Abstract:
All muscle contraction occurs due to the cyclical interaction between sarcomeric thin and thick filament proteins within the myocyte. The thin filament consists of the proteins actin, tropomyosin, Troponin C, Troponin I, and Troponin T. Mutations in these proteins can result in various forms of cardiomyopathy, including hypertrophic, restrictive, and dilated phenotypes and account for as many as 30% of all cases of inherited cardiomyopathy. There is significant evidence that thin filament mutations contribute to dysregulation of Ca2+ within the sarcomere and may have a distinct pathomechanism of disease from cardiomyopathy associated with thick filament mutations. A number of distinct clinical findings appear to be correlated with thin-filament mutations: greater degrees of restrictive cardiomyopathy and relatively less left ventricular (LV) hypertrophy and LV outflow tract obstruction than that seen with thick filament mutations, increased morbidity associated with heart failure, increased arrhythmia burden and potentially higher mortality. Most therapies that improve outcomes in heart failure blunt the neurohormonal pathways involved in cardiac remodeling, while most therapies for hypertrophic cardiomyopathy involve use of negative inotropes to reduce LV hypertrophy or septal reduction therapies to reduce LV outflow tract obstruction. None of these therapies directly address the underlying sarcomeric dysfunction associated with thin-filament mutations. With mounting evidence that thin filament cardiomyopathies occur through a distinct mechanism, there is need for therapies targeting the unique, underlying mechanisms tailored for each patient depending on a given mutation.
摘要:
所有肌肉收缩都是由于肌细胞内肌节细丝和粗丝蛋白之间的周期性相互作用而发生的。细丝由蛋白质肌动蛋白组成,原肌球蛋白,肌钙蛋白C,肌钙蛋白I,这些蛋白质的突变会导致各种形式的心肌病,包括肥厚,限制性的,和扩张表型,占所有遗传性心肌病病例的30%。有大量证据表明,细丝突变会导致肌节内Ca2的失调,并且可能与与粗丝突变相关的心肌病具有不同的疾病病理机制。许多不同的临床发现似乎与细丝突变相关:与粗丝突变相比,限制性心肌病的程度更高,左心室(LV)肥大和LV流出道阻塞相对较少。与心力衰竭相关的发病率增加,增加的心律失常负担和潜在的更高的死亡率。大多数改善心力衰竭结果的疗法都会削弱参与心脏重塑的神经激素途径,而肥厚型心肌病的大多数治疗方法包括使用负性肌力来减少LV肥大或减少室间隔减少治疗以减少LV流出道阻塞。这些疗法都没有直接解决与细丝突变相关的潜在肌节功能障碍。越来越多的证据表明细丝心肌病是通过不同的机制发生的,需要针对独特的疗法,根据给定的突变为每位患者量身定制的潜在机制。