Enhanced left Ventricular Systolic Performance at High Altitude During Operation Everest II

JOSE SUAREZ, MD, JAMES K. ALEXANDER, MD, and CHARLES S. HOUSTON, MD

Serial rest and upright cycle exercise 2-dimensional echocardiographic studies were performed in 7 healthy young men during acclimatization to a simu- lated altitude of 29,000 feet (barometric pressure [PSI 240 torr) in a chamber for 40 days. In all sub- jects left ventricular (LV) end-diastolic, end-systolic and stroke volumes progressively decreased, with mean reductions of 21% , 40 % and 14 % , respec- tively, on ascent to 25,000 feet (Ps 282 torr) at rest, and reductions of 23 % , 43 % and 14 % during 80-W exercise. At Ps 282 torr, mean arterial blood 02 partial pressures were 37 torr (rest) and 32 torr (exercise), with corresponding Oz saturations of 88 % and 59%. All 3 indexes of LV systolic func-

tion examined-ejection fraction, ratio of peak sys- tolic pressure to end-systolic volume and mean nor- malized systolic ejection rate at rest-were sustained in all subjects at high altitude despite re- duced preload, pulmonary hypertension and severe hypoxemia. Increases in ejection fraction of 8% at rest and 10 % during exercise developed at Ps 282 torr and a higher mean normalized systolic ejection rate in association with elevated circulating cate- cholamines reflecting enhanced sympathetic activi- ty. LV systolic function is not a limiting factor in compromising the exercise capacity of normal hu- mans on ascent to high altitude, even to the peak of Mt. Everest. (Am J Cardiol 1987;80:137-142)

I dentification of mechanisms or factors responsible for limitation of man’s exercise capacity on ascent to altitude has long been considered of paramount im- portance in high-altitude physiology. Although such limitation is presumed to be related to the effect of hypoxia, the impact of some environmental factors in the field, such as ambient temperature, humidity and degree of activity, are difficult to quantitate. Operation Everest II was developed to permit assessment of the role of hypoxia alone in an otherwise controlled envi- ronment utilizing a large barometric chamber to house subjects under investigation.

In this setting serial observations could be made during acclimatization while progressively lowering barometric pressure to simulate altitude as great as

From the Departments of Medicine, Cardiology Section, Baylor College of Medicine, Houston, Texas, and University of Ver- mont, Burlington, Vermont. This study was supported by Con- tract DAMD17-85-5208 from the Army Research and Develop- ment Command, and the Arctic Institute of North America. Computational assistance was provided by the CLINFO Project, Grant RR-00350, from the Division of Research Resources of the National Institutes of Health, Bethesda, Maryland. Manuscript received December 8,1986; revised manuscript received Febru- ary 10,1987, accepted February 17,1987.

Address for reprints: James K. Alexander, MD, 6560 Fannin, Suite 817, Houston, Texas 77030.

8,840 meters (29,000 feet), that of Mt. Everest, the high- est elevation on earth. This study assesses the effects of progressively increasing systemic hypoxia on left ven- tricular (LV] function during acclimatization of normal subjects and determines whether severe hypoxemia impairs cardiac function, thus compromising oxygen transport and work capacity at high altitude.

Methods Two-dimensional [2-D) echocardiograms were re-

corded using a Hewlett Packard model 77020A ul- trasound system. A 2.5- or 3.5-MHz transducer was used for visualization of the 2-D echocardiogram and pulsed Doppler velocity recording. All studies were recorded on a standard 0.5-inch VHS videotape. For the rest study, echocardiograms were recorded in the supine left lateral position with electrocardiographic attachments to obtain a simultaneous single standard lead tracing. Parasternal and apical long- and short- axis views were obtained, with Doppler sample vol- ume for systemic flow velocity at the LV outflow tract just below the valve in the apical long-axis view. After positioning the subject on an upright cycle [Monarkj ergometer, apical 4-chamber views were recorded at rest and during exercise.

The subjects were 7 healthy men, aged 21 to 31 years, who had undergone careful medical evaluation

138 OPERATION EVEREST II

2nd had given signed, informed consent. Characteris- tics of the subjects and the conditions under which they were studied have been detailed-l Briefly, the study was performed in the hypobaric chamber locat- ed at the US. Army Research Institute of Environmen- tal Medicine, Natick, Massachusetts, involving de- compression to a simulated altitude of 8,840 m (240 torr], with maintenance of relative humidity at 50 to 84% and temperatures at 18 to 22’C. The subjects lived in the chamber for 40 days with decompression at a rate permitting acclimatization and pauses for a vari- ety of physiologic,measurements.z The study schedule permitted echocardiographic observations as follows: 7 subjects at 760 torr [sea level); 4 subjects at 428 torr (15,000 feet); 7 subjects at 380 torr (18,000 feet), within 24 hours, after 17 decompression days; 4 subjects at 347 torr (20,000 feet]; 3 subjects at 320 torr (22,000 feet); 6 subjects at 282 torr (25,000 feet), with 24 to 48 hours, after 33 decompression days; and 2 subjects at 240 torr (29,000 feet).

The study protocol at sea level involved observa- tions of subjectsbreathing room air and after inhala- tion of 10% O2 for 10 minutes in the supine position, and again at rest after 5 to 10 minutes breathing room air on the cycle ergometer. The subjects then exercised breathing room air at increasing work load levels for 5 minutes each to near-maxima1 capacity, with echocar- diographic observations during the period 3% to 4% minutes at each stage. After a 5- to lo-minute rest, observations were again made during exercise at the highest work load while breathing 100% OZ. This same study protocol was carried out at each of the simulated high altitudes except for 29,000 feet, substituting 100% OZ inhalation for 10% OZ in the supine rest position. At a simulated altitude of 29,000 feet, observations were made only at supine rest while breathing amblent air, and 100% OZ. Observations were designed to correlate with hemodynamic studies carried out separately, us- ing the same protoco1.Q

Sphygmomanometric blood pressure measure- ments on the right arm were secured at supine and upright cycle rest, and after the third minute of each exercise stage.

On completion of the study, each VHS videotape was coded and data recording was carried out by an analyst blinded to the simulated altitude levels for each subject. Echocardiograms were processed using the Microsonic computer system. The best-quality 2-D images were digitized and stored in loop format and the endocardial edge was traced using computer assis- tance for identification of LV end-systolic and end- diastolic images. Apical &chamber and 2-chamber views were analyzed for the supine rest studies, and 2 or more beats were analyzed for cycle rest and exer- cise stages. Analysis of area and volumes were carried out using Simpson’s volume equation, which has heen validated.3

Three indexes of LV systolic performance were ex- amined: ejection fraction, ratio of peak systolic pres- sure to end-systolic volume, and mean normalized sys- tolic ejection rate. Ejection fraction was taken as the ratio (EDV - ESV]/EDV, where EDV = end-diastolic

volume and ESV = end-systolic volume. Use of the peak systolic pressure to end-systolic volume ratio as an index of LV contractility in humans4 and the feasi- bility of its noninvasive application have been demon- stratedB5s6 In this study a single point on this slope, i.e., a ratio of pressure to volume, was taken as reflecting the inotropic state of the left ventricle under condi- tions of varying barometric pressure (Ps) at rest and during exercise. For calculation of peak systolic pres- sure to end-systolic volume ratio, peak systolic pres- sure was taken as the sphygmomanometric measure- ment of brachial artery systolic pressure. The basis for use of mean normalized LV systolic ejection rate as an index of LV systolic performance in both the normal and diseased ventricle has been defined.’ Mean sys- tolic ejection rate was calculated as the ratio of stroke volume to LV ejection time (Doppler measurement) and normalized by dividing by end-diastolic volume.

When all measurements had been made, the data were decoded for statistical analysis. In view of the limited number of subjects studied at other barometric pressures, only data generated at sea level and simu- lated altitudes of 18,000 feet (Pa 380 torr) and 25,000 feet (Pn 282 torr) were selected. Using each subject as his own control, data at the 3 altitudes were tested for differences by paired (2-tailed) t test, taking p <O.O5 as significant.

Results On ascent to altitude, heart rate increased signifi-

cantly at rest and during exercise (Table I). At Pa 282 torr, mean supine heart rate (80 f 17 beats/min) was 25 beats/min higher than that at sea level (55 f 4 beats/ min), and 15 beats/mm higher than that at Pa 386 torr (65 f 13 beats/min). Sitting at rest on the cycle ergome- ter, mean heart rate was somewhat higher than supine heart rate at all 3 altitudes: sea level 61 f 10, PB 380 torr [Sl f 12), Pa 282 torr (95 f 14). At an exercise level of 60 W, mean heart rate increased significantly at Pa 380 torr (112 f 14 vs sea level 87 f 16 beats/min), with no further change at Ps 282 torr (115 $ 15 beats/min].

Sea level systolic blood pressure readings at supine rest [105 f 8 mm Hg), cycle rest (109 f 8 mm Hg), and 60-W exercise (119 f 20 mm Hg) all increased signifi- cantly on ascent to Pa 380 torr (119 f 9, 126 i 12 and 146 f 8 mm Hg), with no further change at Ps 282 torr (112 f 12,118 f 13,138 f 12 mm Hg). Supine and cycle rest diastolic blood pressure levels followed the same pattern as that for systolic pressures. Mean values for supine rest at sea level, Pa 380 torr, and PB 282 torr were 59 f 7,66 f 8,68 f 4 mm Hg, and for cycle rest 68 It 9, 75 f 5, 75 f 8 mm Hg.

In every subject, LV end-diastolic volume, end-sys- tolic volume and stroke volume decreased during su- pine rest, cycle rest and 60-W exercise at altitude. Compared with sea level at both Ps 380 torr and Pn 282 torr, mean values for LV end-diastolic volume, end- systolic volume and stroke volume decreased signifi- cantly, while at supine and cycle rest and during 60-W exercise [Table I). At Ps 282 torr, whi1e resting on the cycle, this represented 2l%, 40% and 14% reductions in mean end-diastolic, end-systolic and stroke vol-

July 1.1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 60 139

TABLE I Heart Rate and Left Ventricular Volumes at Rest and During Exercise at P, 760 torr (Sea Level), P, 380 torr (18 k), and P, 282 torr (25 k)’

Supine rest HR (beats/min) EDV (ml) ESV (ml) SV (ml)

Bicycle rest HR (beats/min) EDV (ml) ESV (ml) SV (ml)

Exercise 60 W HR (beatslmin) EDV (ml) ESV (ml) sv

Exercise RPP 23,460 f 500 mm Hgbeats/min EDV (ml) ESV (ml) SV (ml)

Ps 760 torr

55 i 4 149 f 22

55 f 8 93 f 16

61 f IO 139 f 18

52f 11 86f IO

87 f 16 141 zt 22

44f 18 96i 13

133 f 19 31 f 8

105 f 14

Ps 380 torr

65 f 13’ 123 f 17”

43 f 9’ 79 f 12’

81 f 12’ 112 f 19’

40 f 6’ 73 f 14’

112 i 14’ 116 f 19’

28 i 9’ 87 f 13

110 f 20 23 i 9 86 f 13’

Ps 282 ton

80 f 17’T 113 i 21’

41 f 13’ 71 f 7’7

95 f 14.t 110 f 21’

32 dz 13’ 74 f 7”

115 f 15’ 108 f 23’

25 f 9’ 83f 15

104 f 20’ 18 f 5’ 90 f 10’

l p <0.05 vs Ps 760 torr; Tp <0.05 vs Ps 380 torr. Volumes are mean f standard deviation. EDV = end-diastolic volume; ESV = end-systolic volume: HR = mean heat-i rate; RPP = rate-pressure product;

SV = stroke volume: 18 k altitude equivalent 18,000 feet; 25 k altitude equivalent 25,000 feet.

TABLE II Indexes of Left Ventricular Systolic Performance at P, 760 torr (Sea Level), P, 380 torr (18 k), and P, 282 torr (25 k)’

Ps 780 torr Ps 380 torr Ps 282 torr

EF (%) Supine rest Bicycle rest 60 W exercise Exercise RPP 23,460 f 500

mm Hgbeats min PSPf ESV

Upright cycle rest Peak exercise

MSER (EDV/s) Supine rest

61 f 4 64 f 2 64 f 5 62 f 5 84 f 5 88 f 8+ 69 f 8 76 f 5+ 79 f 2+ 78 f 2 79 i 5 81 f 4

2.2 3.3 4.0 8.4 9.7 10.0

1.96 f 0.22 2.35 i 0.23’ 2.68 f 0.50’

l p <0.05 as compared to Ps 760 torr. Values are mean f standard deviation. EF = ejection fraction; MSER = mean left ventricular systolic ejection rate; PSPlESV = ratio of peak systolic

blood pressure to left ventricular end-systolic volume; RPP = rate-pressure product. 18 k altitude equivalent 18.000 feet; 25 k altitude equivalent 25,000 feet.

umes, respectively. Similar reductions of 2370, 43% and 14% were observed during 60-W exercise. During exercise at a comparable pressure-rate product, reduc- tion in LV end-diastolic volume and stroke volume on altitude ascent attained statistical significance only at Ps 282 torr (Table I), representing decrements of 22%. 42% and 14% in mean end-diastolic, end-systolic and stroke volumes.

In every subject, ejection fraction remained the same or increased at altitude both at rest and during exercise. Increments of 6% and 10% in mean EF at Pa 282 torr during cycle rest and 60-W exercise were sig- nificant (Table II]. Ejection fractions during peak exer- cise at Pa 282 torr were comparable to those at sea level in all subjects (Fig. I]. Serial observations on LV vol-

ume, ejection fraction and heart rate in subject 6 at rest are shown in Figure 2. Mean values for peak systolic pressure to end-systolic volume ratio at rest tended to increase somewhat at altitude, with increments of about 6 mm Hg/ml at sea level, Pa 380 torr and Pa 282 torr during peak exercise (Table II). Thus, the slopes of the relations between rest and exercise were compara- ble at all 3 altitudes (Fig. 3). Mean normalized systolic ejection rate during supine rest was significantly in- creased both at Ps 380 torr and Pa 282 torr (Table II].

The initial intervention, 10% O2 inhalation at sea level rest, brought about an increase in heart rate, no change in systolic blood pressure, a modest decrease in end-diastolic volume, and no difference in ejection fraction (Table III). No changes in heart rate, systol-

140 OPERATION EVEREST 11

ic blood pressure, end-diastolic volume, end-systolic volume, stroke volume or ejection fraction were found during 100% O2 inhalation at rest or during exercise at sea level, nor at rest at Ps 380 torr. A decrease in systolic blood pressure and some slowing of heart rate took place at rest at Pa 282 and during exercise at both Ps 380 torr and Pa 282 torr, with no significant change in LV end-diastolic volume, stroke volume or ejection fraction [Table III).

Discussion A modest increment in LV contractility at altitude is

suggested in this study by (1) maintenance of ejection fraction despite diminished preload at both Pa 380 torr and Pa 282 torr, (2) an increase in ejection fraction at rest and during 60-W exercise at Pa 282 torr, and (3) increases in mean systolic ejection rate at Pn 380 torr and Ps 282 torr. Greater sympathetic nervous activity appears to be the basis for this increase. In this study plasma noradrenaline levels at rest doubled at PB 380 torr, with little further change at Pa 282 torr.8 Despite a

Ejection

Fraction

P/n)

4oj , . My j Go1 , * Me: ]

Cycle Peak Cycle Peak Rest Exercise Rest Exercise

sea Level P B 282 tort

FIGURE 1. Ejection fractions at rest on the cycle ergometer and during peak exercise in all subjects studied at sea level and at simulated altitude 25,000 feet (Ps 282 torr).

200

Left Ventricular 150

Volume (ml) 100

50

SUPINE REST, SUBJECT 6

,” ?j.ijgij::

I 0 5 10 15 20 25 30

Simulated Altitude Above Sea Level (thousands of feet)

FIGURE 2. Serial measurements of left ventricular end-diastolic, F stroke and end-systolic volumes, ejection fraction and heart rate at i rest supine in subject 6 on ascent to a slmulated altitude of 29,000 $ feet (Ps 240 torr). I-

July I,1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 60 141

reduced peak work capacity at PB 380 torr, plasma noradrenaline levels during exhaustive exercise were slightly but nonsignificantly higher than those at sea level. These observations are consistent with previous- ly reported increments in plasma noradrenaline levels in humans at an altitude of 4,560 m.g Increases in heart rate and LV systolic performance are well document- ed effects of /3-adrenergic cardiac stimulation in hu- mans.lO Thus, increased circulating catecholamine levels may account for both higher heart rates and an enhanced LV inotropic state at altitude. In normal sub- jects, diminished venous return and LV preload re- duction alone induced by tilt or nitroglycerin adminis- tration effect no significant changes in LV systolic function.ll Moreover, the absence of a decrease in peak systolic pressure to end-systolic volume ratio at rest or during exercise is noteworthy. This index, rela- tively insensitive to the effects of preload reduction and increased heart rate encountered with diminish- ing Pa, further supports the proposition of sustained LV inotropism at altitude.

At Pg 282 torr, mean O2 partial pressure (POZ) in arterial blood at rest in this group was 37 torr, decreas- ing to 32 torr during exercise, when mixed venous blood POz was 14 torr. At Ps 240 torr, rest values for arterial and mixed venous POz were 29 and 16 torr, respectively.lz Mixed venous blood POz at these alti- tudes was less than coronary sinus blood POz (20 torr) at sea levelI Thus, cpronary sinus POz at Pa 262 torr and Pg 240 torr must be markedly reduced, reflecting severe cardiac hypoxemia. Nevertheless, no ST-seg- ment changes were observed on the electrocardiogram at rest or during exercise at these altitudes.14

In this study pulmonary artery mean pressure ranged from 26 to 41 torr (mean 34) at rest in the 5 subjects studied at Pa ?82 torr; it increased to a mean of 54 torr (range 51 to 60) in 4 of these subjects monitored duiing exercise.l Little change in these levels occurred at Pa 240 torr. Pulmonary hypertension was accompa- nied by rightward deviation of the mean QRS axis on the rest electrocardiogram. We did not try to make right ventricular volumetric measurements from the echocardiograms. However, moderate right ventricu- lar enlargement, paradoxical septal motion and well preserved systolic emptying were apparent on inspec- tion of the echocardiograms in the apical 4-chamber view, both at rest and during exercise in the 6 subjects monitored at PB 282 torr. Thus, LV systolic function remained intact despite these changes, and right ven- tricular filling pressures as reflected by right atria1 mean pressures did not increased at altitude-l No evi- dence of tricuspid regurgitation at rest was found by Doppler examination (performed at the time of 2-D echocardiographic study] at lower barometric pressures.

Studies using M-mode echocardiography show de- creases in LV end-diastolic and end-systolic volumes in normal subjects on ascent to altitudes of 3,100 m I5 and 5,365 rn.16 Diuresis associated with weight reduc- tion and contraction of plasma volume17J* takes place on ascent of normal persons to high altitude. No data on plasma volume are available in this study. How-

10

Ratio Peak 8 Systolic Pressure:

End-Systolic S Volume

(mm Hg/ml) 4

2

D--Q P, 282 torr

-0-o P, 380 torr

L\ Sea Level

0’ I I I Cycle Peak

Rest Exercise

FIGURE 3. Mean ratios of peak systolic pressure to end-systolic volume at rest on the cycle ergometer and duiing peak exercise for all subjects studied at sea level, a simulated altitude bf 18,000 feet (Pe 380 torr) and simulated altitude of 25,000 feet (Ps 282 torr).

ever, all subjects had progressive weight loss on ascent to altitude. Of the 6 who completed the experiment, tlie average weight loss was 7.56 kg (range 4.15 to 11.95).lg Assuming no significant change in the rate of serum protein synthesis or degradation, plastia volume was also reduced, as indicated by an increment in total serum protein concentration from 7.34 f 0.34 g% at sea level to 8.15 f 0.62 g% tit altitude.20 In addition, both pulmonary artery wedge and right atria1 pressures de- creased.l Thus, the observed reduction in LV preload in this study appears to be at least partially related to diminished circulating blood volume.

The response to 10% O2 inhalation at sea level was essentially as anticipated from prior studies. Augmen- tation of cardiac output associated with sinus tatihycar- dia has been recognized ,21,22 while the preservation of LV systolic function observed in this study iS notewor- thy. On inhalation of 100% O2 at high altitude, slowing of heart rate with unchanged btroke volume indicates the fall decrease in cardiac output confirmed by direct measurements at rest and during exercise.2

In summary, on ascent to altitude by normal man at the rate exemplified by this study, diminished cardiac stroke volume is accompanied by increased heart rate, effecting maintenance of cardiac output and body Oz uptake for given work load. Despite reduced preload, right ventricular systolic hypertension, and severe car- diac hypoxemia, LV systolic function is maintained or somewhat enhanced in association witli augmented sympathetic activity to a simulated altitude of 29,000 feet. No evidence has been found to indicate that LV systolic function limits man’s exercise tolerance on as- cent to terrestrial high altitude.

Acknowledgment: We gratefully acknowledge the support of the entire investigational team at the U.S. Army Research Institute of Environmental Medicine which made this study possible, the dedication and cooperation of the subjects, the helpful suggestions and guidance of Miguel A. Quinones, MD, and the perseverance of Molly M. Dye in preparation of the manuscript.

142 OPERATION EVEREST II

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