Heart Rate Variability as a Measure of Disease State in ... · PDF fileAsian Nursing Research March 2008 Vol 2 No 1 5 REVIEW ARTICLE Heart Rate Variability as a Measure of Disease

5Asian Nursing Research ❖ March 2008 ❖ Vol 2 ❖ No 1

REVIEW ARTICLE

Heart Rate Variability as a Measure ofDisease State in Irritable

Bowel Syndrome

Hyo-Jung Park*, RN, PhD

Full-time Lecturer, Division of Nursing Science, College of Health Science, Ewha Womans University, Seoul, Korea

Heart rate variability (HRV) is a noninvasive measure of sympathovagal balance in the autonomic nervoussystem (ANS). This review will: (a) consider HRV measurement in irritable bowel syndrome (IBS); (b) dis-cuss the applicability of HRV measurement in IBS by addressing strengths and limitations; and (c) proposefuture directions in this field of gastrointestinal research and clinical practice. As a strength, analyzing HRVcomponents is a useful method and appears most suitable for detection of changes in ANS sympathovagalbalance in both stress and non-stress conditions with good validity and reliability. Also, it is an appropriatemeasure for ANS in studies with large populations, in both laboratory and clinical settings, and for longi-tudinal studies because of its noninvasive assets. With regard to limitations of measuring HRV, these arepoor standardization, additional human editing, not considering medication or other confounding factors,inconsistent results in gastrointestinal vagal tone study, and different time periods. [Asian Nursing Research2008;2(1):5–16]

Key Words autonomic nervous system, heart rate variability, irritable bowel syndrome

*Correspondence to: Hyo-Jung Park, RN, PhD, Full-time Lecturer, Division of Nursing Science, College ofHealth Science, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Ku, Seoul 120-750, Korea.E-mail: [email protected]

INTRODUCTION

Heart rate variability (HRV) may provide a new andmore powerful approach for evaluating the auto-nomic nervous system (ANS) in patients with irrita-ble bowel syndrome (IBS). IBS is a common chronicfunctional gastrointestinal (GI) disorder character-ized by chronic intermittent symptoms includingabdominal discomfort/pain, diarrhea, constipation,and bloating. More than 80% of IBS patients com-plain of stress-induced exacerbation of GI symptoms(Levy, Cain, Jarrett, & Heitkemper, 1997;Whitehead,

Crowell, Robinson, Heller, & Schuster, 1992). Sev-eral studies have demonstrated an increased visceralsensitivity and gut dysmotility caused by variousstimuli such as mental stress and meals (Clemens,Samsom, Van Berge Henegouwen, & Smout, 2003;Elsenbruch & Orr, 2001; Gupta, Sheffield, & Verne,2002; Hausken et al., 1993; Mayer, 2000; Mertz,Naliboff, Munakata, Niazi, & Mayer, 1995; Naliboffet al., 1997; Verne, Robinson, & Price, 2001). Thepathophysiology of IBS remains poorly understood.Hence many investigators try to seek the pathogenesisof IBS in patients using several tests. Dysfunction of

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the ANS may be important for the development ofabnormalities of GI motility and visceral perception.The first study dates back to 1928, when Bockus,Bank, and Wilkinson suggested IBS symptoms wereassociated with an imbalance of ANS function. Morerecently, there are a growing number of studies usingHRV to assess the function of the ANS in patientswith IBS.

Thus, the objectives of this review are to: (a)consider the relationship between IBS and HRVmeasurement; (b) discuss the applicability of HRVmeasurement in IBS by addressing strengths and limi-tations; and (c) propose future directions in this fieldof GI research and clinical practice. This paper pro-vides a review of current knowledge of the usefulnessof measurement of HRV in IBS.

HRVHRV is a noninvasive, indirect method of measuringbalance/imbalance of the parasympathetic nervoussystem (PSNS) and sympathetic nervous system(SNS). Originally it was assessed manually from cal-culations of the mean R-R interval and its standarddeviation measured on short-term (2–5 minutes)electrocardiograms (ECG). Recently, the availabilityof increased computing power, innovative micropro-cessor technology, and the remarkable technologicaldevelopments in recording have enabled the analysisof 24-hour long-term records (Task Force of the Euro-pean Society of Cardiology and the North AmericanSociety of Pacing and Electrophysiology, 1996).

Analysis of HRV can be divided into time domainanalysis and frequency domain analysis.Time domainanalysis, known as nonspectral or statistical analysis,is a general measure of ANS balance. Time domainanalysis of HRV is correlated with total variance ofthe heart signal and PSNS (Hayano et al., 1991;Kleiger, Stein, Bosner, & Rottman, 1992; Task Forceof the European Society of Cardiology and the NorthAmerican Society of Pacing and Electrophysiology,1996). The SD 24-hr is the simple standard devia-tion of the set of R-R intervals in a 24-hour period.SD-5-min is the mean of the standard deviations ofnormal R-R intervals for all 5-minute blocks in afull 24-hour ECG recording. The root mean square

successive difference (RMSSD) is the squared dif-ference between two adjacent normal R-R intervalscomputed over the entire 24-hour period. The RR50is the total number of occurrences in a 24-hour pe-riod in which the difference between two successiveR-R intervals exceeds 50 milliseconds. The %RR50(pNN50) is the percentage of the absolute differencebetween adjacent normal R-R intervals that are greaterthan 50 milliseconds computed over the entire 24hours (Kleiger et al.;Task Force of the European Soci-ety of Cardiology and the North American Societyof Pacing and Electrophysiology).

Frequency domain analysis of HRV, known aspower spectral analysis, contains two major spectralcomponents: the high frequency (HF) component(0.15–0.40 Hz) and the low frequency (LF) compo-nent (0.03–0.15Hz or 0.04–0.15Hz or 0.05–0.15Hzdepending on the research) (Akselrod et al., 1981).Normal frequency range has not yet been firmlyestablished. Some studies used medium-frequencypower (MF) (0.07–0.15Hz) (Heitkemper et al., 1998;Karling et al., 1998; McCraty,Atkinson,Tiller, Rein, &Watkins, 1995). Total power is the energy in theheart period power spectrum up to 0.40 Hz. Fre-quency domain analysis of HRV has been used as asensitive index of ANS activities because it can helpdistinguish SNS from PSNS regulation of the sino-atrial node. Dominance by the SNS leads to the fight/flight reaction and PSNS dominance tends to have a rest/digest effect.The HF component has been con-sidered the respiratory sinus arrhythmia (RSA) andis mediated solely by the PSNS, whereas the LF com-ponent corresponds to blood pressure oscillationsand is jointly modified by the PSNS and the SNS.Therefore, HF is considered a pure measure of PSNSactivity and LF is less clear and considered a mixedANS marker. HF is highly correlated with the timedomain variables of RMSSD and %RR50; these threecomponents provide an estimate of PSNS activity(Delaney & Brodie, 2000; Kleiger, Miller, Bigger, &Moss, 1987; Ori, Monir, Weiss, Sayhouni, & Singer,1992). In addition, the LF/HF ratio is a useful param-eter that reflects the balance of ANS activities.The LF/HF ratio was significantly greater in healthy subjects(Achten & Jeukendrup, 2003).

H.J. Park

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The polar software system consists of very lowfrequency (VLF) power from 0.0033 Hz to 0.04 Hz,LF power from 0.04 Hz to 0.15 Hz, and HF powerfrom 0.15 Hz to 0.40 Hz. VLF indicates SNS activ-ity. The ultra low frequency (ULF) at 0–0.0033 Hzmay represent humoral and thermoregulatory factors.However, as very slow rhythms are assessed only overlong periods, this component is not always analyzed(Pagani et al., 1986).The physiological mechanisms ofthe ULF and VLF band widths can be modulated byrenin-angiotensin system and/or temperature regula-tion (Akselrod et al., 1981).

The logarithms (e.g. ln%RR50, lnRMSSD, lnHF,lnLF) or logit transformation (e.g., logit50) are some-times chosen because the individual median valuesare not distributed normally, but fit a normal log orlogit distribution.The logarithms or logit transforma-tion are easy to calculate and are highly correlated withthe spectral estimate of cardiac vagal tone. In addition,the logarithm or logit transformation are useful fora small sample and for subjects with a very low levelof HRV (Burr, Motzer, Chen, Cowan, & Heitkemper,2003; Moser et al., 1998). Hence, indicators of ANSimbalance are LF/HF, SD-5-min/RMSSD, and sqLF/HF. These three higher values represent greaterSNS and lower PSNS activity. Indicators of generalANS activity are SD-5-min and lnLF. Indicators ofPSNS activity are HF, RMSSD, and %RR50 (Jarrettet al., 2003; Kleiger et al., 1987).

Effects of confounding variables on HRVThere are several possible different confounding vari-ables that affect HRV, such as gender, age, body posi-tion (supine/standing), breathing frequency, bodymass index (BMI), systolic blood pressure, physicaland mental stress, pain, hormonal fluctuation, familyhistory, genetic, medication, and life-style factors suchas eating, smoking, alcohol, coffee consumption, andhabitual physical activity (Parati & Di Rienzo, 2003).

Age and gender, in particular, have been found toinfluence PSNS tone.There is a significant tendencyfor decreased HRV with increasing age (Cowan,Pike, & Burr, 1994).This is reflective of a reduction inthe absolute values of PSNS and SNS activity (Aubert,Seps, & Beckers, 2003). In general, healthy women

have a lower HRV than do healthy men due to thereduced variance in sympathetic activity (reduced LFand LF/HF) in females (Cowan et al.; Jensen-Urstadet al., 1997;Thayer, Smith, Rossy, Sollers, & Friedman,1998). Also, the luteal phase of the menstrual cyclewas associated with a greater increase in LF and a greater decrease in HF, resulting in a higher LF/HFratio. This suggests SNS activities in young collegewomen (mean age: 19.2 years) are predominant inthe luteal phase as compared with the follicular phaseduring the menstrual cycle despite using a small num-ber of subjects (N = 20) (Sato, Miyake, Akatsu, &Kumashiro, 1995).

HRV decreases significantly with increasing BMIdue to depressed sympathetic modulation of the heartassociated with excessive body weight (Karason,Molgaard, Wikstrand, & Sjostrom, 1999).

Exercise training studies have shown to have asignificantly positive effect on HRV (Aubert et al.,2003). Also, biofeedback and relaxation tasks havebeen found to be beneficial (Cowan, Kogan, Burr,Hendershot, & Buchanan, 1990).

With regard to medication, treatment with tri-cyclic antidepressants (TCAs) reduces HRV (Agelink,Boz, Ullrich, & Andrich, 2002; Khaykin et al., 1998).Treatment with selective serotonin reuptake inhib-itors (SSRIs) normalizes HRV (Tucker et al., 1997;Yeragani & Rao, 2003). The effects of beta-blockersincrease HRV, as reflected by augmented vagal activityunder stress (Sandrone et al., 1994).

FINDINGS

Articles were searched from Medline and CINAHLfrom 1990 through November 2007 to identify stud-ies with the key words IBS and HRV. Studies wherethe measurement of HRV was assessed in a singlegroup of subjects before and after a procedure wereexcluded. Table 1 shows the summary of the mea-surement of HRV in IBS studies including samplesize, characteristics of subjects, methods, parametersof HRV, and results.

Most studies were published recently—all but two(Aggarwal et al., 1994; Jorgensen et al., 1993) since

Heart Rate Variability

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H.J. Park


Table

1

Sum

mar

y of

Stu

dies

on

the

Rel

atio

nshi

p B

etw

een

HR

V a

nd I

BS

Stu

dyS

ubj

ects

(m

ean

age

=yr

)M

eth

ods/

Var

iabl

esP

aram

eter

of

HR

VR

esu

lts

Ade

yem

i IB

S (n

=35

, mea

n ag

e=

39.1

±9.

5,

Supi

ne, s

tand

ing

posi

tion,

FD

(H

F, L

F, V

LF, H

Rav

)*I

BS:

↑SN

S in

the

rest

, ↓P

SNS

in

et a

l., 1

999

M:2

6, F

:9, 2

7 [7

7%]:

C-I

BS)

vs.

and

deep

bre

athi

ngor

thos

tatic

str

ess

heal

thy

C (

n=

18, m

ean

*Men

with

IB

S ha

ve le

ss v

agal

tone

ag

e=

38.2

±6.

5, M

:12,

F:6

) (↓

PSN

S) th

an w

omen

with

IB

S

Agg

arw

al

C-I

BS

(n=

10, F

:7, M

:3)

vs.

VC

(va

soco

nstr

icto

r), P

AR

R

RIV

*C-I

BS:

↓P

SNS

duri

ng d

eep

brea

thin

get

al.,

199

4D

-IB

S (n

=11

, F:5

, M:6

) vs

.(p

ostu

ral a

djus

tmen

t rat

io),

*D-I

BS:

↑SN

S re

spon

seC

(n

=49

, F:2

8, M

:21

-AN

S te

st)

STM

P, d

eep

resp

irat

ion,

*C

-IB

S: ↑

psyc

holo

gica

l dis

tres

s U

sing

man

ning

cri

teri

aR

RI

V(R

-R in

terv

al),

col

on(m

ore

wom

en)

Mea

n ag

e=

42.3

yr

tran

sit (

radi

o-op

aque

*N

o ge

nder

diff

eren

ce a

naly

sis

*Mor

e w

omen

hav

e C

-IB

S sy

mpt

omm

arke

rs)

Bur

r IB

S (n

=10

6, 1

8–45

) w

omen

vs.

HR

V (

Hol

ter-

mon

itori

ng)

TD (

SD-5

-min

, RM

SSD

, *W

omen

with

sev

ere

pain

(39

%)

and

et a

l., 2

000

C (

n=

41, 1

8–45

) w

omen

, %

RR

50, S

D-5

-min

/w

ithou

t pos

tpra

ndia

l pai

n (4

9%):

to

tal m

ean

age:

33

yrR

MSS

D, H

Rat

e 24

-hr)

↓PSN

SFD

(ln

HF,

sqL

F/H

F)

Els

enbr

uch

&P

ostp

rand

ial r

espo

nse

in C

-IB

S Sa

liva

cort

isol

con

cent

ratio

n,FD

(H

F, L

F, L

F/H

F,

*D-I

BS:

↑SN

S/P

SNS

bala

nce

(LF/

HF

Orr

, 200

1(n

=12

) w

omen

vs.

D-I

BS

(n=

12)

HR

, HR

V (

two

30-m

in

%H

F, %

LF)

ratio

), ↓

PSN

S (H

F) a

fter

mea

l and

a

wom

en v

s.C

(n

=20

, po

stm

eal r

ecor

ding

), G

I si

gnifi

cant

pos

tpra

ndia

l in

↑cor

tisol

mea

n ag

e=

32.5

±1.

1) w

omen

, sy

mpt

oms

(bas

elin

e an

d *L

ittle

diff

eren

ce in

oth

er la

bora

tory

IB

S (m

ean

age

=32

.8±

1.4)

afte

r m

eal)

AN

S m

easu

res

Hei

tkem

per

IBS

wom

en (

n=

25, m

ean

HR

V (

Hol

ter-

mon

itori

ng:

FD (

HF,

MF,

LF,

MI,

*I

BS

↓PSN

S (H

F) v

s. C

at n

ight

et a

l., 1

998

age

=32

.6±

8.0)

vs.

C w

omen

m

id-l

utea

l pha

se).

One

LF

/HF)

loga

rith

mic

*3

5% p

rese

nce

of s

igni

fican

tly lo

w le

vel

(n=

15, m

ean

age

=32

.5±

8.6)

men

stru

al c

ycle

with

tr

ansf

orm

s (L

F, M

F,

of v

agal

tone

obs

erve

d in

pat

ient

sa

sym

ptom

dia

ryH

F), s

quar

e-ro

ot

with

IB

S du

ring

the

slee

ping

inte

rval

tran

sfor

m (

LF/H

F)*S

yste

mic

sym

path

ovag

al im

bala

nce

in w

omen

with

IB

S

Hei

tkem

per

IBS

wom

en (

n=

103,

mea

n ag

e=

HR

V (

Hol

ter-

mon

itori

ng:

TD (

SD-5

-min

, SD

AN

N,

*Wom

en w

ith s

ever

e to

ver

y se

vere

et

al.,

200

132

.6±

8.1)

vs.

C w

omen

m

id-lu

teal

pha

se),

E/I

rat

io,

SD-2

4-hr

, RM

SSD

, sy

mpt

om h

ave

diffe

renc

es in

(n

=49

, mea

n ag

e=

32.2

±7.

7)V

alsa

lva,

pos

ture

cha

nges

, %

RR

50, S

D-5

-min

/24

-hr

HR

Vco

ld p

ress

orR

MSS

D),

FD

(H

F, L

F,

*Sev

ere

D-I

BS:

↑P

SNS

& ↓

SNS/

LF/H

F, s

quar

e ro

ot o

f P

SNS

bala

nce

LF/H

F), M

I*S

ever

e C

-IB

S: ↓

PSN

S &

↑S

NS/

PSN

S ba

lanc

e

Jarr

ett

IBS

wom

en (

n=

163,

anx

iety

: 73,

HR

V (

24-h

r H

olte

r TD

(SD

-5-m

in, R

MSS

D,

*No

diffe

renc

es in

SN

S/P

SNS

bala

nce

et a

l., 2

003

depr

essi

on: 8

6) w

ith h

isto

ry o

fm

onito

ring

)%

RR

50, S

D-5

-min

/be

twee

n gr

oups

02-ANR-E1102.qxd 3/22/2008 4:30 PM Page 8

9



anxi

ety

and

depr

essi

ve d

isor

der v

s.R

MSS

D),

FD

(H

F, L

F,

*IB

S-A

nxie

ty &

IB

S-D

epre

ssio

n:

IBS

wom

en w

ithou

t his

tory

of

LF/H

F, s

quar

e ro

ot o

f ↓P

SNS

rela

tive

to I

BS-

Con

trol

anxi

ety

and

depr

essi

ve d

isor

der

LF/H

F)(n

=46

) al

l wom

en: 1

8–49

yea

rs

Jorg

ense

n Fu

nctio

nal a

bdom

inal

pai

n (n

=22

,A

CTH

and

ser

um c

ortis

olTD

(M

SSD

)*P

atie

nts

with

func

tiona

l abd

omin

al

et a

l., 1

993

mea

n ag

e=

37 [1

6–60

], F:

14, M

:8)

HR

and

sys

tolic

blo

od te

st,

pain

: ↑P

SNS

(RM

SSD

[ba

sal P

SNS

vs.o

rgan

ic a

bdom

inal

pai

n (n

=26

, H

RV

(ev

ery

5 m

in d

urin

g ne

ural

effe

ct])

& ↓

SNS

(red

uced

m

ean

age

=42

[18

–62]

, F:1

1,

rest

and

str

ess)

SNS

neur

al r

espo

nse)

in p

atie

nts

M:1

5) v

s.he

alth

y co

ntro

ls (

n=

14,

with

bot

h fu

nctio

nal o

rgan

ic p

ain

mea

n ag

e=

36 [

23–5

0], F

:9, M

:5)

*No

sign

ifica

nce

in H

R, S

BP,

AC

TH,

adre

nalin

e, c

ortis

ol

Kar

ling

IBS

(n=

18, m

ean

age

=31

.6

Dur

ing

supi

ne a

nd ti

lting

FD

(LF

, MF,

HF)

*Sig

nific

ant i

ncre

ased

sym

path

etic

et

al.,

199

8[2

0.6–

52.3

], F

:14,

M:4

) vs

.(u

p to

70°

)ac

tivity

(M

F): ↑

SNS

in I

BS

grou

p C

(n

=36

, mea

n ag

e=

31.4

th

an C

dur

ing

supi

ne a

nd ti

lting

[20.

8–52

.3])

*No

diffe

renc

es in

PSN

S ac

tivity

in

IBS

grou

p

Lee

C-I

BS

(n=

20, m

ean

age

=48

.9±

SSR

, RR

IV (

R-R

inte

rval

R

RIV

*C-I

BS:

↓P

SNS

(RR

IV)

than

D-I

BS

et

al.,

199

816

.3, F

:6, M

:14)

vs.

D-I

BS

(n=

20,

vari

atio

n) d

urin

g re

st a

nd

or C

dur

ing

deep

bre

athi

ngm

ean

age

=49

.2±

15.6

, F:6

, de

ep b

reat

hing

*No

grou

p di

ffere

nces

in

M:1

4) v

s.he

alth

y C

(n

=20

, ps

ycho

logi

cal d

istr

ess

mea

n ag

e=

50.7

±17

.4, F

:6, M

:14)

Orr

IB

S (n

=15

, mea

n ag

e=

34.9

±2.

1,

HR

V: 1

hr

of p

re-s

leep

FD

(LF

, HF,

LF/

HF)

*LF

is s

igni

fican

tly g

reat

er in

IB

S et

al.,

200

0F:

13, M

:2)

vs.C

(n

=15

, w

akin

g an

d 7

hr s

leep

grou

p du

ring

wak

ing.

LF/

HF

ratio

mea

n ag

e=

36.2

±2.

3, F

:13,

M:2

)is

sig

nific

antly

gre

ater

in I

BS

grou

pdu

ring

RE

M s

leep

*IB

S gr

oup

has

grea

ter

sym

path

etic

ac

tivity

dur

ing

wak

ing

and

duri

ng

RE

M s

leep

. Gre

ater

sym

path

etic

do

min

ance

in I

BS

grou

p

Thom

pson

IB

S w

omen

(n

=33

, mea

n ag

e=

37)

HR

V: 3

0 m

in o

f pre

-sle

epFD

(LF

, %H

F, L

F/H

F)*D

urin

g R

EM

sle

ep, I

BS

only

gro

up:

et a

l., 2

002

IBS

(n=

16),

IB

S +

D (

n=

17)

vs.

wak

ing

and

BD

I, G

I ↓P

SNS

rela

tive

to I

BS

+ D

and

he

alth

y C

wom

en (

n=

38,

sym

ptom

que

stio

nnai

reC

gro

upm

ean

age

=38

)*D

urin

g R

EM

sle

ep, t

he r

atio

LF/

HF

Usi

ng R

ome

I cr

iteri

ais

sig

nific

antly

hig

her

in I

BS

only

pat

ient

s

C-I

BS

=co

nstip

atio

n-pr

edom

inan

t IB

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02-ANR-E1102.qxd 3/22/2008 4:30 PM Page 9

1998. A total of 12 studies were identified using cri-teria of key words IBS and HRV, and publication inEnglish.All studies had healthy controls as comparinggroups. One study included an organic abdominalpain group as a comparing group as well (Jorgensenet al.).

Study populationStudies ranged from 30 to 209 total subjects, withan average sample size of 85, and a median samplesize of 60. The number of IBS subjects ranged from12 to 163, with an average sample size of 42, and a median sample size of 22. IBS subjects sometimeswere divided by stool type or severity even though a large sample size was used. Therefore, most studiesutilized a small number of subjects for analysis.

The subgroups of constipation-predominant anddiarrhea-predominant patients with IBS were toosmall to enable comparison (Karling et al., 1998).Many studies failed to clearly describe the numberand characteristics of non-participants. Some stud-ies described only age range or total mean age so itwas difficult to estimate a mean age and a median agein all studies. If selecting studies shown mean age,the mean age of study subjects was 37 years old withthe median age 36 years old. The duration of symp-toms was reported in all studies and was typicallychronic.While all subjects in six studies were women,men participated in six studies in both IBS and con-trol groups, though in smaller numbers than women.However,Adeyemi, Desai,Towsey, and Ghista (1999)used a predominantly male sample of IBS patients(26 men and 9 women) and healthy controls (12 menand 6 women).Average subjects had attained at leasta high school education. Few studies mentioned raceor ethnicity. Most studies used Caucasians.The coun-try was the US in eight studies, United Arab Emiratesin one (Adeyemi et al.), Denmark in one (Jorgensenet al., 1993), Sweden in one (Karling et al.), andTaiwan in one (Lee et al., 1998).

All but two studies (Aggarwal et al., 1994;Jorgensen et al., 1993) used Rome criteria. IBSpatients were referred to gastroenterology clinics orinstitutes of health research in five studies (Adeyemiet al., 1999; Aggarwal et al.; Elsenbruch & Orr, 2001;

Karling et al., 1998; Orr, Elsenbruch, & Harnish, 2000),outpatient clinics in two studies (Jorgensen et al.;Lee et al., 1998), and community care in the otherfive studies.Therefore, several studies mainly recruitedin a restricted geographical area. The selection sub-groups were constipation-predominant IBS versusdiarrhea-predominant IBS, postprandial pain, painseverity, functional versus organic disorders, IBS witha history of depression or anxiety versus IBS withouta history of depression or anxiety, and IBS versusIBS with dyspepsia. Four studies classified sub-groups into predominant bowel habit (Aggarwal et al.; Elsenbruch & Orr; Heitkemper et al., 2001;Lee et al.) and one study divided subgroups into post-prandial pain intensity (Burr, Heitkemper, Jarrett, &Cain, 2000). One study classified subgroups intowomen with a history of anxiety and depressionwho have IBS (Jarrett et al., 2003) and other studiesdivided into IBS versus Control.

Parameters of HRVFour studies used 24-hour Holter monitoring (Burret al., 2000; Heitkemper et al., 1998; Heitkemper et al., 2001; Jarrett et al., 2003) and other studieshave been obtained during a short period of 2–5minutes. The Heitkemper studies used all womensubjects so there is no study using both gender and24-hour Holter monitoring. Selecting between theshort and the long periods of EKG recording dependson the objective of the study. For example, a 24-hourECG recording provides an average value of eachcomponent for the entire recording period. However,there are inconsistent recordings underlying HRVbecause of sleep, exercise, deep breathing, and others(Task Force of the European Society of Cardiologyand the North American Society of Pacing and Elec-trophysiology, 1996). Also, it is important to differ-entiate responses noted under stressful conditionsand data obtained from individuals under restingconditions in short-term recording. If subjects havearrhythmia, ectopic beats, and missing data, long-termrecording is better than short-term recording. Onthe other hand, short-term recording is better thanlong-term recording if subjects do not have ectopicbeats, arrhythmia, or noise effects (Bigger et al., 1992).

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Five studies tested HRV during postural changeor deep breathing or tilting (Adeyemi et al., 1999;Aggarwal et al., 1994; Heitkemper et al., 2001; Karlinget al., 1998; Lee et al., 1998) and two studies testedduring sleep (Orr et al., 2000;Thompson, Elsenbruch,Harnish, & Orr, 2002). The majority of studies usedfemale populations, so it is difficult to find a gender-difference in HRV of IBS. Also, gender-related dif-ferences in HRV have not been studied or analyzedvery well in this area. Comparisons of the vagal tonein males and females based on symptom subgroupsremain to be studied. Most studies used frequencydomain analysis; only one study used time domainanalysis (Jorgensen et al., 1993) and the other twostudies used only RR-interval (Aggarwal et al.; Leeet al.). Frequency domain analysis is a more sophis-ticated method for distinguishing between the dif-ferent components (e.g., PSNS, SNS, SNS/PSNS) inHRV than the time domain method; it would begood to compare the diarrhea-predominant with theconstipation-predominant subgroup of patients withIBS in terms of differences in ANS function.

RESULTS

There were inconsistent results in the studies. It wasdifficult to generalize the conclusions because eachstudy had a small sample size (IBS subgroup sub-jects: 10–86) and used different subgroup categoriesas mentioned before. Twenty-five women with IBShad lower vagal tone compared to 15 healthy controls(Heitkemper et al., 1998). Subjects with constipation-predominant IBS had lower PSNS tone (HF, RRIV)and elevated ANS balance (LF/HF) while those withdiarrhea-predominant IBS had greater PSNS toneand depressed ANS balance (Aggarwal et al., 1994;Heitkemper et al., 2001; Lee et al., 1998). In theHeitkemper study, there was no difference in 24-hourHRV measure between women with IBS (n = 103)compared to controls (n = 49). However, there was adifference in those women who reported severe IBSsymptoms. Therefore, certain subgroups were moreor less suitable for HRV measurement. A similar re-sult was demonstrated in patients in the constipation

group (n=27 out of 35 IBS patients) in deep breathing(Adeyemi et al., 1999). The same result was shownin women in the diarrhea-predominant group (n = 12)after a meal in Elsenbruch and Orr’s study (2001).In this study, there were no significant differencesbetween women with predominant constipation andthe control group related to meals.

Karling et al. (1998) showed significantly increasedSNS activity (MF) in the IBS group (n = 18) whencompared to the control group (n = 36) during thesupine position and tilting (head up to 70°). No dif-ferences in PSNS activity (HF) was found in the IBSgroup (Karling et al.).With regard to symptom sever-ity, HRV measurement was effective in subgroupswho reported severe and very severe symptoms(Heitkemper et al., 2001). In addition, women withsevere pain and without postprandial pain had lowervagal tone (Burr et al., 2000). Both functional andorganic abdominal pain related to reduced SNS re-sponses were shown (Jorgensen et al., 1993). Signifi-cantly greater SNS activity (LF) was shown in IBSpatients (n = 13) during waking and a significantlygreater LF/HF ratio was shown in IBS patients duringREM sleep (Orr et al., 2000). Similarly, higher SNSactivity (elevated LF/HF ratio) during REM sleepwas shown in the IBS only group (n=16) (Thompsonet al., 2002). Regarding anxiety and depression, re-duced vagal tone in women with IBS had been asso-ciated with depression and anxiety (Jarrett et al.,2003); this study provided evidence for the relation-ship between mood state and physiological indicator,which changes visceral motility.

Overall, these studies suggested changes in ANSfunction were shown in patients with IBS and maydiffer among subgroups. For example, the majorityof patients were those with alternating symptomsof diarrhea and constipation, the ANS function ab-normality was obscure. It may be there are differentresults in the alternating IBS symptom subgroup orin those who experience constipation alone. It is stillunclear if ANS function may increase GI symptomsincluding visceral sensitivity and motility alterationor is the result of abdominal pain sensitivity and dis-comfort. Pain and bloating may reflect visceral hyper-sensitivity (Ragnarsson & Bodemar, 1999).They found



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there was no relationship between pain/bloating andprone bowel pattern so there might be differentmechanisms in symptoms. There has been no studyregarding the relationship between bloating symp-toms and ANS function so far. The inclusion of agroup of women with bloating symptoms in a futurestudy is both critical and significant for HRV databasedevelopment and understanding of the underlyingmechanisms of IBS in IBS research.

DISCUSSION

StrengthFirstly, HRV and its components were a useful andsimple method and appeared the most suitable fordetection of changes in integrated ANS sympatho-vagal balance in both static and dynamic conditionsin IBS patients. Many studies have shown HRV wasa useful tool to assess the ANS characteristics andresponses in IBS patients because it could help dis-tinguish sympathetic from parasympathetic regulationof the sinoatrial node. Therefore, it could providevaluable information to health care providers andresearchers. The use of this methodology has provento be pathophysiologically and clinically reliable, validand more sensitive in both psychological and physi-ological variables than conventional cardiovasculartests. It may offer a unique insight, including the pos-sibility of predicting disease outcome and assessinga combination of enhanced mental load and otherstressors. It may allow monitoring of the effect oftherapeutic interventions on gut autonomic regula-tion as compared to other ANS measures. For instance,skin temperature was an insensitive measurementof sympathetic cholinergic response. Studies usinglaboratory measures of ANS function have only founddifferences when stool-type subgroups are compared(diarrhea-predominant vs. constipation-predominant)or in IBS patients with severe symptoms (Burr et al.,2000; Heitkemper et al., 2001). Also, heart rate andblood pressure were found to be less sensitive thanHRV between IBS patients and healthy controls inlaboratory testing (Heitkemper et al.; Huikuri et al.,1999; Jorgensen et al., 1993; Karling et al., 1998;

Sato et al., 1995); there is a difference using HRV asan outcome variable even though there are no dif-ferences using heart rate and blood pressure in thesame study. Thus, study of the effects of exposure to stressors may be misleading if only differences inheart rate are examined.

Secondly, HRV is an appropriate measurement instudying large populations, in both laboratory andclinical settings, and in longitudinal studies becauseit is easily and noninvasively performed. Hence sub-jects have less stress and need only minimal subjectcollaboration. In addition, it suggests cost-effectivemeasurements compared to other cardiovasculartests.

Thirdly, the analysis of continuous 24-hour ECGdata recordings allows one to observe variations oc-curring throughout the day and night for circadianpattern detection. It is a comprehensive assessmentnot only of fast, but also of slower and sometimesless regular, heart rate fluctuations. A more sophisti-cated approach to the study of HRV based on spectralmethodology proves to adequately assess the sym-pathovagal balance. In addition, it provides variousnaturalistic activities under a natural environmentrather than a laboratory environment.

LimitationsFirst of all, even though there have been progressivetechnological improvements in Holter processing sys-tems, most studies require additional human edit-ing. HRV is calculated after removal of aberrant beats.Some software packages contain an automatic defaultfiltering procedure and a removal of any aberrant beatsmanual procedure. Also, ambulatory ECG recordinghas difficulty in controlling for activity, posture, andrespiration. In addition, most software and analysismethods are different. Standardization of HRV mea-surement has remained poor even though it has beenTask force presented (Task Force of the EuropeanSociety of Cardiology and the North American Soci-ety of Pacing and Electrophysiology, 1996). There isa need for standardization in methodology to facil-itate the interpretation and comparison of results.More exact methodology is essential to extract theinformation embedded in HRV.

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Secondly, there is the limitation that cardiac vagaltone may not reflect gastrointestinal vagal tone. Eventhough it is a sensitive method for balance (LF/HF)or PSNS activity (HF), it is less sensitive for SNSactivity (LF: mixed marker of SNS and PSNS) inthe GI system (Jarrett et al., 2003; Jorgensen et al.,1993). Heitkemper and coworkers (2001) have shownit is more sensitive to test ANS symptoms in womenwho report severe and very severe symptoms.There-fore, further studies of the relationship between GIand cardiac vagal tone is needed; is there any differ-ent role between GI vagal fiber and cardiac vagalfiber? Also, it would be better practice to combineHRV measures with biochemical measures such asepinephrine and norepinephrine.

Considering limitations of research design in pre-vious studies, there are issues related to subjects orcovariance variables. Several studies have small sam-ple sizes with limited statistical power. Also, severalstudies have a small number of patients across a widerange of ages, mainly recruited in a restricted geo-graphical area (Aggarwal et al., 1994; Elsenbruch &Orr, 2001; Lee et al., 1998; Orr et al., 2000). Thereare limitations in age and gender differences as wellas ovarian hormone status differences in women.As mentioned earlier, the age dependency of vagaltone is quite pronounced (Cowan et al., 1994; Jensen-Urstad et al., 1997; Thayer et al., 1998). Confound-ing variables might be responsible for IBS patients.Smoking is associated with decreased HRV so re-searchers should try to control for smoking status(Hayano et al., 1990). In addition, several studies didnot include different ethnic groups. Most studiesuse Caucasians. Moreover, control groups have notalways been matched for age and sex even thoughboth factors are known to influence ANS function(Cowan et al.; Jensen-Urstad et al.; Thayer et al.).Some studies did not control for the menstrual cycle(Orr et al.). Even though the above review demon-strates medication or other conditions contribute toHRV, medicated and unmedicated patients were notcarefully separated in some of studies; medicatedpatients are not physiologically comparable to unmed-icated patients. Some studies reported washout peri-ods for their drug free patients or included patients

who were still taking medication at the time of thestudy. Also, some studies do not have a well-definedgroup of patients characterized by the presence orabsence of other disease. Every researcher used dif-ferent criteria for recruiting subjects: community or referral clinics. Some studies (Aggarwal et al.)have Manning criteria rather than Rome criteria toensure maximum sensitivity even though Rome IIwas developed more recently than Manning criteria.

Thirdly, there are issues related to the time period.Some studies have only tested once so they need todetermine stability over time. The short term HRVmeasurement has limitations. It may not adequatelyreflect the day-to-night fluctuation in ANS responses.More complicated analysis of HRV using a long periodis necessary.

Fourthly, it was demonstrated hypnosis can pro-duce a decrease in the LF/HF ratio in cardiovasculardisease (Cowan et al., 1994). However, there is nostudy using HRV in measuring the effect of inter-vention on IBS area. In addition, most studies focuson negative emotions in the IBS field. There are nostudies showing that positive emotions can signifi-cantly influence HRV in IBS patients. Also, manyinvestigators have commonly divided subgroups onlyinto categories of pain, predominant stool type orsymptom severity and frequency, and postprandialpain. To date, there has been very little research onthe bloating symptom. In addition, there is no studyon classifying bloating subgroups using HRV mea-surement even though bloating symptoms are knownto be the most troublesome disease symptoms insome studies (Lembo et al., 1999; Talley, Howell, &Poulton, 2001). Furthermore, there is no study usingHRV in classifying constant pain groups or intermit-tent pain groups. Future research is necessary to takethese into consideration.

Finally, recent studies raise issues related to ge-netic effects on HRV in the Framingham Heart Study(Singh, Larson, O’Donnell, & Levy, 2001; Singh et al.,2002; Singh et al., 1999). In these studies, using a10 cM genome-wide scan in 725 subjects in 230extended families, including 390 sibling pairs, theyfound evidence of linkage of LF to chromosome 1 at153 cM and VLF to chromosome 15 at 62 cM even



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though there are limitations such as predominantlyCaucasian, laboratory evaluation, and intermediateduration recordings (2 hours). Several studies havebeen limited in genetic homogeneity of populations.

Future applicationsA novel approach for studying the abnormality ofANS function in IBS is essential. Further developedapplication of HRV measurements needs to be dis-covered. Also, further study needs to find if the IBSintervention research (both pharmacological and non-pharmacological) is associated with a dose-relateddecrease in HRV using prospective, randomized con-trolled long-term studies. A broader picture of ANSstates in IBS would require HRV with additionalchecking of the sensitivity and specificity and usingmore complicated analysis, other measures of ANSin response to a standardized laboratory stressor test,as well as ambulatory monitor recordings that mea-sure physiological responses to everyday stressors indifferent subgroups of IBS. Larger studies with a vari-ety of individuals assessing the effects of behavioralintervention and examining assessments of HRV andoutcomes are essential to determine the clinical util-ity of intervention. Moreover, gender-related differ-ences in HRV regarding IBS with a larger sample sizeare necessary. To give IBS patients the best qualityof nursing care, nursing should have multi-factorialviews for this health care problem, including physi-ological indicators such as HRV and psychologicaldistress. Nursing may bridge the gap between theory,practice, and research in future IBS study.

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H.J. Park


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