The immune system has been identified to play a significant role in the development and maintenance of many cardiac disorders. Autoantibodies against specific cardiac ion channels have been detected in plasma from patients with arrhythmic disorders such as atrial fibrillation. It is thought that this novel mechanism may impart drastic changes on ion channel function, leading to the manifestation of arrythmia. This was the core idea behind new research into the mechanisms of Brugada syndrome (BrS), an autosomal dominant cardiac disorder characterized by unspecific ECG patterns and reduced cardiac excitability due to altered cardiac sodium channel (Na_V1.5) function. This often results in patients experiencing abnormal cardiac rhythms and can lead to sudden cardiac death.

While many cases of BrS can be attributed to genetic mutations in the SCN5A gene (encoding Na_V1.5) the disease often manifests in patients without a clear genetic cause. To check for potential roles of the immune system in BrS, researchers collected plasma samples from 50 BrS patients and 50 healthy controls to screen for the presence of autoantibodies against Na_V1.5. Their findings revealed that 90% of BrS patients had detectable levels of autoantibodies against Na_V1.5, compared to only 6% of the control group.

To determine the functional effect of these autoantibodies, automated patch clamp of Na_V1.5-expressing HEK cells was conducted using the Patchliner instrument. Application of autoantibodies against Na_V1.5 revealed a significant reduction of sodium current (I_Na) density, consistent with reduced I_Na reported in BrS patients. This was verified in an in vivo mouse model, where autoantibody application resulted in ECG abnormalities similar to those observed in BrS patients.

This research highlights a potentially crucial role of autoimmune mechanisms in the pathogenesis of BrS, offering a unique counterpoint to the traditional but possibly flawed view of BrS as a purely genetic disease. Importantly, screening for Na_V1.5 autoantibodies could vastly improve diagnostic accuracy in the clinic. Further studies into the role of autoantibodies in patients with arrhythmia could also lead to promising and novel therapeutic strategies.

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Find the full article here: https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehae480/7724016#476530982

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