Molecular Mechanisms of Arrhythmias

Question 1

Long-QT syndrome:

Answer 1

prolongation of the duration of the cardiac action potential that leads to ventricular arrhythmia and sudden death. Prolongation of the plateau phase of the fast response action potential in ventricular myocytes initiates a ventricular tachycardiac called torsades de pointes, with subsequent syncope and sudden cardiac death.

Question 2

gene defects in Long QT syndrome

Answer 2

 More than 200 mutations have been identified and associated with the autosomal dominant form of Long-QT syndrome (Romano-Ward syndrome), with the most prevalent ones found in the slow cardiac K+ channel IKs (LQT1), the rapid cardiac K+ channel IKr (LQT2)and the cardiac Na+ channel INa (LQT3).
 In the autosomal recessive form of long QT syndrome, Jervell-Lange-Nielson syndrome (JLNS), homozygous carriers of mutations in IKs (LQT1) suffer in addition from congenital deafness, which heterozygous carriers are asymptomatic.

Question 3

molecular basis of long QT syndrome

Answer 3

 The mutations in the cardiac K+ channel subunits generally reduce the number of K+ channels expressed n the myocyte plasma membrane (loss of function mutations), thereby reducing the size of the K+ current that helps terminate the plateau phase of the fast response and return the membrane to resting potential during diastole.
 Mutations in the myocyte Na+ channel (INa) prevent Na+ channels from inactivating completely (gain of function mutations), thereby prolonging phase 2 of the fast response.
 Depending upon the molecular basis of the syndrome, therapeutic treatment out to employ entirely different kinds of drugs

Question 4

Class I antiarrhythmic drugs:

Answer 4

Na+ channel blockers
o Ia: Na+ channel blockers; slow the upstroke of the fast response (phase 0), prolong refractory period (phase 4) because depolarization (phase 2) is prolonged.
o Ib: Na+ channel blockers; slow upstroke (phase 0) mildly, shorten depolarization (phase 2) and prolong refractory period (phase 4).
o Ic: Na+ channel blockers; pronounced slowing of the upstroke of the fast response (phase 0), mildly prolong depolarization (phase 2).

Question 5

Class II antiarrhythmic drugs:

Answer 5

beta-adrenergic receptor blocker -> decreased Ih, LTCC, and K+ current; reduces the rate of diastolic phase 4 depolarization in pacing cells, reduces the upstroke rate and slows repolarization.

Question 6

Class III antiarrhythmic drugs:

Answer 6

K+ channel blockers; prolongation of fast response phase 2 and prominent prolongation of refractory period.

Question 7

Class IV antiarrhythmic drugs:

Answer 7

Ca2+ channel blockers; slow the Ca2+ -dependent upstroke in slow response tissue (slow rise of action potential), prolong the refractory period (prolonged repolarization).

Question 8

cellular mechanism of triggered (early and delayed) afterdepolarizations

Answer 8

During prolonged phase 2, excessive Ca2+ entry triggers further Ca2+ release from the sarcoplasmic reticulum (CDCR). The pathologically elevated level of intracellular Ca2+ requires increased Na/Ca exchange via NCX1 exchanger. This electrogenic exchanger (3 Na+ in for 1 Ca2+ out) adds one positive charge to the inside of the myocyte on each exchanger cycle, which depolarizes the myocyte and thereby initiates delayed or early afterdepolarizations

Question 9

how a re-entrant, or circus, arrhythmia originates

Answer 9

o Initiation requires two conditions:
1. Uni-directional conduction block in a functional circuit.
2. Conduction time around the circuit is longer than the refractory period.
o 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.

Question 10

use-dependent block of Na+ channels by class I antiarrhythmic drugs.

Answer 10

the block of Na+ channels by class I antiarrhythmic drugs is optimized such that Na+ channels in myocytes with abnormally high firing rates or abnormally depolarized membranes will be blocked to a greater degree than Na+ channels in normal, healthy myocytes.
o	Channels must open before they can be blocked.
o	The channel must be open for the blocker to enter the pore, bind and thereby block the Na+ channel
o	Mechanism of block of cardiac Na+ channels is identical to local anesthetic block of neuronal Na+channels