Effect of High-Altitude Exposure in the Elderly
The Tenth Mountain Division Study
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. V̇o2peak decreased 12% acutely but normalized after acclimatization. The best predictor of V̇o2peak with acute altitude was V̇o2peak 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.
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.
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.
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.
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
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 : (V̇E altitude−V̇E sea level)/(O2sat sea level−O2sat altitude).
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 (V̇o2) 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 V̇o2 was defined as the highest V̇o2 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 pressure×peak heart rate and was used as an index of myocardial oxygen requirements during exercise.
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).
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.
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).
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).
Changes in work capacity, as reflected by V̇o2peak, 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.
For the group as a whole, V̇o2peak 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 V̇o2peak 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 (1.36×hemoglobin×O2 saturation×10) 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 V̇o2peak 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 V̇o2peak with acute altitude exposure was V̇o2peak 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 V̇o2 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 V̇o2peak 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 V̇o2peak at sea level (P=.04), for the prediction of V̇o2peak at altitude. The two variables combined explained 92% of the variance in V̇o2peak 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 rate×systolic 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.
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.
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.
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 (V̇o2max) 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 V̇o2max by ≈1% for every 100 m >1500 m.23 Whether the effect of age and altitude on V̇o2max 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.
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.
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.
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.
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.
- Copyright © 1997 by American Heart Association
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