P102Long QT3 mice have disrupted sympathovagal balance and in vivo ventricular stimulation does not determine risk of sudden cardiac death, suggesting that a second perturbation may be required

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Abstract

Purpose

Long QT 3 (LQT 3) is a cause of sudden cardiac death (SCD) by Torsades de pointes (TdP). SCD often occurs during sleep, rest and bradycardia, suggesting that heightened parasympathetic tone provokes TdP in LQT 3. It is challenging to ascertain the risk of SCD in these patients. We performed in vivo electrophysiological studies (EPS), ventricular tachycardia (VT) stimulation and telemetry in LQT 3 (ΔKPQ) and wild type (WT) mice, without and with provocation with the muscarinic agonist, carbachol.

Methods

EPS were performed in young (8-week) and old (≥6 months of age) anaesthetised mice with a 1.1F catheter inserted into the right ventricle via the internal jugular vein. ECG and EP parameters were recorded. VT stimulation was attempted with 1 to 5 extrastimuli, coupled at 75 to 10ms following a train of 8 beats at 100ms. This was repeated after injection with 0.5mg/kg carbachol. Telemetry probes were inserted intra-abdominally into young (12-week old) mice and old (≥6 months of age) mice. After a 2 week recovery period, ECGs were recorded in conscious mice for 48 hours and studied for VT and ventricular ectopics (VE). An ECG post carbachol was analysed. Heart rate variability (HRV) was measured from 12 to 2pm, when murine vagal tone is highest.

Results

Young ΔKPQ had a prolonged PR interval (41.2 ± 0.5 vs 39.2 ± 0.6ms, P=0.003), QRS duration (11.0 ± 0.6 vs 9.6 ± 0.3ms, P=0.03), as well as a prolonged corrected QT interval (74.2 ± 3.6 vs 57.2 ± 1.4, P < 0.0001), compared to WT. EP parameters were comparable between young and old cohorts and respective WT controls. One young WT developed VT. Of the older mice, 1 WT had a VE pre and post carbachol and 1 ΔKPQ had a VE post carbachol. ΔKPQ mice had disrupted sympathovagal balance shown by normalised low (9.8 ± 3.6 vs 53.2 ± 5.6nu, P=0.004) and high (12.2 ± 3.1 vs 46.7 ± 5.6nu, P=0.004) frequency power. On examination of telemetry ECGs, 1 young ΔKPQ had 2 pauses (435 and 394ms) and 1 old ΔKPQ had 3 pauses (316, 308 and 378ms), but no pauses were seen in WT. No VT was found.

Conclusions

To our knowledge, this is the first report of in vivo EPS in the ΔKPQ mouse. Our results concur with human studies where VT stimulation is unhelpful in predicting risk of SCD.

Conclusions

HRV assessment shows disrupted symapthovagal balance, but an increase in vagal tone with carbachol did not induce VT. However, the effects of carbachol are short. It is feasible that a second perturbation sustaining increased vagal tone, for example, through increased inhibitory G-protein activity, is responsible for TdP and predisposition to SCD in LQT 3 patients.

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