2 - Genetics of CVD Flashcards
QT Interval
QTc
Syncope
Torsade de Pointes
Time between ventricular depolarization and repolarization
QTc is a correction for heart rate
Syncope - transient loss of consciousness
Torsade - Ventricular tachycardia characterized by change in amplitude/twisting of QRS complexes
Phase 0:
Depolarization?
Channel?
Depolarization by sodium influx through fast channel Nav1.5
Phase 1:
Repolarization / Channel?
Repolarization by potassium efflex (Ito1) through voltage-gated potassium channels
Phase 2
Repolarization / Channel?
Calcium influx through L-type Calcium Channel
Some pitassium efflux through slow delayed rectifieer channel
Phase 3
Repolarization / Channel?
Repolarization by potassium efflux through delayed rectifier channels
1. Slow Activating (IKs) current first
2. then Fast Activating (IKr) current
Currents:
INa
Ito1
IKs
IKr
INa - Fast Sodium Channel
Ito1 - Voltage Kated Potassium Channel
IKs - Slow Activating Potassium Channel
IKr - Fast Activating Potassium Channel
Clinical: Long QT Syndrome (LQTS)
Cause?
Type of Mutation?
ECG Finding?
Triggered by?
Symptoms?
Cause: Genetic defects in cardiac voltage-actiavted Na/K channels
Type: Loss-of-Function mutation
ECG: Prolonged QTc, Torsade de Pointes
Triggered by: Physical/emotional stress; syncope
Symptoms: Syncope, sudden death
Clinical: LQT1
Defective Channel
Triggers
Defective Ks Channel (Slow K Rectifier)
Ks current reduced
Triggers: Exercise (>LQT2,3), Emotional/Physical Stress
Clinical: LQT2
Defective Channel
Triggers
Defective Channel: KR (Rapid K delayed rectifier)
Triggers: Sudden loud noises, stress, and rest
Clinical: LQT3
Defective Channel
Triggers
Defective Channel: INa (Fast Inactivating Na+ Channel)
Triggers: Sleep, Inactivity
By what mechanism does a prolonged action potential occure?
- Increased inward current through maintained Na Channel Activity
- Decreased outward current through K Channel Activity
Clinical:
What is treatment for LQT Syndrome?
First: Beta-Blockers
Other Actions: ECG, test family members, genetic testing
Clinical: Short QT Syndrome (SQTS)
Shorter QTc than normal (< 330-340 msec)
Causes: Gain of Function Mutations in Kr, Ks, K1 (inward rectifying channels),increasedefflux of potassium during repolarizations
Symptoms: Dizziness, atrial/ventricular fibrillation, sudden cardiac death
Clinical: Brugada Syndrome
Right Bundle Branch Block and ST Segment Elevation in Right Precordial Leads
Majority fast sodium channel loss-of-function mutations
Gain of Function LQT3
- Pacific Islanders at greater risk
What genes (channels) are associated with Atrial Fibrillation?
What does this lead to?
Gain of Function: K Channel Mutations
- Ks
- Kr
- KCNE2 - Regulates Kr
Increase of efflux of K–increase rate of Phase 2/3
Reduce action poteion, and refractory period
Loss of Function: K Channel Mutations
- KV1.5 (Voltage Gated K Channel)
Increase in atrial repolarization in Phase 1-3
Longer action potential, early afterdepolarizations
What is the importance of connexin 40 in the cardiac cycle?
What can occur if it’s not distributed evenly?
Gap Junction Protein
Dominant connexin for impulse conduction in atria
Atrial Fibrillation can occur if not distributed evenly; uneven contraction rates
Hypertrophic Cardiomyopathy (HCM)
Symptoms
Causes
Most common monogenic cardiac disorder; autosomal dominant
One part of heart is thicker than others
Myofibril disaray
Causes: Myosin Heavy Chain, Myosin Binding Protein C, Troponin T/I, Tropomyosin, Myosin Light Chains
Clinical: Dilated Cardiomyopathy (DCM)
Symptoms
Causes
Treatment
Symptoms: Shortness of breath, swelling of feet and ankles
Left Ventricular Enlargement, Reduced EF
- - -
Cause: Majority of mutations in sarcomere proteins (titin, troponin T, C, I, desmin, myosin heavy chain)
Treat as if they have heart failure.
