Cardiomyopathy and Diastolic Dysfunction in the Embryo and Neonate of a Type 1 Diabetic Mouse Model

Abstract

Objective:

The purpose of this study was to examine the effect of maternal type 1 diabetes on the structure and function of the embryonic and neonatal mouse heart.

Methods:

Type 1 diabetes was induced in female C57BL6/J mice using streptozotocin. Embryonic (n = 105) and neonatal hearts (n = 46) were examined using high-frequency ultrasound (US) and a cohort of E18.5 (n = 34) and 1-day-old pup hearts (n = 27) underwent histological examination.

Results:

Global cardiac hypertrophy in late gestation (E18.5) was evident on US in the diabetic group compared to controls with increased interventricular septal (IVS) thickness (0.44 ± 0.08 mm vs 0.36 ± 0.08 mm, P < .05) and increased left ventricular wall thickness (0.38 ± 0.04 mm vs 0.29 mm ± 0.05, P < .01). Isovolumetric relaxation time was initially prolonged in the diabetic group but resolved by E18.5 to control values. Histological examination at E18.5 demonstrated increased transverse measurements (2.42 ± 0.72 mm/g vs 1.86 ± 0.55 mm/g, P < .05) and increased IVS thickness (0.64 ± 0.20 mm/g vs 0.43 ± 0.15 mm/g, P < .05) in diabetic embryos compared to control embryos.

Conclusion:

Maternal hyperglycemia has severe effects on offspring with evidence of cardiac impairment and cardiac hypertrophy in the embryo. These effects persisted in the 1-day old but attenuated in the 1-week old suggesting cardiac remodeling after the hyperglycemic milieu of pregnancy is removed.

Keywords

diabetes embryogenesis type 1 diabetic mouse model high resolution ultrasound

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References

Corrigan

Brazil

McAuliffe

. Fetal cardiac effects of maternal hyperglycemia during pregnancy. Birth Defects Res A Clin Mol Teratol. 2009;85(6):523–530.

Reece

Homko

Ying-King

. Multifactorial basis of the syndrome of diabetic embryopathy. Teratology. 1996;54(4):171–182.

McAuliffe

Foley

Firth

Drury

Stronge

. Outcome of diabetic pregnancy with spontaneous labour after 38 weeks. Ir J Med Sci. 1999;168(3):160–163.

Eidem

Vangen

Hanssen

Perinatal and infant mortality in term and preterm births among women with type 1 diabetes. Diabetologia. 2011;54(11):2771–2778.

Russell

Foley

Kinsley

Firth

Coffey

McAuliffe

FM.

Effect of pregestational diabetes mellitus on fetal cardiac function and structure. Am J Obstet Gynecol. 2008;199(3):312.e311–312.e317.

Abu-Sulaiman

Subaih

. Congenital heart disease in infants of diabetic mothers: echocardiographic study. Pediatr Cardiol. 2004;25(2):137–140.

Moore

. Diabetes in pregnancy. In: Creasy

, ed. Maternal - Fetal Medicine. 4th ed. Philadelphia, PA: WB Saunders; 1999.

Loffredo

Wilson

Ferencz

. Maternal diabetes: an independent risk factor for major cardiovascular malformations with increased mortality of affected infants. Teratology. 2001;64(2):98–106.

Gardiner

Pasquini

Wolfenden

Kulinskaya

Henein

. Increased periconceptual maternal glycated haemoglobin in diabetic mothers reduces fetal long axis cardiac function. Heart. 2006;92(8):1125–1130.

10.

Jaeggi

Fouron

Proulx

. Fetal cardiac performance in uncomplicated and well-controlled maternal type I diabetes. Ultrasound Obstet Gynecol. 2001;17(4):311–315.

11.

Potter CDK

S. D

. Infant of diabetic mother. www.e-Medicine.com. 2006. Accessed November 4, 2010.

12.

Cooper

Enderlein

Tarnoff

Roge

. Asymmetric septal hypertrophy in infants of diabetic mothers. Fetal echocardiography and the impact of maternal diabetic control. Am J Dis Child. 1992;146(2):226–229.

13.

Sheehan

Rowland

Shah

McGravey

Reiter

. Maternal diabetic control and hypertrophic cardiomyopathy in infants of diabetic mothers. Clin Pediatr (Phila). 1986;25(5):266–271.

14.

Aman

Hansson

Ostlund

Wall

Persson

. Increased fat mass and cardiac septal hypertrophy in newborn infants of mothers with well-controlled diabetes during pregnancy. Neonatology. 2011;100(2):147–154.

15.

Corrigan

Brazil

McAuliffe

. High-frequency ultrasound assessment of the murine heart from embryo through to juvenile. Reprod Sci. 2010;17(2):147–157.

16.

Rizzo

Arduini

Romanini

. Accelerated cardiac growth and abnormal cardiac flow in fetuses of type I diabetic mothers. Obstet Gynecol. 1992;80(3 pt 1):369–376.

17.

Reinking

Wedemeyer

Weiss

Segar

Scholz

. Cardiomyopathy in offspring of diabetic rats is associated with activation of the MAPK and apoptotic pathways. Cardiovasc Diabetol. 2009;8:43.

18.

Gutgesell

Speer

Rosenberg

. Characterization of the cardiomyopathy in infants of diabetic mothers. Circulation. 1980;61(2):441–450.

19.

Ullmo

Vial

Di Bernardo

Pathologic ventricular hypertrophy in the offspring of diabetic mothers: a retrospective study. Eur Heart J. 2007;28(11):1319–1325.

20.

Sardesai

Gray

McGrath

Ford

. Fatal hypertrophic cardiomyopathy in the fetus of a woman with diabetes. Obstet Gynecol. 2001;98(5 pt 2):925–927.

21.

Halliday

. Hypertrophic cardiomyopathy in infants of poorly-controlled diabetic mothers. Arch Dis Child. 1981;56(4):258–263.

22.

Veille

Hanson

Sivakoff

Hoen

Ben-Ami

. Fetal cardiac size in normal, intrauterine growth retarded, and diabetic pregnancies. Am J Perinatol. 1993;10(4):275–279.

23.

Teramo

. Obstetric problems in diabetic pregnancy—The role of fetal hypoxia. Best Pract Res Clin Endocrinol Metab. 2010;24(4):663–671.

24.

Teramo

Kari

Eronen

Markkanen

Hiilesmaa

. High amniotic fluid erythropoietin levels are associated with an increased frequency of fetal and neonatal morbidity in type 1 diabetic pregnancies. Diabetologia. 2004;47(10):1695–1703.

25.

Hagemann

, Zielinsky P. [Prenatal study of hypertrophic cardiomyopathy and its association with insulin levels in fetuses of diabetic mothers]. Arq Bras Cardiol. 1996;66(4):193–198.

26.

Zielinsky

da Costa

Oliveira

Bonow

da Silva

, Hagemann LL. [Natural history of myocardial hypertrophy and its association with hyperinsulinism in infants of diabetic mothers]. Arq Bras Cardiol. 1997;69(6):389–394.

27.

Lindsay

Westgate

Beattie

Inverse changes in fetal insulin-like growth factor (IGF)-1 and IGF binding protein-1 in association with higher birth weight in maternal diabetes. Clin Endocrinol (Oxf). 2007;66(3):322–328.

28.

Hayati

Cheah

Yong

Tan

Norizah

. The role of serum insulin-like growth factor I (IGF-I) in neonatal outcome. J Clin Pathol. 2004;57(12):1299–1301.

29.

Linke

. Sense and stretchability: the role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction. Cardiovasc Res. 2008;77(4):637–648.

30.

Russell

Higgins

Amaruso

Foley

McAuliffe

. Troponin T and pro-B-type natriuretic Peptide in fetuses of type 1 diabetic mothers. Diabetes Care. 2009;32(11):2050–2055.

31.

Van Assche

Holemans

Aerts

. Fetal growth and consequences for later life. J Perinat Med. 1998;26(5):337–346.

32.

Gutierrez

Hrubec

Prater

Smith

Freeman

Holladay

. Aortic and ventricular dilation and myocardial reduction in gestation day 17 ICR mouse fetuses of diabetic mothers. Birth Defects Res A Clin Mol Teratol. 2007;79(6):459–464.

33.

Bunt

Tataranni

Salbe

. Intrauterine exposure to diabetes is a determinant of hemoglobin A(1)c and systolic blood pressure in pima Indian children. J Clin Endocrinol Metab. 2005;90(6):3225–3229.

34.

Wichi

Souza

Casarini

Morris

Barreto-Chaves

Irigoyen

. Increased blood pressure in the offspring of diabetic mothers. Am J Physiol Regul Integr Comp Physiol. 2005;288(5):R1129–R1133.

35.

Manderson

Mullan

Patterson

Hadden

Traub

McCance

. Cardiovascular and metabolic abnormalities in the offspring of diabetic pregnancy. Diabetologia. 2002;45(7):991–996.

36.

Barrow

Taylor

. A rapid method for detecting malformations in rat fetuses. J Morphol. 1969;127(3):291–305.

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