Perinatal Programming Prenatal Determinants of Future Hypertension and CV Disease

Transcription

1 Perinatal Programming Prenatal Determinants of Future Hypertension and CV Disease Julie R. Ingelfinger, M.D. Professor of Pediatrics, Harvard Medical School Senior Consultant in Pediatric Nephrology, MassGeneral Hospital for Children at MGH

2 Objectives of This Talk To discuss relevant organogenesis and developmental progression To consider the concept of developmental origins with respect to hypertension and CV disease To discuss the implications for follow-up and therapy

3 Objectives of This Talk To discuss relevant organogenesis and developmental progression To consider the concept of developmental origins with respect to hypertension and CV disease To discuss the implications for follow-up and therapy

4 Critical Periods in Human Gestation kidneys

5 HUMANS HAVE VARIABLE NEPHRON DOSE WHAT ARE THE IMPLICATIONS Nephron # % HTN Proteinuria Progression 400, ,00 800,000 1,000,000 1,200,000 Time After Brenner, Garcia, and Anderson, 1988

6 Maternal Diabetes Placenta Change in Fetal/ Neonatal Intrarenal Factors (?epigenetics) Altered Organogenesis Permanently Altered Structure/Function In the KIDNEY: Nephron Number Glomerular Volume, Surface Area Impaired Tubular Function Change in Vascular Reactivity Developmental Origins of Health and Disease (DOHaD) *Insult during specific developmental window permanent change in organ system What are mechanisms? Hypertension Renal Dysfunction

7 MAMMALIAN CARDIAC DEVELOPMENT Srivastava D. Cell 126, September 22, Elsevier Inc.

8 Effects on Organs: e.g., Heart Cardiac structure complete by 8 weeks. First organ that is complete.

9 Hyperplasia and Hypertrophy Growth of the working myocardium before midgestation is due entirely to cardiomyocyte hyperplasia. As normal maturation process, cardiomyocytes become terminally differentiated and binucleated (in the sheep, rat and mouse) and generally are no longer capable of proliferation. In the sheep, the proportion of binucleated cardiomyocytes increases during the second half of gestation most cardiomyocytes are terminally differentiated at birth An increasing number of myocytes exit the cell cycle, and then continued growth of the myocardium occurs primarily by cellular hypertrophy and architectural remodelling. In large mammals, cardiomyocyte maturation occurs before birth and during early postnatal life.

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11 Known Maladaptive Intrauterine Exposures Folic Acid Deficiency- neural tube defects folate participates in one-carbon transfers, important in methylation reactions and in purine and pyrimidine synthesis Tobacco Smoke- low BW and orofacial clefts Effect on phase1 and 2 detox pathways Antidepressants- SSRI congenital heart defects, PPHN SSRI may interfere with the hypothalamic-pituitary-adrenal system and circadian rhythms important in fetal development and with subtype of serotonin receptors (5-HT-2B) Swanson et al. Semin Reprod Med 2009; 27:

12 Other Maladaptive Intrauterine Exposures Maternal Diet? Stress? Other?

13 Important Questions What controls the magnitude of effects? How does one detect/ identify changes? What are the mechanisms? How does one manage those at risk? The remainder of this talk discusses these issues, as related to cardiovascular disease.

14 Objectives of This Talk To discuss relevant organogenesis and developmental progression To consider the concept of developmental origins with respect to hypertension and CV disease To discuss the implications for follow-up and therapy

15 Perinatal Programming Epidemiological studies published in the late 1980s -- and since replicated in many populations Demonstrate inverse relation between birthweight and risk of cardiovascular disease, hypertension and renal dysfunction in adult life

16 The early Barker studies High infant mortality ( ) and, later, High incidence of death due to coronary heart disease ( )

17 Association of Birthweight with Raised Blood Pressure in Hertfordshire Population SBP (mm Hg) Birthweight (pounds) Fall et al, BMJ 1995

18 The Dutch Hunger Winter 1944/ calories/day Detailed clinical records enabled cohort follow up.

19 The Dutch Famine (Historical Cohort Study) Timing and AEs Operation Market Garden German reprisals for Dutch resistance- Dec 1944-Apr 1945: daily rations cut to kcal Exposure to famine in mid or late gestation impaired glucose tolerance Exposure to famine in early gestation atherogenic lipid profile obesity increased risk of CHD Roseboom et al Mol. & Cell. Endocrinol 2001; 93-98

20 Perinatal Programming DOHaD The concept of developmental origins of health and disease (DOHaD) evolved from epidemiologic studies of both infant and adult mortality. This is a broader concept, which considers in utero, perinatal, and early childhood influences on later health. oocyte to the infant to beyond.

21 Limitations of Retrospective Epidemiology Cohort studies retrospective Non-representative of current populations Correction for current confounders, e.g., current BMI may be flawed- reverse causation Different populations show correlation with different neonatal variables; plethora of relationships A few studies entirely negative Association with blood pressure weak Birthweight is a poor index of in utero nutrition Is it all explicable by epigenetics or unrecognized genetic propensities?

22 Intrauterine Exposure Adult Outcomes Sexual Dimorphism Maternal undernutrition Maternal diabetes, moderate Glucocorticoid excess Maternal overnutrition ACE inhibition Angiotensin II Receptor Inhibition Growth restriction Hypertension Altered nephrogenesis Growth restriction Hypertension Altered nephrogenesis Hypertension Glomerulosclerosis Hypertension Altered vascular compliance Endothelial dysfunction Hypertension, altered nephrogenesis, other findings +/- M>F M>F M>F M>F Females M>F Adapted from Gilbert JS and Njiland MJ. Am J Physiol Reg Integ Comp Phys 2008; 295:

23 Developmental Programming in Humans? Epidemiological Associations: Low birthweight / disproportionate fetal growth associated with coronary heart disease and stroke (Barker and Osmond, 1986) adulthood hypertension (Barker, 1990) insulin resistance (Phillips et al, 1994) adult obesity (Yanjik, 2000) dyslipidemia (Barker, 1993)

24 Study of 2003 Persons at 62 Years from the Helsinki Birth Cohort TWO DIFFERENT GROWTH PATHWAYS PRECEDE DEVELOPMENT OF HYPERTENSION. ONE GROUP: Already DX D as hypertensive: Small body size at birth and first two years followed by rapid growth. At age 11 they were ~ average body size. As adults, obese and insulin resistant and with coronary heart disease. SECOND GROUP: Not previously diagnosed as hypertensive. Short at birth, low growth first two years, which continued. At age 11, short and thin. As adults, overweight, with atherogenic profiles and with stroke.

25 Prevalence of Hypertension % Lowest Highest > Birth -weight (kg) Fifths of current weight (kg) Eriksson, J. G. et al. Hypertension 2007;49:

26 Birth Size Reduced birth size and ponderal index Surrogates for suboptimal intrauterine environment Patterns of growth reduction informative Boys- low bw and thinness at birth and 1 year, followed by rapid growth increased risk of CV disease. Girls short at birth plus rapid weight gain increased risk of CV disease Placental size also important Placental dysfunction Programming without any size changes

27 Intrauterine Stressors Malnutrition Maternal under- or overnutrition Hypoxemia Maternal hypoxemia or placental dysfunction Glucocorticoids Administered Endogenous Chemicals Administered Environmental

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29 Neovascular Formation is Attenuated in Stressor Such as Low Protein Diet CONTROL Control LOW PROTEIN Low Protein Pladys et al. AJP 2005; 289:1580

30 ABERRANT VASCULATURE Langley-Evans SC. Nutritional programming of disease: unravelling the mechanism. J Anat. 2009; 215: This figure redrawn from Rutland CS et al. Effect of gestational nutrition on Vascular integrity in the murine placenta. Placenta 2007; 28:

31 Preterm Heart in Young Adult Life Lewandowski AJ et al. Preterm Heart in Adult Life CV MR Reveals Distinct Differences in LV Mass, Geometry and Function. Circulation. 2013; 127:

32 Preterm Heart in Young Adult Life Lewandowski AJ et al.circulation. Right Ventricular Systolic Dysfx. In Young Adults Born Preterm. 2013; 128:

33 Preterm Heart in Young Adult Life Lewandowski AJ et al. Preterm Heart in Adult Life CV MR Reveals Distinct Differences in LV Mass, Geometry and Function. Circulation. 2013; 127:

34 CHD related to maternal height and neonatal measurements 1. Oval placental surface in short mothers (<160 cm) 2. Small placental surface in tall mothers with BMI above median 3. Large placental surface related to BW in tall mothers with BMI below median

35 Vasodilation HUMAN DATA Controls vs. Low Birth Weight

36 Other Perinatal Contributors to CVD Maternal obesity Maternal diabetes

37 In vivo studies on the effect of maternal diabetes on the neonatal kidney of the offspring Tran et al JASN 2008; 19: Copyright 2008 American Society of Nephrology

38 In vivo studies on the effect of maternal diabetes on the neonatal kidney of the offspring Zhang, S.-L. et al. J Am Soc Nephrol 2007;18: Copyright 2007 American Society of Nephrology

39 Tran et al. JASN 2008; 19:

40 SBP in MALE OFFSPRING (A) Longitudinal Changes in SBP in Male Offspring 135 Systolic Blood Pressure (Mean SBP, mmhg) *** *** *** *** *** *** Age (weeks) Dia-Offspring (Hyper-M) Dia-Offspring (Normo-M) Con-Offspring (M) Ins-Treated-Offspring (M)

41 Diabetic Offspring and Albuminuria 1.4 *** * Ratio of Urinary Albumin (ug/ml) vs Creatinine (mg/100ml) (D) 0.0 Con-Offspring (M) Dia-Offspring (M) Ins-Treated Offspring (M) Con-Offspring (F) Dia-Offspring (F) Ins-Treated Offspring (F)

42 Real-time PCR 400 Con-Offspring Male Offspring-20wks Ratio of RAS gene mrna / b-actin mrna (% of control, 100%) Dia-Offspring Ins-Offspring *** *** * * *** * * *** *** * *** * 50 AT1R mang mace1 mace2 TGF-b1 PAI-1

43 Nistala R. et al. Cardiorenal Med. 2011; 1:

44 Low vs. Normal BW and SBP in Later Life Juonala et al. J Htn. 2015; 33:

45 Objectives of This Talk To discuss relevant organogenesis and developmental progression To consider the concept of developmental origins with respect to hypertension and CV disease To discuss the implications for follow-up and therapy

46 Coffman T. Nature Medicine 17, (2011)

47 Telemere Length and Association with Hypertension

48 Clinical Implications Known at-risk children Minimimize nephrotoxins Healthy lifestyle Monitor Children who are not identified High index of suspicion

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