Podcast
Questions and Answers
What is the primary role of Nav1.5 in the human heart?
What is the primary role of Nav1.5 in the human heart?
Nav1.5 consists solely of α subunits.
Nav1.5 consists solely of α subunits.
False
What genetic locus is associated with Brugada syndrome according to recent genome-wide association analyses?
What genetic locus is associated with Brugada syndrome according to recent genome-wide association analyses?
SCN5A
The primary consequence of the M1875T-SCN5A mutation in familial atrial fibrillation is an increase in __________.
The primary consequence of the M1875T-SCN5A mutation in familial atrial fibrillation is an increase in __________.
Signup and view all the answers
Which experimental technique is useful for exploring cardiac electrophysiology?
Which experimental technique is useful for exploring cardiac electrophysiology?
Signup and view all the answers
The SCN5A gene is integral to the function of Nav1.5.
The SCN5A gene is integral to the function of Nav1.5.
Signup and view all the answers
Nav1.5 is primarily expressed in the __________.
Nav1.5 is primarily expressed in the __________.
Signup and view all the answers
Which of the following is NOT a focus of research mentioned regarding Nav1.5?
Which of the following is NOT a focus of research mentioned regarding Nav1.5?
Signup and view all the answers
What gene encodes the Nav1.5 protein?
What gene encodes the Nav1.5 protein?
Signup and view all the answers
Type 3 Long QT syndrome is caused by gain-of-function mutations in the SCN5A gene.
Type 3 Long QT syndrome is caused by gain-of-function mutations in the SCN5A gene.
Signup and view all the answers
What syndrome is characterized by loss-of-function mutations in the SCN5A gene?
What syndrome is characterized by loss-of-function mutations in the SCN5A gene?
Signup and view all the answers
Match the syndromes with their characteristics:
Match the syndromes with their characteristics:
Signup and view all the answers
Which of the following is NOT a genetic polymorphism of SCN5A?
Which of the following is NOT a genetic polymorphism of SCN5A?
Signup and view all the answers
The MAPRE2 gene has been identified as a responsible factor for Brugada syndrome.
The MAPRE2 gene has been identified as a responsible factor for Brugada syndrome.
Signup and view all the answers
What characteristic ECG finding can occur in Brugada syndrome?
What characteristic ECG finding can occur in Brugada syndrome?
Signup and view all the answers
What effect does Type 3 Long QT syndrome have on the QT interval?
What effect does Type 3 Long QT syndrome have on the QT interval?
Signup and view all the answers
Which drug has been reported to increase mortality compared to placebo control?
Which drug has been reported to increase mortality compared to placebo control?
Signup and view all the answers
Flecainide has a wide therapeutic window.
Flecainide has a wide therapeutic window.
Signup and view all the answers
What is one major adverse event associated with the 'pill-in-pocket' approach using anti-arrhythmic drugs?
What is one major adverse event associated with the 'pill-in-pocket' approach using anti-arrhythmic drugs?
Signup and view all the answers
A common polymorphism in SCN5A, known as ______, may increase sensitivity to propafenone.
A common polymorphism in SCN5A, known as ______, may increase sensitivity to propafenone.
Signup and view all the answers
Match the following genetic variations with their associated effects:
Match the following genetic variations with their associated effects:
Signup and view all the answers
What is one effect of point mutations in the C-terminus of SCN5A α subunit?
What is one effect of point mutations in the C-terminus of SCN5A α subunit?
Signup and view all the answers
The polymorphism R1193Q in SCN5A does not have any significant clinical implications.
The polymorphism R1193Q in SCN5A does not have any significant clinical implications.
Signup and view all the answers
What are the effects on biophysical properties associated with MAPRE KO hiPSC-CMs?
What are the effects on biophysical properties associated with MAPRE KO hiPSC-CMs?
Signup and view all the answers
Anti-arrhythmic drugs often have a narrow therapeutic ______.
Anti-arrhythmic drugs often have a narrow therapeutic ______.
Signup and view all the answers
Which of the following is NOT a reported major adverse event from the use of flecainide at therapeutic doses?
Which of the following is NOT a reported major adverse event from the use of flecainide at therapeutic doses?
Signup and view all the answers
Study Notes
Biophysical properties of Nav1.5
- The cardiac sodium channel, Na 1.5, is composed of α and β subunits
- α subunit is the pore-forming subunit of voltage-gated sodium channels in the human myocardium
- The function of Na 1.5 drives the sodium current (INa) in the heart
Learning Outcomes
- Describe the biophysical properties of Nav1.5
- Describe genetic polymorphisms in SCN5A and their clinical implications
- Describe appropriate experimental techniques to explore cardiac electrophysiology
Recommended Reading
- Barc et al. (2022) identified new Brugada syndrome risk loci and sodium channel regulation.
- S. O. B. et al. (2022) found that flecainide effectiveness increases due to changes in sodium channels.
- O'Reilly et al. (2023) showed that a SCN5A mutation (M1875T) increases early sodium current.
- O'Shea et al. (2022) used optical mapping to study cardiac electrophysiology in models.
- Wisedchaisri et al. (2019) investigated voltage-gated sodium channel structure and gating.
What is Na 1.5?
- The cardiac sodium channel is composed of α and β subunits
- Na 1.5 is the pore-forming subunit in human myocardium
- INa is the function that drives sodium current in the heart
Nav1.5 Gating
- Described as resting state, activated, inactivated and resting (closed) phases.
- Depolarization and repolarization states are also featured in this process.
SCN5A
- Na 1.5 is encoded by the gene SCN5A
- This gene (SCN5A) produces the protein that forms the pore of Na 1.5
Genetic Polymorphisms of SCN5A
- Long QT syndrome (LQTS)
- Brugada syndrome (BrS)
- Early repolarization syndrome
- Congenital sick sinus syndrome
- Familial atrial fibrillation
- Sudden infant death syndrome
Long QT Syndrome
- Type 3 LQTS is caused by gain-of-function mutations in SCN5A.
- More than 200 mutations exist.
- Prolongs action potential duration (APD) which increases QT interval.
Brugada Syndrome
- BrS type 1 is caused by loss-of-function mutations in SCN5A
- Characteristic ECG patterns can occur spontaneously
- Can be unmasked with sodium channel blockers
- MAPRE2 gene identified recently as having a possible role
Additional Brugada info
- Remaining genes involved are elusive.
- MAPRE2 is a newly identified gene related to Brugada
- Conduction velocity and action potential upstroke are reduced in patients
- Other mutations reduce INa at all holding potentials
Optical mapping for cardiac electrophysiology
- Fluorescence technique using potentiometric dyes measures changes in various regions
- Used in whole tissues/hearts.
- Allows quantification of local/regional or global electrophysiology in paced specimens.
The problem with anti-arrhythmic drugs
- Many have narrow therapeutic windows
- Can lead to pro-arrhythmia by increasing electrical sensitivity of certain cardiac regions.
Major adverse events with the 'pill-in-pocket' approach
- At therapeutic doses of single oral dose of flecainide or propafenone:
- QRS duration prolongation
- Brugada syndrome (BrS)
- Cardiogenic shock
- Flecainide originally used to treat ventricular arrhythmias after myocardial infarction.
- Flecainide increased mortality compared to placebo.
Polymorphisms in SCN5A
- Propafenone can induce a Brugada syndrome ECG pattern in patients with SCN5A polymorphisms.
- Some polymorphisms increase individual sensitivity to propafenone.
Point mutations in SCN5A
- Can decrease sensitivity to flecainide (M1875T).
- Heterozygous point mutations are associated with familial AF.
Biophysical diversity in SCN5A
- There are natural differences in biophysical properties of SCN5A proteins
- Differences in properties and pharmacological sensitivity to flecainide.
- Possible cause is due to differential expressions/production of the pore-forming subunit protein (Na 1.5).
What we discussed
- Na 1.5 gating and structure
- Exploring connections between SCN5A and clinical implications of genetic polymorphisms
- Techniques used for pre-clinical research into genetic polymorphisms
Studying That Suits You
Use AI to generate personalized quizzes and flashcards to suit your learning preferences.
Related Documents
Description
Explore the biophysical properties of the cardiac sodium channel Nav1.5, including its structure, function, and genetic polymorphisms. This quiz will cover experimental techniques and clinical implications related to SCN5A mutations and their impact on cardiac electrophysiology.
