on 05-Jan-2020 (Sun)

Action potential in fast response tissues —

Tissues that depend upon the opening of voltage-sensitive, kinetically rapid (opening in less than a millisecond) sodium channels to initiate depolarization are called fast response tissues [7].

Fast response tissues include the atria, the specialized infranodal conducting system (bundle of His, fascicles and bundle branches, and terminal Purkinje fibers), and the ventricles (figure 2), while the sinoatrial (SA) and atrioventricular (AV) nodes represent slow response tissues.

It is important to recognize that accessory AV pathways (ie, bypass tracts) associated with Wolff-Parkinson-White syndrome are derived from the atria and are thus also fast response tissues dependent upon sodium current for depolarization.

Phase 2 — Following initial repolarization in phase 1, phase 2 represents a plateau that lasts for hundreds of milliseconds and distinguishes the cardiac action potential from nerve and skeletal muscle action potentials, which are significantly shorter. Late inactivating depolarizing calcium and sodium currents are balanced by activating repolarizing potassium currents to maintain the plateau, which is often down-sloping as repolarizing currents begin to dominate.

Critical components for reentry include both of the following:

● The presence of fast and slow conduction with varying refractory/recovery periods

● A fixed or functional core about which the circuit moves

EADs — EADs are triggered during prolonged action potentials. A prolonged action potential allows a longer window for reopening of L-type Ca²⁺ channels during phase 2 (or occasionally phase 3) of the action potential. L-type Ca²⁺ current depolarizes the membrane before repolarization, triggering an afterdepolarization. Due to L-type Ca²⁺ channel time and voltage dependence, EADs occur at slow stimulation rates or after a ventricular pause when action potential duration (phase 2) is prolonged and they are suppressed with faster heart rates. EADs are thought to initiate the polymorphic ventricular arrhythmias torsades de pointes (TdP) found in inherited and acquired long QT syndrome (LQTS), for example drug-induced LQTS

Class I — The class I drugs act by modulating or blocking the sodium channels, thereby inhibiting phase 0 depolarization. They are all at least in part positively charged and presumably interact with specific amino acid residues in the internal pore of the sodium channel.

Class Ic drugs (flecainide and propafenone) primarily block open sodium channels and slow conduction. They dissociate slowly from the sodium channels during diastole, resulting in increased effect at a more rapid rate (use-dependence). This characteristic is the basis for their antiarrhythmic efficacy, especially against supraventricular arrhythmias. Use-dependence may also contribute to the proarrhythmic activity of these drugs, especially in the diseased myocardium, resulting in incessant ventricular tachycardia

By blocking catecholamine and sympathetically mediated actions, beta blockers slow the rate of discharge of the sinus and ectopic pacemakers, and increase the effective refractory period of the AV node. They also slow both antegrade and retrograde conduction in anomalous pathways [18].

Carvedilol is a beta-blocker with unique additional properties. In addition to beta- and alpha-adrenergic blockade, carvedilol can also block potassium (KCNH2, formerly HERG), calcium, and sodium currents and modestly prolong APD. However, when administered chronically, carvedilol increases the number of these channels, which is probably a favorable effect in diseased hearts [19].

Class IV — The class IV drugs are calcium channel blockers. Verapamil has a more pronounced inhibitory effect on the slow response SA and AV nodes than diltiazem.