Omega-3 Fatty Acids, Neurohumoral Activation, and Human Heart Failure

描述（由申请人提供）：心力衰竭（HF）是一种慢性进行性疾病，与显著的发病率和死亡率相关。由于压力反射功能障碍和神经体液激活导致HF相关的进展和不良预后，因此确定有利影响这些因素的治疗非常重要。PI的长期目标是更好地了解HF中自主神经和心血管异常的潜在机制。PI的短期目标是确定补充omega-3脂肪酸对HF患者循环和神经体液激活的压力反射控制的影响。正在测试的一般工作假设是，压力反射功能障碍可能有助于HF中的神经体液激活，并且这些因素可能通过补充omega-3脂肪酸而有利地改变。为了解决这个问题，将进行具有以下特定目的的研究。确定ω-3脂肪酸补充对以下方面的影响：1）HF患者静息时和压力感受器负荷/卸载时的肌肉交感神经活动（MSNA），2）HF患者压力感受器反射卸载时的肾血管收缩反应，3）HF患者静息时和压力感受器反射卸载期间的神经体液激活和肢体血流。用于实现这些目标的方法包括使用腓神经显微神经造影术直接测量传出交感神经系统流出，多普勒超声估计肾血流速度和全肢血流，[中心静脉压]，以及评估神经体液激活状态的许多生化指标。除了获得对压力感受器输入变化的静息响应的测量（即，药物引起的血压变化和对分级的中枢低血容量应激的反应）。这些反应对于研究HF患者的压力反射功能障碍是重要的，因为HF患者的压力反射功能障碍可能是静息时神经体液激活以及生理应激应用期间调制受损的基础。在研究入组（基线）时获得的测量值将在干预（omega-3脂肪酸补充剂）的第6周和第12周重复进行，以了解反应的时间模式。预计HF患者补充ω-3脂肪酸12周后，静息时的神经体液激活和血管阻力将减少，并且包括神经体液激活调节在内的循环压力反射控制异常将至少部分恢复。研究的其他组将包括接受安慰剂（玉米油）的HF患者以及接受omega-3脂肪酸补充剂（健康实验）或玉米油补充剂（健康对照）的2组年龄、BMI和性别匹配的健康成人。总的来说，纳入这些不同的组将允许确定归因于HF的基线差异以及对omega-3脂肪酸反应的特异性。这些新研究的发现将为omega-3脂肪酸在人类HF管理中的治疗潜力提供重要见解。公共卫生相关性：尽管我们用药物治疗心力衰竭的能力有了显著的进步，但这种慢性进行性疾病仍然与过高的发病率和死亡率相关。ω-3脂肪酸（“鱼油”）可能有益地影响与心力衰竭患者预后不良相关的几个重要标志物（神经体液激活和压力反射功能）。本申请中概述的新研究将为omega-3脂肪酸补充剂在心力衰竭患者管理中的治疗潜力提供独特的见解。

DESCRIPTION (provided by applicant): Heart failure (HF) is a chronic and progressive disease associated with significant morbidity and mortality. As baroreflex dysfunction and neurohumoral activation contribute to the progression and poor prognosis associated with HF, therapies that favorably influence these factors are important to identify. The long-term goal of the PI is to better understand mechanisms underlying autonomic and cardiovascular abnormalities in HF. The short-term goal of the PI is to determine the effect omega-3 fatty acid supplementation exerts on baroreflex control of the circulation and neurohumoral activation in HF patients. The general working hypothesis being tested is that baroreflex dysfunction may contribute to neurohumoral activation in HF and that these factors may be favorably modified by omega-3 fatty acid supplementation. To address this topic studies with the following Specific Aims will be performed. To determine the effect of omega-3 fatty acid supplementation on: 1) muscle sympathetic nerve activity (MSNA) at rest and in response to baroreceptor loading/unloading in HF patients, 2) renal vasoconstrictor responses to baroreflex unloading in HF patients, and 3) neurohumoral activation and limb blood flow at rest and during baroreflex unloading in HF patients. Methods used to address these aims will include direct measures of efferent sympathetic nervous system outflow using peroneal microneurography, Doppler ultrasound estimates of renal blood flow velocity and whole limb blood flow, [central venous pressure], and numerous biochemical measures to assess the state of neurohumoral activation. In addition to obtaining measures at rest responses to changes in baroreceptor input (i.e., drug-induced changes in blood pressure and responses to graded central hypovolemic stress) will also be determined. These responses are important to study as baroreflex dysfunction in HF patients may underlie neurohumoral activation at rest as well as impaired modulation during application of physiological stress. Measurements obtained at study entry (baseline) will be repeated at weeks 6 and 12 of the intervention (omega-3 fatty acid supplementation) to gain insight into the temporal pattern of response. It is expected that neurohumoral activation and vascular resistance at rest will be reduced and abnormalities in baroreflex control of the circulation including modulation of neurohumoral activation will be, at least, partially restored by 12 weeks of omega-3 fatty acids supplementation in HF patients. Other groups studied will include HF patients receiving placebo (corn oil) as well as 2 groups of age-, BMI-, and gender-matched healthy adults receiving omega-3 fatty acid supplements (healthy experimental) or corn oil supplements (healthy control). Collectively, inclusion of these distinct groups will allow baseline differences attributable to HF, as well as the specificity of the responses to omega-3 fatty acids, to be determined. The findings from these novel studies will provide important insight into the therapeutic potential of omega-3 fatty acids in the management of human HF. PUBLIC HEALTH RELEVANCE: Despite significant advancements in our ability to treat heart failure with pharmacological substances this chronic and progressive disease still is associated with excessive rates of morbidity and mortality. Omega-3 fatty acids ('fish oil') may beneficially affect several important markers (neurohumoral activation and baroreflex function) associated with poor prognosis in heart failure patients. The novel studies outlined in this application will provide unique insight into the therapeutic potential of omega-3 fatty acid supplementation in the management of patients with heart failure.