Atrial repolarization

Bunaftine (21) is a naphthalenecarboxamide derivative, that has been developed as an antiarrhythmic agent. The compound exhibits both Class I and Class III electrophysiological effects. Fenici and co-workers studied bunaftine in patients with paroxysmal atrial tachyarrhythmia and recorded right atrial monophasic action potentials [72]. A mean increase of 18% in atrial repolarization time and an increase in monophasic APD during pac-... 

The difluoromethyl ether AZD-7009 is in Phase II clinical trials as an atrial repolarization-delaying agent. 

A typical ECG is shown in Figure 4.4, where the P wave corresponds to atrial depolarization and contraction the QRST complex corresponds to atrial repolarization and relaxation and the onset of ventricular depolarization and contraction and the T wave represents ventricular repolarization and relaxation. Analysis of the size and shape of the waves can indicate abnormalities of the heart. 

The Cardiac Cycle. The heart (Eig. lb) performs its function as a pump as a result of a rhythmical spread of a wave of excitation (depolarization) that excites the atrial and ventricular muscle masses to contract sequentially. Maximum pump efficiency occurs when the atrial or ventricular muscle masses contract synchronously (see Eig. 1). The wave of excitation begins with the generation of electrical impulses within the SA node and spreads through the atria. The SA node is referred to as the pacemaker of the heart and exhibits automaticity, ie, it depolarizes and repolarizes spontaneously. The wave then excites sequentially the AV node the bundle of His, ie, the penetrating portion of the AV node the bundle branches, ie, the branching portions of the AV node the terminal Purkinje fibers and finally the ventricular myocardium. After the wave of excitation depolarizes these various stmetures of the heart, repolarization occurs so that each of the stmetures is ready for the next wave of excitation. Until repolarization occurs the stmetures are said to be refractory to excitation. During repolarization of the atria and ventricles, the muscles relax, allowing the chambers of the heart to fill with blood that is to be expelled with the next wave of excitation and resultant contraction. This process repeats itself 60—100 times or beats per minute... 

Kvl.5 In human atria, the Kvl.5 presents the ultrarapid delayed rectifier that contributes to the repolarization in the early phase of cardiac action potential. Selective blockers of Kvl.5 channels could be potentially beneficial in the treatment of atrial fibrillation because blocking Kvl. 5 could delay repolarization and prolong refractoriness selectively in cardiac myocytes. Examples for Kvl.5 blockers include AVE0118, S9947, and analogs of diphenyl phosphine oxide (DPO). 

Figure 13.4 Electrocardiogram. The electrocardiogram (ECG) is a measure of the overall electrical activity of the heart. The P wave is caused by atrial depolarization, the QRS complex is caused by ventricular depolarization, and the T wave is caused by ventricular repolarization.

Type III drugs specifically prolong refractoriness in atrial and ventricular fibers and include very different drugs that share the common effect of delaying repolarization by blocking potassium channels. 

In vitro Disaggregated cells Repolarizing currents (e.g., IKs, IK1, Ito), depolarizing currents (e.g., INa) currents, ICa (whole cell patch-clamp) Disaggregated cells ventricular myocytes mouse atrial tumor cells (AT-1) immortalized cardiac muscle cells (HL-1) Jost et al.,-65 Liu and Antzelevitch 66 Jurkiewicz and Sanguinetti 67 Li et al. 68 Yang and Roden 69 Banyasz et al. 70 Xia et al.71... 

Outward repolarizing currents oppose the effect of the inward Ica on the plateau phase. This current is carried predominantly through delayed rectifier potassium channels (Ik).These channels are voltage sensitive, with slow inactivation kinetics. Three distinct subpopulations of Ik with differing activation and inactivation kinetics have been described. A rapidly activating subset (Ikf), a slowly inactivating subset (Iks), and an ul-tra-rapidly activating subset to date are identified only in atrial tissue (Ikui)-... 

Quinidine also prolongs repolarization in Purkinje fibers and ventricular muscle, increasing the duration of the action potential. As in atrial muscle, quinidine administration results in postrepolarization refractoriness, that is, an extension of refractoriness beyond the recovery of the resting membrane potential. The indirect (anticholinergic) properties of quinidine are not a factor in its actions on ventricular muscle and the His-Purkinje system. 

Schematic representation of the heart and normal cardiac electrical activity (intracellular recordings from areas indicated and ECG). Sinoatrial (SA) node, atrioventricular (AV) node, and Purkinje cells display pacemaker activity (phase 4 depolarization). The ECG is the body surface manifestation of the depolarization and repolarization waves of the heart. The P wave is generated by atrial depolarization, the QRS by ventricular muscle depolarization, and the T wave by ventricular repolarization. Thus, the PR interval is a measure of conduction time from atrium to ventricle, and the QRS duration indicates the time required for all of the ventricular cells to be activated (ie, the intraventricular conduction time). The QT interval reflects the duration of the ventricular action potential.

The ECG consists of the P-wave, the QRS complex, and the T-wave. These components, represented in Figure 4.2, are associated with different aspects of the cardiac cycle atrial activity, excitation of the ventricles, and repolarization of the ventricles, respectively. 

W. R. A mathematical model of an adult human atrial cell the role of K+ currents in repolarization. Circulation Research 1998,82 63-81. 

The first wave form of the standard ECG is the small rounded P wave associated with conduction of the cardiac impulse from the SA node over the atria it represents atrial depolarization. This is followed by the spiky QRS complex, which represents a depolarization of the ventricles. The last major wave form is the rounded T wave, which represents ventricular repolarization repolarization of the atria is hidden amongst the QRS complex. 

Atrial depolarization results in the P wave of the ECG, the QRS complex denotes ventricular depolarization and the T wave represents ventricular repolarization. 

The effect of a beta-blocker (metoprolol 30-40 mg/day or bisoprolol 2.5-5.0 mg/day for 1 month) on the change in QT interval, QT dispersion, and transmural dispersion of repolarization caused by bepridil has been studied in 10 patients with paroxysmal atrial fibrillation resistant to various antidysrhythmic drugs (17). Bepridil significantly prolonged the QTc interval from 0.42 to 0.50 seconds, QT dispersion from 0.07 to 0.14 seconds, and transmural dispersion of repolarization from 0.10 to 0.16 seconds. The addition of a beta-blocker shortened the QTc interval from 0.50 to 0.47 seconds, QTc dispersion from 0.14 to... 

Erythromycin has antidysrhythmic properties similar to those of Class lA antidysrhythmic drugs, and causes an increase in atrial and ventricular refractory periods. This is only likely to be a problem in patients with heart disease or in those who are receiving drugs that delay ventricular repolarization (5). High-doses intravenously have caused ventricular fibrillation and torsade de pointes (6). Each episode of dysrhythmia, QT interval prolongation, and myocardial dysfunction occurred 1-1.5 hours after erythromycin infusion and resolved after withdrawal. 

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