Congenital heart defects (CHD) are the most common birth defects, affecting nearly 1% of live births. The survival rates for CHD patients have greatly improved with surgical advances, shifting medical burden to the care of adult survivors of CHD. The greatest challenge is the poor neurological outcomes of CHD patients. While the etiology remains largely unknown, it is likely to be influenced by genetic factors, compromised hemo- dynamics, and cumulative injury from hypoxia and surgical trauma. Mechanistic insight into the structure-func- tion relationship between heart and brain development and their interaction in CHD is an important area of re- search that is poorly studied. Mouse models will no doubt be invaluable for such studies, as mice have the same cardiac anatomy as humans, similar architecture and pathways for the central nervous system, and a genome that is 99% identical, ensuring most biological processes and molecular pathways are conserved. Fe- tal MRI is emerging as an important prenatal imaging modality complementing prenatal ultrasound for the diag- nosis of congenital anomalies. Although still the predominant clinical imaging modality for prenatal screening given its low cost and ready availability, fetal ultrasound is limited by its prescribed acoustic windows, penetra- tion depth, low contrast, and ineffective tissue characterization. In contrast, fetal MRI are not affected by these limitations. However, live MRI in utero is greatly hampered by the challenge of fetal cardiac motion. In this study, we propose to overcome this problem by developing a gating-free ultra-fast 4D time-resolved fetal MRI using sub-Nyquist sparse sampling for live in utero cardiovascular and brain imaging of fetal mice. We will em- ploy a novel regional partial separability (PS) model to capture fetal and maternal motion and allow sparse (k, t)-space sampling. The two key features of this PS fetal MRI approach are (1) the ability to express incoherent fetal and maternal motion with reduced degrees of freedom; and (2) a unique sub-Nyquist sparse sampling scheme to accelerate acquisition and increase detection sensitivity. This will allow assessments of anatomical structures, such as in the heart and brain, and also the assessment of cardiovascular hemodynamic function and its interaction with the developing brain. As this imaging method is noninvasive, longitudinal follow-up can be pursued to examine whether changes in hemodynamic function may be correlated with emerging brain ab- normalities. We will develop this novel imaging method using wildtype mice, and then further validate its utility in characterizing the cardiac and brain defect phenotypes in two CHD mutant models, including the Ohia mu- tant mouse model of hypoplastic left heart syndrome (HLHS), one of the most lethal CHD. Upon validating the use of sub-Nyqist sparse sampling in the analysis of fetal brain and heart phenotypes in the HLHS mutant mice, this technique can be clinically translated for MRI study of human CHD fetuses. Ultimately, the success of this project will provide the basis to investigate the integration of structure-function in heart and brain devel- opment for new insights into cardiovascular influences on neurodevelopment in the pathogenesis of CHD.

Public Health Relevance

Congenital heart defects (CHD) are the most common birth defects, affecting nearly 1%, or about 40,000, of births per year in the United States, imposing great expenditure, however, the etiology of the neurodevelopmental deficits associated with CHD remains unclear, partly because better tools are needed to understand the emerging structure-functional relationship in CHD pathogenesis during fetal development for both heart and brain. The goal of this proposal is to develop gating-free ultra-fast 4D time-resolved fetal MRI using a unique sub-Nyquist sparse (k,t)-space sampling scheme for live in utero imaging of fetal heart and brain. The success of this project will enable simultaneous correlation of structural and functional relationships in the heart and the brain of the same fetus to interrogate cardiovascular influences of neurodevelopment in both mice and humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21EB023507-01A1
Application #
9530088
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Wang, Shumin
Project Start
2019-03-01
Project End
2020-12-31
Budget Start
2019-03-01
Budget End
2019-12-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213