未经证实:在心脏疾病如心力衰竭中,Na+/Ca2+交换剂(NCX)上调在单细胞水平上促进早期和延迟后去极化(EAD/DAD)作为独立的心律失常因子。因此,NCX抑制在分离的心肌细胞中防止EAD和DAD。我们在这里调查,这些有希望的细胞体外发现是否同样适用于体内设置。
UNASSIGNED:将程序心室刺激(PVS)和异丙肾上腺素应用于小鼠杂合子NCX敲除模型(KO),以研究与野生型(WT)相比的室性心律失常的发生和延续。KO对异丙肾上腺素诱导的室性早搏复合物的敏感性降低。在PVS期间,KO和WT之间单或双异位搏动的启动相似。但惊人的是,KO患者室性心动过速(VT)的持续性显著增加(VT-KO:82%;WT:47%;p=0.0122/VT-KO中位数:4.5(1.0,6.25);WT:0.0(0.0,4.0);p=0.0039).KO的中位VT持续时间延长(单位为s;KO:0.38(0.19,0.96);WT:0.0(0.0,0.60);p=0.0239)。KO的心室不应期(VRP)缩短(以ms为单位;KO:15.1±0.7;WT:18.7±0.7;p=0.0013)。
未经授权:不是启动,但是在KO中,引起的整个心脏在体内室性心律失常的延续增加了。作为一种潜在的机制,我们发现VRP显著降低,这可能会促进折返性室性心律失常的延续。从平移的角度来看,治疗性NCX抑制的抗心律失常概念似乎是矛盾的,因为至少在小鼠模型中,可以防止起效后的去极化,但有利于体内心律失常的延续.
UNASSIGNED: Na+/Ca2+ exchanger (NCX) upregulation in cardiac diseases like heart failure promotes as an independent proarrhythmic factor early and delayed afterdepolarizations (EADs/DADs) on the single cell level. Consequently, NCX inhibition protects against EADs and DADs in isolated cardiomyocytes. We here investigate, whether these promising cellular in vitro findings likewise apply to an in vivo setup.
UNASSIGNED: Programmed ventricular stimulation (PVS) and isoproterenol were applied to a murine heterozygous NCX-knockout model (KO) to investigate ventricular arrhythmia initiation and perpetuation compared to wild-type (WT). KO displayed a reduced susceptibility towards isoproterenol-induced premature ventricular complexes. During PVS, initiation of single or double ectopic beats was similar between KO and WT. But strikingly, perpetuation of ventricular tachycardia (VT) was significantly increased in KO (animals with VT - KO: 82 %; WT: 47 %; p = 0.0122 / median number of VTs - KO: 4.5 (1.0, 6.25); WT: 0.0 (0.0, 4.0); p = 0.0039). The median VT duration was prolonged in KO (in s; KO: 0.38 (0.19, 0.96); WT: 0.0 (0.0, 0.60); p = 0.0239). The ventricular refractory period (VRP) was shortened in KO (in ms; KO: 15.1 ± 0.7; WT: 18.7 ± 0.7; p = 0.0013).
UNASSIGNED: Not the initiation, but the perpetuation of provoked whole-heart in vivo ventricular arrhythmia was increased in KO. As a potential mechanism, we found a significantly reduced VRP, which may promote perpetuation of reentrant ventricular arrhythmia. On a translational perspective, the antiarrhythmic concept of therapeutic NCX inhibition seems to be ambivalent by protecting from initiating afterdepolarizations but favoring arrhythmia perpetuation in vivo at least in a murine model.