Focus on Ventricular Repolarisation in Clinical Medicine

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European Cardiovascular Disease 2006 - Issue 2;2006:2(2):65-66

Conduction and depolarisation in the heart have always interested clinical electrophysiologists. The mapping of conduction is performed more and more in laboratories. Much less attention has been paid to the repolarisation process, although interest in this is increasing.

The repolarisation phase is of great importance for malignant arrhythmias. It is carried by many ionic movements and can be difficult to understand.

Sodium Channels

The SCN5A gene encodes the normal Na+ channel. The fast sodium channel is of greatest importance for the depolarisation of most cardiac cells, while the slow sodium channel affects the repolarisation process. Certain mutations produce dysfunctional Na+ channels that can cause long QT3 syndrome and Brugada syndrome. These syndromes can cause lethal arrhythmias. In both syndromes the ╬öK1500 mutation, which deletes a lysine in a slow inactivation loop, and the 1795insD mutation, which inserts an aspartate into the Na+ channelÔÇÖs carboxyl tail, have been identified.3,4

Long QT time presents as a long QTc on an electrocardiogram (ECG). The mutations seem more common in sudden infant death syndrome than in the general population (unpublished data). LQT3 and Brugada disease seem very rare in my country, Norway. The only effective treatment for LQT3 seems to be implanted cardioverter-defibrillators (ICD) where indication for treatment is found.

Na+ influx also prolongs the repolarisation phase via the sodium-calcium exchanger. This process may be involved in some cardiac diseases with arrhythmias; however, this issue is, at present, unclear.

Slow Inward Current Carried by Calcium Ions

The calcium channel blocker verapamil shortens ventricular action potentials to a very small extent. There is no indication that this drug increases or decreases tendency to ventricular fibrillation. When the slow inward current is involved in arrhythmias, such as a fast junctional rhythm or other ectopic activity, verapamil may have a beneficial effect.

The Potassium Channel
Ik Delayed-rectifier K+ Current

Ik begins weakly early in repolarisation and increases gradually. Rectification is delayed until the rapid phase of repolarisation and reaches a maximum at that time. This channel is highly sensitive to -adrenoreceptors. Mutation of two genes, KCNQ1 and KCNE1, causes dysfunction of this current. Proteins encoded by these two genes co-assemble to form the channel conducting the IKs current. Mutation in one of these genes causes the autosomal dominant Romano-Ward syndrome (RWS), while Jervell and Lange-Nielsen syndrome (JLNS) depends on homozygotes or compound heterozygotes on either of the two genes KCNQ1 and KCNE1.

Mutation in one gene may not necessarily cause prolongation of action potentials as measured by QTc, and the patient can be without symptoms and show a normal QTc throughout their entire life. Prolongation of QTc is related to prognosis both in RWS and JLNS. In particular, a QTc above 500 ms is a marker for possible future events.

While -blockers have minimal effect on cardiac action potentials in myocardial cells in an experimental organ bath, they increase action potential duration and refractoriness in dogs with high sympathetic activity. The same is true for vagus stimulation.

An additional effect of vagus stimulation also seems present. These data may indicate that increasing physical performance by exercise is healthy, while anticholinergic drugs may be harmful.

Since sympathethic fibres are unevenly distributed in the ventricles, -blockers may cause homogenisation during high sympathetic tone and even inhibit ectopic activity in areas with short action potentials. Dispersion of repolarisation is probably the most important electrophysiological variable for induction of ventricular fibrillation.

Action potentials can be very short when ventricular fibrillation starts. This is known as the proximity effect. -blockade inhibits marked shortening. There is reason to believe that -blockers inhibit polymorphic ventricular tachycardias and ventricular fibrillation in patients with dysfunction of IKs in the long QT time syndromes by decreasing ectopic activity, decreasing dispersion of repolarisation and by inhibiting afterpotentials. The clinical characteristics and treatment of JLNS patients have recently been characterised. Patients with this syndrome often show variable QT time, variable polarity of the T waves and R on T phenomenon at the initiation of ventricular arrhythmias.

All signs indicate the presence of increased dispersion of repolarisation. All JLNS patients should be considered for an ICD over the age of five to eight years because -blockade is not sufficient to avoid sudden cardiac death.

Smoking decreases ventricular action potentials in humans. This effect is probably also mediated by nicotinic receptors to IKs. The shortening of action potentials may partly explain why the risk of sudden cardiac death drops so rapidly after smoking cessation. In patients with cardiac insufficiency the risk of sudden cardiac death is decreased by more than 30% with -blocker treatment. In these patients it was found that increased QTc time was related to death or hospitalisation because of cardiac insufficiency and not to sudden cardiac death.

IKr - The Rapid (Delayed-rectifier) K+ Current

This current rapidly attains maximal intensity shortly after initiation of repolarisation. The Ikr channel is produced by the human ether-a-go-go-related gene (HERG); a genetic variation of HERG produces another hereditary variant of long QT time, known as LQT2.

The Ikr current is not affected by -adrenergic stimulation, circulating cathcholamines or synthetic adrenergic analogues. It is also clear from clinical data and personal experience that -blockade has less beneficial effect than in patients with LQT1. There is reason to believe from clinical follow-up studies that patients with LQT2 and QTc above 500 ms should be considered for an ICD.

Many drugs affect Ikr and individuals with this mutation should not be treated with a number of drugs (listed on Lethal effects have been seen in healthy people in the authorÔÇÖs hospital, especially when those drugs are taken in combination with hypopotassaemia.