BS31013 - Biophysical Properties of Nav1.5 - myDundee

Introduction to Nav1.5

  • Nav1.5 is a critical component of cardiac physiology.

  • Dr. Claire Y Hepburn's overview on its biophysical properties.

Learning Outcomes

  • Understand biophysical properties of Nav1.5.

  • Recognize genetic polymorphisms in SCN5A and their clinical relevance.

  • Explore experimental techniques for cardiac electrophysiology.

Recommended Reading

  • Barc J., et al. (2022): Genome-wide association studies on Brugada syndrome, identifying sodium channel regulation mechanisms.

  • S, O. B., et al. (2022): Effects of altered sodium channel properties on flecainide efficacy.

  • O'Reilly, M., et al. (2023): Familial atrial fibrillation mutation's impact on sodium currents.

  • O'Shea C., et al. (2022): High-resolution optical mapping for cardiac studies.

  • Wisedchaisri, G., et al. (2019): Structure and gating mechanisms of sodium channels.

What is Nav1.5?

  • The cardiac sodium channel has α and β subunits; Nav1.5 is the pore-forming subunit.

  • It is expressed in human myocardium and responsible for sodium current (INa).

  • Visual Representation: Diagram showing voltage states of Nav1.5 (Resting, Activated, Inactivated).

Gating Mechanism

  • Structure determines gating: includes pore module and voltage sensor.

  • States of Nav1.5: Resting (closed), Activated (open), and Inactivated (closed).

SCN5A Gene

  • Nav1.5 is encoded by the SCN5A gene.

Genetic Polymorphisms Related to SCN5A

  • Associated with various syndromes: Long QT syndrome (LQTS), Brugada syndrome (BrS), Early repolarisation syndrome, Congenital sick sinus syndrome, Familial atrial fibrillation, and Sudden infant death syndrome.

Long QT Syndrome (LQTS)

  • Type 3 LQTS results from gain-of-function mutations in SCN5A, causing prolonged action potential duration (APD).

  • Over 200 mutations linked to this syndrome.

Brugada Syndrome (BrS)

  • Type 1 BrS is caused by loss-of-function mutations in SCN5A.

  • Characteristic ECG can be spontaneous or induced by sodium channel blockers.

  • MAPRE2 gene potential involvement recently identified.

  • Symptoms include reduced conduction velocity and action potential upstroke velocity.

Optical Mapping in Electrophysiology Studies

  • Fluorescence technique using potentiometric dyes allows visualization of electrophysiology in cardiac tissues.

Issues with Anti-arrhythmic Drugs

  • Anti-arrhythmic drugs often possess narrow therapeutic windows and risk inducing pro-arrhythmia.

Major Adverse Events in Drug Therapy

  • “Pill-in-pocket” approach has led to several reported adverse events from drugs like flecainide and propafenone.

  • Risks include QRS duration prolongation and potential cardiogenic shock.

SCN5A Polymorphisms and Drug Sensitivity

  • Propafenone can induce BrS in patients with specific SCN5A polymorphisms.

  • Differences in threshold for drug sensitivity are observed due to genetic variations.

Point Mutations and Familial AF

  • Specific mutations in SCN5A (e.g., M1875T) affect sensitivity to flecainide.

  • Associated with familial atrial fibrillation.

Biophysical Diversity in SCN5A

  • Left ventricular vs. left atrial cardiomyocytes show natural variations in SCN5A properties.

  • Differential expression of Nav1.5 contributes to these variances.

Review of Discussion Points

  • Covered topics include gating and structure of Nav1.5, implications of SCN5A polymorphisms, and experimental methods in cardiac electrophysiology.

Conclusion

  • Thank you for the attention, open for questions.