Heart repolarization

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... 

Fleca.inide, Elecainide acetate, a fluorobenzamide, is a derivative of procainamide, and has been reported to be efficacious in suppressing both supraventricular and ventricular arrhythmias (26—29). The dmg is generally reserved for patients with serious and life-threatening ventricular arrhythmias. Elecainide depresses phase 0 depolarization of the action potential, slows conduction throughout the heart, and significantly prolongs repolarization (30). The latter effect indicates flecainide may possess some Class III antiarrhythmic-type properties (31). 

Reentrant arrhythmia occurs when due to inhomogeneous repolarization or unidirectional block, heart tissue which is no longer refractory is close beside tissue which is still activated. This may result in a circuit propagation of activation serving as a reverberator. 

In the Long QT Syndrome (LQTS), the repolarization phase of the cardiac muscle is delayed, rendering the heart vulnerable to an arrhythmia known as torsade de pointes. LQTS is associated with five genes encoding ion channels. LQTS type 3 (LQT3) results from mutations of Nav1.5, which cause persistent sodium cunent. In contrast, sodium channel mutations associated with Biugada syndrome reduce the expression level of cardiac sodium channels. 

Several intervals and durations are routinely measured on the ECG. The PR interval represents the time of conduction of impulses from the atria to the ventricles through the AV node the normal PR interval in adults is 0.12 to 0.2 seconds. The QRS duration represents the time required for ventricular depolarization, which is normally 0.08 to 0.12 seconds in adults. The QT interval represents the time required for ventricular repolarization. The QT interval varies with heart rate—the faster the heart rate, the shorter the QT interval, and vice versa. Therefore, the QT interval is corrected for heart rate using Bazett s equation3, which is ... 

Alternatively, a continuous magnesium infusion may be initiated after the first bolus, at a rate of 0.5 to 1 g/hour. Alternative treatments include transvenous insertion of a temporary pacemaker for overdrive pacing, which shortens the QT interval and may terminate torsades de pointes intravenous isoproterenol 2 to 10 mcg/minute, to increase the heart rate and shorten the QT interval intravenous lidocaine, which may shorten the duration of ventricular repolarization or intravenous phenytoin, which may also shorten the duration of ventricular repolarization, administered at a dose of 10 to 15 mg/kg infused at a rate of 25 to 50 mg/minute. 

Rabbits exposed to 72 ppm hydrogen sulfide by inhalation for 1.5 hours developed ventricular repolarization cardiac arrhythmias developed after exposure to this concentration for 0.5 hours/day for 5 days (Kosmider et al. 1967). Cardiac arrhythmia has been reported in rats exposed to 75 ppm hydrogen sulfide for up to 60 minutes along with decreased heart rates (Kohno et al. 1991). Marked, yet temporary, increases in blood pressure were noted in rats exposed to 100 ppm hydrogen sulfide for 1 hour (Higuchi and Fukamachi 1977). 

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.

Procainamide (Class IA antiarrhythmic drug) is an effective agent for ventricular tachycardia. Its mechanism of action involves blockade of the fast Na+ channels responsible for phase 0 in the fast response tissue of the ventricles. Therefore, its effect is most pronounced in the Purkinje fibers. The effects of this drug s activity include a decrease in excitability of myocardial cells and in conduction velocity. Therefore, a decrease in the rate of the phase 0 upstroke and a prolonged repolarization are observed. As a result, duration of the action potential and the associated refractory period is prolonged and the heart rate is reduced. These effects are illustrated by an increase in the duration of the QRS complex. 

The QT interval is a dynamic physiological variable depending on multiple factors such as cardiac cycle length (heart rate), autonomic nervous system activity, age, gender, plasma electrolyte concentrations, genetic variations in ion channels involved in cardiac repolarization. In addition, circadian and seasonal variations of the QT interval have been described [93]. 

Weissenburger, J., Nesterenko, V.V. and Antzelevitch, C. (2000) Transmural heterogeneity of ventricular repolarization under baseline and long QTconditions in the canine heart in vivo torsades de pointes develops with halothane but not pentobarbital anesthesia. Journal of Cardiovascular Electrophysiology, 11, 290-304. 

Escande, D. (2001) Inhibition of repolarizing ionic currents by drugs. European Heart Journal Supplements, 3, K17-K22... 

Figure 4.2 Cartoon representation of an ECC trace and ventricular cardiac action potential, (a) A representation of an ECC trace with its five typical deflections (PQRST) arising from the spread of electrical activitythrough the heart. The QRS wave denotes the ventricular depolarization, while the T wave represents ventricular repolarization. The QT interval therefore estimates the duration of a ventricular action potential, (b) Schematic of the five phases of a ventricular action potential. Phase 0 is the rapid depolarization phase due to a large influx of Na+ ions (Ina). Phase 1 occurs with the inactivation of Na+ channels and the onset of transient outward (repolarizing) currents (/to)...

Heart sounds Sound Si occurs at the beginning of systole as the mitral and tricuspid valves close S2 occurs at the beginning of diastole as the aortic and pulmonary valves close. These points should be in line with the beginning of electrical depolarization (QRS) and the end of repolarization (T), respectively, on the ECG trace. The duration of Si matches the duration of isovolumic contraction (IVC) and that of S2 matches that of isovolumic relaxation (IVR). Mark the vertical lines on the plot to demonstrate this fact. 

Regulatory guidance for non-clinical cardiovascular safety pharmacology testing is given in the ICH S7A and B.25,42 The effects of an NCE on blood pressure, heart rate, and the ECG should be evaluated. Furthermore, in vivo, in vitro, and ex vivo evaluations, including methods for (assessing) repolarization and conductance abnormalities, should... 

Anderson, M.E., Al-Khatib, S.M., Roden, D.M., and Califf, R.M., Cardiac repolarization current knowledge, criticl gaps and new approaches to drug development and patient management, Am. Heart., 144, 769-781, 2002. 

Cardiac arrhythmias result from alterations in the orderly sequence of depolarization followed by repolarization in the heart. Cardiac arrhythmias may result in alterations in heart rate or rhythm and arise from alterations in impulse generation or conduction. The clinical implications of disordered cardiac activation range from asymptomatic palpitations to lethal arrhythmia. 

Acute cardiovascular reactions to procainamide administration include hypotension, A-V block, intraventricular block, ventricular tachyarrhythmias, and complete heart block. The drug dosage must be reduced or even stopped if severe depression of conduction (severe prolongation of the QRS interval) or repolarization (severe prolongation of the QT interval) occurs. 

Flecainide (Tambocor) is a fluorinated aromatic hydrocarbon examined initially for its local anesthetic action and subsequently found to have antiarrhythmic effects. Flecainide inhibits the sodium channel, leading to conduction slowing in all parts of the heart, but most notably in the His-Purkinje system and ventricular myocardium. It has relatively minor effects on repolarization. Flecainide also inhibits abnormal auto-maticity. 

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