Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy.
Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy.
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DOI：
10.1371/journal.pgen.1007502
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发表时间：
2018-07
期刊：
影响因子：
4.5
通讯作者：
Miquerol L
中科院分区：
文献类型：
--
作者：
Choquet C;Nguyen THM;Sicard P;Buttigieg E;Tran TT;Kober F;Varlet I;Sturny R;Costa MW;Harvey RP;Nguyen C;Rihet P;Richard S;Bernard M;Kelly RG;Lalevée N;Miquerol L
左心室致密化不全（LVNC）是一种罕见的心肌病，伴有高小梁表型和多种症状。目前尚不清楚LVNC是否是心室小梁发育缺陷的结果，也不清楚这种病理学不同严重程度的机制基础。为了研究这些问题，我们使用可诱导的Cx40-creERT 2等位基因在小梁形态发生的不同阶段灭活小梁心肌中的心脏转录因子Nkx 2 -5。在胚胎阶段，在小梁形成期间，Nkx 2 -5的条件性缺失引起与内膜下纤维化和浦肯野纤维发育不全相关的严重的过度小梁化表型。在胎儿阶段，在小梁致密化过程中，Nkx 2 -5缺失后观察到较轻的表型。一项对成年Nkx 2 -5条件突变小鼠心脏功能的纵向研究表明，过度小梁形成与复杂的心室传导缺陷相关，逐渐导致应变缺陷，在50%的突变小鼠中，导致心力衰竭。进行性心功能受损与传导和应变缺陷相关，与过度小梁形成的程度无关。分子通路的转录组学分析反映了心肌重塑，在重度与轻度表型中有大量差异表达的基因，并确定Six 1在高小梁化心脏中上调。我们的研究结果提供了对LVNC病因的深入了解，并将其致病性与小梁发育受损（包括致密化缺陷和心室传导系统发育不全）联系起来。在胎儿心脏形态发生过程中，成熟心室壁的形成需要内部小梁层的协调压实和心肌外层的生长。小梁发育受阻与心室致密化不全性心肌病相关的过度小梁形成的发病机制有关。然而，临床医生对心室致密化不全性心肌病的病理生理学，包括其临床特征、预后、分类甚至过度小梁形成的定义仍存在许多不确定性。特别是，区分非压实的病理和非病理亚型是目前的一个主要问题。在这里，我们表明，删除的基因编码的转录因子Nkx 2 -5在关键步骤在小梁发育概括的病理特征的过度小梁形成，提供了第一个模型的心室非致密化心肌病在成年小鼠。我们证明，胎儿发育过程中由于小梁致密化失败而导致的过度小梁形成与浦肯野纤维发育不全和内膜下纤维化有关。纵向功能研究表明，这些小鼠表现出症状性左心室致密化不全心肌病的所有临床体征，包括传导缺陷、应变缺陷和进行性心力衰竭。我们的研究结果，包括转录组学分析，表明致密化不全的病理特征主要是发育缺陷。本研究阐明了与LVNC相关的病理结果的起源，并可能为临床医生提供有关这种罕见心肌病病因的有用信息。
Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. It is still unclear whether LVNC results from a defect of ventricular trabeculae development and the mechanistic basis that underlies the varying severity of this pathology is unknown. To investigate these issues, we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis using an inducible Cx40-creERT2 allele. Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia. A milder phenotype was observed after Nkx2-5 deletion at fetal stages, during trabecular compaction. A longitudinal study of cardiac function in adult Nkx2-5 conditional mutant mice demonstrates that excessive trabeculation is associated with complex ventricular conduction defects, progressively leading to strain defects, and, in 50% of mutant mice, to heart failure. Progressive impaired cardiac function correlates with conduction and strain defects independently of the degree of hypertrabeculation. Transcriptomic analysis of molecular pathways reflects myocardial remodeling with a larger number of differentially expressed genes in the severe versus mild phenotype and identifies Six1 as being upregulated in hypertrabeculated hearts. Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia. During fetal heart morphogenesis, formation of the mature ventricular wall requires coordinated compaction of the inner trabecular layer and growth of the outer layer of myocardium. Arrested trabecular development has been implicated in the pathogenesis of hypertrabeculation associated with ventricular non-compaction cardiomyopathy. However much uncertainty still exists among clinicians concerning the physiopathology of ventricular non-compaction cardiomyopathy, including its clinical characteristics, prognosis, classification and even the definition of hypertrabeculation. In particular, distinguishing between pathological and non-pathological subtypes of non-compaction is currently a major issue. Here we show that deletion of the gene encoding the transcription factor Nkx2-5 at critical steps during trabecular development recapitulates pathological features of hypertrabeculation, providing the first model of ventricular non-compaction cardiomyopathy in adult mice. We demonstrate that excessive trabeculation due to failure of trabecular compaction during fetal development is associated with Purkinje fiber hypoplasia and subendocardial fibrosis. Longitudinal functional studies reveal that these mice present all the clinical signs of symptomatic left ventricular non-compaction cardiomyopathy, including conduction defects, strain defects and progressive heart failure. Our results, including transcriptomic analysis, suggest that pathological features of non-compaction are primarily developmental defects. This study clarifies the origin of the pathological outcomes associated with LVNC and may provide helpful information for clinicians concerning the etiology of this rare cardiomyopathy.
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