DOI: 10.1161/CIRCULATIONAHA.112.

112300

Premature Atrial Contractions in the General Population:

Frequency and Risk Factors

Running title: Conen et al.; PACs in the general population

David Conen, MD, MPH1,2; Martin Adam, PhD2,3; Frederic Roche, MD, PhD4; Jean-Claude
Barthelemy, MD, PhD4; Denise Felber Dietrich, MD, PhD5; Medea Imboden, PhD2,3;
Nino Künzli, MD, PhD2,3; Arnold von Eckardstein, MD6; Stephan Regenass, MD7;
Thorsten Hornemann, PhD6; Thierry Rochat, MD8; Jean Michel Gaspoz,, MD9;
Jean-Michel
Nicole Probst-Hensch, PhD MPH2,3*; David Carballo, MD, MPH
H100*

*These authors contributed equally to this work

1
Dept
D e of Me Medi
Medicine,
diccinne,
di ne, Univ
Univ Hosp;
Hos p; 2Un
osp; Univi ooff Ba
iv B sel; 3S
Basel;
se Swiss
wis isss Tropical
is Trop
Tr opic
op iccal
a aandnd PPublic
ubliic Health
Heal
He alth
al th IInst,
nst,
t, B
Basel,
aseel,
as
Swit
Sw itzerland;; 4La
Switzerland; Laboratory
aboraatorry S SNA-EPIS
N -EPI
NA PIS S EA
EA4607,
A466077, D Dept
ept ooff Ph Phy
Physiology,
ysiioloogy, Un Univ
niv vHHosp
osp off S Saint-Etienne,
ainnt--Etien
ennne,
en
5 6 7
PR
PRES
RES L Lyon,
yoon, F
France;
raancce; S Swiss
wisisss So
Society
Soci
ciet
etty for
fo
or Pu
Pub
Public
bliic H
Health,
eaalt
lthh,
h, BBern;
errn; In
Inst
nstt ooff C
Clinical
liinic
iniccall C
Chemistry;
heemisttryy; D Div
ivv of
Clin
Cl inic
in ical
ic
Clinical al IImmunology,
mmun
mmun
unol olog
ol ogy,
og y, U n v Ho
ni
Univ Hosp
sp,, Zu
sp
Hosp, Zuri
ri ch;; 8De
rich
ch
Zurich; Dept pt ooff Pu
Pulmonary
Pulmlmon
lm onaary
on ary Me
Medi
Medicine;
dici
di ne;; 9De
cine
ci ne Deptpt of
of Community
Comm
Co mmun
mm unit
un ityy
it
Medicine;
Medi
Me dici
di ne;; 10De
cine
ci ne Dept
pt of
of Ca
Cardiology,
Cardrdio
rd iolo
io logy
logy, Un
gy Univ iv H Hosp,
ospp,
os p, G
Geneva,
enev
en evaa,
ev a, Switzerland
Swi
witz tzer
tz erla
er land
land

Address for Correspondence:

David Conen MD MPH
Department of Medicine
University Hospital
Petersgraben 4
4031 Basel, Switzerland
Tel: +41 61 265 2525
Fax: +41 61 265 5734
E-mail: conend@uhbs.ch

Journal Subject Code: [8] Epidemiology

1
 DOI: 10.1161/CIRCULATIONAHA.112.112300

Abstract:

Background - Premature atrial contractions (PACs) are independent predictors of atrial

fibrillation, stroke and death. However, little is known about PAC frequency in the general
population and its association with other cardiovascular risk factors.
Methods and Results - We performed a cross-sectional analysis among participants of the
population-based Swiss cohort Study on Air Pollution and Lung Diseases in Adults
(SAPALDIA). 24-hour Holter electrocardiograms to assess PAC prevalence and frequency were
performed in a random sample of 1742 participants aged •50 years. The median (interquartile
range) number of PACs per hour was 0.8 (0.4-1.8), 1.1 (0.5-2.4), 1.4 (0.7-4.6), 2.3 (0.8-6.9) and
2.6 (1.2-6.5) among participants aged 50-55, 55-60, 60-65, 65-70 and 70+ years, respectively
p ) Onlyy 18 (1.0%)
(p<0.0001). ( ) participants
p p did not have at least 1 PAC duringg Holter monitoring.
g
Inn multivariable negative binomial regression models, PAC frequency was significantly
signif
iffican
ica tly
t ly
associated with age (Risk ratio (RR) per standard deviation (SD) 1.80, p<0.0001), height (RR per
SD 1.52,, p<0.0001),
p<0.0001)), prevalent cardiovascular disease (RR 2.40, p<0.0001), log-transformed N-
erm
rmin
inaal pro
in
terminal pro
o B-type
B-ttyp
ypee natriuretic
natr
na triu
ure
reticc peptides
pept
pe ptides
e (RR
(RR per
perr SD
SD 1.27,
1.27
27,, p<0.0001),
p 0.00
p< 00001),, pphysical
hysicaal ac
hy ty •
aactivity
tivity •22 hours
per day
day (RR 0.69,
0 69
0. 69, p=0.002)
p=00.00
p= 002)
2) and
and
nd HDL
HDL
DL cholesterol
choleesteerol (RR
(R
RR per
per SD 0.80,
0.80,
0, p=0.0002).
p=0.00002)
2 . Hypertension
Hyppert
Hy pertten
nsi
sion
on
n aand
nd
bo
ody m
body ass in
mass nde
d x were
index weree nnot
ot sig
ignnifi
ig nifica
caantl
significantlytlyy rela
rrelated
elattedd to PAC
C ffrequency.
PAC reqquen
re enccy.
Conc
nclu
lusion
ions - To
Conclusions T oour
ur knowledge,
knoowl
w ed
edge
ge, this
t is iss the
th the first
firsst study
fi studdy to assess
ass
sses
ess risk
risk factors
fac
a to
ors
r for
for PAC
PAC frequency
freequ
quen
ency
cy
n the general
in generral population
pop
opul
ulat
ul atio
at ionn aged
io aged 50
50 years
yeear
arss or older.
old
der. PACs
PAC
ACs are
are common
comm
com onn aand
mm nd ttheir
heir
he ir ffrequency
requ
re quen
qu en
ncy
y is
independently associated with age, height, history of cardiovascular disease, natriuretic peptide
levels, physical activity and HDL cholesterol. The underlying mechanisms of these relationships
need to be addressed in future studies.

Key words: atrial fibrillation; cardiovascular disease; epidemiology; premature atrial

contractions

2
 DOI: 10.1161/CIRCULATIONAHA.112.112300

Introduction

Atrial fibrillation (AF) is a highly prevalent arrhythmia 1 and associated with an increased risk of

death, stroke and congestive heart failure 2, 3. In recent years, multiple risk factors for AF

occurrence have been described, including age, elevated blood pressure, body size and

inflammation 1, 4-8. Most of these risk factors, in particular age, hypertension and body size, are

important determinants of left atrial (LA) enlargement 9, 10, suggesting that LA structural

remodeling is an important mediator for AF occurrence 11, 12.

Similar to the effect of LA structural remodeling, an increased number of premature atrial

contractions (PACs) and subclinical atrial tachyarrhythmias have been shown to be strong and

ndependent predictors of incident AF and associated complications 13-18, pointing

independent ngg to
to an

mportant role of atrial electrical activity in AF initiation and maintenance 19-21. However and in
important

co
ont
ntra
rast
rast tto
contrast o th
thee st
tru
ruct
ctural LA component, few if an
structural anyy population ba
ase
s d studies
based stuudies
st ud have assessed risk

ffactors
acttor
o s for an increased
inccreeas
aseed atrial
atr
tria
iall electrical
ia elecctr
elec t ic
i al aactivity
ctiv
vitty in
n ggeneral
ener
eral
er al aand
ndd PA
PAC
AC fr
fre
frequency
equuen
uency
ncy in pparticular.
arrtiicula
cula
lar.
r.

Ther
Th
Therefore,
eref
er efor
oree, the
the aim
im
m off the
th
he present
preesen
pr esen
nt study
stuudy
st udy was
wa to
to aassess
ssses
esss th
thee prevalence
prev
pr eval
evallen
nce of
of and
and risk
ri k factors
facto
acto
orss ffor
o

PAC frequency
frequenc
nccy inn a large
lar
a ge
g representative
rep
epre
r se
re sent
n at
nt a iv
ve sample
samp
sa mple
mplee of
of the
the
h ggeneral
ener
eneral
er al ppopulation
o ul
op ulat
atio
at ionn ag
io aged
ed
d 550
0 ye
year
years
a s or older
older.
r.

Methods

Participants

Design and objectives of the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults

(SAPALDIA) have been described previously 22. In brief, 9651 randomly selected adults, aged

18 to 60 years, from eight different areas of Switzerland that were chosen to represent the variety

of environmental conditions in respect to geography, climate, degree of urbanization and air

pollution in Switzerland had a baseline health interview and health examinations in 1991. During

3
 DOI: 10.1161/CIRCULATIONAHA.112.112300

a follow-up visit in 2002, 8047 of the original participants were reassessed. Every effort was

taken to track enrolled participants for the 2002 follow-up visit, and only 6.8% of the 9651

original participants were lost-to-follow-up, as previously described 22. A random subsample of

all 4417 participants aged •50 years were invited to undergo 24-hour Holter monitoring and

1846 subjects (955 women, 891 men) agreed to participate. Using inverse probability weighting

we only observed minimal changes in effect estimates, suggesting that potential bias due to

differential non-inclusion or non-participation in the 24-hour Holter monitoring study would be

small (data not shown).

Exclusion criteria for the Holter monitoring were general or spinal anesthesia within 8

days prior to the recording (n=5), a myocardial infarction within 3 months (n=2),
), and
n ttaking
nd akin
akingg
in

digitalis (n=6). None of the participants had a prior pacemaker implantation. After exclusion of

eco
ord
rdin
ings
ingss sshowing
recordings h wiing
ho ng AF (n=12), recordings of <1
18 hhours
<18 73)) 23 and recordings of
ours durationn ((n=73)
n=73
73

insufficient
nsuuff
f icient quality
qua
uali
l ty
li y (n=6),
(n=6)
6), 1742
1742 (94.4%)
(94.4
94.4
. %)
%) sub
subjects
bjeects wi
with vvalid
alid
alid
dHHolter
olte
ol terr re
rec
recordings
cordin
ngs w
were
eree re
er ret
retained
tain
in
ned ffor
or

this
his aanalysis.
naly
na ly The
ysiis. T he pprotocol
rottoc
ro tocol
col wa approved
was ap
appr
prov
pr d bby
ovved all
y al regional
egiionnal eethics
ll re thiccs ccommittees
th ommittteees aand
mmit nd aall
lll pparticipants
arrtici
ticiipa
panntss

gave written
n iinformed
nfor
nf orrme
medd co
cconsent.
nssen
nt.

Study variables

For the current analysis, all covariate information and Holter data were obtained at the 2002

SAPALDIA follow-up visit. During the 2002 health interview, standardized information was

obtained on age, history of hypertension, diabetes, smoking, alcohol consumption, physical

exercise, highest education level achieved (primary school, secondary school or

college/university degree), a prior history of cardiovascular disease and intake of beta blockers or

calcium channel blockers. Height, weight and blood pressure (mean of two measurements

performed according to the WHO recommendations) were directly measured in a standardized

4
 DOI: 10.1161/CIRCULATIONAHA.112.112300

manner. For the current analysis, hypertension was defined as a history of hypertension, a mean

visit systolic blood pressure •140 mmHg and/or a mean visit diastolic blood pressure •90

mmHg. Prevalent cardiovascular disease was defined as having physician confirmed heart

disease reported on the questionnaire.

Laboratory measurements

Biomarkers used for the current study were assayed from non-fasting frozen serum samples by

the Institute for Clinical Chemistry at the University Hospital Zürich, Switzerland. Lipids were

determined according to standard methods, low density lipoprotein (LDL) cholesterol was

calculated using the Friedewald formula for subjects who had fasted for •6 hours and had

riglyceride levels of ”4.7 mmol/L. High sensitivity troponin T and NT-proBNP

triglyceride P we r qquantified
were uant
ua ntif
nt ifie
ified

using the Elecsys E170 electrochemoluminscence immunoassay analyser from Roche

diagnostics.
diiag
agno
nost
no stic
st s According
ics.
ic s. ordding to the package insertt of th
Acccor manufacturer,
the m r BNP value •125 ng/L
NT-proBNP
anufacturer,, a NT
T-p
-pro

was
wass considered
d elevated.
c nsidered
co ed eleeva
vatted. The
ted. T he 10%
% functional
10% funncttionaal assay
assaay sensitivity
seens
nsit vitty aand
itiv
iv nd th limit
imitt ooff qu
thee li quantification
quan
anti
an tifi
ti ficaation
fi tionn ooff

the
he troponin
trop
tr opon
op in T test
onin testt are
are 13
13 and
d 3 ng/L,
and ng/ L, respectively.
g/L, resspe
pecctiv
ive y. The
vel he interassay
The int
nteeras
assa
assaay imprecision
impr
im
mpr
preccisionn of NT-proBNP
isio
io NT-pprooBN
oBNP
NP

was 3%.

Holter recording

Holter recordings were performed between August 2001 and March 2003. Participants were

asked to follow their regular daily routine and to complete a time-activity diary during the

recording period. We used digital devices (Aria, Del Mar Medical Systems, Irvine, CA, USA)

with a frequency response of 0.05–40 Hz and a resolution of 128 samples/s for 24-hour Holter

recording. Three lead monitoring (V1, altered V3 with the electrode on the left mid-clavicular

line on the lowest rib, and altered V5 with the electrode on the left anterior axillary line on the

lowest rib) was obtained and mean (SD) duration of the recording period was 22.3 (2.1) hours.

5
 DOI: 10.1161/CIRCULATIONAHA.112.112300

All recordings were scanned through a StrataScan 563 (Del Mar) and interpreted using

the interactive method. The system used was programed to stop at all rhythmic event or ectopic

beat, corresponding to a true count of all events on the full disclosure. A PAC was defined by a

coupling interval to the preceding QRS complex <80% of the mean RR interval before the event,

and a QRS duration of <0.12 seconds unless aberration was suspected. The total number of

PACs was summed during the entire recording period. In order to account for the slight

variations in recording time, the mean number of PACs per hour was used as the primary

outcome variable in this study. The definition of heart rate variability (HRV) measures has been

described in detail previously 24. Total power spectral density (TP) was defined as frequency

domain ”0.40 Hz.

Statistical analysis

Baseline
Base
Ba seli
se linne
li ne ccharacteristics
harractter
ha eris
istics below and above the me
median
ediaan PAC count pper
er hhour
ourr were compared using
ou

Wilcoxon
Willcoxon
lc rankk su
sum tests
m te
est Kruskal-Wallis
stss or K ruskkall-W
rusk tests
Wallis te
ests for continuous
for co
ontin
ntinuo
uous
uo variables
us va
aria b es aand
iabl nd cchi square
hii sq ttests
quare test
qua est
sts for

categorical
ca
ate
tego
gori
go call variables.
r ca
ri v ri
va les. The
riaables. he distribution
The dis
isstriibu
bution of
tion
ti of continuous
conntin
co ntin
inuo vvariables
uoous vari
ari
riab
able
ab was
less wa
w aassessed
ass as d uusing
seesssed ng skewness,
sing
si skewn
wnes
wn ess,
s,,

kurtosis and vvisual

isua
is inspection
uall in
ua insp
s ec
sp e ti on ooff th
tion tthee hi
histogram.
hist
stog
st ogra
og ram.
ra m.

Multivariable negative binomial regression analysis was performed to identify

independent correlates for the number of PACs per hour. Variables entered into the model were

age, sex, body mass index (calculated as weight in kg / height in m squared), hypertension,

history of cardiovascular disease, smoking, alcohol consumption, physical activity, current use of

calcium channel blockers and/or beta blockers, high density lipoprotein (HDL) cholesterol,

troponin T and NT-proBNP. Covariates with a skewed distribution were log-transformed to

improve the linearity of the association. Coefficients of continuous variables were estimated for a

one standard deviation (SD) change, in order to improve comparability across variables.

6
 DOI: 10.1161/CIRCULATIONAHA.112.112300

In order to assess whether other Holter measures such as the number of premature

ventricular contractions (PVCs) or HRV measures were associated with PAC frequency, we

alternatively added the number of PVCs and TP to two separate multivariable models. Spearman

correlation coefficients were used to assess univariate relationships between PAC frequency,

PVC frequency and TP.

Subgroup effects for age, sex, current smoking and prevalent cardiovascular disease were

tested using multiplicative interaction terms in the multivariable regression models. Categorical

variables were entered in the regression models using binary indicator variables. All analyses

were performed using SAS version 9.2 (SAS Institute Inc, Cary, North Carolina). A two-tailed P-

value <0.05 was pre-specified to indicate statistical significance.

Results
Resu
Re sult
su ltss
lt

Baseline
B asseline
se characteristics
chara
actter tiics sstratified
eriisti trat
tr atif
at ifiied
if the
ied by th
he med
he median
diaan nnumber
ed PACs
umbeer off P ACs pe
AC hhour
per ho ur aare
ree sshown
wn iin
hoown Table
n Ta
T abl
b e 1.

Compared
Co
omp a ed tto
mpar
ar individuals
o in
inddividu
div alss with
viduual w th <1.27
wi <1.2
<1 .277 PACs
.2 ACs pper
PA err hhour,
r, tthose
our,
our hose
ho with
se wit •1.27
ithh • 1 27
1. PACs
2 PACs per
ACs peer hour
houur were
ho were
e re

significantly
ignificantlyy older
olde
ol d r (p<0.0001),
de (p<0
(p <0.0
<0. 001), had
001)
1) had a higher
hiigher systolic
gher sys oliic blood
ysto
to b oo
bl oodd pressure
pres
pressu
essuree (p=0.004),
su (p=
p 0.
0.004),, a higher
004)
00 high
higher
ghe

prevalence of cardiovascular diseases (p=0.003), a lower education level (p=0.04), a higher HDL

cholesterol (p=0.02) and higher levels of NT-proBNP and troponin T (both p<0.0001).

Individuals with a higher PAC frequency also had a higher number of PVCs and a greater HRV

(p<0.0001 and p=0.0002, respectively). There was no significant difference in gender,

hypertension prevalence, body mass index, intake of beta blockers and intake of calcium channel

blockers (Table 1). Because gender was not associated with the number of PACs, all analyses

were performed in the overall sample.

PACs were highly prevalent in the current study population. Only 18 of 1742 (1.0%)

7
 DOI: 10.1161/CIRCULATIONAHA.112.112300

participants did not have at least 1 PAC on 24-hour Holter monitoring. As shown in Figure 1,

the median number (interquartile range) of PACs per hour was 0.8 (0.4-1.8), 1.1 (0.5-2.4), 1.4

(0.7-4.6), 2.3 (0.8-6.9) and 2.6 (1.2-6.5) among participants aged 50-55, 55-60, 60-65, 65-70 and

•70 years, respectively (p<0.0001). At least 70 PACs during Holter monitoring were observed in

478 (27.4%) participants 16. Again, the prevalence increased across the age strata 50-55 (14.0%),

55-60 (20.1%), 60-65 (31.4%), 65-70 (42.4%) and •70 years (46.7%) (p<0.0001), as shown in

Figure 2.

Results from the multivariable regression models are shown in Table 2. Independent

correlates for the number of PACs per hour were age (Risk ratio (RR) per SD 1.80, p<0.0001),

height (RR per SD 1.52, p<0.0001), a history of cardiovascular disease (RR 2.40
0, p<
2.40, <0.00
0.00
0001
01),
01
p<0.0001),),

og-transformed NT-proBNP (RR per SD 1.27, p<0.0001), HDL cholesterol (RR per SD 0.80,
log-transformed

p=
=0.
0.00
0002
00 02)) an
02
p=0.0002) andd att least
least
ea 2 hours of physical exerc
cis
ise per
exercise per day (RR 0.
.69
6 , p=0.002).
0.69, p=00.002). The non-
p=

ignnif
i icant relationship
significant rela
lati
tion
ti onshhip
on i of
of height
heig
he ight
ig htt with
wit
ithh the
th number
nuumberr of
of PACs
PA
ACs per
er hour
houur
ur in
in univariate
univ
var
ariiate
iate analysis
analy
naly
lysiis ((Table
Table
Ta

1)) wa
wass mainly
main
ma inly
inly eexplained
xplain
xplain
ned
d bby
y th
thee co
conf
nfou
nf ou
unddin
ingg in
confounding infl
flue
uennce of aage
influence ge aand
nd ssex
nd e ((RR
ex RR pper
RR er S
SDD 11.47,
.477,

p<0.0001 aft
fter
er aadjustment
after djus
dj ustm
us tm
men
e t fo
forr ag
agee an
and se
ssex).
x.
x)

The number of PVCs was moderately correlated with PAC frequency (r=0.32, p<0.0001).

In a multivariable model, the number of PVCs per hour (log transformed) was significantly

associated with PAC frequency (RR 1.17, 95% confidence interval 1.14, 1.21, p<0.0001). TP

was weakly correlated with PAC frequency (r=0.11, p<0.0001). After multivariable adjustment,

TP remained significantly associated with PAC frequency (RR 1.45, 95% CI 1.24, 1.71;

p<0.0001).

In subgroup analyses, we found no evidence that the effect of age, height, NT-proBNP,

exercise and HDL cholesterol differed by sex, smoking status and age (all p values for

8
 DOI: 10.1161/CIRCULATIONAHA.112.112300

interaction >0.05). However, the effect of cardiovascular disease was much stronger among

women than among men (RR 5.30 versus 0.90, p for interaction <0.0001). We also found a

significant interaction of age, (p for interaction 0.002) height (p for interaction 0.002) and HDL

cholesterol (p for interaction 0.0002) with prevalent cardiovascular disease, suggesting that the

association between these factors and PAC frequency significantly differed among participants

with compared to those without cardiovascular disease, as shown in Table 3.

Discussion

In this large, population based study of individuals aged 50 years or older, we found that 99% of

all participants did have at least 1 PAC during 24-hour Holter monitoring. The PAC
PAC prevalence
pre
reva
vale
va lenc
le n e
nc

strongly
trongly increased with age from a median of 0.8 per hour among participants aged 50-55 years

to
o 22.6
.66 pper
er hhour ong those aged •70 years. These
among
ouur am
mon Th e e data are consistent
hes consiist
s en wi a smaller study
nt with

among
amon elderlyy individuals
mong inddiviidu
in alss from
d al from the
the Cardiovascular
Caard ar Health
diovvassculaar Heeal
ealth udyy 255. To oour
Study
lth St
tud ur kknowledge,
nowl
nowl
wled
ed
dgee, th
this
is iss

one
onne of the
the first
fir
irst
st studies
stud
tudies
diess to
to assess
asse
seess risk
ris
iskk factors
faacttor
orss associated
assso
soccia
ciated
d with
wit
ithh PAC
PAC frequency
freq
fr e uenncy
eq ncy in the
thee general
gen
neraal
al

population. Our
Ouur data
dataa show
sho
howw that
tha age,
age
g , height,
heig
he ight
ig ht,, history
ht hist
hi stor
storry of
o ccardiovascular
ardi
ardiov
diovas
ovascu
asc laar di
cu dise
disease,
seas
se ase,
ase, pphysical
hysi
hy siica
call activity,

natriuretic peptide levels and HDL cholesterol were significantly associated with the number of

PACs. While independent replication of our findings in other samples is needed, we nevertheless

believe that this study improves our knowledge on this common phenomenon.

The importance of PACs in the initiation and maintenance of AF has been suggested in

several studies 13-16, 26, 27. For example, PACs have previously been associated with an increased

risk of incident AF in population based cohort studies 13-16. Furthermore, Inoue et al found that

ablation of PACs in addition to pulmonary vein isolation was associated with a high probability

of recurrence-free survival among patients with persistent AF undergoing catheter ablation,

9
 DOI: 10.1161/CIRCULATIONAHA.112.112300

suggesting that these electrical triggers may play an important role in AF initiation 27. In

addition, subclinical atrial arrhythmias like PACs or pacemaker detected atrial tachyarrhythmias

have been related to an increased risk of stroke and death 13-18. Taken together, while our study

may not have immediate clinical implications, more data are urgently needed to better

understand the significance of our findings that PACs are present in the great majority of

individuals aged 50 years or above.

A history of cardiovascular disease and levels of natriuretic peptides were strongly related

with PAC frequency in this study, and the association with elevated troponin levels was of

borderline significance. The relatively small number of individuals with elevated troponin levels

may have limited our power to show an association. As shown in many prior studies,
stu
udies
es, elevated
es elev
elevat
evated
ated

levels
evels of natriuretic peptides and troponin probably reflect a higher burden of subclinical and

cl
lin
nic
ical
al sstructural
clinical truc
tr u turaal heart
uc he disease and increased wa
all tress 28-31, wh
l sstress
wall which
hic
i h in
n tturn
urn may favor PAC
15
occurrence
occu
currence
u . The
The fact
fact that
tha
hatt PVC
PVC frequency
freequ
fr equenncy was
wa strongly
strongl
glyy associated
gl asssooci
ciaateed with
wit
i h PAC
PA
AC frequency
freq
frequuenc
eq uencyy ma
may
ay

suggest
ugg
gges
estt that
es that mechanisms
mec
echa
haani
nissms for
for the
the occurrence
occcurr
oc currren
nce off at
aatrial
riaal
al aand
nd vventricular
enttri
ricu
cu
ulaar pr
premature
rem
mat
atuure
ure co
contractions
ont
ntracctio
ons

partly overlap.
overlap
ap.. Th
ap Thee po
posi
positive
siiti
t ve aassociation
ssoc
ss ocia
ociati
iation
ti n bbetween
e we
etween
en HR
HRVV an
andd PA
PACC fr
ffrequency
eque
equenc
uencyy ccould
nc ouuld be
be due
d e in part
du

to failure to exclude PACs from the RR intervals in the HRV analysis. Future studies using

echocardiography or other imaging tools are needed to clarify the mechanisms of how these

cardiac biomarkers relate to an increased PAC burden in the community, and whether the

severity of the underlying cardiovascular disease may have an impact.

By contrast, it is relatively unclear how adult height is related to PAC burden and incident

AF 8. It has been hypothesized that the increased risk among taller individuals is mainly due to

the close relationship between body size and LA size 8. Interestingly, we have previously shown

that the significant relationship between birth weight and AF is completely attenuated after

10
 DOI: 10.1161/CIRCULATIONAHA.112.112300

taking into account adult height 32, suggesting that genetic and/or early life determinants may

play an important role. Taken together, the available evidence raises the intriguing possibility

that the relationship between height and AF may be partly related to an elevated electrical

activity among taller individuals. Future studies are needed to further assess this hypothesis.

With regard to HDL-cholesterol, the strong inverse relationship with PAC frequency is in

agreement with the overall inverse relationship between HDL-cholesterol and cardiovascular

disease 33. With regard to AF, the data are less clear. While one prior study found an inverse

relationship between HDL cholesterol and incident AF among Japanese individuals 34, this

finding could not be confirmed in a more recent analysis, where no significant association

ustm nt 35. In tthe

between HDL-cholesterol and incident AF was observed after multivariable adjustment
adjuustm
men he

same
ame study, LDL cholesterol was inversely related to incident AF after extensive multivariable

ad
dju
ust ment 35. While
adjustment
stm
ment Whiile
Wh ile the underlying mechanisms
mechanism
ms for
fo these differing
differin
in
ng relationships
reela
lattionships
ti are unclear, it

ha bbeen
has een shown
wn tthat
hat bl
bblood
oood li
lipi
lipids
pids
pi ds ccould
ould
ou d aaffect
ffecct the co
composition
omp
posit
ositio
i n off tthe
io he ccell
e l me
el membranes,
emb
m raane
nes,
s am
s, major
ajo
aj or
or

determinant
dete
de term
te rm
min
inannt of
an of ccell tab liity 36 IIn
elll excitability
el exci
ex cittabi n th
thee fu
futu
future,
turee, th
tu thee role
rolee ooff lipi
llipids
ipiids
d aand
nd llipoproteins
ip
poppro
ote
t in
inss in arr
arrhythmia
rrrhy
yth
thm
miaa

developmentt ne
need
ed
ds to
needs t bbee be
bett
ttter
bettere ddefined.
e in
ef ined
d.

We found an inverse relationship between physical activity and PAC frequency. These

data are in agreement with at least one prior study that found an inverse relationship between the

amount of moderate exercise and incident AF among elderly individuals 37. However, the

association between exercise and AF occurrence is more complicated, as vigorous exercise has

been related to an increased risk of AF 38.

The fact that obesity and hypertension were not significantly related to PAC frequency

also deserves comment. Many studies have shown that obesity and hypertension are the two

most important potentially modifiable risk factors for incident AF 5, 7, 39-41 and that they are

11
 DOI: 10.1161/CIRCULATIONAHA.112.112300

strongly related to an elevated LA size 9, 10. These data in conjunction with the present findings

may suggest that obesity and hypertension are major determinants of structural LA remodeling

but do not influence the electrical activity of the atria.

Strengths and limitations

Strengths of the present study include its population-based design, the large sample size and the

large number of 24-hour Holter recordings available for analysis. Several potential limitations

also need to be taken into account for a balanced interpretation of this study. First, in this study

we evaluated a white, middle-aged to elderly population-based sample and our findings may not

be generalizable to other populations or patient groups. Furthermore, the small number of

ndividuals unwilling to participate or lost to follow-up 22 may be different to tho

individuals those
hose
se w
who
ho ffinally
inal
in ally
al ly

participated in this study. Second, this was a cross-sectional analysis, precluding the possibility

to
o infer
inf
nfer
er causal
cau
ausa
saal relationships
reela
lati
tionships orr provide clinical ou
outcome
tccome data. Thir
Third,
irrd,
d eechocardiography
choocardiography was not
ch

av
available
vaiila
l ble in our
ur sstudy,
tu
udy
dy, an
and
nd fu
futu
future
tu
ure st
sstudies
u iess aree needed
ud need
ded
d too directly
directtly relate
dire rellate the
the current
curr
urrent
rent findings
fin
ndi
dinngs
ngs too

structural
tru u al ccardiac
ucttur ardi
ar acc aalterations.
diac lter
lterrattio
ions Finally,
ns. Fi
ina
nall y, tthe
llyy,
ll hee nnumber
umbe
umb r ooff P
be PACs
AC recorded
Cs re
reco
corrded
co may
rded may hhave certain
avee a ce
av cer dday-to-
rt in day-
rtai ay--to
o-

day variability,
variabilit
ity,
y, w
which
hich
hi c w
ch wee were
wer unable
una
n bl
b e to assess,
ass
sses
ess,
ess, ggiven
iven
ive tthat
en hatt on
ha only
ly oone
ne rrecording
ecoord
ec rdin
i g pe
in perr in
indi
individual
d vidual wa
was
as

obtained. Assuming that this variability is random, this might have slightly reduced our power to

detect significant associations.

Conclusions

In this large population based study of individuals aged 50 years or older, only a small minority

of participants did not have at least one PAC on 24-hour Holter monitoring. Risk factors for PAC

frequency included age, height, a history of cardiovascular disease, physical activity, natriuretic

peptide levels and HDL cholesterol, but not hypertension and body mass index. These findings

may suggest differential risk factors for structural and electrical remodeling in the pathogenesis

12
 DOI: 10.1161/CIRCULATIONAHA.112.112300

of AF. Given the high PAC prevalence in this population and its negative prognostic impact,

more studies are urgently needed in order to better understand this phenomenon.

Acknowledgements: We would like to thank Dr. Christian Schindler for invaluable statistical
advice.

Funding Sources: The SAPALDIA study was supported by the Swiss National Science
Foundation; the Federal Office for Forest, Environment and Landscape; the Federal Office of
Public Health; the Federal Office of Roads and Transport; the canton’s government of Aargau,
Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, and Zurich; the Swiss Lung League; the Lung
g
Leagues of Basel-Stadt/Basel-Landschaft,, Geneva,, Ticino,, and Zurich. Assays
y for the
measurements of troponin T and NT-proBNP (both Roche diagnostics) were provided
prov
ovvid
ded
d ffree
reee of
re
charge by the manufacturer. Dr Conen received research grants from the Swiss National Science
Foundation ((PP00P3_133681).
PP00P3_133681). The funding orga
anizations had no role in the design and conduct
organizations
off the
the study;
study
dyy; in
in the
the collection,
col
olle
lect
ctio
ion, management,
manag
agem
e en
e t, analysis,
ana
naly
ly
ysiis, and
an
nd in
interp
pre
rettatiion ooff th
interpretation he da
the ddata;
ta; or
o iin
n the
prep
par
a ation, rev
preparation, evie
i w, oorr aapproval
ie
review, pppro
rova
vall of tthe
hee manuusc
uscrip
pt.
manuscript.

Conf
nfli
lictt of
Conflict of Interest
In
nte
tereest Disclosures:
Discl
clos
o ur
ures
es:: No
N ne.
None.

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17
 DOI: 10.1161/CIRCULATIONAHA.112.112300

Table 1. Baseline characteristics stratified by the median number of PACs per hour

Characteristic <1.27 PACs/h (N=869) •1.27 PACs/h (N=873) P value*

Number of PACs per hour 0.6 (0.3-0.9) 3.7 (2.0-9.6) -
Male gender, % 434 (49.9) 413 (47.3) 0.27
Age, years 58 (54-63) 63 (57-67) <0.0001
Height, m 1.68 (1.61-1.74) 1.67 (1.61-1.75) 0.48
Body mass index, kg/m2 26.3 (23.7-29.0) 26.3 (23.7-29.3) 0.95
Systolic blood pressure, mmHg 131 (118-142) 132 (121-146) 0.004
Diastolic blood pressure, mmHg 82 (75-88) 82 (75-89) 0.76
Historyy of hypertension,
yp ,% 386 ((44.4)) 416 ((47.7)) 0.18
Total Cholesterol, mmol/L 6.2 (5.5-7.1) 6.2 (5.6-6.9) 0.67
HDL Cholesterol, mmol/L 1.4 (1.2-1.7) 1.5 (1.2-1.8) 0.02
Triglycerides,
ycerides, mmol/L 1.7 (1.2-2.6) 1.6 (1.1-2.4) 00.05
.00
Diabetes,
etes, % 78 (9.0) 93 (10.7) 00.24
.24
2
Current
ent smoking, % 183 (21.1) 154 (17.7) 0.14
History
ry of cardiovascular disease, % 50 (5.8) 83 (9.5) 0.003
0.00
Intakee of beta
beeta blockers, s % 80 (9.2) 1002 (11.7)
102 0.0
0.09
Intakee off ca
calcium
alclciium
ium chchannel
chan
han
anne blockers,
nel bl
ne keers, %
ockers 35 (4.0) 4 (5.3)
46 0.22
Alcohol
holl co
ho consumption,
cons
n um
ns umptio ion,
n, % 0.09
<1x/day
<11x/dad y
da 589
589 (68.1)
( 8.
(6 8.1)
1) 590
59 (68.0)
(6
68.
8 0))
>1-2x/day
>
>1 -2x/
x day
x/ 177 (20.5)
( 0.5)
(2 . 153 (17.6)
5 (117.
7.6)
6))
••3x
3x ppere day
er 99 (11
(11.5)
1 .5)
5 125
2 (14.4)
(1
14.4)
4
4)
Highest
est
es education
s educ
du ation leve level,
el, % 0.04
Primary
Prim
Pr imaryry scschool
cho
h oll 63 ((7.3)
7 3)
7.3) 9900 ((10.3)
10.3)
10
0 )
Secondary
Seco
Se condndar
nd a y school
scho
sc hool
ho ol 572
572 (65.8)
( 5.
(6 5.8)
8) 574
74 (6 (65.8)
(655.8)
5.8)
8
College
Coll leg
egee or
o UniUniversity
nive
vers degree
r ityy de
egree
ee 2344 (2
23 (26.9)
(26.
6 9)
9 2088 (2((23.9)
3 9)
3.
Physical
icall aactivity,
ic cti
cttivit
ivit
ityy, % 00.09
.00
Rarely/Never (40.4)
3477 (4
34 (40.
0.4)
0. 4) (43.3)
3744 (4
37 (43.
3.3)
3))
00.5-1h/day
.5-
5-1h
1h/d/day
ay (32.1)
2755 (3
27 (322.1)
1) 292
292 (33.8)
(333.8)
(3 8)
•2h/day 236 (27.5) 198 (22.9)
NT-proBNP, ng/L 47 (28-82) 78 (45-135) <0.0001
NT-proBNP •125 ng/L 82 (11.7) 182 (26.5) <0.0001
Troponin T levels, ȝg/L <0.0001
<0.003 287 (40.9) 261 (38.1)
0.003-0.014 405 (57.8) 387 (56.4)
•0.014 9 (1.3) 38 (5.5)
Number of PVCs per hour 0.1 (0, 0.8) 0.6 (0.1, 6.2) <0.0001
Total power, ms2 3518 (2304, 5243) 4017 (2580, 5806) 0.0002
Data are median (interquartile range) or numbers (percentages). Number of observations across categories may not sum to the given number because of missing data.
PAC=Premature atrial contraction; HDL=High density lipoprotein, NT-proBNP=N-terminal pro-B-type natriuretic peptide; PVC=Premature ventricular contraction. *Based on
Wilcoxon rank sum tests for continuous variables and Chi-Square tests for categorical variables.

18
 DOI: 10.1161/CIRCULATIONAHA.112.112300

Table 2. Multivariable negative binomial regression model to assess correlates for the number of PACs per hour

Risk factor Risk ratio* 95% confidence interval P value

Age, per SD 1.80 1.60, 2.02 <0.0001
Sex 1.37 0.98, 1.91 0.07
Hypertension 0.95 0.76, 1.18 0.61
Cardiovascular disease 2.40 1.64, 3.51 <0.0001
Body mass index, per SD 0.97 0.88, 1.07 0.55
Current smoking 1.27 0.99, 1.63 0.06
Height,
ght, per SD 1.52 1.30, 1.78 <0.0
<0
<0.0001
.000
0011
Log NT-proBNP, per SD 1.27 1.13, 1.42 <0.0
<0 .000
000
0011
<0.0001
ponin levels
Troponin
<0.003 Reference Reference -
0.003-0.014 1.09 0.99, 1.20 0.08
•0.014 1.18 0.99, 1.40 0.07
HDL L Cholesterol,
Chol
Ch olles
estetero
terol,
ro l, per
per
e SDD 0.80 0.71, 0.90 0.0002
sic
ical
Physical al aactivity
ctiv
ct ivityy
Ra rely
ely
l /Never
Rarely/Never R e erren
ef
Referenceence
ce R eferren
Reference e cee -
00.5-1h/day
0. 5-1h
1h/day 00.92
.922
.9 0.74,
0 74
0. 7 , 1.
11.15
.155 0.46
0.4
.446
••2h/day
2h/d
2h / ay 00.69
.699
.6 00.54,
0. 5 , 00.87
54 .877 0.002
0.002
ciu
ium
Calciumum ch cchannel
annel bl bloc
ockers
oc rs
blockers 0.99
0. 99 00.63,
0. 6 , 11.56
63 .566 00.97
.97
Betaa bblockers
lock
lo
ock
cker erss
er 00.78
0. 78 00.55,
0. 555, 1.
1.11
.111 0.17
.17
Alcohol
ohool consumption
cons
co nsum mptptionn
<1x per dday
<1 ay Reference
R efferencncee Reference
R efference -
1-2x per day 00.96
.96 00.75,
.75 11.23
75, 1.
75 233 0.74
•3x
3 per dday 00.84
84 00.62,
62 11.1313 00.25
25
HDL=High density lipoprotein. NT-proBNP=N-terminal pro-B-type natriuretic peptide. SD=Standard deviation.
*Data are risk ratios per 1 SD increase for continuous variables or compared to the reference category for categorical variables. Risk estimates for all covariates
are adjusted for age, sex, body mass index, hypertension, cardiovascular disease, smoking, height, physical activity, alcohol consumption, use of calcium channel
blockers and/or beta blockers, HDL-Cholesterol, NT-proBNP and troponin.

19
 DOI: 10.1161/CIRCULATIONAHA.112.112300

Table 3 .Multivariable regression models for the number of PACs per hour, stratified by prevalent cardiovascular disease

Risk factor Cardiovascular disease absent Cardiovascular disease present P for interaction*
(n=1609) (n=133)
Age, per SD 1.59 (1.41, 1.80) 2.84 (1.91, 4.23) 0.002
Height, per SD 1.45 (1.24, 1.69) 2.19 (1.12, 4.29) 0.002
HDL Cholesterol, per SD 0.78 (0.69, 0.88) 0.88 (0.47, 1.67) 0.0002
Log NT-proBNP, per SD 1.33 (1.18, 1.49) 0.80 (0.50, 1.30) 0.12
Physical activity 0.14†
Rarely/Never Reference Reference -
0.5-1h/day 0.93 (0.75, 1.17) 3.58 (1.28, 9.99)
•2h/day 0.63 (0.49, 0.79) 2.63 (1.09, 6.38)
HDL=High
High density lipoprotein. NT-proBNP=N-terminal pro-B-type natriuretic peptide. SD=Standard deviation.
Data are
re risk ratios per 1 SD increase for continuous variables or compared to the reference category for categorical variables. Risk estimates for all covaria
covariates
are adjusted
usted for age, sex, body mass index, hypertension, cardiovascular disease, smoking, height, physical activity, alcohol consumption, use of calcium ch channel
blockers
rs and/or
and/o blockers,
/ r beta blo
ock HDL-Cholesterol,
ckers, H DL-Cholesterol, NT-proBNP and troponin.
DL
*P value
ue based
assed on
bas on a multiplicative
mult
mu ltip at vee interaction
iplicati n eraction term in the multivariable adjust
int adjusted,
ed nnon-stratified
d, no n-stratified regression model
†
Overall
all
ll p valu
value
alu
l e usin
using
ng a 2 degr
degree
gree
ee off freedom test.

20
 DOI: 10.1161/CIRCULATIONAHA.112.112300

Figure Legends:

Figure 1. Number of PACs per hour stratified by 5-year age categories. PAC=Premature

atrial contraction. h=hour. Data are medians, whiskers represent interquartile ranges. The p

value is based on a Kruskal-Wallis test across age categories.

Figure 2. Proportion of individuals with >70 PACs during the recording period.

PAC=Premature atrial contraction. Data are percentages. The p value is based on a chi-square

test across age categories.

21
P<0.0001
P<0.0001