PDF(Pubmed)
Abstract：
Developmental causes of the most common arrhythmia, atrial fibrillation (AF), are poorly defined, with compensation potentially masking arrhythmic risk. Here, we delete 9 amino acids (Δ9) within a conserved domain of the giant protein titin\'s A-band in zebrafish and human-induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). We find that ttna Δ9/Δ9 zebrafish embryos\' cardiac morphology is perturbed and accompanied by reduced functional output, but ventricular function recovers within days. Despite normal ventricular function, ttna Δ9/Δ9 adults exhibit AF and atrial myopathy, which are recapitulated in TTN Δ9/Δ9-hiPSC-aCMs. Additionally, action potential is shortened and slow delayed rectifier potassium current (I Ks) is increased due to aberrant atrial natriuretic peptide (ANP) levels. Strikingly, suppression of I Ks in both models prevents AF and improves atrial contractility. Thus, a small internal deletion in titin causes developmental abnormalities that increase the risk of AF via ion channel remodeling, with implications for patients who harbor disease-causing variants in sarcomeric proteins.
摘要：
最常见心律失常的发育原因，心房颤动(AF),定义不清，补偿可能掩盖心律失常风险。这里,我们删除了斑马鱼和人诱导的多能干细胞来源的心房心肌细胞（hiPSC-aCMs）中巨大蛋白TitinA带保守域内的9个氨基酸（Δ9）。我们发现ttnaΔ9/Δ9斑马鱼胚胎的心脏形态受到干扰，并伴有功能输出降低，但心室功能会在几天内恢复.尽管心室功能正常,ttnaΔ9/Δ9成人表现为房颤和心房肌病，在TTNΔ9/Δ9-hiPSC-aCM中概括。此外，由于心房利钠肽（ANP）水平异常，动作电位缩短，缓慢延迟整流钾电流（IKs）增加。引人注目的是，在两种模型中抑制IKs可预防房颤并改善心房收缩力。因此，Titin的一个小的内部缺失导致发育异常，通过离子通道重塑增加AF的风险，对携带肌节蛋白致病变异的患者有影响。
