Renal Denervation in Heart Failure with Preserved Ejection Fraction

项目总结 心力衰竭保留射血分数(HFpEF)已成为一个重要的未得到满足的医疗需求 心血管医学和60%的新心力衰竭诊断是HFpEF。日益盛行的 HFpEF加上FDA批准的有效治疗方法的完全缺乏，进一步加剧了这一关键公众 健康问题。众所周知，交感神经系统的慢性过度激活促进了 左心室肥厚重塑和纤维化，严重的内皮和血管损伤，以及肾脏 功能障碍。 建议的研究将评估肾去神经(RDN)对左心室和左心室的有益影响。 一种新的猪HFpEF模型的血管功能。将在Göttingen小型猪以下动物体内诱导HFpEF 醋酸脱氧皮质酮(DOCA)联合西式饮食治疗慢性前列腺癌 高血压和代谢综合征继发左室舒张功能不全、肺充血、运动 不耐受和临床相关的HFpEF。在HFpEF开始后，将使用 使用射频能量破坏肾交感神经的临床RDN导管系统。 拟议研究的中心假设是RDN治疗将促进心肌修复和减弱 HFpEF通过下调肾脏和心脏的病理信号而进展。 具体目的1是确定RDN治疗对心力衰竭进展和严重程度的影响。 临床相关的HFpEF大动物模型。 具体目标2是确定候选的心脏和心脏外介质，这些介质是 利用基因组、代谢组和蛋白质组学方法研究RDN的心脏保护作用。 这些研究将确定RDN是否可以改善HFpEF的严重程度和进展，并探索 RDN发挥心脏保护和血管保护作用的机制。这些研究将涉及一项 一系列生理、生化、基因组、代谢和蛋白质组学方法来评估潜力 RDN在HFpEF中的疗效。这些研究的结果将极大地扩展我们目前对 HFpEF的病理生物学，并提供关键信息，帮助指导新疗法的开发 治疗患有HFpEF的患者。

PROJECT SUMMARY Heart failure with preserved ejection fraction (HFpEF) has emerged as a significant unmet medical need in cardiovascular medicine and 60% of all new heart failure diagnoses are HFpEF. The increasing prevalence of HFpEF coupled with a complete lack of effective FDA approved treatments further accentuates this critical public health problem. It is well appreciated that chronic over-activation of the sympathetic nervous system promotes left ventricular (LV) hypertrophic remodeling and fibrosis, profound endothelial and vascular injury, and renal dysfunction. The proposed studies will evaluate the beneficial effects of renal denervation (RDN) on left ventricular and vascular function in a novel swine model of HFpEF. HFpEF will be induced in Göttingen mini-swine following chronic treatment with deoxycorticosterone acetate (DOCA) combined with a Western Diet that induces hypertension and metabolic syndrome followed by LV diastolic dysfunction, pulmonary congestion, exercise intolerance, and clinically relevant HFpEF. RDN will be performed following the onset of HFpEF utilizing a clinical RDN catheter system that employs RF energy to destroy the renal sympathetic nerves. The Central Hypothesis of the proposed studies is that RDN therapy will promote myocardial repair and attenuate HFpEF progression via downregulation of pathological signaling in the kidney and heart. Specific Aim 1 is to determine the effects of RDN therapy on heart failure progression and severity in a clinically relevant large animal model of HFpEF. Specific Aim 2 is to identify candidate cardiac and extra-cardiac mediators that underlie the cardioprotective effects of RDN using genomic, metabolomic, and proteomic approaches. These studies will determine if RDN ameliorates the severity and progression of HFpEF and explore the mechanisms by which RDN exerts cardioprotective and vascular protective effects. These studies will involve an array of physiological, biochemical, genomic, metabolomic, and proteomic approaches to assess the potential efficacy of RDN in HFpEF. Results from these studies will significantly extend our current understanding of the pathobiology of HFpEF and provide critical information that helps to guide the development of novel therapies to treat patients that suffer from HFpEF.