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Cardiac response to combined moderate heat and exercise in men with coronary artery disease
Cardiac Response to Combined Moderate Heat and Exercise in Men with Coronary Artery Disease Lois M. Sheldahl, PhD, Nancy A. Wilke, BA, Sara Dougherty, MS, and Felix E. Tristani, MD
The effect of moderate heat stress on cardiac performance during sustained moderate physical work was evaluated in men 26 weeks after a card&c event. Subjects (n = 10) performed upright leg cycle ergometer exercise at approximately SO% of peak oxygen uptake for up to 60 minutes in warm (30.0 f O.S”C) and thermonwtral(21.5 f 0.3X) envhonments. Cardiac output (carbon dioxtde rebreathing method), left ventricular ejection fraction and relative teft venttfcutar end-diastatic vdume (portable nuclear VEST monitor) were pertodkally determined. In both envtronments, heart rate increased (p
eat stresscan increasethe demandson the cardiovascular systemduring exerciseowing to increased thermoregulatory blood flow require ments. The effect of heat stresson cardiac function de pends on exerciseintensity and duration, magnitude of heat stress,hydration level, acclimation state and exercise capacity.1-3Little is known regarding the effect of heat stresson cardiac function during exercise in sub jects with coronary artery disease.Reduced cardiac reserve and maximal oxygen uptake in these subjects could limit the ability to achievecombined thermoregulatory and metabolic blood flow demands.4Fluid and electrolyte reductions together with a possibleaugmented sympathetic nervous activation state1-3*5p6 could also increasethe incidence of arrhythmias. The present study evaluates the influence of heat stresson cardiac function during sustained moderate exercise in men with known coronary artery disease.A moderate rather than a high heat load was selected to promote safety and still provide information on work conditions more likely to be encounteredby cardiac patients with occupational, home or leisure activities.
H
METHODS SubjeetarTen asymptomaticmen (averageage 60 f 2 years, averageweight 86.0 f 5.4 kg) who had a myocardial infarction (8 inferior and 1 non-Q-wave), coronary artery bypasssurgery (n = 4) or percutaneousangioplasty (n = l), or a combination, 16 weeks before the study were examined. All subjects were at low to moderaterisk. Medications included &blockers (n = 3), calcium antagonists (n = 3), digitalis (n = l), diuretics (n = 1) and nitrates (n = 1). All subjectswere participating in an exerciseprogram. The study was conducted from July through September 1990. Subjects agreed to the protocol approved by the Institutional Human Research Review Committee. Preliminary W All subjectsinitially performed a treadmill exercise test using a modified Balke protocol.7 Any subject unable to exercise to fatigue or achieve 15 METS was excluded. A 1Zlead electrocardiogram was periodically recorded. Oxygen uptake was measuredby open-circuit spirometry. ExperimenU m At least 3 days after the treadmill exercisetest, subjects reported for placement From the VA Medical Center and Medical College of Wisconsin, of an ambulatory ventricular function monitor (VEST, Milwaukee, Wiinsin. This study wassupportedby a researchdemon- Capintec, Inc.). The VEST radiation detector was censtration program grant from the Department of Health and Human tered over the left ventricular blood pool with the aid of Services,Baltimore, Maryland. Manuscript receivedJanuary 3,1992; a gamma scintillation camera. A second detector was revisedmanuscript receivedand acceptedMarch 23,1992. Addressfor reprints: Lois M. Sheldahl, PhD, VA Medical Center, placed over the right lung to monitor background radionuclide activity. Before placement of the VEST, red 11lR, 5000 W. National Avenue, Milwaukee, Wisconsin53295. 186
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
JULY 15. 1992
blood cells were labeled in vivo with 25 to 30 mCi of technetium-99m, and left ventricular ejection fraction was determined at rest (seatedposition) in the left ante rior oblique view using multigated acquisition imaging procedures.A red marker was placed at the top edgeof the VEST garment on the subject’schest to enableevaluation of possiblemovement of the garment during the experimental sessions. Baseline VEST measurementswere obtained with the subject in the seated posture. The subject then underwent 2 leg cycle ergometer tests separated by ap proximately 3 hours; 1 study was performed in a thermoneutral (21.5 f 0.3OC) laboratory and the other outdoors in a warm (30.0 f 0.9OC) environment. Humidity averaged 53 f 1% indoors and 47 f 2% outdoors. The order of testing was rotated so that the same number of subjectswas testedfirst in each environment. The subject wore shorts and a T-shirt. The procedures for the exercisetests in the 2 environments were the same.The subject sat on a leg cycle ergometer for 10 minutes and then exercisedfor up to 60 minutes at a work load estimated to need approximately 50%of peak oxygen uptake. Work load (W) was the samein both environments. Measurementsobtained at rest and during exerciseat minutes 6, 20, 40 and 60 included oxygen uptake by open-circuit spirometry (me teorologic balloon usedto collect expired air), heart rate by telemetry, cardiac output by the carbon dioxide re breathing procedure,8rating of perceivedeffort according to the Borg 6- to 2Opoint scale,9and blood pressure by mercury sphygmomanometer.The electrocardiogram was monitored for 9 minutes after exercise. Sweat was wiped off the subject’s face and extremities, and body weight was reassessedbefore drinking water. The change in weight with each exercise sessionwas used to estimate sweat loss, although sweat loss from the trunk region was not accounted for because the clothing (T-shirt and shorts) underneath the VEST garment was not removed. Between the 2 tests, the subject rested in the upright position. Fluid intake was encouraged, and the subject was instructed to eat lunch 12 hours before the second test. At the end of the second test, the subject returned to the nuclear testing laborato ry. The positioning of the VEST detector mount was checkedvisually, as well as with the gamma scintillation camera. VEST dnta -sIsr The VEST-recorded tape was analyzed at 30-secondintervals for left ventricular ejection fraction and relative left ventricular end-diastolic and end-systolic volumes by an independent, experienced technician. In the determination of relative left ventricular volumes, end-diastolic volume at the beginning of the tape in the seated position in the nuclear laboratory was designated as lOO%,and all other enddiastolic and end-systolic volumes were calculated relative to this volume. Incidence of arrhythmias and electrocardiographic ST-segment changes were also evaluated from the VEST tape. Before each tape was analyzed, the technical adequacy of the data was assessed in a 3-step processas follows: (1) comparison of static gamma camera images obtained before and after completion of the study to assesspossiblechangesin VEST
TABLE
I Initial
Adjustments
to Exercise
Parameter
Environment
Heart rate (beatslmin) Stroke volume (ml/beat) LV ejection fraction (%I LV end-diastolic volume (%) LV end-systolic volume f%) Systolic pressure (mm Hg)
Thermoneutral Warm Thermoneutral Warm Thermoneutral Warm Thermoneutral Warm Thermoneutral Warm Thermoneutral Warm
Exercise fmin 6)
Rest
73 74 58 50 45 45 88 79 48 43 138 135
f 2 + 2 f 2 2 k 2 k f 5
3 3 4 4 5 4 5 4 7 3 7 9
92 95 91 84 49 53 99 90 50 41 175 165
k k 2 f f k f f k f 2 2
3* 2* 10* 6* 5 5* 4* 4* 7 3 1* 9*
*p < 0.05 versus rest. Valuesare mean 2 SE (n = 10). LV = left ventricular.
detector positioning, (2) evaluation of trend plots of left ventricular and background counts over time for any abrupt change suggestive of detector movement, and (3) evaluation of individual time-activity curves. Other studies1°-r6showedthat left ventricular ejection fraction data obtained from the VEST at rest or with dynamic exercise, or both, is accurate compared with gamma camera data, and is highly reproducible and consistent with known responsesin cardiac patients. StatIstkal analysis: Analysis of variance with repeatedmeasureswas usedto evaluate the effect of exercise time (6 to 60 minutes) within each environment and that of environmental temperature (thermoneutral and warm) at minutes 20 through 60. In evaluating the latter effect, 3 subjects prescribed fl blockers were excluded owing to different elapsed periods of time between receiving this medication and the beginning of the exercise sessionin the 2 environments. This was done becausethe depressiveeffect on heart rate (and presumably other parametersof cardiac function) could vary with time after ingestion of /3 blockers.r7 Differences between means were assessedwith Fisher’s protected least significant difference test. Paired 1 tests were usedto compareresponsesfrom rest to minute 6 of exercisein each environment and between rest data in the 2 environments. Significance levels were tested at the 0.05 level. All values are reported as mean f SE. RESULTS Preliminary tre&n# ti Peak oxygen uptake, heart rate, systolic pressure,respiratory exchange ratio and rating of perceived effort in the 10 subjects averaged 25.6 f 0.9 ml/kg/mm, 140 f 6 beats/mm, 199 f 9 mm Hg, 1.14 f 0.03 and 18 f 0, respectively. Peak METS ranged from 5.8 to 8.6. No subject had an ischemit response based on electrocardiographic ST-segment analysis or symptoms. lnltial adjmbmW to exedse in two environmentr: Table I lists responsesat rest and at minute 6 of exercise. No significant differences existed between the 2 environmentsat rest. Heart rate, stroke volume, cardiac output, end-diastolic volume and systolic pressure increased (p <0.05) with exercise at minute 6 in both environments, and end-systolic volume decreased (p EXERCISE AND HEAT STRESS
187
<0.05) with the onset of exercise.Left ventricular ejection fraction increased (p <0.05) at minute 6 in the warm environment, but the increasedid not attain significance by minute 6 in the thermoneutral condition. Tolemnce to modera exerdse in heal streasr One subject stopped the exercise test at 40 minutes in the warm environment and indicated before the test in the thermoneutral environment that he did not want to exercise >40 minutes. All other subjects completed 60 minutes of exercisein the 2 environments. Oxygen uptake during exercise at minutes 6, 20, 40 and 60 averaged 12.2 f 0.7, 12.8 f 0.8, 12.9 f 0.6 and 12.7 f 0.7 ml/kg/nun, respectively, in the thermoneutral environment, and 12.3 f 0.8, 12.9 f 0.7, 13.0 f 0.5 and 12.8 f 0.8 ml/kg/nun, respectively, in the warm environment. No differences were observedin oxygen uptake with exercisetime or environment. Rating of perceived effort increased (p <0.05) progressively with exercise time in both environments, but did not differ between the 2 environments.The ratings determined at 6,20,40 and 60 minutes averaged10 f 1,ll f 1,12 f 1 and 13 f 1, respectively,in the thermoneutral condition, and 9 f 1,ll f 1, 12 f 1 and 13 f 1, respectively,with heat stress.
--o--Warm -e--Thermoneutral I
6
20
Exercise
188
I
40
Time
60
(minutes)
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
CardIae~toexerdseinh&stresarHeart rate, stroke volume and cardiac output during exercise in the 2 environments are shown in Figure 1 (all sub jects) and Table II (subjectsnot prescribedfl blockers). With exercisetime in both environments,heart rate increased(p <0.05), stroke volume decreased(p <0.05), and cardiac output did not change. Heart rate was increased(p <0.05) at minute 20 comparedwith minute 6 in both environments. In the warm environment, a further increase (p <0.05) was observedat minute 40 comparedwith minute 20. At minutes 40 and 60, heart rate was higher (p <0.05) in the warm than in the thermoneutral environment (Table II). Exercise stroke volume decreased(p <0.05) at minute 40 comparedwith minute 6, as well as at minute 60 compared with minute 20 in the warm environment (Figure 1). In the thermoneutral condition, stroke volume was decreased(p <0.05) at minute 60 compared with minute 6. Betweenthe 2 environments,stroke volume tended (p <0.08) to be lower with heat stressthan in the thermoneutral environment. Cardiac output did not differ between environments. Left ventricular ejection fraction and relative enddiastolic and end-systolicvolumesare shown in Figure 2 and Table II. Ejection fraction did not change during exercise from minute 6 to 60 in each environment. In comparing the responsebetween the 2 environments, left ventricular ejection fractions were similar (Table II). Relative left ventricular end-diastolic volumes decreased(p <0.05) with exercise time in both environments (Figure 2). The initial decreaseoccurred at minutes 20 and 40 in the warm and thermoneutral environments, respectively. A further decrease(p <0.05) was observed from minute 20 to 60 in the thermoneutral condition. Relative end-diastolic volume tended to be decreased(p <0.06) in the warm environment (Table II). Left ventricular end-systolic volume decreased (p <0.05) at minute 20 with exercisetime in the thermoneutral condition, with no further significant change with exerciseup to 60 minutes (Figure 2). In the warm environment, no significant change was observed from minute 6 through 60. Relative left ventricular end-systolic volumes tended to be decreased(p <0.09) in the warm environment (Table II). Systolic pressure determined at minutes 6, 20, 40 and 60 of exercise,averaged178 f 12,174 f 10,175 f 11 and 169 f 11 mm Hg, respectively, in the therms neutral condition, and 168 f 9,159 Z!Z11,168 f 13 and 164 f 12 mm Hg, respectively, in the warm environment. The only changes(p
JULY 15, 1992
TABLE II Responsesof Patients Not Prescribed p Blockers to Exercise at Minutes 6,20,40
1
and 60
Exercise Parameter Heart rate (beats/min) Stroke volume (ml/beat) LV ejection fraction (%) LV end-diastolic volume (%I LV end-systolic volume f%) Systolic pressure (mm Hg) Diastolic pressure (mm Hg)
Environment
Minute 6
Minute 20
Minute 40
Minute 60
Thermoneutral Warm Thermoneutral Warm Thermoneutral Warm Thermoneutral Warm Thermoneutral Warm Thermoneutral
94 f 3
103 + 4 106 + 4 802 12
106 k 5 115+4* 82 t 10
79 k 7
71 f 7
112 120 78 69 52 53 94 83 47 39 172 167 82 77
Warm Thermoneutral Warm
96 e 3 89 ZL 14 81 29
50 2 4 50 2 7 100 + 4 89 + 4 54 + 8 43 f 4
52 52 97 86 50 40
2 + + + + k
4 6 5 4 9 5
181 lr 14
176?
170 -t 12
163 f 13*
86 2 5
82 + 5
81 + 5
81 2 4
50 50 96 84 50 41 179 172 84
13
2 k + + + f 2 2 +
3 6 4 3 8 4 15 16 6
81 + 4
p Value
2 5 f 5* + 8 + 8 k 4 -c 6 + 4 + 2 r 7 f 4 f 14 2 14 + 5 + 3
0.01 0.08 0.21 0.06 0.08 0.04 0.19
*p <0.05
versus thermoneutral. Values are mean + SE (II = 7). LV = left ventricular.
diastolic pressure was decreased(p <0.05) at 60 minutes compared with 6 minutes. Between environments, no significant difference was observedfor diastolic pressure. No subject had frequent or complex ventricular arrhythmias during exercisein either environment. Occasional (3 to 6/min) ventricular arrhythmias were ob served in 2 subjects in the thermoneutral and 1 in the heat exerciseperiods. Except for 1 subject who had frequent arrhythmias during minute 7 of recovery in the thermoneutral environment, arrhythmia rate was not increased in the immediate recovery period. No subject reported angina1symptoms or had electrocardiographic evidence of myocardial ischemia. Body weight reduction averaged 0.4 kg in the thermoneutral environment (n = 6) and 0.5 kg in the warm environment (n = 7). DISCUSSION Subjects with coronary artery disease had an increase in heart rate, a decreasein stroke volume, and maintenance of cardiac output during sustained moderate exercise combined with moderate heat stress. These directional responsesas well as the magnitude of changes are consistent with those reported in normal subjects under similar temperature and exerciseconditions.18J9 Most evidence indicates that the increase in heart rate with sustained moderate work in both thermoneutral and warm conditions is a compensatoryresponseto maintain cardiac output with a decreasing stroke volume; the latter is generally attributed to decreasedcardiac preload associatedwith increasedcutaneous blood volume, vascular fluid filtration and body water reduction.‘-’ Central blood volume and venouspressurehave been shown to decreaseduring exercise in normal sub jects with exposure to heat stress,1-3~20 although the effeet on left ventricular volume during exercise has not (to our knowledge) beenevaluated. In the presentstudy, men with coronary artery diseasedemonstrateda significant reduction in relative left ventricular end-diastolic
65 60
120
1
60’
3
,
I
I
I
40
60
65-
6
1
20
Exercise
Time
(minutes)
I vcmMadu(LV)eJectbnfmlknmdreleUve “OURE 2’ bn -endand~vehmles4h8ing60-el exm h ,,,- d hmmmubdem&omwd(n= 10). *p
~p<0.osvsminub20.
EXERCISEAND HEAT STRESS 189
volume in both the warm and thermoneutral environments. Although less accepted, another hypothesis postulated to account for the decreasein stroke volume with exercise time in a warm environment is reduced myocardial function.1*3Based on left ventricular ejection fraction, myocardial function did not appear to deteriorate with exercisetime in men with coronary artery disease.Mean ejection fraction remained unchanged from minute 6 to 60 in the warm environment, and no subject (even those [n = 31 with a resting left ventricular ejm tion fraction <40%) had a decreasein ejection fraction less than resting levels at minute 60 of exercisein the warm environment (Figure 3). Thus, despite significant alterations in stroke volume, heart rate and left ventrio ular end-diastolic volumes with exercise time, ejection fraction was preserved during moderate exercise combined with moderateheat stress.Comparedwith at rest, mean ejection fraction increased 28% at minute 20 in both environments.This magnitude of increaseis generally considereda normal responseand suggeststhe ab senceof ischemia. The unchanged systolic pressure at minute 60 compared with minute 6 in the warm environment further indicates that the cardiac output responsewas adequate to maintain peripheral perfusion pressure. It is possiblethat heat stresscould increasearrhythmogenesis through electrolyte changes, or increased myocardial oxygen requirements or sympathetic nervous activation, or a combination. Subjects in the present study did not have a greater incidence of arrhythmias with work time or heat stress.Although decreased venous return and increasedcirculating catecholamines in the immediate recovery period could theoretically provoke an increase in the incidence of arrhythmias in the warm environment, this was not observed. Study m One limitation of the study was that core temperature was not measured. In normal subjects, other studies showed that core temperature during 1 hour of moderate exerciseis independentof air temperature betweenthe range of 5 and 30°C.21,22The mean temperature in the warm environment was 30°C, suggestingthat the increasein core temperature proba-
bly did not differ substantially between the 2 environments. Further support for an appropriate core temperature was the ability of subjectsto maintain systolic pressure from 6 to 60 minutes. Rowel12reported that mean arterial pressure decreasedwhen core temperature was >39OC. The 2 exercisesessionswere scheduledon the same day owing to the use of a radioisotope. Thus, patients were tested at a different time of day in the 2 environments. An equal number were tested first in each environment, and subjects prescribed /3 blockers were excluded from the statistical analysis of the environmental factor owing to the drug’s potential variable impact on heart rate and other indexesof cardiac function in relation to the elapsedtime between receiving the medication and performing exercise. With regard to application to the occupational setting, the work intensity selectedonly slightly exceededthe average8-hour intensity level (i.e., 40% of peak oxygen uptake) frequently cited as appropriate.23Thus, the conditions of this study (in which subjectsperformed 1 hour of work at 50% of peak oxygen uptake in the morning and 1 hour in the afternoon) are within this guideline and could be found in the occupational work setting. Clinkal i~r: The maintenance of cardiac output, left ventricular ejection fraction and systolic pressure during sustained work in the warm environment suggeststhat cardiac function did not deteriorate during sustainedmoderateexercisecombined with moderate heat stressin stable patients with coronary artery diseasewho have relatively good functional exercisetolerance. The progressiveincrease in heart rate over exercise time suggeststhat clinicians may advise patients to use heart rate to assessthe magnitude of cardiovascular drift occurring during sustained work with heat stress. Although it appears logical to predict that an upright drift in heart rate would increasemyocardial oxygen re quirements, the effect of thii drift on myocardial ischemit thresholds remains unknown. A decreasein left ventricular end-diastolic volume with exercisetime, together with some tendency for systolic pressure to be decreasedin the warm environment, may decreaseleft
80 Warm
Thermoneutral
2 0
I
I
Rest muRE3.bldivmdleftrantrialv vhmmnte.
190
Exercise tww*-=P-=
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
0 Rest atreetandendofexerdeeh~mdwmman-
JULY 15, 1992
I Exercise
ventricular wall tension or afterload, or both, and thereby offset someof the increasein myocardial oxygen requirements expected from the increased heart rate. Perceivedeffort increasedover time, indicating that it may be used by workers to adjust work rates during sustainedwork. However, rating of perceivedeffort did not reflect the differences between the warm and thermoneutral environments, suggestingthat heart rate provides a more sensitive marker of increasedthermoregulatory cardiovascular demands. AdmowkdgmeM We gratefully acknowledge the valuable technical expertiseof Barbara Blaney, CNMT, with the VEST monitor data collection.
REFERENCES
1. Rowe11LB. Human cardiovascularadjustmentsto exerciseand thermal stress.
Physiol Reo 1974;54:75-159.
2. Rowe11LB. Cardiovascular adjustmentsto thermal stress.In: Handbook of Physiology.The Cardiovascular System.PeripheralCirculation and Grgan Blood Flow. Bethesda,MD: Am Physiol Sot, 1983:967-1023. 3. Rowe11LB. Human Circulation. Regulation During Physical Stress. New York: Oxford University Press, 1986363406. 4. Raven PB. Heat and air pollution: The cardiac patient. In: Pollock ML, Schmidt DH, eds. Heart Diiease and Rehabilition, 2nd cd. New York: John Wiley & Sons, 1986549-574. 5. Rowe11LB, Blackman JR, Martin RH, Mazrarella JA, Bruce RA. Hepatic clearanceof indocyaninegreenin man underthermal and exercisestresses.J Appl Physiol 1965;20:384-394. 6. Radigan LR, RobinsonS. Effects of environmentalheat stressand exerciseon renal blood flow and filtration rate. J Appl Physiol 1949;2:185-191. 7. American College of Sports Medicine. Guidelines for Exercise Testing and Prescription, 4th ed. Philadelphia: Lea & Febiier, 198660-62. 8. Sheldahl LM, Tristani FE, Clifford PS,Kalbfleisch JH, Smits G, HughesCV. Effect of head-out water immersionon the responseto exercisetraining. J Appl Physiol 1986;60:1878-1881. 9. Borg G. Psychophysical basesof perceivedexertion. Med Sci Sports Exert
McKusick KA, StraussHW. An ambulatory ventricular function monitor: validation and preliminary clinical results. Am J Cardiol 1983;52:601-606. 11. Breisblatt WM. Weiland FL, McLam JR, TomlinsonGC, Bums MJ, SpatcaventoLJ. Usefulnessof ambulatory radionuclide monitoring of left ventricular function early after acute myccardial infarction for predicting residual myocardial &hernia. Am J Cardiol 1988;62:100-1010. 12. Tamaki N, YasudaT, Moore RH, Gill JB, BoucherCA, Hutter Jr AM, Gold HK, Strauss HW. Continuous monitoring of left ventricular function by an ambulatory radionuclidedetector in patientswith coronary artery disease.J Am Co11 Cardiol 1988;12:669-679.
13. Kayden DS, Wackers FJT, Zaret BL. Silent left ventricular dysfunction during routine activity after thrombolytic therapy for acutemyocardial infarction. J Am Cofl Cardiol 1990;15:1500-1507. 14. Ishibashi M, Yasuda T, Rocco TP, Alpert N, Moore RH, Strauss HW. Evaluation of left ventricular diastolic function usingan ambulatory radionuclide monitor: relationship to left ventricular systolic performance. Am Heart J 1990;120:96-103. 15. de Yang L, Bairey CN, BermanDS, Nichols KJ, Gdom-Maryon T, Rozanski A. Accuracy and reproducibility of left ventricular ejection fraction measurementsusingan ambulatory radionuclide left ventricular function monitor. J Nucl Med 1991;32:796-802. 16. Kayden DS, Remetx MS, Cabin HS, Deckelbaum LI, Cleman MW, Wackers FJT, Zaret BL. Validation of continuousradionuclide left ventricular functioning monitoring in detecting silent myocardial ischemia during balloon angioplasty of the left anterior descendingcoronary artery. Am J Cordial 1991;676:1339-1343. 17. Pollock ML, Lowenthal DT, FosterC, PelsAE III, Rod J, Stoiber J, Schmidt DH. Acute and chronic responsesto exercise in patients treated with beta blockers.J Cardiopulmonary Rehobil 1991;11:132-144. 18. Nose H, Mack GW, Shi X, Morimoto K, Nadel ER. Effect of salineinfusion during exerciseon thermal and circulatory regulations.J Appl Physio/ 1990;69: 609-616.
1982;14:377-381.
IS. Tripathi A, Mack GW, Nadel ER. Cutaneous vascular reflexes during exercise in the heat. Med Sci Sports Exert 1990;22:796-803. 20. Rowe11LB, Marx HJ, BruceRA, Conn RD. Kusumi F. Reductionsin cardiac output, central blood volume, and stroke volume with thermal stressin normal men during exercise.J Clin Invest 1966;45:1801-1816. 21. Nielsen M. Heat productionand body temperatureduring rest and work. In: Hardy JD, GaggeAP, Stolwijk JAJ, eds.Physiologicaland Behavioral Temperature Regulation. Springfield, IL: Charles C Thomas, 1970:205-214. 22. Lind AR. A physiologicalcriterion for setting thermal environmentallimits for everyday work. J Appl Physiol 1963;18:51-56. 23. Haskell WL, Brachfeld N, Bruce RA, Davis PG. Dennis CA, Fox III SM, Hanson P, Leon AS. Task Force II: determination of occupational working capacity in patients with ischemic heart disease.J Am Colt Cordial 1989;14:
10. Wilson RA, Sullivan PJ, Moore RH, Zielonka JS, Alpert NM, BoucherCA,
1016-1042.
EXERCISE AND HEAT STRESS 191
The effect of moderate heat stress on cardiac performance during sustained moderate physical work was evaluated in men 26 weeks after a card&c event. Subjects (n = 10) performed upright leg cycle ergometer exercise at approximately SO% of peak oxygen uptake for up to 60 minutes in warm (30.0 f O.S”C) and thermonwtral(21.5 f 0.3X) envhonments. Cardiac output (carbon dioxtde rebreathing method), left ventricular ejection fraction and relative teft venttfcutar end-diastatic vdume (portable nuclear VEST monitor) were pertodkally determined. In both envtronments, heart rate increased (p
eat stresscan increasethe demandson the cardiovascular systemduring exerciseowing to increased thermoregulatory blood flow require ments. The effect of heat stresson cardiac function de pends on exerciseintensity and duration, magnitude of heat stress,hydration level, acclimation state and exercise capacity.1-3Little is known regarding the effect of heat stresson cardiac function during exercise in sub jects with coronary artery disease.Reduced cardiac reserve and maximal oxygen uptake in these subjects could limit the ability to achievecombined thermoregulatory and metabolic blood flow demands.4Fluid and electrolyte reductions together with a possibleaugmented sympathetic nervous activation state1-3*5p6 could also increasethe incidence of arrhythmias. The present study evaluates the influence of heat stresson cardiac function during sustained moderate exercise in men with known coronary artery disease.A moderate rather than a high heat load was selected to promote safety and still provide information on work conditions more likely to be encounteredby cardiac patients with occupational, home or leisure activities.
H
METHODS SubjeetarTen asymptomaticmen (averageage 60 f 2 years, averageweight 86.0 f 5.4 kg) who had a myocardial infarction (8 inferior and 1 non-Q-wave), coronary artery bypasssurgery (n = 4) or percutaneousangioplasty (n = l), or a combination, 16 weeks before the study were examined. All subjects were at low to moderaterisk. Medications included &blockers (n = 3), calcium antagonists (n = 3), digitalis (n = l), diuretics (n = 1) and nitrates (n = 1). All subjectswere participating in an exerciseprogram. The study was conducted from July through September 1990. Subjects agreed to the protocol approved by the Institutional Human Research Review Committee. Preliminary W All subjectsinitially performed a treadmill exercise test using a modified Balke protocol.7 Any subject unable to exercise to fatigue or achieve 15 METS was excluded. A 1Zlead electrocardiogram was periodically recorded. Oxygen uptake was measuredby open-circuit spirometry. ExperimenU m At least 3 days after the treadmill exercisetest, subjects reported for placement From the VA Medical Center and Medical College of Wisconsin, of an ambulatory ventricular function monitor (VEST, Milwaukee, Wiinsin. This study wassupportedby a researchdemon- Capintec, Inc.). The VEST radiation detector was censtration program grant from the Department of Health and Human tered over the left ventricular blood pool with the aid of Services,Baltimore, Maryland. Manuscript receivedJanuary 3,1992; a gamma scintillation camera. A second detector was revisedmanuscript receivedand acceptedMarch 23,1992. Addressfor reprints: Lois M. Sheldahl, PhD, VA Medical Center, placed over the right lung to monitor background radionuclide activity. Before placement of the VEST, red 11lR, 5000 W. National Avenue, Milwaukee, Wisconsin53295. 186
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
JULY 15. 1992
blood cells were labeled in vivo with 25 to 30 mCi of technetium-99m, and left ventricular ejection fraction was determined at rest (seatedposition) in the left ante rior oblique view using multigated acquisition imaging procedures.A red marker was placed at the top edgeof the VEST garment on the subject’schest to enableevaluation of possiblemovement of the garment during the experimental sessions. Baseline VEST measurementswere obtained with the subject in the seated posture. The subject then underwent 2 leg cycle ergometer tests separated by ap proximately 3 hours; 1 study was performed in a thermoneutral (21.5 f 0.3OC) laboratory and the other outdoors in a warm (30.0 f 0.9OC) environment. Humidity averaged 53 f 1% indoors and 47 f 2% outdoors. The order of testing was rotated so that the same number of subjectswas testedfirst in each environment. The subject wore shorts and a T-shirt. The procedures for the exercisetests in the 2 environments were the same.The subject sat on a leg cycle ergometer for 10 minutes and then exercisedfor up to 60 minutes at a work load estimated to need approximately 50%of peak oxygen uptake. Work load (W) was the samein both environments. Measurementsobtained at rest and during exerciseat minutes 6, 20, 40 and 60 included oxygen uptake by open-circuit spirometry (me teorologic balloon usedto collect expired air), heart rate by telemetry, cardiac output by the carbon dioxide re breathing procedure,8rating of perceivedeffort according to the Borg 6- to 2Opoint scale,9and blood pressure by mercury sphygmomanometer.The electrocardiogram was monitored for 9 minutes after exercise. Sweat was wiped off the subject’s face and extremities, and body weight was reassessedbefore drinking water. The change in weight with each exercise sessionwas used to estimate sweat loss, although sweat loss from the trunk region was not accounted for because the clothing (T-shirt and shorts) underneath the VEST garment was not removed. Between the 2 tests, the subject rested in the upright position. Fluid intake was encouraged, and the subject was instructed to eat lunch 12 hours before the second test. At the end of the second test, the subject returned to the nuclear testing laborato ry. The positioning of the VEST detector mount was checkedvisually, as well as with the gamma scintillation camera. VEST dnta -sIsr The VEST-recorded tape was analyzed at 30-secondintervals for left ventricular ejection fraction and relative left ventricular end-diastolic and end-systolic volumes by an independent, experienced technician. In the determination of relative left ventricular volumes, end-diastolic volume at the beginning of the tape in the seated position in the nuclear laboratory was designated as lOO%,and all other enddiastolic and end-systolic volumes were calculated relative to this volume. Incidence of arrhythmias and electrocardiographic ST-segment changes were also evaluated from the VEST tape. Before each tape was analyzed, the technical adequacy of the data was assessed in a 3-step processas follows: (1) comparison of static gamma camera images obtained before and after completion of the study to assesspossiblechangesin VEST
TABLE
I Initial
Adjustments
to Exercise
Parameter
Environment
Heart rate (beatslmin) Stroke volume (ml/beat) LV ejection fraction (%I LV end-diastolic volume (%) LV end-systolic volume f%) Systolic pressure (mm Hg)
Thermoneutral Warm Thermoneutral Warm Thermoneutral Warm Thermoneutral Warm Thermoneutral Warm Thermoneutral Warm
Exercise fmin 6)
Rest
73 74 58 50 45 45 88 79 48 43 138 135
f 2 + 2 f 2 2 k 2 k f 5
3 3 4 4 5 4 5 4 7 3 7 9
92 95 91 84 49 53 99 90 50 41 175 165
k k 2 f f k f f k f 2 2
3* 2* 10* 6* 5 5* 4* 4* 7 3 1* 9*
*p < 0.05 versus rest. Valuesare mean 2 SE (n = 10). LV = left ventricular.
detector positioning, (2) evaluation of trend plots of left ventricular and background counts over time for any abrupt change suggestive of detector movement, and (3) evaluation of individual time-activity curves. Other studies1°-r6showedthat left ventricular ejection fraction data obtained from the VEST at rest or with dynamic exercise, or both, is accurate compared with gamma camera data, and is highly reproducible and consistent with known responsesin cardiac patients. StatIstkal analysis: Analysis of variance with repeatedmeasureswas usedto evaluate the effect of exercise time (6 to 60 minutes) within each environment and that of environmental temperature (thermoneutral and warm) at minutes 20 through 60. In evaluating the latter effect, 3 subjects prescribed fl blockers were excluded owing to different elapsed periods of time between receiving this medication and the beginning of the exercise sessionin the 2 environments. This was done becausethe depressiveeffect on heart rate (and presumably other parametersof cardiac function) could vary with time after ingestion of /3 blockers.r7 Differences between means were assessedwith Fisher’s protected least significant difference test. Paired 1 tests were usedto compareresponsesfrom rest to minute 6 of exercisein each environment and between rest data in the 2 environments. Significance levels were tested at the 0.05 level. All values are reported as mean f SE. RESULTS Preliminary tre&n# ti Peak oxygen uptake, heart rate, systolic pressure,respiratory exchange ratio and rating of perceived effort in the 10 subjects averaged 25.6 f 0.9 ml/kg/mm, 140 f 6 beats/mm, 199 f 9 mm Hg, 1.14 f 0.03 and 18 f 0, respectively. Peak METS ranged from 5.8 to 8.6. No subject had an ischemit response based on electrocardiographic ST-segment analysis or symptoms. lnltial adjmbmW to exedse in two environmentr: Table I lists responsesat rest and at minute 6 of exercise. No significant differences existed between the 2 environmentsat rest. Heart rate, stroke volume, cardiac output, end-diastolic volume and systolic pressure increased (p <0.05) with exercise at minute 6 in both environments, and end-systolic volume decreased (p EXERCISE AND HEAT STRESS
187
<0.05) with the onset of exercise.Left ventricular ejection fraction increased (p <0.05) at minute 6 in the warm environment, but the increasedid not attain significance by minute 6 in the thermoneutral condition. Tolemnce to modera exerdse in heal streasr One subject stopped the exercise test at 40 minutes in the warm environment and indicated before the test in the thermoneutral environment that he did not want to exercise >40 minutes. All other subjects completed 60 minutes of exercisein the 2 environments. Oxygen uptake during exercise at minutes 6, 20, 40 and 60 averaged 12.2 f 0.7, 12.8 f 0.8, 12.9 f 0.6 and 12.7 f 0.7 ml/kg/nun, respectively, in the thermoneutral environment, and 12.3 f 0.8, 12.9 f 0.7, 13.0 f 0.5 and 12.8 f 0.8 ml/kg/nun, respectively, in the warm environment. No differences were observedin oxygen uptake with exercisetime or environment. Rating of perceived effort increased (p <0.05) progressively with exercise time in both environments, but did not differ between the 2 environments.The ratings determined at 6,20,40 and 60 minutes averaged10 f 1,ll f 1,12 f 1 and 13 f 1, respectively,in the thermoneutral condition, and 9 f 1,ll f 1, 12 f 1 and 13 f 1, respectively,with heat stress.
--o--Warm -e--Thermoneutral I
6
20
Exercise
188
I
40
Time
60
(minutes)
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
CardIae~toexerdseinh&stresarHeart rate, stroke volume and cardiac output during exercise in the 2 environments are shown in Figure 1 (all sub jects) and Table II (subjectsnot prescribedfl blockers). With exercisetime in both environments,heart rate increased(p <0.05), stroke volume decreased(p <0.05), and cardiac output did not change. Heart rate was increased(p <0.05) at minute 20 comparedwith minute 6 in both environments. In the warm environment, a further increase (p <0.05) was observedat minute 40 comparedwith minute 20. At minutes 40 and 60, heart rate was higher (p <0.05) in the warm than in the thermoneutral environment (Table II). Exercise stroke volume decreased(p <0.05) at minute 40 comparedwith minute 6, as well as at minute 60 compared with minute 20 in the warm environment (Figure 1). In the thermoneutral condition, stroke volume was decreased(p <0.05) at minute 60 compared with minute 6. Betweenthe 2 environments,stroke volume tended (p <0.08) to be lower with heat stressthan in the thermoneutral environment. Cardiac output did not differ between environments. Left ventricular ejection fraction and relative enddiastolic and end-systolicvolumesare shown in Figure 2 and Table II. Ejection fraction did not change during exercise from minute 6 to 60 in each environment. In comparing the responsebetween the 2 environments, left ventricular ejection fractions were similar (Table II). Relative left ventricular end-diastolic volumes decreased(p <0.05) with exercise time in both environments (Figure 2). The initial decreaseoccurred at minutes 20 and 40 in the warm and thermoneutral environments, respectively. A further decrease(p <0.05) was observed from minute 20 to 60 in the thermoneutral condition. Relative end-diastolic volume tended to be decreased(p <0.06) in the warm environment (Table II). Left ventricular end-systolic volume decreased (p <0.05) at minute 20 with exercisetime in the thermoneutral condition, with no further significant change with exerciseup to 60 minutes (Figure 2). In the warm environment, no significant change was observed from minute 6 through 60. Relative left ventricular end-systolic volumes tended to be decreased(p <0.09) in the warm environment (Table II). Systolic pressure determined at minutes 6, 20, 40 and 60 of exercise,averaged178 f 12,174 f 10,175 f 11 and 169 f 11 mm Hg, respectively, in the therms neutral condition, and 168 f 9,159 Z!Z11,168 f 13 and 164 f 12 mm Hg, respectively, in the warm environment. The only changes(p
JULY 15, 1992
TABLE II Responsesof Patients Not Prescribed p Blockers to Exercise at Minutes 6,20,40
1
and 60
Exercise Parameter Heart rate (beats/min) Stroke volume (ml/beat) LV ejection fraction (%) LV end-diastolic volume (%I LV end-systolic volume f%) Systolic pressure (mm Hg) Diastolic pressure (mm Hg)
Environment
Minute 6
Minute 20
Minute 40
Minute 60
Thermoneutral Warm Thermoneutral Warm Thermoneutral Warm Thermoneutral Warm Thermoneutral Warm Thermoneutral
94 f 3
103 + 4 106 + 4 802 12
106 k 5 115+4* 82 t 10
79 k 7
71 f 7
112 120 78 69 52 53 94 83 47 39 172 167 82 77
Warm Thermoneutral Warm
96 e 3 89 ZL 14 81 29
50 2 4 50 2 7 100 + 4 89 + 4 54 + 8 43 f 4
52 52 97 86 50 40
2 + + + + k
4 6 5 4 9 5
181 lr 14
176?
170 -t 12
163 f 13*
86 2 5
82 + 5
81 + 5
81 2 4
50 50 96 84 50 41 179 172 84
13
2 k + + + f 2 2 +
3 6 4 3 8 4 15 16 6
81 + 4
p Value
2 5 f 5* + 8 + 8 k 4 -c 6 + 4 + 2 r 7 f 4 f 14 2 14 + 5 + 3
0.01 0.08 0.21 0.06 0.08 0.04 0.19
*p <0.05
versus thermoneutral. Values are mean + SE (II = 7). LV = left ventricular.
diastolic pressure was decreased(p <0.05) at 60 minutes compared with 6 minutes. Between environments, no significant difference was observedfor diastolic pressure. No subject had frequent or complex ventricular arrhythmias during exercisein either environment. Occasional (3 to 6/min) ventricular arrhythmias were ob served in 2 subjects in the thermoneutral and 1 in the heat exerciseperiods. Except for 1 subject who had frequent arrhythmias during minute 7 of recovery in the thermoneutral environment, arrhythmia rate was not increased in the immediate recovery period. No subject reported angina1symptoms or had electrocardiographic evidence of myocardial ischemia. Body weight reduction averaged 0.4 kg in the thermoneutral environment (n = 6) and 0.5 kg in the warm environment (n = 7). DISCUSSION Subjects with coronary artery disease had an increase in heart rate, a decreasein stroke volume, and maintenance of cardiac output during sustained moderate exercise combined with moderate heat stress. These directional responsesas well as the magnitude of changes are consistent with those reported in normal subjects under similar temperature and exerciseconditions.18J9 Most evidence indicates that the increase in heart rate with sustained moderate work in both thermoneutral and warm conditions is a compensatoryresponseto maintain cardiac output with a decreasing stroke volume; the latter is generally attributed to decreasedcardiac preload associatedwith increasedcutaneous blood volume, vascular fluid filtration and body water reduction.‘-’ Central blood volume and venouspressurehave been shown to decreaseduring exercise in normal sub jects with exposure to heat stress,1-3~20 although the effeet on left ventricular volume during exercise has not (to our knowledge) beenevaluated. In the presentstudy, men with coronary artery diseasedemonstrateda significant reduction in relative left ventricular end-diastolic
65 60
120
1
60’
3
,
I
I
I
40
60
65-
6
1
20
Exercise
Time
(minutes)
I vcmMadu(LV)eJectbnfmlknmdreleUve “OURE 2’ bn -endand~vehmles4h8ing60-el exm h ,,,- d hmmmubdem&omwd(n= 10). *p
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EXERCISEAND HEAT STRESS 189
volume in both the warm and thermoneutral environments. Although less accepted, another hypothesis postulated to account for the decreasein stroke volume with exercise time in a warm environment is reduced myocardial function.1*3Based on left ventricular ejection fraction, myocardial function did not appear to deteriorate with exercisetime in men with coronary artery disease.Mean ejection fraction remained unchanged from minute 6 to 60 in the warm environment, and no subject (even those [n = 31 with a resting left ventricular ejm tion fraction <40%) had a decreasein ejection fraction less than resting levels at minute 60 of exercisein the warm environment (Figure 3). Thus, despite significant alterations in stroke volume, heart rate and left ventrio ular end-diastolic volumes with exercise time, ejection fraction was preserved during moderate exercise combined with moderateheat stress.Comparedwith at rest, mean ejection fraction increased 28% at minute 20 in both environments.This magnitude of increaseis generally considereda normal responseand suggeststhe ab senceof ischemia. The unchanged systolic pressure at minute 60 compared with minute 6 in the warm environment further indicates that the cardiac output responsewas adequate to maintain peripheral perfusion pressure. It is possiblethat heat stresscould increasearrhythmogenesis through electrolyte changes, or increased myocardial oxygen requirements or sympathetic nervous activation, or a combination. Subjects in the present study did not have a greater incidence of arrhythmias with work time or heat stress.Although decreased venous return and increasedcirculating catecholamines in the immediate recovery period could theoretically provoke an increase in the incidence of arrhythmias in the warm environment, this was not observed. Study m One limitation of the study was that core temperature was not measured. In normal subjects, other studies showed that core temperature during 1 hour of moderate exerciseis independentof air temperature betweenthe range of 5 and 30°C.21,22The mean temperature in the warm environment was 30°C, suggestingthat the increasein core temperature proba-
bly did not differ substantially between the 2 environments. Further support for an appropriate core temperature was the ability of subjectsto maintain systolic pressure from 6 to 60 minutes. Rowel12reported that mean arterial pressure decreasedwhen core temperature was >39OC. The 2 exercisesessionswere scheduledon the same day owing to the use of a radioisotope. Thus, patients were tested at a different time of day in the 2 environments. An equal number were tested first in each environment, and subjects prescribed /3 blockers were excluded from the statistical analysis of the environmental factor owing to the drug’s potential variable impact on heart rate and other indexesof cardiac function in relation to the elapsedtime between receiving the medication and performing exercise. With regard to application to the occupational setting, the work intensity selectedonly slightly exceededthe average8-hour intensity level (i.e., 40% of peak oxygen uptake) frequently cited as appropriate.23Thus, the conditions of this study (in which subjectsperformed 1 hour of work at 50% of peak oxygen uptake in the morning and 1 hour in the afternoon) are within this guideline and could be found in the occupational work setting. Clinkal i~r: The maintenance of cardiac output, left ventricular ejection fraction and systolic pressure during sustained work in the warm environment suggeststhat cardiac function did not deteriorate during sustainedmoderateexercisecombined with moderate heat stressin stable patients with coronary artery diseasewho have relatively good functional exercisetolerance. The progressiveincrease in heart rate over exercise time suggeststhat clinicians may advise patients to use heart rate to assessthe magnitude of cardiovascular drift occurring during sustained work with heat stress. Although it appears logical to predict that an upright drift in heart rate would increasemyocardial oxygen re quirements, the effect of thii drift on myocardial ischemit thresholds remains unknown. A decreasein left ventricular end-diastolic volume with exercisetime, together with some tendency for systolic pressure to be decreasedin the warm environment, may decreaseleft
80 Warm
Thermoneutral
2 0
I
I
Rest muRE3.bldivmdleftrantrialv vhmmnte.
190
Exercise tww*-=P-=
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
0 Rest atreetandendofexerdeeh~mdwmman-
JULY 15, 1992
I Exercise
ventricular wall tension or afterload, or both, and thereby offset someof the increasein myocardial oxygen requirements expected from the increased heart rate. Perceivedeffort increasedover time, indicating that it may be used by workers to adjust work rates during sustainedwork. However, rating of perceivedeffort did not reflect the differences between the warm and thermoneutral environments, suggestingthat heart rate provides a more sensitive marker of increasedthermoregulatory cardiovascular demands. AdmowkdgmeM We gratefully acknowledge the valuable technical expertiseof Barbara Blaney, CNMT, with the VEST monitor data collection.
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2. Rowe11LB. Cardiovascular adjustmentsto thermal stress.In: Handbook of Physiology.The Cardiovascular System.PeripheralCirculation and Grgan Blood Flow. Bethesda,MD: Am Physiol Sot, 1983:967-1023. 3. Rowe11LB. Human Circulation. Regulation During Physical Stress. New York: Oxford University Press, 1986363406. 4. Raven PB. Heat and air pollution: The cardiac patient. In: Pollock ML, Schmidt DH, eds. Heart Diiease and Rehabilition, 2nd cd. New York: John Wiley & Sons, 1986549-574. 5. Rowe11LB, Blackman JR, Martin RH, Mazrarella JA, Bruce RA. Hepatic clearanceof indocyaninegreenin man underthermal and exercisestresses.J Appl Physiol 1965;20:384-394. 6. Radigan LR, RobinsonS. Effects of environmentalheat stressand exerciseon renal blood flow and filtration rate. J Appl Physiol 1949;2:185-191. 7. American College of Sports Medicine. Guidelines for Exercise Testing and Prescription, 4th ed. Philadelphia: Lea & Febiier, 198660-62. 8. Sheldahl LM, Tristani FE, Clifford PS,Kalbfleisch JH, Smits G, HughesCV. Effect of head-out water immersionon the responseto exercisetraining. J Appl Physiol 1986;60:1878-1881. 9. Borg G. Psychophysical basesof perceivedexertion. Med Sci Sports Exert
McKusick KA, StraussHW. An ambulatory ventricular function monitor: validation and preliminary clinical results. Am J Cardiol 1983;52:601-606. 11. Breisblatt WM. Weiland FL, McLam JR, TomlinsonGC, Bums MJ, SpatcaventoLJ. Usefulnessof ambulatory radionuclide monitoring of left ventricular function early after acute myccardial infarction for predicting residual myocardial &hernia. Am J Cardiol 1988;62:100-1010. 12. Tamaki N, YasudaT, Moore RH, Gill JB, BoucherCA, Hutter Jr AM, Gold HK, Strauss HW. Continuous monitoring of left ventricular function by an ambulatory radionuclidedetector in patientswith coronary artery disease.J Am Co11 Cardiol 1988;12:669-679.
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IS. Tripathi A, Mack GW, Nadel ER. Cutaneous vascular reflexes during exercise in the heat. Med Sci Sports Exert 1990;22:796-803. 20. Rowe11LB, Marx HJ, BruceRA, Conn RD. Kusumi F. Reductionsin cardiac output, central blood volume, and stroke volume with thermal stressin normal men during exercise.J Clin Invest 1966;45:1801-1816. 21. Nielsen M. Heat productionand body temperatureduring rest and work. In: Hardy JD, GaggeAP, Stolwijk JAJ, eds.Physiologicaland Behavioral Temperature Regulation. Springfield, IL: Charles C Thomas, 1970:205-214. 22. Lind AR. A physiologicalcriterion for setting thermal environmentallimits for everyday work. J Appl Physiol 1963;18:51-56. 23. Haskell WL, Brachfeld N, Bruce RA, Davis PG. Dennis CA, Fox III SM, Hanson P, Leon AS. Task Force II: determination of occupational working capacity in patients with ischemic heart disease.J Am Colt Cordial 1989;14:
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