Confidential: For Review Only - BMJ · Confidential: For Review Only Exercise capacity and muscle strength and risk of vascular ... death) and arrhythmias in total and in subgroups

Confidential: For Review O

nly

Exercise capacity and muscle strength and risk of vascular

disease and arrhythmias: A cohort study of 1.1 million young men

Journal: BMJ

Manuscript ID: BMJ.2015.025407

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 12-Feb-2015

Complete List of Authors: Andersen, Kasper; Uppsala University, Department of Medical Sciences Rasmussen, Finn; Karolinska Institutet, Public Health Held, Claes; Uppsala University, Uppsala Clinical Research Center Neovius, Martin; Karolinska Institutet, Department of Medicine Tynelius, Per; Karolinska Institutet, Public Health Sundström, Johan; Uppsala University, Department of Medical Sciences

Keywords: Arrhythmias, Vascular Disease, Exercise Capacity, Muscle Strength, Epidemiology, Cohort Study

https://mc.manuscriptcentral.com/bmj

BMJ


nlyExercise capacity and muscle strength

and risk of vascular disease and

arrhythmias: A cohort study of 1.1 million

young men

Kasper Andersen (KA), PhD1

Finn Rasmussen (FR), PhD3

Claes Held (CH), PhD1

Martin Neovius (MN), PhD2

Per Tynelius (PT), MSc3

Johan Sundström (JS), PhD1

1Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala,

Sweden

2Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden

3Child and Adolescent Public Health Epidemiology Unit, Department of Public Health Sciences,

Karolinska Institutet, Stockholm, Sweden

Corresponding author:

Kasper Andersen, MD PhD

Department of Medical Sciences

Entrance 40, 5th floor

Uppsala University Hospital

SE-751 85 Uppsala, Sweden

Cell: +46 7 61680671

Fax: +46 18 509297

[email protected]

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nlyAbstract

Objective: To investigate associations of exercise capacity and muscle strength to risk of vascular

disease and arrhythmias.

Design: Cohort study

Setting: General population

Participants: 1.1 million Swedish men who participated in mandatory military conscription between

1972 and 1995 at a median age of 18.2 years.

Main Outcomes: Associations between exercise capacity and muscle strength to risk of vascular

disease in total and in subgroups (ischemic heart disease, heart failure, stroke and cardiovascular

death) and arrhythmias in total and in subgroups (atrial fibrillation/flutter, bradyarrhythmias, supra

ventricular tachycardias and ventricular arrhythmias/sudden cardiac death)

Results: During a median follow-up of 26.3 years, 26,088 vascular disease events and 17,312

arrhythmia events occurred. Exercise capacity was inversely associated with risk of vascular disease

and subgroups (ischemic heart disease, heart failure, stroke and cardiovascular death). Also muscle

strength was inversely associated with vascular disease risk, driven by associations of higher muscle

strength with lower risk of heart failure and cardiovascular death. Exercise capacity was associated

with risk of arrhythmias in a U-shaped fashion, driven by a direct association with risk of atrial

fibrillation and a U-shaped association with bradyarrhythmias. Higher muscle strength was

associated with lower risk of arrhythmias, specifically lower risk of bradyarrhythmias and ventricular

arrhythmias. The combination of high exercise capacity/high muscle strength was associated with a

hazard ratio (HR) of 0.67 (95% confidence interval 0.65-0.70) for vascular events and 0.92 (0.88-0.97)

for arrhythmias compared to the combination of low exercise capacity/low muscle strength.

Conclusions: Exercise capacity and muscle strength in late adolescence are independently and jointly

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nlyassociated with long-term risk of vascular disease and arrhythmias. The health-benefit of lower risk

of vascular events with higher exercise capacity was not outweighed by higher risk of arrhythmias.

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nlyCopyright Statement

“The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of

all authors, a worldwide license to the Publishers and its licensees in perpetuity, in all forms, formats

and media (whether known now or created in the future), to i) publish, reproduce, distribute, display

and store the Contribution, ii) translate the Contribution into other languages, create adaptations,

reprints, include within collections and create summaries, extracts and/or, abstracts of the

Contribution, iii) create any other derivative work(s) based on the Contribution, iv) to exploit all

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party material where-ever it may be located; and, vi) licence any third party to do any or all of the

above.”

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nlyIntroduction

Although prevention and treatment of cardiovascular diseases have improved for decades, their

share as causes of death is increasing due to the increased longevity globally.[1] The incidence of

arrhythmias increases with age, and increased longevity has increased also the burden of these

diseases.[2]

While physical activity and high exercise capacity prevents vascular disease,[3-6] strenuous exercise

may induce life-threatening ventricular arrhythmias in athletes with pre-existing heart disease.[7]

Further, an increased risk of atrial fibrillation and bradyarrhythmias has been observed in athletes.[8-

12] Several lines of evidence point towards a causal role of exercise for the development of

arrhythmias, including substrate, modulator, and trigger mechanisms.[8] It is unknown if different

modes of training, for example endurance-type and strength-type training, differ in their potential

for causing arrhythmias, or their preventive effect on vascular disease.

We hypothesized that exercise capacity and muscle strength are each directly related to the risk of

subsequent arrhythmias and inversely related to the risk of subsequent vascular disease. Many

previous studies of such associations have been conducted in middle-aged or elderly people, with a

high risk of bias due to reverse causality. In order to minimize such bias, we investigated these

associations in a prospective cohort of 1.1 million Swedish young men examined at mandatory

military conscription in 1972-1995.

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nlyMethods

Sample

This study used data from all Swedish males who underwent conscription between August 1st

1972

and December 31st

1995. During that period, military conscription for men was mandatory in

Sweden, and only a small fraction (2-3%) did not undergo conscription (mainly because of severe

disease or handicap). The conscriptions were performed in a standardized fashion, and a total of

1,257,032 men were enrolled in the cohort. The conscripts had a median age of 18.2 years (10th

percentile 17.8; 90th

percentile 18.9). We excluded 17,316 men with a history of prior vascular

disease (ICD 10 code I.00-99 or similar ICD-8/ICD-9 code). Men without data on any of the variables

exercise capacity, muscle strength, weight, height, systolic or diastolic blood pressure were excluded

from the analyses (n=64,395; 0,5%). Further, all observations with missing data on the key variables

maximal exercise capacity (n=31,482), muscle strength (5,206), and conscription date (11,734) were

excluded (total n=48,422; 0,4%). Since the number of observations with any missing data after this

procedure was only 1.2% and assumed to be mainly due to administrative reasons, we decided to

limit all analyses to observations with complete data. This rendered a sample of 1,126,899 individuals

available for analysis.

Baseline examinations

The available protocol from 2001 is similar to the examination years during the study period.

Maximal exercise capacity was estimated by use of an ergometer bicycle test. After 5 min of

submaximal bicycling at 60-70 rpm, the load was gradually increased by 25W per min and the

conscript continued to bicycle to exhaustion. If the conscript did not obtain a maximal heart rate

>180 bpm, the instructor decided if the conscript should be re-tested. We found a minor shift in the

distribution of maximal exercise capacity in August 1984 (probably due to a minor change of

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nlyexamination protocol) and the observations in groups before and after August 1984 were

standardized to the whole sample mean and standard deviation. Of the available measures of muscle

strength, we used handgrip strength measured by a hand dynamometer, which has shown good

correlation with lean body mass[13-15], has previously been investigated in relation to risk of

cardiovascular disease,[16] and is the strength measure least correlated with body weight in this

cohort. Height and weight were measured, and after five to ten minutes of rest, supine systolic and

diastolic blood pressure was measured.

Follow-up and outcome parameters

Using the unique Swedish national registration number, we linked the Military Service Conscription

Register to the Swedish National Patient Register, the Swedish Causes of Death Register and the

Statistics Sweden registers of emigration and education level. All registers cover the whole

population. Participants were followed until December 31st

2010 and were considered at risk until

the first of 1) the outcome under study, 2) death, 3) emigration, or 4) end of follow-up.

Using the registries, we defined two primary outcomes: Vascular disease (all ICD-codes mentioned in

subgroup outcomes) and arrhythmia (all ICD-codes mentioned in subgroup outcomes, plus ICD 10

I47.9). For vascular disease the subgroup outcomes were 1) ischemic heart disease (ICD-10: I20.0-

I25.9), 2) heart failure (ICD-10: I11.0; I50.0-I50.9), 3) stroke (ICD-10: I60.0-I60.9, I61.0-I61.9; I63.0-

I63.9; I64.0-I64.9) and 4) cardiovascular death (ICD-10: I00-I99). For arrhythmias, the subgroup

outcomes were 1) atrial fibrillation/flutter (ICD-10: I48.9), 2) bradyarrhythmias (ICD-10 I44.1; I44.2;

I45.2; I45.3; I45.9; I49.5), 3) supraventricular arrhythmias (I45.6; I47.1) and 4) ventricular

arrhythmias/sudden cardiac death (I46.0; I46.1, I46.9; I47.0; I47.2; I49.0; R96.0). Corresponding

codes for ICD-9 and ICD-8 were used. For a complete list of ICD-codes, see Supplementary Document

1.

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nlyStatistical analyses

We used Cox proportional hazards models to examine the associations of the exposures muscle

strength and exercise capacity with risk of arrhythmias or vascular disease; each outcome in a

separate model. We assessed the proportional hazards assumptions for all outcomes by inspecting

Nelson-Aalen plots.

Using directed acyclic graphs (Supplementary Figure 1), two models were identified to evaluate total

and direct effects: A) Total effect: Adjusted for age, conscription date, region, education level, height

and muscle strength/exercise capacity (muscle strength adjusted for exercise capacity, and vice

versa) B) Direct effect: As model A, additionally adjusted for systolic and diastolic blood pressure,

weight and ischemic heart disease (the latter for arrhythmia outcomes only).

In order to assess the nature of the associations, we used multivariable regression spline models (a

piecewise fitting of polynomial equations) with up to four degrees of freedom allowed for the

exposure variable, body weight and height (and one degree of freedom for the other covariates).

Knots were placed at the 25th, 50th and 75th centiles. We investigated interactions between the two

main exposures, and between them and the continuous baseline variables using the general

multivariable fractional interaction approach.[17] We investigated interactions between the main

exposures and categorical covariates using multiplicative factors and likelihood ratio tests. After

inspection of all the statistically significant interactions (Supplementary Figures 2,3 and 4), these

were regarded as clinically irrelevant and produced by the large sample size. In addition to these

interaction analyses, we described joint effects of exercise capacity and muscle strength by

constructing a four-group variable with combinations of maximal exercise capacity and muscle

strength dichotomized by the median.

In order to describe the incidence of outcomes in absolute terms, we also analysed risk of outcomes

by fifths of exposures. Stata 13 (StataCorp LP, USA) was used for all calculations, and two-tailed 95%

confidence intervals (CI) were used.

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nlyResults

The participants were followed until a median age of 44.6 years (median time at risk 26.3 years). This

resulted in 29.8 million person-years at risk. During follow-up in total 33,089 persons died. Baseline

characteristics are shown in Table 1.

Vascular disease

During follow-up, we identified 26,088 hospitalizations for vascular disease (ischemic heart disease:

12,188; heart failure: 3,949; stroke: 7,350; cardiovascular death: 5,873; a person could contribute to

more than one subgroup endpoint). Cumulative incidence of vascular disease is shown in Figure 1.

We observed an inverse association of exercise capacity with risk of vascular disease, with a more

pronounced association after adjusting for blood pressure and weight (Figure 2, Supplementary

Table 1 and Supplementary Figure 5). The association was of similar strength with all of the subgroup

endpoints; ischemic heart disease, heart failure, stroke and cardiovascular death (Figure 3,

Supplementary Table 2 and Supplementary Figure 5).

Similarly, we found an inverse association of muscle strength with the risk of vascular disease,

although of smaller magnitude than that of exercise capacity (Figure 2). Again, associations were

more pronounced in models adjusting for blood pressure and weight than in those without these

covariates (Supplementary table 1 and 2 and Supplementary Figure 5). The associations with

cardiovascular death and heart failure were stronger than those with stroke and ischemic heart

disease (Figure 3 and Supplementary Table 1).

There was no evidence of a deviation from a multiplicative effect of exercise capacity and muscle

strength; their joint effects are shown in Figure 1 and Table 2. The combination of high exercise

capacity/high muscle strength was associated with a 33% lower risk of vascular events than the

combination of low exercise capacity/low muscle strength (Table 2).

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nlyArrhythmias

During follow-up, we identified 17,312 arrhythmia events (atrial fibrillation/flutter: 9,668;

bradyarrhythmias 1,384; supraventricular tachycardias: 3,278; ventricular arrhythmias/sudden

cardiac deaths 1,630; unspecified arrhythmias 1,352). Cumulative incidence of arrhythmias is shown

in Figure 1, which indicates that arrhythmias on average occurred at a younger age than vascular

disease events. We found a U-shaped association of exercise capacity with risk of arrhythmias. The

association was similar after additionally adjusting for blood pressure, weight and ischemic heart

disease (Figure 2, Supplementary Table 1 and Supplementary Figure 6). This pattern was driven by an

association of higher exercise capacity with higher risk of atrial fibrillation/flutter and a U-shaped

association with bradyarrhythmias (Figure 4 and Supplementary Table 3). No associations of exercise

capacity with supraventricular arrhythmias or ventricular arrhythmias/sudden cardiac deaths were

found (Figure 4 and Supplementary Table 3).

Higher muscle strength was associated with lower risk of arrhythmias. This association was more

pronounced after adjusting for weight, blood pressure and ischemic heart disease (Supplementary

table 1 and 3 and Supplementary Figure 6). The main associations were of higher muscle strength

with lower risk of bradyarrhythmia and ventricular arrhythmias/cardiac arrest (Figure 4 and

Supplementary Table 2). No associations of muscle strength with atrial fibrillation/flutter or

supraventricular arrhythmias were found.

There was no evidence of a deviation from a multiplicative effect of exercise capacity and muscle

strength; their joint effects are shown in Table 2. The combination of high exercise capacity/high

muscle strength was associated with an 8% lower risk of arrhythmias than the combination of low

exercise capacity/low muscle strength (Table 2).

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nlyDiscussion

In this cohort of 1.1 million men, we observed inverse independent associations of exercise capacity

and muscle strength in late adolescence with risk of subsequent vascular disease. Additionally, there

was a U-shaped association of exercise capacity with arrhythmias. The joint associations of high

exercise capacity/high muscle strength compared to low exercise capacity/low muscle strength with

lower risk of vascular disease were pronounced, while weak joint associations with risk of

arrhythmias were observed.

The most obvious strength of this study is the very large number of participants almost including the

whole Swedish male population during 25 years. Further, the cohort is unique by including directly

measured exercise capacity and muscle strength in a very large population. By use of the unique

national registration number and the population-based registers, the loss of follow-up is limited to

emigrated persons. We only used National Patient Register data on hospitalisations, and the

accuracy of those diagnoses is good.[18] The low age of the participants at inclusion minimizes the

risk of reverse causation by pre-existing cardiac disease, but on the other hand limits the follow-up to

early events. Some limitations of the study are worth noting. Exercise capacity and muscle strength

were only measured at the time of conscription, and the applicability of those measures to exposures

before and after the conscription are uncertain; any changes in those measures would tend to bias

findings towards the null. It is possible that other factors linked to the exposure (e.g. genetic factors

or exercise factors in childhood) rather than the amount of exercise in later life is contributing to the

associations. Of note, studies suggest that physically active children also are more active as

adults[19] and changes in level of physical activity later in life affect risk of cardiovascular events.[20

21] Another issue is that both exercise capacity and muscle strength were related to body height and

weight. Very few were overweight or obese in this cohort,[22] suggesting that this association may

be explained by a large contribution of muscle mass rather than adipose tissue. The causal pathways

may include increased muscle strength indicating a large muscle mass leading to higher body weight;

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nlybut also increased adiposity leading to higher muscle mass because of a higher weight load to carry.

Hence, body weight could be a mediating factor as well as a confounder. This could explain the

augmenting effect of additionally adjusting for body weight and blood pressure on the associations

of muscle strength with vascular disease. By using handgrip as estimate of muscle strength, which

was the available strength measure least correlated with body weight, we have minimized that

effect. We also used splines to adjust for both weight and height. Lack of some potential confounding

variables, including smoking, may lead to residual confounding. Smoking status was unknown for the

majority of this cohort,[22] but education level was included in our models and accounts well for

health behaviour. Because the cohort only includes 18-year-old men of mainly Caucasian origin,

generalizability to women, other races or age groups is unknown.

The preventive effect of exercise capacity against both all-cause and cardiovascular mortality is well

known among middle-aged and elderly,[6] but the association of exercise capacity in youth with risk

of vascular disease events has to our knowledge not been explored before. The relative contributions

of exercise capacity and muscle strength to risk of vascular events are also hitherto unknown. The

coherent, strong, graded associations that we observed with several vascular disease subgroups

support a causal association. Several mechanisms have been proposed, including better insulin

sensitivity, lipid profile, body composition, blood pressure and autonomic balance.[6] Further, in

children and adolescents, cardiorespiratory fitness has been related to lower incidence of obesity,

better insulin resistance and lower incidence of cardiovascular risk factors.[23-25] Several studies

have also shown associations of higher muscle strength with lower risk of all-cause mortality and

vascular disease.[16] It has been speculated that the effect is mediated through a lower incidence of

abdominal adiposity, weight gain, insulin resistance, metabolic syndrome, hypertension and chronic

inflammation.[16 26] Previous studies in these adolescents[27 28] did not account for the interplay

between exercise capacity and muscle strength or assess non-linear associations. The associations of

exercise capacity and muscle strength with risk of arrhythmias are important. Endurance trained

athletes with underlying cardiac disease have a higher risk of potentially fatal arrhythmias during

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nlysports activity.[7] Further, athletes are at higher risk of atrial fibrillation and bradyarrhythmias,[8-12]

which might be related to increased pulmonary vein ectopy, vagal tone, pressure/volume load and

atrial stretch, dilatation and fibrosis, alone or in combination.[8] Most previous studies are small

case-control studies comparing active athletes with sedentary persons, and lack objective measures

of cardiorespiratory fitness. The present study extends those observations to the whole spectrum of

cardiorespiratory fitness, using a direct measure of exercise capacity. Of note, in order to only

capture clinically relevant bradyarrhythmias (potentially requiring a pacemaker), sinus bradycardia

and grade I atrioventricular block were not part of this outcome. Importantly, although the present

study found an association of exercise capacity with incidence of atrial fibrillation/flutter that did not

translate into an increased risk of stroke. Further, we did not find a higher risk of ventricular

arrhythmias with higher exercise capacity. The similarity of the independent associations of exercise

capacity and muscle strength with vascular disease is noteworthy. This may indicate that different

modes of training trigger the same or similar biological responses; or that the two tests capture

different aspects of similarly trained people because of factors unrelated to their training. Seemingly

disputing the former interpretation is the observation of different cardiac adaptations in athletes of

different sports.[29] These mechanisms may be related to risk of arrhythmias, but other mechanisms

than cardiac geometry may be more important for atherosclerotic vascular disease, as outlined

above.

In conclusion, higher exercise capacity and higher muscle strength in late adolescence were

independently associated with lower risk of subsequent vascular disease in this large cohort of young

men. We observed a U-shaped association of exercise capacity with arrhythmias, driven by a direct

association with risk of atrial fibrillation/flutter and a U-shaped association with bradyarrhythmias.

Higher muscle strength was associated with lower risk of arrhythmias, driven by a lower risk of

bradyarrhythmias and ventricular arrhythmias. The combined associations of high exercise

capacity/high muscle strength versus low exercise capacity/low muscle strength with lower risk of

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nlyvascular disease were prominent. The lower risk of vascular events with higher exercise capacity did

not appear to be outweighed by higher risk of arrhythmias.

Contributors: KA and JS conceived and coordinated the investigations. KA wrote the first draft of the

manuscript. FR and PS were responsible for the preparation of data. KA, FR, CH, MN, PT and JS

undertook revisions and contributed intellectually to the development of this Paper.

Ethical approval: The study protocol was approved by the Regional Ethical Review Board at

Karolinska Institutet, Stockholm, Sweden.

Funding: Dr Sundström was funded by the Swedish Research Council (grant 2010-1078). Kasper

Andersen received a grant from the Geriatric Fund, Sweden.

Competing interests: All authors have completed the ICMJE uniform disclosure form at

www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted

work; no financial relationships with any organisations that might have an interest in the submitted

work in the previous three years; no other relationships or activities that could appear to have

influenced the submitted work. JS and MN are on an advisory board for Itrim and MN reports

personal fees from Strategic Health Resources, grants and personal fees from Pfizer, grants from

Astra Zeneca, outside the submitted work.

Data sharing: Additional data regarding technical details, statistical code, and derivative data are

available from the principal investigator at [email protected]. Data access for further

analyses is possible through direct collaborative agreement or through locally managed access

arranged through the study’s principal investigator. Consent was not obtained but the presented

data are anonymised and risk of identification is low

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nlyTransparency: The lead author (the manuscript’s guarantor) affirms that the manuscript is an honest,

accurate, and transparent account of the study being reported; that no important aspects of the

study have been omitted; and that any discrepancies from the study as planned (and, if relevant,

registered) have been explained.

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17. Royston P, Sauerbrei W. A new approach to modelling interactions between treatment and

continuous covariates in clinical trials by using fractional polynomials. Statistics in medicine

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18. Ludvigsson JF, Andersson E, Ekbom A, et al. External review and validation of the Swedish national

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21. Blair SN, Kohl HW, 3rd, Barlow CE, et al. Changes in physical fitness and all-cause mortality. A

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22. Neovius M, Sundstrom J, Rasmussen F. Combined effects of overweight and smoking in late

adolescence on subsequent mortality: nationwide cohort study. Bmj 2009;338:b496 doi:

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23. Ortega FB, Ruiz JR, Castillo MJ, et al. Physical fitness in childhood and adolescence: a powerful

marker of health. International journal of obesity 2008;32(1):1-11 doi:

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nly24. Lee S, Bacha F, Gungor N, et al. Cardiorespiratory fitness in youth: relationship to insulin

sensitivity and beta-cell function. Obesity 2006;14(9):1579-85 doi:

10.1038/oby.2006.182[published Online First: Epub Date]|.

25. Berman LJ, Weigensberg MJ, Spruijt-Metz D. Physical activity is related to insulin sensitivity in

children and adolescents, independent of adiposity: a review of the literature.

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26. Andersen K, Pedersen BK. The role of inflammation in vascular insulin resistance with focus on IL-

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27. Silventoinen K, Magnusson PK, Tynelius P, et al. Association of body size and muscle strength with

incidence of coronary heart disease and cerebrovascular diseases: a population-based cohort

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28. Ortega FB, Silventoinen K, Tynelius P, et al. Muscular strength in male adolescents and premature

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29. Pluim BM, Zwinderman AH, van der Laarse A, et al. The athlete's heart. A meta-analysis of cardiac

structure and function. Circulation 2000;101(3):336-44

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nlyTable 1 – Baseline characteristics

Total Sample

(n= 1,122,255)

Low exercise

capacity/Low

muscle strength

(n=326,462)

Low exercise

capacity/High

muscle strength

(n=246,767)

High exercise

capacity/Low

muscle strength

(n=218,156)

High exercise

capacity/High

muscle strength

(n=330,870)

Age at conscription 18.3 (0.7) 18.3 (0.8) 18.4 (0.9) 18.2 (0.6) 18.3 (0.6)

Height (cm) 179 (7) 176 (6) 179 (6) 178(6) 181 (6)

Weight (kg) 70 (10) 64 (9) 70(10) 69 (8) 75 (9)

Muscle strength -

Handgrip (N)

616 (98) 529 (57) 681 (62) 547 (47) 701 (68)

Exercise capacity (w) 261 (47) 220 (26) 228 (22) 292 (29) 301 (34)

Systolic Blood

pressure

129 (11) 127 (11) 128 (11) 129 (11) 130 (11)

Diastolic blood

pressure

67 (10) 67 (10) 68 (10) 66 (11) 66 (10)

Educational level*

Primary school <

9 years

0.5% 0.7% 0.8% 0.2% 0.3%

Primary school 9

years

12.2% 15.0% 18.8% 6.6% 8.7%

Secondary school

< 2 years

37.0% 39.3% 44.5% 29.8% 34.5%

Secondary school

2-3 years

15.8% 15.6% 13.8% 17.1% 16.5%

Higher education

> 2 years

15.1% 13.1% 11.4% 18.5% 17.8%

Higher education

> 3years

17.8% 15.1% 10.0% 25.6% 20.7%

PhD 1.5% 1.3% 0.7% 2.3% 1.6%

Data are Mean (SD) or %. * Conscripts highest registered educational level of the year 2010.

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nlyTable 2 – Incidence rates and cox proportional hazard ratios (95%CI) for vascular disease and

arrhythmias, comparing joint groups of maximal exercise capacity and muscle strength defined as

high/low by median values.

Low exercise

capacity/Low

muscle strength

Low exercise

capacity/High

muscle strength

High exercise

capacity/Low

muscle strength

High exercise

capacity/High

muscle strength

Number at risk 324,416 223,530 216,716 328,643

Vascular disease

Number of events 9,512 6,798 3,630 5,715

Incidence ratea 10.9 (10.7-11.2) 11.0 (10.7-11.2) 6.6 (6.4-6.8) 6.8 (6.6-7.0)

Model A [HR (95% CI)]b 1.00 (ref) 0.96 (0.93-0.99) 0.84 (0.81-0.87) 0.85 (0.82-0.88)

Model B [HR (95% CI)]c 1.00 (ref) 0.84 (0.81-0.87) 0.75 (0.73-0.79) 0.67 (0.65-0.70)

Arrhythmias

Number of events 4,867 4,329 2,810 5,092

Incidence ratea 5.6 (5.4-5.8) 6.4 (6.2-6.6) 5.1 (4.9-5.3) 6.1 (5.9-6.3)

Model A [HR (95% CI)]b 1.00 (ref) 0.99 (0.95-1.03) 0.99 (0.95-1.04) 1.05 (1.01-1.10)

Model B [HR (95% CI)]c 1.00 (ref) 0.91 (0.87-0.95) 0.95 (0.90-1.00) 0.92 (0.88-0.97)

HR: hazard ratio; 95% CI: 95% confidence interval

a per 10,000 person-years at risk

b Adjusted for age, conscription date, region, education level and height

c Additionally adjusted for systolic and diastolic blood pressure, mass and ischemic heart disease (for arrhythmia outcomes

only)

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nlyFigure Legends

Figure 1 - Cumulative hazard estimates of vascular disease and arrhythmias by joint groups of

exercise capacity and muscle strength defined as high/low by median values. E: Exercise capacity S:

Muscle Strength

Figure 2 - Relations of exercise capacity and muscle strength to risk of vascular disease and

arrhythmias. Solid line represents relative hazard and dashed lines are 95% confidence interval limits;

from multivariable regression spline Cox proportional hazards. Model B adjusted for age,

conscription date, region, education level, height and muscle strength/exercise capacity (muscle

strength adjusted for exercise capacity, and vice versa) systolic and diastolic blood pressure, weight

and ischemic heart disease (for arrhythmia outcomes only). Only observations between 1 and 99

percentiles are shown.

Figure 3 - Relations of exercise capacity and muscle strength to risk of subgroups of vascular disease.

Solid line represents relative hazard and dashed lines are 95% confidence interval limits, from

multivariable regression spline Cox proportional hazards Model B adjusted for age, conscription

date, region, education level, height and muscle strength/exercise capacity (muscle strength

adjusted for exercise capacity, and vice versa) systolic and diastolic blood pressure and weight. Only

observations between 1 and 99 percentiles are shown.

Figure 4 - Relations of exercise capacity and muscle strength to risk of subgroups of arrhythmias.

Solid line represents relative hazard and dashed lines are 95% confidence interval limits; from

multivariable regression spline Cox proportional hazards Model B Adjusted for age, conscription

date, region, education level, height and muscle strength/exercise capacity (muscle strength

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nlyadjusted for exercise capacity, and vice versa) systolic and diastolic blood pressure, weight and

ischemic heart disease. Only observations between 1 and 99 percentiles are shown.

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nlyFigure 1

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nlyFigure 2

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nlyFigure 3

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nlyFigure 4

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nly

Arrhythmias

Vascular disease

Supplementary figure 1 - Directed acyclic graphs of suggested causal relations of exercise capacity to arrhythmias and vascular disease

Minimal sufficient adjust-ment sets for estimating the total effect of Exercise ca-pacity on Vascular disease:

Region/Age/Date, Educa-tion, Height,

Minimal sufficient adjust-ment sets for estimating the direct effect of Exercise ca-pacity on Vascular disease:

Region/Age/Date, Edu-cation, Height, Weight, Blood Pressure and Muscle Strength

Minimal sufficient adjust-ment sets for estimating the total effect of Exercise capacity on Arrhythmias:

Region/Age/Date, Educa-tion, Height,

Minimal sufficient adjust-ment sets for estimating the direct effect of Exercise capacity on Arrhythmias:

Region/Age/Date, Educa-tion, Height, Weight, Blood Pressure, Muscle Strength and Ischemic heart diseases (IHD)

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nly

Supplementary Figure 2 - Relations of exercise capacity to risk of vascular disease by quartiles of weight. Solid line represents relative hazard and dashed lines are 95% confidence interval limits; from multivariable regression spline Cox proportional haz-ards (adjusted for age, conscription date, region, educational level, height, muscle strength, systolic and diastolic blood pressure). Only observations between 1 and 99 percentiles are shown.

12

34

Rel

ativ

e ha

zard

150 200 250 300 350 400

12

34

Rel

ativ

e ha

zard

150 200 250 300 350 400

1st quartile of weight 2nd quartile of weight

3rd quartile of weight 4th quartile of weight

Exercise capacity (W) Exercise capacity (W)

12

34

Rel

ativ

e ha

zard

150 200 250 300 350 400

12

34

Rel

ativ

e ha

zard

150 200 250 300 350 400

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nly

Supplementary Figure 3 - Relations of muscle strength to risk of arrhythmias by quartiles of height. Solid line represents relative hazard and dashed lines are 95% confidence interval limits; from multivariable regression spline Cox proportional hazards (ad-justed for age, conscription date, region, educational level, maximal exercise capacity, systolic and diastolic blood pressure and ischemic heart disease). Only observations between 1 and 99 percentiles are shown.

11.

52

2.5

Rel

ativ

e ha

zard

400 500 600 700 800 900

11.

52

2.5

Rel

ativ

e ha

zard

400 500 600 700 800 900

1st quartile of height 2nd quartile of height

3rd quartile of height 4th quartile of height

Muscle strength (N) Muscle strength (N)

11.

52

2.5

Rel

ativ

e ha

zard

400 500 600 700 800 900

11.

52

2.5

Rel

ativ

e ha

zard

400 500 600 700 800 900

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nly

Supplementary Figure 4 - Relations of muscle strength to risk of arrhythmias by educational level. Solid line represents relative hazard and dashed lines are 95% confidence interval limits; from multivariable regression spline Cox proportional hazards (ad-justed for age, conscription date, region, educational level, maximal exercise capacity, systolic and diastolic blood pressure and ischemic heart disease). Only observations between 1 and 99 percentiles are shown.

02

46

Rel

ativ

e ha

zard

400 500 600 700 800 900

11.

52

2.5

Rel

ativ

e ha

zard

400 500 600 700 800 900

11.

52

2.5

Rel

ativ

e ha

zard

400 500 600 700 800 900

11.

52

2.5

Rel

ativ

e ha

zard

400 500 600 700 800 900

11.

52

2.5

Rel

ativ

e ha

zard

400 500 600 700 800 900

11.

52

2.5

Rel

ativ

e ha

zard

400 500 600 700 800 900

12

34

Rel

ativ

e ha

zard

400 500 600 700 800 900

Exercise capacity (W) Exercise capacity (W)

Primary school < 9 years

Primary school 9 years

Secondary school 2-3 years Higher education > 2 years

Higher education > 3years PhD

Secondary school < 2 years

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nly

Supplementary Figure 5 - Relations of exercise capacity and muscle strength to risk of arrhythmias by ischemic heart disease. Solid line represents relative hazard and dashed lines are 95% confidence interval limits; from multivariable regression spline Cox proportional hazards (adjusted for age, conscription date, region, educational level, maximal exercise capacity, systolic and diastolic blood pressure). Only observations between 1 and 99 percentiles are shown.

11.

52

2.5

Rel

ativ

e ha

zard

400 500 600 700 800 900

11.

52

2.5

Rel

ativ

e ha

zard

150 200 250 300 350 400

With ischemic heart disease With ischemic heart disease

Without ischemic heart disease Without ischemic heart disease

Exercise capacity (W) Muscle strength (N)

11.

52

2.5

Rel

ativ

e ha

zard

400 500 600 700 800 900

11.

52

2.5

Rel

ativ

e ha

zard

150 200 250 300 350 400

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nly

12

34

Rel

ativ

e ha

zard

400 500 600 700 800 900

12

34

Rel

ativ

e ha

zard

150 200 250 300 350 400

12

34

Rel

ativ

e ha

zard

400 500 600 700 800 900

12

34

Rel

ativ

e ha

zard

150 200 250 300 350 400

12

34

Rel

ativ

e ha

zard

400 500 600 700 800 900

12

34

Rel

ativ

e ha

zard

150 200 250 300 350 400

12

34

Rel

ativ

e ha

zard

400 500 600 700 800 900

12

34

Rel

ativ

e ha

zard

150 200 250 300 350 400

Ischemic heart disease

Heart failure

Stroke

Cardiovascular death


Supplementary figure 6 - Relations of exercise capacity and muscle strength to risk of subgroups of vascular disease.Solid line represents relative hazard and dashed lines are 95% confidence interval limits, from multivariable regression spline Cox propor-tional hazards. Model A (adjusted for age, conscription date, region, height, education level and muscle strength/exercise capac-ity [muscle strength adjusted for exercise capacity, and vice versa]). Only observations between 1 and 99 percentiles are shown.

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nly

Supplementary figure 7 - Relations of exercise capacity and muscle strength to risk of subgroups of arrhythmias. Solid line rep-resents relative hazard and dashed lines are 95% confidence interval limits; from multivariable regression spline Cox proportional hazards. Model A (adjusted for age, conscription date, region, height, education level, muscle strength/exercise capacity [muscle strength adjusted for exercise capacity, and vice versa]) Only observations between 1 and 99 percentiles are shown.

11.

52

2.5

Rel

ativ

e ha

zard

400 500 600 700 800 900

11.

52

2.5

Rel

ativ

e ha

zard

150 200 250 300 350 400

11.

52

2.5

Rel

ativ

e ha

zard

400 500 600 700 800 900

11.

52

2.5

Rel

ativ

e ha

zard

150 200 250 300 350 400

11.

52

2.5

Rel

ativ

e ha

zard

150 200 250 300 350 400

11.

52

2.5

Rel

ativ

e ha

zard

400 500 600 700 800 900

11.

52

2.5

Rel

ativ

e ha

zard

150 200 250 300 350 400

Atrial fibrillation

Bradyarrhythmia

Supraventricular tachycardia

Ventricular arrhythmias/Sudden cardiac death


11.

52

2.5

Rel

ativ

e ha

zard

400 500 600 700 800 900

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Confidential: For Review Only

Supplementary table 1 – Cox proportional hazard ratios (95% CI) for vascular disease and arrhythmias comparing fifths of exercise capacity

and muscle strength.

Vascular disease Arrhythmia

Exercise capacity (in fifth) Model A* Model B** Model A* Model B**

1st 1.00 (ref) 1.00 (ref) 1.00 (ref) 1.00 (ref)

2nd 0.92 (0.89-0.95) 0.85 (0.82-0.88) 0.93 (0.90-0.99) 0.91 (0.87-0.96)

3rd 0.90 (0.87-0.93) 0.79 (0.76-0.82) 0.97 (0.93-1.02) 0.91 (0.87-0.96)

4th 0.81 (0.78-0.84) 0.70 (0.67-0.73) 0.97 (0.92-1.02) 0.91 (0.86-0.96)

5th 0.77 (0.73-0.80) 0.64 (0.61-0.67) 1.07 (1.01-1.13) 0.99 (0.94-1.04)

Per category 0.94 (0.93-0.95) 0.90 (0.89-0.90) 1.02 (1.00-1.03) 1.00 (0.98-1.01)

Muscle Strength (in fifth) Model A* Model B** Model A* Model B**

1st 1.00 (ref) 1.00 (ref) 1.00 (ref) 1.00 (ref)

2nd 0.96 (0.93-1.00) 0.92 (0.89-0.95) 0.92 (0.87-0.96) 0.89 (0.85-0.93)

3rd 0.94 (0.90-0.98) 0.86 (0.82-0.90) 0.95 (0.90-1.00) 0.90 (0.86-0.95)

4th 0.95 (0.91-0.99) 0.83 (0.80-0.87) 0.95 (0.90-0.99) 0.87 (0.83-0.92)

5th 0.99 (0.95-1.03) 0.79 (0.76-0.83) 0.99 (0.94-1.04) 0.87 (0.83-0.91)

Per category 1.00 (0.99-1.01) 0.95 (0.94.0.95) 1.00 (0.99-1.02) 0.97 (0.96-0.98)

* Adjusted for age, conscription date, region, education level, height and muscle strength/exercise capacity (muscle strength adjusted for exercise capacity, and vice versa).

** Additionally adjusted systolic and diastolic blood pressure, weight and ischemic heart disease (for arrhythmia outcomes only).

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Supplementary table 2 – Cox proportional hazard ratios (95% CI) for subgroups of vascular disease comparing fifths of exercise capacity and

muscle strength.

Ischemic heart disease Heart Failure Stroke Cardiovascular death

Exercise capacity

(in fifths)

Model A* Model B** Model A* Model B** Model A* Model B** Model A* Model B**

1st 1.00 (ref) 1.00 (ref) 1.00 (ref) 1.00 (ref) 1.00 (ref) 1.00 (ref) 1.00 (ref) 1.00 (ref)

2nd 0.93 (0.89-0.98) 0.86 (0.82-0.91) 0.91 (0.83-0.99) 0.82 (0.76-0.90) 0.91 (0.85-0.97) 0.87 (0.81-0.93) 0.89 (0.83-0.96) 0.82 (0.77-0.88)

3rd 0.95 (0.91-1.01) 0.83 (0.79-0.88) 0.88 (0.80-0.96) 0.74 (0.67-0.81) 0.84 (0.78-0.90) 0.77 (0.72-0.83) 0.83 (0.77-0.89) 0.72 (0.66-0.77)

4th 0.86 (0.81-0.91) 0.73 (0.68-0.77) 0.81 (0.73-0.89) 0.66 (0.60-0.74) 0.78 (0.72-0.84) 0.71 (0.66-0.77) 0.73 (0.67-0.79) 0.62 (0.56-0.67)

5th 0.78 (0.73-0.83) 0.64 (0.60-0.68) 0.75 (0.66-0.84) 0.60 (0.53-0.67) 0.74 (0.68-0.80) 0.66 (0.61-0.72) 0.70 (0.64-0.77) 0.58 (0.53-0.64)

Per category 0.95 (0.93-0.96) 0.90 (0.89-0.91) 0.93 (0.91-0.96) 0.88 (0.86-0.90) 0.92 (0.91-0.94) 0.90 (0.88-0.92) 0.91 (0.89-0.93) 0.87 (0.85-0.88)

Muscle Strength

(in fifths)



2nd 1.02 (0.97-1.08) 0.97 (0.92-1.03) 0.83 (0.76-0.91) 0.78 (0.71-0.85) 1.02 (0.96-1.10) 0.99 (0.93-1.07) 0.82 (0.76-0.89) 0.78 (0.72-0.84)

3rd 1.01 (0.96-1.08) 0.92 (0.87-0.98) 0.78 (0.71-0.87) 0.70 (0.63-0.77) 0.96 (0.88-1.03) 0.91 (0.84-0.98) 0.84 (0.77-0.91) 0.76 (0.70-0.82)

4th 1.02 (0.96-1.08) 0.88 (0.83-0.94) 0.75 (0.68-0.83) 0.63 (0.57-0.70) 1.00 (0.93-1.08) 0.92 (0.86-1.00) 0.82 (0.75-0.89) 0.70 (0.64-0.76)

5th 1.10 (1.04-1.17) 0.87 (0.82-0.93) 0.79 (0.71-0.88) 0.58 (0.52-0.64) 1.01 (0.94-1.10) 0.89 (0.82-0.96) 0.86 (0.79-0.94) 0.67 (0.62-0.73)

Per category 1.02 (1.01-1.03) 0.96 (0.95-0.98) 0.94 (0.92-0.97) 0.88 (0.86-0.90) 1.00 (0.98-1.02) 0.97 (0.95-0.99) 0.97 (0.95-0.99) 0.91 (0.90-0.93)


** Additionally adjusted systolic and diastolic blood pressure and weight.

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Supplementary table 3 - Cox proportional hazard ratios (95% CI) for subgroups of arrhythmias, comparing fifths of exercise capacity and

muscle strength.

Atrial fibrillation/flutter Bradyarrhythmias Supraventricular tachycardias Ventricular arrhythmias/

Sudden cardiac death

Exercise capacity (in

fifth)



2nd 0.99 (0.93-1.06) 0.95 (0.89-1.02) 0.89 (0.76-1.05) 0.88 (0.75-1.04) 0.94 (0.84-1.04) 0.93 (0.83-1.04) 0.95 (0.82-1.10) 0.97 (0.84-1.12)

3rd 1.07 (1.00-1.14) 0.99 (0.93-1.06) 0.88 (0.74-1.04) 0.86 (0.72-1.01) 0.94 (0.84-1.05) 0.94 (0.83-1.05) 0.95 (0.81-1.11) 0.96 (0.81-1.12)

4th 1.11 (1.04-1.19) 1.02 (0.95-1.09) 0.95 (0.80-1.13) 0.93 (0.78-1.11) 0.90 (0.80-1.01) 0.90 (0.80-1.01) 0.87 (0.74-1.03) 0.90 (0.77-1.06)

5th

1.31 (1.23-1.40) 1.17 (1.09-1.25) 1.03 (0.86-1.23) 1.01 (0.84-1.21) 0.88 (0.79-0.99) 0.89 (0.79-1.00) 1.04 (0.88-1.23) 1.09 (0.92-1.29)

Per category 1.07 (1.05-1.09) 1.04 (1.03-1.06) 1.01 (0.97.1.05) 1.01 (0.96-1.05) 0.97 (0.95-1.00) 0.97 (0.95-1.00) 1.00 (0.96-1.04) 1.01 (0.97-1.05)

Muscle Strength (in

fifth)



2nd 0.95 (0.89-1.02) 0.92 (0.86-0.99) 0.95 (0.80-1.11) 0.93 (0.79-1.10) 0.94 (0.84-1.04) 0.93 (0.83-1.04) 0.87 (0.75-1.01) 0.86 (0.75-1.00)

3rd 0.98 (0.92-1.05) 0.93 (0.87-1.00) 0.95 (0.80-1.13) 0.92 (0.77-1.10) 1.00 (0.89-1.12) 1.00 (0.89-1.12) 0.96 (0.82-1.13) 0.95 (0.81-1.12)

4th 0.99 (0.93-1.06) 0.91 (0.85-0.98) 0.91 (0.77-1.09) 0.87 (0.74-1.04) 1.03 (0.92.1.15) 1.03 (0.92-1.16) 0.74 (0.63-0.87) 0.72 (0.61-0.85)

5th 1.05 (0.98-1.12) 0.91 (0.85-0.98) 0.85 (0.71-1.02) 0.79 (0.65-0.95) 1.09 (0.97-1.22) 1.09 (0.96-1.22) 0.79 (0.67-0.93) 0.74 (0.63-0.88)

Per category 1.02 (1.00-1.03) 0.98 (0.97-1.00) 0.96 (0.93-1.00) 0.95 (0.91-0.99) 1.03 (1.00-1.06) 1.03 (1.00-1.06) 0.94 (0.90-0.97) 0.93 (0.89-0.96)


** Additionally adjusted systolic and diastolic blood pressure, weight and ischemic heart disease.

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nlySupplementary Document 1 - Complete list of ICD-diagnoses used in the study

Arrhythmias - Primary Outcome

All ICD- codes mentioned in secondary outcomes, plus ICD 10 - I47.9 /ICD 9 - 427.A / ICD-8 427.98

Arrhythmias - Secondary Outcomes

Atrial fibrillation/flutter ICD-10

I48.9 Atrial fibrillation and flutter

ICD-9

427D Atrial fibrillation and flutter

ICD-8

427.92 Atrial fibrillation

Bradyarrhythmias ICD -10

I44.1 Atrioventricular block, second degree

I44.2 Atrioventricular block, complete

I45.2 Bifascicular block

I45.3 Trifascicular block

I45.9 Conduction disorder, unspecified

I49.5 Sick sinus syndrome

ICD-9

426A Atrioventricular block, third degree

426B Atrioventricular block, second degree

426G Sinoatrial heart block

426X Conduction disorder, unspecified

ICD-8

427.20 Syndroma Adams-Stokes

427.28 Dissociatio cordis alia

Other supraventricular arrhythmias ICD-10

I45.6 Pre-excitation syndrome

I47.1 Supraventricular tachycardia

ICD-9

426H Atrioventricular excitation, anomalous

427A Tachycardia, paroxysmal supraventricular

ICD-8

427.90 Tachycardia, paroxysmal supraventricular

Cardiac arrest and ventricular arrhythmias ICD-10

I46.0 Cardiac arrest with successful resuscitation

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nlyI46.1 Sudden cardiac death, so described Excludes: sudden death:

I46.9 Cardiac arrest, unspecified

I47.0 Re-entry ventricular arrhythmia

I47.2 Ventricular tachycardia

I49.0 Ventricular fibrillation and flutter

R96.0 Instantaneous death

ICD-9

427B Paroxysmal ventricular tachycardia

427E Ventricular fibrillation and flutter

427F Cardiac arrest

798B Sudden death, cause unknown

ICD-8

427.91 Paroxysmal ventricular tachycardia

795,99 Sudden death, cause unknown

Vascular disease – primary outcome

All ICD- codes mentioned in secondary outcomes

Vascular disease – secondary outcomes

Ischemic heart disease ICD-10

I20-I25 Ischemic heart diseases

ICD-9

410-414 Ischemic heart diseases

ICD-8

410-414 Ischemic heart diseases

Heart Failure ICD-10

I11.0 Hypertensive heart disease with (congestive) heart failure

I50.0-9 Heart failure

ICD-9

428A Chronic heart failure

428B Left heart failure

428X Heart failure, unspecified

ICD-8

427,00 Uncompensated heart failure

427,10 Pulmonary edema

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nlyStroke ICD-10

I60.0-9 Subarachnoid haemorrhage

I61.0-9 Intracerebral haemorrhage

I63.0-9 Cerebral infarction

I64.0-9 Stroke, not specified as haemorrhage or infarction

ICD-9

430-438 Cerebrovascular disease

ICD-8

430-438 Cerebrovascular disease

Cardiovascular death ICD-10

I.00-99 Diseases of the circulatory system

ICD-9

390-459 Diseases of the circulatory system

ICD-8

390-458 Diseases of the circulatory system

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Confidential: For Review Only - BMJ · Confidential: For Review Only Exercise capacity and muscle strength and risk of vascular ... death) and arrhythmias in total and in subgroups