Cardio-renal phenotype and prognosis in chronic heart failure

描述（由申请人提供）：本提案描述了一个为期五年的强化指导培训计划，目标是将主要研究者（PI）培养成一名独立、高影响力、以患者为导向的研究人员。PI是一名经过全面培训的成人心脏病专家，已获得转化研究硕士课程的正式研究培训，目前正在宾夕法尼亚大学完成高级心力衰竭（HF）和心脏移植临床研究。迄今为止，他的临床研究指导 由Stephen Kimmel博士（本提案的主要导师）领导，PI在Kimmel博士的监督下发表了11篇第一作者出版物，证明了这是一种高效的导师关系。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密集的指导职业发展。因此，提出了一项全面的培训建议，以促进上述工作，其中包括：1）Kimmel博士领导的团队的强化指导2）高级教学课程3）前瞻性患者导向研究的实践经验4）John Burnett博士和Robert Schrier博士等著名心肾学者的科学咨询5）有组织的职业发展和建立一个科学工作机构，以此作为向独立过渡的基础。 本提案科学方面的总体目标是更好地定义心肾表型及其在HF中的预后重要性。肾功能不全（RD）是HF的常见并发症，也是这些患者死亡的最大风险因素之一。严重HF及其治疗（即，袢利尿剂）已知会导致进行性神经激素激活和外周器官功能障碍（即，RD）。归因于RD的风险似乎仅限于血尿素氮/肌酐比值（BUN/Cr）升高的患者，BUN/Cr是肾神经激素激活的替代指标。如果神经激素激活确实是上述观察结果的基础，那么直接的治疗意义是巨大的。然而，BUN/Cr受神经激素激活以外因素的影响，这些非神经激素因素在RD相关死亡率中也可能很重要。本提案的目的是量化RD和BUN/Cr升高的HF患者神经激素升高的程度，研究袢利尿剂在这些神经激素异常发生中的影响，并确定是否是BUN/Cr的神经系统依赖性方面导致这些死亡率观察结果。我们将通过以下方式实现这些目标：1）在临床和转化研究中心，在袢利尿剂暴露前后，直接表征高或低BUN/Cr的RD HF患者的神经激素参数。2)在大型前瞻性HF队列（Penn心力衰竭研究）中确定尿素排泄分数（捕获BUN/Cr的神经系统介导方面）是否是BUN/Cr区分RD高风险和低风险形式的能力的原因。这一系列研究的结果将成为这些高风险患者未来介入治疗的基础。 正式的高级研究培训和指导的以患者为导向的研究经验相结合，将确保PI成为HF和心肾相互作用方面非常成功的以患者为导向的独立研究者。

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.