Blood Pressure and Metabolic Risk: From Birth to Adulthood

Transcription

1 Blood Pressure and Metabolic Risk: Fro Birth to Adulthood Epar Lurbe, MD, PhD, FAHA Cardiovascular Risk Unit Hospital General Universitario University of Valencia CIBERObn Instituto de Salud Carlos III Madrid, Spain

2 Roots of Cardio-Metabolic risk factors Cardiovascular coplications occurring in adults find their roots in risk factors operating early in life Subtle alterations in risk factors can be observed in youths The presence of these risk factors forsees future increents to abnoral levels

3 Cardio-Metabolic risk factors detected in children and adolescents

4 Factors related to Cardio-Metabolic phenotype

5 Factors related to Cardio-Metabolic phenotype

6

7 Publications related to Cardio-Metabolic risk in PubMed Early origins Birth weight

8 Fro birth weight to cardiovascular disease: an integrated odel Developent Exposure Mother and Father Anthropoetric and diet Soking habits Genetic susceptibility Child Nutrition Passive soke exposure Risk factors for adult cardiovascular disease Growth Fetal and placental growth and birth weight Childhood growth Risk factors adult cardiovascular disease in childhood Blood pressure Arterial stifness Atherosclerosis Coronary heart disease Cardiovascular developent changes Vascular adaptations Arterial stiffness Endothelial dysfunction Microvascular structures Renal adaptations Kidney volue Renal function RAAS prograing Cardiac adaptations Left ventricular growth Aortic root diaeter

9 Early origins of Cardio-Metabolic risk factors Factors related to BW BW and vascular phenotype The addition of postnatal weight gain Molecular iprinting

10 Early origins of Cardio-Metabolic risk factors Factors related to BW

11 Fro birth weight to cardiovascular disease: an integrated odel Developent Exposure Mother and Father Anthropoetric and diet Soking habits Genetic susceptibility Child Nutrition Passive soke exposure Risk factors for adult cardiovascular disease Growth Fetal and placental growth and birth weight Childhood growth Risk factors adult cardiovascular disease in childhood Blood pressure Arterial stifness Atherosclerosis Coronary heart disease Cardiovascular developent changes Vascular adaptations Arterial stiffness Endothelial dysfunction Microvascular structures Renal adaptations Kidney volue Renal function RAAS prograing Cardiac adaptations Left ventricular growth Aortic root diaeter

12 Maternal factors influencing fetal growth and developent Environental Diet and Nutrition Constraints

13 Maternal BMI during pregnancy and BW Ay L et al. BJOG 2009;116:

14 Differences in BW in relation to aternal age p=0.064 Prevalence p= , ,9 2,1 6,2 2, ,3 6,4 4,8 4,8 4,1 0 <20 yr yr yr yr yr >39.9 yr SGA LGA Bakker R et al. BJOG 2011;118:

15 Maternal parity and fetal growth Shah PS et al. Acta Obstet Gynecol Scand 2010;89:

16 Ipact of cotinine levels on size at birth p<0.05 p<0.05 Ivorra C et al. Drug and Alcohol Dependence 2014;134:

17 Early origins of Cardio-Metabolic risk factors Factors related to BW BW and vascular phenotype

18 Fro birth weight to cardiovascular disease: an integrated odel Developent Exposure Mother and Father Anthropoetric and diet Soking habits Genetic susceptibility Child Nutrition Passive soke exposure Risk factors for adult cardiovascular disease Growth Fetal and placental growth and birth weight Childhood growth Risk factors adult cardiovascular disease in childhood Blood pressure Arterial stifness Atherosclerosis Coronary heart disease Cardiovascular developent changes Vascular adaptations Arterial stiffness Endothelial dysfunction Microvascular structures Renal adaptations Kidney volue Renal function RAAS prograing Cardiac adaptations Left ventricular growth Aortic root diaeter

19 Relationship between Birth Weight and Awake Blood Pressure in Children and Adolescents in Absence of Intrauterine Growth Retardation A J Hypertens 1996;9:

20 Relationship between awake systolic BP, birth weight, age, current weight and height Height () r=0.35 Age (yr) r= ,2 1,4 1,6 1,8 Birth weight (kg) r= ,5 3 3,5 4 4, Weight (kg) r=0.38 Lurbe E et al. A J Hypertens 1996;9:

21 Birth weight and awake SBP in children and adolescents 120 Awake SBP (Hg) kg kg BMI tertiles Lurbe E et al. A J Hypertens 1996;9: Birth Weight

22 24-hour SBP (Hg) 24-hour systolic BP averages and variability grouped by birth weight < >3.599 Birth Weight (kg) 9 Lurbe E et al. Hypertension 2001;38: Values adjusted for sex, age, current weight and height

23 Arterial phenotype in children and adolescents Genetic Environental Fetal Systolic BP (peripheral and central) Copliance (PWV) Reflected waves (AI)

24 Augentation Index grouped by birth weight AI (Hg) Values adjusted for sex, height, HR and DBP AI (%) P< P< <2.5 kg kg kg >3.5 kg 0 Lurbe E et al. Hypertension 2003;41: Birth Weight

25 Pulse wave velocity grouped by birth weight 5,0 4,5 4,0 3,5 3 <2.5 kg kg kg >3.5 kg Birth Weight Lurbe E et al. Unpublished data

26 Pressure-natriuresis relationship BP (+) (+) Na + Na +

27 Sleep Urinary Sodiu Excretion Rate (ol) Sleep BP and UNa excretion Birth weight kg kg Sleep SBP (Hg) Lurbe E et al. Hypertension 1998;31:

28 Vascular phenotype of children with the lowest birth weight Tend to have the highest Pulse Pressure and Augentation Index, expressing an early ipairent in aortic elasticity and/or higher peripheral resistance Have an increase in BP variability May have a restricted ability to excrete sodiu

29 Early origins of Cardio-Metabolic risk factors Factors related to BW BW and vascular phenotype The addition of postnatal weight gain

30 Fro birth weight to cardiovascular disease: an integrated odel Developent Exposure Mother and Father Anthropoetric and diet Soking habits Genetic susceptibility Child Nutrition Passive soke exposure Risk factors for adult cardiovascular disease Fetal and placental growth and birth weight Childhood growth Risk factors adult cardiovascular disease in childhood Blood pressure Arterial stiffness Growth Cardiovascular developent changes Vascular adaptations Arterial stiffness Endothelial dysfunction Microvascular structures Renal adaptations Kidney volue Renal function RAAS prograing Cardiac adaptations Left ventricular growth Aortic root diaeter

31 Postnatal weight gain and Cardio-Metabolic risk The effects of prenatal growth on adult disease has been an established field of research Interest in postnatal growth and weight gain was priarily related to diagnosing the causes of failure to thrive Concern about rapid growth was virtually non-existent Controversy exists as to whether accelerated growth in infancy is disadvantageous Rapid weight gain in the early postnatal period sees to have adverse consequences for later health

32 Trajectories of growth aong children who have coronary events as adults Barker DJ et al. N Engl J Med 2005;353:

33 Systolic Blood Pressure (Hg) Ipact of birth weight and obesity on SBP in Spanish adolescents 125 Office p=0.005 Awake p=0.004 Sleep p= No Obese No Low BW n=340 No Obese Low BW n=63 Obese No Low BW n=89 Obese Low BW n=22 Lurbe E et al. Hypertension 2009;53: Values adjusted for sex, current age and height

34 Systolic BP (Hg) Twenty-four hour systolic blood pressure pattern in adolescents grouped by current and birth weight O/LBW NO/LBW O/NBW NO/NBW SBP 24-hours p=0.001 vs p <0.005 vs p <0.005 vs p < Tie (hours) Lurbe E et al. Hypertension 2009;53: Adjusted for sex, current age and height

35 The relevance of prospective studies Knowledge on BP at birth is relevant as a proxy of fetal influences Intrauterine life ipacts on BP and etabolic phenotypes Postnatal growth odulates the fetal prograing

36 Ipact of fetal size and postnatal growth in cardioetabolic risk: Study design Growth 5 yr Birth Insulin Uric acid Lipids ABPM Ubilical cord BPs

37 Blood pressure (Hg) Blood pressure values in the newborns grouped by birth weight p<0.001 for trend SBP p<0.008 for trend DBP Lurbe E et al. J Hypertens 2007;25:81-86

38 Factors related to systolic blood pressure estiated by ultiple regression analysis b sd p R 2 SBP Sex ( vs f) Mother age Parity Soker Gestational age Birth weight <0.001 Length Head circuf Lurbe E et al. J Hypertens 2007;25:81-86

39 BMI changes grouped by birth weight 20,00 Body Mass Index (kg/ 2 ) ** 15,00 * * 10,00 Birth 1 6 1y 2y 3y 4y 5y SGA AGA LGA * * p<0.05 with SGA and AGA p<0.05 with SGA and LGA ** p<0.05 with SGA

40 Systolic BP changes grouped by birth weight * * Lurbe E et al. Hypertension 2014;63: * * p<0.05 with SGA p<0.05 with SGA

41 Systolic BP deterinants fro birth to 5 years old Lurbe E et al. Hypertension 2014;63:

42 Fasting insulin U/l Fasting insulin values grouped by birth and current weight at 5 years old Weight tertiles at 5 year Birth weight categories Lurbe E et al. Hypertension 2014;63:

43 HOMA index HOMA index values grouped by birth and current weight at 5 years old Weight tertiles at 5 year Birth weight categories Lurbe E et al. Hypertension 2014;63:

44 Metabolic paraeters and BMI at 5 years grouped by size at birth BMI (kg/2) p<0.05 SGA AGA LGA Uric acid (g/dl) p<0.05 SGA AGA LGA HDL (g/dl) p< SGA AGA LGA Lurbe E et al. Hypertension 2014;63:

45 Correlation coefficient between insulin, uric acid and SBP at 5 years Insulin Uric acid SBP Lurbe E et al. Hypertension 2014;63:

46 Early origins of Cardio-Metabolic risk factors Factors related to BW BW and vascular phenotype The addition of postnatal weight gain Molecular iprinting

47 Ubilical cord endothelial and sooth uscle cells characterization in priary cell cultures Morphological and iunohistocheical characterization of arteries and vein fro ubilical cord -OMICS Ubilical cord blood Genetic and epigenetics

48 Cell density ( 10-3 cell/c 2 ) Ubilical cord arteries and vein cell cultures and birth weight HUAEC, HUVEC, HUASMC, and HUVSMC: fro individuals of birth weight <2.8 kg or >3.5 kg no difference in cell viability (>95%) no difference in cell culture growing speed A HUAEC B HUVEC 40 Difference in cell density at confluence (only observed in HUAEC) C HUASMC D HUVSMC Martin de Llano JJ et al. J Transl Med 2009;7: Tie after seeding (h)

49 A A PCA of the etaboloic plasa profile in newborns and others B C Ivorra C et al. J Transl Med ;10:142

50 PCA of the etaboloic plasa profile in newborns Ivorra C et al. J Transl Med ;10:142

51 PCA of the etaboloic plasa profile in newborns Inversely associated with Type 2 diabetes risk Linked to insulin resistance states and risk to develop Type 2 diabetes Ivorra C et al. J Transl Med ;10:142

52 PCA of the etaboloic plasa profile in newborns Linked to DNA ethylation with ipact in gene activity Ivorra C et al. J Transl Med ;10:142

53 Hierarchical clustering and heatap of differentially ethylated probes in cord and 5-year-old blood saples % relative DNA Methylation Hyperethylation enriched in biological process related to tissue and cell developent Hypoethylation in inune related genes Urdinguio R et al. J Transl Med 2016 ;14:160

54 Cord blood global DNA ethylation status in exposed and non exposed to in utero tobacco Maternal soking during pregnancy is a ajor risk factor for adverse health outcoes in children Consequences are not only iediate, such as LBW, but it also leads to long-ter risk for obesity, type 2 diabetes and elevated BP The echaniss behind the relationship between in utero tobacco exposure and its effects are not well understood Epigenetics can help to unravel the echaniss underlying

55 Cord blood global DNA ethylation and Manhattan plot for ethylation status in exposed and non exposed to in utero tobacco Ivorra C et al. J Transl Med 2015 ;13:25

56 Hierarchical clustering heat ap of the CpG sites with significant differential ethylation between exposed and non-exposed newborns to tobacco Ivorra C et al. J Transl Med 2015 ;13:25

57 Conclusions The early postnatal period is a critical window for individuals who have experienced a growth insult in fetal life, reflected by sall size at birth Birth weight and postnatal gain exert independent influences on cardio-etabolic paraeters at 5 years of age Metabolic alterations anifested by the highest values of insulin, HOMA index, triglycerides, uric acid, and lowest HDL, are present even as early as 5 years of age Blood Pressure becae progressively dependent on body size while the ipact of birth weight disappeared. Research in ubilical cords ay help in understanding the ipact of intrauterine life on cardiovascular disease later in life

58 To understand the phenoenon of perinatal prograing it will be necessary to take careful phenotypic observation and pair the with olecular echaniss The olecular ability to do so is increasingly available and has the potential to deepen our understanding of fetal origins of chronic diseases such as hypertension and diabetes ellitus Falkner B, Ingelfinger J. Hypertension 2014;63: