SGLT-inhibitors in patients with hypertrophic cardiomyopathy

项目总结 肥厚型心肌病(HCM)患者经历进展性病程并承受 严重的症状性负担，以心力衰竭、房性和室性心律失常以及早期死亡为标志。 有症状但无左室流出道梗阻(所谓的非梗阻)的患者 梗阻性HCM)是一个特别需要管理的挑战，因为没有任何治疗方法被证明在改善方面有效 症状或影响疾病发展轨迹的。这项提案将重点放在葡萄糖钠上。 辅转运蛋白2抑制剂(SGLT2i)作为非梗阻性肥厚性心肌病的潜在治疗选择。最初 作为治疗2型糖尿病(T2 DM)的降血糖药物，SGLT2i出人意料地授予了一种 显著的心脏保护效益，心血管死亡率和住院率大幅下降 心力衰竭，与糖尿病状态或射血分数无关。虽然它的作用机制 SGLT2i是否对心血管起到如此有益的作用尚不清楚，对心脏有改善作用 基于心肌酮增加的证据，能量学被认为是一种合理的机制 临床前心力衰竭模型的氧化和三磷酸腺苷含量。这项研究的总体目标是确定 SGLT2i治疗非梗阻性肥厚性心肌病的安全性、可行性和初步疗效。其基本原理是 因为进行这项研究是基于非梗阻性肥厚性心肌梗死和心力衰竭之间的相似性 保存的射血分数，以及HCM独特的结构和功能特征，使早期 在实施更大阶段的临床试验或采用“非标签”使用之前，阶段试验是必不可少的。我们会 对26例患者进行随机、双盲、交叉试验，比较SGLT2i达格列酮与安慰剂 非梗阻性肥厚型心肌病，射血分数50%。我们的主要安全成果将是节律监测 超声心动图评价左室壁内压差。我们的初步疗效终点 将改变峰值氧耗量(VO2)、左心室收缩和舒张期功能 超声心动图、NT-proBNP、动态肌动描记和生活质量评估。在一个探索性的目标中， 我们将使用31P-MR波谱来测试SGLT2i是否改善了肥厚性心肌病的心脏能量代谢 心肌能量储存的相对数量，特别是磷酸肌酸和三磷酸腺苷。这项早期研究 寻求扩展SGLT2i最近证明的对心力衰竭的显著心血管益处 减少和保留射血分数，给肥厚性心肌病患者。研究小组包括具有 在宾夕法尼亚大学大容量HCM中心进行的HCM早期临床试验中，有良好的记录 宾夕法尼亚州，与经验丰富的内分泌学和放射学临床医生研究员合作 宾夕法尼亚州儿童医院。本研究的结果将为以下工作提供必要的初步数据 确定是否应该在肥厚性心肌病中进行更大规模的SGLT2i临床试验，并探索代谢的转变 底物利用作为一种潜在的被授予利益的作用机制。

Project summary Patients with hypertrophic cardiomyopathy (HCM) experience a progressive disease course and bear a substantial symptomatic burden, marked by heart failure, atrial and ventricular arrhythmias and early mortality. Patients with symptomatic HCM, but without obstruction of the left ventricular outflow tract (so-called non- obstructive HCM), are a particular challenge to manage, as no treatments have proven effective at improving symptoms or impacting the trajectory of disease progression. This proposal will focus on sodium-glucose cotransporter 2 inhibitors (SGLT2i) as a potential therapeutic option for non-obstructive HCM. Initially developed as hypoglycemic drugs to treat type-2 diabetes mellitus (T2DM), SGLT2i unexpectedly conferred a remarkable cardioprotective benefit with robust reductions in cardiovascular mortality and hospitalizations for heart failure, irrespective of diabetic status or ejection fraction. While the mechanisms of action by which SGLT2i are exerting such beneficial cardiovascular effects are still unclear, an improvement in cardiac energetics has been proposed as one plausible mechanism based on evidence for increased cardiac ketone oxidation and ATP content in preclinical models of heart failure. The overall goal of this study is to determine the safety, feasibility, and preliminary efficacy of SGLT2i in patients with non-obstructive HCM. The rationale for conducting this study is based on the similarities between non-obstructive HCM and heart failure with preserved ejection fraction, and also the unique structural and functional features of HCM that make an early phase trial essential before implementation of larger phase clinical trials or adoption of “off label” use. We will perform a randomized, double-blind, cross-over study of the SGLT2i dapagliflozin vs placebo in 26 patients with non-obstructive HCM and ejection fraction >50%. Our primary safety outcomes will be rhythm monitoring and intracavitary left ventricular gradients assessed by echocardiography. Our preliminary efficacy endpoints will be change in peak oxygen consumption (VO2), left ventricular systolic and diastolic function by echocardiography, NT-proBNP, ambulatory actigraphy, and quality of life assessment. In an exploratory aim, we will test whether SGLT2i improve cardiac energetics in HCM using 31P-MR spectroscopy to quantify relative amounts of myocardial energy stores, specifically phosphocreatine and ATP. This early phase study seeks to extend the marked cardiovascular benefits of SGLT2i recently demonstrated for heart failure with reduced and preserved ejection fraction, to patients with HCM. The study team includes investigators with a strong track record in early phase clinical trials in HCM, at a high volume HCM center at the University of Pennsylvania, in collaboration with experienced clinician investigators in endocrinology and radiology at the Children's Hospital of Pennsylvania. The results of this study will provide essential preliminary data to determine if larger scale clinical trials of SGLT2i in HCM should be pursued, and explore a shift in metabolic substrate utilization as a potential mechanism of action of conferred benefit.