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

描述(由申请人提供)：心力衰竭(HF)是一种慢性进展性疾病，与显著的发病率和死亡率有关。由于压力感受器反射功能障碍和神经体液激活与心力衰竭的进展和预后不良有关，因此确定有利影响这些因素的治疗方法是很重要的。PI的长期目标是更好地了解心力衰竭患者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脂肪酸对心衰患者压力感受性反射控制循环和神经体液激活的影响。正在测试的一般工作假设是，压力感受器反射功能障碍可能有助于心衰患者的神经体液激活，这些因素可能会被补充omega-3脂肪酸有利地修改。为解决这一问题，将进行以下具体目标的研究。目的：探讨补充omega-3脂肪酸对心衰患者静息状态和压力感受器负荷/卸载时的肌交感神经活动(MSNA)、肾血管对压力反射负荷的收缩反应、静息状态和压力反射负荷时的神经体液活动和肢体血流量的影响。用于解决这些目标的方法将包括使用腓骨显微神经照相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整个肢体血流，[中心静脉压]，以及许多生化指标来评估神经体液激活状态。除了获得静态测量外，还将确定对压力感受器输入变化的反应(即药物引起的血压变化和对分级的中枢低血容量性应激的反应)。这些反应值得研究，因为心力衰竭患者的压力感受性反射障碍可能是静息状态下神经体液激活和生理应激时调节功能受损的原因。在研究开始时(基线)获得的测量将在干预(补充omega-3脂肪酸)的第6周和第12周重复，以深入了解反应的时间模式。预计静息状态下的神经体液激活和血管阻力将减少，压力反射控制循环的异常，包括神经体液激活的调节，将至少通过补充12周的omega-3脂肪酸在心衰患者中部分恢复。其他研究小组将包括服用安慰剂(玉米油)的心衰患者，以及两组年龄、体重指数和性别匹配的健康成年人，服用omega-3脂肪酸补充剂(健康实验)或玉米油补充剂(健康对照)。总体而言，纳入这些不同的组将允许确定可归因于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脂肪酸在人类心力衰竭治疗中的治疗潜力提供重要的见解。公共卫生相关性：尽管我们用药理物质治疗心力衰竭的能力有了很大的进步，但这种慢性和进行性疾病仍然与过高的发病率和死亡率有关。Omega-3脂肪酸(‘鱼油’)可能有益于影响几个与心力衰竭患者预后不良相关的重要标志物(神经体液激活和压力感受器反射功能)。在本申请中概述的新研究将为补充omega-3脂肪酸在治疗心力衰竭患者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.