Sedmera David, Olejnickova Veronika, Sankova Barbora, Kolesova Hana, Bartos Martin, Kvasilova Alena, Phillips Lauren C, Bamforth Simon D, Phillips Helen M
Institute of Anatomy, First Faculty of Medicine, Charles University, Prague, Czechia.
Laboratory of Developmental Cardiology, Institute of Physiology, Czech Academy of Sciences, Prague, Czechia.
Front Cell Dev Biol. 2024 Oct 7;12:1471751. doi: 10.3389/fcell.2024.1471751. eCollection 2024.
Left ventricular noncompaction cardiomyopathy is associated with heart failure, arrhythmia, and sudden cardiac death. The developmental mechanism underpinning noncompaction in the adult heart is still not fully understood, with lack of trabeculae compaction, hypertrabeculation, and loss of proliferation cited as possible causes. To study this, we utilised a mouse model of aberrant Rho kinase (ROCK) signalling in cardiomyocytes, which led to a noncompaction phenotype during embryogenesis, and monitored how this progressed after birth and into adulthood. The cause of the early noncompaction at E15.5 was attributed to a decrease in proliferation in the developing ventricular wall. By E18.5, the phenotype became patchy, with regions of noncompaction interspersed with thick compacted areas of ventricular wall. To study how this altered myoarchitecture of the heart influenced impulse propagation in the developing and adult heart, we used histology with immunohistochemistry for gap junction protein expression, optical mapping, and electrocardiography. At the prenatal stages, a clear reduction in left ventricular wall thickness, accompanied by abnormal conduction of the ectopically paced beat in that area, was observed in mutant hearts. This correlated with increased expression of connexin-40 and connexin-43 in noncompacted trabeculae. In postnatal stages, left ventricular noncompaction was resolved, but the right ventricular wall remained structurally abnormal through to adulthood with cardiomyocyte hypertrophy and retention of myocardial crypts. Thus, this is a novel model of self-correcting embryonic hypertrabeculation cardiomyopathy, but it highlights that remodelling potential differs between the left and right ventricles. We conclude that disruption of ROCK signalling induces both morphological and electrophysiological changes that evolve over time, highlighting the link between myocyte proliferation and noncompaction phenotypes and electrophysiological differentiation.
左心室致密化不全心肌病与心力衰竭、心律失常和心源性猝死相关。成人心肌致密化不全的发育机制仍未完全明确，小梁致密化缺失、小梁肥厚及增殖丧失被认为是可能的病因。为研究此机制，我们利用了一种心肌细胞中Rho激酶（ROCK）信号异常的小鼠模型，该模型在胚胎发育过程中导致致密化不全表型，并监测其出生后及成年期的进展情况。胚胎期第15.5天早期致密化不全的原因是发育中的心室壁增殖减少。到胚胎期第18.5天，表型变得斑驳，致密化不全区域与心室壁增厚的致密区域相间分布。为研究这种心脏肌结构改变如何影响发育中和成年心脏的冲动传导，我们采用组织学结合免疫组化检测缝隙连接蛋白表达、光学标测和心电图检查。在产前阶段，突变心脏中观察到左心室壁厚度明显减小，同时该区域异位起搏搏动的传导异常。这与致密化不全小梁中连接蛋白40和连接蛋白43的表达增加相关。在出生后阶段，左心室致密化不全得到缓解，但右心室壁直至成年仍存在结构异常，表现为心肌细胞肥大和心肌隐窝残留。因此，这是一种自我纠正的胚胎期小梁肥厚型心肌病的新模型，但它强调了左右心室的重塑潜力不同。我们得出结论，ROCK信号的破坏会诱导形态学和电生理学变化，且这些变化会随时间演变，突出了心肌细胞增殖与致密化不全表型及电生理分化之间的联系。
