■限制性心肌病(RCM)代表一种罕见的心血管疾病,源于细丝相关基因。尽管如此,治疗RCM带来了相当大的挑战,特别是关于装置植入和机械支持。此外,阐明特定变体的分子功能有望使患者受益并改善预后,考虑到RCM变体之间的显著异质性。
■先证者,一个八岁的女性,因心脏骤停在心肺复苏后入院。超声心动图提示双侧心房增大。全外显子组测序发现了一个新的杂合突变(c.509G>A,p.R170Q)在TNNI3中。使用MutationTaster应用的评估认为c.509G>A致病性(概率=0.99)。根据临床表现,成像评估,和基因筛查,先证者接受了RCM诊断.建议使用ECMO和连续肾脏替代疗法。然而,ECMO停药后出现持续性房扑.尝试通过心脏复律恢复心律,美托洛尔,胺碘酮被证明是徒劳的。随后的心力衰竭导致患者因心源性休克而死亡。基于晶体蛋白结构分析,我们观察到cTnI-R170Q和R170W对蛋白质结构稳定性和形成具有相似的影响。然而,两者都与cTnI-R170G有显著不同,主要影响氨基酸区域32-79和129-149,参与TnC和肌动蛋白结合。因此,揭示了cTnI-R170Q通过与cTnI-R170W相同的分子机制诱导RCM。
■管理RCM仍然是一个关键挑战。这项研究强调了在RCM中不鼓励植入心脏泵功能支持的装置。特别是对于非短期预定的HTX。此外,建议考虑导管消融治疗心房纤维化诱导的房颤.机械上,cTnI-R170Q主要减少肌钙蛋白-肌动蛋白相互作用并使细丝不稳定。
UNASSIGNED: Restrictive cardiomyopathy (RCM) represents a rare cardiovascular disorder stemming from filament-associated genes. Nonetheless, treating RCM presents considerable challenges, particularly concerning device implantation and mechanical support. Furthermore, elucidating the molecular function of specific variants holds promise in benefiting patients and enhancing prognosis, given the significant heterogeneity among RCM variants.
UNASSIGNED: The proband, an eight-year-old female, was admitted to our hospital post cardiopulmonary resuscitation due to sudden cardiac arrest. Echocardiography revealed bilateral atrial enlargement. Whole-exome sequencing uncovered a novel heterozygous mutation (c.509G>A, p.R170Q) in TNNI3. Evaluation using the MutationTaster application deemed c.509G>A pathogenic (probability = 0.99). Following clinical manifestations, imaging assessments, and genetic screening, the proband received an RCM diagnosis.
ECMO was recommended along with continuous renal replacement therapy. However, persistent atrial flutter ensued post-
ECMO withdrawal. Attempts to restore cardiac rhythm with cardioversion, metoprolol, and amiodarone proved futile. Subsequent heart failure led to the patient\'s demise due to cardiac shock. Based on crystal protein structural analysis, we observed that cTnI-R170Q and R170W exerted similar impacts on protein structural stability and formation. However, both differed significantly from cTnI-R170G, primarily influencing amino acid regions 32-79 and 129-149, involved in TnC and actin binding. Therefore, cTnI-R170Q was revealed to induce RCM via the same molecular mechanism as cTnI-R170W.
UNASSIGNED: Managing RCM remains a critical challenge. This study underscores the discouragement of device implantations for cardiac pump functional support in RCM, particularly for non-short-term scheduled HTx. Additionally, considering catheter ablation for atrial fibrosis-induced AFs is recommended. Mechanistically, cTnI-R170Q primarily diminishes troponin-actin interactions and destabilizes thin filaments.