Cardio-renal phenotype and prognosis in chronic heart failure

描述(由申请人提供)：本提案描述了一项为期五年的强化导师培训计划，目标是将首席调查员(PI)培养成一名独立的、高影响力的、以患者为导向的研究人员。PI是一位训练有素的成人心脏病专家，在翻译研究硕士项目中获得了正式的研究培训，目前正在完成宾夕法尼亚大学的高级心力衰竭(HF)和心脏移植临床奖学金。到目前为止，他在临床研究方面的指导 由斯蒂芬·基梅尔博士(这项提议的主要导师)领导，并由基梅尔博士监督下的11本第一作者出版物证明，这是一种非常有效的指导关系。然而，PI向研究独立性的成功过渡将需要大量的额外培训和紧张的指导职业发展。因此，提出了一项全面的培训建议，以促进上述工作，其中将包括：1)由基梅尔博士领导的团队的密集指导；2)高级教学课程；3)以病人为导向的未来研究的实践经验；4)由著名的心肾学者约翰·伯内特博士和罗伯特·施里尔博士提供科学咨询；5)有条理的职业发展和建立一个科学工作机构，作为向独立的过渡的基础。这项建议的科学方面的总体目标是更好地确定心肾表型及其在心力衰竭预后中的重要性。肾功能不全(RD)是心力衰竭的常见并发症，也是这些患者死亡的最大危险因素之一。已知严重心衰及其治疗(如环状利尿剂)可导致神经激素的逐渐激活和外周器官功能障碍(如RD)。可归因于RD的风险似乎与血尿素氮/肌酐比值(BUN/Cr)升高的患者无关，BUN/Cr是肾脏神经激素激活的替代指标。如果神经激素的激活确实是上述观察的基础，那么直接的治疗意义是实质性的。然而，BUN/Cr受到神经激素激活以外的因素的影响，这些非神经激素因素也可能在RD相关死亡率中起重要作用。这项建议的目的是量化伴有RD和BUN/Cr升高的心衰患者的神经激素升高的程度，调查环状利尿剂在这些神经激素异常的发生中的影响，并确定是否是BUN/Cr的神经激素依赖方面推动了这些死亡率的观察。我们将通过以下方式实现这些目标：1)在临床和翻译研究中心，在环状利尿剂暴露前后，直接表征患有RD且BUN/Cr高或低的心衰患者的神经激素参数。2)在一项大型的前瞻性心力衰竭队列研究中，宾夕法尼亚大学心力衰竭研究确定，尿素的排泄分数(捕捉神经激素调节的BUN/Cr)是否与BUN/Cr区分高风险和低风险RD的能力有关。这一系列调查的结果将形成未来对这些高危患者进行介入性试验的基础。正规的高级研究培训和以患者为导向的指导研究经验相结合，将确保PI成为心衰和心肾相互作用领域非常成功的独立、以患者为导向的研究人员。

DESCRIPTION (provided by applicant): This proposal describes a five year intensive mentored training program with the goal of developing the Principal Investigator (PI) into an independent and high impact, patient-oriented researcher. The PI is a fully trained adult cardiologist, has obtained formal research training in the Masters in Translational Research program, and is currently completing an advanced heart failure (HF) and cardiac transplantation clinical fellowship at the University of Pennsylvania. His clinical research mentorship to date has been lead by Dr. Stephen Kimmel (Primary Mentor of this proposal) and as evidenced by the PI's 11 first author publications under Dr. Kimmel's supervision, this is a highly effective mentoring relationship. However, successful transition of the PI to research independence will require substantial additional training and intense mentored career development. A comprehensive training proposal is thus proposed to facilitate the above, which will include: 1) Intensive mentoring from a team lead by Dr. Kimmel 2) Advanced didactic coursework 3) Hands on experience in prospective patient-oriented research 4) Scientific advisory by eminent cardio-renal scholars such as Drs. John Burnett and Robert Schrier 5) Structured career development and establishment of a body of scientific work with which the transition to independence will be based. The overall objective of the scientific aspect of this proposal is to better define cardio-renal phenotypes and their prognostic importance in HF. Renal dysfunction (RD) is a common complication of HF and one of the strongest risk factors for death in these patients. Severe HF and its treatment (i.e., loop diuretics) are known to result in progressive neurohormonal activation and peripheral organ dysfunction (i.e., RD). The risk attributable to RD appears to be isolated to patients with an elevated blood urea nitrogen to creatinine ratio (BUN/Cr), which is a surrogate for renal neurohormonal activation. If neurohormonal activation is indeed underlying the above observations, the direct treatment implications are substantial. However, BUN/Cr is influenced by factors external to neurohormonal activation, and these non-neurohormonal factors may also be important in RD- associated mortality. The aims of this proposal are to quantify the degree to which neurohormones are elevated in HF patients with RD and elevated BUN/Cr, investigate the influence of loop diuretics in the genesis of these neurohormonal abnormalities, and establish whether it is the neurohormonally dependent aspects of BUN/Cr that are driving these mortality observations. We will achieve these aims by: 1) Direct characterization of neurohormonal parameters in HF patients with RD and either a high or low BUN/Cr in the Clinical and Translational Research Center, before and after loop diuretic exposure. 2) Determination in a large prospective HF cohort, the Penn Heart Failure Study, if the fractional excretion of urea (which captures the neurohormonally mediated aspect of BUN/Cr) is responsible for the ability of BUN/Cr to differentiate high and low risk forms of RD. The results of this line of investigation will form the basis upon which future interventional trias in these high risk patients can be based. The combination of formal advanced research training and mentored patient-oriented research experience will ensure the PI emerges as a highly successful independent patient-oriented researcher in HF and cardio- renal interactions.