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Leisure-Time Physical Activity Levels and Risk of Coronary Heart Disease and Death

The Multiple Risk Factor Intervention Trial


Arthur S. Leon, MD; John Connett, PhD; David R. Jacobs, Jr, PhD; Rainer Rauramaa, MD

The relation of self-selected leisure-time physical activity (LTPA) to first major coronary heart disease (CHD) events and overall mortality was studied in 12 138 middle-aged men participating in the Multiple Risk Factor Intervention Trial. Total LTPA over the preceding year was quantitated in mean minutes per day at baseline by questionnaire, with subjects classified into tertiles (low, moderate, and high) based on LTPA distribution. During seven years of follow-up, moderate LTPA was associated with 63% as many fatal CHD events and sudden deaths, and 70% as many total deaths as low LTPA (P<.01). Mortality rates with high LTPA were similar to those in moderate LTPA; however, combined fatal and nonfatal major CHD events were 20% lower with high as compared with low LTPA (P<.05). These risk differentials persisted after statistical adjustments for possible confounding variables, including other baseline risk factors and Multiple Risk Factor Intervention Trial group assignments. It is concluded that LTPA has a modest inverse relation to CHD and overall mortality in middle-aged men at high risk for CHD. (JAMA 1987;258:2388-2395)

The use of a quantitative leisure-time physical activity (LTPA) questionnaire during the Multiple Risk Factor Inter vention Trial (MRFIT) permitted us to further evaluate the possible relation of LTPA to CHD and overall mortality in middle-aged men at high risk for CHD.

METHODS

Study Population
The MRFIT was a randomized, multicenter primary prevention trial de signed to determine whether multifactor intervention would result in a significant reduction in CHD mortality in middle-aged men who at the time of entry were in the upper 10% to 15% of a risk score distribution derived from Framingham Heart Study data but who had no clinical evidence of CHD. The risk score was based on levels of ciga rette smoking, diastolic blood pressure, and serum cholesterol.6 During 1973 to 1976, MRFIT screening of 361662 men, aged 35 to 57 years, was performed at 22 US clinical centers. Of these, 12866 were selected for the trial following written informed consent. Exclusion criteria included clinical evidence of CHD by history, physical examination, and/or resting electrocardiogram (ECG); serum cholesterol levels of 9.05 mmol/L (350 mg/dL) or greater; diastolic blood pressure readings of 115 mm Hg or greater; or a body weight of 50% or greater over standard weight for height. The study design has been de scribed in detail previously.7 Essentially it consisted of randomly assigning male volunteers to either a special interven tion (SI) group or a usual care (UC)

All parts of the body which have afunction, if used in moderation and exercised in labours in which each is accustomed, become thereby healthy, well-developed and age more slowly, but if unused and left idle they become liable to disease, defective in growth, and age

quickly.

Hippocrates1

From the Division of Epidemiology (Drs Leon, Jacobs, and Rauramaa) and Biometry (Dr Connett), School of Public Health, University of Minnesota, Min-

Dr Rauramaa is currently with the Kuopio Research Institute of Exercise Medicine, Kuopio, Finland. Preliminary data were presented at the 1984 American Heart Association Scientific Sessions, Miami Beach, Fla, Nov 13, 1984, and at the 1987 annual meeting of the American College of Sports Medicine, Las Vegas, May 30, 1987, and published in abstract

neapolis.

form.34,35

Reprint requests to Division of Epidemiology, School of Public Health, University of Minnesota, Stadium Gate 27, 611 Beacon St SE, Minneapolis, MN 55455 (Dr Leon).

AS EVIDENCED by this quote, the value of exercise has been extolled since antiquity as a means of preserving or enhancing health. In industrialized na tions, such as the United States, mod ern technology has largely eliminated the need for physical exertion on the job, in the home, and for transporta tion. For example, a century ago, a third of the energy expended in US factories and farms was supplied by muscle power as compared with only about 1% today.2 The hypothesis of a contributing role of a sedentary lifestyle to the etiology of coronary heart disease (CHD) has been extensively scrutinized over the past 30 years by observational epidemiologic, postmortem, and phys iologic studies. The bulk of the evidence that was recently reviewed appears to support this hypothesis.3"5

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group. The SI group received simul taneous dietary instructions for reduc

ing blood cholesterol levels, a smoking cessation program, and stepped-care drug therapy for hypertension. Formal
exercise was not part of the MRFIT program. Men assigned to the UC group were invited to return for reevaluation each year, with the results sent to their usual source of medical care. During the six- to eight-year fol low-up period (mean, seven years), risk factors declined substantially in both groups, but to a greater degree in the men in the SI group. Mortality from CHD was 1.79% in the SI group and 1.93% in the UC group, a statistically nonsignificant difference.7 Rates of total mortality and nonfatal acute myocardial infarctions also were not significantly different between groups.78 In addition,

based

on total LTPA in mean minutes per day for the year preceding the base

bicycling, fishing, and bowling; moder ate: gardening, yard work, home re pairs, dancing, swimming, and home exercise; and heavy: jogging, stair climbing, singles in tennis, snow skiing, cross-country hiking, and backpacking. In this article the results reported are

line questionnaire. Questionnaires re porting an average of 360 min/d or more of LTPA were excluded from analysis,
since it
was were

not

perhaps incorrectly including work-re

assumed that these reports accurate, with participants

a similar relation of LTPA to fatal CHD events for the SI and UC groups. For these rea sons, and to enhance the statistical power in light of the low seven-year CHD mortality rate, the data for the two MRFIT groups were pooled in this

preliminary analysis showed

lated activities. Of the original 12866 MRFIT cohort, 12138 (94.3%) had com plete and acceptable LTPA baseline questionnaire results and were included in this study; 278 were excluded for reporting 360 min/d or greater of LTPA, and 450 because of missing data. Risk Factor Assessments Methods for determination of levels of blood lipids and lipoproteins, blood pressure, and cigarette smoking have previously been described.7 The Jenkins Activity Survey for behavior pattern was performed in 12 772 study participants.13 Positive Jenkins Activity Survey scores indicate type A re sponses; negative scores indicate type B responses. Behavior pattern was also assessed in MRFIT by structured inter view, but only in 24% of the study participants, and these results were not considered herein. Body mass index represents the weight in kilograms di vided by height in meters squared.14 A graded treadmill exercise test us ing a modified Bruce protocol was per formed during the third screening visit. This protocol calls for stepwise in creases in three-minute stages of the treadmill speed and slope until a target heart rate of 85% of predicted maximal heart rate for age is reached, unless the test must be terminated earlier for symptoms or ECG abnormalities. The ECG was recorded on magnetic tape cassettes with a standard three-channel ECG recorder (Marquette series 3500) at each clinical center and sent to the ECG Center in Halifax, Nova Scotia, for analysis by computer. Details of this test protocol and results in the MRFIT have recently been published.15

clinic visits, responses to postcards sent twice yearly to UC participants, and searches of publicly accessible files of deceased persons. Cause of death was assigned by a three-member panel of cardiologists not associated with a MRFIT center and not privy to group assignments. Details on mortality as certainment have been previously re ported.7 Reports of autopsy results were available to the panel on 32% of the decedents. Nonfatal myocardial infarctions were determined by another three-member panel of cardiologists also not privy to group assignments through a review of hospital records or diagnostic changes in resting ECGs taken at annual visits as compared with baseline tracings or both.8

report.

Assessment of Physical Activity Leisure-time physical activity was assessed by the Minnesota question naire9 at baseline (second screening visit) and at the first, fourth, and sixth annual examinations. This question naire lists 18 major activity groups and 62 individual physical activities. Sub jects indicated the number of occasions per month during the previous 12 months that they performed each activ ity and its average duration in minutes. The questionnaire was self-adminis tered at baseline and trained interview ers helped on subsequent evaluations. The questionnaire was previously vali dated against treadmill exercise perfor mance and energy intake from dietary records.910 It also was shown to have high short-term test-retest reliability in both a general population sample and 150 MRFIT participants in Minnesota.11 An earlier version of this questionnaire was used in the US Railroad Study.12 Activities included in the questionnaire are classified by intensity as light, mod erate, and heavy. Light activities are those requiring approximately 8.4 to 16.8 kJ/min (2 to 4 kcal/min); moderate, 18.9 to 23.0 kJ/min (4.5 to 5.5 kcal/min); and heavy, 25.2 kJ/min (6.0 kcal/min) or more. Total LTPA is the sum of all three classes. Each subject's LTPA was deter mined in average minutes and energy expenditure per day for each of the activity classes and for total LTPA. Examples of activities in each class are as follows: light: walking for pleasure,

Mortality and Morbidity Ascertainment All participants were followed up for a minimum of six and a maximum of eight years, with a mean period of observa tion of about seven years. Deaths were ascertained by clinic staff through con tact with family or friends of the deceased, routine follow-up of missed

Statistical Methods The mortality and morbidity data presented in this article include deaths and nonfatal myocardial infarctions for all MRFIT participants (SI plus UC) as of Feb 28,1982, the end of active followup in MRFIT. The Kaplan-Meier prod uct-limit method16 was used to compute the cumulative event rates for each of the study end points shown in Fig 1. Tertiles of baseline total LTPA in minutes per day during a year were examined in relation to the study end points using x2 analysis. In addition, one-way analysis of variance and Tukey's Honestly Significant Difference test17 were used to compare the three LTPA tertiles for levels of major CHD risk factors and other variables. The Cox proportional hazards method with both fixed and time-de pendent variables (ie, baseline levels of LTPA, other risk factors and other vari ables, and their changes during the course of the trial) was used for multivariate analysis to investigate the con tribution of possible confounding fac tors to the relation of LTPA with study end points.18 The LTPA was repre sented in the proportional hazards model by indicator variables for tertiles 2 and 3. Covariates used in the model reported herein included age, plasma cholesterol levels, diastolic blood pres sure levels, number of cigarettes re ported smoked per day, and treatment group assignment (ie, SI or UC). Addi tional covariates tested in other models included occupational class (ie, white collar, which includes technical, profes sional, and clerical workers; craftsmen, eg, carpenters; and blue collar, or ser vice workers); years of education; al cohol consumption; Jenkins Activity Survey behavioral activity score; con centration of high-density lipoprotein cholesterol; and frequency of physician

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Time From Randomization, y

Fig 1.Cumulative coronary heart disease (CHD) mortality (top left), sudden cardiac death (top right), fatal and nonfatal CHD events (bottom left), and mortality from all causes (bottom right) by fertile of leisure-time physical activity. Solid line represents men with lowest third of leisure-time physical activity (fertile 1); dotted line, middle third (fertile 2); and broken line, upper third (fertile 3).

probability values

cited were deter mined with two-tailed tests.

visits, days in bed, and days of hospi talizaron during the preceding year. All

negative in tertile 2 as compared with tertile 1, and it became weakly positive in tertile 3, indicating a slight predomi
nance

density lipoprotein cholesterol concen trations. An inverse relationship was evident between smoking behavior and tertile of LTPA (overall, P<.001). The high-density lipoprotein cholesterol concentration in tertile 3 was slightly higher than in tertile 1 (P<.05). Daily energy intake also was slightly higher with increasing LTPA (P<.05); how ever, no significant differences between tertiles were noted in the body mass index. A small negative Jenkins Activity
dominance of type B behavioral charac teristics, was observed in tertile 1. The Jenkins Activity Survey score was less

RESULTS Baseline characteristics of the men in the MRFIT included in this study are shown by the tertile of LTPA in Table 1. Tertile 1 represents the participants who reported the third lowest mean minutes per day of LTPA, while tertile 3 represents those reporting the third highest mean minutes per day of LTPA. Major risk factors for CHD were not significantly different across tertiles, except for cigarette smoking and high-

et al19 proposed grouping the Jenkins Activity Survey scores into three cate gories based on the relationship to the structured interview: type A, a score of 5 or greater; mixed A/B, a score be tween + 5 and 5; and type B, a score of -5 or less. By this classification, the
-

of type A behavior characteristics (overall, P<.001). Recently Weidner

mean scores

study
gory.

in all three tertiles in our would fall in the mixed A/B cate

The six-year probability of CHD mor tality based on the risk score obtained from Framingham Heart Study data6 was inversely related to LTPA level (P<.001), primarily caused by differ ences in levels of cigarette smoking. Furthermore, the more active men

Survey

score,

indicating

slight

pre

tended to be slightly better educated and were more likely to be white-collar workers as compared with the least active men. Mean minutes per day of baseline LTPA over the preceding year and the associated estimated mean daily energy cost are shown in Table 2 by LTPA tertiles. The least active men (tertile 1) averaged about 16 minutes of LTPA per day and 311 kJ (74 kcal) in daily energy cost as compared with about 48 minutes and 940 kJ (224 kcal)

for the moderately active men (tertile 2) and 134 minutes and 2680 kJ (638 kcal) for the most active men (tertile 3). Light- and moderate-intensity activi ties were more commonly reported than heavy-intensity activity in each tertile. The percent reporting any heavy LTPA increased significantly across tertiles (58.5%, 83.6%, and 90.2% for tertiles 1, 2, and 3, respectively). There also was a progressive increment in reported time spent for each intensity class of LTPA between tertile 1 and 3. Only 570 men (4.7%) reported an hour or more a week of heavy LTPA, the recommended qual ity and quantity of exercise for develop ing and maintaining physical fitness.20 Figure 2 shows a comparison of mean levels of total LTPA at baseline and at three subsequent follow-up evaluations. A significant increase in total LTPA between baseline and the first annual visit was noted in tertile 1 (P<.001). In contrast, during the same interval, ter tile 3 showed a significant decline in total LTPA (P<.001). Both of these changes probably reflect regression to ward the mean. Total LTPA in tertiles 1 and 3 remained relatively constant at subsequent evaluations during the fourth and sixth annual visits. In con trast, in tertile 2, total LTPA remained relatively constant throughout the study. The Pearson correlation coeffi-

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cients among levels of total LTPA at baseline and at the first, fourth, and sixth annual visits were .38, .31, and .30, respectively. We also compared total LTPA levels for the SI and UC groups separately. Both groups had similar mean levels of LTPA at baseline and at the fourth annual visits, but the SI group showed slightly higher LTPA levels as compared with the UC group at the first and sixth annual evaluations Table 3 shows the percent of subjects reporting specific types of activities by LTPA tertile. Working around the yard and garden, walking, and home repairs were among the most frequently re ported activities. Water sports, espe cially swimming, were the most com mon category of sports reported.

Table 1.Baseline Characteristics

Physical Activities (LTPAs)


Variablef Age,
y

(Mean SD) of MRFIT* Participants by Tertile of Total Leisure-Time


Tertile of LTPAs

P*
46.5 5.9 27.7 3.6 10080 3975
46.4 6.0
27.7 3.4 10290 3902

BMI, kg/m2 Energy intake, kj/d

46.3 + 6.0 27.7 3.4 10307 4217

.297 .639 .021


1

(kcal/d)

(2400 947)
6.19 + 0.95

(2450 929)
6.24

(2454 1004)
6.22 0.95

vs3

Total cholesterol, mmol/L


HDL

(mg/dL)_
cholesterol, mmol/L
_

0.94

.061 .015

(239.6 36.8)
1.08 0.31

(241.4 36.4)
(42.0 11.5)
17.85.5

(240.9 37.0)
1.09 0.30

(P<.02).

(mg/dL)
HDL cholesterol/total cholesterol
x

(41.8 12.0)
102
17.8 5.9 91.1 8.8 63.1+48.3 66.4 47.2

1.08 3.41

(42.5 11.7)
18.05.7 90.9 8.7 61.8 48.6 62.0 48.6

1vs3
.090

Diastolic BP, mm Hg Hypertensive, % Cigarette smokers, %

90.9 8.8 61.8 48.6 61.9 48.6

.452
.406

<.001

1vs2 1vs3

Cigarettes smoked, No./d||


Alcohol intake, drinks/wk JAS score

23.0 20.6

20.8 20.2

20.8 20.1 12.611.8


0.169.67

<.001
1 1

vs2 vs3

Dancing, golf, bowling, biking, hunting, and fishing were other popular activi ties. Jogging or running (included under conditioning exercises) was reported by only 6.2%, 11.2%, and 17.7% of men in tertiles 1, 2, and 3, respectively. The percent reporting each type of LTPA
and the
mean

12.913.2
-1.81 9.67

12.1 12.1 -0.90 9.48

.254 <.001

1vs2 1vs3 2vs3


Education, y
13.43.4 13.8 3.2
14.0 3.2 <.001

the baseline exercise treadmill tests were compared by tertile of LTPA. Both treadmill test duration and the percent achieving target heart rate were signifi cantly higher with increasing level of LTPA (P<.001). In addition, heart rates at rest and during stages 1 and 2 of the Bruce exercise test protocol were slightly lower with increasing tertile of LTPA (P<.001). The estimated mean functional capacity of the men in the most active tertile was 8.2 METs (1 MET being the energy requirement of the body in the inactive state sitting quietly, or about 3.5 mL of oxygen kg"1 min"1), which falls in the average range for their age group,21 while the least active tertile was below average in fit ness. There was no significant differ ence between tertiles in percent with ischmie ECG changes during exercise (overall mean, 12.4%). Over the mean seven-year follow-up period there were 488 total deaths, of which 225 (46.1%) were related to CHD, among the 12138 men included in this study. Cancer (n 134), violent deaths (n 46), and cerebrovascular accidents (n 26) were other major causes of death. In addition, 554 nonfatal myocar dial infarctions were documented. Twenty-eight percent of these nonfatal myocardial infarctions were silent and diagnosed by the appearance of new diagnostic Q waves on the ECG (Minne sota code 1-1 to 1-3). Figure 1 and Table 4 show the rates of CHD mortality, sudden death, death by
= = =

gressively increased across tertiles. Physical fitness data obtained from

time spent

on

each pro

1vs2 1 vs 3 2vs3
63.4 48.2 68.0 46.6

White-collar workers, %

67.5 46.9
29.7 + 16.0

<,001
1 1

vs2 vs3

Framingham risk scorel

31.818.7

29.9 16.2

<.001
1 1

vs2 vs3

Multiple Risk Factor Intervention Trial. fBMI indicates body mass index; HDL, high-density lipoprotein; BP, blood pressure; and JAS, Jenkins Activity Survey. ^Probabilities of overall significant differences by one-way analysis of variance for quantitative variables and by 2 x 2 x2 analysis for proportions. P<.05 by Tukey's test. IJAII subjects. ISix-year probability of coronary heart disease death per 1000.
Table 2.MRFIT* Study: Tertile (MeanSD)

*MRFIT indicates

Quantity and

Percent of Time at Different

Intensity Levels of Physical Activity by

Tertile

_Variable_(N=3486)_(N 4097)_(N 4055)_(N mean


= =

12

All
=

12318)

Intensity of LTPA.t Light


Moderate

time

min/d_5.1 5.8_17.813.3_52.8 50.7_25.3 36.5 % of total LTPA_33^_3^6_39^5_38^6_


min/d_5.8 5.9_16.9 12.6_40.8 39.5_21.2 28.3
38.2

% of total LTPA

35.7

30.5

32.5

Heavy

% of total LTPA

min/d_2.94.2_9.0 10.0_27.5 35.8_13.2 24.0


19.1

19.0

20.6

20.1

Other}

min/d_052.1_2.5 7.2_11.332.1_4.8
% of total LTPA

19.7

3.3

5.3

8.6

7.3

Total LTPA, min/d

mean

(range)

15.2 + 8.3
309.1 163.8

_(0-29)_(30-69)_(70-359)_(0-359) kJ/d
(kcal/d)
939.6222.6
2681.3213.1

47.4 11.4

133.6 63.4

65.6 62.4 1309.9 + 579.2

(73.639.0) (0-592.2 [0-141])

[142-327])

(223.753.0) (596.4-1373.4

(638.450.7) (1377.6-11230.8 [328-2674])

(0-11230.8 [0-2674])

(311.9137.9)

*MRFIT indicates Multiple Risk Factor Intervention Trial. -fLTPA indicates leisure-time physical activity. vindicates a variety of activities not otherwise included in the questionnaire; intensity coded as 5 when computing kilojoules per day (kilocalories per day) of total LTPA. Cases excluded if an energy expenditure during LTPA was reported as 360 min/d or greater or 12600 kJ/d (3000 kcal/d) or greater.

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Table

4.Age-Adjusted Rate per 1000 of Coronary Heart Disease (CHD)


CHD Death Sudden Death
No.
per 1000

Events and All-Cause

Mortality*

i50r

Fatal and Nonfatal CHD


No. per 1000 No.

Death, All
Causes

Tertile 3

(n 3986)_98_24J5_62_15.6 286_7JL8_190_47.7 2 (n 4097)_63_154_40_SUS_260_6U5_138_33.7 3 (n 4055)_64 235 58.0 160 39.5 15.8_41_10.1 225 781 64.3 488 40.2 18.5 143 11.8 AM(N 12138) Excluded subjects 14 10 13.7 44 60.4 37 50.8 19.2 (N 728)
= = =

Tertile_No.

per 1000

per 1000

*By tertile of total leisure-time physical activities in

men

in the

Multiple

Risk Factor Intervention Trial.

Table 5.Risk Ratios of Major Endpoints (and 95% Confidence Physical Activities (LTPAs) in Men in MRFIT*

Limits) by Tertile of Total Leisure-Time

_L BL

A1

J_ A4

J_ A6
End

Tertile of LTPAs

Observation Visit

Fig 2.Mean level of total leisure-time physical activity (LTPA) at baseline (BL) and at first annual (A1), fourth annual (A4), and sixth annual (A6) follow-up visits.
Table 3.Major Types of Leisure-Time Physical Activities (LTPAs) Reported by Men in MRFIT* by Tertile of Total LTPAs

CHD Sudden Fatal/nonfatal All-cause

Points*_1_2_3 Age-Adjusted Risk Ratios death_1_00_0.63t-(0.43-0.86)_0.64^(0.47-0.88) death_1_00_0.63*(0.42-0.93)_0.65(0.44-0.96) Ml_U)0_0.88 (0.75-1.04)_0.81^(0.68-0.95) deaths_1_00_0.71+.(0.57-0.88)_0.83|| (0.67-1.01) Risk Ratios Adjusted by Proportional Hazards Regression! CHD death_^00_0.64+(0.47-0.88)_0.67(0.49-0.92) Sudden death_1_00_0.64^(0.43-0.96)_0.67(0.45-1.00) Fatal/nonfatal Ml_;_1JD0_0.90 (0.76-1.06)_0.83(0.70-0.99) All-cause
deaths
1.00

0.73i(0.59-0.91)

0.87

(0.70-1.07)

Major Types
of LTPA

Tertile, % Reporting
1 76.6 55.5 46.9 32.2 86.7 73.4 68.9 88.7 79.9 75.4 45.5 32.1 31.0 41.7 4.6 61.7 31.1 58.1

tCHD indicates coronary heart disease; and Ml, myocardial infarction.


*P<.01.

*MRFIT indicates

Multiple

Risk Factor Intervention Trial.

Lawn/garden Walking Home repairs Dancing Conditioning exercises Biking Fishing/hunting Horseback riding Water sportst
Golf Other

P<.05. ||P<.07. [mg/dL]),

sportst-

22.3 17.3 22.1 1.9 46.0 15.8 38.0

43.1 34.0 27.6 35.0 3.6 59.0 28.0 56.3

levels of ^Regression of end points of age (years),treatment diastolic blood pressure (mm and total cholesterol (mmol/L Hg), number and usual

of cigarettes per day,

group (1, special intervention;

2,

care).

*MRFIT indicates

Trial,

Multiple

Risk Factor Intervention

tincludes swimming, the most popular in this class. ^Includes bowling, the most popular in this class.

all causes, and combined fatal and nonfatal CHD by tertile of baseline LTPA. The upper portion of Table 5 shows the relative risks for the study end points by tertile of LTPA and their 95% confi dence limits after adjustment for age alone; and the lower portion, the rela tive risks after proportional hazards regression analysis adjusting for age, MRFIT group assignment, and base line levels of blood cholesterol, diastolic blood pressure, and cigarette smoking. The moderately active (tertile 2) as com pared with the least active men (tertile 1) had 63% of the gross and age-adjusted rates and risk ratios for CHD mortality and sudden death. No further decre ment in these end-point rates occurred between tertiles 2 and 3. The differen tial in risk between tertiles 1 and 2 of LTPA for sudden death were similar for those dying within one hour as com pared with those dying 24 hours after

initial onset of symptoms. The associa tion of total LTPA level to combined fatal and nonfatal CHD events and over all mortality were weaker than with fatal CHD. A decrement in combined fatal and nonfatal CHD events with increasing LTPA only achieved statis tical significance in the third tertile (P<.01). The risk of mortality from any cause was significantly lower in tertile 2 as compared with tertile 1 (P<.05), while the differential between tertile 3 and tertile 1 did not quite reach statis tical significance (P<.07). Thus, it ap pears that a relatively small mean gra dient of 32 min/d between tertiles 1 and 2 of LTPA was associated with reduction in CHD and overall mortality. Addi tional physical activity beyond a mean of about an hour a day was not associated with any additional reduction in mor tality rates. Further analysis of these data showed that the inverse rela tionship between tertile 3 vs tertile 1 of LTPA and combined fatal and nonfatal CHD events was due primarily to the reduction in fatal CHD events, although there also was a favorable trend for reduction of nonfatal myocardial infarc tions. End-point rates also were analyzed for the 728 subjects excluded from this

infarctions for which the rates were similar. Proportional hazards regression anal ysis was used to correct for the possible confounding effects of MRFIT group assignment and levels ofthe major CHD risk factors at baseline. This statistical adjustment failed to significantly weaken the inverse association of LTPA levels to study end points. Further more, the inclusion in the proportional hazards regression model of baseline levels of high-density lipoprotein choles terol, years of education, alcohol intake, occupational class, Jenkins Activity Survey score, and number of physician visits, days in bed, and days of hospitalization during the preceding year only slightly weakened these inverse relationships. However, as would be ex pected correcting for changes in levels of diastolic blood pressure, total plasma cholesterol, cigarettes per day, and min utes per day of LTPA during the course of the study (ie, time-dependent analy sis) considerably weakened the inverse relationship of LTPA to CHD end

study. A trend was noted for these subjects as compared with those in cluded in the main analysis for higher rates for all study end points, except for combined fatal and nonfatal myocardial

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points. Nevertheless, the -coefficients remained statistically significant

(P<.05), except for combined fatal and nonfatal CHD (P<.35).


COMMENT Evidence for validity of the measur ing instrument used to assess LTPA, the Minnesota questionnaire, included the parallel increases in reported daily dietary energy intake and physical fit ness as LTPA increased. The more ac tive men had slightly lower heart rates at rest and during submaximal stages of treadmill exercise tests and longer ex ercise test durations and were more likely to reach near maximal target heart rate levels based on age as com pared with the least active men (P<.05). These findings are in agree ment with previous studies in our labo ratory910 and elsewhere.22 The cohort as a whole was relatively unfit, with the most active tertile only average in fit ness for their age, and only about 5% of the entire cohort reported the usually recommended quality and quantity of exercise to significantly improve cardiorespiratory endurance. An inverse association was observed in this study between LTPA levels and the baseline Framingham CHD risk score, primarily because of more ciga rette smoking in the least active men. High-density lipoprotein cholesterol concentration also showed a slight in crease with increasing LTPA. In addi tion, the least active men were found to have a slightly lower educational level and a lower percentage of white-collar workers among them than the more active men. Folsom et al,23 using the Minnesota questionnaire in a popula tion-based sample in the Minneapolis-St Paul area, reported similar rela tionships between LTPA and CHD risk and socioeconomic status. This prospective observational study provides supporting evidence for the hypothesis that CHD and overall mor tality are inversely related to regular physical exertion, even in men at high risk for CHD. In our study population, the major decrement in mortality rates was associated with a moderate in crease in predominately light- and mod erate-intensity LTPA over sedentary levels, with no apparent further decre ment associated with additional LTPA. Although these associations persisted after statistical adjustments to elimi nate the contributions of possible con founding baseline variables, it remains possible that unknown factors could in fluence both LTPA habits and rates of CHD mortality and overall mortality. These data do not exclude the pos sibility that more vigorous regular exer-

eise could further reduce CHD inci dence and mortality rates since very few of the men in this study had such an exercise program. A prospective, ran domized, controlled exercise interven tion trial would be required to confirm the findings here, as well as in the other observational studies discussed below, of an apparent inverse relation between LTPA and CHD as well as overall mor tality. However, it is extremely unlikely that a major trial dealing with the issue will be forthcoming because of the large sample size required, the associated costs, and overwhelmingly logistical problems involved. An earlier version of the Minnesota questionnaire was used in our labora tory to assess the relationship of LTPA to CHD mortality in 3043 healthy mid dle-aged male railroad workers followed up for 17 to 20 years.12 As in the present study, age-adjusted CHD mortality rate was inversely related to LTPA lev els, with the least active men having about a 30% greater chance of dying of CHD as compared with the most active men after statistically adjusting for other risk factors. A positive rela tionship also was found between LTPA level and physical fitness ascertained by heart rate on a submaximal treadmill test, again in agreement with the pres ent study. It was further established that the men with the lowest level of physical fitness were at increased risk of dying of CHD during mean follow-up of 20 years.24 In another relevant prospective study, 2779 middle-aged male employ ees of the Los Angeles County Fire and Law Enforcement departments were followed up for a mean of 4.8 years.25 Men with below average physical fitness on a submaximal bicycle ergometer ex ercise test had a relative risk of 2.2 for a myocardial infarction as compared with those with average or higher fitness. Furthermore, if those with below aver age fitness had two or more of the three major CHD risk factors present at base line, the relative risk for a myocardial infarction was increased to 6.6. It would appear then from these studies and ours that a reduced CHD rate with increas ing LTPA is related to improved phys ical fitness. An associated lower exertional heart rate decreases myocardial oxygen demands. This may reduce the possibility or severity of a myocardial infarction or of a fatal cardiac ar rhythmia in the presence of significant coronary artery disease. Several other large-scale prospective observational studies reported reduced CHD mortality and morbidity in men in sedentary occupations who performed similar types of LTPAs commonly re-

20 years of about 17000 Harvard Col lege alumni by Paffenbarger et al26,27 and an 8.5-year follow-up by Morris et al28,29 of about 18000 British executive-class civil servants. In the Harvard alumni study, age-ad justed incidence of CHD was inversely related to the energy expenditure in kilocalories per week of walking, stair climbing, and sports. Men expending fewer than 8400 kJ/wk (2000 kcal/wk) were at 64% higher risk than ex-class mates who were more active. For com parison in our study, the men in the middle tertile of LTPA expended on the average about 6300 kJ/wk (1500 kcal/wk) during LTPA as compared with about 2100 kJ/wk (500 kcal/wk) in tertile 1. The association in the college alumni study remained strong when adjustments were made for several other CHD risk factors as in our study. More recently, in the same population Paffenbarger et al30 reported an inverse relationship be tween overall mortality and a similar range of weekly energy expenditure, again consistent with findings in our study. In a population-based represent ative sample of men and women in Eastern Finland, Salonen et al31 also reported a reduction in "death due to any disease" with increasing levels of LTPA after multivariate statistical ad justments for possible confounding var iables. In another relevant study, Magnus et al32 obtained information about LTPA by interviewing 473 subjects or nearest relatives following fatal or nonfatal myo cardial infarctions and 815 matched con trols from the same region in Holland. A significant inverse relationship was found between acute coronary events and habitual, but not occasional or sea

ported by the men in our study. These studies include follow-up for more than

combination of these. More vigorous exercise did not appear to offer addi tional protection from CHD than did these moderate-intensity activities, in agreement with findings in our study. The death rate within four weeks of an acute coronary event also was signifi cantly higher in the least active group. Haskell,33 after a careful review of the relevant literature, recently came to the conclusion that a threshold of about 630 kJ/d (150 kcal/d) of energy expen diture during LTPA was required to decrease CHD risk. In addition, he be lieved that risk becomes lower as activi ties increase energy expenditure up to approximately 1680 kJ/d (400 kcal/d). In our study, the mean baseline energy daily expenditure during LTPA was 310 kJ (74 kcal) in tertile 1 as compared with about 980 kJ (234 kcal) in tertile 2,

sonal, walking, cycling, gardening, or a

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where we observed a significant reduc tion in CHD mortality, with no further reduction in tertile 3 where the mean daily energy expenditure was 2680 kJ tions. The

optimal amount of energy expenditure for reducing CHD mor tality in tertile 2 was accomplished by 30 to 69 minutes daily of predominately light- and moderate-intensity activities. This is an encouraging finding from the preventive medicine and public health standpoint, since most people should be

(638 kcal). Thus, our findings essentially are in agreement with Haskell's calcula

The principal investigators and senior staff of the clinical, coordinating, and support centers, the National Heart, Lung, and Blood Institute, and members of the MRFIT Policy Advisory Board and Mortality Review Committee are as follows: American Health Foundation, New York Principal investigator: Charles Arnold, MD, MPH; senior staff: Rebecca Mandriota, MS, MEd; Richard Ames, MD; Joan Ruff Eisenbach,

St Louis Heart Association

Dolececk, PhD, RD. Rutgers Medical School, Piscataway, NJ Principal investigator: Nicholas Wright, MD, PhD; coprincipal investigator: Steven Kopel, PhD; senior staff: Kenneth Suckerman, PhD; Marilyn Schorin, MPH, RD.

RN. Boston

University Principal investigator: H. Emerson Thomas, Jr, MD; coprincipal investigator: William Kannel,

Deckman. Cox Heart Institute,

MD; senior staff: L. Kent Smith, MD, Charles

able to schedule this amount of LTPA as part of their daily routine. Further more, it is encouraging that pre dominately low- to moderate-intensity LTPA appears to be sufficient to reduce premature mortality, since there is the potential risk of sudden cardiac death during heavy exercise in people with coronary risk factors6,33; however, it should be pointed out that in the MRFIT population habitual heavy LTPA was not associated with excess sudden death. In conclusion, data from the MRFIT showed that men at high risk for CHD who self-selected moderate amounts of predominately light and moderate nonwork physical activity had lower rates of CHD mortality, sudden death, and over all mortality than more sedentary men. The principal mechanism may be the effects of improved physical fitness on the heart. Additional potential benefits of regular physical activity include help ing maintain body weight, as a substi tute for cigarette smoking, and for increasing high-density lipoprotein cho lesterol levels, lowering of blood pres sure levels, and improved glucose-in sulin dynamics. Since physical activity habits are commonly established early in life, a population strategy to enhance physical activity throughout the lifespan appears appropriate to help pre vent CHD and promote health and lon

MS. Dade County Miami

Kettering, Ohio Principal investigator: Paul Kezdi, MD; coprin cipal investigator: Edwin Stanley, MD; senior staff: Frederick Ernst, PhD; E. Jean Case, RN, Department of Public Health,

Principal investigator: George Christakis, MD, MPH; coprincipal investigators: Janice Burr, MD; Terence Gerace, PhD; senior staff: Mary Ellen Wilcox, RD, MEd. Dalhousie University, Halifax Nova Scotia, Can ada (MRFIT ECG Center) Principal investigator: Pentti Rautaharju, MD, PhD; senior staff: Hermann Wolf, PhD. Harvard University, Boston Principal investigator: Robert Benfari, PhD; coprincipal investigator (former chairperson, Steering Committee): Oglesby Paul, MD; senior staff: Elinor Danielson, MA; Judith Ockene, PD. Kaiser Foundation Research Institute, Portland,
Ore

Principal investigator: Nathan Simon, MD; coprincipal investigator: Jerome Cohen, MD; senior staff: Elizabeth Bunkers, RD. University of Alabama in Birmingham Principal investigator: Harold Schnaper, MD; coprincipal investigator: Glenn Hughes, PhD; senior staff: Ralph Allen, PA; Phillip Johnson. University of California, Davis Principal investigator: Nemat Borhani, MD; sen ior staff: Carolyn Sugars, RD; Karen Kirkpatrick; Marshall Lee, MD; Frances LaBaw, RN. University of Maryland, Baltimore Principal investigator: Roger Sherwin, MB, BChir; coprincipal investigator: Mary McDill Sexton, PhD, MPH; senior staff: Query de Bar ros, MS; Patricia Dischinger, PhD; Jutta Heiner, MD; Mary Pilkington, RN, MSN; Barbara Scanion, MA. University of Minnesota, Minneapolis Principal investigator: Richard Grimm, Jr, MD, PhD; coprincipal investigators: Henry Black burn, MD; Richard Crow, MD; Maurice Mittel mark, PhD; senior staff: Arthur S. Leon, MD; David R. Jacobs, Jr, PhD; Mary McDonald, RN,
MS.

gevity.

This research was carried out in MRFIT centers collaborative research undertaking with con tract support from the National Heart, Lung, and Blood Institute, Bethesda, Md. The authors dedicate this article to the memory of our deceased colleague, Henry L. Taylor, PhD, whose pioneering work on the association of phys ical activity to CHD and efforts in developing the Minnesota Leisure-Time Physical Activity Ques tionnaire and having it included in the MRFIT protocol laid the foundation for this study. Thanks are expressed to Albert Oberman, MD, and Steven Blair, PhD, for constructive criticisms, and Marilyn Borkon for preparing the manuscript. The following companies generously supplied drugs used in this study: Ciba-Geigy Corpora
as a

tionhydrochlorothiazide (Esidrix), hydralazine (Apresoline), and guanethidine (Ismelin) sulfate; USV Pharmaceuticalchlorthalidone (Hygroton); Ayerst Laboratoriespropranolol (Inderal); Merck, Sharp & Dohmea-methyldopa (Aldomet).

MD; senior staff: James Allaire, MEd; Diane Fellon, RN; Barbara Feinstein, MSA; Diana Hutchins, MD. National Center for Disease Control, Atlanta Principal investigator: Gerald Cooper, PhD. New Jersey Medical School, Newark Principal investigator: Norman Lasser, MD, PhD; coprincipal investigator: Norman Hymowitz, PhD. Northwestern University, Chicago Principal investigator: Jeremiah Stamler, MD; senior staff: Dorothy Moss, MS, RD; Victoria Persky, MD; Linda Van Horn, PhD, RD; Kay Shannon, MA; David Meyers, MD. University of Chicago Principal investigator: Louis Cohen, MD; coprin cipal investigator: Juliet Morgan, PhD; senior staff: Gayle Grundmann, MS, RD; Thomas Ves tal, PA; Ben Huang. St Joseph's Hospital, Chicago Principal investigator: David Berkson, MD; sen ior staff: Gary Lauger, MS; Steven Gruijic, MD; David Obradovic, MD. Institutes of Medical Sciences-University of California, San Francisco and Berkeley Principal investigator: James Billings, PhD, MPH; coprincipal investigators: Stephen Hulley, MD, MPH; W. McFate Smith, MD, MPH; S. Leonard Syme, PhD; senior staff: Richard Cohen, MS; Lisa Dzvonik, MA, RD; Leslie Roos; Mary Kahn, RN. Institutes of Medical Sciences, San Francisco Central Laboratory Coprincipal investigators: Graham Williams, MD, Stephen Hulley, MD, MPH. Rush-Presbyterian-St Luke's Medical Center, Chicago Principal investigator: James Schoeberger, MD; senior staff: Joseph Schoenenberg, PhD; Richard Shekelle, PhD; Gilberto Neri, MD; Thrse

Principal investigator: John Wild, MD; coprin cipal investigators: M. R. Greenlick, PhD; John Grover, MD; senior staff: Sara Lamb; Jeffrey Bailey; Judith Dyer, MPH; Barbara Brokop, RN; Victor Stevens, PhD; Graldine Bailey, RN. Lankenau Hospital, Philadelphia Principal investigator: William Holmes, PhD; coprincipal investigator: J. Edward Pickering,

University of Minnesota ECG Coding Center, Minneapolis Director: Ronald Prineas, MB, PhD; associate director: Richard Crow, MD. University of Minnesota Nutrition Coding Center, Minneapolis Director: Ida Buzzard, PhD; associate director: Joyce Wenz, MS, RN. University of Minnesota Coordinating Center, Minneapolis Principal investigator: Marcus Kjelsberg, PhD; coprincipal investigators: Glenn Bartsch, ScD; James Neaton, PhD; senior staff: Steven Broste, MS, John Connett, PhD; Alain DuChene; Diane Gorder, MS; Gregory Grandits, MS; Kenneth Svendsen, MS. University of Pittsburgh Principal investigator: Lewis Kuller, MD, DPH; coprincipal investigators: Robert McDonald, MD, Lorita Falvo-Gerard, MN, MPH; Arlene Caggiula, PhD, RD; senior staff: Elizabeth Gahagan, RN; Robert Moyer, RN; Mary Alman, RN; Karen Southwick, ASCP. University of South Carolina, Columbia Principal investigator: Warren Giese, PhD; coprincipal investigators: J. Frank Martin, MD; James Keith, PhD; senior staff: Harriet Har rison, RN. University of Southern California, Los Angeles Principal investigator: Eugene Fishman, MD; senior staff: Laurence Wampler, PhD; Gretchen Newmark, MA, RD; Shahida Siddiqui, MD; Lau ren Paquet, RN. Policy Advisory Board Chairperson: William Insull, Jr, MD; members: John Farquhar, MD; C. David Jenkins, PhD; Elliot Rapaport, MD; Donovan Thompson, PhD; Herman Tyroler, MD; Park Willis III, MD; William Friedewald, MD (ex officio); William Zukel, MD (ex officio). Mortality Review Committee Chairman: Joseph Doyle, MD; members: Howard Burchell, MD; Paul Yu, MD; Park Willis III, MD
National Heart, Lung, and Blood Institute Staff, Bethesda, Md Program director: William Friedewald, MD; project office director: Curt Furberg, MD; scien tific project officer: Jeffrey Cutler, MD; former program director: William Zukel, MD; former scientific project officers: Eugene Passamani, MD, Charles Kaelber, MD; members: Joel Verter, PhD; Margaret Wu, PhD.

(former member).

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