Cardiac Beta-Adrenergic Adaptation in Pediatric Heart Failure

描述（由申请方提供）：2-肾上腺素能系统的功能变化在成人心力衰竭（HF）的病理生理学中起重要作用。实验数据已广泛定义了HF中2-肾上腺素能受体（2-AR）反应所涉及的许多组分，导致临床治疗模式转变为包括2-AR阻滞剂治疗，以改善发病率和死亡率。然而，在心力衰竭儿童中，包括2-肾上腺素能系统中的肌细胞变化知之甚少。事实证明，这是改善这一弱势群体的护理和临床结果的关键障碍。尽管HF儿童和成人的循环儿茶酚胺水平均升高，但HF儿童缺乏β受体阻滞剂（BB）治疗的临床获益，这与支持BB对HF成人有益的压倒性证据形成鲜明对比，并表明儿童和成人之间心脏β 2-肾上腺素能系统对心力衰竭的肌细胞反应可能存在重要差异。不幸的是，在我们的知识的进步是阻碍了在儿科人群中进行临床研究的困难和缺乏特定的儿童特发性心肌病的动物模型。当前建议的中心假设是，BB治疗的临床反应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，包括AR水平及其细胞内信号传导途径。因此，当前提案的目的是使用我们现有的成人和儿科移植心脏组织库[1]来确定HF儿科患者心脏β 2-肾上腺素能受体的关键肌细胞变化，[2]测量参与儿科心力衰竭患者β 2-肾上腺素能反应的中心下游信号传导因子和microRNA效应物的表达。此外，该提案将开发一种小鼠模型，用于儿童心脏对HF患者中升高的儿茶酚胺水平的反应。未来的研究将使用该模型来剖析HF儿童中肾上腺素能刺激增加的分子机制，从而确定哪些疗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，人们对心力衰竭儿童心脏发生的变化知之甚少。目前的提案将提高我们对儿童心脏对心力衰竭的反应方式的理解，以便我们能够改善这种毁灭性疾病的医疗。

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.