PDE5 INHIBITION AS ADJUNCTIVE MEDICAL THERAPY IN AORTIC STENOSIS

描述(由申请者提供)：本建议书描述了一项为期3年的研究和培训计划，该计划将使Brian Lindman博士发展成为一名独立的临床翻译研究员，专注于钙化性主动脉狭窄(AS)。AS的科学和临床需求尚未得到满足，这点燃了林德曼博士追求研究人员道路的愿望。该奖项申请的重点是林德曼博士作为一名研究人员的发展，他将能够促进我们对AS病理生理学的理解，识别新的和有希望的药物治疗目标，并设计和执行具有替代终点的概念验证临床试验，为使用临床终点的更大规模试验铺平道路。研究目标、职业发展活动和导师团队的设计是为了填补林德曼博士培训中特定的教育和经验空白。 职业目标： *成为一名富有成效的独立临床翻译研究员，为我们对AS的理解做出重大贡献，目的是以改善患者结果的方式改变我们的临床实践。 *阐明AS患者的心脏和血管重构的不良影响和机制。 *为强直性脊柱炎确定和测试新的医疗疗法 环境与职业发展计划。在机构层面上，特别是在心血管部门，华盛顿大学为林德曼博士提供了一个极其丰富和支持性的智力和协作研究环境，为他成功实现研究和职业发展目标提供了充足的资源和机会。导师团队代表了一个多学科的个人小组，他们被特别挑选来相互补充，并仔细考虑了PI特定的科学和职业发展目标。主要导师是道格拉斯·曼医学博士，他是国际公认的心力衰竭专家，在将基础科学发现转化为临床试验和确定新的治疗靶点方面有着长期的记录。临床和翻译科学研究所(CTSA资助)提供了广泛的合作机会，为华盛顿大学的临床和翻译研究注入了活力，并提供了许多核心设施来简化研究活动。职业发展计划包括课程、会议和几次量身定制的实践学习经验，并结合具体活动应用所学到的知识。总体而言，这些都应补充研究目标，以解决私人投资的培训和知识方面的差距，使其能够独立进行研究学习。 研究计划。AS的管理和治疗的重点传统上局限于瓣膜，导致我们经常治疗瓣膜而不是患者。然而，很明显的是，脑室和血管系统的不适应性重塑对该病的发病率和死亡率有很大的影响。新出现的临床前和临床数据表明，抑制磷酸二酯酶5(PDE5)可能在这方面有所帮助。在最近的KL2支持期间，PI进行了新的观察，发现单次剂量的PDE5抑制剂对重度AS患者是安全和耐受性良好的，并与肺和全身血流动力学的急性改善有关，从而导致双室卸载。这一发现提出了一种有趣的可能性，即在对AS进行更明确的治疗之前，PDE5抑制剂可能作为AS的辅助药物治疗有用，它可以卸载左、右室，改善异常血流动力学，稳定心力衰竭症状。在这项申请中，PI建议在单剂量研究结果的基础上进行两项更长期的临床研究，旨在探索应用PDE5抑制的辅助药物治疗将改善AS患者临床结果的可能性。拟议的研究将测试PDE5抑制在使用替代终点的AS患者中的作用，为未来评估以患者为中心的临床终点的研究奠定基础。目的1将对有症状的患者进行短期(2周)PDE5抑制的评估，以了解它是否能提供持续的血流动力学益处，这可能是通往瓣膜置换最终治疗的稳定桥梁。目的2评价慢性(6个月)PDE5抑制治疗对无症状患者的作用，以了解该疗法是否能减少肥厚的心脏重构，改善心功能，从而延缓症状的出现，为手术做更好的心室准备。AIM 3将评估一种新的MRI序列来评估心脏纤维化，这可能会改善我们对AS患者的风险分层，并为评估抗纤维化治疗的反应提供一种非侵入性工具。拟议的研究与计划中的职业发展活动将使PI做好准备，以进行未来的临床研究，评估辅助药物治疗AS的独立治疗、使用PDE5抑制剂和其他新兴疗法。

DESCRIPTION (provided by applicant): This proposal describes a 3-year research and training program that will allow Dr. Brian Lindman to develop into an independent clinical translational investigator with a focus on calcific aortic stenosis (AS). The unmet scientific and clinical needs for AS were what ignited Dr. Lindman's desire to pursue an investigator path. The emphasis of the award application is Dr. Lindman's development as an investigator who will be able to advance our understanding of the pathophysiology of AS, identify novel and promising targets for medical therapy, and design and execute proof of concept clinical trials with surrogate endpoints that pave the way for larger trials with clinical endpoints. The research aims, career development activities, and mentorship team have been designed to fill particular educational and experiential gaps in Dr. Lindman's training. Career Goals: * To become a productive, independent clinical translational investigator who makes a significant contribution to our understanding of AS, with the intent of changing our clinical practice in ways that improve patient outcomes. * To elucidate the adverse impact of and mechanisms contributing to ventricular and vascular remodeling in patients with AS. * To identify and test novel medical therapies for AS Environment and Career Development Plan. At an institutional level and specifically within the cardiovascular division, Washington University provides an incredibly rich and supportive intellectual and collaborative research environment with ample resources and opportunities available for Dr. Lindman to successfully accomplish his research and career development goals. The mentorship team represents a multidisciplinary group of individuals specifically chosen to complement one another with the PI's particular scientific and career development goals carefully considered. The primary mentor is Douglas Mann, MD, an internationally recognized expert in heart failure, who has a long track record of translating basic science discoveries into clinical trials and identifying novel targets for therapy. The Institute for Clinial and Translational Sciences (CTSA funded) provides extensive opportunities for collaboration, has energized clinical and translation research at Washington University, and provides numerous core facilities to streamline research activity. The career development plan includes coursework, conferences, and several tailored practical learning experiences combined with specific activities to apply the knowledge gained. Collectively, these should complement the research aims to address gaps in the PI's training and knowledge to enable him to pursue his research studies independently. Research plan. The focus of the management and treatment of AS has traditionally been limited to the valve, causing us to often treat the valve rather than the patient. However, it is nw clear that maladaptive remodeling in the ventricle and vasculature contribute substantially to the morbidity and mortality of the disease. Emerging preclinical and clinical data suggest that phosphodiesterase type 5 (PDE5) inhibition may help in this regard. During the recent period of KL2 support, the PI made the novel observation that a single dose of a PDE5 inhibitor is safe and well-tolerated in patients with severe AS and is associated with acute improvements in pulmonary and systemic hemodynamics, resulting in biventricular unloading. This finding raises the interesting possibility that PDE5 inhibitors may be useful as adjunctive medical therapy in AS by unloading the left and right ventricles, improving abnormal hemodynamics, and stabilizing heart failure symptoms prior to more definitive therapies for AS. In this application, the PI proposes to build upon the findings of the single-dose study by conducting two longer term clinical studies that are intended to explore the possibility that adjunctive medical therapy with PDE5 inhibition will improve clinical outcomes in patients with AS. The proposed studies will test the role of PDE5 inhibition in patients with AS using surrogate endpoints, laying the foundation for future studies evaluating patient-centered, clinical endpoints. Aim 1 will evaluate short-term (2 weeks) PDE5 inhibition in patients with symptomatic AS to see whether it can provide sustained hemodynamic benefits, which could serve as a stabilizing bridge to definitive therapy with valve replacement. Aim 2 will evaluate chronic (6 months) PDE5 inhibition in patients with asymptomatic AS to see whether this therapy could decrease hypertrophic cardiac remodeling and improve ventricular function, which may delay symptom onset and prepare the ventricle better for surgery. Aim 3 will evaluate a novel MRI sequence to assess cardiac fibrosis, which may improve our risk stratification of patients with AS and provide a non- invasive tool for assessing the response to anti-fibrotic therapies. The proposed studies combined with the planned career development activities will prepare the PI to pursue future clinical studies evaluating adjunctive medical therapy in the treatment of AS independently, employing PDE5 inhibitors and other emerging therapies.