Subtle increases in heart size persist into adulthood in growth restricted babies: the Cardiovascular Risk in Young Finns Study
Abstract
BACKGROUND AND OBJECTIVES: Impaired fetal growth is associated with increased cardiovascular morbidity and mortality in adulthood. We sought to determine whether adults born with intrauterine growth restriction have primary maladaptive changes in cardiac structure. METHODS: Study participants were adults (34-49 years) who attended the 31-year follow-up of the Cardiovascular Risk in Young Finns Study (longitudinal cohort). Transthoracic echocardiograms and demographic and cardiovascular risk surveys were completed for 157 adults born small for gestational age (SGA, birth weight <10th population centile) and 627 born average for gestational age (average for gestational age (AGA), birth weight 50th-90th population centile). RESULTS: Those born growth restricted had subtly enlarged hearts with indexed left ventricular (LV) end-systolic and end-diastolic diameters slightly greater in the SGA individuals than the AGA group (LVESD 18.7 mm/m(2) SGA vs 18.1 mm/m(2) AGA, p<0.01; LVEDD 27.5 mm/m(2) SGA vs 26.6 mm/m(2) AGA, p<0.01); LV base-to-apex length (47.4 mm/m(2) SGA vs 46.0 mm/m(2) AGA, p<0.01); LV basal diameter (26.4 mm/m(2) SGA vs 25.7 mm/m(2) AGA, p<0.01); and right ventricular base-to-apex length (40.1 mm/m(2) SGA vs 39.2 mm/m(2) AGA, p=0.02). LV stroke volume was greater in those born AGA (74.5 mL SGA vs 78.8 mL AGA, p<0.01), with no significant difference in cardiac output (5 L/min SGA vs 5.2 L/min AGA, p=0.06), heart rate, diastolic indices or sphericity index. CONCLUSIONS: Adults born SGA have some statistically significant but subtle changes in cardiac structure and function, which are less marked than have been described in childhood, and are unlikely to play a pathogenic role in their elevated cardiovascular risk.
Full text
Sub le inc eases in hea size pe sis
in o adul hood in g ow h es ic ed
babies: he Ca dio ascula Risk in
Young Finns S udy
Cla e A no ,
1,2,3
Michael R Skil on,
4
Saku Ruohonen,
5
Ma kus Juonala,
6,7
Jo ma S A Viika i,
8
Mika Kähönen,
9
Te ho Leh imäki,
10
Tomi Lai inen,
11
Da id S Cele maje ,
2,12
Olli T Rai aka i
5,13
To ci e: A no C, Skil on MR,
Ruohonen S, e al. Sub le
inc eases in hea size pe sis
in o adul hood in g ow h
es ic ed babies: he
Ca dio ascula Risk in Young
Finns S udy. Open Hea
2015;2:e000265.
doi:10.1136/openh -2015-
000265
▸Addi ional ma e ial is
a ailable. To iew please isi
he jou nal (h p://dx.doi.o g/
10.1136/openh -2015-
000265).
Recei ed 13 Ma ch 2015
Re ised 29 June 2015
Accep ed 2 Augus 2015
Fo numbe ed a ilia ions see
end o a icle.
Co espondence o
P o esso Da id Cele maje ;
da[email p o ec ed].
nsw.go .au
ABSTRACT
Backg ound and objec i es: Impai ed e al g ow h
is associa ed wi h inc eased ca dio ascula mo bidi y
and mo ali y in adul hood. We sough o de e mine
whe he adul s bo n wi h in au e ine g ow h es ic ion
ha e p ima y maladap i e changes in ca diac s uc u e.
Me hods: S udy pa icipan s we e adul s (34–
49 yea s) who a ended he 31-yea ollow-up o he
Ca dio ascula Risk in Young Finns S udy (longi udinal
coho ). T ans ho acic echoca diog ams and
demog aphic and ca dio ascula isk su eys we e
comple ed o 157 adul s bo n small o ges a ional
age (SGA, bi h weigh <10 h popula ion cen ile) and
627 bo n a e age o ges a ional age (a e age o
ges a ional age (AGA), bi h weigh 50 h–90 h
popula ion cen ile).
Resul s: Those bo n g ow h es ic ed had sub ly
enla ged hea s wi h indexed le en icula (LV) end-
sys olic and end-dias olic diame e s sligh ly g ea e in
he SGA indi iduals han he AGA g oup (LVESD
18.7 mm/m
2
SGA s 18.1 mm/m
2
AGA, p<0.01; LVEDD
27.5 mm/m
2
SGA s 26.6 mm/m
2
AGA, p<0.01); LV
base- o-apex leng h (47.4 mm/m
2
SGA s 46.0 mm/m
2
AGA, p<0.01); LV basal diame e (26.4 mm/m
2
SGA s
25.7 mm/m
2
AGA, p<0.01); and igh en icula base-
o-apex leng h (40.1 mm/m
2
SGA s 39.2 mm/m
2
AGA,
p=0.02). LV s oke olume was g ea e in hose bo n
AGA (74.5 mL SGA s 78.8 mL AGA, p<0.01), wi h no
signi ican di e ence in ca diac ou pu (5 L/min SGA s
5.2 L/min AGA, p=0.06), hea a e, dias olic indices o
sphe ici y index.
Conclusions: Adul s bo n SGA ha e some s a is ically
signi ican bu sub le changes in ca diac s uc u e and
unc ion, which a e less ma ked han ha e been
desc ibed in childhood, and a e unlikely o play a
pa hogenic ole in hei ele a ed ca dio ascula isk.
INTRODUCTION
Impai ed e al g ow h (bi h weigh <10 h
popula ion cen ile) has well-es ablished epi-
demiological links wi h inc eased ca dio as-
cula mo bidi y and mo ali y in
adul hood.
12
The mechanisms esponsible
o his link a e no well defined; howe e ,
low bi hweigh babies ha e ea ly onse and
ea ly inc eased p og ession o subclinical a h-
e oscle osis.
3–6
The e is also e idence in he
li e a u e ha p ima y maladap i e s uc u al
ca diac changes occu in u e o; wi h dila ed
ca diomyopa hy-like changes and subse-
quen ly a mo e globula hea , wi h
inc eased ans e se diame e s (by app oxi-
ma ely 20%) in childhood.
7
This is accom-
panied by sub ly educed s oke olume,
which appea s o be compensa ed o by an
inc eased hea a e (by app oxima ely 10%).
KEY QUESTIONS
Wha is al eady known abou his subjec ?
▸Fe al g ow h es ic ion has a well-es ablished
associa ion wi h inc eased ca dio ascula mo bid-
i y and mo ali y in adul hood. The unde lying
pa hogenic p ocess is no well unde s ood;
howe e , he e is e idence o p ema u e endo he-
lial dys unc ion, ea ly p og ession o a he oscle -
osis and ca diac s uc u al changes in ea ly li e.
Wha does his s udy add?
▸In 784 young adul s ollowed since bi h, we
ound ha young adul s who had been bo n
small o ges a ional age ha e only e y sub le
changes in ca diac s uc u e and unc ion, com-
pa ed o hose bo n a no mal weigh .
How migh his impac on clinical p ac ice?
▸This s udy will help o ocus he in es iga ions
in o he ele a ed ca dio ascula isk in hose
bo n small o ges a ional age on o he possible
mechanisms such as endo helial dys unc ion
and p ema u e a he oscle o ic p og ession.
Despi e he p edominan ly neu al esul s in his
s udy, i is ex emely aluable in e ms o shed-
ding ligh on he mechanisms con ibu ing o
his coho ’s ca dio ascula isk p o ile.
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Special popula ions
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These changes ha e been shown o ex end in o adul -
hood in expe imen al animal models o e al g ow h
es ic ion; howe e , whe he hese changes in ca diac
s uc u e and unc ion pe sis in o adul hood in low
bi hweigh humans emains unknown.
78
Recen s udies
do, howe e , indica e ha low bi h weigh does signifi-
can ly co ela e wi h le en icula (LV) mass, an inde-
penden p edic o o long- e m ca dio ascula mo bidi y
and mo ali y, in adolescence.
9
I hese s uc u al
changes do pe sis in o adul hood, he long- e m clinical
amifica ions o a educed s oke olume and ela i e
sinus achyca dia ha e no been clea ly defined.
Acco dingly, we sough o de e mine whe he ca diac
s uc u e and unc ion a e al e ed in adul s who we e
bo n wi h e al g ow h es ic ion, when compa ed o
hose bo n wi h heal hy bi h weigh . Specifically, we
hypo hesised ha he changes in LV and igh en icula
(RV) s uc u e and unc ion seen in childhood, no ably a
globula o less elonga ed hea ,
8
pe sis in o adul hood.
METHODS
Popula ion
The Ca dio ascula Risk in Young Finns S udy is an
ongoing longi udinal communi y-based s udy, ini ia ed
in 1980, ha en olled 3596 child en and adolescen s
aged 3–18 yea s.
10
I encompasses fi e Finnish Uni e si y
ci ies wi h medical schools and he su ounding a ea,
wi h pa icipan s in i ed a andom om he Na ional
Popula ion Regis y. The pa icipan s a ended ollow-up
isi s a h ee yea ly in e als be ween 1980 and 1992
wi h comp ehensi e da a collec ion pe o med a each
ime poin . This included comple ion o a ques ionnai e
ega ding hei bi h weigh , ges a ion a bi h, and psy-
chosocial da a; physical examina ion, blood es s and ca -
dio ascula diagnos ic s udies. They we e asked o b ing
hei eco ds om he well-baby clinics, which we e
e iewed by he s udy nu ses.
610
The 31-yea ollow-up isi s we e comple ed in 2011 a
age 34–49 yea s. Ca diac da a we e ob ained on a subse
o indi iduals (1680; figu e 1). All pa icipan s we e
bo n a e m, wi h small o ges a ional age (SGA) p o-
spec i ely defined as <10 h coho -specific pe cen ile o
bi h weigh s a ified by gende , and app op ia e weigh
o ges a ional age (AGA) defined as 50 h–90 h popula-
ion cen ile. A his isi , he p ospec i ely defined pa i-
cipan s o in e es (n=157 bo n SGA and n=627 bo n
AGA consen ed o pa icipa e) unde wen a ans ho -
acic echoca diog am wi h s anda d iews ob ained.
O he ele an ollow-up da a ob ained a his isi
included socioeconomic, li es yle and ca dio ascula isk
p ofiles.
10–12
This s udy complies wi h he Decla a ion o
Helsinki and was app o ed by local e hics commi ees.
Pa icipa ing indi iduals ga e w i en in o med consen .
T ans ho acic echoca diog ams
The examina ions we e pe o med acco ding o
Ame ican and Eu opean guidelines.
13 14
Sonog aphe s
om di e en loca ions we e ained o ca diac echo-
ca diog aphy and s udy p o ocol. T ans ho acic echoca -
diog ams we e pe o med wi h Acuson Sequoia 512
(Acuson Moun ain View, Cali o nia, USA) ul asonog-
aphy, using a 3.5 MHz scanning equency phased-a ay
ansduce . Analysis o he echo images we e pe o med
by a single obse e using he ComPACS 10.7.8 analysis
p og am (MediMa ic Solu ions, Geno a, I aly). Bo h he
sonog aphe and he obse e we e blinded o he indi-
idual’s bi h weigh ca ego y. S anda d echoca dio-
g aphic iews we e ob ained in all pa icipan s;
pa as e nal long and sho axis, and apical ou -
chambe . Comple e wo-dimen ional, M mode, con inu-
ous and pulsed-wa e Dopple , and issue eloci ies o he
ca diac chambe s we e pe o med.
All dimensions we e indexed o body su ace a ea
(BSA) du ing analysis, as pe he Eu opean Socie y o
Ca diology guidelines. The o mula used o calcula e
BSA was DuBois and DuBois ((weigh )kg o he powe
o 0.425×(heigh )m o he powe o 0.725×0.007184).
Dila ed le en icula end-dias olic (LVED) diame e
indexed o BSA was defined as >32 mm/m
2
in women
and >31 mm/m
2
in men.
13 15 16
Assessmen o demog aphics and ca dio ascula isk
ac o s
Blood p essu e was measu ed using a andom ze o
sphygmomanome e (Hawksley & Sons), wi h an a e age
o h ee measu emen s eco ded. Hea a e was
eco ded manually by ial nu ses. A sel -adminis e ed
ques ionnai e was used o de e mine cu en heal h
s a us (medica ions, medical condi ions), smoking s a us,
employmen and ma i al s a us.
STATISTICAL ANALYSIS
On he basis o he changes no ed in p e ious s udies in
he low bi h weigh child en, ou p ospec i ely defined
Figu e 1 S udy popula ion (AGA, app op ia e bi h weigh o
ges a ional age; SGA, small o ges a ional age).
2A no C, Skil on MR, Ruohonen S, e al.Open Hea 2015;2:e000265. doi:10.1136/openh -2015-000265
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p ima y ou comes we e end-dias olic en icula dimen-
sions (LVED diame e and olume, RV end-dias olic
diame e and olume), LV s oke olume, hea a e,
ca diac ou pu and sphe ici y indices o bo h
en icles.
7
No mal dis ibu ion o da a was assessed using a isual
assessmen o his og ams and confi med by he
Kolmogo o -Smi no es . Skewed da a was log ans-
o med o analysis. Desc ip i e da a a e shown as he
mean (SD) o no mally dis ibu ed da a and as he
median (IQR) o non-no mally dis ibu ed da a, wi h χ
2
es s o ca ego ical da a. The associa ions o bi h
weigh ca ego y wi h ca diac measu es we e analysed by
analysis o co a iance, adjus ing o age, sex, blood p es-
su e, physical ac i i y and socioeconomic s a us.
In aobse e a iabili y was assessed in 50 andomly
selec ed pa icipan s ( om all bi h weigh ca ego ies)
o le and RV chambe size and mass using in aclass
co ela ion coe ficien (ICC) wi h 5 h and 95 h cen ile
CIs and coe ficien o a iance (mean±SE). This demon-
s a ed excellen ep oducibili y (ICC 0.77–0.94, able
no included). A wo- ailed alue o p<0.05 was consid-
e ed s a is ically significan . S a is ical analysis was ca ied
ou using SPSS V.22.0.
RESULTS
S udy popula ion
The pe ina al cha ac e is ics o he s udy popula ion a e
ou lined in able 1. As expec ed, he SGA coho had a
lowe mean bi h weigh o 2816 g (SD 220.9), com-
pa ed wi h 3844 g (SD 193.2) in he AGA g oup
(p<0.01). Bi h leng h in he wo g oups was also signifi-
can ly di e en , wi h a mean o 48.2 cm (SD 1.7) in SGA
and 51.4 cm (SD 1.3) in AGA (p<0.01). The mean pon-
de al index was 2.5 (SD 0.3) o hose bo n SGA, and
2.8 (SD 0.2) in he AGA g oup (p<0.01).
Table 1 Cha ac e is ics o s udy popula ion
Pa icipan cha ac e is ics SGA (n=157) AGA (n=627) p Value
Age (yea s)
Mean (SD) 41.7 (4.91) 41.2 (4.87) 0.39
Median (IQR) 43.0 (9.00) 40.0 (9.00)
Gende (%) 49.7 M, 50.3 F 45.0 M, 55.0 F 0.29
Bi h cha ac e is ics
Bi h weigh (g)
Mean (SD) 2815.7 (220.9) 3844.0 (193.2) <0.01
Median (IQR) 2860.0 (223.0) 3825.0 (280.0)
Bi h leng h (cm)
Mean (SD) 48.2 (1.7) 51.4 (1.3) <0.01
Median (IQR) 48.0 (2.0) 51.0 (2.0)
Ponde al Index
Mean (SD) 2.5 (0.3) 2.8 (0.2) <0.01
Median (IQR) 2.5 (0.3) 2.8 (0.3)
Cu en cha ac e is ics
Cu en heigh (cm)
Mean (SD) 169.2 (8.5) 173.8 (9.7) 0.01
Median (IQR) 169.0 (14.0) 173.0 (15.0)
Cu en weigh (kg)
Mean (SD) 76.5 (16.0) 80.9 (18.2) 0.48
Median (IQR) 74.0 (22.0) 79.0 (23.0)
Cu en BMI
Mean (SD) 26.6 (4.7) 26.7 (5.2) 0.49
Median (IQR) 26.2 (6.4) 25.8 (6.0)
Cu en BSA
Mean (SD) 1.9 (0.2) 2.0 (0.2) 0.50
Median (IQR) 1.9 (0.3) 1.9 (0.3)
Cu en sys olic BP (mm Hg)
Mean (SD) 119.1 (14.0) 118.1 (14.1) 0.05
Median (IQR) 117.3 (19.3) 116.5 (17.3)
Cu en dias olic BP (mm Hg)
Mean (SD) 74.8 (10.3) 74.5 (10.3) 0.07
Median (IQR) 73.7 (14.0) 73.3 (13.3)
Cu en exe cise le els
Exe cise a leas once/week (%) 83.9 84.7 0.80
Da a p esen ed as means (SD) and medians (IQR).
AGA, app op ia e weigh o ges a ional age; BMI, body mass index; BP, blood p essu e; BSA, body su ace a ea; F, emale; M, male; SGA,
small o ges a ional age.
A no C, Skil on MR, Ruohonen S, e al.Open Hea 2015;2:e000265. doi:10.1136/openh -2015-000265 3
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In adul li e, he e was no significan di e ence in
mean weigh be ween SGA (76.5 kg, SD 16.0) and AGA
(80.9 kg, SD 18.2); he SGA coho was, howe e , no ed
o be significan ly sho e in s a u e (169.2 cm SGA, SD
8.5 compa ed o 173.8 cm AGA, SD 9.7; p=0.01). The e
was a 1 mm Hg di e ence in mean sys olic blood p es-
su e be ween he wo coho s (119.1 mm Hg sys olic
SGA, SD 14.0 compa ed o 118.1 mm Hg sys olic AGA,
SD 14.1; p=0.05); howe e , he e was no s a is ically sig-
nifican di e ence in body mass index o BSA. Cu en
exe cise le els we e simila be ween he wo coho s wi h
83.9% bo n SGA and 84.7% bo n AGA engaging in
physical ac i i y a leas once pe week (p=0.80; able 1).
T ans ho acic echoca diog am
Geome y
Le en icula end-sys olic (LVESD) and LVEDD we e
sub ly bu significan ly g ea e in he SGA indi iduals
han he AGA g oup (LVESD 18.7 mm/m
2
SGA s
18.1 mm/m
2
, p<0.01; LVEDD 27.5 mm/m
2
SGA s
26.6 mm/m
2
, p<0.01). This inc ease in dimensions ela-
i e o body size in hose bo n SGA was also seen in he
indexed ou -chambe LV base- o-apex leng h and basal
diame e s. The e was a non-significan inc ease in
indexed LVED olumes in he SGA g oup (62.4 mL/m
2
SGA s 60.5 mL/m
2
, p=0.06). In emales, he OR o
ha ing abno mally inc eased LVEDD (>32 mm/m
2
)was
3.1 (95% CI 1.2 o 7.9, p=0.02) in hose bo n SGA ela-
i e o AGA adul s. ( ables 2 and 3)
A e indexing o BSA, indexed RV longi udinal
base- o-apex leng h was significan ly g ea e o he SGA
e sus AGA adul s (40.1 mm/m
2
SGA s 39.2 mm/m
2
AGA, p=0.02), wi h no di e ence no ed in he indexed
basal diame e o olumes. Despi e he di e ences in
indexed dimensions be ween he wo g oups, he e was
no di e ence in LV o RV sphe ici y index ( ables 2
and 3;figu e 2).
Absolu e le a ial a eas (LAA) ad igh a ial a eas
(RAA) and olumes, no indexed o BSA, we e smalle
in he SGA indi iduals as compa ed o he AGA coho ;
howe e hese alues we e no significan ly di e en
when indexed o BSA ( ables 2 and 3).
A sensi i i y analysis was pe o med whe e echoca di-
og aphy pa ame e s we e indexed o heigh a he han
BSA, gi en he significan di e ence in cu en heigh
be ween he wo coho s. Indexed LAA was simila
be ween bo h g oups (9.3 cm
2
/m SGA s 9.5 cm
2
/m
AGA, p=0.25), while RAA was smalle in he SGA g oup
(9.7 cm
2
/m SGA s 10.1 cm
2
/m AGA, p=0.02). LVEDD
emained la ge in he SGA coho (30 mm/m SGA s
29 mm/m AGA, p=0.01). LVESD and base- o-apex
leng h, while sligh ly la ge in hose bo n SGA, we e no
longe s a is ically significan when indexed o heigh
(LVEDD: 21 mm/m SGA s 20 mm/m AGA, p=0.10.
Base o apex: 52 mm/m SGA s 51 mm/m AGA,
p=0.06). LV basal diame e , RV base- o-apex leng h and
RV basal diame e we e no significan ly di e en
be ween he wo g oups when indexed o heigh . S oke
Table 2 Ca diac olumes and dimensions (non-indexed)
Ca diac mo phome y SGA (95% CI) AGA (95% CI) p Value
Le a ium
Le a ial a ea (cm
2
) 15.8 (15.1 o 16.4) 16.6 (16.1 o 17.0) 0.01
Le a ial olume (mL) 41.1 (38.5 o 43.8) 44.4 (42.6 o 46.2) 0.01
Le en icle
Sphe ici y Index 1.8 (1.8 o 1.8) 1.8 (1.8 o 1.8) 0.94
End-dias olic diame e (mm) 50.5 (49.6 o 51.4) 50.8 (50.2 o 51.4) 0.51
End-sys olic diame e (mm) 34.6 (33.8 o 35.4) 34.9 (34.4 o 35.5) 0.40
Base- o-apex leng h (mm) 88.2 (86.9 o 89.5) 89.4 (88.5 o 90.3) 0.06
Basal diame e (mm) 49.3 (48.5 o 50.1) 50.0 (49.5 o 50.6) 0.07
In e en icula sep um (mm) 6.9 (6.7 o 7.0) 7.0 (6.9 o 7.1) 0.07
Pos e io wall (mm) 7.0 (6.8 o 7.1) 7.2 (7.1 o 7.3) 0.02
End-dias olic olume (mL) 115.0 (110.8 o 119.2) 116.3 (113.5 o 119.2) 0.52
End-sys olic olume (mL) 44.6 (42.6 o 46.8) 45.4 (44.0 o 46.9) 0.42
Mass (g) 129.7 (124.1 o 135.2) 134.7 (130.9 o 138.4) 0.06
Righ a ium
Righ a ial a ea (cm
2
) 16.0 (15.4 o 16.6) 17.1 (16.7 o 17.5) <0.01
Righ a ial olume (mL) 25.3 (23.5 o 27.1) 26.5 (25.3 o 27.8) 0.16
Righ en icle
Sphe ici y Index 2.2 (2.1 o 2.2) 2.2 (2.2 o 2.2) 0.61
Base- o-apex leng h (mm) 74.6 (73.2 o 76.1) 76.1 (75.1 o 77.1) 0.05
Basal diame e (mm) 34.5 (33.6 o 35.4) 35.4 (34.7 o 36.0) 0.04
End-dias olic olume (mL) 42.7 (40.0 o 45.6) 46.0 (44.0 o 48.1) 0.02
End-sys olic olume (mL) 17.5 (16.4 o 18.8) 18.7 (17.9 o 19.6) 0.05
All da a shown as means (95% CI) and adjus ed o age, sex, blood p essu e, physical ac i i y le els and socioeconomic s a us.
AGA, app op ia e bi h weigh o ges a ional age; SGA, small o ges a ional age. LV olumes calcula ed using Z-de i ed me hod; RV
olumes using Simpson Single-Plane 4 chambe ; LV mass using sho -axis a ea-leng h me hod.
4A no C, Skil on MR, Ruohonen S, e al.Open Hea 2015;2:e000265. doi:10.1136/openh -2015-000265
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olume indexed o heigh was smalle in he SGA g oup,
bu his was no s a is ically significan (44 mL/m SGA s
45 mL AGA, p=0.14).
Ven icula sys olic and dias olic unc ion
LV s oke olume was lowe in hose bo n SGA (74.5 mL
SGA s 78.8 mL AGA, p<0.01);howe e , his was no s a -
is ically significan when indexed o BSA (p=0.51) o
heigh (p=0.14). The e was some e idence o sligh ly
lowe ca diac ou pu in he SGA g oup (5 L/min SGA s
5.2 L/min AGA, p=0.06). Mean hea a e did no di e
be ween he wo g oups (63.4 bpm SGA s 62.9 bpm
AGA, p=0.51), and he e was no significan di e ence in
LV ejec ion ac ion, LV ac ional a ea change o RV
ac ional a ea change ( able 4).
LV dias olic unc ion was assessed using mi al al e
(MV) E and A wa e eloci ies, MV E p ime eloci ies,
MV decele a ion ime and E o E p ime a io. No signifi-
can di e ence was no ed be ween he wo g oups in
any o hese pa ame e s ( able 4).
DISCUSSION
This s udy indica es ha some o he changes in ca diac
geome y and unc ion p e iously desc ibed in child en
and adolescen s bo n SGA a e p esen in adul s. When
Table 3 TTE indices adjus ed o BSA
TTE cha ac e is ic indexed o BSA SGA (95% CI) AGA (95% CI) p Value
LAA (cm
2
/m
2
) 8.2 (7.9 o 8.6) 8.3 (8.1 o 8.5) 0.79
LA olume (mL/m
2
) 22.3 (20.9 o 23.7) 23.0 (22.1 o 24.0) 0.29
RAA (cm
2
/m
2
) 8.6 (8.3 o 8.9) 8.8 (8.6 o 9.0) 0.22
RA olume (mL/m
2
) 14.5 (13.5 o 15.6) 14.7 (14.0 o 15.4) 0.75
LV end-dias olic diame e (mm/m
2
) 27.5 (26.9 o 28.0) 26.6 (26.3 o 27.0) <0.01
LV end-sys olic diame e (mm/m
2
) 18.7 (18.2 o 19.1) 18.1 (17.8 o 18.4) <0.01
LV base- o-apex leng h (mm/m
2
) 47.4 (46.5 o 48.2) 46.0 (45.5 o 46.6) <0.01
LV basal diame e (mm/m
2
) 26.4 (25.9 o 26.9) 25.7 (25.3 o 26.0) <0.01
LV end-sys olic olume (mL/m
2
) 24.1 (23.1 o 25.2) 23.6 (22.9 o 24.2) 0.31
LV end-dias olic olume (mL/m
2
) 62.4 (60.3 o 64.5) 60.5 (59.1 o 61.9) 0.06
LV mass (g/m
2
) 68.7 (66.2 o 71.3) 68.5 (66.8 o 70.3) 0.86
LV s oke olume (mL/m
2
) 39.5 (38.1 o 41.0) 40.0 (39.0 o 41.0) 0.51
RV base- o-apex (mm/m
2
) 40.1 (39.3 o 41.0) 39.2 (38.7 o 39.8) 0.02
RV basal diame e (mm/m
2
) 18.6 (18.1 o 19.1) 18.3 (18.0 o 18.7) 0.25
RV end-sys olic olume (mL/m
2
) 9.9 (9.3 o 10.6) 10.2 (9.7 o 10.7) 0.44
RV end-dias olic olume (mL/m
2
) 24.4 (22.8 o 26.1) 25.1 (23.9 o 26.2) 0.44
All da a shown as means (95% CI) and adjus ed o age, sex, blood p essu e, physical ac i i y le els and socioeconomic s a us.
AGA, app op ia e bi h weigh o ges a ional age; BSA, body su ace a ea; LA, le a ial; LAA, LA a ea; LV, le en icula ; RA, igh a ial;
RAA, RA a ea; RV, igh en icula ; SGA, small o ges a ional age; TTE, ans ho acic echoca diog ams.
Figu e 2 Dimensions indexed o
body su ace a ea (AGA,
app op ia e bi h weigh o
ges a ional age; SGA, small o
ges a ional age; LVED, le
en icula end-dias olic; LVES,
le en icula end-sys olic; RV,
igh en icula ). All da a shown
as means (95% CI) and adjus ed
o age, sex, blood p essu e,
physical ac i i y le els and
socioeconomic s a us.
A no C, Skil on MR, Ruohonen S, e al.Open Hea 2015;2:e000265. doi:10.1136/openh -2015-000265 5
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indexed o BSA, hose in he SGA coho consis en ly
exhibi ed sligh ly g ea e LV sys olic and dias olic dimen-
sions and RV base- o-apex leng h. This indica es ha
SGA adul s ha e sligh ly la ge hea s ela i e o hei
BSA, as compa ed wi h adul s bo n AGA. Indeed, in
emales bo n SGA, hei OR o ha ing a dila ed
indexed LVED dimension was 3.1 (95% CI 1.2 o 7.9).
Ou da a we e indexed o BSA as he e is ex ensi e e i-
dence ha ca diac dimensions a e dependen on age,
sex and BSA.
13 15 16
A sensi i i y analysis indexing o
heigh a he han BSA also demons a ed sub ly
inc eased LV dimension in hose bo n SGA; howe e ,
se e al pa ame e s did no each s a is ical significance.
Fu he mo e, SGA pa icipan s had a end owa ds
lowe LV s oke olumes (74.5 mL s 78.8 mL, p<0.01;
indexed 39.5 mL/m
2
SGA s 40 mL/m
2
AGA, p=0.51) as
compa ed o hei a e age bi h size con empo a ies.
This educ ion in s oke olume has been no ed in
childhood, bu his is he fi s ime he e is some e i-
dence ha i may pe sis , albei o a smalle ex en , in o
adul hood.
7
I is accompanied by no significan change
in hea a e, bu a end owa ds educed o e all
ca diac ou pu (5 L/min SGA s 5.2 L/min AGA,
p=0.06). Impo an ly, while significan di e ences in
bo h ca diac geome y and sys olic unc ion we e no ed
in his s udy be ween hose bo n SGA and hose bo n
AGA, all mean alues we e s ill wi hin no mal adul
anges.
13
While hese changes we e s a is ically significan , hey
a e unlikely o be clinically ele an , gi en hei e y
small magni ude. This is pa icula ly ue when we no e
ha he e a e conside ably less ma ked di e ences han
we e seen in childhood (app oxima ely 2% s 10%
mean di e ences).
7
The lesse di e ences in ca diac
pa ame e s in adul hood be ween he SGA and AGA
g oups, compa ed wi h he di e ences seen in child-
hood, migh sugges p og essi e adap a ion o e ime.
In e es ingly, hose bo n SGA demons a ed a sys olic
blood p essu e 1 mm Hg g ea e han hose bo n AGA
(119.1 mm Hg s 118.1 mm Hg, p=0.05). Whils his
esul was s a is ically significan , we a e no able o
quan i y he clinical ele ance o implica ions o his di -
e ence due o ou small sample size.
Un o una ely, his s udy was no su ficien ly powe ed
o de e mine i he e was a subg oup o se e e SGA in
whom he e we e mo e ma ked changes in ca diac s uc-
u e and unc ion. An analysis o IQR o all echoca dio-
g aphic pa ame e s, howe e , did no demons a e
significan ly la ge IQRs in he SGA g oup han was
seen in he AGA g oup (see online supplemen a y
ables S1–S3).
The associa ion be ween low bi h weigh and
inc eased isk o ca dio ascula disease in adul hood has
been well es ablished o e decades. Ba ke e al
2
e iewed bi h weigh s om men bo n du ing 1911–
1930 and documen ed ha hose wi h he lowes weigh s
a bi h and 1 yea had he highes dea h a es om
ischaemic hea disease. Despi e knowledge o his co -
ela ion, he unde lying pa hological p ocesses ha e
been mo e di ficul o elucida e.
17
The e a e nume ous heo ies ha ha e been iden i-
fied as po en ial mechanisms o his associa ion. ‘Small
baby synd ome’, whe e low bi h weigh / e al malnu i-
ion is associa ed wi h endo helial dys unc ion and subse-
quen inc eased isk o p ema u e hype ension, s oke
and co ona y a e y disease, is suppo ed by nume ous
in e na ional s udies, including he Ca dio ascula Risk in
Young Finns S udy, based on ca o id in ima-media hick-
ness, b achial flow-media ed dila ion and ca dio ascula
isk ac o s.
3561718
Ou s udy sough o p obe one o he o he main he-
o ies ha ha e been hypo hesised o be mechanis ic in
his p ocess, ha g ow h es ic ion in u e o migh be
associa ed wi h pe sis en significan changes in ca diac
Table 4 Ven icula sys olic and dias olic unc ion (non-indexed)
Ca diac unc ion SGA (95% CI) AGA (95% CI) p Value
Sys olic unc ion
Hea a e (bpm) 63.4 (61.6 o 65.4) 62.9 (61.6 o 64.1) 0.51
MV S0la e al (cm/s) 13.0 (12.3 o 13.7) 13.6 (13.2 o 14.0) 0.06
LV s oke olume (mL) 74.5 (71.5 o 77.6) 78.8 (76.7 o 80.9) <0.01
LV ejec ion ac ion (Simpson’s) 57.6 (56.9 o 58.2) 58.0 (57.5 o 58.5) 0.18
Ca diac ou pu (L/min) 5.0 (4.7 o 5.2) 5.2 (5.0 o 5.3) 0.06
LV ac ional a ea change (%) 42.2 (41.6 o 42.8) 42.6 (42.1 o 43.0) 0.22
RV ac ional a ea change (%) 42.8 (41.1 o 44.6) 43.7 (42.5 o 44.9) 0.30
Dias olic unc ion
MV E wa e (m/s) 0.8 (0.7 o 0.8) 0.7 (0.7 o 0.8) 0.09
MV A wa e (m/s) 0.5 (0.5 o 0.5) 0.5 (0.5 o 0.5) 0.19
MV E0medial (cm/s) 14.3 (13.9 o 14.7) 14.4 (14.2 o 14.7) 0.45
MV E0la e al (cm/s) 17.7 (17.1 o 18.3) 17.6 (17.2 o 18.0) 0.69
MV E/E’4.3 (4.1 o 4.5) 4.2 (4.1 o 4.4) 0.41
MV decele a ion ime (s) 207.9 (200.7 o 215.3) 211.9 (206.6 o 217.0) 0.28
All da a shown as means (95% CI) and adjus ed o age, sex, blood p essu e, physical ac i i y le els and socioeconomic s a us.
AGA, app op ia e bi h weigh o ges a ional age; MV, mi al al e; LV, le en icula ; RV, igh en icula ; SGA, small o ges a ional age.
6A no C, Skil on MR, Ruohonen S, e al.Open Hea 2015;2:e000265. doi:10.1136/openh -2015-000265
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s uc u e in o adul li e.
7
Indeed, he e is good e idence
ha in au e ine g ow h es ic ion and hypoxia esul s
in a dila ed ca diomyopa hic p ocess in u e o in he
de eloping e us, bo h in humans and in animal
models.
819
The e a e also haemodynamic da a in he
newbo n pe iod ha SGA babies ha e ela i e ca diac
hype ophy and ele a ed b ain na iu e ic pep ide
le els, possibly indica i e o inc eased ca diac wo kload
and en icula dys unc ion.
20
Popula ion s udies ha e
also indica ed ha bi h weigh independen ly co ela es
wi h LV mass in adolescence.
9
Ou da a, howe e , indi-
ca ed ha , in p opo ion o body size, he le (and pos-
sibly igh ) en icle was e y sub ly dila ed in adul s who
we e bo n SGA, as dis inc om p e ious s udies in
childhood ha showed a mo e globula hea wi h
inc eased ans e se diame e s and educed longi udinal
leng hs.
7
This is suppo ed by he lack o di e ence in
he sphe ici y index, a ma ke o a globula hea ,
be ween he SGA and AGA g oups in ou s udy. A p o-
posed mechanism o his change in ca diac s uc u e is
al e ed loading condi ions in u e o. Inc eased placen al
ascula esis ance leads o hypoxia and unde nu i ion,
wi h a subsequen inc ease in a e load, dec ease in
a e ial compliance, and esul an inc eased wall s ess.
7
Suppo ing his, e al g ow h es ic ion has been p o en
o be associa ed wi h highe placen al esis ance indices
in i o.
19 21
These maladap i e changes may lead o a
mo e ine ficien hea in childhood, wi h educed s oke
olumes and esul an eliance on ela i e sinus achyca -
dia in o de o main ain ca diac ou pu . These changes,
howe e , a enua e o e ime. We demons a ed ha by
adul hood he e was only an app oxima e 5% dec ease
in LV s oke olume (compa ed o app oxima ely 20%
in childhood),
7
wi h no significan change in he hea
a e, ca diac ou pu o LV dias olic unc ion.
In ou s udy, we defined AGA as he 50 h–90 h cen ile
o bi h weigh . A sensi i i y analysis compa ing SGA
babies wi h AGA babies, whe e ha was defined as
10 h–90 h cen ile bi h weigh , esul ed in no s a is ically
significan changes in he esul s ob ained. Fu he , we
pe o med ano he sensi i i y analysis whe e echoca dio-
g aphic measu es we e indexed o cu en heigh (sig-
nifican ly di e en be ween he 2 coho s) a he han
BSA. This demons a ed sligh ly g ea e LV dimensions
in he SGA g oup (al hough only LVEDD eached s a is-
ical significance), bu no di e ence in RV dimensions.
The s eng hs o his s udy include he la ge sample
size, comp ehensi e in o ma ion on bi h weigh and
bi h leng h, and he ex ensi e a ailable in o ma ion on
po en ial con ounding ac o s such as socioeconomic
s a us and physical ac i i y le els. The s anda dised
me hod used o ob aining ans ho acic da a is also
no ewo hy, educing po en ial a ia ions in esul s
depending on indi idual sonog aphe echniques.
Ou s udy also has limi a ions. As dis inc om p e i-
ous s udies,
7
we did no use p ena al Dopple o classi y
SGA in o se e e and mild. Thus, i is possible ha a
milde SGA coho could be pa ially esponsible o he
a enua ion in ca diac s uc u al and unc ional changes
ha we had no ed in adul hood, as compa ed o o he
s udies pe o med in childhood such as ha by C ispi
e al
7
Fu he mo e, ca diac MRI may be a mo e sensi i e
way o measu e en icula olumes and mass han ans-
ho acic echoca diog aphy.
22
Lewandowski e al ha e
shown (using ca diac MRI) ha indi iduals bo n
p e e m exhibi unique LV geome y and unc ion in
adul hood, specifically inc eased LV and RV mass,
smalle LV and RV olumes, and educed LV and RV sys-
olic and dias olic unc ion. They ha e no , howe e ,
been able o de e mine i he e a e any s uc u al and
unc ional changes in hose bo n a e m bu SGA, due
o he s udy size and powe .
23 24
CONCLUSION
This s udy indica es ha adul s bo n SGA ha e some s a -
is ically significan bu sub le changes in ca diac s uc-
u e and unc ion, al hough hese a e less ma ked han
ha e been desc ibed in childhood. These s uc u al and
unc ional changes a e unlikely o be clinically signifi-
can o con ibu e o he pa hogenesis o he inc eased
ca dio ascula isk p ofile seen in indi iduals bo n SGA.
Au ho a ilia ions
1
Facul y o Medicine, Uni e si y o Sydney, Sydney, Aus alia
2
Depa men o Ca diology, Royal P ince Al ed Hospi al, Sydney, Aus alia
3
Depa men o Ca diology, P ince o Wales Hospi al, Sydney, Aus alia
4
Boden Ins i u e o Obesi y, Nu i ion, Exe cise and Ea ing Diso de s,
Uni e si y o Sydney, Sydney, Aus alia
5
Resea ch Cen e o Applied and P e en i e Ca dio ascula Medicine,
Uni e si y o Tu ku, Tu ku, Finland
6
Di ision o Medicine, Tu ku Uni e si y Hospi al, Tu ku, Finland
7
Depa men o Medicine, Uni e si y o Tu ku, Finland and Mu doch
Child en’s Resea ch Ins i u e, Melbou ne, Aus alia
8
Depa men o Medicine, Uni e si y o Tu ku and Di ision o Medicine, Tu ku
Uni e si y Hospi al, Tu ku, Finland
9
Depa men o Clinical Physiology, Uni e si y o Tampe e and Tampe e
Uni e si y Hospi al, Tampe e, Finland
10
Depa men o Clinical Chemis y, Fimlab Labo a o ies and Uni e si y o
Tampe e School o Medicine, Tampe e, Finland
11
Depa men o Clinical Physiology and Nuclea Medicine, Kuopio Uni e si y
Hospi al and Uni e si y o Eas e n Finland, Finland
12
Facul y o Medicine, Uni e si y o Sydney, Sydney, Aus alia
13
Depa men o Clinical Physiology and Nuclea Medicine, Tu ku Uni e si y
Hospi al, Tu ku, Finland
Con ibu o s CA analysed and in e p e ed he da a, d a ed he a icle, edi ed
and inalised he documen and is accoun able o all aspec s o he wo k’s
accu acy and in eg i y. MRS assis ed wi h analysis and in e p e a ion o da a,
edi ed and inalised he documen and is accoun able o all aspec s o he
wo k’s accu acy and in eg i y. SR con ibu ed o he concep ual design and
da a acquisi ion, in e p e a ion o da a, e ision o he a icle, inal app o al o
he documen and is accoun able o all aspec s o he wo k’s accu acy and
in eg i y. MJ con ibu ed o he concep ual design and da a acquisi ion,
in e p e a ion o da a, e ision o he a icle, inal app o al o he documen
and is accoun able o all aspec s o he wo k’s accu acy and in eg i y. JSAV
con ibu ed o he concep ual design and da a acquisi ion, in e p e a ion o
da a, e ision o he a icle, inal app o al o he documen and is accoun able
o all aspec s o he wo k’s accu acy and in eg i y. MK con ibu ed o he
concep ual design and da a acquisi ion, in e p e a ion o da a, e ision o he
a icle, inal app o al o he documen and is accoun able o all aspec s o
A no C, Skil on MR, Ruohonen S, e al.Open Hea 2015;2:e000265. doi:10.1136/openh -2015-000265 7
Special popula ions
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he wo k’s accu acy and in eg i y. TLe con ibu ed o he concep ual design
and da a acquisi ion, in e p e a ion o da a, e ision o he a icle, inal
app o al o he documen and is accoun able o all aspec s o he wo k’s
accu acy and in eg i y. TLa con ibu ed o he concep ual design and da a
acquisi ion, in e p e a ion o da a, e ision o he a icle, inal app o al o he
documen and is accoun able o all aspec s o he wo k’s accu acy and
in eg i y. DSC analysed and in e p e ed he da a, d a ed he a icle, edi ed and
inalised he documen and is accoun able o all aspec s o he wo k’s
accu acy and in eg i y. OTR con ibu ed o he concep ual design, da a
aquisi ion, da a analysis and in e p e a ion, documen edi ing and inalising,
and is accoun able o all aspec s o he wo k’s accu acy and in eg i y.
Funding The Young Finns S udy has been inancially suppo ed by he
Academy o Finland: g an s 134309 (Eye), 126925, 121584, 124282, 129378
(Sal e), 117797 (Gendi), and 41071 (Skidi), he Social Insu ance Ins i u ion
o Finland, Kuopio, Tampe e and Tu ku Uni e si y Hospi al Medical Funds,
Juho Vainio Founda ion, Sig id Juselius Founda ion, Paa o Nu mi Founda ion,
Finnish Founda ion o Ca dio ascula Resea ch and Finnish Cul u al
Founda ion, Tampe e Tube culosis Founda ion and Emil Aal onen Founda ion.
D Skil on is suppo ed by a Na ional Heal h and Medical Resea ch Council o
Aus alia ellowship (g an numbe 1004474).
Compe ing in e es s None decla ed.
E hics app o al This s udy complies wi h he Decla a ion o Helsinki and was
app o ed by local e hics commi ees, Finland.
P o enance and pee e iew No commissioned; ex e nally pee e iewed.
Da a sha ing s a emen No addi ional da a a e a ailable.
Open Access This is an Open Access a icle dis ibu ed in acco dance wi h
he C ea i e Commons A ibu ion Non Comme cial (CC BY-NC 4.0) license,
which pe mi s o he s o dis ibu e, emix, adap , build upon his wo k non-
comme cially, and license hei de i a i e wo ks on di e en e ms, p o ided
he o iginal wo k is p ope ly ci ed and he use is non-comme cial. See: h p://
c ea i ecommons.o g/licenses/by-nc/4.0/
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8A no C, Skil on MR, Ruohonen S, e al.Open Hea 2015;2:e000265. doi:10.1136/openh -2015-000265
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Ca dio ascula Risk in Young Finns S udy
adul hood in g ow h es ic ed babies: he
Sub le inc eases in hea size pe sis in o
Cele maje and Olli T Rai aka i
S A Viika i, Mika Kähönen, Te ho Leh imäki, Tomi Lai inen, Da id S
Cla e A no , Michael R Skil on, Saku Ruohonen, Ma kus Juonala, Jo ma
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