Abstract 13848: Provocation of an Autoimmune Response to Cardiac Voltage-Gated Sodium Channel NaV1.5 Induces Cardiac Conduction Defects in Rats
Introduction Emerging evidence indicates that autoantibodies play an important role in the pathogenesis of cardiac arrhythmias. Voltage-gated sodium channel NaV1.5 is crucial for myocardial depolarization and action potential propagation. Mutations in NaV1.5 are associated with severe channelopathies such as Brugada syndrome and cardiac conduction defects. We assessed the hypothesis that inducing an autoimmune response against NaV1.5 might also induce arrhythmias.
Methods Lewis rats (n=6) were immunized with a peptide sequence derived from the third extracellular loop of the first domain of the NaV1.5. Controls (n=5) received buffer. On day 28, we evaluated in vivo both the electrical and mechanical aspects of cardiac function. Histopathology and myocardial gene expression were assessed and whole-cell patch clamp was used to measure the density of voltage-gated sodium current INa in isolated myocytes.
Results Rats immunized with NaV1.5 peptide had high titers of autoantibodies against NaV1.5. On ECG recording, NaV1.5 immunized animals showed prolonged PR intervals in comparison to controls (51±1 ms vs 46±1 ms, p<0.05). Furthermore, during holter ECG monitoring we observed repeated prolonged episodes of third-degree atrioventricular block and sinoatrial block in every NaV1.5 immunized rat, but not in controls. Immunization had no effect on cardiac function and there was no evidence of myocardial inflammation or fibrosis. Compared with controls, mRNA level for NaV1.5 was significantly decreased in immunized rats, whereas there was no difference in matrix metalloproteinases (MMP)-2, -9, -14, or tissue inhibitor of MMP-1 mRNA expression. Whole-cell patch clamp analyses demonstrated a reduction of the density of INa in cardiomyocytes incubated with sera from NaV1.5 immunized rats in comparison to cardiomyocytes incubated with sera from controls (4.20±0.27 pA/pF vs 5.95±0.37 pA/pF, p<0.05).
Conclusion Provocation of an autoimmune response against NaV1.5 induces an exclusively electrophysiological phenotype with conductance defects without signs of structural heart disease or inflammation. This may include both reduced expression level and inhibition of NaV1.5 in the plasma membrane by autoantibodies, resulting in a decrease of INa.
- © 2012 by American Heart Association, Inc.