Barth syndrome cardiomyopathy: targeting the mitochondria with elamipretide.
Barth syndrome cardiomyopathy: targeting the mitochondria with elamipretide.
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DOI：
10.1007/s10741-020-10031-3
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发表时间：
2021-03
影响因子：
4.6
通讯作者：
Sabbah HN
中科院分区：
文献类型：
--
作者：
Sabbah HN
巴斯综合征（BTHS）是一种罕见的x连锁隐性婴儿发病衰弱性疾病，以早发性心肌病、骨骼肌病、生长迟缓和中性粒细胞减少为特征，全球发病率为1/30 - 40万活产婴儿。婴儿期BTHS患者的高死亡率主要与进行性心肌病和免疫系统减弱有关。BTHS是由编码他法津（tafazzin）的TAZ基因缺陷引起的，他法津是一种负责线粒体磷脂心磷脂（CL）重塑和成熟的转酰基化酶，对正常线粒体结构和功能（即ATP生成）至关重要。缺乏他法嗪可导致结构成熟CL水平降低95%。由于心脏是体内代谢最活跃的器官，是所有组织中线粒体含量最高的，因此线粒体功能障碍在BTHS患者心力衰竭的发展中起着关键作用。线粒体氧化磷酸化的变化降低了线粒体满足人体心脏和骨骼肌ATP需求的能力，即ATP合成与ATP消耗速度不匹配。BTHS中存在几种心肌病表型，包括扩张性心肌病、左心室不致密化（单独或与其他心肌病表型合并）、心内膜纤维弹性增生、肥厚性心肌病和尖型肥厚性心肌病等，所有这些都可以直接归因于缺乏CL合成、重塑和成熟以及随后的线粒体功能障碍。已经提出了这些心肌病表型存在的几种机制，从而确定了潜在的治疗靶点。肌浆网Ca2+- atp酶泵的功能障碍和循环线粒体成分可能引发的炎症已经被确定。目前，治疗方式旨在解决BTHS中HF的症状，但不解决潜在病理。一种新的治疗方法包括埃拉米肽，它穿过线粒体外膜定位到内膜，在那里它与心磷脂结合，增强包括心脏在内的几个器官的ATP合成。使用依拉米普肽治疗BTHS患者的令人鼓舞的临床结果支持该药物用于治疗这种罕见疾病的潜在应用。
Barth syndrome (BTHS) is a rare, X-linked recessive, infantile-onset debilitating disorder characterized by early-onset cardiomyopathy, skeletal muscle myopathy, growth delay, and neutropenia, with a worldwide incidence of 1/300,000–400,000 live births. The high mortality rate throughout infancy in BTHS patients is related primarily to progressive cardiomyopathy and a weakened immune system. BTHS is caused by defects in the TAZ gene that encodes tafazzin, a transacylase responsible for the remodeling and maturation of the mitochondrial phospholipid cardiolipin (CL), which is critical to normal mitochondrial structure and function (i.e., ATP generation). A deficiency in tafazzin results in up to a 95% reduction in levels of structurally mature CL. Because the heart is the most metabolically active organ in the body, with the highest mitochondrial content of any tissue, mitochondrial dysfunction plays a key role in the development of heart failure in patients with BTHS. Changes in mitochondrial oxidative phosphorylation reduce the ability of mitochondria to meet the ATP demands of the human heart as well as skeletal muscle, namely ATP synthesis does not match the rate of ATP consumption. The presence of several cardiomyopathic phenotypes have been described in BTHS, including dilated cardiomyopathy, left ventricular noncompaction, either alone or in conjunction with other cardiomyopathic phenotypes, endocardial fibroelastosis, hypertrophic cardiomyopathy, and an apical form of hypertrophic cardiomyopathy, among others, all of which can be directly attributed to the lack of CL synthesis, remodeling, and maturation with subsequent mitochondrial dysfunction. Several mechanisms by which these cardiomyopathic phenotypes exist have been proposed, thereby identifying potential targets for treatment. Dysfunction of the sarcoplasmic reticulum Ca2+-ATPase pump and inflammation potentially triggered by circulating mitochondrial components have been identified. Currently, treatment modalities are aimed at addressing symptomatology of HF in BTHS, but do not address the underlying pathology. One novel therapeutic approach includes elamipretide, which crosses the mitochondrial outer membrane to localize to the inner membrane where it associates with cardiolipin to enhance ATP synthesis in several organs, including the heart. Encouraging clinical results of the use of elamipretide in treating patients with BTHS support the potential use of this drug for management of this rare disease.
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