PDE5 INHIBITION AS ADJUNCTIVE MEDICAL THERAPY IN AORTIC STENOSIS

描述（由申请人提供）：本提案描述了一项为期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转化研究者，重点关注钙化性主动脉瓣狭窄（AS）。尚未满足的AS科学和临床需求点燃了Lindman博士追求研究者道路的愿望。奖项申请的重点是Lindman博士作为一名研究者的发展，他将能够促进我们对AS病理生理学的理解，确定新的和有前途的药物治疗靶点，设计和执行具有替代终点的概念验证临床试验，为具有临床终点的大型试验铺平道路。研究目标，职业发展活动和导师团队的设计，以填补特定的教育和经验的差距博士。 职业目标： * 成为一名富有成效的独立临床翻译研究者，为我们对AS的理解做出重大贡献，旨在以改善患者结局的方式改变我们的临床实践。 * 阐明AS患者心室和血管重构的不良影响和机制。 * 确定和测试AS的新药物疗法 环境和职业发展计划。在机构层面，特别是在心血管部门，华盛顿大学提供了一个令人难以置信的丰富和支持的智力和协作研究环境，有充足的资源和机会，可供林德曼博士成功地完成他的研究和职业发展目标。导师团队代表了一个多学科的个人群体，专门选择与PI的特定科学和职业发展目标相互补充。主要导师是医学博士道格拉斯曼，他是国际公认的心力衰竭专家，长期以来一直将基础科学发现转化为临床试验，并确定新的治疗靶点。临床和转化科学研究所（CTSA资助）提供了广泛的合作机会，为华盛顿大学的临床和转化研究注入了活力，并提供了众多的核心设施来简化研究活动。职业发展计划包括课程，会议和几个量身定制的实践学习经验，结合具体的活动，以应用所获得的知识。总的来说，这些应该补充研究的目的，以解决PI的培训和知识的差距，使他能够独立地追求他的研究学习。 研究计划。传统上，AS的管理和治疗重点仅限于瓣膜，导致我们经常治疗瓣膜而不是患者。然而，目前还清楚的是，心室和血管系统的适应不良重构在很大程度上导致了疾病的发病率和死亡率。新出现的临床前和临床数据表明，磷酸二酯酶5型（PDE5）抑制剂可能有助于这方面的研究。在最近的KL 2支持期间，PI进行了新的观察，即PDE5抑制剂单次给药在重度AS患者中安全且耐受性良好，并与肺和全身血液动力学的急性改善相关，导致双心室卸载。这一发现提出了一种有趣的可能性，即PDE5抑制剂可能在AS的更明确治疗之前通过卸载左心室和右心室、改善异常血流动力学和稳定心力衰竭症状而用作AS的连续药物治疗。在本申请中，PI建议在单次给药研究结果的基础上，进行两项长期临床研究，旨在探索PDE5抑制的连续药物治疗改善AS患者临床结局的可能性。拟议的研究将使用替代终点测试PDE5抑制在AS患者中的作用，为未来评价以患者为中心的临床终点的研究奠定基础。目标1将评价症状性AS患者的短期（2周）PDE5抑制，以观察其是否可提供持续的血流动力学获益，这可作为瓣膜置换术确定性治疗的稳定桥梁。目的2将评估无症状AS患者的长期（6个月）PDE5抑制，以观察该治疗是否可以减少肥厚性心脏重塑并改善心室功能，这可能会延迟症状发作并为手术更好地准备心室。目的3将评价一种新的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，并提供一种评估抗纤维化治疗反应的无创工具。拟定的研究与计划的职业发展活动相结合，将使PI准备好进行未来的临床研究，评价采用PDE 5抑制剂和其他新兴疗法独立治疗AS的连续性药物治疗。

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.