Cardiac Beta-Adrenergic Adaptation in Pediatric Heart Failure

描述（由申请人提供）：2-肾上腺素能系统的功能改变在成人心力衰竭（HF）的病理生理中起重要作用。实验数据广泛定义了HF中2-肾上腺素能受体（2-AR）反应的许多成分，导致临床治疗范式的转变，包括2-AR阻断剂治疗，以改善发病率和死亡率。然而，在患有心力衰竭的儿童中，心肌细胞的变化，包括2-肾上腺素能系统的变化，却知之甚少。事实证明，这一事实是改善这一弱势群体的护理和临床结果的关键障碍。尽管儿童和成人心衰患者的循环儿茶酚胺水平均升高，但儿童心衰患者服用β受体阻滞剂（BB）缺乏临床益处，这与支持BB对成人心衰有益的大量证据形成鲜明对比，这表明儿童和成人在心脏2-肾上腺素能系统对心力衰竭的心肌细胞反应方面可能存在重要差异。不幸的是，在儿科人群中进行临床研究的困难和缺乏针对儿童特发性心肌病的动物模型阻碍了我们知识的进步。当前建议的中心假设是，临床对BB治疗反应的差异是儿童和成人心脏肾上腺素能系统对HF反应差异的产物，无论是在AR水平还是在其细胞内信号通路上。因此，本研究的目的是利用我们现有的成人和儿童外植心脏组织库[1]鉴定小儿心衰患者心脏2-肾上腺素能受体的关键心肌细胞变化，[2]检测小儿心衰患者参与2-肾上腺素能反应的中枢下游信号因子和microRNA效应物的表达。此外，该提案将开发一个小鼠模型，用于儿童心脏对HF患者中儿茶酚胺水平升高的反应。未来的研究将使用该模型来剖析心衰儿童肾上腺素能刺激增加的分子机制，从而确定哪种治疗方法可能对儿科患者最有益。公共卫生相关性：心力衰竭是儿童的一种致命疾病。与成人相比，儿童心力衰竭的心脏发生的变化尚不清楚。目前的提议将提高我们对儿童心脏对心力衰竭的反应方式的理解，这样我们就可以改善这种毁灭性疾病的医学治疗。

DESCRIPTION (provided by applicant): Functional changes in the 2-adrenergic system play an important role in the pathophysiology of heart failure (HF) in adults. Experimental data has extensively defined many of the components involved in the 2-adrenergic receptor (2-AR) response in HF resulting in a shift of the clinical treatment paradigm to include 2-AR blocker therapy to improve morbidity and mortality. In children with heart failure, however, myocellular changes, including those in the 2-adrenergic system, are poorly understood. This fact proves to be a critical barrier for improving care and clinical outcomes in this vulnerable population. Although circulating catecholamine levels are elevated in both children and adults with HF, the lack of clinical benefit of betablocker (BB) therapy in children with HF is in stark contrast to the overwhelming evidence supporting beneficial BB effects in adults with HF and suggests that there may be important differences between children and adults in the myocellular response of the cardiac 2-adrenergic system to heart failure. Unfortunately, advances in our knowledge are hindered by the difficulty of performing clinical studies in pediatric populations and a lack of animal models specific to pediatric idiopathic cardiomyopathy. The central hypothesis of the current proposal is that the differences in clinical response to BB therapy is a product of differences in the response of the cardiac adrenergic system to HF in children and adults, both at the level of the AR as well as in its intracellular signaling pathways. Therefore the purpose of the current proposal is use our existing adult and pediatric explanted heart tissue banks [1] to identify key myocellular changes in cardiac 2-adrenergic receptors of pediatric patients with HF, and [2] measure the expression of central downstream signaling factors and microRNA effectors that are involved in the 2-adrenergic response in pediatric heart failure patients. In addition, the proposal will develop a mouse model for the response of the pediatric heart to the elevated catecholamine levels present in HF patients. Future investigations will use this model to dissect the molecular mechanisms of increased adrenergic stimulation in children with HF and thereby determine which therapies may be most beneficial in pediatric patients. PUBLIC HEALTH RELEVANCE: Heart failure is a deadly disease in children. In contrast to in adults, the changes that occur in the heart of children with heart failure are poorly understood. The current proposal will improve our understanding of the way a child's heart responds to heart failure so that we can improve medical treatment of this devastating disease.