Renal Denervation in Heart Failure with Preserved Ejection Fraction

项目摘要 射血分数正常的心力衰竭（HFpEF）已成为一个重要的未满足的医疗需求， 心血管药物和60%的所有新的心力衰竭诊断是HFpEF。的日益流行 HFpEF加上完全缺乏有效的FDA批准的治疗方法，进一步加剧了这一关键的公众 健康问题。很好地理解，交感神经系统的慢性过度激活促进了交感神经系统的过度激活。 左心室（LV）肥厚性重塑和纤维化，严重的内皮和血管损伤，以及肾 功能障碍 拟议的研究将评估肾脏去神经支配（RDN）对左心室和 HFpEF新猪模型中的血管功能。在哥廷根小型猪中， 醋酸脱氧皮质酮（DOCA）联合西方饮食的慢性治疗， 高血压和代谢综合征，其次是左室舒张功能障碍、肺充血、运动 不耐受和临床相关HFpEF。将在HFpEF发作后使用临床 使用超声能量破坏肾交感神经的RDN导管系统。 提出的研究的中心假设是RDN治疗将促进心肌修复， HFpEF通过肾脏和心脏中病理信号的下调进展。 具体目标1是确定RDN治疗对心力衰竭进展和严重程度的影响， HFpEF的临床相关大型动物模型。 具体目标2是确定候选的心脏和心外介质，这些介质是 使用基因组学、代谢组学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是否能改善HFpEF的严重程度和进展，并探索其治疗作用。 RDN发挥心血管保护作用的机制。这些研究将涉及一个 一系列生理学、生物化学、基因组学、代谢组学和蛋白质组学方法来评估 RDN在HFpEF中的功效。这些研究的结果将显着扩展我们目前对 HFpEF的病理生物学，并提供关键信息，有助于指导新疗法的开发， 治疗HFpEF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 miniswine 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 ultrasound 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.