Total beta-adrenoceptor knockout slows conduction and reduces inducible arrhythmias in the mouse heart

Abstract

Introduction: Beta-adrenoceptors (β-AR) play an important role in the neurohumoral regulation of cardiac function. Three β-AR subtypes (β(1), β(2), β(3)) have been described so far. Total deficiency of these adrenoceptors (TKO) results in cardiac hypotrophy and negative inotropy. TKO represents a unique mouse model mimicking total unselective medical β-blocker therapy in men. Electrophysiological characteristics of TKO have not yet been investigated in an animal model.

Methods: In vivo electrophysiological studies using right heart catheterisation were performed in 10 TKO mice and 10 129SV wild type control mice (WT) at the age of 15 weeks. Standard surface ECG, intracardiac and electrophysiological parameters, and arrhythmia inducibility were analyzed.

Results: The surface ECG of TKO mice revealed a reduced heart rate (359.2±20.9 bpm vs. 461.1±33.3 bpm; p<0.001), prolonged P wave (17.5±3.0 ms vs. 15.1±1.2 ms; p = 0.019) and PQ time (40.8±2.4 ms vs. 37.3±3.0 ms; p = 0.013) compared to WT. Intracardiac ECG showed a significantly prolonged infra-Hisian conductance (HV-interval: 12.9±1.4 ms vs. 6.8±1.0 ms; p<0.001). Functional testing showed prolonged atrial and ventricular refractory periods in TKO (40.5±15.5 ms vs. 21.3±5.8 ms; p = 0.004; and 41.0±9.7 ms vs. 28.3±6.6 ms; p = 0.004, respectively). In TKO both the probability of induction of atrial fibrillation (12% vs. 24%; p<0.001) and of ventricular tachycardias (0% vs. 26%; p<0.001) were significantly reduced.

Conclusion: TKO results in significant prolongations of cardiac conduction times and refractory periods. This was accompanied by a highly significant reduction of atrial and ventricular arrhythmias. Our finding confirms the importance of β-AR in arrhythmogenesis and the potential role of unspecific beta-receptor-blockade as therapeutic target.

Figure 1. Representative ECG recordings of TKO and WT mice.

A: Surface ECG. B: Intracardiac ECG at His–bundle level (A: first intracardiac atrial signal. H: His signal. V: first intracardiac ventricular signal).

Figure 2. Baseline ECG parameters.

Cycle lenghth, spontaneous heart rate, P wave duration and PQ time (A–D) showed a siginificant prolongation in TKO. QRS duration and QTc interval did not differ (E–F). n = 10 for TKO and n = 10 for WT.

Figure 3. Intracardiac ECG parameters and functional testing during the electrophysiological investigation.

Significant differences were found in the infra-Hisian conduction that was markedly delayed in TKO (B). The 2∶1-AV-block occurred at significantly slower fixed atrial pacing cycle lengths in TKO (D). Both the atrial and the ventricular refractory period demonstrated significant prolongation in TKO (G–H). AH: Interval from first atrial signal to His signal. HV: Interval from His to first intracardiac ventricular signal. 2∶1-block: 2∶1-AV-nodal-block. SNRT: sinus node recovery time. AVNRP: AV nodal refractory period. n = 10 for TKO and n = 10 for WT.

Figure 4. Induction of atrial fibrillation.

Representative tracings of A: TKO mice and B: WT mice. Atrial burst stimulation close to the refractory period (S1S1: 30 ms) failed to induce atrial fibrillation (AF) in TKO. The same burst led to the induction of an AF episode in WT that terminated spontaneously after 8.7 seconds. Surf: Surface ECG. His: Intracardiac ECG close to His bundle.

Figure 5. Induction of ventricular tachycardias.

Representative tracings of A: TKO mice and B: WT mice. Ventricular extrastimulus (VES) pacing close to the ventricular refractory time did not lead to ventricular tachycardias (VTs) in TKO mice (S1S2: 40 ms). In WT a short VT was induced by VES pacing (S1S2: 30 ms). Surf: Surface ECG. His: Intracardiac ECG close to HIS bundle.

Figure 6. Probability of induction of arrhythmias.

The probability of induction of AF was significantly lower in TKO compared to WT. The probability of induction of VTs was highly significant lower in TKO as in this group not any VTs could be induced during the electrophysiological study. n = 10 for TKO and n = 10 for WT.