Effect of Mechanical Circulatory Support on Exercise Capacity in Heart Failure

 简介(申请人提供)：我的职业目标是成为一名由美国国立卫生研究院资助的独立RO1研究员，为晚期心力衰竭患者的机械循环支持(“机械心脏”)的进步做出贡献。到目前为止，我的工作主要集中在连续流(CF)左心室辅助装置(LVADs)对脑血管生理学、交感神经活动和血压的影响。这项工作导致了几次在国家会议上的演讲，第一作者出版物是 已发表或正在评审和研究的奖项。然而，有两个直接的研究目标对于我自己的职业发展和该领域的发展是必要的，包括：1)获得心血管和自主神经系统评估的新技能；2)将我的研究计划从静息条件下的心血管系统和CF-LVAD相互作用的研究扩展到运动条件下的动态条件。为了实现这些目标，我制定了一份严格的职业发展计划，其中包括体验式学习、有机会熟练掌握可以纳入我的研究计划的程序、获得临床科学硕士学位的正式课程，以及来自各自领域的国际专家的导师和顾问的监督。我将继续与本杰明·莱文博士建立成功的导师关系，他将担任我的主要导师，马克·H·德拉兹纳博士将担任我的共同导师，傅齐福博士和杰尔·米切尔博士将继续担任研究顾问。此外，我还将与莫里·埃斯勒博士建立新的合作关系，他是心血管和运动生理学方面的国际专家，在自主神经系统评估方面拥有专业知识。我的长期目标是了解心血管系统在CF-LVAD存在时是如何运作的。这项建议的目的是确定CF-LVAD如何影响运动升压反射，并确定决定使用这些设备的晚期心力衰竭患者运动能力的因素(S)。在这里，我将检验一个中心假设，即运动加压反射在植入CF-LVAD后有所改善，运动能力的主要决定因素是左心室的收缩能力。这项建议的目标将通过追求两个具体目标来实现：1)确定CF-LVAD对心力衰竭患者运动升压反射的影响；以及2)确定心力衰竭患者植入CF-LVAD前后运动能力的主要决定因素(S)。这些特定目标的成果将对该领域做出重大贡献，并为开发新的策略提供信息，以提高这一独特患者群体的生活质量和存活率，并改进设备技术，使下一代LVAD可以在运动过程中调节血流，类似于正常心脏。这项拟议的研究将在德克萨斯大学西南医学中心(UTSW)和德克萨斯州达拉斯的运动与环境医学研究所(IEEM)进行。UTSW提供非凡的翻译研究机会和教师发展计划，而IEEM拥有世界知名的生理学研究实验室。我将完全访问这两个机构的所有可用资源，以确保我在K23获奖期间取得成功，并实现我的职业目标。根据我到目前为止的培训，指导研究经验和机构环境，我相信我有独特的地位来实现这个职业发展项目中列出的所有目标。这一成功将确保我转变为一名由RO1资助的独立研究员，在晚期心力衰竭患者的心血管和运动生理学方面拥有专业知识，并在自主神经系统评估方面拥有独特的技能，这是很少有研究人员拥有的。

 DESCRIPTION (provided by applicant): My career goal is to become an independent NIH-funded RO1 investigator contributing to advancements in mechanical circulatory support ("mechanical hearts") for patients with advanced heart failure. My work to date has focused on the impact of continuous-flow (CF) left ventricular assist devices (LVADs), a type of mechanical heart, on cerebrovascular physiology, sympathetic neural activity and blood pressure. This work has led to several presentations at national conferences, first-author publications that are either published or in review and research awards. However, there are two immediate research goals that are necessary for my own career development and to advance the field, including: 1) acquire new skills in the assessment of the cardiovascular and autonomic nervous system; and 2) extend my research program from the study of the cardiovascular system and CF-LVAD interactions under resting conditions, to dynamic conditions during exercise. To accomplish these goals, I have assembled a rigorous career development plan with experiential learning, opportunities to gain proficiency in procedures that I can incorporate into my research program, formal coursework to obtain a Master in Clinical Science degree, and oversight from mentors and advisors who are international experts in their respective fields. I will continue my successful mentored relationship with Dr. Benjamin Levine, who will serve as my primary mentor, Dr. Mark H. Drazner, who will serve as my co-mentor, as well as Drs Qi Fu and Jere Mitchell, who will continue to serve as research advisors. In addition, I will form a new collaborative relationship with Dr. Murray Esler, an international expert in cardiovascular and exercise physiology, with expertise in assessment of the autonomic nervous system. My long term goal is to understand how the cardiovascular system operates in the presence of a CF-LVAD. The objectives of this proposal are to determine how CF-LVADs impact exercise pressor reflexes and to identify the factor(s) which determine exercise capacity in advanced heart failure patients with these devices. Here, I will test the central hypothesis that exercise pressor reflexe improve following CF-LVAD implantation and that the primary determinant of exercise capacity is contractility of the left ventricle. The objectives of this proposal will be accomplished by pursuing two specific aims: 1) Determine the effect of a CF-LVAD on exercise pressor reflex in heart failure patients; and 2) Define the primary determinant(s) of exercise capacity in heart failure patients prior to and following CF-LVAD implantation. Results delivered from these specific aims will provide major contributions to the field and inform development of novel strategies to improve quality of life and survival in this unique patient population, and contribut to refinements in device technology, such that future-generation LVADs can modulate flow during exercise, similar to the normal heart. The proposed research will be conducted at the University of Texas Southwestern Medical Center (UTSW) and the Institute of Exercise and Environmental Medicine (IEEM) in Dallas, Texas. UTSW provides extraordinary translational research opportunities and faculty development programs, while the IEEM houses a world- renowned physiology research laboratory. I will have complete access to all resources available at these two institutions that will ensure my success during this K23 award period and that my career goals are achieved. Based on my training to date, mentored research experience and institutional environment, I believe that I am uniquely positioned to accomplish all objectives outlined in this career development project. This success will ensure that I transition into an independent RO1 funded investigator with expertise in cardiovascular and exercise physiology in patients with advanced heart failure, with a unique skillset in assessment of the autonomic nervous system, which few researchers possess.