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Nicotine and congenital heart disease

Institution: Stanford University
Investigator(s): Ching-Pin Chang, M.D., PH.D
Award Cycle: 2008 (Cycle 17) Grant #: 17RT-0102 Award: $629,797
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards

Initial Award Abstract
Smoking during pregnancy is associated with congenital heart defects. In the US, about 1 in 8 women smokes during pregnancy. The situation is even more serious in California, where about 1 in 4 women smokes during pregnancy. Although smoking harms both pregnant women and the fetus, only about 20 percent of women who smoke quit during pregnancy. This is a major health problem for both women and children. It is therefore important to understand how smoking during pregnancy causes congenital heart disease.

Heart malformations associated with maternal smoking most commonly involves particular regions of the heart - the outflow tract of the heart and heart valves. Abnormal outflow tract formation may result in mixing of blood and poor oxygenation. Or, it may cause significant shunting of the blood and overloading of the heart. Similarly, heart valve malformations may cause blockage or leakage of the blood flow. Children with these congenital heart diseases often have poor circulation, congestion in the lungs and heart failure. Some infants are more susceptible to maternal smoking during pregnancy. Infants with Down syndrome (due to an extra copy of chromosome 21) have 5 times higher risk of having defects in the outflow region of the heart if their mother smoked during pregnancy. This suggests that underlying genetic factors can predispose the fetus to smoking-related heart defects.

Despite the medical importance of fetal congenital heart defects related to maternal smoking, there are surprisingly few studies of how nicotine may affect fetal heart development. We have generated several mouse models that have heart defects, very similar to those associated with maternal smoking. We plan to use these animal models to study how nicotine causes abnormal heart formation, and how nicotine interacts with genetic factors in congenital heart disease. Detailed understanding of the underlying mechanisms will enhance our awareness of this smoking-related disease and pave the way for better prevention and treatment.

Pbx/Meis deficiencies demonstrate multi-gentic origins of congenital heart disease.
Periodical: Circulation Research Index Medicus:
Authors: Stankunas; Shang; Twu; Kao, S; Jekins, N; Copeland, N; Sanyal; Selleri; Cleary; Chang, CP ART
Yr: 2008 Vol: 103 Nbr: Abs: Pg: 702-709

Spatial and temporal regulation of coronary vessel formation by calcincurin/NFAT signaling.
Periodical: Developmental Biology Index Medicus:
Authors: Zeini, M; Hang, CT; Lehrer-Graiwer, J; Zhou, B; Chang CP ART
Yr: 2009 Vol: 136 Nbr: 19 Abs: Pg: 3335-3345

Chromatin regulation by Brgl underlies heart muscle development and disease.
Periodical: Nature Index Medicus:
Authors: Hang, CT; Yang, J; Han, P; Cheng, HL; Ashley, E; Zhou, B; Chang, CP ART
Yr: 2010 Vol: Nbr: Abs: Pg:

Chromatin remodeling in cardiovascular development and physiology
Periodical: Circulation Research Index Medicus:
Authors: Han P, Hang CT, Yang J, Chang CP ART
Yr: 2011 Vol: Nbr: 108 Abs: Pg: 378-96

The secondary heart field is a new site of calcineurin/Nfatc1 signaling for semilunar valve development
Periodical: Journal of Molecular and Cellular Cardiology Index Medicus:
Authors: Lin CY, Lin CJ, Chen CH, Chen RM, Zhou B, Chang CP ART
Yr: 2012 Vol: 52 Nbr: 5 Abs: Pg: 1096-102

Partitioning the heart: mechanisms of cardiac septation and valve development
Periodical: Development Index Medicus:
Authors: Lin CJ, Lin CY, Chen CH, Zhou B, Chang CP ART
Yr: 2012 Vol: 139 Nbr: 18 Abs: Pg: 3277-99

Whole embryo culture for heart development studies
Periodical: Methods in Molecular Biology Index Medicus:
Authors: Hang C, Chang CP ART
Yr: 2012 Vol: Nbr: 843 Abs: Pg: 3-9

Analysis of the patterning of great arteries with angiography and vascular casting
Periodical: Methods in Molecular Biology Index Medicus:
Authors: Chang CP ART
Yr: 2012 Vol: Nbr: 843 Abs: Pg: 21-8

Analysis of the endocardial-to-mesenchymal transformation of heart valve_x000D_ development by a collagen gel culture assay
Periodical: Methods in Molecular Biology Index Medicus:
Authors: Xiong Y, Zhou B, Chang CP ART
Yr: 2012 Vol: Nbr: 843 Abs: Pg: 101-9