PDE5 INHIBITION AS ADJUNCTIVE MEDICAL THERAPY IN AORTIC STENOSIS

PDE5 抑制作为主动脉瓣狭窄的辅助药物治疗

• 批准号: 8581283
• 负责人: Brian Richard Lindman
• 金额: $ 15.01万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-20 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581283
• 关键词: Acute; Address; Aortic Valve Stenosis; Area; Award; Basic Science; Blood Vessels; Cardiac; Cardiovascular system; Chronic; Clinical; Clinical Data; Clinical Management; Clinical Research; Clinical Trials; Collaborations; Collagen; Complement; Core Facility; Data; Development; Development Plans; Disease; Disease Progression; Dose; Echocardiography; Elderly; Enrollment; Environment; Fibrosis; Foundations; Functional disorder; Funding; Future; Gadolinium; Goals; Heart Valve Diseases; Heart failure; Hypertrophy; Imaging Device; Individual; Institutes; Knowledge; Learning; Left ventricular structure; Longitudinal Studies; Lung; Magnetic Resonance Imaging; Maps; Measures; Medical; Mentors; Mentorship; Morbidity - disease rate; Myocardium; New York Heart Association Class III/IV; Operative Surgical Procedures; Oral; Outcome; Patients; Pilot Projects; Placebos; Population; Postoperative Period; Pulmonary Hypertension; Quality of life; Randomized; Research; Research Activity; Research Personnel; Research Training; Resources; Right ventricular structure; Risk; Role; Safety; Specimen; Stenosis; Stratification; Stroke Volume; Structure; Surrogate Endpoint; Symptoms; Testing; Time; Tissues; Training; Training Programs; Translating; Translational Research; Universities; Ursidae Family; Vascular remodeling; Ventricular; Ventricular Function; Ventricular Remodeling; Washington; career; career development; clinical practice; design; experience; extracellular; gadolinium oxide; hemodynamics; improved; indexing; inhibitor/antagonist; interest; mortality; multidisciplinary; novel; patient oriented; phosphoric diester hydrolase; pre-clinical; pressure; prevent; research and development; research study; response; symposium; symptomatic improvement; therapy design; tool; valve replacement

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.

描述（由申请人提供）：该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 博士发展成为一名专注于钙化性主动脉瓣狭窄 (AS) 的独立临床转化研究者。 AS 未满足的科学和临床需求激发了 Lindman 博士追求研究者之路的愿望。该奖项申请的重点是 Lindman 博士作为一名研究者的发展，他将能够增进我们对 AS 病理生理学的理解，识别新颖且有前途的药物治疗靶点，并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旨在填补林德曼博士培训中特定的教育和经验空白。 职业目标： * 成为一名高效、独立的临床转化研究者，为我们对 AS 的理解做出重大贡献，旨在以改善患者治疗结果的方式改变我们的临床实践。 * 阐明 AS 患者心室和血管重塑的不利影响及其机制。 * 识别和测试针对 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，华盛顿大学提供了极其丰富和支持性的智力和协作研究环境，为林德曼博士成功实现他的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小组，由经过精心挑选的 PI 特定科学和职业发展目标相互补充而精心挑选的个人组成。主要导师是医学博士道格拉斯·曼 (Douglas Mann)，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拥有长期的记录。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，并提供了众多核心设施来简化研究活动。职业发展计划包括课程、会议和一些量身定制的实践学习经验，以及应用所获得知识的具体活动。总的来说，这些应该补充研究目标，以解决 PI 培训和知识方面的差距，使他能够独立地进行研究。 研究计划。传统上，AS 管理和治疗的重点仅限于瓣膜，导致我们经常治疗瓣膜而不是患者。然而，目前很清楚的是，心室和脉管系统的适应不良重塑在很大程度上导致了该疾病的发病率和死亡率。新出现的临床前和临床数据表明，5 型磷酸二酯酶 (PDE5) 抑制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，即单剂量的 PDE5 抑制剂对于严重 AS 患者是安全的且耐受性良好，并且与肺和全身血流动力学的急剧改善相关，从而导致双心室减负荷。这一发现提出了一个有趣的可能性，即在更明确的 AS 治疗之前，PDE5 抑制剂可以通过减轻左心室和右心室负荷、改善异常血流动力学并稳定心力衰竭症状，作为 AS 的辅助药物治疗。在此申请中，PI 提议在单剂量研究结果的基础上开展两项长期临床研究，旨在探索 PDE5 抑制辅助药物治疗改善 AS 患者临床结果的可能性。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，为未来评估以患者为中心的临床终点的研究奠定基础。目标 1 将评估有症状的 AS 患者的短期（2 周）PDE5 抑制，看看它是否可以提供持续的血流动力学益处，这可以作为瓣膜置换明确治疗的稳定桥梁。目标 2 将评估无症状 AS 患者的慢性（6 个月）PDE5 抑制，看看这种疗法是否可以减少肥厚的心脏重塑并改善心室功能，这可能会延迟症状发作并使心室更好地为手术做好准备。目标 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非侵入性工具。拟议的研究与计划的职业发展活动相结合，将使 PI 做好准备，以便开展未来的临床研究，评估使用 PDE5 抑制剂和其他新兴疗法独立治疗 AS 的辅助药物治疗。