New England, New York and Quebec Regional Clinical Center

描述（由申请人提供）：本申请是NHLBI心力衰竭研究网络的新英格兰、纽约和魁北克区域临床中心的更新申请，由佛蒙特大学的Martin LeWinter博士和弗莱彻艾伦医疗保健（UVM/FAHC）指导。通过此应用程序，我们提出了一个新的领导结构，在Marvin Konyant博士的指导下与塔夫茨医疗中心（Tufts MC）建立多个PI/PD合作伙伴关系，并对RCC进行重大扩展。我们相信，这一扩张将显着提高我们对网络的科学贡献和我们的招生能力。作为我们的临床试验，我们计划研究雷诺嗪对射血分数正常的心力衰竭（HFNEF）患者的影响。约50%的HF患者EF正常。目前尚无针对HFNEF的循证治疗方法。我们已经发表了使用从接受冠状动脉旁路移植术的患者中获得的可兴奋左心室（LV）心肌条的体外研究，该研究表明，HFNEF患者中常见的向心性LV肥大（LVH）的存在与异常低刺激频率下舒张张力增加的外观相关。我们还发现，抗心绞痛药物雷诺嗪可抑制晚期肌膜钠电流，使这种心率依赖性舒张功能障碍正常化。因此，我们建议在HFNEF和LVH患者中进行一项雷诺嗪与安慰剂的24周随机试验，以检验雷诺嗪改善运动能力的假设，评估为跑步机或自行车运动期间的峰值V02。次要结果变量包括症状问卷调查结果、次极量运动表现、LV质量变化、舒张功能和神经体液激活的血清生物标志物。这项试验的积极结果将为雷诺嗪治疗HFNEF这一非常困难的问题的更大、莫尔明确的试验奠定基础。 相关性（参见说明）：在过去的二十年中，HF已成为一个主要问题。在改善射血分数降低的HF患者的功能能力和生存率方面取得了重要进展。然而，大约50%射血分数正常的患者的进展令人失望。拟议的试验，沿着我们RCC的扩展，有可能对这一主要临床问题产生积极影响。

DESCRIPTION (provided by applicant): This application is a renewal of the New England, New York and Quebec Regional Clinical Center of the NHLBI Heart Failure Research Network, under the direction of Dr. Martin LeWinter of the University of Vermont and Fletcher Allen Health Care (UVM/FAHC). With this application we propose a new leadership structure, a multiple PI/PD partnership with Tufts Medical Center (Tufts MC) under the direction of Dr. Marvin Konstam, and a major expansion of the RCC. We believe that this expansion will markedly enhance both our scientific contribution to the Network and our enrollment capabilities. As our clinical trial, we propose to study the effects of ranolazine in patients with heart failure with normal ejection fraction (HFNEF). About 50% of HF patients have a normal EF. There are currently no evidence-based treatments for HFNEF. We have published in vitro studies using excitable left ventricular (LV) myocardial strips obtained from patients undergoing coronary bypass grafting which show that the presence of concentric LV hypertrophy (LVH), which is common in patients with HFNEF, is associated with the appearance of increasing diastolic tension at abnormally low stimulation frequencies. We have also shown that the anti-anginal drug ranolazine, which inhibits the late sarcolemmal Na current, normalizes this rate-dependent diastolic dysfunction. Accordingly, we propose a 24 week randomized trial of ranolazine versus placebo in patients with HFNEF and LVH to test the hypothesis that ranolazine improves exercise performance, assessed as peak V02 during either treadmill or cycle exercise. Secondary outcome variables include results of a symptom questionnaire, submaximal exercise performance, and changes in LV mass, diastolic function, and serum biomarkers of neurohumoral activation. A positive result of this trial would lay the foundation for a larger, mor definitive trial of ranolazine in treating the very difficult problem of HFNEF. RELEVANCE (See instructions): HF has become a problem of major proportions over the last two decades. Important strides have been made in improving functional capacity and survival in HF with reduced ejection fraction. However, progress in the approximately 50% of patients with normal ejection fraction has been disappointing. The proposed trial, along with expansion of our RCC, has the potential to positively impact this major clinical problem.