Understanding mechanisms of Fontan failure and key predictors for patient outcome

描述(由申请人提供)：单心室性心脏缺陷，其中体静脉和肺静脉回流混合在单个功能性心室部，是最复杂的先天性心脏缺陷形式。外科修复被称为Fontan修复，将全身静脉回流直接改道到肺动脉，从而防止静脉回流混合并恢复正常的氧合饱和度水平。不幸的是，这些修复只是姑息性的，Fontan患者受到许多慢性并发症的影响。在过去的20年里，研究人员试图通过这种外科结构来了解血流动力学，以努力优化其效率，并将施加在单心室上的工作量降至最低。虽然这项工作在外科手术入路方面取得了重要进展，包括发展了全腔静脉-肺连接(TCPC)，但缺乏将这些定量标记物与最终患者预后联系起来的综合实验和临床方法。这样的研究将是推进治疗努力的关键一步，因为它将确定控制结果的临床标记物，并阐明Fontan失败的机制。了解这些相互联系还将提供制定最佳医疗战略以改善这些结果的手段。因此，这笔赠款的目的是调查TCPC血流动力学和心功能之间的关系，并随后确定这些参数如何影响患者的生活质量(QOL)。为了实现这些目标，PI组建了一支多学科的研究团队，他们在该领域拥有成熟的记录，一套新的成熟的分析工具，以及世界上最大的单心室解剖和血流数据收集。我们将通过以下协同方法利用这些资产：(1)我们将对TCPC血流动力学和心功能进行纵向分析；(2)我们将使用CMR运动方案比较休息和运动时单心室和TCPC的动力学；(3)我们将对患者的生活质量进行横断面评估，以量化临床结果，将它们与测量的血流动力学和功能参数相关联，并确定哪些参数是生活质量的关键决定因素和预测因素。这一方法的新组成部分包括使用与CMR兼容的自行车来获取患者在休息和运动条件下的血流动力学和功能数据；在一项针对150多名患者的横断面研究中，系统量化TCPC血流动力学(例如，功率损失)以及在休息和运动时的心血管功能；以及在纵向研究中描述它们的时间演变。这些代谢物与生活质量测量的相关性将确定用于患者诊断的最强结果预测因素。同时，将这些预测因素与简单的机械方法相结合，将指出患者预后恶化的原因。这反过来将有助于设计改进的外科和临床管理策略。 公共卫生相关性：这项拨款调查了出生时患有单室心脏缺陷的患者Fontan血流动力学和心功能之间的关系。这些替代者随后将与生活质量测量相关联，以确定用于患者诊断的最强结果预测因素。了解这些相互联系将提供制定最佳医疗战略以改善这些结果的手段。

DESCRIPTION (provided by applicant): Single ventricle heart defects, where systemic and pulmonary venous returns mix in the single functional ventricle, represent the most complex form of congenital heart defect. Surgical repairs, termed "Fontan Repairs," reroute the systemic venous return directly to the pulmonary arteries, thus preventing venous return mixing and restoring normal oxygenation saturation levels. Unfortunately, these repairs are only palliative and Fontan patients are subjected to a multitude of chronic complications. Over the past 20 years, researchers have sought to understand the hemodynamics through this surgical construct in an effort to optimize its efficiency and minimize the imposed workload on the single ventricle. While this work has led to important advances in the surgical approach, including the development of the total cavopulmonary connection (TCPC), an integrated experimental and clinical approach relating these quantitative markers to ultimate patient outcomes has been lacking. Such a study would represent a critical step in the advancement of treatment efforts as it will identify the clinical markers that control outcomes, and elucidate the mechanisms of Fontan failure. Understanding these interconnections would also provide the means to develop optimal medical strategies to improve those outcomes. Therefore, the objective of this grant is to investigate the relationship between TCPC hemodynamics and ventricular function, and subsequently determine how those parameters impact patient quality of life (QOL). To achieve these objectives, the PI has assembled a multidisciplinary research team with a proven track record in the field, a novel set of established analytical tools, and the largest collection of single ventricle anatomy and flow data in the world. These assets will be utilized through the following synergistic approach: (1) we will perform a longitudinal analysis of TCPC hemodynamics and ventricular function; (2) we will compare the dynamics of the single ventricle and TCPC between rest and exercise using a CMR exercise protocol; and (3) we will conduct a cross-sectional assessment of patient QOL to quantify clinical outcomes, relate them to the measured hemodynamic and functional parameters, and determine which parameters are critical determinants and predictors of QOL. The novel components of this approach include the use of a CMR-compatible bike to obtain patient hemodynamic and function data under both resting and exercise conditions; the systematic quantification of TCPC hemodynamic (e.g. power loss) and cardiovascular function at rest and exercise in a cross-sectional study of over 150 patients; and the characterization of their temporal evolution in a longitudinal study. Correlation of these surrogates to quality of life measures will identify the strongest outcome predictors to be used for patient diagnosis. In parallel, combining these predictors with the simple mechanistic approaches will point to the cause of the deteriorating patient outcome. This will in turn help design improved surgical and clinical management strategies. PUBLIC HEALTH RELEVANCE: This grant investigates the relationship between Fontan hemodynamics and ventricular function in patients born with single-ventricle heart defects. These surrogates will subsequently be correlated to quality of life measures to identify the strongest outcome predictors to be used for patient diagnosis. Understanding these interconnections will provide the means to develop optimal medical strategies to improve those outcomes.