Increased in vivo perpetuation of whole-heart ventricular arrhythmia in heterozygous Na+/Ca2+ exchanger knockout mice

Nils Bögeholz; Vincent Knappe; Paul Pauls; Jan S Schulte; Joshua I Goldhaber; Frank U Müller; Georg Nickenig; Lars Eckardt; Jan W Schrickel; Thomas Beiert

doi:10.1016/j.ijcha.2022.101168

Increased in vivo perpetuation of whole-heart ventricular arrhythmia in heterozygous Na⁺/Ca²⁺ exchanger knockout mice

Int J Cardiol Heart Vasc. 2022 Dec 30:44:101168. doi: 10.1016/j.ijcha.2022.101168. eCollection 2023 Feb.

Authors

Affiliations

¹ Department of Cardiology II - Electrophysiology, University Hospital Münster, Münster, Germany.
² Department of Cardiology, Schuechtermann-Klinik, Bad Rothenfelde, Germany.
³ Department of Internal Medicine II, University Hospital Bonn, Bonn, Germany.
⁴ Institute of Pharmacology and Toxicology, University Hospital Münster, Münster, Germany.
⁵ Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Abstract

Aims: 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.

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.

Keywords: AV, Atrioventricular; AVNRP, AV-nodal refractory period; Antiarrhythmic strategies; Arrhythmia mechanisms; CL, Cycle length; CorrSNRP, Corrected sinus node recovery period; DAD, Delayed afterdepolarization; EAD, Early afterdepolarization; EPS, Electrophysiological study; ICa, voltage-dependent l-type Ca2+-current; IQR, Interquartile range; KO, Heterozygous Na+/Ca2+ exchanger knockout mouse model; NCX, Na+/Ca2+ exchanger; Na+/Ca2+ exchanger; PCR, Polymerase chain reaction; PVC, Premature ventricular complex; PVS, Programmed ventricular stimulation; SEM, Standard error of the mean; VRP, Ventricular refractory period; VT, Ventricular tachycardia; Ventricular arrhythmia; WBP, Wenckebach periodicity; WT, Wild-type.