SGLT-inhibitors in patients with hypertrophic cardiomyopathy

项目摘要 肥厚型心肌病（HCM）患者的病程进行性， 严重的症状负担，以心力衰竭、房性和室性心律失常和早期死亡为标志。 有症状的HCM患者，但没有左心室流出道梗阻（所谓的非梗阻性）， 阻塞性HCM）是一个特殊的挑战，因为没有治疗方法被证明可以有效地改善 症状或影响疾病进展的轨迹。该提案将重点关注钠-葡萄糖 协同转运蛋白2抑制剂（SGLT 2 i）作为非梗阻性HCM的潜在治疗选择。最初 作为治疗2型糖尿病（T2 DM）的降糖药物，SGLT 2 i意外地赋予了 显著的心脏保护益处，心血管死亡率和住院率大幅降低， 心力衰竭，与糖尿病状态或射血分数无关。虽然作用机制， SGLT 2 i是否发挥这种有益的心血管作用尚不清楚， 能量学被认为是一种基于心脏酮增加证据的合理机制 氧化和ATP含量的临床前心力衰竭模型。本研究的总体目标是确定 SGLT 2 i在非梗阻性HCM患者中的安全性、可行性和初步疗效。的理由 进行这项研究是基于非梗阻性HCM和心力衰竭之间的相似性， 保留射血分数，以及HCM独特的结构和功能特征，使HCM的早期 在实施更大的临床试验或采用“标签外”使用之前，必须进行阶段试验。我们将 在26例患者中进行一项SGLT 2 i达格列净与安慰剂的随机、双盲、交叉研究 非梗阻性肥厚型心肌病射血分数> 50%我们的主要安全性结果将是心律监测 和通过超声心动图评估的腔内左心室梯度。我们的初步疗效终点 将是峰值氧耗量（VO 2）、左心室收缩和舒张功能的变化， 超声心动图、NT-proBNP、动态体动记录和生活质量评估。在一个探索性的目标， 我们将使用31 P-MR光谱检测SGLT 2 i是否改善HCM的心脏能量学， 心肌能量储存的相对量，特别是磷酸肌酸和ATP。这项早期研究 旨在扩展最近证实的SGLT 2 i对心力衰竭的显著心血管获益， 减少和保留射血分数，HCM患者。研究小组包括研究人员， 在HCM的早期临床试验中有着良好的记录，在密歇根大学的一个高容量HCM中心， 宾夕法尼亚州，与内分泌学和放射学方面经验丰富的临床研究人员合作， 宾夕法尼亚州儿童医院这项研究的结果将提供必要的初步数据， 确定是否应该进行更大规模的SGLT 2 i治疗HCM的临床试验，并探索代谢 底物利用作为赋予益处的潜在作用机制。

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.