Biophysical Properties of Nav1.5 PDF

BS31013 – Biophysical properties of Nav1.5 Dr Claire Y Hepburn  Learning outcomes Describe the biophysical properties of Nav1.5 Describe genetic polymorphisms in SCN5A and the clinical implications Describe appropriate experimental techniques to explore cardiac electrophy...

BS31013 – Biophysical properties of Nav1.5 Dr Claire Y Hepburn  Learning outcomes Describe the biophysical properties of Nav1.5 Describe genetic polymorphisms in SCN5A and the clinical implications Describe appropriate experimental techniques to explore cardiac electrophysiology Biophysical properties of Nav1.5  Recommended reading Barc J., et al. (2022). "Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility. " Nat Genet 54: 232-239. Erratum in: Nat Genet. 2022 May;54(5):735. S, O. B., et al. (2022). "Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels." J Mol Cell Cardiol 166: 23-35. O'Reilly, M., et al. (2023). "Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide." Europace 25(3): 1152- 1161. O'Shea C., et al. (2022). "High resolution optical mapping of cardiac electrophysiology in pre-clinical models." Scientific Data 9: 1-12. doi: 10.1038/s41597-022-01253-1. Wisedchaisri, G., et al. (2019). “Resting-State Structure and Gating Mechanism of a Voltage-Gated Sodium Channel." Cell 178: 993–1003. Biophysical properties of Nav1.5  What is Nav1.5? The cardiac sodium channel is composed of α and β subunits Nav1.5 is the pore-forming subunit of the voltage-gated sodium channel expressed in the human myocardium Function drives the sodium current (INa) in the human heart 1; Ito 0mV 0; INa 2 3, IKr 4 - 100mV Biophysical properties of Nav1.5 Dong et al., Front Physiol., Adapted from de Lucia, Eguchi and Koch. Front. Pharmacol., 2018; 9,904. 2020; 11  Nav1.5 gating Cardiovascular Physiology Concepts, Wisedchaisri et al., Cell., 2020; 3e, 2022 178 Biophysical properties of Nav1.5  SCN5A Nav1.5 is encoded by the gene SCN5A Biophysical properties of Nav1.5 Dong et al., Front Physiol., 2020; 11  Genetic polymorphisms of SCN5A Long QT syndrome (LQTS) Brugada syndrome (BrS) Early repolarisation syndrome Congenital sick sinus syndrome Familial atrial fibrillation Sudden infant death syndrome Biophysical properties of Nav1.5  Long QT syndrome Type 3 LQTS is caused by gain-of-function mutations in SCN5A There are more than 200 of these mutations Prolongs action potential duration (APD) and therefore, QT interval 1; Ito 0mV 0; INa 2 4 - 100mV Biophysical properties of Nav1.5  Brugada syndrome BrS type 1 is caused by loss-of-function mutations in SCN5A Characteristic ECG can occur spontaneously but can also be unmasked by sodium-channel blockers Remaining genes responsible have been elusive MAPRE2 identified recently (Barc et al., 2022) Biophysical properties of Nav1.5  Brugada syndrome Remaining genes responsible have been elusive MAPRE2 identified recently Biophysical properties of Nav1.5 Barc et al., Nat Gen., 2022; 54  Brugada syndrome Remaining genes responsible have been elusive MAPRE2 identified recently Reduced conduction velocity and action potential upstroke velocity (CL 600 ms) Biophysical properties of Nav1.5 Barc et al., Nat Gen., 2022; 54  Optical mapping for cardiac electrophysiology Fluorescence-technique using potentiometric dyes in whole tissues/hearts to permit quantification of local/regional or global changes in electrophysiology in paced specimens Biophysical properties of Nav1.5 O’Shea et al., Sci. Data., 2022; 9  Brugada syndrome Remaining genes responsible have been elusive MAPRE2 identified recently Reduced Vmax and APDs in MAPRE KO hiPSC-CMs Reduced INa at all holding potentials Biophysical properties of Nav1.5 Barc et al., Nat Gen., 2022; 54  The problem with anti-arrhythmic drugs Anti-arrhythmic drugs often have narrow therapeutic window Can cause pro-arrhythmia… some of which can be explained by understanding more about polymorphisms or biophysical properties of SCN5A Biophysical properties of Nav1.5  Major adverse events with the ‘pill-in- pocket’ approach At therapeutic doses of single oral dose of flecainide or propafenone, major adverse events have been reported, including but not limited to: QRS duration prolongation Brugada syndrome (BrS; Li et al., 2019) Cardiogenic shock (Gjermeni et al., 2019) Flecainide was originally developed for used in management of ventricular arrhythmia after myocardial infarction Flecainide (and encainide) increase mortality compared with placebo control (Echt et al., 1991) Biophysical properties of Nav1.5  Polymorphisms in SCN5A Propafenone has been shown to induce a BrS ECG pattern in a patient with a common polymorphism in SCN5A (R1193Q; Hwang et al., 2005; Matsusue et al., 2016) And, this gene polymorphism may increase sensitivity to propafenone Li et al., Front. Physiol., 2019; 10, 1-8 Biophysical properties of Nav1.5  Point mutations in SCN5A Conversely, a point mutation in the C-terminus of SCN5A α subunit can decrease sensitivity to flecainide (M1875T) This heterozygous point mutation in SCN5A is associated with familial AF (Makiyama et al., 2008) O’Reilly et al., Europace., 2022; 25, 1152-1161 Biophysical properties of Nav1.5  Biophysical diversity in SCN5A There are natural differences in biophysical properties of SCN5A in left ventricular vs. left atrial cardiomyocytes at physiological holding potentials O’Brien et al., JMCC., 2022; 166, 23-35 Biophysical properties of Nav1.5  Biophysical diversity in SCN5A These differences in biophysical properties and pharmacological sensitivity to flecainide may be linked to differential expression of the primary sodium channel pore forming subunit protein, Nav1.5 O’Brien et al., JMCC., 2022; 166, 23-35 Biophysical properties of Nav1.5  What we discussed Nav1.5 - it’s gating and structure SCN5A and the clinical implications of genetic polymorphisms Techniques currently being used to understand the pre-clinical implications of genetic polymorphisms in SCN5A (cardiac electrophysiology) Biophysical properties of Nav1.5 Thank you. Questions?