Central Autonomic Nervous System Regulation in Heart Failure

描述(由申请人提供)：目的是确定受损的大脑自主神经系统(ANS)调节区(下丘脑、脑岛皮质和小脑)如何应对ANS挑战，并评估心力衰竭(HF)受试者对该挑战的功能反应的偏侧性。心力衰竭患者自主神经系统活动异常与发病率和死亡率增加有关。目前尚不清楚在中央ANS控制区看到的结构性破坏是否反映了功能ANS的异常。我们的初步研究发现，在高频时，ANS控制区的损伤伴随着对ANS挑战的偏侧化、改变(钝化、倒置或延迟性)功能缺陷，这些改变优先发生在右侧。右侧损害和功能反应受损的偏侧化会增加心律失常的风险，增加ANS异常。然而，这些受损的脑区对ANS挑战的反应尚不清楚，而且偏侧性损伤在多大程度上促进了HF中ANS的异常反应还有待描述。因此，采用两组对比设计，我们将在40名HF和40名年龄和性别匹配的健康对照组中，使用扩散张量成像程序和功能反应来检查大脑和控制区的结构完整性，并使用功能磁共振成像(MRI)程序检查这些信号变化的偏侧性。其具体目的是：1)在HF和健康对照组中，使用功能MRI程序评估ANS刺激在一组ANS调节脑区(下丘脑、岛叶皮质和小脑)中诱发顺序交感和副交感神经动作(Valsalva动作)的功能反应；2)评估HF受试者调节ANS音调的脑区域的结构完整性(使用扩散张量成像程序)和功能活动(通过功能MRI)之间的关系。这些研究将有助于确定、开发和评估新的治疗策略，以保护和重新训练中枢神经系统区域，以恢复ANS功能，并改善这一高危患者群体的生存和生活质量。对这些结构性和功能性ANS异常的潜在未来干预措施可能包括外周或中枢作用的药理学药物(如他汀类药物或血管紧张素-肾素阻滞剂)，或神经保护干预，包括重新培训/重组替代脑结构以恢复ANS脑功能。

DESCRIPTION (provided by applicant): The objective is to determine how damaged brain autonomic nervous system (ANS) regulatory areas (hypothalamus, insula cortex, and cerebellum) respond to an ANS challenge, and to assess the laterality of functional responses to that challenge in heart failure (HF) subjects. Abnormal autonomic nervous system activity in HF is associated with increased morbidity and mortality. It is unclear if the structural damage seen in central ANS control regions reflects functional ANS abnormalities. Our preliminary studies found that injury in ANS control regions was accompanied by lateralized, altered (blunted, inverted, or time-delayed) functional deficits to ANS challenges in HF, and these changes preferentially occurred on the right side. The lateralization of damage and impaired functional responses on the right-side can increase risk for cardiac dysrhythmias and increase ANS abnormalities. However, responses of these damaged brain regions to ANS challenges are unclear, and the extent to which the lateralized injury contributes to abnormal ANS reactivity in HF has yet to be described. Therefore, using a two-group comparative design, we will examine the structural integrity in brain ANS control areas using diffusion tensor imaging procedures and functional responses and laterality of those signal changes to an ANS challenge using functional magnetic resonance imaging (MRI) procedures in 40 HF and 40 age- and gender-matched healthy controls. The specific aims are to:1) evaluate functional responses to an ANS challenge eliciting sequential sympathetic and parasympathetic actions (Valsalva maneuver) in a set of ANS regulatory brain regions (hypothalamus, insular cortices, and cerebellum) using functional MRI procedures in HF and healthy controls; 2) evaluate the relationships between structural integrity (using diffusion tensor imaging procedures) and functional activity (via functional MRI) of brain regions which regulate ANS tone in HF subjects. These studies will aid in the identification, development, and evaluation of new therapeutic strategies to protect and retrain central nervous system regions to restore ANS function, and improve survival and quality of life in this high risk patient population. Potential future interventions for these structural and functional ANS abnormalities could include peripheral or centrally-acting pharmacologic agents (such as statins or angiotensin-renin blockers), or neuroprotective interventions, including retraining/reorganization of alternative brain structures to restore ANS brain functions.