Heart Failure in Single Right Ventricle Physiology: Pathologic Mechanisms and Novel Assessment

项目概要/摘要 最严重的先天性心脏病包括单右心室（SRV）患者 在生理学上表现出40%的5岁死亡率。这些患者都有很高的心力衰竭风险。 在这些患者中进行的临床药物试验表明，在成人中被证明有效的治疗似乎并不 改善具有SRV生理学患者心力衰竭。有很多假设可以解释 这些差异，都围绕着心脏力学的理论差异， 双心室和单心室生理学。然而，这些假设目前都无法得到检验 因为1）在患有SRV的患者中心力衰竭发展背后的病理生理机制 尚未进行全面研究，2）目前没有可靠的方法来非侵入性评估 SRV患者的心脏力学，以及3）这些指标与患者之间的关联 结果还没有研究。 我的长期目标是成为一名独立的科学家，评估患有心力衰竭的患者。 单心室生理学，这样我就可以通过领导临床试验来研究新的心力衰竭治疗方法， 这些患者并使用血清/非侵入性心力衰竭生物标志物来深入了解这些结果。 审判为了达到这一目标，完成以下目标：1）研究导致 SRV患者心力衰竭的发展，2）评估超声心动图测量的准确性 通过评估其与参考标准测量的相关性来评估心脏力学，以及3）调查 通过评估这些血清和非侵入性心肌功能指标之间的相关性， 短期的结果。 由此产生的对SRV生理学的理解将导致新的和创新的疗法，理想情况下， 改善这一弱势群体的成果。从这个职业的执行中获得的技能 发展计划和研究方案将使我成为心肌领域的领导者 力学，单心室生理学，以及儿科人群的临床药物和介入试验。

Project Summary/Abstract The most severe form of congenital heart disease includes patients with single right ventricle (SRV) physiology who exhibit 40% mortality by 5 years of age. These patients are all at very high risk for heart failure. Clinical drug trials in these patients show that therapies proven to be efficacious in adults do not appear to improve heart failure in patients with SRV physiology. There exist numerous hypotheses to potentially explain these differences, all of which revolve around the theoretical differences in cardiac mechanics between biventricular and single ventricle physiology. However, none of these hypotheses can currently be tested because 1) the pathophysiologic mechanisms behind the development of heart failure in patients with SRV have not been comprehensively studied, 2) there are currently no reliable methods to non-invasively assess cardiac mechanics in patients with SRV, and 3) the associations between these measures and patient outcomes has not been studied. My long term goal is to become an independent scientist in the evaluation of heart failure in patients with single ventricle physiology so that I may investigate novel heart failure therapies by leading clinical trials in these patients and use serum/non-invasive heart failure biomarkers to gain insight into the results of such trials. To reach this goal, complete the following aims: 1) Investigate pathophysiologic mechanisms that lead to the development of heart failure in patients with SRV, 2) assess the accuracy of echocardiographic measures of cardiac mechanics by assessing their correlation with reference-standard measures, and 3) investigate the clinical utility of these serum and non-invasive measures of myocardial function by assessing their association with short-term outcomes. The resultant understanding of SRV physiology will lead to new and innovative therapies, and ideally, improve outcomes in this vulnerable population. The skills gained from the execution of this career development plan and research protocol will uniquely qualify me to be a leader in the fields of myocardial mechanics, single ventricle physiology, and clinical drug and interventional trials in the pediatric population.