Disturbances of Impulse Formation The interval between depolarizations of a pacemaker cell is the sum of the duration of the action potential and the duration of the diastolic interval.Shortening of either duration results in an increase in pacemaker rate.The more important of the two, diastolic interval,is determined primarily by the slope of phase 4 depolarization (pacemaker potential).Vagal discharge and -receptor-blocking drugs slow normal pacemaker rate by reducing the phase 4 slope(acetylcholine also makes the maximum diastolic potential more negative).Acceleration of pacemaker discharge is often brought about by increased phase 4 depolarization slope,which can be caused by hypokalemia,-adrenoceptor stimulation,positive chronotropic drugs,fiber stretch, acidosis,and partial depolarization by currents of injury. Latent pacemakers(cells that show slow phase 4 depolarization even under normal conditions,eg,some Purkinje fibers)are particularly prone to acceleration by the above mechanisms.However,all cardiac cells,including normally quiescent atrial and ventricular cells,may show repetitive pacemaker activity when depolarized under appropriate conditions,especially if hypokalemia is also present. Afterdepolarizations (Figure 5)are depolarizations that interrupt phase 3 (early afterdepolarizations,EADs)or phase 4 (delayed afterdepolarizations,DADs). EADs are usually exacerbated at slow heart rates and are thought to contribute to the development of long QT-related arrhythmias.DADs on the other hand,often occur when intracellular calcium is increased.They are exacerbated by fast heart rates and are thought to be responsible for some arrhythmias related to digitalis excess,to catecholamines,and to myocardial ischemia. MOLECULAR GENETIC BASIS OF CARDIAC ARRHYTHMIAS It is now possible to define the molecular basis of several congenital and acquired cardiac arrhythmias.The best example is the polymorphic ventricular tachycardia known as torsade de pointes (shown in Figure 7),which is associated with prolongation of the QT interval (especially at the onset of the tachycardia),syncope, and sudden death.This must represent prolongation of the action potential of at least some ventricular cells (Figure 1).The effect can,in theory,be attributed either to increased inward current (gain of function)or decreased outward current (loss of function)during the plateau of the action potential.In fact,recent molecular genetic studies have identified up to 300 different mutations in at least eight ion channel genes that produce the congenital long QT (LQT)syndrome (Table 1),and each mutation may have different clinical implications.Loss of function mutations in potassium channel genes produce decreases in outward repolarizing current and are responsible for LQT subtypes 1,2,5,6,and 7.HERG and KCNE2 (MiRPI)genes 1010 Disturbances of Impulse Formation The interval between depolarizations of a pacemaker cell is the sum of the duration of the action potential and the duration of the diastolic interval. Shortening of either duration results in an increase in pacemaker rate. The more important of the two, diastolic interval, is determined primarily by the slope of phase 4 depolarization (pacemaker potential). Vagal discharge and -receptor-blocking drugs slow normal pacemaker rate by reducing the phase 4 slope (acetylcholine also makes the maximum diastolic potential more negative). Acceleration of pacemaker discharge is often brought about by increased phase 4 depolarization slope, which can be caused by hypokalemia, -adrenoceptor stimulation, positive chronotropic drugs, fiber stretch, acidosis, and partial depolarization by currents of injury. Latent pacemakers (cells that show slow phase 4 depolarization even under normal conditions, eg, some Purkinje fibers) are particularly prone to acceleration by the above mechanisms. However, all cardiac cells, including normally quiescent atrial and ventricular cells, may show repetitive pacemaker activity when depolarized under appropriate conditions, especially if hypokalemia is also present. Afterdepolarizations (Figure 5) are depolarizations that interrupt phase 3 (early afterdepolarizations, EADs) or phase 4 (delayed afterdepolarizations, DADs). EADs are usually exacerbated at slow heart rates and are thought to contribute to the development of long QT-related arrhythmias. DADs on the other hand, often occur when intracellular calcium is increased. They are exacerbated by fast heart rates and are thought to be responsible for some arrhythmias related to digitalis excess, to catecholamines, and to myocardial ischemia. MOLECULAR  GENETIC BASIS OF CARDIAC ARRHYTHMIAS It is now possible to define the molecular basis of several congenital and acquired cardiac arrhythmias. The best example is the polymorphic ventricular tachycardia known as torsade de pointes (shown in Figure 7), which is associated with prolongation of the QT interval (especially at the onset of the tachycardia), syncope, and sudden death. This must represent prolongation of the action potential of at least some ventricular cells (Figure 1). The effect can, in theory, be attributed either to increased inward current (gain of function) or decreased outward current (loss of function) during the plateau of the action potential. In fact, recent molecular genetic studies have identified up to 300 different mutations in at least eight ion channel genes that produce the congenital long QT (LQT) syndrome (Table 1), and each mutation may have different clinical implications. Loss of function mutations in potassium channel genes produce decreases in outward repolarizing current and are responsible for LQT subtypes 1, 2, 5, 6, and 7. HERG and KCNE2 (MiRP1) genes