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IUGR AND LONG TERM CV FUNCTION
Eduard Gratacós
www.fetalmedicinebarcelona.org
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
1. Fetal growth and cardiovascular function
2. IUGR and cardiac programming
3. Clinical implications
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
1. Fetal growth and cardiovascular function
2. IUGR and cardiac programming
3. Clinical implications
martes 18 de junio de 13
GROWTH RESTRICTION AND THE FETAL HEART
Adaptive responseProgressive failure
Permanent Epigenetic changes
CLINICAL MONITORING
CARDIAC PROGRAMMING
martes 18 de junio de 13
IUGRtarget organ in hypoxic centralization
GROWTH RESTRICTION AND THE FETAL HEART
Adaptive responseProgressive failure
Permanent Epigenetic changes
CLINICAL MONITORING
CARDIAC PROGRAMMING
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
Cardiac function
Cardiac dysfunction: early event & progression
termAGA
IUGR-s1 s2 s3
0
1
2
3
4
*
*
*
M
od-M
PI (
z-sc
ores
)
0
50
100
150
200
250
300
350
400
*
*
*BN
P (p
g/m
L)termAGA
IUGR-s1 s2 s3pretermAGA
Myocardial Performance Index Cord blood BNP
Data are mean(SEM). *P<0.01 compared to AGA. Doppler parameters in Z-scores
Girsen et al UOG 2007Crispi et al. AJOG 2008
martes 18 de junio de 13
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CARDIOVASCULAR DYSFUNCTION IS A COMMON FEATURE OF IUGR
0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
-30 -25 -20 -15 -10 -5 0Days before delivery
Z-scores
DVAoITEI
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
CARDIOVASCULAR DYSFUNCTION IS A COMMON FEATURE OF IUGR
Cruz-‐Mar(nez, 2010
0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
-30 -25 -20 -15 -10 -5 0Days before delivery
Z-scores
DVAoITEI
martes 18 de junio de 13
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CARDIOVASCULAR DYSFUNCTION IN LATE-ONSET IUGR
50
CONTROL
SGA
0
10
20
30
40
Tiss
ue D
oppl
er E
’ > 9
0th
cent
ile (%
)
*
LEFT RIGHT
0
5
10
15
20
25
30
DV AoI MPI
Freq
uenc
y of
abn
orm
ality
(%
)
ControlsSGA
*
*
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
CARDIOVASCULAR DYSFUNCTION IN LATE-ONSET IUGR
50
CONTROL
SGA
0
10
20
30
40
Tiss
ue D
oppl
er E
’ > 9
0th
cent
ile (%
)
*
LEFT RIGHT
Comas 2011
0
5
10
15
20
25
30
DV AoI MPI
Freq
uenc
y of
abn
orm
ality
(%
)
ControlsSGA
*
*
Crus-‐Mar(nez 2009
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
1. Fetal growth and cardiovascular function
2. IUGR and cardiac programming
3. Clinical implications
martes 18 de junio de 13
1986 Barker (MRC Unit, Southampton, UK):
Coronary heart disease mortality rates
Cardiovascular risk factors
martes 18 de junio de 13
Low birth weight
Cardiovascular risk factors
Barker Lancet 1989, Barker BMJ 1993, Osmond BMJ 1993, Barker BMJ 1995, Fall BMJ 1995, Stein Lancet 1996, Leon BMJ 1998, Forsen BMJ 1999, Eriksson BMJ 2001, Osmond Stroke 2007
cardiovascular mortality
coronary heart diseasehypertension
stroketype 2 diabetes
obesity
FETAL GROWTH RESTRICTION: 6-7% NEWBORNS
martes 18 de junio de 13
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“The Barker hypothesis”
Fetal programming:Coronary heart disease originates through responses to under nutrition during fetal life, which permanently change the body's structure, physiology and metabolism
martes 18 de junio de 13
Fetal growth restriction
Epigenetic changes in metabolic regulation
Normalization of diet (or overnutrition)
Insulin resistance
Obesity/Diabetes/
Hypertension
Cardiovascular disease
CLASSIC HYPOTHESIS
martes 18 de junio de 13
Fetal growth restriction
Epigenetic changes in metabolic regulation
Normalization of diet (or overnutrition)
Insulin resistance
Obesity/Diabetes/
Hypertension
Cardiovascular disease
Fetal growth restriction
Epigenetic changes in cardiac regulation
Persistence of abnormal cardiac function
Lack of ability to further adaptation
Cardiovascular disease
CLASSIC HYPOTHESIS ALTERNATIVE/COMPLEMENTARY HYPOTHESIS
martes 18 de junio de 13
Animal data: restriction of oxygen leads to dilated and less-efficient hearts
Chicken embryo model
Effects of hypoxia on the embryonic heart
Tintu et al. Plos One 2009
martes 18 de junio de 13
Evidence of the impact of IUGR in postnatal cardiac function
Maria
Height 106 cm (normal)Weight 21 kg (normal)
Carlota
Height 104 cm (p3)Weight 16 kg (p9)
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Maria (N)
Normal cardiac function
E/A mitralE = 91 cm/s
76 ms
Tissue Doppler:Myocardial velocities (septal annulusl)
E’ = 15 cm/s
S’ = 10 cm/s
E/E’ = 6
martes 18 de junio de 13
Maria (N)
Normal cardiac function
E/A mitralE = 91 cm/s
76 ms
Tissue Doppler:Myocardial velocities (septal annulusl)
E’ = 15 cm/s
S’ = 10 cm/s
E/E’ = 6
martes 18 de junio de 13
Maria (N)
Normal heart
martes 18 de junio de 13
Maria (N)
Normal heart
Carlota (IUGR)
Globular heart
martes 18 de junio de 13
Maria (N)
Normal heart
Carlota (IUGR)
Globular heart
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/ Crispi et al. Circulation 2010
Cardiac remodelling in IUGR
Cardiac shape
Systolic function
Diastolic function
martes 18 de junio de 13
control IUGR
Crispi 2010
Impact of prenatal severity on cardiovascular programming in late-IUGR
martes 18 de junio de 13
control IUGR
Crispi 2010
Impact of prenatal severity on cardiovascular programming in late-IUGR
Fetuses EFW<p10 evaluated at 5 years
Classified by CPR, p3 and UtA Doppler:• All normal: SGA• Any abnormal: late-IUGR
martes 18 de junio de 13
control IUGR
Crispi 2012
Crispi 2010
Impact of prenatal severity on cardiovascular programming in late-IUGR
Fetuses EFW<p10 evaluated at 5 years
Classified by CPR, p3 and UtA Doppler:• All normal: SGA• Any abnormal: late-IUGR
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
1. Fetal growth and cardiovascular function
2. IUGR and cardiac programming
3. Clinical implications
martes 18 de junio de 13
PREDIMED NEJM 2013
ADULTHOOD
Effect of dietary interventions on CV disease
martes 18 de junio de 13
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CAPS Pediatrics 2012
CHILDHOOD
Effect of dietary interventions on CV disease
Childhood Asthma Prevention Study
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
To evaluate the effect of postnatal diet on cardiovascular remodelling in SGA
Factors associated to cIMT
Characteristics Adjusted coef. (n=88)Adjusted coef. (n=88)Characteristics
Coef. (95%CI) P value
IUGR 0.0264(0.0170; 0.0358) <0.001
Gestational age at delivery
-0.0024(-0.0036;-0.0011) <0.001
Female sex -0.0003(-0.0096;0.0090) 0.95
Formula/Mix feeding 0.0110(0.0020;0.0200) 0.02
BMI at follow up 0.0035(0.0013;0.0057) 0.01
direct effect
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
To evaluate the effect of postnatal diet on cardiovascular remodelling in SGA
Factors associated to cIMT
Characteristics Adjusted coef. (n=88)Adjusted coef. (n=88)Characteristics
Coef. (95%CI) P value
IUGR 0.0264(0.0170; 0.0358) <0.001
Gestational age at delivery
-0.0024(-0.0036;-0.0011) <0.001
Female sex -0.0003(-0.0096;0.0090) 0.95
Formula/Mix feeding 0.0110(0.0020;0.0200) 0.02
BMI at follow up 0.0035(0.0013;0.0057) 0.01
direct effect
% polyunsaturated fats
AGA
SGA/IUGR
cIMT
martes 18 de junio de 13
Fetal CV score versus perinatal prognostic factors to predict postnatal hypertension and increased intima-media thickness in IUGR
ABNORMAL CV OUTCOME:
DBP >95th centile
Aortic IMT >95th centile
martes 18 de junio de 13
IUGR: EFW / birthweight <p10.
Fetal CV score versus perinatal prognostic factors to predict postnatal hypertension and increased intima-media thickness in IUGR
IUGRn=100
Conventional Doppler
Fetal Echocardiography
ABNORMAL CV OUTCOME:
DBP >95th centile
Aortic IMT >95th centile
martes 18 de junio de 13
IUGR: EFW / birthweight <p10.
Fetal CV score versus perinatal prognostic factors to predict postnatal hypertension and increased intima-media thickness in IUGR
IUGRn=100
Conventional Doppler
Fetal Echocardiography
ABNORMAL CV OUTCOME:
DBP >95th centile
Aortic IMT >95th centile
martes 18 de junio de 13
IUGR: EFW / birthweight <p10.
Fetal CV score versus perinatal prognostic factors to predict postnatal hypertension and increased intima-media thickness in IUGR
IUGRn=100
Conventional Doppler
Fetal Echocardiography
ABNORMAL CV OUTCOME:
DBP >95th centile
Aortic IMT >95th centile
martes 18 de junio de 13
IUGR: EFW / birthweight <p10.
Fetal CV score versus perinatal prognostic factors to predict postnatal hypertension and increased intima-media thickness in IUGR
IUGRn=100
Conventional Doppler
Fetal Echocardiography
ABNORMAL CV OUTCOME:
DBP >95th centile
Aortic IMT >95th centile
Logistic Regression
martes 18 de junio de 13
DBP >95th centile + aIMT>95th centile
YES26%
NO74%
CV Risk in IUGR children at 6 months
n=100
martes 18 de junio de 13
Prediction of hypertension and increased vascular thickness at 6 months of age in fetuses with IUGR
CV score: DR 90% - FPR 25% (PPV 38%, NPV 98%)
Cruz, 2013
martes 18 de junio de 13
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Conclusions
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
Conclusions• Cardiac dysfunction/adaptation is a
constitutional feature of IUGR
• Cardiac dysfunction in fetal life induces permanent CV programming and remodelling resulting in child conditions demonstrated to increase susceptibility to cardiovascular disease later in life
• This opens new public health opportunities for the prevention of cardiovascular disease from early life, and new research lines exploring early intervention.
martes 18 de junio de 13
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