PAPERS

Sodium and potassium intake and blood pressure change inchildhood

Johanna M Geleijnse, Diederick E Grobbee, Albert Hofman

Department ofEpidemiology andBiostatistics, ErasmusUniversity Medical School,RotterdamJohanna M Geleiinse, MSC,research fellowDiederick E Grobbee, MD,associate professor ofepidemiologyAlbert Hofman, MD,professor ofepidemiology

Correspondence andrequests for reprints to: DrD E Grobbee, Departmentof Epidemiology andBiostatistics, ErasmusUniversity Medical School,PO Box 1738, 3000 DRRotterdam, TheNetherlands.

BrAfedJ 1990;300:899-902

AbstractObjective-To assess the association between

sodium and potassium intake and the rise in bloodpressure in childhood.Design-Longitudinal study ofa cohort ofchildren

with annual measurements during an average followup period of seven years.Setting- Epidemiological survey ofthe population

of a suburban town in western Netherlands.Subjects-Cohort of 233 children aged 5-17 drawn

at random from participants in the population survey.Main outcome measures-At least six annual timed

overnight urine samples were obtained. The mean 24hour sodium and potassium excretion during thefollow up period was estimated for each participantand the sodium to potassium ratio calculated.Individual slopes of blood pressure over time werecalculated by linear regression analysis.Results-No significant association was observed

between sodium excretion and the change in bloodpressure overtime. The mean systolic blood pressureslopes, however, were lower when potassiumintake was higher (coefficient of linear regression-0-045 mm Hg/year/mmol; 95% confidence interval-0-069 to -0.020), and the change in systolicpressure was greater when the urinary sodium topotassium ratio was higher (0.356mm Hg/year/unit;95% confidence interval 0-069 to 0.642). In relation topotassium this was interpreted as a rise in bloodpressure that was on average 1-0mm Hg (95% confi-dence interval -1-65 to -0-35) lower in children inthe upper part of the distribution of intake comparedwith those in the lower part. The mean yearly rise insystolic blood pressure for the group as a whole was1.95mm Hg. Urinary electrolyte excretion was notassociated with diastolic blood pressure.Conclusion-Dietary potassium and the dietary

sodium to potassium ratio are related to the rise inblood pressure in childhood and may be important inthe early pathogenesis of primary hypertension.

IntroductionPrimary hypertension is one of the most important

risk factors for cardiovascular disease and probably hasits onset in the first decades of life.' Study of bloodpressure in childhood may shed light on the aetiologyofhypertension and indicate opportunities for measuresto prevent hypertension in adult life. Blood pressure inchildren is determined by genetic and environmentalfactors. Race, sex, and anthropometric characteristicssuch as height and body weight have been identified asdeterminants of blood pressure and the rise in child-hood.2' Although the effect of biological maturation isstill a subject of debate, alterations in growth and sexhormones may also be related to changes in bloodpressure.The part played by dietary factors has been thorough-

ly studied. Sodium intake has been the main topic, butmost studies have been concerned with adults. Find-ings in some but not all interpopulation studies suggestthat the prevalence of hypertension is lower in areaswith a low sodium intake, although considerable doubtremains about the nature and significance of this.6 Inchildren and young adults findings are even lessconsistent.7 Moreover, the rise in blood pressure withage might to some extent be dependent on the averagelevel of sodium intake in a population. Recently theIntersalt Cooperative Research Group found anadditional rise in systolic blood pressure of 0 003mmHg with a sodium intake that was on average 1 mmol/24 h higher in adults.' If such an effect of the diet wasalready acting in childhood and persisted over alifetime the consequences for the incidence of hyper-tension in a population might be substantial.9 Aninverse association of blood pressure with the intake ofpotassium has been noted occasionally, although thisfinding remains controversial. 1' Moreover, there maybe an interaction among various dietary electrolytes. Inparticular, the sodium to potassium ratio may beimportant.

Because advice on diet may well play a part inintervention, studies on the effect of dietary com-ponents on blood pressure remain important. In thisstudy children with high intakes of sodium andpotassium were compared with those having lowintakes with regard to their individual changes in bloodpressure over time. Change in blood pressure ratherthan actual blood pressure in children may be apredictor of adult blood pressure and of hyperten-sion. " 2

Population and methodsBetween 1975 and 1978 the total population aged 5

years and over in two districts of Zoetermeer, asuburban town in the western part of the Netherlands,was invited to take part in a study of risk factors forcardiovascular disease.34 Of 5670 eligible subjects aged5-19 years, 4649 (82%) were examined. From thisgroup a random sample of 596 children was selected forannual follow up in a study of blood pressure trackingand its determinants.34 They were examined fourweeks after the initial examination and subsequently atyearly intervals. Children with established secondaryhypertension were excluded. For the present analysiswe selected children aged up to 17 at entry into thestudy and whose follow up included at least six yearlyexaminations. Of the 233 subjects in the cohort, 108were boys and 125 girls. Their average follow up periodwas seven years.

MeasurementsBlood pressure measurements were performed with

a random zero sphygmomanometer as detailed else-

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where.' Paramedical workers were trained to measuresystolic and diastolic blood pressure according to astandardised protocol. Cuffs 23 cm by 10 or 14 cm wereused, depending on the arm circumference. In childrenaged over 10 generally the largest cuff was used. Bloodpressure was measured in the left arm after 15minutes' sitting. Diastolic blood pressure was recordedat the fifth Korotkoff phase. Two blood pressurereadings were taken and the average used for analysis.Height and body weight were measured with theparticipant wearing light indoor clothing withoutshoes. Urine samples were analysed for sodium andpotassium concentrations by flame photometry. Urinewas collected as six timed overnight samples." '4 Thecollection began at supper and ended with the firsturine voided the next morning. Labelled containerswere provided, on which the subjects noted the timesof starting and finishing each collection. From thesethe mean 24 hour sodium and potassium intakes werecalculated. Electrolyte excretion measured in timedovernight urine samples correlates reasonably wellwith true mean 24 hour excretion rates in youngsubjects."'14 The main difference between the two

rABLE I-Characteristics of total study group at entry into study

Mean (SD) Range

Age (years) 13 2 (2-7) 5-9 - 17-0Height (cm) 159-3 (16-2) 1150 -193-0Body weight (kg) 48-8 (14-6) 20-0 - 80-0Systolic blood pressure (mm Hg) 1 12-4 (12-9) 81-0 - 153-0Diastolic blood pressure (mm Hg) 68-4 (8-7) 44 0 - 97-0

TABLE II-Yearly rate ofchange in height, body weight, systolic bloodpressure, and diastolic blood pressure during follow up

Rate of change* (95% confidenceinterval)

Height (cm/year) 2-61 (2-31 to 2-91)Body weight (kg/year) 2-85 (2-60 to 3- 10)Systolic blood pressure (mm Hg/year) 1-95 (1-65 to 2-25)Diastolic blood pressure (mm lhg/year) 0-58 (0-39 to 0-77)

*Coefficient of linear regression.

TABLE i -Average sodium excretion, potassium excretion, and sodium to potassium ratio, and rangesaccording to thirds ofdistributions of electrolyte excretion in study groups dunrng follow up period

Range

Mean Lower third Upper third

Sodium excretion (mmol/24 h):Total studygroup 135-6 61-5 117-7 147-5 25 16-5Boys 140-8 61U5 - 127-2 158-2 251-5Girls 131-1 68-5 115-0 139-8 215 -

Youngergroup 138-4 68-5 119-8 147-5 -6251-5Oldergroup 132-8 61-5 113-5 147-5 215 -63

Potassium excretion (mmoUl24 h):Total study group 43-7 15U8 37-7 47-8 -177-3Boys 47-0 20-2 41-5 51-2 -277-3Girls 40-9 15-8 - 35-3 43-5 -71-0Youngergroup 43-3 15-8 37-2 47-3 -177-3Older group 44-1 20-2 -238-5 47-8 - 75-8

Sodium to potassium ratio:Totalstudygroup 3-3 1-1 2-8 3-6 7-4Boys 3-1 1-1 2-6 3-4 -17-4Girls 3-3 1-6 2-8 3-7 - 5U8Youngergroup 3-3 1-6 2-8 3-6 -15-8Older group 3-2 1U1 2-6 3-6 7-4

TABLE IV-Associatiotn betwecnt vearly rate of change in systolic blood pressure in children and urinarysodium and potassium excretion and urlnary sodium to potassium ratio. Findings expressed as regressioncoefficients (mm Hglyearlmmol for sodium and potassiuim; mm Hglyearlunit for sodium to potassium ratio)for group as a whole and as mean blood pressure slopes in subgroups of children based on thirds of bloodpressure distribution (mm Hglyear). * (95's Confidence intervals given in parentheses)

Blood pressure slope Sodium Potassium Sodium to potassium ratio

Regression coefficientLev-el in lower thirdLevel in middle thirdLevel in upper third

0-003 ( 0-006 to 0-012)2-04(1-56 to2-52)1-64 (1-19to2-092 12 (1-65 to2-59

*Adjustmetits made for diffcrenccs in scx, initial -'adjusted for potassium excretion; fihoditigs for pota

00045 (- 0 069 to -0-020)'44 99 to 2-89)

7 1-42to2-32),; 0-98to 1-88)

0-356 (0-069 to 0-642)1-43 (0-97 to 1-88)1-91 (1-46to2-36)2-24 (1-79 to 2-69)

in height and hody- weight. Findings for sodiumfor sodium excretion.

measurements is a somewhat higher within personvariability in the overnight samples. Both methodsrequire multiple samples, and plainly these are moreeasily collected overnight.

DATA ANALYSIS

Six complete annual records of each subject wereused in the analysis. To quantify the change in bloodpressure during the follow up period individual slopesof blood pressure against time were calculated by usinglinear regression analysis. The association betweensodium excretion, potassium excretion, urinary sodiumto potassium ratio, and blood pressure slope wasanalysed by multiple linear regression analysis. Toadjust for differences in sex, initial age, and change inheight and body weight during follow up these variableswere included in the model. When analysing the effectof high sodium intake adjustments were made forpotassium intake, and vice versa. Further to assess theeffect of electrolyte intake on the change in bloodpressure the study group was divided into subgroupsbased on thirds of the distributions of mean sodiumand potassium intake and mean sodium to potassiumratio over the follow up period. In all analyses lowerand upper thirds are compared. Data are presented asmean changes per year and 95% confidence intervals.Equality of group means was tested for both high andlow sodium, potassium, and sodium to potassium ratiogroups by using analysis of variance. Significanceof differences was assessed by two tailed tests through-out. To see whether the relation between electrolyteintake and change in blood pressure was different inboys and girls or in different age groups the data wereanalysed by sex and age at the initial survey. Themedian of the initial age distribution was used instratifying the children for age. In the younger groupthe age range was 5 9-13 7 years and in the older group13 8-17-0 years.

ResultsTable I gives the characteristics of the subjects at the

start of the study. Changes in height, body weight,systolic blood pressure, and diastolic blood pressureduring the follow up period are given in table II. TableIII shows the mean values and ranges of averagesodium and potassium excretion and sodium topotassium ratio in the lower and upper thirds of thestudy groups during the follow up. In boys the mean 24hour sodium excretion ranged between 615 and2515 mmol, which reflects a daily salt intake of 3 6-14 7g. In girls the mean 24 hour sodium excretionranged between 68 5 and 215-3 mmol, correspondingto a salt intake of 4 0-12 -6 g/day. Potassium intake washigher in boys than in girls and therefore the sodium topotassium ratio was higher in girls. During the studyperiod age showed no independent association withelectrolyte intake.

Table IV shows the association between the yearlyrate of change in systolic blood pressure and urinaryelectrolyte excretion. No significant relation betweensodium excretion and change in systolic blood pressurecould be detected. Urinary potassium excretion,however, was strongly and inversely associated withsystolic blood pressure in this cohort (coefficient oflinear regression -0-45 mm Hg/year/mmol; p= 0-0004)whereas the systolilc blood pressure slope was higherwhen the sodium to potassium ratio was higher(0 356mm Hg/year/unit; p=0 02). The effects of theseassociations were reflected in the levels of annualincrease in systolic blood pressure in children in thelower, middle, and upper thirds of the distribution ofelectrolyte excretion (table IV).

Figure 1 shows the differences in rise in systolicblood pressure during follow up between subjects with

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-2.0 -1..51 .1.0 O.0.5' 0.5

-2.0 -1:5 4~~~~~~10 -0.5 0 05

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:-2.0 -1.5 -1.0 -0.5. 0 0.5Difference in systolic blood pressure -slope (mm.Hg/Iyear)

IFIG -Differences in yearly rate ofchange in systolic blood pressure (systolic blood pressure slope (mm Hg!

year)) during follow up between children with high and low potassium intakes. Adjustments made fordiffcrences in sex, initial age, change in height and body weight, and sodium intake (mean differences and

950% confidence intervals)

Total study.

group

-0

Boys

.Girils.

-0

0.5~A 1.0 1.5 '2.0 2.5

1.5 0- O~~~5 1.0 1.5~~~~~~ 2.0 .2.5

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i .,-: .0 .., -1.5.., i.O .'s -

.2.0 ,.. ...2.5,

-i~ein sure ,.sIoge im H /'y ear)

FIG 2 -Differences in yearly rate ofchange in systolic blood pressure (systolic blood pressure slope (mm Hg!year)) during follow up between children with high and low urinary sodium to potassium ratios. Adjustmentsmade for differences in sex, ini'tial age, and change in hei'ght and body weight (mean differences and 95O%confidence intervals)

high and low potassium intakes for the group as a

whole and for subgroups based on sex and age. Mean

yearly change in systolic blood pressure was I1-4mm Hgin the group with a high potassium intake and

2 -4mm Hg in the group with a low potassium intake

(p=0-007). The difference (10Omm Hg) amounted to

half the average yearly change in systolic blood pressure

recorded in the group as a whole (table II). This findingseemed to be most pronounced for boys- 2 -1 mm Hg!

year in those with a high intake and 31- mm Hg/year in

those with a low intake (p=0-04). The stratified

analysis disclosed no clear difference in effect in

different age groups.

Figure 2 shows the differences in rise in systolicblood pressure between groups with high and low

urinary sodium to potassium ratios. In children with a

high sodium to potassium ratio a slope of 2-2 mm Hg!

year was recorded compared with 1-4mm Hg/yearin children with a low sodium to potassium ratio

(p=-OO2). The difference in blood pressure slopebetween groups with high and low ratios was present inboth boys and girls. The effect of sodium to potassiumratio on change in systolic blood pressure seemed to bestronger in older children. In the group initiallyaged 13-8-17O0 years the difference between groupswith high and low sodium to potassium ratios was11Imm Hg/year (p =-O O2).Neither sodium nor potassium nor the sodium to

potassium ratio was significantly related.to the changein diastolic blood pressure. When the data werereanalysed taking initial blood pressure readings intoaccount results were unaffected.

DiscussionThe main findings in this longitudinal study were

that both potassium intake and the ratio of sodiumintake to potassium intake were related to the change insystolic blood pressure in childhood. Children with ahigh dietary intake of potassium had a smaller annualincrease in systolic blood pressure than children with alow intake. The sodium to potassium ratio also showedan inverse relation with blood pressure. Interestingly,in this age group there was no clear effect of sodiumintake alone. These findings corroborate the report byLever et al who hypothesised that in the early stages ofhypertension blood pressure is raised by a processrelated more to potassium than to sodium.'II Moreover,findings in experimental studies suggest that an effectof sodium intake on blood pressure may be presentonly in older age groups.'6 One trial conducted innewborn infants, however, found a small but significanteffect of sodium intake on the blood pressure slopeduring the first months of life.'1The inverse association between potassium intake

and the rise in systolic blood pressure was similar in thetwo age groups. By contrast, the relation between thesodium to potassium ratio and the blood pressure slopewas stronger with age. As this age related phenomenoncould nut be ascribed to either sodium or potassium itwas probably related to an age dependent interactionbetween the two. Khaw and Barrett-Connor found anincreased sensitivity of blood pressure to the dietarysodium to potassium ratio with aging in men."Some studies have failed to detect a relation between

potassium or the sodium to potassium ratio and bloodpressure in children or adults.7I 192 This may beexplained in several ways. Firstly, in some studies onlyone urine sample was used to estimate the daily sodiumand potassium intake. The large intraindividualvariability of urinary cation excretion, notably sodium,may obscure results.2' This calls for repeated measure-ments of electrolyte excretion.'4 In our study sodiumand potassium intakes were assessed by calculating themean daily sodium and potassium excretion from sixtimed overnight urine samples. By averaging multiplemeasurements the effect of intraindividual day to dayvariability is reduced and sodium and potassiumintakes are estimated more precisely. Secondly, if therelation between potassium and blood pressure existsonly in childhood or in the early stages of hypertensionno observable effect might be present in study popula-tions that are older.' Thirdly, in some surveys onpotassium the study period was quite short. If theeffect of potassium becomes evident only after asufficient time of exposure it might be too weak to bedetected in these studies.There are several ways by which potassium intake

might affect the rise in blood pressure.2 Potassiummay reduce blood pressure by vasodilatation, therebycausing a decrease in total peripheral resistance and anincrease in cardiac output. Some studies suggest thatpotassium might lower blood pressure by acting as adiuretic or by altering the activity of the renin-angio-

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Girls

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tensin system. Others give evidence that potassiummight modify peripheral and central neural regulationof blood pressure. We can draw no conclusions fromour study about the way that potassium acts. Nor isthere a ready explanation for a possible mechanism ofsodium-potassium interaction. Finally, there remainsa possibility that potassium intake and the urinarysodium to potassium ratio are indicators of another, asyet unknown, determinant of blood pressure change inchildhood rather than being direct causal factors inblood pressure regulation.

In conclusion, this study supports the view thatdietary potassium and the dietary sodium to potassiumratio may be important in the early pathogenesis ofhypertension. Possibly a sufficient intake of potassiumor a reduction of the dietary sodium to potassium ratioin youth may prove to be beneficial in the earlyprevention of hypertension.

I Hofman A, Grobbee DE, Schalekamp MADH, eds. I'he earlv pathogenisis ofprimarv hvpertension. Amsterdam: Elsevier, 1987.

2 Akinkugbe 00, Akinkugbe FM, Aveni 0, et al. Biracial study of arterialpressures in the first and second decades of life. Br.rMedj 1977;i: 1132-4.

3 Hofman A, Valkenburg HA. Determinants of change in blood pressure durinigchildhood. AmJ Epidemiol 1983;117:735-43.

4 Hofman A, Valkenburg HA. Maas J, Groustra FN. Thc natural histors ofblood pressure in children. IntJEpidemiol 1985;14:91-6.

S LaBarthe DR, Morris DL, Freer BS. Blood pressure during growth anddevelopment. .4nn Clin Res 1984;16 (suppl 4):35-43.

6 Simpson FO. Salt and hypertension: current data, attitudes, and policies._7 Cardiovasc Pharmacol 1984;6: S4-9.

7 Grobbee DE, Bak AAA. Electrolyte intake and hypertension in children. In:

Rettig R, (ianten D, Luft 1FC, eds. .Sa/t and hvpri nsiion. 1Berlin: SprinlgerVerlag, 1989.

X Intersalt Cooperative Research Group. Intersalt: an internaiontial study of'clectrolytc excretion anid bloiod prcssurc. Results for 24 hour urinary sodiurand potassium cxcretioti. BrMecd] 1988;297:319-28.

9 Hofman A. Blood pressure in childhood: an epidemiologic approach to theaetiology of hypertension. J' I-Ipertens 1984;2:32 3-8.

10 Khaw& KT, Thom S. Randomized double-blind crossover trial otlpotassiuim onblood pressure in normal subjects. Lancet 1982;ii: 1 127-9.

11 Szklo N. Epidemiologic pattcrns of blood pressuire in childreti. Epidnmiol Rev1979;1: 143-69.

12 Lauer RAM, Burns TL, Clarke W'R. Epidemiologv ot' blotod pressure inchildhood. In: Hofman A, Grobbee DE, Schalekamp NADH, eds. Thti carlpathogenesis ofpnrmarv tvpertension. Amsterdam: Elsexier, 1987.

13 Liu K, Dyer AR, Cooper RS, Stamler R, Stamler J. Can overnight urinereplace 24-hour urine collection to assess salt intake? HYpertension 1979;1:529-36.

14 Knuiman JT, san Poppel G, Burema J, san der Heijden I., Hatitvast GAJ.Mlultiple overnight urine collections may be used for estimating theexcretion of electrolytes and creatinine. Clin C/tem 1988;34:135-8.

15 Leser AF, Beretta-Piccoli C, Brown JJ, Das-is DL, Fraser R, Robcrtson JIS.Sodium and potassium in essential hypertension. BrMed] 1981;283:463-7.

16 Grobbee DE, Hofman A. Does sodium restriction lower blood prcssure;BrMAedJ 1986;293:27-9.

17 Hofman A, Hazebrock A, Valkenburg HA. A randomized trial of sodiumintake and blood pressure in newborn infants.JAM,4 1983;250:370-3.

18 Khaw KT, Barrett-Connor E. The association between blood pressure, age,aiid dietarv sodium and potassium: a population study. Circulation 1988;77:53-61.

19 Frank GC, Beresiin GS, Webber LS. Dietary sttudies and the relationship ofdiet to cardiovascular disease risk factor sariables in l10-vear-old children.'T'he Bogalusa heart study. Am 7 Clin Nutr 1978;31:328-4().

20 (,ooper R, I.iu K, 'I'revisan 1\, Miller W, Stamler J. Urinary sodium excrctionand blood pressure in children: absence of a reproducible association.Hvpertension 1983;5:135-9.

21 Liu K, Cooper RS, Soltero 1, Stamler J. Variability iIn 24-hour urine sisiumexcretion it children. Hspertension 1979;1:631-6.

22 Treasure J, Ploth D. Role of dietary potassium in the treatment of hyperten-sin. Hvpertension 1983;5:864-71.

Accepted 3 januanr 1990)

Long term propranolol treatment and changes in body weight aftermyocardial infarction

Stephan R6ssner, Carol L Taylor, Robert P Byington, Curt D Furberg

Department of PublicHealth Sciences, Bowman-Gray School of Medicine,Winston-Salem, NorthCarolina 27103, UnitedStatesStephan Rossner, Mo,visiting professorCarol L Taylor, MAS,statisticianRobert P Byington, PHD,assistant professorCurt D Furberg, PHD,chairman

Correspondence to:Dr S Rossner, Obesity Unit,Karolinska Hospital,S- 104 01 Stockholm,Sweden.

Rr Medj7 1990;300:902-3

AbstractObjective-To determine the effect of long term

propranolol treatment on body weight.Design-Retrospective analysis of data from a

placebo controlled randomised double blind clinicaltrial (the Ji blocker heart attack trial).Patients-3837 Men and women randomised 5-21

days after an acute myocardial infarction to treat-ment with placebo or propranolol for up to 40months. Patients were followed up at annual visits.Main outcome measure-Changes in body weight.Results-At the first annual visit patients treated

with propranolol had gained more weight than thosegiven placebo (mean weight gain 2-3 kg v 1-2 kgrespectively, mean difference 1-2 kg (95% confi-dence interval 0 9 to 1-5)). These group differencesremained at the second and third annual visits. Thedifference in weight gain could not be explained bydiscrepancies in the use of diuretics or in physicalactivity and was similar in patients of both sexes andof all ages.Conclusion-Long term Ji blockade results in a

sustained weight gain.

IntroductionRecently it has become increasingly clear that

obesity is a multifactorial condition. Though thedevelopment of obesity implies at least a temporarypositive energy balance, factors that explain why somepeople become overweight and others do not havebeen surprisingly difficult to identify. A recent studyshowing that large eaters in fact weighed less thansmall eaters has underscored the complexity of theproblem.

As the autonomic system affects energy metabolism23alterations in autonomic activity might be expected topromote obesity in some human subgroups. Despitenumerous studies showing the effects of 13 blockadeon thermogenesis it has been argued that long termJi blockade does not result in weight gain in humans.This might be because small drug induced increases inweight over time are obscured by the continuousincrease in body weight seen with age. We used datafrom the ri blocker heart attack trial to analyseretrospectively the effect of long term treatment withpropranolol compared with placebo on body weight inpatients who had had a myocardial infarction.

Patients and methodsA detailed description of the design of the II blocker

heart attack trial and its methods has been reportedelsewhere.4 In summary, 3837 men and women whohad survived an acute myocardial infarction wererandomised within five to 21 days after the infarction totreatment with propranolol or placebo. During anaverage follow up of 25 months mortality from allcauses and fatal and non-fatal myocardial infarctionswere significantly reduced.We analysed height, body weight, and heart rate at

baseline and after one, two, and three years of followup from the trial database by sex, age, concomitant useof diuretics, and reported changes in physical activity.We used a multivariate repeated measures analysis ofcovariance that adjusted for age, sex, and use ofdiuretics to determine the possible effect of proprano-lol on body weight.' As a large proportion of subjectswere not followed up for two or three vears severalestimation methods were applied, which produced the

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