ARRHYTHMOGENIC REMODELING IN HUMAN HEART FAILURE

描述（由申请人提供）：心力衰竭（HF）是死亡和发病的主要原因，困扰着570万美国人。HF管理包括外科手术、植入式器械和靶向血管紧张素和肾上腺素能信号传导的药物治疗。已经产生了许多心力衰竭的动物模型并研究了数十年，以努力鉴定用于治疗人类HF患者的治疗靶点。然而，越来越明显的是，这种策略已经产生了有限的治疗HF的治疗选择。物种间显著的遗传、分子、细胞、解剖和系统差异可能是导致从细胞系和动物模型向人类翻译失败的原因。心脏节律紊乱是这种翻译失败的突出例子。尽管花费巨资进行了超过半个世纪的研究，对许多离子通道、泵和交换剂的生物物理性质有了深入的了解，但目前用于治疗心律失常的药物治疗是非特异性的，并且通常无效。这种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，但我们知道更多的离子通道和动作电位在小鼠，大鼠，豚鼠，兔子和狗相比，我们自己的物种-智人。我们最近开发了一个程序，它允许在体外活体人类心脏中研究致心律失常性重构的机制。在这个项目中，我们将调查一些机制的假设连接HF和心律失常在活的心脏组织从供体和HF患者。总之，我们将开发，完善和扩展实验方法，目前仅适用于基础生理学实验室的动物心脏制剂，以加深我们对人类心脏病理生理学的理解。这种方法将修改和增强目前占主导地位的翻译范式，并提供新的重要研究方向，这将刺激和重振生物医学研究界，忽视了人类生理学，从而延迟了HF和心源性猝死所需疗法的有效翻译。

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.