidity between 30% and 35%. One to 4 weeks after the testing in
Dallas, all subjects were studied again by the same research team using
the same methods, after 5 days of acclimatization to an altitude of
2500 m at Vail Medical Center in Colorado.
Biochemistry Evaluation
To provide a global index of sympathetic
activation,13 urine was collected over 24 hours in vessels
containing 6N HCl and kept on ice for the analysis of
catecholamines by high-performance liquid
chromatography (SmithKline Laboratories). Subjects were
ambulatory but performed no specific exercise testing during this
period. This analysis was performed twice: during the first 24
hours after arrival in Dallas and the first 24 hours after arrival at
Vail. Subjects were unavailable for urinary catecholamine
measurement after acclimatization.
Routine laboratory tests were obtained at 8 AM in the fasting condition by standard methods and included hemoglobin, hematocrit, total protein, and serum albumin. This analysis was performed once in Dallas and once after 5 days of acclimatization to 2500 m. An index of the change in plasma volume at altitude was obtained from the change in hematocrit and total protein concentration after acclimatization.14
Pulmonary Function
Baseline routine spirometry and diffusing capacity were measured
at sea level only in a pressure-compensated volume displacement body
plethysmograph (SensorMedics 6200 DL). In addition, resting
ventilation was measured in the seated position after 20 minutes of
quiet rest by collecting 5 minutes of expired gas in a Douglas bag at
sea level, acute simulated altitude, and after acclimatization. Gas
volume was measured using a Tissot Spirometer (Dallas) or a dry gas
meter (Vail).
Immediately after the collection of resting ventilation, an
arterial blood sample was obtained from the radial artery
in a syringe containing dry heparin, placed on ice, and
analyzed within 30 minutes for PO2,
PCO2, and pH (Instrument Laboratories 1400) and
oxyhemoglobin saturation (IL 482 Co-Oximeter). Samples were obtained at
sea level and simulated high altitude only. No arterial
blood samples were obtained after acclimatization. Oxyhemoglobin
saturation was measured during all three conditions using pulse
oximetry (CM-8, Schiller America). A measure of the hypoxic ventilatory
response (HVR) to 2500 m altitude was calculated by dividing the
difference between resting ventilation at altitude and at sea level by
the difference in O2 saturation15 :
(E altitude-E sea
level)/(O2sat sea level-O2sat altitude).
Cardiovascular Evaluation
Cardiovascular evaluation was performed after
20 minutes of quiet, supine rest and during symptom-limited treadmill
exercise at all three conditions. Treadmill exercise was performed
according to standard protocols (Naughton, Balke, or modified Balke),
which were selected individually for each subject. The same protocol
was used for all tests on an individual subject.
A resting 12-lead ECG (CS-100, Schiller America) was analyzed
according to standard criteria. During exercise, the 12-lead ECG was
recorded every 2 minutes with computer analysis of the ST
segment for ST depression. ST depression was considered
"present" when 1.0 mV of additional flat, downsloping, or
slowly upsloping ST depression occurred in any lead compared with
baseline and persisted 80 ms after the J point. Maximal ST depression
was considered the maximal degree of ST depression identified with the
computer in any lead at peak exercise or during recovery. All exercise
ECGs were reviewed by a cardiologist experienced in the interpretation
of exercise ECGs. All ECG complexes during rest, exercise, and recovery
were recorded digitally and then displayed in full disclosure
format for rhythm analysis as described below.
Transthoracic echocardiography was performed in the supine or left lateral decubitus position (Apogee CX, Interspec) both at rest and immediately after symptom-limited exercise. Windows were marked before exercise, and all postexercise images were obtained within 1 to 2 minutes of peak work rate. Images were recorded on VHS tape and then digitized off-line for side-by-side comparison (Echoloops, Vingmed). Wall motion was analyzed blindly according to standard scoring systems16 by an independent echocardiographer who was experienced in the interpretation of stress-echo images.
In addition, pulsed Doppler samples were obtained at rest from the right ventricular outflow tract, just proximal to the pulmonic valve, and an estimate of mean pulmonary arterial pressure was obtained from the acceleration time of the waveform normalized for ejection time using the nomogram by Yagi et al.17 This formula was derived specifically for evaluating the pulmonary vascular response to hypoxia of altitude.18 Continuous wave Doppler signals were also obtained from the left ventricular outflow tract (LVOT) from the suprasternal notch, and the cross-sectional area of the LVOT was estimated from its diameter in the parasternal long-axis window, to allow estimation of cardiac output.18 All Doppler waveforms were analyzed by a single experienced technician who was blinded as to condition.
To assess the risk for potentially life-threatening arrhythmias at altitude in this population, we evaluated an index of both the substrate and trigger for reentry under all three conditions.19 To evaluate changes in arrhythmic substrate, we used the signal-averaged ECG with a 12-lead system of acquisition and a high-pass filter cutoff frequency of 40 Hz (CS-100, Schiller America).20 Sufficient QRS complexes were averaged to reduce the signal noise level to <0.8 mV. The parameters measured included QRS duration, root-mean-square of the terminal 40 ms of the QRS, and the duration of the low-amplitude signals according to standard criteria.20 Although for logistical reasons, 24-hour Holter monitoring was not possible during this study, we used the provocation of ventricular arrhythmias during exercise as an additional tool to evaluate the risk of serious arrhythmias.21 The frequency and severity of ventricular arrhythmias were quantified under the controlled conditions of rest, treadmill exercise, and 10 minutes of recovery. An experienced nurse tabulated all premature ventricular complexes (PVCs) during the recording period and divided them into single PVCs or repetitive forms (defined as two or more PVCs in a row).
Peak and submaximal oxygen uptake (O2)
were measured using the Douglas bag technique. Gas fractions were
determined using a mass spectrometer (Marquette MGA 1100) and gas
volumes with a Tissot spirometer (Dallas) or dry gas meter (Vail). Peak
O2 was defined as the highest
O2 obtained with sequential 45-second
Douglas bags at symptom-limited peak exercise. A common absolute work
rate of 4 metabolic equivalents (METS) was chosen to represent
submaximal cardiovascular performance. Heart
rate was measured via ECG and blood pressure by sphygmomanometry at
each 2-minute level of exercise. The peak double product was
defined as the peak systolic blood pressurexpeak heart rate
and was used as an index of myocardial oxygen requirements during
exercise.
Statistical Analysis
All variables are reported as mean±SD. Continuous
variables were compared among conditions using a repeated measures
ANOVA, with the Newman-Keuls post hoc test for multiple comparisons. An
F value of <.05 was considered significant. To determine the
predictors of functional capacity at altitude, a multiple regression
analysis was performed using peak oxygen uptake at altitude as
the dependent variable and baseline characteristics with a
univariate correlation with altitude peak oxygen uptake
(P<.10) as the independent variables. Statistics were
performed using a PC-based statistical package, ABSTAT
(AndersonBell).
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Results |
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Subject Characteristics
Subjects included 15 men and 5 women (mean age, 68±3 years). Thirty-five percent (7 of 20) had known coronary artery disease (two coronary artery bypass surgeries, two percutaneous transluminal coronary angioplasties, three myocardial infarctions without revascularization), and an additional 50% (10 of 20) were considered to be at high risk for having underlying coronary heart disease as defined above (total of 17 of 20, or 85% either with known disease or at high risk for coronary artery disease). Ten percent (2 of 20) had a history of significant arrhythmias, including 1 with recurrent, sustained but hemodynamically stable ventricular tachycardia, and a second with chronic atrial flutter. Both of these patients had known coronary artery disease. Fifteen percent (3 of 20) had previously undetected cardiovascular disease, including 1 with uncontrolled hypertension, and 2 patients had previously unknown myocardial infarctions. One patient had extensive evidence of provocable ischemia in Dallas both at sea level and at simulated altitude and underwent urgent revascularization. This patient did not participate in the acclimatization portion of the study in Vail.
Clinical Outcome
Despite the relatively high prevalence of
cardiovascular disease in this population, most of the
subjects tolerated their sojourn at moderate high altitude well.
Forty-five percent had mild symptoms consistent with acute
mountain sickness during the first 3 days at altitude (B. Honigman,
University of Colorado, personal communication, 1996), but all were
well by the time they were studied after 5 days of acclimatization. One
patient with an ischemic cardiomyopathy and
known recurrent ventricular tachycardia had his
arrhythmia occur at Vail. However, similar to his usual
presentation at sea level, the arrhythmia was well
tolerated and in fact was asymptomatic and discovered
during routine testing. The arrhythmia converted spontaneously
to sinus rhythm without specific treatment, and the patient had no
adverse sequelae. One patient sustained a myocardial infarction after
his exercise test at Vail and in retrospect may have had some symptoms
consistent with acute coronary insufficiency. This
patient had a history of a previous myocardial infarction,
coronary artery bypass surgery, and chronic atrial flutter
requiring treatment with digoxin. Moreover, his peak work capacity was
limited to 4 METS by a chronic peripheral
neuropathy, thus reducing the sensitivity of his exercise
test in detecting provocable ischemia.
Quantification of the Stimulus of High Altitude
Acute altitude exposure in the environmental chamber resulted in a
fall in arterial PaO2 from 78±10
at sea level to 54±3 mm Hg at 2500 m (P<.01).
Oxyhemoglobin saturation decreased acutely from 96±2% to 92±2%
(P<.01) but recovered slightly after acclimatization
(93±4%, P=.02 compared with acute hypoxia).
Ventilation increased appropriately from 11.0±2.9 L/min at sea level
to 12.6±5.9 L/min (P<.05) with this acute hypoxia,
primarily due to an increase in tidal volume (706±261 to 885±635 mL).
The hypoxic ventilatory response with acute altitude exposure was
estimated to be 0.62±0.54 L ·
min-1 · %-1,
consistent with values we have reported for a younger, healthy
population,22 and did not increase after 5 days of
acclimatization (0.83±0.38, P=.46).
This hypoxemia was associated with activation of the sympathetic nervous system. Urinary norepinephrine excretion increased from 36.6±17.1 mg/24 hr at sea level to 60.2±29.0 mg/24 hr at altitude (P<.01). Urinary epinephrine did not change (4.8±2.3 mg/24 hr at sea level to 5.3±2.6 mg/24 hr at altitude). These values are similar to those reported for younger subjects at higher altitude.13
Acclimatization was associated with a small but significant decrease in
plasma volume of 3% to 4%. This estimation is derived from a
concomitant increase in hematocrit (from 43.5±4.7 to 45.1±3.7,
calculated increase of 3.9%; P<.05) and total plasma
proteins (from 6.9±0.5 to 7.1±0.3 mg/dL, increase of 3.0%;
P<.05).
Hemodynamics
Hemodynamic data for all three conditions are
presented in Table 1
. Hypoxemia
and sympathetic activation were associated with pulmonary
hypertension. Estimated mean pulmonary artery pressure
increased by 43% with acute altitude exposure (P<.01) and
was still present after 5 days of acclimatization. Heart rate at
rest increased slightly acutely and remained slightly elevated after 5
days of acclimatization (P<.05). Blood pressure (both
systolic and diastolic) decreased with acute
altitude exposure (P<.01) and returned to baseline after
acclimatization. This acute fall in blood pressure was due to a fall in
total peripheral resistance, which decreased by 16%.
Cardiac output was correspondingly elevated acutely by 14%, due to an
increase in both heart rate and stroke volume. With acclimatization,
cardiac output fell to below baseline values due to a fall in stroke
volume, and total peripheral resistance was modestly
elevated (-6% and +25%, respectively, compared with
baseline).
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Exercise Responses
Changes in work capacity, as reflected by
O2peak, are presented in Fig 1. Peak heart rate was 100% predicted
(220-age) at all three conditions (Fig 2), supporting the contention that
near-maximal exercise was achieved.
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For the group as a whole, O2peak
decreased by 12% (24.0±1.2 to 21.1±1.2 mL ·
kg-1 · min-1,
P<.01) from sea level to acute altitude exposure and
returned to baseline after acclimatization (24.2±4.8). The magnitude
of this reduction was consistent with reductions reported
previously for young, healthy individuals.23 This
reduction was similar in those with (11%) and without (13%)
documented coronary artery disease, although the patients with
known coronary artery disease had a limited absolute
O2peak of only 18.4±2.5 mL ·
kg-1 · min-1
with acute altitude exposure. Treadmill endurance was similarly reduced
acutely in all subjects from 12.2±4.2 to 11.4±4.2 minutes
(P=.01) but returned to baseline after acclimatization
(12.1±3.9 minutes).
Although hemoglobin concentration was not measured in the chamber
with acute exposure, calculated blood O2 content
(1.36xhemoglobinxO2 saturationx10) was equivalent after
acclimatization (193±17 mL/L) compared with sea level (188±18 mL/L),
explaining at least in part the restoration of peak oxygen uptake with
acclimatization. To examine the extent to which the changes in peak
oxygen uptake are related to blood oxygen content, we also estimated
O2 content in the chamber by assuming that hemoglobin
concentration did not change within the short duration of acute
altitude exposure. Within the limits of this assumption, O2
content decreased to 182±18 mL/L, which was significantly less than
either sea level or Vail (P<.01). A regression of blood
O2 content versus O2peak
through the origin demonstrated a strong proportional relationship
between estimated O2 content and peak oxygen uptake, with
an r2 value of .99 (P<.01),
providing additional supportive evidence of the importance of oxygen
availability for oxygen uptake and work capacity in this
population.
The single best predictor of O2peak with
acute altitude exposure was O2peak at
sea level. In a univariate analysis, the
r value for this regression was .94 with an SEE of 0.16
L/min (P<.01). Other baseline sea level variables that
had significant univariate correlations with
O2 peak at altitude were maximal
ventilatory volume (r=.46, P=.04), hemoglobin
(r=.54, P=.03), and forced vital capacity
(r=.78, P=.01). HVR did not have a significant
univariate relationship with
O2peak at altitude but was included in
the multiple regression analysis because of its previously
described relationship with work capacity at altitude.15
After inclusion in a multiple regression analysis, only HVR
added significantly to O2peak at sea
level (P=.04), for the prediction of
O2peak at altitude. The two
variables combined explained 92% of the variance in
O2peak at altitude in these subjects
(r2=.92; SEE, 0.136 L/min;
P<.01).
Evaluation of Ischemia
At rest, no subject had new ECG changes or
echocardiographic abnormalities suggestive of
altitude-induced myocardial ischemia (Fig 2
). Ten subjects had 1-mm ST depression
during exercise at sea level. Six of these subjects had known
coronary artery disease (6 of 7 of the subjects with known
coronary artery disease), and 3 of the other 4 were in the
"high-risk" group. Nine of these 10 subjects also had 1-mm ST
depression with acute high-altitude exposure, with an additional 3
subjects (2 of 3 in high-risk group) meeting ST-segment criteria for
ischemia only with acute high altitude. In 1
representative subject who had a coronary
artery bypass graft procedure 4 years previously, this was manifested
as more prominent ST depression at the same double product (heart
ratexsystolic blood pressure, a measure of myocardial oxygen
requirements) at simulated altitude compared with sea level (Fig 3). For these subjects with
exercise-induced ischemia, the double product required to
induce 1-mm ST depression during exercise with acute altitude exposure
was 5% less and the systemic work rate at this level was 8% less than
at sea level (Fig 4). However, after 5
days of acclimatization, the systemic (MET level) and myocardial
(double product) work rates that induced 1-mm ST depression had
returned to sea level values. Notably, the heart rate at this work rate
was identical among all three conditions, reducing its reliability as
an indicator of safe work rates at altitude, at least with acute
exposure.
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In contrast to the onset of ischemia, the maximal degree of
myocardial ischemia induced by symptom-limited exercise
appeared the same under all three conditions. Thus, the maximal amount
of ST depression at peak exercise was not significantly different among
sea level, acute exposure, or after acclimatization (1.2±1.2,
1.4±1.3, and 1.6±2.0 mm, respectively; P=.60),
although some individual patients did have greater ST depression with
acute altitude exposure (Fig 3). Moreover, the wall motion scores for
the echocardiographic images obtained immediately after
exercise did not differ among conditions. No subject had a new wall
motion abnormality appear at altitude that was not detected at sea
level.
Arrhythmia Risk
Single PVCs increased by 63% in our defined setting of rest,
exercise, and recovery (usually 1 hour) from 8±16 to 13±21
(P<.01) but returned to baseline levels after
acclimatization (7±10) (Table 2).
However, there was no significant increase in higher-grade ectopy, such
as repetitive forms. Moreover, there were no changes in any
signal-averaged ECG parameter, including QRS duration,
root-mean-square of the terminal 40 ms of the QRS, and the duration of
the low-amplitude signals (Table 2). No subject had a newly abnormal
signal- averaged ECG at altitude, either acutely or after
acclimatization, that was not abnormal at sea level.
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Discussion |
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This study provides new information regarding the effect of high altitude on the elderly that will assist in providing appropriate clinical recommendations for altitude exposure. The principal new observations include (1) the physiological response to hypobaric hypoxia in this elderly population was remarkably similar to that reported in younger, healthy subjects. (2) In general, those individuals who were well at sea level and without clinically apparent coronary artery disease performed well at moderate altitude. (3) For patients with either manifest or previously undetected coronary artery disease, this degree of altitude exposure was associated with a small but significant reduction in the work required to provoke myocardial ischemia and a minor increase in ventricular ectopic activity during exercise. (4) Fortunately, the elderly appear to acclimatize well and after 5 days of acclimatization were physiologically almost indistinguishable from sea level. Thus, aging does not appear to impair the physiological adaptive response to either acute or chronic hypoxia, even in the presence of substantial comorbidity. However, in light of the acute reduction in ischemic threshold during maximal exercise testing and the one myocardial infarction observed in this cohort, we urge caution during heavy exertion with acute high-altitude exposure unless careful screening has been performed first at sea level.
The generalizability of these observations depends on two factors: (1)
how well the subjects reflect the elderly population at large and (2)
whether the detailed physiological measurements
provide a strategy for physicians to approach individual patients who
may wish to travel to altitude. The subjects in the present cohort
were recruited from a larger population of US Army veterans (1000
living members of the Tenth Mountain Division). A report of a more
general description of a larger cohort of these subjects (n=97) and
their clinical response at altitude has been published.12
The present cohort was similar to the subjects in the larger survey
study, including age and gender distribution and prevalence of known
coronary artery disease (P=.23 by Fisher's exact
test). Although the prevalence of known coronary disease may be
slightly higher in this population than in a population of elderly
nonveterans,4 they are similar in most respects to other
veterans groups.24 Moreover, it has recently been
recognized that coronary artery disease is not a discrete
variable that is present or absent but rather a continuous
process with coronary events determined by plaque composition
and other specific triggers.25 Thus, the distinction in
our and other populations into groups with and without known
coronary artery disease is relatively arbitrary and entirely
dependent on the techniques used to detect the presence of disease. In
the present study, we used discrete clinical events to facilitate
broad groupings of the subjects and to assist in the identification of
patients who may have a greater burden of disease. However, we
intentionally avoided overemphasizing the relatively artificial
distinction between groups of elderly patients and instead focused
predominantly on the physiological response to
acute and chronic altitude exposure in the entire cohort as a
whole.
Physiological Effects of High Altitude in the
Elderly at Rest
There are remarkably little data in the literature regarding the
physiological response to hypoxia or high
altitude in elderly humans, with or without known coronary
artery disease.9 10 11 26 This study characterizes this
response by four cardinal features: (1) hypoxemia, (2)
pulmonary hypertension, (3) sympathetic activation, and with
acclimatization, (4) a modest reduction in plasma volume. The ultimate
hemodynamic outcome of these responses depends on a
balance between autonomic neural activity and local
metabolic regulation. In the present study, with acute
altitude exposure, vasodilation prevailed as manifested by a decrease
in total peripheral resistance, accompanied by
tachycardia and increased cardiac output,
consistent with previous studies in younger
subjects.27 With short-term acclimatization and increased
blood oxygen–carrying capacity, cardiac filling appeared reduced,
resulting in decreased stroke volume and cardiac output. Both
cardiopulmonary and arterial baroreceptors thus
were unloaded, likely resulting in a further increase in sympathetic
tone.28 Together, these adaptations led over time to an
increase in total peripheral resistance above sea level
values.
Effect of Aging and High Altitude on Cardiopulmonary
Exercise Performance
Both age and hypoxia may influence the ability to perform
physical work at high altitude, which depends on the matching of
systemic/regional oxygen transport to metabolic demands.
Aging results in substantial physiological changes
that may impair oxygen transport, both secondary to the development of
degenerative diseases such as atherosclerotic coronary artery
disease and senescence. Thus, maximal oxygen uptake
(O2max) decreases 5 mL ·
kg-1 · min-1
per decade in sedentary individuals at sea level starting at age
20.29 The reasons for this decrease are incompletely
understood, although reductions in maximal heart rate,30
cardiac contractility,31 and
peripheral skeletal muscle oxygen extraction32
have been implicated.
Altitude also results in a decrease in
O2max by 1% for every 100 m
>1500 m.23 Whether the effect of age and altitude on
O2max is additive or synergistic is
unknown, although some evidence exists to suggest an important
interaction. For example, studies in normal humans have shown that
aging is associated with a reduced ventilatory response to
hypoxia.7 33 The heart rate response to
hypoxia also appears blunted with age.34 However,
cardiac contractility is well preserved after
acclimatization, even to extreme altitudes in young
individuals,35 and this response appears to be unaffected
by age.36 Together, these changes in oxygen transport
associated with aging and high altitude raise the concern that the
elderly might have a greater reduction in work capacity with altitude
than healthy younger individuals.
However, in the present study, we observed that the magnitude of the relative reduction in maximal aerobic power with acute hypoxia was virtually identical to that predicted from studies in younger subjects.23 This was true regardless of whether the subjects were apparently healthy or had known coronary artery disease. Morgan et al37 demonstrated a similar reduction in maximal aerobic power of 11% in patients from Denver (1500 m) with documented coronary disease ascending to 3000 m, thus confirming the linear predictability of this response at different altitudes.
It is important to emphasize, however, that the patients with coronary disease had limited maximal aerobic power in absolute terms, at both sea level and moderate altitude. Consequently, although these elderly patients tolerated the moderate altitude of 2500 m well, we would predict that at higher altitudes, >4000 m, activities of daily living would require relative work rates that are near-maximal aerobic power, resulting in markedly impaired functional capacity.
Importantly, the process of acclimatization proceeded normally in the elderly and restored maximal exercise capacity and treadmill endurance to sea level values. This adaptation appeared to be a function of both an increase in hemoglobin concentration (due to contraction of plasma volume) and an increase in oxyhemoglobin saturation (due to increased ventilation). Arterial oxygen content was thereby restored to sea level values, although this response is likely to be limited to the relatively modest altitudes examined in the present study, as has been observed in younger subjects.38
This observation is important for making recommendations for activity levels for elderly patients at altitude. Given adequate time to acclimatize, exercise capacity at the moderate altitude examined in this study is likely to approach that at sea level. It is also important to emphasize that the best predictor of exercise capacity with altitude exposure was exercise capacity at sea level. Thus, preexposure sea level exercise testing is likely to be useful in providing activity guidelines for individual patients.
Risk of Moderate High-Altitude Exposure to the Patient With
Coronary Artery Disease
For patients with coronary artery disease, the critical
questions are whether high altitude (1) increases ischemia, (2)
increases the risk of arrhythmias, or (3) provokes the
transition to unstable syndromes such as unstable angina or acute
myocardial infarction. Numerous anecdotal reports exist describing
clinical exacerbation of underlying coronary disease by high
altitude,26 but it is difficult to determine whether such
instances are a direct consequence of high altitude or simply a
variable manifestation of the coronary artery disease.
Myocardial ischemia may develop by alterations in either side of the myocardial oxygen supply/demand ratio. In the face of fixed coronary stenoses, the reduction in arterial oxygen content at high altitude would be expected to reduce oxygen supply and increase ischemia, depending on the degree of oxyhemoglobin desaturation and the severity of the coronary lesions. Thus, in this study, at rest and during submaximal exercise, heart rate was higher with acute altitude exposure, increasing myocardial oxygen demand and resulting in ischemia at lower systemic work rates.
In addition to the increased demand, the sympathetic activation associated with hypoxia39 may cause coronary vasoconstriction in regions with abnormal endothelial vasomotor control, further compromising myocardial oxygen delivery. Abnormal coronary vasomotion due to atherosclerosis has been reported during exercise40 or after infusion of acetylcholine,41 but not to our knowledge during hypoxia. It is likely that in the present study, one or both mechanisms (reduction in oxygen content and coronary vasoconstriction) were operational as we observed the induction of ischemia with acute altitude exposure at a lower myocardial oxygen demand than at sea level. This acute response is in contrast to that observed by Morgan et al37 in long-term acclimatized patients with coronary disease or in our patients after short-term acclimatization. We speculate that acclimatization may reduce abnormal coronary vasomotion in response to hypoxia, although this question requires further study.
We are disturbed by the occurrence of a myocardial infarction in one of our patients after an exercise test at altitude. However, there is no evidence that altitude exposure results in hematological changes that would increase the risk of plaque rupture, vascular thrombosis, and myocardial infarction.42 Exercise is associated with a small but finite risk of myocardial infarction, particularly after heavy exertion.43 Although many high-altitude activities, such as hiking, require absolute work rates that are of low intensity, for elderly patients at high altitude, the present study suggests that these relative intensities may actually be extremely high. It is also possible that this patient was demonstrating the natural history of his disease and would have had a myocardial infarction at sea level. However, we cannot exclude an interaction between altitude and exercise in this individual patient. Moreover, our small numbers preclude our being able to quantify any clear risk of acute coronary syndromes associated with high-altitude exposure. We are reassured, however, by the results of the larger survey study, which did not identify any other elderly individuals with a myocardial infarction at this same altitude.12
In addition to the risk of ischemia, we were concerned with the possibility of altitude exacerbating ventricular arrhythmias because of the well-described association of such arrhythmias with sympathetic activation, particularly in patients with known coronary artery disease.44 In the present study, we were unable to identify any change in arrhythmic substrate, at least within the limits of the signal-averaged ECG to detect delays in ventricular activation and late potentials from the surface. The negative predictive value of the signal-averaged ECG for identifying patients who are not at risk for sustained ventricular arrhythmias is very high, identifying >95% of patients after a myocardial infarction who are at low risk for developing life-threatening ventricular arrhythmias.45 Moreover, although we could not perform 24-hour Holter monitoring to quantify ambient ectopy, we were able to use exercise testing, which provokes repetitive ventricular premature beats in the majority of patients with a history of sustained ventricular arrhythmias.21 Although single PVCs during exercise appeared to increase modestly with acute altitude exposure, there was no increase in repetitive forms, and the frequency of this inducible ectopy returned to baseline levels within 5 days of acclimatization. It is important to emphasize that there is substantial interindividual and intraindividual variability in the frequency of PVCs,46 which may reduce the sensitivity of this measure as a reliable index of the trigger for ventricular arrhythmias. We therefore must interpret the observation of a small, albeit statistically significant, increase in frequency of premature ventricular contractions during and after exercise with caution. However, we are reassured by the example of the one patient with known recurrent ventricular tachycardia who had his arrhythmia occur at altitude and who tolerated it as well as at sea level. The sum of evidence available suggests that although minor inducible ectopy may increase acutely, it appears unlikely that moderate high altitude substantially alters the risk for life-threatening arrhythmias in the elderly or patients with coronary artery disease.
Study Limitations
There are a number of limitations to the present study that
must be acknowledged. First of all, the number of patients studied was
small, and our methods for quantifying coronary artery disease
were entirely noninvasive, making it difficult to provide true
estimates of the risk associated with altitude exposure in this
population or to clearly categorize the subjects into statistically
meaningful groups according to the presence or absence of
coronary artery disease. Nevertheless, the
physiological response of the elderly to moderate
high altitude appears to be predictable based on careful testing at sea
level, thereby allowing the physician to individualize recommendations
for specific patients. Second, the period of acclimatization was short,
consisting of only 5 days, during which time acclimatization is
certainly not complete, particularly with regard to the autonomic
nervous system.28 However, most of the acute response to
high altitude, namely, hyperventilation with metabolic
compensation, is likely to be completed within the first few days at
high altitude.47 In addition, this exposure pattern is
typical of many travels for business or recreational purposes. Finally,
we studied only one altitude of 2500 m, and our results may not be
applicable to higher altitudes.
Conclusions
In conclusion, we demonstrated that moderate high-altitude
exposure (2500 m) in the elderly is associated with hypoxemia,
activation of the sympathetic nervous system, pulmonary
hypertension, and a small reduction in plasma volume, all similar in
direction and magnitude to the physiological
responses observed in younger individuals. These changes result in a
reduced maximal exercise capacity and endurance that is predictable
based on exercise performance at sea level. Patients with
coronary artery disease who are well compensated at sea level
are likely to do well at moderate high altitude, although with acute
exposure, ischemia may be provoked at lower myocardial and
systemic work rates. Although there may be a small increase in minor
ventricular ectopy with acute exposure, there does not
appear to be any substantially increased risk for complex or
life-threatening ventricular arrhythmias. Finally,
the elderly appear to acclimatize well to 2500 m with
near-complete restoration of sea level performance after 5
days. We suggest that a prudent policy would be for elderly
individuals, particularly those with coronary artery disease,
to limit their activity during the first few days at high altitude to
allow this acclimatization process to occur.
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Acknowledgments |
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This work was supported in part by USPHS grant M01-RR-00633 and an institutional grant from Presbyterian Hospital of Dallas. We gratefully acknowledge the contributions of Max Rabbe and the organizers of the 10th Mountain Division reunion for allowing us to recruit their members for participation in this study. The overall study would not have been possible without the inspiration and tireless work of Dr Charles Houston, as well as Drs Rob Roach and Ben Honigmann from the Colorado Altitude Research Institute. We would like to thank Drs Jack Reeves, Herb Hultgren, and Jim Alexander who provided important critical comments regarding experimental design, and Drs Tony Babb and Paul Grayburn, who were extremely helpful reviewers of the manuscript. Susie McMinn provided exceptional technical assistance. We are extremely grateful to the Vail Medical Center, which graciously provided us with the use of their facilities for the conduction of the studies in Vail. A number of vendors assisted us by providing extra equipment for the studies in Vail: Trackmaster treadmills, Schiller America ECG systems, Interspec echo machine, and Medical Physics of Colorado mass spectrometer. We thank Dr Paul Grayburn for his assistance with interpretation of the stress echo images and Julie Thwing, Joe O'Kroy, Tom Sundly, Lee Murray, and Ken Willis for their technical assistance. Finally, we would like to dedicate this article to four members of the 10th who have died since the completion of the study: Harry Johnson, Gordon Craig, Steve Porter, and M.W. Hechler.
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Footnotes |
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Reprint requests to Benjamin D. Levine, MD, Director, Institute for Exercise and Environmental Medicine, Presbyterian Hospital of Dallas, 7232 Greenville Ave, Dallas, TX 75231.
Received September 9, 1996; revision received March 25, 1997; accepted March 28, 1996.
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Levy RL, Bruenn HG, Russell NG Jr. The use of electrocardiographic changes caused by induced anoxemia as a test for coronary insufficiency. Am J Med Sci. 1939;186:241-247.
2. Moore LG. Altitude aggravated illness: examples from pregnancy and prenatal life. Ann Emerg Med. 1987;16:965-973.[Medline] [Order article via Infotrieve]
3.
Honigman B, Theis MK, Koziol-McClain J, Roach RC, Yip
R, Houston C, Moore LG. Acute mountain sickness in a general
tourist population at moderate altitudes. Ann Intern
Med. 1993;118:587-592.
4.
Kennedy RD, Andrews GR, Caird FI.
Ischemic heart disease in the elderly. Br
Heart J. 1977;39:1121-1127.
5.
Elveback L, Lie JT. Continued high incidence of
coronary artery disease at autopsy in Olmstead County,
Minnesota, 1950-1979. Circulation. 1984;70:345-349.
6. Stamford BA. Exercise and the elderly. Exerc Sports Sci Rev. 1988;16:341-379.
7. Peterson DD, Pack AI, Silage DA, Fishman AP. Effects of aging on ventilatory and occlusion pressure responses to hypoxia and hypercapnia. Am Rev Respir Dis. 1981;124:387-391.[Medline] [Order article via Infotrieve]
8. Squires RW. Moderate altitude exposure and the cardiac patient. J Cardiopul Rehab. 1985;5:421-426.
9.
Rennie D. Will mountains trekkers have heart
attacks? JAMA. 1989;261:1045-1046.
10. Froelicher VF, West JB. Trekking in Nepal: safety after coronary bypass surgery. JAMA. 1988;259:3184.
11. Hultgren HN (in reply to West JB). The safety of trekking at high altitude after coronary bypass surgery. JAMA. 1989;260:2218-2219.
12. Roach RC, Houston CS, Honigman B, Nicholas RA, Yaron M, Grisson CK, Alexander JK, Hultgren HN. How well do older persons tolerate moderate altitude? West J Med. 1995;162:32-36.[Medline] [Order article via Infotrieve]
13. Mazzeo RS. Pattern of sympatho-adrenal activation at altitude. In: Sutton JR, Houston CS, Coates G, eds. Hypoxia and Molecular Medicine. Burlington, VT: Queen City Printers; 1993:53-61.
14.
Dill DB, Costill DL. Calculation of percentage
changes in volumes of blood, plasma, and red cells in
dehydration. J Appl Physiol. 1974;37:247-248.
15.
Schoene RB, Lahiri S, Hackett PH. Relationship
of hypoxic ventilatory response to exercise performance on
Mount Everest. J Appl Physiol. 1984;56:1478-1483.
16. Schiller NB, Shah PM, Crawford M, De Maria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I, Silverman HN, Tajik AJ. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr. 1989;2:358-367.[Medline] [Order article via Infotrieve]
17. Yagi H, Yamada H, Kobayashi T, Sekiguchi M. Doppler assessment of pulmonary hypertension induced by hypoxic breathing in subjects susceptible to high altitude pulmonary edema. Am Rev Respir Dis. 1990;142:796-801.[Medline] [Order article via Infotrieve]
18.
Ihlen H, Amlie JP, Dale J, Forfang K, Nitter-Hauge S,
Otterstad JE, Simonsen S, Myhre E. Determination of cardiac
output by Doppler echocardiography.
Br Heart J. 1984;51:54-59.
19. Myerburg RJ. A biological approach to sudden cardiac death: structure, function, and cause. Am J Cardiol. 1989;63:1512-1523.[Medline] [Order article via Infotrieve]
20. Breithardt G, Cain ME, El-Sherif N, Flowers NC, Hombach V, Janse J, Simson MB, Steinbeck G. Standards for analysis of ventricular late potentials using high-resolution or signal-averaged electrocardiography. J Am Coll Cardiol. 1991;17:999-1006.[Abstract]
21. Podrid PJ, Venditti FJ, Levine PA, Klein MD. The role of exercise testing in evaluation of arrhythmias. Am J Cardiol. 1988;62:24H-28H.[Medline] [Order article via Infotrieve]
22. Levine BD, Engfred K, Friedman D, Clifford P, Hanel B, Saltin B, Kjaer M, Secher N. The effect of hypoxic or hypobaric hypoxic endurance training on the hypoxic ventilatory response. Med Sci Sports Exerc. 1992;24:769-775.[Medline] [Order article via Infotrieve]
23. Buskirk ER. Physiology and performance of track athletes at various altitudes in the United States and Peru. In: Goddard RF, ed. The Effects of Altitude on Physical Performance. Chicago, Ill: Athletic Institute; 1966:65-72.
24. Rogot E, Hrubec A. Trends in mortality from coronary heart disease and stroke among US veterans: 1954–1979. J Clin Epidemiol. 1989;42:245-256.[Medline] [Order article via Infotrieve]
25.
Davies MJ, Thomas AC. Plaque fissuring: the
cause of acute myocardial infarction, sudden ischaemic death, and
crescendo angina. Br Heart J. 1985;53:363-373.
26. Hultgren HN. Coronary heart disease and trekking. J Wilderness Med. 1990;1:154-161.
27.
Vogel JA, Hartley LH, Cruz JC, Hogan RP. Cardiac
output during exercise in sea-level residents at sea level and high
altitude. J Appl Physiol. 1974;36:169-172.
28.
Mazzeo RS, Bender PR, Brooks GA, Butterfield GE, Groves
BM, Sutton JR, Wolfel EE, Reeves JT. Arterial
catecholamine responses during exercise with acute and
chronic high-altitude exposure. Am J Physiol. 1991;261:E419-E424.
29. Astrand PO, Rodahl K. Textbook of Work Physiology. New York, NY: McGraw-Hill; 1986:333.
30.
Hossack KF, Bruce RA. Maximal cardiac function
in sedentary normal men and women: comparison of age-related
changes. J Appl Physiol. 1982;53:799-804.
31. Weisfeldt ML, Lakatta EG, Gerstenblith G. Aging and the heart. In: Braunwald E, ed. Heart Disease. Philadelphia, Pa: WB Saunders; 1992:1656-1669.
32. Rogers MA, Evans WJ. Changes in skeletal muscle with aging: effects of exercise training. Exerc Sports Sci Rev. 1993;21:65-102.
33. Chapman KR, Cherniak NS. Aging effects on the interaction of hypercapnia and hypoxia as ventilatory stimuli. J Gerontol. 1987;42:202-209.
34. Kronenberg RS, Drage CW. Attenuation of the ventilatory and heart rate responses to hypoxia and hypercapnia with aging in normal men. J Clin Invest. 1973;52:1812-1819.
35. Suarez J, Alexander JK, Houston CS. Enhanced left ventricular systolic performance at high altitude during Operation Everest II. Am J Cardiol. 1987;60:137-142.[Medline] [Order article via Infotrieve]
36. Hoffmeister HM, Seiper L. Tolerance of myocardium of aged animals to repeated oxygen deficiency. Basic Res Cardiol. 1992;87:161-172.
37. Morgan BJ, Alexander JK, Nicoli SA, Brammell HL. The patient with coronary heart disease at altitude: observations during acute exposure to 3100 meters. J Wilderness Med. 1990;1:147-153.
38. Mariburl H, Schobersberger W, Humpeler E, Hasibeder W, Fischer W, Raas E. Beneficial effects of exercising at moderate altitude on red cell oxygen transport and on exercise performance. Pflugers Arch. 1986;406:594-599.[Medline] [Order article via Infotrieve]
39.
Saito M, Mano T, Iwase I, Koga K, Abe H, Yamazaki
Y. Responses in muscle sympathetic activity to acute
hypoxia in humans. J Appl Physiol. 1988;65:1548-1542.
40. Gordon JB, Ganz P, Nabel EG, Fish D, Zebede J, Mudge GH, Alexander RW, Selwyn AP. Atherosclerosis influences the vasomotor response of epicardial coronary arteries to exercise. J Clin Invest. 1989;83:1946-1952.
41.
Werns SW, Walton JA, Hsia HH, Nabel EG, Sanz ML, Pitt
B. Evidence of endothelial dysfunction in
angiographically normal coronary arteries of patients with
coronary artery disease. Circulation. 1989;79:287-291.
42.
Bartsch P, Haebverli A, Franciolli M, Kruithof EK,
Straub PW. Coagulation and fibrinolysis in acute
mountain sickness and beginning pulmonary edema.
J Appl Physiol. 1989;66:2136-2144.
43.
Mittleman MA, Maclure M, Tofler GH, Sherwood JB,
Goldberg RJ, Muller JE. Triggering of acute myocardial
infarction by heavy physical exertion: protection against triggering by
regular exertion. N Engl J Med. 1993;329:1677-1683.
44. Podrid PJ, Fuchs T, Cardinas R. Role of the sympathetic nervous system in the genesis of ventricular arrythmias. Circulation. 1990;82(suppl I):I-103-I-113.
45. Kjellgren O, Gomes JA. Current usefulness of the signal-averaged electrocardiogram. Curr Probl Cardiol. 1993;18:361-418.[Medline] [Order article via Infotrieve]
46. Steinbach K, Glogar D, Weber H, Joskowicz G, Kaindl F. Frequency and variability of ventricular premature contractions: the influence of heart rate and circadian rhythms. Pacing Clin Electrophysiol. 1982;5:38-51.[Medline] [Order article via Infotrieve]
47. Hackett PH, Roach RC, Sutton JR. High altitude medicine. In: Auerbach PS, Gehr EC, eds. Management of Wilderness and Environmental Emergencies. St Louis, Mo: CV Mosby; 1989:1-34.
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