Cardio-renal phenotype and prognosis in chronic heart failure

慢性心力衰竭的心肾表型和预后

• 批准号: 8653700
• 负责人: JEFFREY M TESTANI
• 金额: $ 15.51万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-10 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8653700
• 关键词: Cardio; renal; phenotype; prognosis; chronic

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.

描述（由申请人提供）：该提案描述了一项为期五年的强化指导培训计划，其目标是将首席研究员 (PI) 培养成为一名独立、高影响力、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，已获得转化研究硕士项目的正式研究培训，目前正在宾夕法尼亚大学完成高级心力衰竭 (HF) 和心脏移植临床奖学金。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 博士的监督下发表的 11 篇第一作者出版物证明了这一点，这是一种非常有效的指导关系。然而，PI 向研究独立的成功过渡将需要大量的额外培训和严格指导的职业发展。因此，提出了一项全面的培训建议，以促进上述目标，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) 前瞻性以患者为导向的研究的实践经验 4) 知名人士的科学咨询心肾学者，如博士。约翰·伯内特 (John Burnett) 和罗伯特·施里尔 (Robert Schrier) 5) 结构化的职业发展和科学工作体系的建立是向独立过渡的基础。 该提案的科学方面的总体目标是更好地定义心力衰竭的心肾表型及其预后重要性。肾功能障碍（RD）是心力衰竭的常见并发症，也是这些患者死亡的最强危险因素之一。已知严重心力衰竭及其治疗（即袢利尿剂）会导致进行性神经激素激活和外周器官功能障碍（即 RD）。 RD 的风险似乎仅限于血尿素氮与肌酐比值 (BUN/Cr) 升高的患者，该比值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，那么直接的治疗影响是巨大的。然而，BUN/Cr 受到神经激素激活外部因素的影响，这些非神经激素因素也可能对 RD 相关死亡率很重要。该提案的目的是量化 RD 和 BUN/Cr 升高的心力衰竭患者神经激素升高的程度，研究袢利尿剂对这些神经激素异常发生的影响，并确定这是否与神经激素依赖性有关。 BUN/Cr 推动了这些死亡率观察。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，直接表征 RD 和 BUN/Cr 较高或较低的心力衰竭患者在使用袢利尿剂之前和之后的神经激素参数。 2) 在大型前瞻性心力衰竭队列（宾夕法尼亚心力衰竭研究）中确定尿素排泄分数（捕获 BUN/Cr 的神经激素介导方面）是否与 BUN/Cr 区分高风险和低风险形式的能力有关研发中心。这一系列调查的结果将构成未来对这些高危患者进行干预试验的基础。 正式的高级研究培训和受指导的以患者为中心的研究经验相结合，将确保 PI 成为心力衰竭和心肾相互作用方面非常成功的、以患者为中心的独立研究人员。