Cardiovascular Division, Northwest Heart Centre, Manchester University NHS Foundation Trust, Manchester, UK.
Division of Cardiovascular Sciences, The University of Manchester, Manchester, UK.
Open Heart. 2022 Feb;9(1). doi: 10.1136/openhrt-2021-001803.
Disturbances of copper (Cu) homeostasis can lead to hypertrophic cardiac phenotypes (eg, Wilson's disease). We previously identified abnormal Cu homeostasis in patients with hypertrophic cardiomyopathy (HCM) and, therefore, hypothesised that Cu-selective chelation with trientine dihydrochloride may slow or reverse disease progression in HCM. The aim of this study was, therefore to explore the clinical efficacy, safety and tolerability of trientine in HCM.
In this medicines and healthcare products regulatory agency (MHRA) registered open-label pilot study, we treated 20 HCM patients with trientine for 6 months. Patients underwent a comprehensive assessment schedule including separate cardiac magnetic resonance imaging (CMR) and CMR P-spectroscopy at baseline and end of therapy. Predefined end points included changes in left ventricular mass (LVM), markers of LV fibrosis, markers of LV performance and myocardial energetics. Ten matched patients with HCM were studied as controls.
Trientine treatment was safe and tolerated. Trientine caused a substantial increase in urinary copper excretion (0.42±0.2 vs 2.02±1.0, p=0.001) without affecting serum copper concentrations. Treatment was associated with significant improvements in total atrial strain and global longitudinal LV strain using both Echo and CMR. LVM decreased significantly in the treatment arm compared with the control group (-4.2 g v 1.8 g, p=0.03). A strong trend towards an absolute decrease in LVM was observed in the treatment group (p=0.06). These changes were associated with a significant change in total myocardial volume driven by a significant reduction in extracellular matrix (ECM) volume (43.83±18.42 mL vs 41.49±16.89 mL, p=0.04) as opposed to pure cellular mass reduction and occurred against a background of significant ECM volume increase in the control group (44.59±16.50 mL vs 47.48±19.30 mL, p=0.02). A non-significant 10% increase in myocardial phosphocreatine/adenosine triphosphate (PCr/ATP) ratio with trientine therapy (1.27±0.44 vs 1.4±0.39) was noted.
Cu-selective chelation with trientine in a controlled environment is safe and a potential future therapeutic target. A phase 2b trial is now underway.
铜（Cu）稳态的紊乱可导致心肌肥厚表型（如威尔逊病）。我们之前发现肥厚型心肌病（HCM）患者存在 Cu 稳态异常，因此假设三乙膦酸二氢盐的 Cu 选择性螯合可能会减缓或逆转 HCM 的疾病进展。因此，本研究旨在探讨三乙膦酸二氢盐在 HCM 中的临床疗效、安全性和耐受性。
在这项由药品和保健品管理局（MHRA）注册的开放性先导研究中，我们用三乙膦酸二氢盐治疗 20 名 HCM 患者 6 个月。患者接受了包括心脏磁共振成像（CMR）和 CMR P-波谱分析在内的综合评估方案，基线和治疗结束时分别进行。预先确定的终点包括左心室质量（LVM）、LV 纤维化标志物、LV 功能标志物和心肌能量代谢标志物的变化。另外，选择 10 名患有 HCM 的匹配患者作为对照组进行研究。
三乙膦酸二氢盐治疗安全且耐受。三乙膦酸二氢盐治疗导致尿铜排泄量显著增加（0.42±0.2 比 2.02±1.0，p=0.001），而血清铜浓度无变化。治疗后，使用 Echo 和 CMR，总心房应变和整体纵向左心室应变均有显著改善。与对照组相比，治疗组的左心室质量显著下降（-4.2 g 比 1.8 g，p=0.03）。治疗组的左心室质量绝对下降呈明显趋势（p=0.06）。这些变化与总心肌体积的变化有关，主要是由于细胞外基质（ECM）体积的显著减少（43.83±18.42 mL 比 41.49±16.89 mL，p=0.04），而不是单纯的细胞质量减少，而对照组的 ECM 体积则明显增加（44.59±16.50 mL 比 47.48±19.30 mL，p=0.02）。三乙膦酸二氢盐治疗后心肌磷酸肌酸/三磷酸腺苷（PCr/ATP）比值有非显著的 10%增加（1.27±0.44 比 1.4±0.39）。
在受控环境中用三乙膦酸二氢盐进行 Cu 选择性螯合是安全的，可能是未来的治疗靶点。目前正在进行一项 2b 期试验。
