Molecular Mechanisms of Arrhythmias

Question 1

Define a Long-QT Syndrome

Answer 1

Delayed repolarization of the heart following a heartbeat increases the risk of episodes of torsades de pointes

• These episodes may lead to palpitations, fainting, and sudden death due to ventricular fibrillation

Question 2

Define Torsades de Pointes

Answer 2

• Form of irregular heartbeat that originates from the ventricles

Question 3

What gene defects are associated with a long-QT syndrome?

Answer 3

Autosomal Dominant Form

• slow cardiac K+ channel IKs (LQT1)
• Rapid cardiac K+ channel IKr (LQT2)
• Cardiac Na+ channel INa (LQT3)

Auto Recessive Form

• Homozygous IKs (LQT1) suffer in addition from congenital deafness - hetero’s are asymptomatic

Question 4

Outline the two molecular basis for a long-QT syndrome?

*Note: depending on which one it is, treatment is different

Answer 4

1. Mutations reduce number of K+ channels expressed in the myocyte plasma membrane (loss of function mutation)
   
   • Reduces size of K+ current that helps terminate plateau phase of the fast response
2. Mutations prevent Na+ channels from inactivating completely (gain of function mutations)
   • Thereby prolonging phase 2 of the fast response

Question 5

What is the name of Class I antiarrhythmic drugs?

Answer 5

Na+ channel blockers

Question 6

What are the 3 ion channels targeted by class I antiarrythmic drugs and what phases of the slow & fast response do they target?

Answer 6

1. Ia: Slow the upstroke of the fast response (phase 0), prolong refractory period (phase 4) because depolarization (phase 2) is prolonged.
2. Ib: Slow upstroke (phase 0) mildly, shorten depolarization (phase 2) and prolong refractory period (phase 4).
3. Ic: Pronounced slowing of the upstroke of the fast response (phase 0), mildly prolong depolarization (phase 2).

Question 7

What is the name of Class II antiarythmic drugs?

Answer 7

Beta-adrenergic receptor blockers

Question 8

What ion channels and phases of the slow and fast response does class II antiarrythmic drugs target?

Answer 8

• LTCC, and K+ current
• reduces the rate of diastolic phase 4 depolarization in pacing cells, reduces the upstroke rate and slows repolarization.

Question 9

Class III Antiarrythmic Drugs

1. Name
2. What phases do they target?

Answer 9

1. K+ channel blockers
2. • Prolongation of fast response phase 2
   • Prominent prolongation of refractory period.

Question 10

Class IV Antiarrythmic Drugs

1. Name
2. Phases of the slow & fast response targeted

Answer 10

1. Ca2+ channel blockers
2. • Slow the Ca2+ -dependent upstroke in slow response tissue (slow rise of action potential)
   • Prolong the refractory period (prolonged repolarization)

Question 11

What phases are effected in an early afterdeporlarization (EAD)?

Answer 11

• Phases 2 & 3
  
  • caused by an increase in the frequency of abortive action potentials before normal repolarization is completed
  • Phase 2 due to augmented opening of calcium channels
  • Phase 3 interruptions due to the opening of sodium channels

Question 12

What phase is affected in a delayed afterdpolarization (DAD)?

Answer 12

Phase 4

• After repolarization is completed but before another action potential would normally occur
• Due to elevated cytosolic calcium concentrations
  
  • Classically seen with Dogoxin toxcitiy

Question 13

What is a Re-entry arrythmia?

Answer 13

• Electric signal not completing the normal circuit, but rather an alternative circuit looping back upon itself
  
  • Causes Paroxysmal tachycardia occurring in the ventricle

Question 14

What two conditions are required for a Re-entry arrythmia?

Answer 14

Reentry occurs when there is a unidirectional block and slowed conduction through the reentry pathway

• After the slow reentry the previously depolarized tissue has recovered and reentry into it will occur.