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、植入式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，为了确定治疗人类心衰患者的治疗靶点，已经建立和研究了许多心力衰竭动物模型。然而，越来越明显的是，这种策略对心衰的治疗选择有限。物种之间显著的遗传、分子、细胞、解剖和系统差异可能是细胞系和动物模型向人类翻译失败的原因。心律失常是这种转化失败的显著例子。尽管经过半个多世纪的巨额研究，人们对众多离子通道、泵和交换器的生物物理特性有了深入的了解，但目前用于治疗心律失常的药物疗法是非特异性的，而且往往无效。这种失败的主要原因是人类心脏生理在分子、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、兔子和狗的离子通道和动作电位的了解要多得多。我们最近开发了一个程序，该程序允许在体外研究活体人类心脏的心律失常重塑机制。在这个项目中，我们将研究一些机制假说，将心衰和心衰患者活体心脏组织中的心衰和心律失常联系起来。综上所述，我们将发展、完善和扩展目前仅应用于基础生理学实验室动物心脏制剂的实验方法，以加深我们对人类心脏病理生理学的理解。该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体生理学的生物医学研究界，从而延迟了HF和心源性猝死所需治疗方法的有效翻译。

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.