New England, New York and Quebec Regional Clinical Center

描述（由申请人提供）：该申请是在佛蒙特大学和弗莱彻艾伦医疗保健（UVM/FAHC）的Martin LeWinter博士的指导下，对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。通过这一申请，我们提出了一个新的领导结构，在Marvin Konstam博士的指导下，与塔夫茨医学中心（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，这一扩张将显著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，我们建议研究雷诺嗪在正常射血分数（HFNEF）心力衰竭患者中的作用。约50%的心衰患者EF正常。目前尚无针对HFNEF的循证治疗方法。我们发表了体外研究，使用从接受冠状动脉旁路移植的患者获得的可兴奋左室（LV）心肌条，表明HFNEF患者常见的同心型左室肥厚（LVH）的存在与异常低刺激频率下舒张张力增加的表现有关。我们还发现，抗心绞痛药物雷诺嗪可以抑制晚期肌层钠电流，使这种速率依赖性舒张功能障碍正常化。因此，我们建议在HFNEF和LVH患者中进行一项为期24周的雷诺嗪与安慰剂的随机试验，以验证雷诺嗪改善运动表现的假设，评估在跑步机或循环运动期间的V02峰值。次要结局变量包括症状问卷的结果、次极限运动表现、左室质量、舒张功能和神经体液激活的血清生物标志物的变化。该试验的积极结果将为更大规模、更明确的雷诺嗪治疗HFNEF的试验奠定基础。

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.