The Jefferson Regional Clinical Center for Heart Failure Network

描述（由申请人提供）：心力衰竭（HF）的病理生理模型已经从简单的血流动力学模型发展到包括神经激素和细胞因子成分的更复杂的模型。促炎细胞因子的表达早于神经激素，在细胞外基质转换中发挥关键作用，包括基质金属蛋白酶（MMPs）的调节。目前，还没有批准的药物直接针对肿瘤坏死因子(TNF) -a或MMPs。TNF-a和MMP的表达增加与心脏重构不适应相关，并已被确定为心衰患者生存的独立预测因子。亚抗菌多西环素（SDD）已被证明可降低其他慢性疾病患者的TNF-a和MMPs，但尚未对HF患者进行评估，部分原因是它不再具有专利保护并作为仿制药出售。亚抗菌多西环素治疗对心力衰竭患者身体功能结局和舒张末期容积模式的影响（stop -HF）研究是一项双盲随机前瞻性2期临床试验，在200名左心室功能降低的心力衰竭患者中进行SDD的影响。主要假设是SDD在治疗12个月后会显著降低HF患者左室舒张末期容积指数的变化。此外，SDD将改善身体功能和生活质量；降低MMP和肿瘤坏死因子。药物不良反应也将作为研究的一部分。stop - hf研究是由Jefferson区域临床中心（RCC）提出的科学方案，用于申请参与NHLBI的心力衰竭临床研究网络。杰斐逊RCC汇集了特拉华山谷3个最大的医疗保健系统：托马斯·杰斐逊大学（Pl：大卫·惠伦博士；共同调查员拉斐尔·博尼塔博士），天普大学（共同调查员：阿尔弗雷德·博夫博士）和克里斯蒂安娜护理（共同调查员：米切尔·萨尔茨伯格博士）。这些中心将为大量的心衰患者提供参与心衰网络协议的机会，其中包括重要的少数民族和女性人群。认识到纳入保留左室功能的心衰患者的目标，申请包括家庭医学系的参与（共同研究者；Geoffrey Mills博士）。杰斐逊RCC将利用其参与HF网络，已建立的K30计划和世界知名的HF研究人员来建立杰斐逊临床研究技能发展核心(核心负责人：Walter Kraft博士；导师：dr。亚瑟·费尔德曼、托马斯·福斯、保罗·马瑟和大卫·惠伦)。

DESCRIPTION (provided by applicant): The pathophysiologic model for heart failure (HF) has advanced from a simple hemodynamic model to a more complicated model that includes neurohormonal and cytokine components. Proinflammatory cytokines, which are expressed earlier than neurohormones, play a critical role in extracellular matrix turnover, including the regulation of matrix metalloproteinases (MMPs). Currently, there are no approved medications that directly target tumor necrosis factor (TNF) -a or MMPs. Increased expression of TNF-a and MMP is associated with maladaptive cardiac remodeling and has been identified as an independent predictor of survival in HF patients. Sub-antimicrobial doxycycline (SDD) has been shown to reduce TNF-a and MMPs in other chronic diseases but has not been evaluated in HF patients due in part to it no longer having patent protection and being sold as a generic drug. The Sub-antimicrobial Doxycycline Therapy on Outcomes of Physical Function and Patterns of End-Diastolic Volume in Heart Failure Patients (STOPPED-HF) Study is a double blinded randomized prospective phase 2 clinical trial of the effects of SDD in a cohort of 200 HF subjects with reduced left ventricular function. The primary hypothesis is that SDD will significantly reduce left ventricular end diastolic volume index changes in HF patients over 12 months of treatment. In addition, SDD will improve physical function and quality of life; and reduce MMP and tumor necrosis factor alpha. Adverse drug reactions will also be followed as part of the study. The STOPPED-HF study is the scientific protocol proposed by the Jefferson Regional Clinical Center (RCC) for its application to participate in the NHLBI's Heart Failure Clinical Research Network. The Jefferson RCC brings together 3 of the largest healthcare systems in the Delaware Valley: Thomas Jefferson University (Pl: Dr. David Whellan; co investigator Dr. Raphael Bonita), Temple University (co-investigator: Dr. Alfred Bove) and Christiana Care (co-investigator: Dr. Mitchell Saltzberg). These centers will offer participation i HF Network protocols to a large HF patient population, including a significant minority and female population. Recognizing the goal of including HF patients with preserved LV function, the application includes participation of the Department of Family Medicine (co-investigator; Dr. Geoffrey Mills). The Jefferson RCC will leverage its participation in the HF Network, the established K30 program and world-renowned HF researchers to establish the Jefferson Clinical Research Skills Development Core (Core Leader: Dr. Walter Kraft; mentors: Drs. Arthur Feldman, Thomas Force, Paul Mather and David Whellan). RELEVANCE (See instructions): Enhancing the pipeline of new therapies for heart failure patients is critical to reducing the high morbidity and mortality that this patient population continues to suffer. Evaluating low-cost treatments, such as the generically available sub-antimicrobial dosing of doxycycline, in smaller phase 2 clinical trials provides the necessary data to inform researchers and funding agencies prior to organizing larger clinical trials.