2 - Genetics of CVD

Question 1

QT Interval

QTc

Syncope

Torsade de Pointes

Answer 1

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

Question 2

Phase 0:

Depolarization?

Channel?

Answer 2

Depolarization by sodium influx through fast channel Na_v1.5

Question 3

Phase 1:

Repolarization / Channel?

Answer 3

Repolarization by potassium efflex (I_to1) through voltage-gated potassium channels

Question 4

Phase 2

Repolarization / Channel?

Answer 4

Calcium influx through L-type Calcium Channel

Some pitassium efflux through slow delayed rectifieer channel

Question 5

Phase 3

Repolarization / Channel?

Answer 5

Repolarization by potassium efflux through delayed rectifier channels

1. Slow Activating (I_Ks) current first

2. then Fast Activating (I_Kr) current

Question 6

Currents:

I_Na

I_to1

I_Ks

I_Kr

Answer 6

I_Na - Fast Sodium Channel

I_to1 - Voltage Kated Potassium Channel

I_Ks - Slow Activating Potassium Channel

I_Kr - Fast Activating Potassium Channel

Question 7

Clinical: Long QT Syndrome (LQTS)

Cause?

Type of Mutation?

ECG Finding?

Triggered by?

Symptoms?

Answer 7

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

Question 8

Clinical: LQT1

Defective Channel

Triggers

Answer 8

Defective K_s Channel (Slow K Rectifier)

Ks current reduced

Triggers: Exercise (>LQT2,3), Emotional/Physical Stress

Question 9

Clinical: LQT2

Defective Channel

Triggers

Answer 9

Defective Channel: K_R (Rapid K delayed rectifier)

Triggers: Sudden loud noises, stress, and rest

Question 10

Clinical: LQT3

Defective Channel

Triggers

Answer 10

Defective Channel: I_Na (Fast Inactivating Na+ Channel)

Triggers: Sleep, Inactivity

Question 11

By what mechanism does a prolonged action potential occure?

Answer 11

1. Increased inward current through maintained Na Channel Activity
2. Decreased outward current through K Channel Activity

Question 12

Clinical:

What is treatment for LQT Syndrome?

Answer 12

First: Beta-Blockers

Other Actions: ECG, test family members, genetic testing

Question 13

Clinical: Short QT Syndrome (SQTS)

Answer 13

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

Question 14

Clinical: Brugada Syndrome

Answer 14

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

Question 15

What genes (channels) are associated with Atrial Fibrillation?

What does this lead to?

Answer 15

Gain of Function: K Channel Mutations

1. Ks
2. Kr
3. 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

1. K_V1.5 (Voltage Gated K Channel)

Increase in atrial repolarization in Phase 1-3

Longer action potential, early afterdepolarizations

Question 16

What is the importance of connexin 40 in the cardiac cycle?

What can occur if it’s not distributed evenly?

Answer 16

Gap Junction Protein

Dominant connexin for impulse conduction in atria

Atrial Fibrillation can occur if not distributed evenly; uneven contraction rates

Question 17

Hypertrophic Cardiomyopathy (HCM)

Symptoms

Causes

Answer 17

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

Question 18

Clinical: Dilated Cardiomyopathy (DCM)

Symptoms

Causes

Treatment

Answer 18

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.