Background

Alterations in intracellular Na⁺ and Ca²⁺ have been observed in patients with Duchenne muscular dystrophy (DMD) and in animal models of DMD, and inhibition of Na⁺-H⁺ exchanger 1 (NHE1) by rimeporide has previously demonstrated cardioprotective effects in animal models of myocardial ischemia and heart failure. Since heart failure is becoming a predominant cause of death in DMD patients, this study aimed to demonstrate a cardioprotective effect of chronic administration of rimeporide in a canine model of DMD.

Methods

Golden retriever muscular dystrophy (GRMD) dogs were randomized to orally receive rimeporide (10 mg/kg, twice a day) or placebo from 2 months to 1 year of age. Left ventricular (LV) function was assessed by conventional and advanced echocardiography.

Results

Compared with placebo-treated GRMD, LV function deterioration with age was limited in rimeporide-treated GRMD dogs as indicated by the preservation of LV ejection fraction as well as overall cardiac parameters different from placebo-treated dogs, as revealed by composite cardiac scores and principal component analysis. In addition, principal component analysis clustered rimeporide-treated GRMD dogs close to healthy control dogs.

Conclusions

Chronic administration of the NHE1 inhibitor rimeporide exerted a protective effect against LV function decline in GRMD dogs. This study provides proof of concept to explore the cardiac effects of rimeporide in DMD patients.

中文翻译：

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利美泊利对金毛肌营养不良症犬左心室功能的保护作用。

背景

在杜氏肌营养不良症 (DMD) 患者和 DMD 动物模型中观察到细胞内 Na ⁺和 Ca ²⁺的变化，并且利美泊利对 Na ⁺ -H ⁺交换器 1 (NHE1) 的抑制先前已在动物中证明具有心脏保护作用心肌缺血和心力衰竭模型。由于心力衰竭正在成为 DMD 患者死亡的主要原因，本研究旨在证明在 DMD 犬模型中长期服用利美泊利的心脏保护作用。

方法

金毛肌营养不良症 (GRMD) 犬在 2 个月至 1 岁时被随机口服利美泊利（10 毫克/公斤，每天两次）或安慰剂。通过传统和先进的超声心动图评估左心室（LV）功能。

结果

与安慰剂治疗的 GRMD 相比，利美泊利治疗的 GRMD 狗的左心室功能随年龄的恶化受到限制，如左心室射血分数的保留以及与安慰剂治疗的狗不同的整体心脏参数（如综合心脏评分和主要指标所示）成分分析。此外，主成分分析将利美泊来治疗的 GRMD 狗与健康对照狗相近。

结论

长期服用 NHE1 抑制剂利美泊利对 GRMD 犬的左心室功能下降具有保护作用。这项研究为探索利美泊利对 DMD 患者的心脏影响提供了概念验证。