BEU, Alm.del - 2020-21 - Bilag 290: Orientering om offentliggørelse af NFA-artikel om fysisk aktivitet i forbindelse med arbejde og fritid og risiko for hjertekarsygdom og førtidig død, fra beskæftigelsesministeren

Beskæftigelsesudvalget 2020-21
BEU Alm.del Bilag 290
Offentligt

European Heart Journal (2021)

00,

1–14

doi:10.1093/eurheartj/ehab087

CLINICAL RESEARCH

Epidemiology and prevention

The physical activity paradox in cardiovascular

disease and all-cause mortality: the

contemporary Copenhagen General

Population Study with 104 046 adults

Andreas Holtermann

*, Peter Schnohr

, Børge Grønne Nordestgaard

and Jacob Louis Marott

2,3

2,3,4,5

National Research Centre for the Working Environment, Lersø Parkalle 105, Copenhagen 2100, Denmark;

The Copenhagen City Heart Study, Bispebjerg and Frederiksberg

Hospital, Copenhagen University Hospital, Nordre Fasanvej 57, Hovedvejen, Indgang 5, Frederiksberg 2000, Denmark;

The Copenhagen General Population Study, Herlev and

Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark;

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital,

Herlev, Denmark; and

Faculty of Health and Medical Sciences, University of Copenhagen, Denmark

Received 1 July 2020; revised 13 December 2020; editorial decision 2 February 2021; accepted 3 February 2021

Aims

Leisure time physical activity associates with reduced risk of cardiovascular disease and all-cause mortality, while

these relationships for occupational physical activity are unclear. We tested the hypothesis that leisure time physic-

al activity associates with reduced major adverse cardiovascular events (MACE) and all-cause mortality risk, while

occupational physical activity associates with increased risks.

...................................................................................................................................................................................................

Methods

We studied 104 046 women and men aged 20–100 years in the Copenhagen General Population Study with base-

line measurements in 2003–2014 and median 10-year follow-up. Both leisure and occupational physical activity

and results

were based on self-report with four response categories. We observed 7913 (7.6%) MACE and 9846 (9.5%) deaths

from all causes. Compared to low leisure time physical activity, multivariable adjusted (for lifestyle, health, living

conditions, and socioeconomic factors) hazard ratios for MACE were 0.86 (0.78–0.96) for moderate, 0.77 (0.69–

0.86) for high, and 0.85 (0.73–0.98) for very high activity; corresponding values for higher occupational physical ac-

tivity were 1.04 (0.95–1.14), 1.15 (1.04–1.28), and 1.35 (1.14–1.59), respectively. For all-cause mortality, corre-

sponding hazard ratios for higher leisure time physical activity were 0.74 (0.68–0.81), 0.59 (0.54–0.64), and 0.60

(0.52–0.69), and for higher occupational physical activity 1.06 (0.96–1.16), 1.13 (1.01–1.27), and 1.27 (1.05–1.54),

respectively. Similar results were found within strata on lifestyle, health, living conditions, and socioeconomic fac-

tors, and when excluding individuals dying within the ﬁrst 5 years of follow-up. Levels of the two domains of physic-

al activity did not interact on risk of MACE (P = 0.40) or all-cause mortality (P = 0.31).

...................................................................................................................................................................................................

Conclusion

Higher leisure time physical activity associates with reduced MACE and all-cause mortality risk, while higher occu-

pational physical activity associates with increased risks, independent of each other.

* Corresponding authors. Tel:

þ45

39165352, Email:

[email protected]

(A.H.); Tel:

þ45

38163673, Email:

[email protected]

(J.L.M.)

The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/),

which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact

[email protected]

BEU, Alm.del - 2020-21 - Bilag 290: Orientering om offentliggørelse af NFA-artikel om fysisk aktivitet i forbindelse med arbejde og fritid og risiko for hjertekarsygdom og førtidig død, fra beskæftigelsesministeren

A. Holtermann

et al.

Graphical Abstract

Copenhagen General Popula on Study

(

N=104 046, 10 years follow-up, MACE=7913, Deaths=9846)

Physical ac vity in leisure me

MACE

Increased risk

Test for

interac on

P=0.40

Reduced risk

40%

reduced risk for

Death

HR=0.60 (95% CI: 0.52-0.69)

Highe

ac vity r physical

in leisu

re me

Physical ac vity at work

Death

Increased risk

Test for

interac on:

P=0.31

35%

increased risk for

MACE

HR=1.35 (95% CI: 1.14-1.59)

27%

increased risk for

Death

HR=1.27 (95% CI: 1.05-1.54)

Highe

ac vity r physical

in leisu

re me

Risk of major adverse cardiovascular events (MACE) and all-cause mortality as a function of different categories of leisure time physical activity and occupa-

tional physical activity in individuals in the Copenhagen General Population Study.

...................................................................................................................................................................................................

Keywords

Physical activity

•

Stroke

•

Cardiovascular disease

•

Occupational health

•

Morbidity

•

Mortality

Introduction

Physical activity is a strong preventive measure of cardiovascular

disease and all-cause mortality.

1,2

However, recent studies have

observed that the potential health effect of physical activity depends

on the domain in which it is performed.

3–5

While leisure time physical

activity (e.g. sports, recreation, and transportation) is well docu-

mented to be beneficially associated with cardiovascular disease and

all-cause mortality,

1,2,6

then occupational physical activity is not con-

sistently reported to associate with improved health.

7–10

A systemat-

ic review even found that men with high vs. low occupational physical

activity had increased risk of all-cause mortality.

A recent umbrella

review found that high occupational physical activity is associated

with reduced risk of some health outcomes (i.e. cancers, coronary

heart disease, and type 2 diabetes), but with increased risk of other

health outcomes (i.e. osteoarthritis, poor sleep quality, and all-cause

mortality in men).

The authors concluded that ‘there is a need for

better quality evidence to provide a unequivocal statement on the

health effects of occupational physical activity’.

This potential contrasting health effect of leisure time physical ac-

tivity and occupational physical activity is termed the ‘physical activity

paradox’.

An explanation for the physical activity paradox likely is

the very different characteristics of physical activity when performed

during leisure time and work.

Leisure time physical activity often

includes dynamic movements at conditioning intensity levels sufficient

to improve cardiorespiratory fitness over short time periods with

enough recovery time.

In contrast, work often requires static load-

ing, monotonous and awkward working postures, and other non-

conditioning activities over several hours per day without sufficient

recovery time.

However, recent physical activity guidelines do not differentiate

between work and leisure time domains.

1,2

Work constitutes the

main domain for physical activity for a large fraction of the adult

population worldwide.

15,16

We are not aware of any international or

national physical activity guidelines differentiating on occupational

physical activity and leisure time physical activity. If the physical activ-

ity paradox holds true, this can contribute to the understanding and

interventions on the generally poor health of individuals with high oc-

cupational physical activity.

We hypothesized that leisure time physical activity associates with

reduced cardiovascular disease and all-cause mortality while occupa-

tional physical activity associates with increased risks. To do so, we

investigated the risk of major adverse cardiovascular events (MACE)

and death from all causes in relation to occupational physical activity

ac ghe

vit r ph

y a ys

t w ica

or l

ac gher

vit ph

y a ysi

t w cal

Higher ac vity

15%

reduced risk for

MACE

HR=0.85 (95% CI: 0.73-0.98)

Higher ac vity

Increased risk

Physical activity in cardiovascular disease and all-cause mortality

and leisure time physical activity in the large contemporary

Copenhagen General Population Study with baseline measurements in

2003–2014. To minimize risk for confounding and reverse causation,

we performed multivariable adjusted analyses including extensive

adjustments for potential lifestyle, health, living conditions, and socioe-

conomic confounders, as well as in strata of potential confounders, and

when excluding individuals dying within the first 5 years of follow-up.

Methods

The Copenhagen General Population Study was established in 2003–

2014. Women and men aged 20–100 years were randomly invited from

the general population of the greater Copenhagen area including both

high- and low-income areas, using the Danish Central Person

Registration number, which uniquely identifies all individuals living in

Denmark. All individuals were Whites and of Danish descent. The

study was approved by a Danish ethics committee (H-KF-01-144/01) and

by Herlev Gentofte Hospital, Copenhagen University Hospital. The study

was conducted according to the Declaration of Helsinki, and all partici-

pants gave written informed consent. Of the 256 761 individuals invited,

43% participated. In

Supplementary material online,

Figure S1,

we show

MACE and all-cause mortality as a function of follow-up time for res-

ponders and non-responders separately.

Covariates

The participants filled out a questionnaire and underwent a physical health

examination including measurements of height, weight [from which body

mass index (BMI) was calculated as kg/m

] and resting blood pressure and

heart rate. From the questionnaire, information was obtained about leis-

ure time physical activity, occupational physical activity, educational back-

ground [categorized as below middle school (<8 years), middle school

(8–10 years), high school (>10 years), and university], living conditions and

socioeconomic status (household income, longest employment since

school, cohabitation, marital status), smoking (categorized as never

smoker, former smoker, and current smoking), alcohol consumption

(reported drinks per week), adherence to dietary guidelines,

blood

pressure medication, and a vital exhaustion score. Diabetes was based on

self-report or a non-fasting blood glucose >

_11.1 mmol/L (200 mg/dL).

Information on previous cardiovascular disease was based on register

data. Standard hospital assays measured low-density lipoprotein (LDL)

cholesterol, high-density lipoprotein (HDL) cholesterol, plasma triglycer-

ides, and plasma glucose on non-fasting blood samples drawn at study

examination. Chronic obstructive pulmonary disease (COPD) according

to GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages

1–4 was based on baseline spirometry. The Danish Central Person

Registration number provides data on age and sex.

Exposures

Occupational physical activity was quantitated using the following ques-

tion used in numerous previous studies

: ‘What is your physical activity

at work within the last year?’

(1)

(2)

(3)

(4)

Predominantly sedentary work.

Sedentary or standing, sometimes walking work.

Walking, sometimes lifting work.

Heavy manual work.

Leisure time physical activity was quantitated by the following question

used in numerous previous studies

: ‘What is your physical activity during

leisure time (including transport to and from work) within the last year?’

(1) Almost completely sedentary or light physical activity less than 2

hours per week.

(2) Light physical activity for 2–4 hours per week.

(3) Light physical activity for more than 4 hours per week or vigorous

per week.

(4) physical activity for 2–4 hoursmore than 4 hours per week or regu-

Vigorous physical activity for

lar heavy exercise or competitive sports several times per week.

Outcomes

The follow-up on outcomes started the day after the baseline measure-

ments. MACE consisted of fatal and non-fatal myocardial infarction (MI),

fatal and non-fatal stroke, and other coronary death. Individuals with pre-

existing MACE (n = 5282) were excluded from the statistical analyses to

avoid reverse causality.

These outcomes were identified by linkage to the national Danish

Patient Registry covering all Danish hospitals and to the national Danish

Cause of Death Registry, using the following ICD-10 codes: I21 and I22

for non-fatal MI and I20-I25 for fatal coronary heart disease. Possible

stroke events (among hospitalized patients) were identified with the

ICD-10 codes I60, I61, I63, I64, and G45 and subsequently validated using

the World Health Organization definition of stroke, that is an acute dis-

turbance of focal or global cerebral function with symptoms lasting longer

than 24 h or leading to death, with presumably no other reasons than of

vascular origin.

Deaths were obtained until December 2018 from the Civil Registration

System and causes of death until December 2016 from the Danish

(Q1–Q3: 6.8–11.9; maximum: 15.0) for cardiovascular events and 9.9 years

(Q1–Q3: 7.1–12.3; maximum: 15.0 years) for all-cause mortality.

Statistical analyses

The median follow-up time was based on the reverse Kaplan–Meier

method.

The associations between predictors (i.e. leisure time physical

activity and occupational physical activity) and all-cause mortality were

studied using Cox proportional hazards regression analysis and cause-

specific Cox proportional hazards regression analysis for MACE, where

deaths from other causes were considered a competing risk. All models

had follow-up time as underlying time scale. Adjustments were done in

three steps: model A, age and sex; a multivariable adjusted model B,

model A

BMI, smoking, years in school, diabetes, systolic blood pres-

sure, blood pressure medication, dietary preferences, alcohol consump-

tion, COPD by GOLD stage, LDL cholesterol, HDL cholesterol, and

triglycerides; and an extended multivariable sensitivity model C, model B

resting heart rate, vital exhaustion score, occupation, cohabitation,

marital status, and household income.

physical activity and occupational phys-

icalMissing answers in leisure timesingle category and kept in the statistical

activity were grouped into a

model (see description of participants with missing information of leisure

time physical activity and occupational physical activity in

Supplementary

material online,

Table S1).

Furthermore, we performed combined Cox proportional hazards re-

gression analyses on the interplay between leisure time physical activity

and occupational physical activity with a common reference (i.e. high leis-

ure time physical activity and low occupational physical activity) on

MACE and all-cause mortality with adjustment for age, sex, BMI, smoking,

years in school, diabetes, systolic blood pressure, blood pressure medica-

tion, dietary preferences, alcohol consumption, COPD by GOLD stage,

LDL cholesterol, HDL cholesterol, and triglycerides.

Moreover, we investigated the associations of

higher leis-

ure time physical activity (or occupational physicalone level with risk of

activity)

MACE and all-cause mortality, overall and after stratification on several

A. Holtermann

et al.

Table 1

Baseline characteristics of the 104 046 individuals in the Copenhagen General Population Study free of major

adverse cardiovascular events at baseline (784 individuals did not report their physical activity in leisure time)

Characteristic

Low,

6340

Men

Age (years)

Physical activity at work

Low

Moderate

High

Very high

Non-responders

Education

<Middle school

Middle school

High school

University

Years in school

Household income

Low

Moderate

High

Longest employment since school

Self-employed

Skilled worker

Unskilled worker

Ofﬁce worker

Housewife

Unemployed or senior citizen

Cohabitation

Living with spouse/cohabitant

Living alone

Living with others

Marital status

Married/cohabiting

Unmarried

Separated/divorced

Widow/widower

Smoking

Never smoker

Former smoker

Current smoker

Body mass index (kg/m

)

<18.5

18.5–29.9

_30

Adherence to dietary guidelines

Very high

High

Intermediate

Low

Very low

65 (1)

4223 (67)

2035 (32)

256 (5)

544 (10)

2677 (47)

827 (15)

1343 (24)

389 (1)

34 554 (80)

8212 (19)

3420 (9)

6258 (16)

21 801 (55)

3573 (9)

4572 (12)

392 (1)

40 810 (88)

5413 (12)

5140 (12)

8415 (19)

23 813 (55)

2961 (7)

2834 (7)

42 (1)

6359 (91)

604 (9)

<0.0001

681 (10)

1229 (19)

3613 (56)

529 (8)

440 (7)

Continued

579 (9)

1177 (19)

816 (13)

3406 (54)

161 (3)

166 (3)

4417 (70)

1707 (27)

209 (3)

4371 (69)

744 (12)

734 (12)

471 (7)

2060 (34)

2116 (35)

1906 (31)

3520 (8)

8266 (19)

3764 (9)

25 535 (59)

1352 (3)

559 (1)

32 125 (74)

9928 (23)

1128 (3)

31 937 (74)

3227 (7)

4314 (10)

3681 (9)

16 401 (39)

16 820 (40)

8341 (20)

3966 (9)

8187 (18)

2737 (6)

30 206 (65)

886 (2)

409 (1)

36 221 (78)

9205 (20)

1219 (3)

36 009 (77)

3342 (7)

4331 (9)

2925 (6)

19 573 (44)

18 914 (42)

6249 (14)

817 (12)

1301 (19)

456 (7)

4228 (61)

79 (1)

62 (1)

<0.0001

5340 (76)

1398 (20)

273 (4)

<0.0001

5308 (76)

745 (11)

655 (9)

287 (4)

<0.0001

3107 (47)

2724 (41)

785 (12)

<0.0001

2924 (46)

56 ± 14

2502 (39)

1401 (22)

839 (13)

242 (4)

1356 (21)

716 (11)

2772 (44)

2082 (33)

747 (12)

10.4 ± 1.9

1011 (16)

2832 (45)

2412 (39)

Physical activity in leisure time

P-value

Very high,

7017

4667 (67)

54 ± 14

2596 (37)

1346 (19)

988 (14)

345 (5)

1742 (25)

<0.0001

4339 (10)

18 293 (42)

14 353 (33)

6103 (14)

10.5 ± 1.9

5814 (14)

19 811 (46)

16 983 (40)

3695 (8)

16 471 (35)

16 667 (36)

9740 (21)

10.9 ± 1.8

4593 (10)

19 265 (42)

22 354 (48)

502 (7)

2320 (33)

2525 (36)

1652 (24)

11.0 ± 1.8

697 (10)

2626 (38)

3634 (52)

<0.0001

......................................................................................................................

Moderate,

43 224

16 689 (39)

58 ± 13

12 404 (29)

11 418 (26)

6156 (14)

911 (2)

12 335 (29)

High,

46 681

21 336 (46)

57 ± 13

14 792 (32)

10 747 (23)

6525 (14)

1043 (2)

13 574 (29)

....................................................................................................................................................................................................................

Physical activity in cardiovascular disease and all-cause mortality

Table 1

Continued

Physical activity in leisure time

P-value

Very high,

7017

<0.0001

838 (14)

3908 (67)

1083 (19)

399 (6)

139 ± 22

1299 (22)

4687 (81)

469 (8)

514 (9)

126 (2)

23 (0)

1.8 ± 1.6

77 ± 13

1.45 ± 0.51

3.30 ± 0.98

2.0 ± 1.4

3646 (9)

29 891 (73)

7506 (18)

1788 (4)

139 ± 21

8335 (21)

32 846 (83)

3502 (9)

2600 (7)

400 (1)

58 (0)

1.2 ± 1.4

74 ± 12

1.61 ± 0.52

3.31 ± 0.96

1.7 ± 1.2

2830 (6)

34 176 (76)

8141 (18)

1285 (3)

137 ± 21

6667 (16)

35 482 (85)

4058 (10)

1865 (4)

182 (0)

21 (0)

0.9 ± 1.2

70 ± 12

1.67 ± 0.51

3.23 ± 0.92

1.6 ± 1.0

521 (8)

5141 (76)

1118 (16)

146 (2)

135 ± 20

770 (13)

5297 (86)

558 (9)

248 (4)

23 (0)

2 (0)

0.7 ± 1.1

65 ± 12

1.63 ± 0.51

3.13 ± 0.90

1.5 ± 1.0

<0.0001

Characteristic

Low,

6340

Alcohol intake (women/men)

Non-drinker

1–14/1–21 drinks/week

>14/>21 drinks/week

Diabetes

Systolic blood pressure (mmHg)

Blood pressure medication

COPD

No COPD

GOLD stage 1

GOLD stage 2

GOLD stage 3

GOLD stage 4

Vital exhaustion score

Resting heart rate (bpm)

HDL cholesterol (mmol/L)

LDL cholesterol (mmol/L)

Triglycerides (mmol/L)

......................................................................................................................

Moderate,

43 224

High,

46 681

Data are

(%) or mean ± SD.

COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

lifestyle, health, living condition and socioeconomic factors in Cox re-

gression models adjusted for age, sex, smoking, BMI, years in school,

dietary preferences, alcohol, COPD by GOLD stage, systolic blood

pressure, blood pressure medication, diabetes, LDL cholesterol, HDL

cholesterol, triglycerides, and physical activity at work (or physical ac-

tivity in leisure time). Test for interactions was conducted by introduc-

ing interaction terms in the individual Cox models.

To address the issue of reverse causation, we performed an analysis of

the associations between leisure time physical activity and occupational

physical activity with MACE and all-cause mortality in models adjusted

for age, sex, smoking, BMI, years in school, dietary preferences, alcohol

consumption, COPD by GOLD stage, systolic blood pressure, blood

pressure medication, diabetes, LDL cholesterol, HDL cholesterol, and tri-

glycerides with start of follow-up 1, 3, and 5 years after baseline.

The assumption of proportionality in the Cox regression models was

tested with the Lin

et al.

score process test.

Two-sided

P-values

<0.05

were considered statistically significant. Statistical analyses were per-

formed with R, version 3.5.2 (https://cran.r-project.org/).

Results

In the eligible study population, we observed 7913 (7.6%) MACE and

9846 (9.5%) deaths from all causes during the median follow-up

period of 10 years (range 0.1–15 years).

Table

illustrates lifestyle and other characteristics stratified into

low, moderate, high, and very high leisure time physical activity. The

level of leisure time physical activity was strongly associated with sex

and, to a lesser degree, with age. There was an uneven distribution of

occupational physical activity across levels of leisure time physical ac-

tivity. The prevalence of current smokers, BMI > kg/m

, short edu-

_30

cation, low household income, low adherence to dietary guidelines,

COPD GOLD stage 4, and diabetes was highest among the group

with low leisure time physical activity. Accordingly, the group with

low leisure time physical activity had a higher vital exhaustion score,

resting heart rate, LDL cholesterol, and triglycerides compared with

the very high leisure time physical activity group.

Table

illustrates lifestyle and other characteristics stratified into

low, moderate, high, and very high occupational physical activity. The

level of occupational physical activity was strongly associated with

sex. While more women than men performed moderate and high

occupational physical activity, very high occupational physical activity

was predominantly performed by men. The age was relatively stable

across the groups of occupational physical activity. The very high oc-

cupational physical activity group had a higher prevalence of very high

leisure time physical activity, current smokers, BMI > kg/m

, short

_30

education, low adherence to dietary guidelines, and high alcohol con-

sumption per week compared with the low occupational physical ac-

tivity group.

Figure

shows the associations between leisure time physical activ-

ity and occupational physical activity with the outcomes MACE and

all-cause mortality, respectively. Compared to low leisure time phys-

ical activity, multivariable adjusted (for lifestyle, health, living condi-

tions, and socioeconomic factors) hazard ratios for MACE were 0.86

(0.78–0.96) for moderate, 0.77 (0.69–0.86) for high, and 0.85 (0.73–

0.98) for very high activity; corresponding values for higher

A. Holtermann

et al.

Table 2

Baseline characteristics of the 104 046 individuals in the Copenhagen General Population Study free of major

adverse cardiovascular events at baseline (29 481 individuals did not report their physical activity at work, e.g. due to

retirement)

Characteristic

Low,

32 391

Men

Age (years)

Physical activity in leisure time

Low

Moderate

High

Very high

Non-responders

Education

<Middle school

Middle school

High school

University

Years in school

Household income

Low

Moderate

High

Longest employment since school

Self-employed

Skilled worker

Unskilled worker

Ofﬁce worker

Housewife

Unemployed or senior citizen

Cohabitation

Living with spouse/cohabitant

Living alone

Living with others

Marital status

Married/cohabiting

Unmarried

Separated/divorced

Widow/widower

Smoking

Never smoker

Former smoker

Current smoker

Body mass index (kg/m )

<18.5

18.5–29.9

_30

Adherence to dietary guidelines

Very high

High

Intermediate

Low

Very low

Physical activity at work

P-value

Very high,

2562

2370 (93)

51 ± 11

242 (9)

911 (36)

1043 (41)

345 (13)

21 (1)

<0.0001

353 (14)

1752 (68)

432 (17)

21 (1)

9.5 ± 1.6

152 (6)

1599 (63)

783 (31)

<0.0001

449 (18)

1281 (50)

549 (22)

254 (10)

2 (0)

10 (0)

<0.0001

2013 (79)

468 (18)

79 (3)

<0.0001

1963 (77)

327 (13)

227 (9)

36 (1)

<0.0001

776 (31)

845 (34)

848 (34)

<0.0001

9 (0)

1924 (75)

626 (24)

<0.0001

40 (2)

179 (8)

1090 (48)

385 (17)

565 (25)

Continued

<0.0001

........................................................................................................................

Moderate,

25 032

8708 (35)

54 ± 11

1401 (6)

11 418 (46)

10 747 (43)

1346 (5)

120 (0)

1140 (5)

8987 (36)

10 834 (43)

4008 (16)

11.1 ± 1.7

1690 (7)

9994 (40)

13 040 (53)

2359 (9)

4467 (18)

1431 (6)

15 708 (63)

743 (3)

182 (1)

19 683 (79)

4485 (18)

843 (3)

19 573 (78)

1890 (8)

2435 (10)

1082 (4)

10 282 (43)

9579 (40)

4146 (17)

250 (1)

21 124 (85)

3609 (14)

2618 (11)

4309 (19)

12 658 (55)

1778 (8)

1737 (8)

High,

14 580

5599 (38)

51 ± 11

839 (6)

6156 (42)

6525 (45)

988 (7)

72 (0)

956 (7)

7195 (49)

5715 (39)

682 (5)

10.5 ± 1.8

944 (7)

8090 (56)

5379 (37)

1275 (9)

5903 (41)

2382 (16)

4624 (32)

223 (2)

91 (1)

11 017 (76)

2895 (20)

652 (4)

10 880 (75)

1706 (12)

1569 (11)

403 (3)

5336 (38)

5217 (37)

3460 (25)

125 (1)

12 022 (83)

2408 (17)

1184 (9)

1988 (15)

7095 (53)

1394 (11)

1613 (12)

16 692 (52)

51 ± 10

2502 (8)

12 404 (38)

14 792 (46)

2596 (8)

97 (0)

434 (1)

7786 (24)

13 153 (41)

10 947 (34)

11.6 ± 1.4

977 (3)

8529 (27)

22 675 (70)

2601 (8)

1829 (6)

659 (2)

26 773 (83)

122 (0)

190 (1)

26 380 (82)

4989 (15)

998 (3)

26 221 (81)

2626 (8)

2797 (9)

696 (2)

14 561 (47)

11 931 (39)

4196 (14)

236 (1)

27 760 (86)

4343 (13)

2899 (9)

5470 (18)

17 618 (58)

2466 (8)

2072 (7)

Physical activity in cardiovascular disease and all-cause mortality

Table 2

Continued

Physical activity at work

P-value

Very high,

2562

<0.0001

1869 (6)

24 598 (78)

4871 (16)

650 (2)

133 ± 19

3181 (11)

25 929 (90)

1874 (6)

936 (3)

79 (0)

18 (0)

1.1 ± 1.3

69 ± 12

1.56 ± 0.49

3.24 ± 0.92

1.6 ± 1.1

1886 (8)

18 081 (75)

4017 (17)

663 (3)

135 ± 20

3288 (14)

19 720 (87)

1756 (8)

956 (4)

108 (0)

12 (0)

1.1 ± 1.3

72 ± 12

1.65 ± 0.51

3.28 ± 0.94

1.6 ± 1.1

1560 (11)

10 074 (74)

2025 (15)

336 (2)

134 ± 20

1436 (11)

11 711 (88)

962 (7)

609 (5)

58 (0)

5 (0)

1.2 ± 1.3

73 ± 12

1.60 ± 0.50

3.23 ± 0.93

1.6 ± 1.1

203 (8)

1651 (67)

609 (25)

80 (3)

139 ± 19

283 (12)

2076 (87)

169 (7)

129 (5)

14 (1)

1 (0)

1.2 ± 1.3

73 ± 12

1.43 ± 0.46

3.34 ± 0.94

2.0 ± 1.8

<0.0001

Characteristic

Low,

32 391

Alcohol intake (women/men)

Non-drinker

1–14/1–21 drinks/week

>14/>21 drinks/week

Diabetes

Systolic blood pressure (mmHg)

Blood pressure medication

COPD

No COPD

GOLD stage 1

GOLD stage 2

GOLD stage 3

GOLD stage 4

Vital exhaustion score

Resting heart rate (bpm)

HDL cholesterol (mmol/L)

LDL cholesterol (mmol/L)

Triglycerides (mmol/L)

........................................................................................................................

Moderate,

25 032

High,

14 580

Data are

(%) or mean ± SD.

COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

occupational physical activity were 1.04 (0.95–1.14), 1.15 (1.04–

1.28), and 1.35 (1.14–1.59), respectively (Figure

model B). For all-

cause mortality, corresponding hazard ratios for higher leisure time

physical activity were 0.74 (0.68–0.81), 0.59 (0.54–0.64), and 0.60

(0.52–0.69), and for higher occupational physical activity 1.06 (0.96–

1.16), 1.13 (1.01–1.27), and 1.27 (1.05–1.54), respectively. The sensi-

tivity analyses with adjustments for a range of additional potential

confounders (Figure

model C) found similar associations for both

leisure time and occupational physical activity with risk of MACE and

all-cause mortality.

Figure

illustrates the interplay between four leisure time physical

activity categories and four occupational physical activity categories

in the multivariable model with adjustment for lifestyle, health, living

conditions, and socioeconomic factors with the common reference

category (i.e. high leisure time physical activity and low occupational

physical activity) with the lowest risks of MACE and all-cause mortal-

ity. There was no evidence of interaction between leisure time and

occupational physical activity on risk of MACE (P = 0.40) or all-cause

mortality (P = 0.31), implying that risk of both endpoints increased

with higher occupational physical activity and with lower leisure time

physical activity, independent of the level of each other. Accordingly,

we found a general tendency of a higher risk for both outcomes with

higher levels of occupational physical activity across the levels of leis-

ure time physical activity. For the low and moderate levels of occupa-

tional physical activity, higher levels of leisure time physical activity

were clearly associated with lower risk for both outcomes. For the

high and very high levels of occupational physical activity, less clear

associations for both outcomes with higher levels of leisure time

physical activity were seen. However, the statistical power in these

groups was modest due to relatively low number of individuals and

events.

Figures

and

show multivariable adjusted hazard ratios per

one level higher leisure time or occupational physical activity on

risk of MACE and all-cause mortality, overall and after stratification

into 20 lifestyle, health, living condition, and socioeconomic fac-

tors. Consistent reduced and increased hazard ratios for higher

levels of leisure time and occupational physical activity, respective-

ly, were observed in strata of all covariates; there was no convinc-

ing evidence of interaction between leisure time or occupational

physical activity and the 20 lifestyle, health, living condition, and

socioeconomic factors on risk of MACE or all-cause mortality,

which implies that the overall findings did not differ in the different

strata (Figures

and

*P > 0.05 after correction for 4

20 mul-

tiple comparison according to the Bonferroni method; required

< 0.05/40 or

< 0.001).

Figure

shows the associations between leisure time physical activ-

ity and occupational physical activity with the outcomes MACE and

all-cause mortality, respectively, adjusted for age, sex, smoking, BMI,

years in school, dietary preferences, alcohol consumption, COPD by

GOLD stage, systolic blood pressure, blood pressure medication,

diabetes, LDL cholesterol, HDL cholesterol, and triglycerides in mod-

els with the start of follow-up 1, 3, and 5 years after baseline. The

results are in line with estimates reported in the main statistical

model presented in

Figure

A. Holtermann

et al.

Figure 1

Associations of leisure time physical activity and occupational physical activity with risk of major adverse cardiovascular events and all-

cause mortality. Cox regression models were adjusted for: model A, age and sex; model B, model A

body mass index, smoking, years in school, dia-

betes, systolic blood pressure, blood pressure medication, dietary preferences, alcohol consumption, chronic obstructive pulmonary disease by

Global Initiative for Chronic Obstructive Lung Disease stage, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycer-

ides; and an extended multivariable sensitivity model C, model B

resting heart rate, vital exhaustion score, occupation, cohabitation, marital status,

and household income. The analyses were based on individuals from the Copenhagen General Population Study with a median follow-up of 10 years.

CI, confidence interval. *P < 0.05, **P < 0.01, ***P < 0.001.

Discussion

In 104 046 individuals from the Copenhagen General Population

Study with 7913 MACE and 9846 deaths during 10 years of follow-

up, we observed that higher leisure time physical activity was associ-

ated with reduced risk of MACE and all-cause mortality while higher

occupational physical activity was associated with increased risks, in-

dependent of each other. The novel demonstration of the independ-

ent association of the two domains of physical activity with risk of

MACE and all-cause mortality supports the physical activity paradox.

Mechanistically, leisure time physical activity is generally shown to

cause improved cardiorespiratory and metabolic fitness and health,

while the characteristics of occupational physical activity are predom-

inantly associated with fatigue, insufficient recovery, elevated 24-h

blood pressure, and heart rate without improvements in cardio-

respiratory fitness and health.

For example, a recent study found

leisure time physical activity to be beneficially associated with the sys-

temic inflammation marker high-sensitivity C-reactive protein, but

occupational physical activity to be associated with detrimental lev-

els.

The physical activity paradox is suggested to be explained by

the different characteristics of physical activity during work and

leisure time, where leisure time physical activity primarily comprises

dynamic activities of higher intensity and shorter durations, while oc-

cupational physical activity is composed of more static and con-

strained activities of lower intensity and long durations.

Further

investigation of the association between occupational physical activity

and health was recently encouraged by the World Health

Organization (WHO) guidelines on physical activity and sedentary

behaviour to improve our understanding and evidence based on the

potential domain-specific effects of physical activity on health.

2,23

We found beneficial dose–response associations for MACE and

all-cause mortality with higher levels of leisure time physical activity

in the fully adjusted models. This finding of a strong beneficial associ-

ation of MACE and all-cause mortality with high leisure time physical

activity is in accordance with many previous studies

1,2

and supports

the importance of high leisure time physical activity for preventing

MACE and premature mortality. In contrast, we observed a harmful

association for MACE and all-cause mortality with higher levels of oc-

cupational physical activity in the model adjusted for lifestyle, health,

living conditions, and socioeconomic factors (Figure

model B). This

finding remained in the model with adjustments for additional poten-

tial lifestyle, health, living condition, and socioeconomic confounders

Physical activity in cardiovascular disease and all-cause mortality

Hazard ratio for MACE

Major adverse cardiovascular events

1.8

Hazard ratio for all-cause death

3.5

3.0

2.5

2.0

1.5

1.0

All-cause mortality

1.6

1.4

1.2

Very high

High

Moderate

Low

1.0

ysi

at l ac t

wo ivit

Low

Moderate

Very high

Physica

l activity

in leisur

e time

Test for interaction: P=0.40

High

Moderate

Very high

Physica

l activity

in leisur

e time

Test for interaction: P=0.31

Hazard ra o (95% conﬁdence interval) for all-cause mortality

Physical

ac vity

at work

Very high

High

Moderate

Low

Physical ac vity in leisure me

Low

3.34 (1.81-6.17)

2.54 (1.56-4.13)

2.11 (1.34-3.32)

2.23 (1.46-3.41)

Moderate

1.97 (1.22-3.18)

1.85 (1.23-2.78)

1.71 (1.15-2.54)

High

1.46 (0.89-2.40)

1.47 (0.98-2.23)

1.50 (1.00-2.24)

1.29 (0.86-1.93)

High

Very high

High

Moderate

Low

Hazard ra o (95% conﬁdence interval) for major adverse cardiovascular events

Physical

Physical ac vity in leisure me

ac vity at

Low

Moderate

High

Very high

work

Very high

1.76 (1.01-3.07) 1.35 (0.94-1.96) 1.54 (1.08-2.19) 1.80 (1.11-2.92)

High

1.26 (0.83-1.92) 1.33 (1.00-1.77) 1.22 (0.91-1.62) 1.62 (1.09-2.40)

Moderate

1.52 (1.07-2.15) 1.25 (0.95-1.65) 1.04 (0.78-1.37) 1.05 (0.69-1.60)

Low

1.37 (0.99-1.87) 1.16 (0.88-1.52) 1.06 (0.81-1.40) 1.00 (reference)

Number of individuals/major adverse cardiovascular events

Physical

ac vity at

work

Very high

High

Moderate

Low

Physical ac vity in leisure me

Low

171/16

578/36

998/74

1830/117

Moderate

687/56

4528/269

8619/571

9422/468

High

785/67

4884/252

8082/351

11113/410

Very high

254/23

704/44

958/35

1905/58

Very high

2.53 (1.42-4.51)

1.69 (0.99-2.87)

1.30 (0.74-2.26)

1.00 (reference)

Number of individuals/all-cause deaths

Physical

ac vity at

work

Very high

High

Moderate

Low

Physical ac vity in leisure me

Low

171/17

578/45

998/67

1830/127

Moderate

687/47

4528/231

8619/544

9422/418

High

785/39

4884/190

8082/318

11113/257

Very high

254/21

704/29

958/24

1905/26

Figure 2

Interplay between four leisure time physical activity categories and four occupational physical activity categories on risk of (A) major ad-

verse cardiovascular events and (B) all-cause mortality. Cox regression models were adjusted for age, sex, body mass index, smoking, years in school,

diabetes, systolic blood pressure, blood pressure medication, dietary preferences, alcohol consumption, chronic obstructive pulmonary disease by

Global Initiative for Chronic Obstructive Lung Disease stage, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycer-

ides. The common reference category (i.e. high leisure time physical activity and low occupational physical activity) had the lowest risk of major ad-

verse cardiovascular events and all-cause mortality. The analyses were based on individuals from the Copenhagen General Population Study with a

median follow-up of 10 years.

(Figure

model C), and across groups of individuals with different

lifestyle, health, living condition, and socioeconomic factors (Figures

and

4),

as well as when excluding individuals dying within the first

5 years of follow-up (Figure

5).

Our finding of harmful associations of

higher levels of occupational physical activity with increased risk of

MACE and all-cause mortality is in line with recent prospective stud-

ies.

3–5

A recent systematic review found that men, but not women,

with high occupational physical activity had 18% increased risk of all-

cause mortality.

However, as shown by a recent umbrella review,

no consistent association between occupational physical activity and

various health outcomes was found.

Thus, there is a need for better

quality evidence to provide a unequivocal statement on the health

effects of occupational physical activity.

Our study meets this need.

The main criticism to previous studies finding an increased risk for

cardiovascular morbidity and all-cause mortality associated with high

occupational physical activity has been the potential risk for insuffi-

cient adjustment for confounding factors, such as socioeconomic

class.

To meet these limitations, we did a sensitivity analyses with

adjustments for a long list of potential confounding factors in the as-

sociation between physical activity and health, such as age, sex, BMI,

smoking, years in school, diabetes, systolic blood pressure, blood

pressure medicine, dietary preferences, alcohol intake, LDL choles-

terol, HDL cholesterol, triglycerides, resting heart rate, vital exhaus-

tion score, COPD by GOLD stage, occupation, cohabitation, marital

status, and household income. This did not change the main finding.

Moreover, we found consistent decreased risk associated with higher

levels of leisure time physical activity and increased risk associated

with higher levels of occupational physical activity across strata of 20

potential lifestyle, health, living condition, and socioeconomic con-

founders. For both leisure time physical activity and occupational

physical activity, we found no convincing evidence of interaction with

the 20 lifestyle, health, living conditions, and socioeconomic factors

and the health outcomes on risk of MACE and all-cause mortality,

indicating that the overall findings did not differ across subgroups.

Furthermore, the risk estimates remained similar when excluding

participants dying within 1, 3, and 5 years of follow-up, suggesting no

ysi

at l act

wo ivit

A. Holtermann

et al.

Per 1 level higher

PA at work

Per 1 level higher

PA at work

Figure 3

Association of one level higher leisure time physical activity (A) or occupational physical activity (B) with risk of major adverse cardiovas-

cular events overall and after stratification on 20 lifestyle, health, living condition, and socioeconomic factors. Cox regression models adjusted for

age, sex, smoking, body mass index, years in school, dietary preferences, alcohol, chronic obstructive pulmonary disease by Global Initiative for

Chronic Obstructive Lung Disease stage, systolic blood pressure, blood pressure medication, diabetes, low-density lipoprotein cholesterol, high-

density lipoprotein cholesterol, triglycerides, and physical activity at work or physical activity in leisure time. *P > 0.05 after correction for 2

(Figure

multiple comparison according to the Bonferroni method (required

< 0.05/40 or

< 0.001). The analyses were based on individuals from

the Copenhagen General Population Study with a median follow-up of 10 years. CI, confidence interval.

major influence of reverse causation on our results (Figure

5).

However, we acknowledge that reverse causation can always be an

issue in observational studies. These findings support that the physical

activity paradox is not just a matter of insufficient adjustments for

confounding factors or reverse causation.

Moreover, the analyses of the interplay between four leisure time

physical activity categories and four occupational physical activity cat-

egories (Figure

showed that the group with the combination of

high leisure time physical activity and low occupational physical activ-

ity had the lowest risk of MACE and all-cause mortality. Importantly,

we found no evidence of interaction between leisure time and occu-

pational physical activity on risk of MACE (P = 0.40) or all-cause mor-

tality (P = 0.31). This result implies that the risk of both endpoints

increased with higher occupational physical activity and with lower

leisure time physical activity, independent of the level of each other.

The previous studies investigating the interplay between occupational

Physical activity in cardiovascular disease and all-cause mortality

Per 1 level higher

PA at work

Per 1 level higher

PA at work

Figure 4

Association of one level higher leisure time physical activity (A) or occupational physical activity (B) with risk of all-cause mortality, overall

and after stratification on 20 lifestyle, health, living condition, and socioeconomic factors. Cox regression models adjusted for age, sex, smoking, body

mass index, years in school, dietary preferences, alcohol, chronic obstructive pulmonary disease by Global Initiative for Chronic Obstructive Lung

Disease stage, systolic blood pressure, blood pressure medication, diabetes, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol,

triglycerides, and physical activity at work. *P > 0.05 after correction for 2

40 (Figure

multiple comparison according to the Bonferroni method

(required

< 0.05/40 or

< 0.001). The analyses were based on individuals from the Copenhagen General Population Study with a median follow-

up of 10 years. CI, confidence interval.

and leisure time physical activity on cardiovascular disease and mor-

tality are relatively few, had lower statistical power than the present

study and reported varying findings.

8,25,26

Thus, to help establish rec-

ommendations on leisure time physical activity particularly among

adults with high levels of occupational physical activity, we need

further research on the potential independent association of leisure

time and occupational physical activity with risk of cardiovascular dis-

ease and all-cause mortality.

Work constitutes the main domain for physical activity for a large

fraction of the adult population worldwide.

15,16

We are not aware of

A. Holtermann

et al.

Figure 5

Associations of leisure time physical activity and occupational physical activity with risk of major adverse cardiovascular events and all-

cause mortality with start of follow-up 1, 3, and 5 years after baseline, respectively. Cox regression models were adjusted for age, sex, body mass

index, smoking, years in school, diabetes, systolic blood pressure, blood pressure medication, dietary preferences, alcohol consumption, chronic ob-

structive pulmonary disease by Global Initiative for Chronic Obstructive Lung Disease stage, low-density lipoprotein cholesterol, high-density lipo-

protein cholesterol, and triglycerides. The analyses were based on individuals from the Copenhagen General Population Study with a median follow-

up of 10 years. CI, confidence interval. *P < 0.05, **P < 0.01, ***P < 0.001.

any international or national physical activity guidelines differentiating

on occupational physical activity and leisure time physical activity.

1,2

the physical activity paradox holds true, this can contribute to the

understanding and interventions on the generally poor health of indi-

viduals with high occupational physical activity. Thus, we applaud the

recent WHO guidelines for physical activity and sedentary behaviour

to take the physical activity paradox into consideration and request

further research on the domain of physical activity on health.

Strengths and limitations

A methodological strength of this study is the large general popula-

tion study permitting sufficient statistical power to investigate associ-

ations of both occupational physical activity and leisure time physical

activity with MACE and all-cause mortality using multivariable

adjusted models. Moreover, the possibility to perform subgroup anal-

yses is a methodological strength for further investigation of potential

confounding. A methodological limitation of this study is that infor-

mation of both leisure time physical activity and occupational physical

activity is based on self-assessment, which may entail some degree of

misclassification. The questions used for measuring both leisure time

physical activity and occupational physical activity have been used for

decades in several cohorts, and because they are very similar in con-

tent and wording, the questions cannot explain the different charac-

teristics of physical activity at work and leisure time being the

potential underlying reason to the contrasting associations of leisure

time physical activity and occupational physical activity with risk of

MACE and all-cause mortality in the present study. It is also a limita-

tion that the participation rate in our study was 43%, which is lower

than in many cohorts examined 30–40 years ago; however, this is a

general tendency in contemporary cohort studies globally, likely due

to the higher number of requests to participate in surveys and other

studies today compared to 30–40 years ago.

The group with sedentary work could theoretically be expected

to have an increased risk for cardiovascular disease and all-cause

mortality. However, we found this group to have the lowest risk.

Our observation is in line with previous studies showing that it is par-

ticularly sitting during leisure time (particularly TV viewing) that is

associated with increased cardiovascular disease and all-cause mor-

tality risk, and that occupational sitting is not associated with a similar

increased risk.

27,28

This can likely be explained by a different time-

pattern and behaviour of sitting during work and leisure,

where for

example abruption during sitting is more likely to occur at work (e.g.

regular breaks, walk to meeting/printer) than during leisure time. As

our findings represent observational associations, it is not possible to

infer causality from our data. The study sample was from the general

population of Whites of Danish descent from the greater

Copenhagen area in Denmark including both high- and low-income

areas and might thus not be generalizable to all other countries in

Europe and elsewhere. Because the working conditions (i.e. the

prevalence of high occupational physical activity such as heavy lifting

at work), living environment, and lifestyle in Denmark are generally

more advanced than in some Southern and Eastern European

Physical activity in cardiovascular disease and all-cause mortality

countries,

the observed harmful health associations from occupa-

tional physical activity can potentially be even stronger in these coun-

tries than observed in the present study. The results might therefore

not be directly generalizable to all other countries, and we recom-

mend researchers to perform studies on the physical activity paradox

in particularly low-income and less-privileged populations.

Conclusion

Higher leisure time physical activity is associated with reduced risk of

MACE and all-cause mortality while higher occupational physical ac-

tivity is associated with increased risks, independent of each other.

The novel demonstration of the independent association of the two

types of physical activity on risk of MACE and all-cause mortality

supports the physical activity paradox. These findings may be consid-

ered by those writing guidelines on cardiovascular disease prevention

in relation to physical activity.

Supplementary material

is available at

European Heart Journal

online.

Funding

This work was supported by the Capital Region of Copenhagen, The

Danish Heart Foundation, The Danish Lung Association, Velux

Foundation, and Lundbeck Foundation.

Data availability

The Danish Data protection Agency does not allow open access to

our data; however, upon reasonable request the steering committee

of the Copenhagen General Population Study may allow further fol-

low-up analyses.

Conflict of interest:

The authors declare to have no conflict of

interest.

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