Gating-Free Ultra-Fast Fetal Cardiac MRI with Sub-Nyquist Sampling for Live in Utero Imaging and Cardiovascular Phenotyping of Fetal Mice

采用亚奈奎斯特采样的无门控超快速胎儿心脏 MRI，用于胎儿小鼠的子宫内活体成像和心血管表型分析

• 批准号: 9530088
• 负责人: Yijen Lin Wu
• 金额: $ 25.29万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9530088
• 关键词: 3-Dimensional; Acoustics; Acute; Adult; Affect; Anatomy; Architecture; Area; Biological Process; Birth; Brain; Brain imaging; CHD1 gene; Cardiac; Cardiovascular Physiology; Cardiovascular system; Caring; Cine Magnetic Resonance Imaging; Clinical; Complement; Complex; Congenital Abnormality; Congenital Heart Defects; Data; Defect; Detection; Development; Diagnosis; Ensure; Etiology; Evaluation; Expenditure; Fetal Development; Fetal Heart; Fetus; Freedom; Functional Magnetic Resonance Imaging; Genetic; Genome; Goals; Heart; High Prevalence; Human; Hypoplastic Left Heart Syndrome; Hypoxia; Image; Imaging Device; Injury; Intrinsic factor; Left; Live Birth; Magnetic Resonance Imaging; Medical; Modality; Modeling; Molecular; Motion; Mus; Mutant Strains Mice; Neuraxis; Neurodevelopmental Deficit; Neurological outcome; Normalcy; Operative Surgical Procedures; Organ; Outcome; Palliative Surgery; Pathogenesis; Pathway interactions; Patients; Pattern; Penetration; Phase; Phenotype; Positioning Attribute; Randomized; Research; Resolution; Sampling; Scheme; Screening procedure; Secondary to; Sensitivity and Specificity; Structure; Structure-Activity Relationship; Survival Rate; Survivors; Syndrome; Techniques; Time; Tissues; Translating; Trauma; Ultrasonography; Uncertainty; United States; Visceral; Weight; brain abnormalities; brain tissue; cardiovascular imaging; care burden; clinical imaging; congenital anomaly; congenital heart disorder; cost; fetal; follow-up; heart motion; hemodynamics; imaging modality; improved; in utero; insight; interest; mortality; mouse model; mutant; mutant mouse model; neurodevelopment; novel; palliation; prenatal; prenatal testing; soft tissue; structural heart disease; success; tool

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.

先天性心脏缺陷（CHD）是最常见的出生缺陷，影响近1%的活产婴儿。的 随着外科技术的进步，冠心病患者的生存率大大提高， 成人CHD幸存者的护理。最大的挑战是CHD患者的神经系统结局较差。 虽然病因仍在很大程度上未知，但它可能受到遗传因素，受损的血液， 动力学以及缺氧和手术创伤造成的累积损伤。对结构-功能- 冠心病患者心脑发育的关系及其相互作用是研究冠心病的重要领域。 这是一个研究得不好的问题。小鼠模型无疑对于此类研究非常宝贵，因为小鼠具有 与人类相同的心脏解剖结构，中枢神经系统的相似结构和通路，以及 基因组99%相同，确保大多数生物过程和分子途径保守。铁- 胎儿MRI作为一种重要的产前成像方式正在兴起， 先天性异常的诊断。尽管产前筛查的主要临床成像方式 考虑到其低成本和容易获得，胎儿超声受到其规定的声窗的限制， 成像深度、低对比度和无效的组织定征。相比之下，胎儿MRI不受这些影响 局限性。然而，胎儿心脏运动的挑战极大地阻碍了子宫内的实时MRI。在这 研究中，我们建议通过开发无门控超快速4D时间分辨胎儿MRI来克服这个问题 使用亚奈奎斯特稀疏采样对胎鼠进行子宫内心血管和脑成像。我们会- 采用新的区域部分可分性（PS）模型来捕获胎儿和母体运动并允许稀疏（k， t）-空间采样。这种PS胎儿MRI方法的两个关键特征是（1）表达不连贯的能力， 自由度降低的胎儿和母体运动;以及（2）独特的亚奈奎斯特稀疏采样 加速捕获并提高检测灵敏度的方案。这将允许评估解剖结构 结构，如心脏和大脑，以及心血管血流动力学功能的评估 以及它与发育中的大脑的相互作用。由于这种成像方法是无创的，纵向随访可以 进行研究，以检查血液动力学功能的变化是否可能与新兴的脑ab- - 是的我们将利用野生型小鼠开发这种新的成像方法，然后进一步验证其实用性 在两种CHD突变模型中表征心脏和脑缺陷表型，包括Ohia mu- 左心发育不良综合征（HLHS）是最致命的CHD之一。在确认 亚Nyqist稀疏采样在HLHS突变体胎儿脑和心脏表型分析中的应用 小鼠，该技术可以临床转化为人类CHD胎儿的MRI研究。最终，成功 本项目的研究成果将为研究心脑发育的结构-功能整合提供基础。 为进一步了解冠心病发病机制中心血管对神经发育的影响提供了新的视角。