The Jefferson Regional Clinical Center for Heart Failure Network

心力衰竭(HF)的病理生理模型已从简单的血流动力学模型发展到 更复杂的模型，包括神经激素和细胞因子成分。促炎细胞因子， 它们比神经激素更早表达，在细胞外基质的更新中起着关键作用， 包括对基质金属蛋白酶(MMPs)的调节。目前，还没有获得批准的药物 直接靶向肿瘤坏死因子-a或MMPs的药物。肿瘤坏死因子-α和基质金属蛋白酶的表达增加 与不良适应性心脏重塑有关，并已被确定为 心衰患者的存活率。亚抗菌素多西环素(SDD)被证明可以减少肿瘤坏死因子-a和基质金属蛋白酶。 其他慢性疾病，但尚未在心力衰竭患者中进行评估，部分原因是它不再具有专利 保护并作为仿制药出售。多西环素亚抗菌药物治疗对慢性阻塞性肺疾病疗效的影响 心力衰竭患者的身体功能和舒张末容量模式(STOP-HF)是一项研究 SDD对200例心衰患者影响的随机双盲前瞻性2期临床试验 左心功能减退的受试者。主要的假设是SDD将显著减少 心衰患者治疗12个月后左室舒张末容量指数的变化。此外, SDD可以改善身体功能和生活质量，降低基质金属蛋白酶和肿瘤坏死因子α。 药物不良反应也将作为研究的一部分进行跟踪。停用心衰的研究是科学的 由杰斐逊地区临床中心(RCC)提出的申请参加 NHLBI心力衰竭临床研究网络。杰斐逊RCC汇集了三个最大的 特拉华河谷的医疗系统：托马斯·杰斐逊大学(PL：Dr.David Whellan；co 调查员拉斐尔·博尼塔博士)、坦普尔大学(联合调查员：阿尔弗雷德·博夫博士)和克里斯蒂安娜关怀 (联合调查员：Mitchell Saltzberg博士)这些中心将提供短波网络协议的参与， 大量心力衰竭患者群体，包括相当多的少数民族和女性群体。认识到 包括左心功能保留的心力衰竭患者，申请包括 家庭医学(共同研究员；杰弗里·米尔斯博士)。杰斐逊RCC将利用其参与的 短波网络，既定的K30计划和世界知名的短波研究人员建立的杰斐逊 临床研究技能开发核心(核心领导：沃尔特·克拉夫特博士；导师：亚瑟·费尔德曼博士， 托马斯·福斯、保罗·马瑟和大卫·惠兰)。 相关性(请参阅说明)： 加强心力衰竭患者新疗法的渠道对于降低心力衰竭的高发病率和 这一患者群体继续遭受的死亡率。评估低成本的治疗方法，如 在较小的2期临床试验中，普遍可获得的亚抗菌剂量的多西环素提供了 在组织更大规模的临床试验之前，向研究人员和资助机构通报必要的数据。

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 eariier 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 in 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 worid-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.