Increased in vivo perpetuation of whole-heart ventricular arrhythmia in heterozygous Na+/Ca2+ exchanger knockout mice. (February 2023)

• Record Type: Journal Article
• Authors: Bögeholz, Nils; Knappe, Vincent; Pauls, Paul; Schulte, Jan S.; Goldhaber, Joshua I.; Müller, Frank U.; Nickenig, Georg; Eckardt, Lars; Schrickel, Jan W.; Beiert, Thomas
• Is Part Of: IJC heart & vasculature. Volume 44(2023)
• Publication Date: 2023-02
• Subjects: Arrhythmia mechanisms -- Antiarrhythmic strategies -- Na+/Ca2+ exchanger -- Ventricular arrhythmia; NCX Na+/Ca2+ exchanger -- EAD Early afterdepolarization -- DAD Delayed afterdepolarization -- KO Heterozygous Na+/Ca2+ exchanger knockout mouse model -- PCR Polymerase chain reaction -- EPS Electrophysiological study -- CorrSNRP Corrected sinus node recovery period -- WBP Wenckebach periodicity -- AV Atrioventricular -- AVNRP AV-nodal refractory period -- VT Ventricular tachycardia -- PVS Programmed ventricular stimulation -- CL Cycle length -- VRP Ventricular refractory period -- SEM Standard error of the mean -- IQR Interquartile range -- WT Wild-type -- PVC Premature ventricular complex -- ICa voltage-dependent l-type Ca2+-current; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Pathophysiology -- Periodicals; 616.1005
• DOI: 10.1016/j.ijcha.2022.101168
• Languages: English
• ISSNs: 2352-9067

Abstract

Abstract: Aims: Na + /Ca 2+ 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. Methods/Results: 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). Conclusions: 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.