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

项目摘要/摘要 最严重的先天性心脏病包括单右室(SRV)患者。 在5岁前表现出40%死亡率的生理学疾病。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，被证明对成人有效的治疗方法似乎并没有 改善SRV生理学患者的心力衰竭。有许多假设可以潜在地解释 这些差异，所有这些都围绕着心脏力学的理论差异 双室和单室生理学。然而，这些假说目前都无法检验。 因为1)SRV患者发生心力衰竭的病理生理机制 2)目前还没有可靠的非侵入性评估方法 SRV患者的心脏力学，以及3)这些测量与患者之间的关系 结果还没有被研究。 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疗法 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 审判。为了实现这一目标，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 通过评估它们与参考标准测量的相关性，以及3)调查 通过评估这些血清和无创性心肌功能指标的相关性来评估它们的临床应用价值 有短期的结果。 对SRV生理学的理解将导致新的和创新的治疗方法，理想的情况是， 改善这一弱势群体的结果。从执行这一职业中获得的技能 发展计划和研究方案将使我唯一有资格成为心肌领域的领导者 儿科人群中的力学、单心室生理学、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.