Redox Modification of the Arrhythmic Substrate in Heart Failure

描述（由申请人提供）：心力衰竭是一种在世界范围内发病率不断上升的疾病。在美国，近600万人患有心力衰竭，这是老年人最常见的住院诊断。2009年的经济影响估计为372亿美元。用肾素-血管紧张素信号的2-阻滞剂和/或抑制剂治疗这种疾病，多年来降低了死亡率和发病率，但在诊断后5年内死亡率仍接近60%。致死性心律失常，即心源性猝死（SCD），约占心力衰竭早期死亡的一半，其余为进行性心脏失代偿。许多因素导致HF的病理，包括神经体液环境的改变，离子通道和转运体活性的改变，细胞死亡途径的调节，以及组织固有结构的重塑。最近的证据表明，心脏细胞质、肌浆网和线粒体的还原氧化（氧化还原）电位的改变可能是参与心脏肥厚和衰竭进展的关键因素。在心力衰竭（HF）中，有证据表明氧化应激可能导致功能受损，这可能是离子稳态改变、能量不足和蛋白质靶点翻译后修饰的结果。此外，大量的离子通道、转运体和信号通路已被证明可以直接被活性氧（ROS）或硫醇状态或氧化还原载体浓度的变化所调节。这些靶点中的一些或许多靶点可能有助于增强衰竭心脏对心律失常和SCD的易感性。全面了解代谢和氧化还原平衡的变化如何影响电生理底物，需要系统生物学的方法来解决这个问题，包括解构单个离子通道、转运体和信号通路如何受到氧化还原调节剂的影响，以及如何改变综合系统的性能。具体来说，在本提案中，我们的目标是研究氧化应激增强如何改变心力衰竭心肌细胞的电生理、Ca2+调节过程和心律失常易感性（压力过载模型）。将采用结合“水平”和“垂直”整合的迭代，实验/计算系统生物学方法。这些方法将用于建立氧化还原/抗氧化途径及其对离子通道和转运体的下游影响的生物物理详细的细胞和全心脏模型，目的是确定代谢和氧化应激如何导致心律失常、泵衰竭和SCD。最重要的目标将是确定对整个心脏功能影响最大的特定改变，从而缩小治疗干预的目标数量。

DESCRIPTION (provided by applicant): Heart failure is a disease that is continually increasing in prevalence worldwide. In the United States, nearly 6 million people suffer from heart failure and it is the most common inpatient diagnosis in the elderly. The economic impact for 2009 has been estimated at $37.2 billion. Treatment of this disease with 2-blockers and/or inhibitors of renin-angiotensin signaling has decreased mortality and morbidity over the years, but mortality still approaches 60% within 5 years of diagnosis. Fatal arrhythmias, known as Sudden Cardiac Death (SCD), account for about half of the early deaths in HF, with progressive cardiac decompensation accounting for the remainder. Many factors contribute to the pathology of HF, including changes in the neurohumoral environment, alterations in ion channel and transporter activity, modulation of cell death pathways, and remodeling of the inherent structure of the tissue. Recent evidence indicates that alterations in the reduction- oxidation (redox) potential of the cytoplasm, sarcoplasmic reticulum, and the mitochondria of the heart may be a key factor involved in the progression of cardiac hypertrophy and failure. In heart failure (HF), there is evidence that oxidative stress may contribute to impaired function, and this may arise as a consequence of altered ion homeostasis, energetic deficiencies, and post-translational modification of protein targets. Moreover, a large number of ion channels, transporters, and signaling pathways have been shown to be modulated either directly by reactive oxygen species (ROS), or by changes in the thiol status or redox carrier concentration. Some, or many, of these targets, could contribute to an enhanced susceptibility of the failing heart to arrhythmogenesis and SCD. A comprehensive view of how shifts in metabolism and redox balance influence the electrophysiological substrate requires a systems biology approach to the problem, involving deconstruction of how individual ion channels, transporters and signaling pathways are affected by redox modulators, and how the performance of the integrated system is changed. Specifically, in this proposal, our objective is to examine how enhanced oxidative stress alters the electrophysiology, Ca2+ regulatory processes, and arrhythmia susceptibility of myocytes from failing hearts (pressure-overload model). An iterative, experimental/computational systems biology approach combining both "horizontal" and "vertical" integration will be taken. These approaches will be used to build biophysically-detailed cellular and whole-heart models of redox/antioxidant pathways and their downstream effects on ion channels and transporters, with the goal of defining how metabolic and oxidative stress leads to arrhythmias, pump failure, and SCD. An overriding goal will be to define the specific alterations that have the greatest influence on whole heart function, so as to narrow down the number of targets to pursue for therapeutic intervention. PUBLIC HEALTH RELEVANCE: Narrative Heart failure is a disease that is continually increasing in prevalence worldwide. In this proposal, our objective is to examine how enhanced oxidative stress alters the electrophysiology, Ca2+ regulatory processes, and arrhythmia susceptibility of myocytes from failing hearts. An overriding goal will be to define the specific alterations that have the greatest influence on whole heart function, so as to narrow down the number of targets to pursue for therapeutic intervention to treat heart failure.