Abstract 12836: Immunization of Rats With an Extracellular Sequence of the Cardiac Voltage-Gated Sodium Channel NaV1.5 Induces QT Prolongation and Arrhythmias
Background Increased evidence suggests the involvement of autoimmunity in heart failure. Voltage-gated sodium channels (NaV1.5) are responsible for the depolarisation of the myocardium. Mutations in the channel have been linked to long QT syndrome which is associated with life-threatening arrhythmias and sudden cardiac death. In the present study we investigated the effects of inducing an autoimmune response to NaV1.5 in rats.
Methods Lewis rats were immunized with a peptide representing an extracellular sequence of the cardiac voltage-gated sodium channel NaV1.5 on days 0, 7, 14 and were compared to a control group receiving a control buffer. ECG patterns 21 and 28 days after first immunization were evaluated. On day 28, histological examination, and left-ventricular pressure-volume analysis to assess cardiac function were performed. Anti-NaV1.5 antibody titers were measured in sera.
Results Rats immunized with NaV1.5 developed high titers of autoantibodies against NaV1.5. Although, there was no inflammation and no fibrosis in the myocardium, ECG analysis on days 21 and 28 showed significantly prolonged corrected QT-intervals in rats immunized with NaV1.5 compared to the controls (74±2ms vs. 64±3ms; p<0.05). Interestingly, one rat immunized with NaV1.5 revealed frequent ventricular extrasystoles, while another rat developed P wave inversions upon immunization. Control rats showed no altered ECG findings. Furthermore, two rats immunized with NaV1.5 died on day 21 during the ECG anaesthetic period, whereas none of the control rats died during the follow-up time of 28 days. Immunization of rats with NaV1.5 had no effect on LV pressures, isovolumic contraction phase indexes, active phase of relaxation indexes and end-diastolic stiffness. However, after immunization significant increased end-diastolic volume (128±7µl vs. 96±13µl; p<0.05 and decrease in maximum of time-varying elastance (2.64±0.28 vs. 4.03±0.48; p<0.05) was observed.
Conclusion Our results show that autoimmunity against an extracellular sequence of the cardiac voltage-gated sodium channel NaV1.5 is associated with QT interval prolongation, ventricular extrasystoles and increased mortality but with no signs of myocardial inflammation. S.K. and J.L. contributed equally
- © 2011 by American Heart Association, Inc.