ARRHYTHMOGENIC REMODELING IN HUMAN HEART FAILURE

描述(由申请人提供)：心力衰竭(HF)是导致死亡和发病的主要原因，困扰着570万美国人。心衰的治疗包括手术、植入性装置和针对血管紧张素和肾上腺素能信号的药物治疗。几十年来，人们已经建立和研究了许多心力衰竭的动物模型，以努力确定治疗人类心力衰竭患者的靶点。然而，越来越明显的是，这种策略在治疗心力衰竭方面产生了有限的治疗选择。物种间显著的遗传、分子、细胞、解剖学和系统差异可能是导致从细胞系和动物模型到人类的翻译失败的原因。心律失常就是这种翻译失败的明显例子。尽管对许多离子通道、泵和交换器的生物物理性质有深入的了解，但半个多世纪的研究花费巨大，目前用于治疗心律失常的药物治疗是非特异性的，而且往往无效。失败的主要原因是人类心脏生理学在分子、细胞和组织水平上的复杂性。这是自相矛盾的，但与我们自己的物种-智人相比，我们对小鼠、大鼠、豚鼠、兔和狗的离子通道和动作电位了解得更多。我们最近开发了一个程序，可以在体外研究活体人心脏的致心律失常重塑机制。在这个项目中，我们将从供者和心力衰竭患者的活体心肌组织中研究一些将心力衰竭与心律失常联系起来的机制假说。综上所述，我们将发展、完善和推广目前仅适用于基础生理学实验室中的动物心脏制剂的实验方法学，以加深我们对人类心脏病理生理学的理解。这一方法将修改和加强目前占主导地位的翻译范式，并提供新的重要研究方向，这将刺激和重振忽视人类生理学的生物医学研究社区，从而推迟心力衰竭和心源性猝死所需疗法的有效翻译。 公共卫生相关性：我们的项目旨在弥合人类心力衰竭动物模型的基本发现与临床试验验证之间的差距。我们会 开发方法学，利用移植患者的移植心脏和被拒绝移植的供者心脏，产生关于人类物种心脏功能的至关重要的新生理学知识。这些珍贵的活人心脏礼物将产生关于人类心力衰竭期间发生的病理过程的至关重要的新知识，这些过程导致数十万患者心源性猝死。

DESCRIPTION (provided by applicant): Heart failure (HF) is the leading cause of mortality and morbidity, which afflicts 5.7 million Americans. HF management includes surgery, implantable device and pharmacological therapy targeting angiotensin and adrenergic signaling. Numerous animal models of heart failure have been generated and studied for decades in effort to identify therapeutic targets for treatment of human HF patients. However, it is becoming increasingly evident that this strategy has yielded limited therapeutic options for the treatment o HF. Significant genetic, molecular, cellular, anatomical, and systemic differences among species are likely to be responsible for failure of translation from cell lines and animal models t humans. Cardiac rhythm disorders are striking examples of such translational failure. Despite deep knowledge of the biophysical properties of numerous ion channels, pumps, and exchangers gained over half a century of research conducted at huge expense, current pharmacological therapies used to treat arrhythmias are nonspecific and often ineffective. The main reason for this failure is the complexity of human cardiac physiology at the molecular, cellular and tissue levels. It is paradoxical, but we know much more about ion channels and action potentials in the mouse, rat, guinea pig, rabbit, and canine as compared to our own species - Homo sapiens. We have recently developed a program, which allows investigation of the mechanisms of arrhythmogenic remodeling in live human hearts in vitro. In this project we will investigate a number of mechanistic hypothesis linking HF and arrhythmia in live cardiac tissue from donors and patients with HF. In summary, we will develop, refine and extend experimental methodology, which is currently applied only to animal cardiac preparations in basic physiology laboratories, to deepen our understanding of human cardiac pathophysiology. This approach will modify and enhance the currently dominant translational paradigm and provide new important directions of research, which will stimulate and reinvigorate a biomedical research community that has ignored human physiology and thus delayed effective translation of needed therapies for HF and sudden cardiac death. PUBLIC HEALTH RELEVANCE: Our project aims to bridge the gap between fundamental discoveries in animal models of human heart failure and its validation in clinical trials. We will develop methodology to produce critically important new physiological knowledge about the cardiac function of the human species, using explanted hearts of transplantation patients and donor hearts rejected from transplantation. These precious gifts of live human hearts will yield critically important new knowledge about pathological processes occurring during heart failure in humans that lead to sudden cardiac death of hundreds of thousands of patients.